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Background: There are limited data regarding the prevalence of distinct clinical, neuroimaging and genetic markers among patients diagnosed with cerebral amyloid angiopathy–related inflammation (CAA-ri). We sought to determine the prevalence of clinical, radiological, genetic and cerebrospinal fluid biomarker findings in patients with CAA-ri. Methods: A systematic review and meta-analysis of published studies including patients with CAA-ri was conducted to determine the prevalence of clinical, neuroimaging, genetic and cerebrospinal fluid biomarker findings. Subgroup analyses were performed based on (1) prospective or retrospective study design and (2) CAA-ri diagnosis with or without available biopsy. We pooled the prevalence rates using random-effects models and assessed the heterogeneity using Cochran-Q and I 2 -statistics. Results: We identified 4 prospective and 17 retrospective cohort studies comprising 378 patients with CAA-ri (mean age, 71.5 years; women, 52%). The pooled prevalence rates were as follows: cognitive decline at presentation 70% ([95% CI, 54%–84%]; I 2 =82%), focal neurological deficits 55% ([95% CI, 40%–70%]; I 2 =82%), encephalopathy 54% ([95% CI, 39%–68%]; I 2 =43%), seizures 37% ([95% CI, 27%–49%]; I 2 =65%), headache 31% ([95% CI, 22%–42%]; I 2 =58%), T2/fluid-attenuated inversion recovery-hyperintense white matter lesions 98% ([95% CI, 93%–100%]; I 2 =44%), lobar cerebral microbleeds 96% ([95% CI, 92%–99%]; I 2 =25%), gadolinium enhancing lesions 54% ([95% CI, 42%–66%]; I 2 =62%), cortical superficial siderosis 51% ([95% CI, 34%–68%]; I 2 =77%) and lobar macrohemorrhage 40% ([95% CI, 11%–73%]; I 2 =88%). The prevalence rate of the ApoE (Apolipoprotein E) ε4/ε4 genotype was 34% ([95% CI, 17%–53%]; I 2 =76%). Subgroup analyses demonstrated no differences in these prevalence rates based on study design and diagnostic strategy. Conclusions: Cognitive decline was the most common clinical feature. Hyperintense T2/fluid-attenuated inversion recovery white matter lesions and lobar cerebral microbleeds were by far the most prevalent neuroimaging findings. Thirty-four percent of patients with CAA-ri have homozygous ApoE ε4/ε4 genotype and scarce data exist regarding the cerebrospinal fluid biomarkers and its significance in these patients.

Introduction: Internal carotid artery dissection (ICAD) is a rare cause of acute ischemic stroke with large vessel occlusion (AIS-LVO). We aimed investigating the impact on outcome of internal carotid artery (ICA) patency after mechanical thrombectomy (MT) for AIS-LVO due to occlusive ICAD. Patients and methods: We included consecutive patients with AIS-LVO due to occlusive ICAD treated with MT from January 2015 to December 2020 in three European stroke centers. We excluded patients with unsuccessful intracranial reperfusion after MT (modified Thrombolysis in Cerebral Infarction (mTICI) score Results: Among 70 included patients, ICA was patent in 54/70 (77%) at the end of MT, and in 36/66 (54.5%) patients with 24-h follow-up imaging. Among patients with ICA patency at the end of MT, 32% presented ICA occlusion at 24-h control imaging. Favorable 3-month outcome occurred in 41/54 (76%) patients with ICA patency post-MT and in 9/16 (56%) patients with occluded ICA post-MT ( p = 0.21). Rates of favorable outcome were significantly higher in patients with 24-h ICA patency compared to patients with 24-h ICA occlusion (32/36 [89%] vs 15/30 [50%]), with an adjusted odds ratio of 4.67 (95% CI: 1.26–17.25). Discussion and conclusion: Obtaining sustained (24-h) ICA patency after MT could be a therapeutic target for improving functional outcome in patients with AIS-LVO due to ICAD.

Contains fulltext : 290906.pdf (Publisher’s version ) (Open Access) OBJECTIVE: Determining the underlying causes of intracerebral hemorrhage (ICH) is of major importance, because risk factors, prognosis, and management differ by ICH subtype. We developed a new causal CLASsification system for ICH Subtypes, termed CLAS-ICH, based on recent advances in neuroimaging. METHODS: CLAS-ICH defines 5 ICH subtypes: arteriolosclerosis, cerebral amyloid angiopathy, mixed small vessel disease (SVD), other rare forms of SVD (genetic SVD and others), and secondary causes (macrovascular causes, tumor, and other rare causes). Every patient is scored in each category according to the level of diagnostic evidence: (1) well-defined ICH subtype; (2) possible underlying disease; and (0) no evidence of the disease. We evaluated CLAS-ICH in a derivation cohort of 113 patients with ICH from Massachusetts General Hospital, Boston, USA, and in a derivation cohort of 203 patients from Inselspital, Bern, Switzerland. RESULTS: In the derivation cohort, a well-defined ICH subtype could be identified in 74 (65.5%) patients, including 24 (21.2%) with arteriolosclerosis, 23 (20.4%) with cerebral amyloid angiopathy, 18 (15.9%) with mixed SVD, and 9 (8.0%) with a secondary cause. One or more possible causes were identified in 42 (37.2%) patients. Interobserver agreement was excellent for each category (kappa value ranging from 0.86 to 1.00). Despite substantial differences in imaging modalities, we obtained similar results in the validation cohort. INTERPRETATION: CLAS-ICH is a simple and reliable classification system for ICH subtyping, that captures overlap between causes and the level of diagnostic evidence. CLAS-ICH may guide clinicians to identify ICH causes, and improve ICH classification in multicenter studies. ANN NEUROL 2023;93:16-28. 01 januari 2023

© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.562 This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made., Objective: Cerebral venous thrombosis (CVT) caused by vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare adverse effect of adenovirus-based severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) vaccines. In March 2021, after autoimmune pathogenesis of VITT was discovered, treatment recommendations were developed. These comprised immunomodulation, non-heparin anticoagulants, and avoidance of platelet transfusion. The aim of this study was to evaluate adherence to these recommendations and its association with mortality. Methods: We used data from an international prospective registry of patients with CVT after the adenovirus-based SARS-CoV-2 vaccination. We analyzed possible, probable, or definite VITT-CVT cases included until January 18, 2022. Immunomodulation entailed administration of intravenous immunoglobulins and/or plasmapheresis. Results: Ninety-nine patients with VITT-CVT from 71 hospitals in 17 countries were analyzed. Five of 38 (13%), 11 of 24 (46%), and 28 of 37 (76%) of the patients diagnosed in March, April, and from May onward, respectively, were treated in-line with VITT recommendations (p < 0.001). Overall, treatment according to recommendations had no statistically significant influence on mortality (14/44 [32%] vs 29/55 [52%], adjusted odds ratio [OR] = 0.43, 95% confidence interval [CI] = 0.16-1.19). However, patients who received immunomodulation had lower mortality (19/65 [29%] vs 24/34 [70%], adjusted OR = 0.19, 95% CI = 0.06-0.58). Treatment with non-heparin anticoagulants instead of heparins was not associated with lower mortality (17/51 [33%] vs 13/35 [37%], adjusted OR = 0.70, 95% CI = 0.24-2.04). Mortality was also not significantly influenced by platelet transfusion (17/27 [63%] vs 26/72 [36%], adjusted OR = 2.19, 95% CI = 0.74-6.54). Conclusions: In patients with VITT-CVT, adherence to VITT treatment recommendations improved over time. Immunomodulation seems crucial for reducing mortality of VITT-CVT. ANN NEUROL 2022;92:562-573., This research was funded by The Netherlands Organisation for Health Research and Development (ZonMw, grant number 10430072110005) and the Dr. C. J. Vaillant Foundation.

Background: Diffusion-weighted imaging lesion reversal (DWIR) is frequently observed after mechanical thrombectomy for acute ischemic stroke, but little is known about age-related differences and impact on outcome. We aimed to compare, in patients Methods: We retrospectively analyzed data of patients treated for an anterior circulation acute ischemic stroke with large vessel occlusion in 2 French hospitals, who underwent baseline and 24-hour follow-up magnetic resonance imaging, with baseline DWI lesion volume ≥10 cc. The percentage of DWIR (DWIR%), was calculated as follows: DWIR%=(DWIR volume/baseline DWI volume)×100. Data on demographics, medical history, and baseline clinical and radiological characteristics were collected. Results: Among 433 included patients (median age, 68 years), median DWIR% after mechanical thrombectomy was 22% (6–35) in patients ≥80, and 19% (interquartile range, 10–34) in patients P =0.948). In multivariable analyses, successful recanalization after mechanical thrombectomy was associated with higher median DWIR% in both ≥80 ( P =0.004) and P =0.002) patients. In subgroup analyses performed on a minority of subjects, collateral vessels status score (n=87) and white matter hyperintensity volume (n=131) were not associated with DWIR% ( P >0.2). In multivariable analyses, DWIR% was associated with increased rates of favorable 3-month outcomes in both ≥80 ( P =0.003) and P =0.013) patients; the effect of DWIR% on outcome was not influenced by the age group ( P interaction=0.185) Conclusions: DWIR might be an important and nonage-dependent effect of arterial recanalization, as it seems to beneficially impact 3-month outcomes of both younger and older subjects treated with mechanical thrombectomy for acute ischemic stroke and large vessel occlusion.

AsToxoplasma gondiidisseminates through its host, the parasite must sense and adapt to its environment and scavenge nutrients. Oxygen (O2) is one such environmental factor and cytoplasmic prolyl 4-hydroxylases (PHDs) are evolutionarily conserved O2cellular sensing proteins that regulate responses to changes in O2availability.Toxoplasmaexpresses two PHDs. One of them, TgPHYa hydroxylates SKP1, a subunit of the SCF-E3 ubiquitin ligase complex.In vitro,TgPHYa is important for growth at low O2levels. However, studies have yet to examine the role that TgPHYa or any other pathogen encoded PHD plays in virulence and disease. Using a type II ME49ToxoplasmaTgPHYa knockout, we report that TgPHYa is important for Toxoplasma virulence and brain cyst formation in mice. We further find that while TgPHYa mutant parasites can establish an infection in the gut they are unable to efficiently disseminate to peripheral tissues because the mutant parasites are unable to survive within recruited immune cells. Since this phenotype abrogated in IFNγ knockout mice, we studied how TgPHYa mediates survival in IFNγ-treated cells. We find that TgPHYa is not required for release of parasite-encoded effectors into host cells that neutralize anti-parasitic processes induced by IFNγ. In contrast, we find that TgPHYa is required for the parasite to scavenge tryptophan, which is an amino acid whose levels are decreased after IFNγ upregulates the tryptophan-catabolizing enzyme, indoleamine dioxygenase (IDO). We further find that relative to wild-type mice that IDO knockout mice display increased morbidity when infected with TgPHYa knockout parasites. Together, these data identify the first parasite mechanism for evading IFNγ-induced nutritional immunity and highlight a novel role that oxygen sensing proteins play in pathogen growth and virulence.

The past decade has seen significant advances in stroke prevention. These advances include new antithrombotic agents, new options for dyslipidemia treatment, and novel techniques for surgical stroke prevention. In addition, there is greater recognition of the benefits of multifaceted interventions, including the role of physical activity and dietary modification. Despite these advances, the aging of the population and the high prevalence of key vascular risk factors pose challenges to reducing the burden of stroke. Using a cause-based framework, current approaches to prevention of cardioembolic, cryptogenic, atherosclerotic, and small vessel disease stroke are outlined in this paper. Special emphasis is given to recent trials of antithrombotic agents, including studies that have tested combination treatments and responses according to genetic factors.

Background: To further our understanding of the pathophysiology of spontaneous intracerebral hemorrhage (ICH) and related injury, we provided a postmortem neuropathological examination of acute microvascular lesions (microbleeds and microinfarcts) within the perihematomal area. Methods: We included all consecutive cases (2005–2019) from the Lille University Hospital brain bank of ICH patients who died within the first month. Paraffin-embedded tissue sections from the perihematomal area were processed for several stainings and immunolabelings to investigate the presence of acute microbleeds and microinfarcts in the perihematomal area and to characterize surrounding neuronal and systemic inflammatory reaction (macrophages and neutrophils). Results: We included 14 ICH cases (median age, 78 years; 10 females). Acute microbleeds were observed in the perihematomal area in 12/14 patients (86%, ranging from 1 through >10) and microinfarcts in 5/14 (36%, ranging from 1 through 4). Microbleeds were observed whatever the delay from ICH onset to death was, while most cases with acute microinfarcts were observed between day 3 and day 7 (n=3/5). Both lesions were characterized by an abundant accumulation of systemic inflammatory cells and necrotic areas. Conclusions: Acute microbleeds and microinfarcts might contribute to the propagation of secondary brain tissue damages after ICH. Our examinations also question the potential role of massive systemic inflammatory cells recruitment in the genesis of these microvascular injuries.

Distal medium vessel occlusions (DMVOs) are increasingly recognized as a next target for endovascular thrombectomy (EVT). Our objective was to investigate safety and clinical outcomes of EVT for DMVO of the middle cerebral artery (MCA).We analyzed data of the Lille Reperfusion Registry from January 2017 to September 2020. Patients with a primary or secondary DMVO of the MCA seen on pretreatment angiogram were included. Only patients with a eTICI score 2b50-2b67 on initial angiogram were considered. Baseline characteristics, angiographic clinical, and safety outcomes were compared between patients treated with EVT or standard medical treatment (no-EVT).Of the 171 patients included, 96 received EVT (46.9% male, 68.7 ± 15.8 years) and 75 received standard medical treatment (44% male, 73.9 ± 13.1 years). EVT patients had a better improvement of the NIHSS score at discharge (adjusted mean difference: 3.71; 95% CI: 1.18-6.24). In the distal M2 occlusions subgroup, EVT was significantly associated with a higher rate of early neurologic improvement (adjusted OR: 3.62 95% CI: 1.31-10.03), NIHSS improvement at discharge (adjusted mean difference: 5.23; 95% CI: 2.18-8.29), and improved modified Rankin Scale score at 3 months (adjusted common OR for 1 point improvement: 3.06; 95% CI: 1.30 to 7.23). Symptomatic intracranial hemorrhage occurred in 3.1% in the EVT group and in 9.5% in the no-EVT group.EVT for DMVO of the MCA appears to be safe and may lead to improved clinical outcomes. This effect was especially pronounced in patients with distal M2 occlusions, warranting randomized trials to validate this result.

Background: Although anxiety is common in several neurological conditions, it has been poorly investigated after spontaneous intracerebral hemorrhage (ICH). Aims: In consecutive ICH survivors, we assessed the long-term prevalence of anxiety and its clinical and radiological determinants. Methods: Using the Hospital Anxiety and Depression Scale (HADS), we evaluated ICH survivors enrolled in the prospective, single-center Prognosis of Intracerebral Hemorrhage (PITCH) study. The prevalence of anxiety (defined as a HADS-anxiety subscale score >7) was evaluated at three time points (1–2, 3–5, and 6–8 years after ICH), along with neurological symptoms severity, functional disability, and cognitive impairment scores. Clinical and radiological characteristics associated with anxiety were evaluated in univariate and multivariable models. Results: Of 560 patients with spontaneous ICH, 255 were alive 1 year later, 179 of whom completed the HADS questionnaire and were included in the study. Thirty-one patients (17%; 95% confidence interval (CI) = 12–23) had anxiety 1–2 years, 38 (27%; 95% CI = 19–34) 3–5 years, and 18 (21%; 95% CI = 12–30) 6–8 years after ICH. In patients with anxiety, the prevalence of associated depressive symptoms was 48% 1–2 years, 61% 3–5 years, and 56% 6–8 years after ICH. Among clinical and radiological baseline characteristics, only lobar ICH location was significantly associated with anxiety 1–2 years after ICH (odds ratio = 2.8; 95% CI = 1.2–6.5). Anxiety was not associated with concomitant neurological symptoms severity, functional disability, or cognitive impairment. Conclusion: Anxiety is frequent in ICH survivors, often in association with depressive symptoms, even many years after the index event.

Resume La prevention secondaire medicamenteuse post accident vasculaire cerebral (AVC) fait appel aux memes medicaments que la pathologie coronaire, mais la specificite d’organe influence certaines indications : (i) les AVC sont des pathologies plus heterogenes que la pathologie coronaire, et chaque sous type d’ischemie et d’hemorragie cerebrale expose a un risque evolutif different, qui va modifier la balance benefice/risque et influencer le choix du traitement ; (ii) le cerveau peut saigner, la transformation hemorragique faisant partie de l’histoire naturelle de l’ischemie cerebrale ; ce risque est une limite a l’utilisation de traitements thrombolytiques et anticoagulants ; (iii) Les troubles cognitifs sont frequents et influencent la tolerance aux medicaments. Pour ces raisons dans les ischemies cerebrales cardioemboliques, l’introduction des anticoagulants est souvent differee de quelques jours, et dans les ischemies secondaires a l’atherosclerose, lorsque la combinaison aspirine-clopidogrel est indiquee, elle ne doit pas etre poursuivie plus de 3 semaines.

Patients with anterior circulation ischemic strokes due to large vessel occlusion (AIS-LVO) and very severe neurological deficits (National Institutes of Health Stroke Scale (NIHSS) score > 25) were under-represented in clinical trials on endovascular treatment (EVT). We aimed to evaluate safety and outcomes of EVT in patients with very severe vs. severe (NIHSS score 15–25) neurological deficits. We included consecutive patients undergoing EVT for AIS-LVO between January 2015 and December 2019 at Lille University Hospital. We compared rates of parenchymal hemorrhage (PH), symptomatic intracranial hemorrhage (SICH), procedural complications, and 90-day mortality between patients with very severe vs. severe neurological deficit using univariable and multivariable logistic regression analyses. Functional outcome (90-days modified Rankin Scale) was compared between groups using ordinal logistic regression analysis. Among 1484 patients treated with EVT, 108 (7%) had pre-treatment NIHSS scores > 25, 873 (59%) with NIHSS scores 15–25 and 503 (34%) with NIHSS scores 25 and NIHSS 15–25. Patients with NIHSS > 25 had a lower likelihood of improved functional outcome (adjcommon OR 0.31[95% CI 0.21–0.47]) and higher odds of mortality at 90 days (adjOR 2.3 [95% CI 1.5–3.7]) compared to patients with NIHSS 15–25. Successful recanalization was associated with better functional outcome (adjcommon OR 3.8 [95% CI 1.4–10.4]), and lower odds of mortality (adjOR 0.3 [95% CI 0.1–0.9]) in patients with very severe stroke. The therapeutic effect of recanalization on functional outcome and mortality was similar in both groups. In patients with very severe neurological deficit, EVT was safe and successful recanalization was strongly associated with better functional outcome at 90 days.

Background and ObjectivesCurrent guidelines do not address recommendations for mechanical thrombectomy (MT) in the extended time window (>6 hours after time last seen well [TLSW]) for large vessel occlusion (LVO) patients with preexisting modified Rankin Scale (mRS) > 1. In this study, we evaluated the outcomes of MT vs medical management in patients with prestroke disability presenting in the 6- to 24-hour time window with acute LVO.MethodsWe analyzed a multinational cohort (61 sites, 6 countries from 2014 to 2020) of patients with prestroke (or baseline) mRS 2 to 4 and anterior circulation LVO treated 6–24 hours from TLSW. Patients treated in the extended time window with MT vs medical management were compared using multivariable logistic regression and inverse probability of treatment weighting (IPTW). The primary outcome was the return of Rankin (ROR, return to prestroke mRS by 90 days).ResultsOf 554 included patients (448 who underwent MT), the median age was 82 years (interquartile range [IQR] 72–87) and the National Institutes of Health Stroke Scale (NIHSS) was 18 (IQR 13–22). In both MV logistic regression and IPTW analysis, MT was associated with higher odds of ROR (adjusted OR [aOR] 3.96, 95% CI 1.78–8.79 and OR 3.10, 95% CI 1.20–7.98, respectively). Among other factors, premorbid mRS 4 was associated with higher odds of ROR (aOR, 3.68, 95% CI 1.97–6.87), while increasing NIHSS (aOR 0.90, 95% CI 0.86–0.94) and decreasing Alberta Stroke Program Early Computed Tomography Scale score (aOR per point 0.86, 95% CI 0.75–0.99) were associated with lower odds of ROR. Age, intravenous thrombolysis, and occlusion location were not associated with ROR.DiscussionIn patients with preexisting disability presenting in the 6- to 24-hour time window, MT is associated with a higher probability of returning to baseline function compared with medical management.Classification of EvidenceThis investigation's results provide Class III evidence that in patients with preexisting disability presenting 6–24 hours from the TLSW and acute anterior LVO stroke, there may be a benefit of MT over medical management in returning to baseline function.

Background: The probability to receive intravenous thrombolysis (IVT) for treatment of acute ischemic stroke declines with increasing age and is consequently the lowest in very elderly patients. Safety concerns likely influence individual IVT treatment decisions. Using data from a large IVT registry, we aimed to provide more evidence on safety of IVT in the very elderly. Methods: In this prospective multicenter study from the TRISP (Thrombolysis in Ischemic Stroke Patients) registry, we compared patients ≥90 years with those Results: Of 16 974 eligible patients, 976 (5.7%) were ≥90 years. Patients ≥90 years had higher median National Institutes of Health Stroke Scale on admission (12 versus 8) and were more often dependent prior to the index stroke (prestroke modified Rankin Scale score of ≥3; 45.2% versus 7.4%). Occurrence of symptomatic intracranial hemorrhage (5.7% versus 4.4%, odds ratio adjusted 1.14 [0.83–1.57]) did not differ significantly between both groups. However, the probability of death (odds ratio adjusted 3.77 [3.14–4.53]) and poor functional outcome (odds ratio adjusted 2.63 [2.13–3.25]) was higher in patients aged ≥90 years. Results for the sample of centenarians (n=21) were similar. Conclusions: The probability of symptomatic intracranial hemorrhage after IVT in very elderly patients with stroke did not exceed that of their younger counterparts. The higher probability of death and poor functional outcome during follow-up in the very elderly seems not to be related to IVT treatment. Very high age itself should not be a reason to withhold IVT.

Background: We aimed to evaluate different measures of adverse cardiovascular events between non-traumatic intracranial hemorrhage (ICrH) and ischemic stroke (IS) survivors with and without atrial fibrillation (AF). Methods: Using a national hospitalization database we compared incidences and risks of all-cause in-hospital death, cardiovascular death, non-cardiovascular death, MACE-HF (in-hospital cardiovascular death, myocardial infarction, IS or new-onset heart failure [HF]) between ICrH and IS survivors with and without AF. Propensity-score matching was also performed. Results: We identified 40,523 survivors of IS and 12,028 survivors of an ICrH without AF, and 20,449 IS survivors and 3574 ICrH survivors with AF. In unadjusted, adjusted and matched analyses, ICrH patients without AF had a higher risk of all-cause in-hospital death (Hazard Ratio (HR; for matched analyses) 1.80; 95% confidence interval (CI) 1.74–1.86), cardiovascular death (HR; 2.79; CI 2.64–2.94), MACE-HF (HR 1.97; CI 1.89–2.06) and new cerebrovascular events (HR 1.75; CI 1.57–1.96) but with lower risk of myocardial infarction (HR 0.81; CI 0.70–0.94), major bleeding (HR 0.92; CI 0.87–0.98) and new onset HF (HR 0.85; CI 0.79–0.91) compared to IS survivors without AF. Similar results were found for ICrH and IS survivors with AF except for myocardial infarction (HR 1.05; CI 0.79–1.34) and new onset HF (HR 0.94; CI 0.84–1.06) that were similar between the two groups. Conclusions: Adverse cardiovascular events are more frequent in ICrH survivors compared to IS survivors. New onset HF is a relatively frequent event after ICrH, especially in those patients with comorbid atrial fibrillation.

As of 4 April 2021, a total of 169 cases of cerebral venous sinus thrombosis (CVST) and 53 cases of splanchnic vein thrombosis were reported to EudraVigilance among around 34 million people vaccinated in the European Economic Area and United Kingdom with COVID-19 Vaccine AstraZeneca, a chimpanzee adenoviral vector (ChAdOx1) encoding the spike protein antigen of the SARS-CoV-2 virus. The first report of the European Medicines Agency gathering data on 20 million people vaccinated with Vaxzevria® in the UK and the EEA concluded that the number of post-vaccination cases with thromboembolic events as a whole reported to EudraVigilance in relation to the number of people vaccinated was lower than the estimated rate of such events in the general population. However, the EMA's Pharmacovigilance Risk Assessment Committee concluded that unusual thromboses with low blood platelets should be listed as very rare side effects of Vaxzevria®, pointing to a possible link. The same issue was identified with the COVID-19 Vaccine Janssen (Ad26.COV2.S). Currently, there is still a sharp contrast between the clinical or experimental data reported in the literature on COVID-19 and the scarcity of data on the unusual thrombotic events observed after the vaccination with these vaccines. Different hypotheses might support these observations and should trigger further in vitro and ex vivo investigations. Specialized studies were needed to fully understand the potential relationship between vaccination and possible risk factors in order to implement risk minimization strategies.

ObjectiveTo determine whether the association between increasing number of clot retrieval attempts (CRA) and unfavorable outcome is due to an increase in emboli to new territory (ENT) and greater infarct growth (IG) in successfully recanalized patients with acute ischemic stroke due to large vessel occlusion (AIS-LVO).MethodsData were extracted from 2 pooled multicentric prospective registries of consecutive patients with anterior AIS-LVO treated with mechanical thrombectomy (MT) between January 2016 and 2019. Patients with pretreatment and 24-hour posttreatment diffusion-weighted imaging (DWI) achieving successful recanalization, defined as expanded Thrombolysis in Cerebral Infarction Scale score of 2B, 2C, or 3, were included. ENT were assessed and IG was measured by voxel-based segmentation after DWI coregistration. Associations between number of CRA, ENT, IG, and 3-month outcome were analyzed.ResultsFour hundred nineteen patients achieving successful recanalization were included. ENT occurrence was strongly correlated with increasing CRA (ρ = 0.73, p = 10−4). In multivariable linear analysis, IG was independently associated with CRA (β = 1.6 per retrieval attempt, 95% confidence interval [CI] 0.97–9.74, p = 0.03) and ENT (β = 2.7 [95% CI 1.21–4.1], p = 0.03). Unfavorable functional outcome (3-month modified Rankin Scale score >2) increased with each additional CRA. IG was an independent predictor of unfavorable outcome (odds ratio 1.05 [95% CI 1.02–1.07] per 1-mL IG increase, p = 10−4) in binary logistic regression analysis.ConclusionsIncreasing number of CRA in acute stroke is correlated with an increased ENT rate and increased IG volume, affecting functional outcome even when successful recanalization is achieved.Classification of EvidenceThis study provides Class II evidence that, for patients with acute stroke undergoing successful recanalization, an increasing number of CRA is associated with poorer functional outcome.

Background and Purpose: Although statins are effective in secondary prevention of ischemic stroke, they are also associated with an increase risk of intracranial hemorrhage (ICH) in certain conditions. In the TST trial (Treat Stroke to Target), we prespecified an exploration of the predictors of incident ICH. Methods: Patients with ischemic stroke in the previous 3 months or transient ischemic attack within the previous 15 days and evidence of cerebrovascular or coronary artery atherosclerosis were randomly assigned in a 1:1 ratio to a target LDL (low-density lipoprotein) cholesterol of Results: Among 2860 patients enrolled, 31 incident ICH occurred over a median follow-up of 3 years (18 and 13 in the lower and higher target group, 3.21/1000 patient-years [95% CI, 2.38–4.04] and 2.32/1000 patient-years [95% CI, 1.61–3.03], respectively). While there were no baseline predictors of ICH, uncontrolled hypertension (HR, 2.51 [95% CI, 1.01–6.31], P =0.041) and being on anticoagulant (HR, 2.36 [95% CI, 1.00–5.62], P =0.047)] during the trial were significant predictors. On-treatment low LDL cholesterol was not a predictor of ICH. Conclusions: Targeting an LDL cholesterol of Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01252875; EUDRACT identifier: 2009-A01280-57.

Optimal antithrombotic management after intracerebral hemorrhage remains one of the central unresolved issues for patients who survive, especially for those patients with atrial fibrillation. Given the observational nature of the studies regarding anticoagulation resumption after intracerebral hemorrhage, there is uncertainty regarding resumption of oral anticoagulation therapy and its timing. There is limited high-quality evidence to guide clinical practice, leading to significant practice variation and uncertainty for patients and providers. Here, we aim to provide the key elements to guide clinicians in their individual decision: whether or not to start or resume anticoagulation in patients with a history of intracerebral hemorrhage.

Background: Cerebral microbleeds (CMBs) have been observed in healthy elderly people undergoing systematic brain magnetic resonance imaging. The potential role of acute triggers on the appearance of CMBs remains unknown. We aimed to describe the incidence of new CMBs after transcatheter aortic valve replacement (TAVR) and to identify clinical and procedural factors associated with new CMBs including hemostatic measures and anticoagulation management. Methods: We evaluated a prospective cohort of patients with symptomatic aortic stenosis referred for TAVR for CMBs (METHYSTROKE [Identification of Epigenetic Risk Factors for Ischemic Complication During the TAVR Procedure in the Elderly]). Standardized neurologic assessment, brain magnetic resonance imaging, and analysis of hemostatic measures including von Willebrand factor were performed before and after TAVR. Numbers and location of microbleeds on preprocedural magnetic resonance imaging and of new microbleeds on postprocedural magnetic resonance imaging were reported by 2 independent neuroradiologists blinded to clinical data. Measures associated with new microbleeds and postprocedural outcome including neurologic functional outcome at 6 months were also examined. Results: A total of 84 patients (47% men, 80.9±5.7 years of age) were included. On preprocedural magnetic resonance imaging, 22 patients (26% [95% CI, 17%–37%]) had at least 1 microbleed. After TAVR, new microbleeds were observed in 19 (23% [95% CI, 14%–33%]) patients. The occurrence of new microbleeds was independent of the presence of microbleeds at baseline and of diffusion-weighted imaging hypersignals. In univariable analysis, a previous history of bleeding ( P =0.01), a higher total dose of heparin ( P =0.02), a prolonged procedure ( P =0.03), absence of protamine reversion ( P =0.04), higher final activated partial thromboplastin time ( P =0.05), lower final von Willebrand factor high-molecular-weight:multimer ratio ( P =0.007), and lower final closure time with adenosine–diphosphate ( P =0.02) were associated with the occurrence of new postprocedural microbleeds. In multivariable analysis, a prolonged procedure (odds ratio, 1.22 [95% CI, 1.03–1.73] for every 5 minutes of fluoroscopy time; P =0.02) and postprocedural acquired von Willebrand factor defect (odds ratio, 1.42 [95% CI, 1.08–1.89] for every lower 0.1 unit of high-molecular-weight:multimer ratio; P =0.004) were independently associated with the occurrence of new postprocedural microbleeds. New CMBs were not associated with changes in neurologic functional outcome or quality of life at 6 months. Conclusions: One out of 4 patients undergoing TAVR has CMBs before the procedure and 1 out of 4 patients develops new CMBs. Procedural or antithrombotic management and persistence of acquired von Willebrand factor defect were associated with the occurrence of new CMBs. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02972008.

Supplemental Digital Content is available in the text., Background and Purpose: Timely reperfusion is an important goal in treatment of eligible patients with acute ischemic stroke. However, during the coronavirus disease 2019 (COVID-19) pandemic, prehospital and in-hospital emergency procedures faced unprecedented challenges, which might have caused a decline in the number of acute reperfusion therapy applied and led to a worsening of key quality measures for this treatment during lockdown. Methods: This prospective multicenter cohort study used data from the TRISP (Thrombolysis in Ischemic Stroke Patients) registry of patients with acute ischemic stroke treated with reperfusion therapies, that is, intravenous thrombolysis or endovascular therapy. We compared prehospital and in-hospital time-based performance measures (stroke-onset-to-admission, admission-to-treatment, admission-to-image, and image-to-treatment time) during the first 6 weeks after announcement of lockdown (lockdown period) with the same period in 2019 (reference period). Secondary outcomes included stroke severity (National Institutes of Health Stroke Scale) after 24 hours and occurrence of symptomatic intracranial hemorrhage (following the ECASS [European-Australasian Acute Stroke Study]-II criteria). Results: Across 20 stroke centers, 540 patients were treated with intravenous thrombolysis/endovascular therapy during lockdown period compared with 578 patients during reference period (−7% [95% CI, 5%–9%]). Performance measures did not change significantly during the lockdown period (2020/2019 minutes median: onset-to-admission 133/145; admission-to-treatment 51/48). Same was true for admission-to-image (20/19) and image-to-treatment (31/30) time in patients with available time of first image (n=871, 77.9%). Median National Institutes of Health Stroke Scale on admission (2020/2019: 11/11) and after 24 hours (2020/2019: 6/5) and percentage of symptomatic intracranial hemorrhage (2020/2019: 6.2/5.7) did not differ significantly between both periods. Conclusions: The COVID-19 pandemic lockdown resulted in a mild decline in the number of patients with stroke treated with acute reperfusion therapies. More importantly, the solid stability of key quality performance measures between the 2020 and 2019 period may indicate resilience of acute stroke care service during the lockdown, at least in well-established European stroke centers.

ObjectiveTo determine whether functional MRI connectivity can predict long-term cognitive function 36 months after minor stroke.MethodsSeventy-two participants with first-ever stroke were included at baseline and followed up for 36 months. A ridge regression machine learning algorithm was developed and used to predict cognitive scores 36 months poststroke on the basis of the functional networks measured using MRI at 6 months (referred to here as the poststroke cognitive impairment [PSCI] network). The prediction accuracy was evaluated in 4 domains (memory, attention/executive, language, and visuospatial functions) and compared with clinical data and other functional networks. The models' statistical significance was probed with permutation tests. The potential involvement of cortical atrophy was assessed 6 months poststroke. A second, independent dataset (n = 40) was used to validate the results and assess their generalizability.ResultsBased on the PSCI network, a machine learning model was able to predict memory, attention, visuospatial functions, and language functions 36 months poststroke (r2: 0.67, 0.73, 0.55, and 0.48, respectively). The PSCI-based model was at least as accurate as models based on other functional networks or clinical data. Specific patterns were demonstrated for the 4 cognitive domains, with involvement of the left superior frontal cortex for memory, attention, and visuospatial functions. The cortical thickness 6 months poststroke was not correlated with cognitive function 36 months poststroke. The independent validation dataset gave similar results.ConclusionsA machine learning model based on the PSCI network can predict long-term cognitive outcome after stroke.

Background and Purpose: Accumulating evidence from randomized controlled clinical trials suggests that tenecteplase may represent an effective treatment alternative to alteplase for acute ischemic stroke. In the present systematic review and meta-analysis, we sought to compare the efficacy and safety outcomes of intravenous tenecteplase to intravenous alteplase administration for acute ischemic stroke patients with large vessel occlusions (LVOs). Methods: We searched MEDLINE (Medical Literature Analysis and Retrieval System Online) and Scopus for published randomized controlled clinical trials providing outcomes of acute ischemic stroke with confirmed LVO receiving intravenous thrombolysis with either tenecteplase at different doses or alteplase at a standard dose of 0.9 mg/kg. The primary outcome was the odds of modified Rankin Scale score of 0 to 2 at 3 months. Results: We included 4 randomized controlled clinical trials including a total of 433 patients. Patients with confirmed LVO receiving tenecteplase had higher odds of modified Rankin Scale scores of 0 to 2 (odds ratio, 2.06 [95% CI, 1.15–3.69]), successful recanalization (odds ratio, 3.05 [95% CI, 1.73–5.40]), and functional improvement defined as 1-point decrease across all modified Rankin Scale grades (common odds ratio, 1.84 [95% CI, 1.18–2.87]) at 3 months compared with patients with confirmed LVO receiving alteplase. There was little or no heterogeneity between the results provided from included studies regarding the aforementioned outcomes (I 2 ≤20%). No difference in the outcomes of early neurological improvement, symptomatic intracranial hemorrhage, any intracranial hemorrhage, and the rates of modified Rankin Scale score 0 to 1 or all-cause mortality at 3 months was detected between patients with LVO receiving intravenous thrombolysis with either tenecteplase or alteplase. Conclusions: Acute ischemic stroke patients with LVO receiving intravenous thrombolysis with tenecteplase have significantly better recanalization and clinical outcomes compared with patients receiving intravenous alteplase.

Antithrombotic therapy is a cornerstone for secondary prevention of ischaemic events, cerebral and extra-cerebral. A number of clinical questions remain unanswered concerning the impact of antithrombotic drugs on the risk of first-ever and recurrent macro or micro cerebral haemorrhages, raising the clinical dilemma on the risk/benefit balance of giving antiplatelets and anticoagulants in patients with potential high risk of brain bleeds. High field magnetic resonance imaging (MRI) blood-weighted sequences, including susceptibility weighted imaging (SWI), have expanded the spectrum of these clinical questions, because of their increasing sensitivity in detecting radiological markers of small vessel disease. This review will summarise the literature, focusing on four main clinical questions: how do cerebral microbleeds impact the risk of cerebrovascular events in healthy patients, in patients with previous ischaemic stroke or transient ischaemic attack, and in patients with intracerebral haemorrhage? Is the risk/benefit balance of oral anticoagulants shifted by the presence of microbleeds in patients with atrial fibrillation after recent ischaemic stroke or transient ischaemic attack? Should we restart antiplatelet drugs after symptomatic intracerebral haemorrhage or not? Are oral anticoagulants allowed in patients with a history of atrial fibrillation and previous intracerebral haemorrhage?

Introduction and Purpose: Cerebral amyloid angiopathy (CAA) can be observed in patients with progressive supranuclear palsy (PSP), though to a lesser degree than in Alzheimer&rsquo, s disease. The present post-mortem 7.0-tesla magnetic resonance imaging (MRI) evaluates whether CAA has an influence on the degree of hippocampal atrophy (HA) and on the incidence of associated micro-infarcts (HMIs) and cortical micro-bleeds (HMBs). Material and Methods: Eight brains with PSP-CAA were compared to 20 PSP brains without CAA. In addition to the neuropathological examination, the hippocampus was evaluated on the most representative coronal section with T2 and T2*-weighted MRI sequences. The average degree of HA was determined in both groups. The incidence of HMIs and HMBs was also compared as well as the frequency of cortical micro-infarcts (CoMIs) and cortical micro-bleeds (CoMBs) in the hemispheric neocortex. Results: The neuropathological examination showed a higher incidence of lacunar infarcts in the PSP-CAA brains compared to the PSP ones. With magnetic resonance imaging (MRI), the severity of HA and the incidence of HMIs and HMBs was similar between both groups. Additionally, the frequency of CoMIs and CoMBs in the neocortex was comparable. Conclusions: The association of CAA in PSP brains has no influence on the degree of HA and on the incidence of the small cerebrovascular lesions in the hippocampus as well as in the neocortex.

Background: Limited data exist regarding the prevalence of clinical and neuroimaging manifestations among patients diagnosed with cerebral amyloid angiopathy (CAA). We sought to determine the prevalence of clinical phenotypes and radiological markers in patients with CAA. Methods: Systematic review and meta-analysis of studies including patients with CAA was conducted to primarily assess the prevalence of clinical phenotypes and neuroimaging markers as available in the included studies. Sensitivity analyses were performed based on the (1) retrospective or prospective study design and (2) probable or unspecified CAA status. We pooled the prevalence rates using random-effects models and assessed the heterogeneity using the Cochran Q and I 2 statistics. Results: We identified 12 prospective and 34 retrospective studies including 7159 patients with CAA. The pooled prevalence rates were cerebral microbleeds (52% [95% CI, 43%–60%]; I 2 =93%), cortical superficial siderosis (49% [95% CI, 38%–59%]; I 2 =95%), dementia or mild cognitive impairment (50% [95% CI, 35%–65%]; I 2 =97%), intracerebral hemorrhage (ICH; 44% [95% CI, 27%–61%]; I 2 =98%), transient focal neurological episodes (48%; 10 studies [95% CI, 29%–67%]; I 2 =97%), lacunar infarcts (30% [95% CI, 25%–36%]; I 2 =78%), high grades of perivascular spaces located in centrum semiovale (56% [95% CI, 44%–67%]; I 2 =88%) and basal ganglia (21% [95% CI, 2%–51%]; I 2 =98%), and white matter hyperintensities with moderate or severe Fazekas score (53% [95% CI, 40%–65%]; I 2 =91%). The only neuroimaging marker that was associated with higher odds of recurrent ICH was cortical superficial siderosis (odds ratio, 1.57 [95% CI, 1.01–2.46]; I 2 =47%). Sensitivity analyses demonstrated a higher prevalence of ICH (53% versus 16%; P =0.03) and transient focal neurological episodes (57% versus 17%; P =0.03) among retrospective studies compared with prospective studies. No difference was documented between the prevalence rates based on the CAA status. Conclusions: Approximately one-half of hospital-based cohort of CAA patients was observed to have cerebral microbleeds, cortical superficial siderosis, mild cognitive impairment, dementia, ICH, or transient focal neurological episodes. Cortical superficial siderosis was the only neuroimaging marker that was associated with higher odds of ICH recurrence. Future population-based studies among well-defined CAA cohorts are warranted to corroborate our findings.

Background: Recent studies in the general stroke population treated with endovascular treatment (EVT) reported that higher pre-treatment lesional volumes were independently associated with poor neurological outcome and functional dependence after stroke. However, it has been not evaluated in older patients. Aim: We test the association between the pre-treatment lesional volume on diffusion-weighted magnetic resonance imaging and relevant outcome measures in older adults with stroke treated with EVT. Methods: We included consecutive older adults with stroke (⩾80 years old) treated with EVT in two academic comprehensive stroke centers. The association between pre-treatment lesional volume and relevant outcome measures (poor outcome (modified Rankin scale 4–6), 3-month mortality and symptomatic intracerebral hemorrhage (sICH)) was evaluated using univariate and multivariable models. Results: Five hundred seventy-nine patients were included (mean age: 85.6 ± 4.1, median lesional volume was 10 ml; interquartile range: 3–30 ml). Pre-treatment lesional volume was associated with poor functional outcome (adjusted odds ratio (aOR): 1.87, 95% confidence interval (CI): 1.60–2.20, for +1 logarithmic increase of lesional volume), 3-month mortality (aOR: 1.50, CI: 1.28–1.76), and sICH (aOR: 1.67, CI: 1.27–2.20). A threshold lesional volume >35 ml predicted 90% of patients with poor functional outcome and a cut-off >51 ml predicted 90% of patients dead at 3 months. Conclusions: Pre-treatment lesional volume might contribute, in association with other relevant clinical features, to the selection of older stroke patients who will benefit from EVT.

We have provided an overview on the profound impact of COVID‐19 upon older people with Alzheimer's disease and other dementias and the challenges encountered in our management of dementia in different health‐care settings, including hospital, out‐patient, care homes, and the community during the COVID‐19 pandemic. We have also proposed a conceptual framework and practical suggestions for health‐care providers in tackling these challenges, which can also apply to the care of older people in general, with or without other neurological diseases, such as stroke or parkinsonism. We believe this review will provide strategic directions and set standards for health‐care leaders in dementia, including governmental bodies around the world in coordinating emergency response plans for protecting and caring for older people with dementia amid the COIVD‐19 outbreak, which is likely to continue at varying severity in different regions around the world in the medium term.

Background and Purpose: Infarct volumes predict malignant infarcts in patients undergoing decompressive hemicraniectomy (DH) for large middle cerebral artery territory infarcts. The aim of the study was to determine the optimal magnetic resonance imaging infarct volume threshold that predicts a catastrophic outcome at 1 year (modified Rankin Scale score of 5 or death). Methods: We included consecutive patients who underwent DH for large middle cerebral artery infarcts. We analyzed infarct volumes before DH with semi-automated methods on b1000 diffusion-weighted imaging sequences and apparent diffusion coefficient maps. We studied infarct volume thresholds for prediction of catastrophic outcomes, and analyzed sensitivity, specificity, and the area under the curve, a value ≥0.70 indicating an acceptable prediction. Results: Of 173 patients (109 men, 63%; median age 53 years), 42 (24.3%) had catastrophic outcomes. Magnetic resonance imaging b1000 diffusion-weighted imaging and apparent diffusion coefficient infarct volumes were associated to the occurrence of 1-year catastrophic outcome (adjusted odds ratio, 9.17 [95% CI, 2.00–42.04] and odds ratio, 4.18 [95% CI, 1.33–13.19], respectively, per 1 log increase). The optimal volume cutoff of were 211 mL on b1000 diffusion-weighted imaging and 181 mL on apparent diffusion coefficient maps. The 2 methods showed similar sensitivities and specificities and overlapping area under the curve of 0.64 (95% CI, 0.54–0.74). Conclusions: In patients with large middle cerebral artery infarcts, optimal magnetic resonance imaging infarct volume thresholds showed poor accuracy and low specificity to predict 1-year catastrophic outcome, with different b1000 diffusion-weighted imaging and apparent diffusion coefficient thresholds. In the setting of DH, optimal infarct volumes alone should not be used to deny DH, irrespectively of the method used.