Andexanet for Factor Xa Inhibitor-Associated Acute Intracerebral Hemorrhage.

BACKGROUND: Patients with acute intracerebral hemorrhage who are receiving factor Xa inhibitors have a risk of hematoma expansion. The effect of andexanet alfa, an agent that reverses the effects of factor Xa inhibitors, on hematoma volume expansion has not been well studied. METHODS: We randomly assigned, in a 1:1 ratio, patients who had taken factor Xa inhibitors within 15 hours before having an acute intracerebral hemorrhage to receive andexanet or usual care. The primary end point was hemostatic efficacy, defined by expansion of the hematoma volume by 35% or less at 12 hours after baseline, an increase in the score on the National Institutes of Health Stroke Scale of less than 7 points (scores range from 0 to 42, with higher scores indicating worse neurologic deficit) at 12 hours, and no receipt of rescue therapy between 3 hours and 12 hours. Safety end points were thrombotic events and death. RESULTS: A total of 263 patients were assigned to receive andexanet, and 267 to receive usual care. Efficacy was assessed in an interim analysis that included 452 patients, and safety was analyzed in all 530 enrolled patients. Atrial fibrillation was the most common indication for factor Xa inhibitors. Of the patients receiving usual care, 85.5% received prothrombin complex concentrate. Hemostatic efficacy was achieved in 150 of 224 patients (67.0%) receiving andexanet and in 121 of 228 (53.1%) receiving usual care (adjusted difference, 13.4 percentage points; 95% confidence interval [CI], 4.6 to 22.2; P = 0.003). The median reduction from baseline to the 1-to-2-hour nadir in anti-factor Xa activity was 94.5% with andexanet and 26.9% with usual care (P<0.001). Thrombotic events occurred in 27 of 263 patients (10.3%) receiving andexanet and in 15 of 267 (5.6%) receiving usual care (difference, 4.6 percentage points; 95% CI, 0.1 to 9.2; P = 0.048); ischemic stroke occurred in 17 patients (6.5%) and 4 patients (1.5%), respectively. There were no appreciable differences between the groups in the score on the modified Rankin scale or in death within 30 days. CONCLUSIONS: Among patients with intracerebral hemorrhage who were receiving factor Xa inhibitors, andexanet resulted in better control of hematoma expansion than usual care but was associated with thrombotic events, including ischemic stroke. (Funded by Alexion AstraZeneca Rare Disease and others; ANNEXA-I ClinicalTrials.gov number, NCT03661528.).

Cerebrovascular Complications of COVID-19 and COVID-19 Vaccination.

The risk of stroke and cerebrovascular disease complicating infection with SARS-CoV-2 has been extensively reported since the onset of the pandemic. The striking efforts of many scientists in cooperation with regulators and governments worldwide have rapidly brought the development of a large landscape of vaccines against SARS-CoV-2. The novel DNA and mRNA vaccines have offered great flexibility in terms of antigen production and led to an unprecedented rapidity in effective and safe vaccine production. However, as mass vaccination has progressed, rare but catastrophic cases of thrombosis have occurred in association with thrombocytopenia and antibodies against PF4 (platelet factor 4). This catastrophic syndrome has been named vaccine-induced immune thrombotic thrombocytopenia. Rarely, ischemic stroke can be the symptom onset of vaccine-induced immune thrombotic thrombocytopenia or can complicate the course of the disease. In this review, we provide an overview of stroke and cerebrovascular disease as a complication of the SARS-CoV-2 infection and outline the main clinical and radiological characteristics of cerebrovascular complications of vaccinations, with a focus on vaccine-induced immune thrombotic thrombocytopenia. Based on the available data from the literature and from our experience, we propose a therapeutic protocol to manage this challenging condition. Finally, we highlight the overlapping pathophysiologic mechanisms of SARS-CoV-2 infection and vaccination leading to thrombosis.

PAD4-Induced NETosis Via Cathepsin G-Mediated Platelet-Neutrophil Interaction in ChAdOx1 Vaccine-Induced Thrombosis-Brief Report.

BACKGROUND: Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare syndrome characterized by platelet anti-PF4 (platelet-activating antiplatelet factor 4)-related thrombosis. Platelet-neutrophil interaction has been suggested to play a role, but the underlying mechanism has not been fully elucidated. METHODS: The study included 10 patients with VITT after ChAdOx1 (chimpanzee adenovirus Oxford 1) nCoV-19 (Oxford-AstraZeneca) vaccine administration, 10 patients with ischemic stroke (IS), 10 patients with acute deep vein thrombosis, and 10 control subjects in whom blood levels of neutrophil extracellular traps (NETs), soluble TF (tissue factor), and thrombin generation were examined. Furthermore, we performed in vitro studies comparing the effect of serum from patients and controls on NETs formation. Finally, immunohistochemistry was performed in cerebral thrombi retrieved from a patients with VITT and 3 patients with IS. RESULTS: Compared with patients with IS, patients with deep vein thrombosis, controls, and patients with VITT had significantly higher blood values of CitH3 (citrullinated histone H3), soluble TF, D-dimer, and prothrombin fragment 1+2 (P<0.0001). Blood CitH3 significantly correlated with blood soluble TF (Spearman rank correlation coefficient=0.7295; P=0.0206) and prothrombin fragment 1+2 (Spearman rank correlation coefficient=0.6809; P<0.0350) in patients with VITT. Platelet-neutrophil mixture added with VITT plasma resulted in higher NETs formation, soluble TF and thrombin generation, and platelet-dependent thrombus growth under laminar flow compared with IS and deep vein thrombosis plasma; these effects were blunted by PAD4 (protein arginine deiminase 4) and cathepsin G inhibitors, anti-FcγRIIa (Fc receptor for IgG class IIa), and high doses of heparin. Immunohistochemistry analysis showed a more marked expression of PAD4 along with more diffuse neutrophil infiltration and NETs formation as well as TF and cathepsin expression in VITT thrombus compared with thrombi from patients with IS. CONCLUSIONS: Patients with VITT display enhanced thrombogenesis by PAD4-mediated NETs formation via cathepsin G-mediated platelet/neutrophil interaction.

Workflow and Outcome of Thrombectomy in Late Time Window: A Pooled Multicenter Analysis.

BACKGROUND: We investigated the impact of workflow times on the outcomes of patients treated with endovascular thrombectomy (EVT) in the late time window. METHODS: Individual patients' data who underwent EVT in the late time window (onset to imaging >6 hours) were pooled from seven registries and randomized clinical trials. Multiple time intervals were analyzed. Mixed-effects logistic regression was used to estimate the likelihood of functional independence at 90 days (modified Rankin Scale 0-2). Mixed-effects negative binomial regression was used to evaluate the relationship between patient characteristics and workflow time intervals. RESULTS: 608 patients were included. The median age was 70 years (IQR: 58-71), 307 (50.5%) were female, and 310 (53.2%) had wake-up strokes. Successful reperfusion was achieved in 493 (81.2%) patients, and 262 (44.9%) achieved 90-day mRS 0-2. The estimated odds of functional independence decreased by 13% for every 30 minute delay from emergency department (ED) arrival to imaging time and by 7% from ED arrival to the end of EVT in the entire cohort. Also, the estimated odds of functional independence decreased by 33% for every 30 minute delay in the interval from arterial puncture to end of EVT, 16% in the interval from arrival in ED to end of EVT and 6% in the interval from stroke onset to end of EVT among patients who had a wake-up stroke. CONCLUSION: Faster workflow from ED arrival to end of EVT is associated with improved functional independence among stroke patients treated in the late window.

Reperfusion Treatments in Disabling Versus Nondisabling Mild Stroke due to Anterior Circulation Vessel Occlusion.

BACKGROUND: The benefit of distinguishing between disabling versus nondisabling deficit in mild acute ischemic stroke due to endovascular thrombectomy-targetable vessel occlusion (EVT-tVO; including anterior circulation large and medium-vessel occlusion) is unknown. We compared safety and efficacy of acute reperfusion treatments in disabling versus nondisabling mild EVT-tVO. METHODS: From the Safe Implementation of Treatments in Stroke-International Stroke Thrombolysis Register, we included consecutive acute ischemic stroke patients (2015-2021) treated within 4.5 hours, with full NIHSS items availability and score ≤5, evidence of intracranial internal carotid artery, M1, A1-2, or M2-3 occlusion. After propensity score matching, we compared efficacy (3-month modified Rankin Scale score of 0-1, modified Rankin Scale score of 0-2, and early neurological improvement) and safety (nonhemorrhagic early neurological deterioration, any intracerebral or subarachnoid hemorrhage, symptomatic intracranial hemorrhage, and death at 3-month) outcomes in disabling versus nondisabling patients-adopting an available definition. RESULTS: We included 1459 patients. Propensity score matched analysis of disabling versus nondisabling EVT-tVO (n=336 per group) found no significant differences in efficacy (modified Rankin Scale score 0-1: 67.4% versus 71.5%, P=0.336; modified Rankin Scale score 0-2: 77.1% versus 77.6%, P=0.895; early neurological improvement: 38.3% versus 44.4%, P=0.132) and safety (nonhemorrhagic early neurological deterioration: 8.5% versus 8.0%, P=0.830; any intracerebral hemorrhage or subarachnoid hemorrhage: 12.5% versus 13.3%, P=0.792; symptomatic intracranial hemorrhage: 2.6% versus 3.4%, P=0.598; and 3-month death: 9.8% versus 9.2%, P=0.844) outcomes. CONCLUSIONS: We found similar safety and efficacy outcomes after acute reperfusion treatment in disabling versus nondisabling mild EVT-tVO; our findings suggest to adopt similar acute treatment approaches in the 2 groups. Randomized data are needed to clarify the best reperfusion treatment in mild EVT-tVO.

Predictors for clinical and functional outcomes in stroke patients with first-pass complete recanalization after thrombectomy.

BACKGROUND AND PURPOSE: The aim was to identify baseline clinical and radiological/procedural predictors and 24-h radiological predictors for clinical and functional outcomes in stroke patients obtaining complete recanalization in one pass of mechanical thrombectomy (MT) in an optimal baseline and procedural setting. METHODS: A retrospective analysis was conducted of prospectively collected data from 924 stroke patients with anterior large vessel occlusion, Alberta Stroke Program Early Computed Tomography (ASPECT) score ≥6 and pre-stroke modified Rankin Scale score 0, who started MT ≤6 h from symptom onset and obtained first-pass complete recanalization. A first logistic regression model was performed to identify baseline clinical predictors and a second model to identify baseline radiological/procedural predictors. A third model including baseline clinical and radiological/procedural predictors was performed, and a fourth model including independent baseline predictors from the third model plus 24-h radiological variables (hemorrhagic transformation [HT] and cerebral edema [CED]). RESULTS: In the fourth model, higher National Institutes of Health Stroke Scale (NIHSS) score (odds ratio [OR] 1.089) and higher ASPECT score (OR 1.292) were predictors of early neurological improvement (ENI) (NIHSS score ≤4 points from baseline or NIHSS score of 0 at 24 h), whereas older age (OR 0.973), longer procedure time (OR 0.990), HT (OR 0.272) and CED (OR 0.569) were inversely associated with ENI. Older age (OR 0.970), diabetes mellitus (OR 0.456), higher NIHSS score (OR 0.886), general anesthesia (OR 0.454), longer onset-to-groin time (OR 0.996), HT (OR 0.340) and CED (OR 0.361) were inversely associated with 3-month excellent functional outcome (mRS score 0-1), whereas higher ASPECT score (OR 1.294) was a predictor of excellent outcome. CONCLUSIONS: Higher NIHSS score was a predictor of ENI but inversely associated with 3-month excellent outcome. Older age, HT and CED were inversely associated with both good outcomes.

Mechanical thrombectomy in young patients with large vessel occlusion-related ischemic stroke: Data from the Italian Registry of Endovascular Treatment in Acute Stroke.

BACKGROUND AND PURPOSE: The weight of outcome predictors in acute ischemic stroke (AIS) patients older than 60 years is not necessarily mirrored in the younger population, posing the question of whether outcome determinants specific for the latter might vary. Very few data are available on predictors of outcome in young AIS patients receiving endovascular treatment (EVT). METHODS: We analyzed data for patients aged between 16 and 55 years from the Italian Registry of Endovascular Treatment in Acute Stroke. We divided our population into patients <45 years old and patients aged between 45 and 55 years. After testing the differences between groups in terms of 90-day modified Rankin Scale (mRS) 0-2, mortality, and symptomatic intracranial hemorrhage, we looked for predictors of poor outcome (mRS 3-6), death, and symptomatic intracerebral hemorrhage in the two groups. RESULTS: A total of 438 patients younger than 45 years and 817 aged 45-55 years were included; 284 (34.8%) patients aged 45-55 years and 112 (25.6%) patients younger than 45 years old showed poor 90-day functional outcome (p = 0.001). Predictors of poor outcome in the older group were baseline National Institutes of Health Stroke Scale (NIHSS; p < 0.001), diabetes (p = 0.027), poor collateral status (p = 0.036), and groin puncture-to-recanalization time (p = 0.010), whereas Thrombolysis in Cerebral Infarction (TICI) 2b-3 had an inverse association (p < 0.001). Predictors of poor outcome in patients younger than 45 years were baseline NIHSS (p < 0.001) and groin puncture-to-recanalization time (p = 0.015), whereas an inverse association was found for baseline Alberta Stroke Program Early CT Score (p = 0.010) and TICI 2b-3 (p < 0.001). CONCLUSIONS: Approximately one third of young adults treated with EVT do not reach a good functional outcome. Fast and successful recanalization, rather than common risk factors, has a major role in determining clinical outcome.

A transient magnetic resonance spectroscopy peri-ischemic peak: a possible radiological biomarker of post-stroke neurogenesis.

BACKGROUND AND AIMS: In adult human brain, neurogenesis seems to persist throughout life and ischemic stroke was proved to stimulate this process. Using magnetic resonance spectroscopy (MRS), a 1.28-ppm peak, putative biomarker of neural progenitor cells (NPCs), was identified both in vitro and in vivo, i.e., in normal rat and healthy human brain. The aim of our study was to identify a 1.28-ppm peak in adult human ischemic brain by using 3.0 T multivoxel MRS. METHODS: We studied 10 patients, six males, and four females, with a mean (± SD) age of 59.3 (± 17.3), at three different time points from ischemic stroke onset (T0: < 5 days; T14: 14 ± 2 days; T30: 30 ± 2 days). RESULTS: In all patients except one, a 1.28-ppm peak at T14 was detected at the ischemic boundary (all p values < 0.05). MRS performed on six voluntary age-matched healthy subjects did not detect any 1.28-ppm peak. CONCLUSIONS: The nature of this 1.28-pm peak is uncertain; however, our data support the hypothesis that it might represent a marker of NPCs in post-stroke human brain.

No-reflow phenomenon in acute ischemic stroke: an angiographic evaluation.

BACKGROUND: Futile recanalization (FR) is de fined as a poor 90-day outcome or lack of neurological improvement at 24 h despite successful recanalization in acute ischemic stroke (AIS) with large vessel occlusion (LVO) treated by mechanical throbectomy (MT). The No-reflow phenomenon (NRP) could be a possible cause of FR, but its evidence in AIS patients is scarce. METHODS: We retrospectively analyzed 185 digital subtraction angiographies (DSA) of AIS patients with anterior circulation LVO after endovascular treatment. To better define NRP, we designed a score called the modified capillary index score (mCIS). The score is obtained by dividing the middle cerebral artery territory in three segments. For each segment, we gave 2 points if the capillary blush was present without any delay, 1 if delayed, and 0 if absent. The primary endpoint was to use mCIS to identify NRP on post-interventional DSA and to test whether this marker may predict FR and failure of early neurological improvement (fENI). The secondary endpoint was to search for a correlation between NRP, lesion volume, and hemorrhagic transformation. We used the ROC curve to define mCIS ≤ 3 as the cut-off and marker of NRP. RESULTS: NRP was present in 35.1% of patients. NRP predicted fENI at 24 h (aOR 2.825, 95% CI 1.265-6.308, P = 0.011) and at 7 days (aOR 2.191, 95% CI 1.008-4.762, P = 0.048), but not 90-day FR. Moreover, NRP predicted hemorrhagic transformation (aOR 2.444, 95% CI 1.266-4.717, P = 0.008). CONCLUSIONS: The modified capillary index score (mCIS) seems useful in identifying NRP in AIS. In addition, mCIS was able to predict NRP that correlated with early clinical outcome and hemorrhagic transformation of the ischemic lesion. An external validation of the score is warranted.

Sex-Related Differences in Outcomes After Endovascular Treatment of Patients With Late-Window Stroke.

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 (Pinteraction=0.003) and symptomatic intracranial hemorrhage (Pinteraction=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.

Recurrent Ischemic Stroke and Bleeding in Patients With Atrial Fibrillation Who Suffered an Acute Stroke While on Treatment With Nonvitamin K Antagonist Oral Anticoagulants: The RENO-EXTEND Study.

BACKGROUND: In patients with atrial fibrillation who suffered an ischemic stroke while on treatment with nonvitamin K antagonist oral anticoagulants, rates and determinants of recurrent ischemic events and major bleedings remain uncertain. METHODS: This prospective multicenter observational study aimed to estimate the rates of ischemic and bleeding events and their determinants in the follow-up of consecutive patients with atrial fibrillation who suffered an acute cerebrovascular ischemic event while on nonvitamin K antagonist oral anticoagulant treatment. Afterwards, we compared the estimated risks of ischemic and bleeding events between the patients in whom anticoagulant therapy was changed to those who continued the original treatment. RESULTS: After a mean follow-up time of 15.0±10.9 months, 192 out of 1240 patients (15.5%) had 207 ischemic or bleeding events corresponding to an annual rate of 13.4%. Among the events, 111 were ischemic strokes, 15 systemic embolisms, 24 intracranial bleedings, and 57 major extracranial bleedings. Predictive factors of recurrent ischemic events (strokes and systemic embolisms) included CHA2DS2-VASc score after the index event (odds ratio [OR], 1.2 [95% CI, 1.0-1.3] for each point increase; P=0.05) and hypertension (OR, 2.3 [95% CI, 1.0-5.1]; P=0.04). Predictive factors of bleeding events (intracranial and major extracranial bleedings) included age (OR, 1.1 [95% CI, 1.0-1.2] for each year increase; P=0.002), history of major bleeding (OR, 6.9 [95% CI, 3.4-14.2]; P=0.0001) and the concomitant administration of an antiplatelet agent (OR, 2.8 [95% CI, 1.4-5.5]; P=0.003). Rates of ischemic and bleeding events were no different in patients who changed or not changed the original nonvitamin K antagonist oral anticoagulants treatment (OR, 1.2 [95% CI, 0.8-1.7]). CONCLUSIONS: Patients suffering a stroke despite being on nonvitamin K antagonist oral anticoagulant therapy are at high risk of recurrent ischemic stroke and bleeding. In these patients, further research is needed to improve secondary prevention by investigating the mechanisms of recurrent ischemic stroke and bleeding.

Dabigatran for Prevention of Stroke after Embolic Stroke of Undetermined Source.

BACKGROUND: Cryptogenic strokes constitute 20 to 30% of ischemic strokes, and most cryptogenic strokes are considered to be embolic and of undetermined source. An earlier randomized trial showed that rivaroxaban is no more effective than aspirin in preventing recurrent stroke after a presumed embolic stroke from an undetermined source. Whether dabigatran would be effective in preventing recurrent strokes after this type of stroke was unclear. METHODS: We conducted a multicenter, randomized, double-blind trial of dabigatran at a dose of 150 mg or 110 mg twice daily as compared with aspirin at a dose of 100 mg once daily in patients who had had an embolic stroke of undetermined source. The primary outcome was recurrent stroke. The primary safety outcome was major bleeding. RESULTS: A total of 5390 patients were enrolled at 564 sites and were randomly assigned to receive dabigatran (2695 patients) or aspirin (2695 patients). During a median follow-up of 19 months, recurrent strokes occurred in 177 patients (6.6%) in the dabigatran group (4.1% per year) and in 207 patients (7.7%) in the aspirin group (4.8% per year) (hazard ratio, 0.85; 95% confidence interval [CI], 0.69 to 1.03; P = 0.10). Ischemic strokes occurred in 172 patients (4.0% per year) and 203 patients (4.7% per year), respectively (hazard ratio, 0.84; 95% CI, 0.68 to 1.03). Major bleeding occurred in 77 patients (1.7% per year) in the dabigatran group and in 64 patients (1.4% per year) in the aspirin group (hazard ratio, 1.19; 95% CI, 0.85 to 1.66). Clinically relevant nonmajor bleeding occurred in 70 patients (1.6% per year) and 41 patients (0.9% per year), respectively. CONCLUSIONS: In patients with a recent history of embolic stroke of undetermined source, dabigatran was not superior to aspirin in preventing recurrent stroke. The incidence of major bleeding was not greater in the dabigatran group than in the aspirin group, but there were more clinically relevant nonmajor bleeding events in the dabigatran group. (Funded by Boehringer Ingelheim; RE-SPECT ESUS ClinicalTrials.gov number, NCT02239120.).

Stroke and stroke-like episodes in inborn errors of metabolism: Pathophysiological and clinical implications.

Inborn errors of metabolism causing stroke (ischemic or haemorrhagic) or stroke-like episodes (e.g., that are also called "metabolic strokes" and include acute brain lesions not related with alterations of blood flow) cover a wide range of diseases in which acute metabolic decompensations after trigger events (e.g., fever, dehydration, sepsis etc.) may have a variable frequency. The early diagnosis of these conditions is essential because, despite their rarity, effective symptomatic treatments may be available for acute settings (e.g., arginine for Mitochondrial myopathy, Encephalopathy, Lactic Acidosis, and Stroke-like episodes- MELAS) while in other cases disease modifying therapies may be useful to prevent stroke occurrence, recurrence, or relapse (e.g., Fabry disease). The detection of a non-vascular distribution of lesions and the diffuse use of 1HMRS are often diriment in the differential of ischemic and metabolic strokes. This review summarized the main clinical features and the pathophysiological mechanisms of stroke and stroke-like episodes in inborn errors of metabolism presenting with stroke as part of natural history of the disease. These conditions belong to different etiological groups, such as organic acidurias, mitochondrial encephalopathies, homocystinuria and remethylation disorders, urea cycle disorders, lysosomal diseases (e.g. Fabry disease, glycogen storage disease), congenital disorders of glycosylation, neurotransmitter disorders, adenosine deaminase 2 deficiency and few other neurometabolic disorders.

Stroke imaging prior to thrombectomy in the late window: results from a pooled multicentre analysis.

BACKGROUND AND PURPOSE: Collateral 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. METHODS: We 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. RESULTS: In 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). CONCLUSION: This 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 NUMBER: CRD42020222003.

Acute ischemic stroke in childhood: a comprehensive review.

This review provides an updated analysis of the main aspects involving the diagnosis and the management of children with acute ischemic stroke. Acute ischemic stroke is an emergency of rare occurrence in children (rate of incidence of 1/3500 live birth in newborns and 1-2/100,000 per year during childhood with peaks of incidence during the perinatal period, under the age of 5 and in adolescence). The management of ischemic stroke in the paediatric age is often challenging because of pleomorphic age-dependent risk factors and aetiologies, high frequency of subtle or atypical clinical presentation, and lacking evidence-based data about acute recanalization therapies. Each pediatric tertiary centre should activate adequate institutional protocols for the optimization of diagnostic work-up and treatments.Conclusion: The implementation of institutional standard operating procedures, summarizing the steps for the selection of candidate for neuroimaging among the ones presenting with acute neurological symptoms, may contribute to shorten the times for thrombolysis and/or endovascular treatments and to improve the long-term outcome. What is Known: •Acute ischemic stroke has a higher incidence in newborns than in older children (1/3500 live birth versus 1-2/100,000 per year). •Randomized clinical trial assessing safety and efficacy of thrombolysis and/or endovascular treatment were never performed in children What is New: •Recent studies evidenced a low risk (2.1% of the cases) of intracranial haemorrhages in children treated with thrombolysis. •A faster access to neuroimaging and hyper-acute therapies was associated with the implementation of institutional protocols for the emergency management of pediatric stroke.

Association of the careggi collateral score with radiological outcomes after thrombectomy for stroke with an occlusion of the middle cerebral artery.

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.

Fabry-Stroke Italian Registry (FSIR): a nationwide, prospective, observational study about incidence and characteristics of Fabry-related stroke in young-adults. Presentation of the study protocol.

BACKGROUND: TIA and stroke, both ischemic and hemorrhagic, may complicate Fabry disease at young-adult age and be the first manifestation that comes to the clinician's attention. No definite indications have yet been elaborated to guide neurologists in Fabry disease diagnostics. In current practice, it is usually sought in case of cryptogenic strokes (while Fabry-related strokes can also occur by classical pathogenic mechanisms) or through screening programs in young cerebrovascular populations. Data on recurrence and secondary prevention of Fabry's stroke are scanty. METHODS: The study had a prospective observational design involving 33 Italian neurological Stroke Units. Considering the incidence of TIA/stroke in the European population aged < 60 years and the frequency of Fabry disease in this category (as foreseen by a pilot study held at the Careggi University-Hospital, Florence), we planned to screen for Fabry disease a total of 1740 < 60-year-old individuals hospitalized for TIA, ischemic, or hemorrhagic stroke. We investigated TIA and stroke pathogenesis through internationally validated scales and we gathered information on possible early signs of Fabry disease among all cerebrovascular patients. Every patient was tested for Fabry disease through dried blood spot analysis. Patients who received Fabry disease diagnosis underwent a 12-month follow-up to monitor stroke recurrence and multi-system progression after the cerebrovascular event. DISCUSSION: The potential implications of this study are as follows: (i) to add information about the yield of systematic screening for Fabry disease in a prospective large cohort of acute cerebrovascular patients; (ii) to deepen knowledge of clinical, pathophysiological, and prognostic characteristics of Fabry-related stroke.

European position paper on the management of patients with patent foramen ovale. Part II - Decompression sickness, migraine, arterial deoxygenation syndromes and select high-risk clinical conditions.

Patent foramen ovale (PFO) is implicated in the pathogenesis of a number of medical conditions but to date only one official position paper related to left circulation thromboembolism has been published. This interdisciplinary paper, prepared with the involvement of eight European scientific societies, reviews the available evidence and proposes a rationale for decision making for other PFO-related clinical conditions. In order to guarantee a strict evidence-based process, we used a modified grading of recommendations, assessment, development, and evaluation (GRADE) methodology. A critical qualitative and quantitative evaluation of diagnostic and therapeutic procedures was performed, including assessment of the risk/benefit ratio. The level of evidence and the strength of the position statements were weighed and graded according to predefined scales. Despite being based on limited and observational or low-certainty randomised data, a number of position statements were made to frame PFO management in different clinical settings, along with suggestions for new research avenues. This interdisciplinary position paper, recognising the low or very low certainty of existing evidence, provides the first approach to several PFO-related clinical scenarios beyond left circulation thromboembolism and strongly stresses the need for fresh high-quality evidence on these topics.

Intravenous alteplase for stroke with unknown time of onset guided by advanced imaging: systematic review and meta-analysis of individual patient data.

BACKGROUND: Patients who have had a stroke with unknown time of onset have been previously excluded from thrombolysis. We aimed to establish whether intravenous alteplase is safe and effective in such patients when salvageable tissue has been identified with imaging biomarkers. METHODS: We did a systematic review and meta-analysis of individual patient data for trials published before Sept 21, 2020. Randomised trials of intravenous alteplase versus standard of care or placebo in adults with stroke with unknown time of onset with perfusion-diffusion MRI, perfusion CT, or MRI with diffusion weighted imaging-fluid attenuated inversion recovery (DWI-FLAIR) mismatch were eligible. The primary outcome was favourable functional outcome (score of 0-1 on the modified Rankin Scale [mRS]) at 90 days indicating no disability using an unconditional mixed-effect logistic-regression model fitted to estimate the treatment effect. Secondary outcomes were mRS shift towards a better functional outcome and independent outcome (mRS 0-2) at 90 days. Safety outcomes included death, severe disability or death (mRS score 4-6), and symptomatic intracranial haemorrhage. This study is registered with PROSPERO, CRD42020166903. FINDINGS: Of 249 identified abstracts, four trials met our eligibility criteria for inclusion: WAKE-UP, EXTEND, THAWS, and ECASS-4. The four trials provided individual patient data for 843 individuals, of whom 429 (51%) were assigned to alteplase and 414 (49%) to placebo or standard care. A favourable outcome occurred in 199 (47%) of 420 patients with alteplase and in 160 (39%) of 409 patients among controls (adjusted odds ratio [OR] 1·49 [95% CI 1·10-2·03]; p=0·011), with low heterogeneity across studies (I2=27%). Alteplase was associated with a significant shift towards better functional outcome (adjusted common OR 1·38 [95% CI 1·05-1·80]; p=0·019), and a higher odds of independent outcome (adjusted OR 1·50 [1·06-2·12]; p=0·022). In the alteplase group, 90 (21%) patients were severely disabled or died (mRS score 4-6), compared with 102 (25%) patients in the control group (adjusted OR 0·76 [0·52-1·11]; p=0·15). 27 (6%) patients died in the alteplase group and 14 (3%) patients died among controls (adjusted OR 2·06 [1·03-4·09]; p=0·040). The prevalence of symptomatic intracranial haemorrhage was higher in the alteplase group than among controls (11 [3%] vs two [<1%], adjusted OR 5·58 [1·22-25·50]; p=0·024). INTERPRETATION: In patients who have had a stroke with unknown time of onset with a DWI-FLAIR or perfusion mismatch, intravenous alteplase resulted in better functional outcome at 90 days than placebo or standard care. A net benefit was observed for all functional outcomes despite an increased risk of symptomatic intracranial haemorrhage. Although there were more deaths with alteplase than placebo, there were fewer cases of severe disability or death. FUNDING: None.

Rivaroxaban for Stroke Prevention after Embolic Stroke of Undetermined Source.

BACKGROUND: Embolic strokes of undetermined source represent 20% of ischemic strokes and are associated with a high rate of recurrence. Anticoagulant treatment with rivaroxaban, an oral factor Xa inhibitor, may result in a lower risk of recurrent stroke than aspirin. METHODS: We compared the efficacy and safety of rivaroxaban (at a daily dose of 15 mg) with aspirin (at a daily dose of 100 mg) for the prevention of recurrent stroke in patients with recent ischemic stroke that was presumed to be from cerebral embolism but without arterial stenosis, lacune, or an identified cardioembolic source. The primary efficacy outcome was the first recurrence of ischemic or hemorrhagic stroke or systemic embolism in a time-to-event analysis; the primary safety outcome was the rate of major bleeding. RESULTS: A total of 7213 participants were enrolled at 459 sites; 3609 patients were randomly assigned to receive rivaroxaban and 3604 to receive aspirin. Patients had been followed for a median of 11 months when the trial was terminated early because of a lack of benefit with regard to stroke risk and because of bleeding associated with rivaroxaban. The primary efficacy outcome occurred in 172 patients in the rivaroxaban group (annualized rate, 5.1%) and in 160 in the aspirin group (annualized rate, 4.8%) (hazard ratio, 1.07; 95% confidence interval [CI], 0.87 to 1.33; P=0.52). Recurrent ischemic stroke occurred in 158 patients in the rivaroxaban group (annualized rate, 4.7%) and in 156 in the aspirin group (annualized rate, 4.7%). Major bleeding occurred in 62 patients in the rivaroxaban group (annualized rate, 1.8%) and in 23 in the aspirin group (annualized rate, 0.7%) (hazard ratio, 2.72; 95% CI, 1.68 to 4.39; P<0.001). CONCLUSIONS: Rivaroxaban was not superior to aspirin with regard to the prevention of recurrent stroke after an initial embolic stroke of undetermined source and was associated with a higher risk of bleeding. (Funded by Bayer and Janssen Research and Development; NAVIGATE ESUS ClinicalTrials.gov number, NCT02313909 .).