Valeria Caso

Remarkable financial and political efforts have been focused on the reduction of child mortality during the past few decades. Timely measurements of levels and trends in under-5 mortality are important to assess progress towards the Millennium Development Goal 4 (MDG 4) target of reduction of child mortality by two thirds from 1990 to 2015, and to identify models of success.We generated updated estimates of child mortality in early neonatal (age 0-6 days), late neonatal (7-28 days), postneonatal (29-364 days), childhood (1-4 years), and under-5 (0-4 years) age groups for 188 countries from 1970 to 2013, with more than 29,000 survey, census, vital registration, and sample registration datapoints. We used Gaussian process regression with adjustments for bias and non-sampling error to synthesise the data for under-5 mortality for each country, and a separate model to estimate mortality for more detailed age groups. We used explanatory mixed effects regression models to assess the association between under-5 mortality and income per person, maternal education, HIV child death rates, secular shifts, and other factors. To quantify the contribution of these different factors and birth numbers to the change in numbers of deaths in under-5 age groups from 1990 to 2013, we used Shapley decomposition. We used estimated rates of change between 2000 and 2013 to construct under-5 mortality rate scenarios out to 2030.We estimated that 6·3 million (95% UI 6·0-6·6) children under-5 died in 2013, a 64% reduction from 17·6 million (17·1-18·1) in 1970. In 2013, child mortality rates ranged from 152·5 per 1000 livebirths (130·6-177·4) in Guinea-Bissau to 2·3 (1·8-2·9) per 1000 in Singapore. The annualised rates of change from 1990 to 2013 ranged from -6·8% to 0·1%. 99 of 188 countries, including 43 of 48 countries in sub-Saharan Africa, had faster decreases in child mortality during 2000-13 than during 1990-2000. In 2013, neonatal deaths accounted for 41·6% of under-5 deaths compared with 37·4% in 1990. Compared with 1990, in 2013, rising numbers of births, especially in sub-Saharan Africa, led to 1·4 million more child deaths, and rising income per person and maternal education led to 0·9 million and 2·2 million fewer deaths, respectively. Changes in secular trends led to 4·2 million fewer deaths. Unexplained factors accounted for only -1% of the change in child deaths. In 30 developing countries, decreases since 2000 have been faster than predicted attributable to income, education, and secular shift alone.Only 27 developing countries are expected to achieve MDG 4. Decreases since 2000 in under-5 mortality rates are accelerating in many developing countries, especially in sub-Saharan Africa. The Millennium Declaration and increased development assistance for health might have been a factor in faster decreases in some developing countries. Without further accelerated progress, many countries in west and central Africa will still have high levels of under-5 mortality in 2030.Bill & Melinda Gates Foundation, US Agency for International Development.

Early hemorrhagic transformation (HT) is a complication of ischemic stroke but its effect on patient outcome is unclear. The aims of this study were to assess: (1) the rate of early HT in patients admitted for ischemic stroke, (2) the correlation between early HT and functional outcome at 3 months, and (3) the risk factors for early HT.Consecutive patients with ischemic stroke were included in this prospective study in 4 study centers. Early HT was assessed by CT examination performed at day 5+/-2 after stroke onset. Study outcomes were 3-month mortality or disability. Disability was assessed using a modified Rankin score (> or = 3 indicating disabling stroke) by neurologists unaware of the occurrence of HT in the individual cases. Outcomes in patients with and without early HT were compared by chi(2) test. Multiple logistic regression analysis was used to identify predictors for HT.Among 1125 consecutive patients (median age 76.00 years), 98 (8.7%) had HT, 62 (5.5%) had hemorrhagic infarction, and 36 (3.2%) parenchymal hematoma. At 3 months, 455 patients (40.7%) were disabled or died. Death or disability was seen in 33 patients with parenchymal hematoma (91.7%), in 35 patients with hemorrhagic infarction (57.4%) as compared with 387 of the 1021 patients without HT (37.9%). At logistic regression analysis, parenchymal hematoma, but not hemorrhagic infarction, was independently associated with an increased risk for death or disability (OR 15.29; 95% CI 2.35 to 99.35). At logistic regression analysis, parenchymal hematoma was predicted by large lesions (OR 12.20, 95% CI 5.58 to 26.67), stroke attributable to cardioembolism (OR 5.25; 95% CI 2.27 to 12.14) or to other causes (OR 6.77; 95% CI 1.75 to 26.18), high levels of blood glucose (OR 1.01; 95% CI 1.00 to 1.01), and thrombolytic treatment (OR 3.54, 95% CI 1.04 to 11.95).Early HT occurs in about 9% of patients. Parenchymal hematoma, seen in about 3% of patients, is associated with an adverse outcome. Parenchymal hematoma was predicted by large lesions attributable to cardioembolism or other causes, high blood glucose, and treatment with thrombolysis.

Two previous pan-European consensus meetings, the 1995 and 2006 Helsingborg meetings, were convened to review the scientific evidence and the state of current services to identify priorities for research and development and to set targets for the development of stroke care for the decade to follow. Adhering to the same format, the European Stroke Organisation (ESO) prepared a European Stroke Action Plan (ESAP) for the years 2018 to 2030, in cooperation with the Stroke Alliance for Europe (SAFE). The ESAP included seven domains: primary prevention, organisation of stroke services, management of acute stroke, secondary prevention, rehabilitation, evaluation of stroke outcome and quality assessment and life after stroke. Research priorities for translational stroke research were also identified. Documents were prepared by a working group and were open to public comments. The final document was prepared after a workshop in Munich on 21–23 March 2018. Four overarching targets for 2030 were identified: (1) to reduce the absolute number of strokes in Europe by 10%, (2) to treat 90% or more of all patients with stroke in Europe in a dedicated stroke unit as the first level of care, (3) to have national plans for stroke encompassing the entire chain of care, (4) to fully implement national strategies for multisector public health interventions. Overall, 30 targets and 72 research priorities were identified for the seven domains. The ESAP provides a basic road map and sets targets for the implementation of evidence-based preventive actions and stroke services to 2030.

The original version of this consensus statement on mechanical thrombectomy was approved at the European Stroke Organisation (ESO)-Karolinska Stroke Update conference in Stockholm, 16–18 November 2014. The statement has later, during 2015, been updated with new clinical trials data in accordance with a decision made at the conference. Revisions have been made at a face-to-face meeting during the ESO Winter School in Berne in February, through email exchanges and the final version has then been approved by each society. The recommendations are identical to the original version with evidence level upgraded by 20 February 2015 and confirmed by 15 May 2015. The purpose of the ESO-Karolinska Stroke Update meetings is to provide updates on recent stroke therapy research and to discuss how the results may be implemented into clinical routine. Selected topics are discussed at consensus sessions, for which a consensus statement is prepared and discussed by the participants at the meeting. The statements are advisory to the ESO guidelines committee. This consensus statement includes recommendations on mechanical thrombectomy after acute stroke. The statement is supported by ESO, European Society of Minimally Invasive Neurological Therapy (ESMINT), European Society of Neuroradiology (ESNR), and European Academy of Neurology (EAN).

The role of anticoagulant treatment for acute cardioembolic stroke is uncertain. We performed an updated meta-analysis of all randomized trials to obtain the best estimates of the efficacy and safety of anticoagulants for the initial treatment of acute cardioembolic stroke.Using electronic and manual searches of the literature, we identified randomized trials comparing anticoagulants (unfractionated heparin or low-molecular-weight heparin or heparinoids), started within 48 hours, with other treatments (aspirin or placebo) in patients with acute ischemic cardioembolic stroke. Two reviewers independently selected studies and extracted data on study design, quality, and clinical outcomes, including death or disability, all strokes, recurrent ischemic stroke, and cerebral symptomatic bleeding. Odds ratios for individual outcomes were calculated for each trial and data from all the trials were pooled using the Mantel-Haenszel method.Seven trials, involving 4624 patients with acute cardioembolic stroke, met the criteria for inclusion. Compared with other treatments, anticoagulants were associated with a nonsignificant reduction in recurrent ischemic stroke within 7 to 14 days (3.0% versus 4.9%, odds ratio 0.68, 95% CI: 0.44 to 1.06, P=0.09, number needed to treat=53), a significant increase in symptomatic intracranial bleeding (2.5% versus 0.7%, odds ratio 2.89; 95% CI: 1.19 to 7.01, P=0.02, number needed to harm=55), and a similar rate of death or disability at final follow up (73.5% versus 73.8%, odds ratio 1.01; 95% CI: 0.82 to 1.24, P=0.9).Our findings indicate that in patients with acute cardioembolic stroke, early anticoagulation is associated with a nonsignificant reduction in recurrence of ischemic stroke, no substantial reduction in death and disability, and an increased intracranial bleeding.

High blood pressure is associated with poor outcome after stroke. Whether blood pressure should be lowered early after stroke, and whether to continue or temporarily withdraw existing antihypertensive drugs, is not known. We assessed outcomes after stroke in patients given drugs to lower their blood pressure.In our multicentre, partial-factorial trial, we randomly assigned patients admitted to hospital with an acute ischaemic or haemorrhagic stroke and raised systolic blood pressure (systolic 140-220 mm Hg) to 7 days of transdermal glyceryl trinitrate (5 mg per day), started within 48 h of stroke onset, or to no glyceryl trinitrate (control group). A subset of patients who were taking antihypertensive drugs before their stroke were also randomly assigned to continue or stop taking these drugs. The primary outcome was function, assessed with the modified Rankin Scale at 90 days by observers masked to treatment assignment. This study is registered, number ISRCTN99414122.Between July 20, 2001, and Oct 14, 2013, we enrolled 4011 patients. Mean blood pressure was 167 (SD 19) mm Hg/90 (13) mm Hg at baseline (median 26 h [16-37] after stroke onset), and was significantly reduced on day 1 in 2000 patients allocated to glyceryl trinitrate compared with 2011 controls (difference -7·0 [95% CI -8·5 to -5·6] mm Hg/-3·5 [-4·4 to -2·6] mm Hg; both p<0·0001), and on day 7 in 1053 patients allocated to continue antihypertensive drugs compared with 1044 patients randomised to stop them (difference -9·5 [95% CI -11·8 to -7·2] mm Hg/-5·0 [-6·4 to -3·7] mm Hg; both p<0·0001). Functional outcome at day 90 did not differ in either treatment comparison-the adjusted common odds ratio (OR) for worse outcome with glyceryl trinitrate versus no glyceryl trinitrate was 1·01 (95% CI 0·91-1·13; p=0·83), and with continue versus stop antihypertensive drugs OR was 1·05 (0·90-1·22; p=0·55).In patients with acute stroke and high blood pressure, transdermal glyceryl trinitrate lowered blood pressure and had acceptable safety but did not improve functional outcome. We show no evidence to support continuing prestroke antihypertensive drugs in patients in the first few days after acute stroke.UK Medical Research Council.

Acute stroke unit care, intravenous thrombolysis and endovascular treatment significantly improve the outcome for patients with ischaemic stroke, but data on access and delivery throughout Europe are lacking. We assessed best available data on access and delivery of acute stroke unit care, intravenous thrombolysis and endovascular treatment throughout Europe.A survey, drafted by stroke professionals (ESO, ESMINT, EAN) and a patient organisation (SAFE), was sent to national stroke societies and experts in 51 European countries (World Health Organization definition) requesting experts to provide national data on stroke unit, intravenous thrombolysis and endovascular treatment rates. We compared both pooled and individual national data per one million inhabitants and per 1000 annual incident ischaemic strokes with highest country rates. Population estimates were based on United Nations data, stroke incidences on the Global Burden of Disease Report.We obtained data from 44 European countries. The estimated mean number of stroke units was 2.9 per million inhabitants (95% CI 2.3-3.6) and 1.5 per 1000 annual incident strokes (95% CI 1.1-1.9), highest country rates were 9.2 and 5.8. Intravenous thrombolysis was provided in 42/44 countries. The estimated mean annual number of intravenous thrombolysis was 142.0 per million inhabitants (95% CI 107.4-176.7) and 72.7 per 1000 annual incident strokes (95% CI 54.2-91.2), highest country rates were 412.2 and 205.5. Endovascular treatment was provided in 40/44 countries. The estimated mean annual number of endovascular treatments was 37.1 per million inhabitants (95% CI 26.7-47.5) and 19.3 per 1000 annual incident strokes (95% CI 13.5-25.1), highest country rates were 111.5 and 55.9. Overall, 7.3% of incident ischaemic stroke patients received intravenous thrombolysis (95% CI 5.4-9.1) and 1.9% received endovascular treatment (95% CI 1.3-2.5), highest country rates were 20.6% and 5.6%.We observed major inequalities in acute stroke treatment between and within 44 European countries. Our data will assist decision makers implementing tailored stroke care programmes for reducing stroke-related morbidity and mortality in Europe.

Background and Purpose— The best time for administering anticoagulation therapy in acute cardioembolic stroke remains unclear. This prospective cohort study of patients with acute stroke and atrial fibrillation, evaluated (1) the risk of recurrent ischemic event and severe bleeding; (2) the risk factors for recurrence and bleeding; and (3) the risks of recurrence and bleeding associated with anticoagulant therapy and its starting time after the acute stroke. Methods— The primary outcome of this multicenter study was the composite of stroke, transient ischemic attack, symptomatic systemic embolism, symptomatic cerebral bleeding and major extracranial bleeding within 90 days from acute stroke. Results— Of the 1029 patients enrolled, 123 had 128 events (12.6%): 77 (7.6%) ischemic stroke or transient ischemic attack or systemic embolism, 37 (3.6%) symptomatic cerebral bleeding, and 14 (1.4%) major extracranial bleeding. At 90 days, 50% of the patients were either deceased or disabled (modified Rankin score ≥3), and 10.9% were deceased. High CHA 2 DS 2 -VASc score, high National Institutes of Health Stroke Scale, large ischemic lesion and type of anticoagulant were predictive factors for primary study outcome. At adjusted Cox regression analysis, initiating anticoagulants 4 to 14 days from stroke onset was associated with a significant reduction in primary study outcome, compared with initiating treatment before 4 or after 14 days: hazard ratio 0.53 (95% confidence interval 0.30–0.93). About 7% of the patients treated with oral anticoagulants alone had an outcome event compared with 16.8% and 12.3% of the patients treated with low molecular weight heparins alone or followed by oral anticoagulants, respectively ( P =0.003). Conclusions— Acute stroke in atrial fibrillation patients is associated with high rates of ischemic recurrence and major bleeding at 90 days. This study has observed that high CHA 2 DS 2 -VASc score, high National Institutes of Health Stroke Scale, large ischemic lesions, and type of anticoagulant administered each independently led to a greater risk of recurrence and bleedings. Also, data showed that the best time for initiating anticoagulation treatment for secondary stroke prevention is 4 to 14 days from stroke onset. Moreover, patients treated with oral anticoagulants alone had better outcomes compared with patients treated with low molecular weight heparins alone or before oral anticoagulants.

Stéphanie Debette and colleagues report the results of a genome-wide association study of cervical artery dissection, a major cause of ischemic stroke in young adults. They show that common variation in PHACTR1, previously associated with lower risk of migraine and increased risk of myocardial infarction, is associated with reduced risk of cervical artery dissection. Cervical artery dissection (CeAD), a mural hematoma in a carotid or vertebral artery, is a major cause of ischemic stroke in young adults although relatively uncommon in the general population (incidence of 2.6/100,000 per year)1. Minor cervical traumas, infection, migraine and hypertension are putative risk factors1,2,3, and inverse associations with obesity and hypercholesterolemia are described3,4. No confirmed genetic susceptibility factors have been identified using candidate gene approaches5. We performed genome-wide association studies (GWAS) in 1,393 CeAD cases and 14,416 controls. The rs9349379[G] allele (PHACTR1) was associated with lower CeAD risk (odds ratio (OR) = 0.75, 95% confidence interval (CI) = 0.69–0.82; P = 4.46 × 10−10), with confirmation in independent follow-up samples (659 CeAD cases and 2,648 controls; P = 3.91 × 10−3; combined P = 1.00 × 10−11). The rs9349379[G] allele was previously shown to be associated with lower risk of migraine and increased risk of myocardial infarction6,7,8,9. Deciphering the mechanisms underlying this pleiotropy might provide important information on the biological underpinnings of these disabling conditions.

Direct-acting oral anticoagulant use for stroke prevention in atrial fibrillation is limited by bleeding concerns. Asundexian, a novel, oral small molecule activated coagulation factor XIa (FXIa) inhibitor, might reduce thrombosis with minimal effect on haemostasis. We aimed to determine the optimal dose of asundexian and to compare the incidence of bleeding with that of apixaban in patients with atrial fibrillation.In this randomised, double-blind, phase 2 dose-finding study, we compared asundexian 20 mg or 50 mg once daily with apixaban 5 mg twice daily in patients aged 45 years or older with atrial fibrillation, a CHA2DS2-VASc score of at least 2 if male or at least 3 if female, and increased bleeding risk. The study was conducted at 93 sites in 14 countries, including 12 European countries, Canada, and Japan. Participants were randomly assigned (1:1:1) to a treatment group using an interactive web response system, with randomisation stratified by whether patients were receiving a direct-acting oral anticoagulant before the study start. Masking was achieved using a double-dummy design, with participants receiving both the assigned treatment and a placebo that resembled the non-assigned treatment. The primary endpoint was the composite of major or clinically relevant non-major bleeding according to International Society on Thrombosis and Haemostasis criteria, assessed in all patients who took at least one dose of study medication. This trial is registered with ClinicalTrials.gov, NCT04218266, and EudraCT, 2019-002365-35.Between Jan 30, 2020, and June 21, 2021, 862 patients were enrolled. 755 patients were randomly assigned to treatment. Two patients (assigned to asundexian 20 mg) never took any study medication, resulting in 753 patients being included in the analysis (249 received asundexian 20 mg, 254 received asundexian 50 g, and 250 received apixaban). The mean age of participants was 73·7 years (SD 8·3), 309 (41%) were women, 216 (29%) had chronic kidney disease, and mean CHA2DS2-VASc score was 3·9 (1·3). Asundexian 20 mg resulted in 81% inhibition of FXIa activity at trough concentrations and 90% inhibition at peak concentrations; asundexian 50 mg resulted in 92% inhibition at trough concentrations and 94% inhibition at peak concentrations. Ratios of incidence proportions for the primary endpoint were 0·50 (90% CI 0·14-1·68) for asundexian 20 mg (three events), 0·16 (0·01-0·99) for asundexian 50 mg (one event), and 0·33 (0·09-0·97) for pooled asundexian (four events) versus apixaban (six events). The rate of any adverse event occurring was similar in the three treatment groups: 118 (47%) with asundexian 20 mg, 120 (47%) with asundexian 50 mg, and 122 (49%) with apixaban.The FXIa inhibitor asundexian at doses of 20 mg and 50 mg once daily resulted in lower rates of bleeding compared with standard dosing of apixaban, with near-complete in-vivo FXIa inhibition, in patients with atrial fibrillation.Bayer.

Background and Purpose— Although current guidelines advocate pretreatment with intravenous thrombolysis (IVT) in all eligible patients with acute ischemic stroke with large-vessel occlusion before mechanical thrombectomy, there are observational data questioning the efficacy of this approach. One of the main arguments in favor of IVT pretreatment is the potential for tissue-type plasminogen activator–induced successful reperfusion (SR) before the onset of endovascular procedure. Methods— We performed a systematic review and meta-analysis of randomized controlled clinical trials and observational cohorts providing rates of SR with IVT in patients with large-vessel occlusion before the initiation of mechanical thrombectomy. We also performed subgroup analyses according to study type (randomized controlled clinical trials versus observational) and according to the inclusion per protocol of patients with tandem (intracranial/extracranial) occlusions. Results— We identified 13 eligible studies (7 randomized controlled clinical trials and 6 observational cohorts), including 1561 patients with acute ischemic stroke (median National Institutes of Health Stroke Scale score, 17) with large-vessel occlusion. SR following IVT and before mechanical thrombectomy was documented in 11% (95% confidence interval, 7%–16%), with no difference among cohorts derived from randomized controlled clinical trials and observational studies. There was significant heterogeneity across included studies both in the overall analysis and among subgroups (I 2 &gt;84%; P for Cochran Q, &lt;0.001). Higher tissue-type plasminogen activator–induced SR rates were documented in studies reporting the exclusion of tandem occlusions (17%; 95% confidence interval, 11%–23%) compared with the rest (7%; 95% confidence interval, 4%–11%; P for subgroup differences, 0.003). Conclusions— Pretreatment with systemic thrombolysis in patients with large-vessel occlusion eligible for mechanical thrombectomy results in SR in 1 of 10 cases, negating the need for additional endovascular reperfusion. Tandem occlusions seem to be the least responsive to IVT pretreatment.

Objective It is not known whether patients with atrial fibrillation (AF) with ischemic stroke despite oral anticoagulant therapy are at increased risk for further recurrent strokes or how ongoing secondary prevention should be managed. Methods We conducted an individual patient data pooled analysis of 7 prospective cohort studies that recruited patients with AF and recent cerebral ischemia. We compared patients taking oral anticoagulants (vitamin K antagonists [VKA] or direct oral anticoagulants [DOAC]) prior to index event (OAC prior ) with those without prior oral anticoagulation (OAC naive ). We further compared those who changed the type (ie, from VKA or DOAC, vice versa, or DOAC to DOAC) of anticoagulation (OAC changed ) with those who continued the same anticoagulation as secondary prevention (OAC unchanged ). Time to recurrent acute ischemic stroke (AIS) was analyzed using multivariate competing risk Fine–Gray models to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Results We included 5,413 patients (median age = 78 years [interquartile range (IQR) = 71–84 years]; 5,136 [96.7%] had ischemic stroke as the index event, median National Institutes of Health Stroke Scale on admission = 6 [IQR = 2–12]). The median CHA 2 DS 2 ‐Vasc score (congestive heart failure, hypertension, age≥ 75 years, diabetes mellitus, stroke/transient ischemic attack, vascular disease, age 65–74 years, sex category) was 5 (IQR = 4–6) and was similar for OAC prior (n = 1,195) and OAC naive (n = 4,119, p = 0.103). During 6,128 patient‐years of follow‐up, 289 patients had AIS (4.7% per year, 95% CI = 4.2–5.3%). OAC prior was associated with an increased risk of AIS (HR = 1.6, 95% CI = 1.2–2.3, p = 0.005). OAC changed (n = 307) was not associated with decreased risk of AIS (HR = 1.2, 95% CI = 0.7–2.1, p = 0.415) compared with OAC unchanged (n = 585). Interpretation Patients with AF who have an ischemic stroke despite previous oral anticoagulation are at a higher risk for recurrent ischemic stroke despite a CHA 2 DS 2 ‐Vasc score similar to those without prior oral anticoagulation. Better prevention strategies are needed for this high‐risk patient group. ANN NEUROL 2020;87:677–687

The novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in Wuhan, China and rapidly spread worldwide, with a vast majority of confirmed cases presenting with respiratory symptoms. Potential neurological manifestations and their pathophysiological mechanisms have not been thoroughly established. In this narrative review, we sought to present the neurological manifestations associated with coronavirus disease 2019 (COVID-19). Case reports, case series, editorials, reviews, case-control and cohort studies were evaluated, and relevant information was abstracted. Various reports of neurological manifestations of previous coronavirus epidemics provide a roadmap regarding potential neurological complications of COVID-19, due to many shared characteristics between these viruses and SARS-CoV-2. Studies from the current pandemic are accumulating and report COVID-19 patients presenting with dizziness, headache, myalgias, hypogeusia and hyposmia, but also with more serious manifestations including polyneuropathy, myositis, cerebrovascular diseases, encephalitis and encephalopathy. However, discrimination between causal relationship and incidental comorbidity is often difficult. Severe COVID-19 shares common risk factors with cerebrovascular diseases, and it is currently unclear whether the infection per se represents an independent stroke risk factor. Regardless of any direct or indirect neurological manifestations, the COVID-19 pandemic has a huge impact on the management of neurological patients, whether infected or not. In particular, the majority of stroke services worldwide have been negatively influenced in terms of care delivery and fear to access healthcare services. The effect on healthcare quality in the field of other neurological diseases is additionally evaluated.

Asundexian (Bayer AG, Leverkusen, Germany), an oral small molecule factor XIa (FXIa) inhibitor, might prevent thrombosis without increasing bleeding. Asundexian's effect for secondary prevention of recurrent stroke is unknown.In this randomised, double-blind, placebo-controlled, phase 2b dose-finding trial (PACIFIC-Stroke), patients with acute (within 48 h) non-cardioembolic ischaemic stroke were recruited from 196 hospitals in 23 countries. Patients were eligible if they were aged 45 years or older, to be treated with antiplatelet therapy, and able to have a baseline MRI (either before or within 72 h of randomisation). Eligible participants were randomly assigned (1:1:1:1), using an interactive web-based response system and stratified according to anticipated antiplatelet therapy (single vs dual), to once daily oral asundexian (BAY 2433334) 10 mg, 20 mg, or 50 mg, or placebo in addition to usual antiplatelet therapy, and were followed up during treatment for 26-52 weeks. Brain MRIs were obtained at study entry and at 26 weeks or as soon as possible after treatment discontinuation. The primary efficacy outcome was the dose-response effect on the composite of incident MRI-detected covert brain infarcts and recurrent symptomatic ischaemic stroke at or before 26 weeks after randomisation. The primary safety outcome was major or clinically relevant non-major bleeding as defined by International Society on Thrombosis and Haemostasis criteria. The efficacy outcome was assessed in all participants assigned to treatment, and the safety outcome was assessed in all participants who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov, NCT04304508, and is now complete.Between June 15, 2020, and July 22, 2021, 1880 patients were screened and 1808 participants were randomly assigned to asundexian 10 mg (n=455), 20 mg (n=450), or 50 mg (n=447), or placebo (n=456). Mean age was 67 years (SD 10) and 615 (34%) participants were women, 1193 (66%) were men, 1505 (83%) were White, and 268 (15%) were Asian. The mean time from index stroke to randomisation was 36 h (SD 10) and median baseline National Institutes of Health Stroke Scale score was 2·0 (IQR 1·0-4·0). 783 (43%) participants received dual antiplatelet treatment for a mean duration of 70·1 days (SD 113·4) after randomisation. At 26 weeks, the primary efficacy outcome was observed in 87 (19%) of 456 participants in the placebo group versus 86 (19%) of 455 in the asundexian 10 mg group (crude incidence ratio 0·99 [90% CI 0·79-1·24]), 99 (22%) of 450 in the asundexian 20 mg group (1·15 [0·93-1·43]), and 90 (20%) of 447 in the asundexian 50 mg group (1·06 [0·85-1·32]; t statistic -0·68; p=0·80). The primary safety outcome was observed in 11 (2%) of 452 participants in the placebo group versus 19 (4%) of 445 in the asundexian 10 mg group, 14 (3%) of 446 in the asundexian 20 mg group, and 19 (4%) of 443 in the asundexian 50 mg group (all asundexian doses pooled vs placebo hazard ratio 1·57 [90% CI 0·91-2·71]).In this phase 2b trial, FXIa inhibition with asundexian did not reduce the composite of covert brain infarction or ischaemic stroke and did not increase the composite of major or clinically relevant non-major bleeding compared with placebo in patients with acute, non-cardioembolic ischaemic stroke.Bayer AG.

Improving stroke services is critical for reducing the global stroke burden. The World Stroke Organization-World Health Organization-Lancet Neurology Commission on Stroke conducted a survey of the status of stroke services in low and middle-income countries (LMICs) compared to high-income countries.Using a validated World Stroke Organization comprehensive questionnaire, we collected and compared data on stroke services along four pillars of the stroke quadrangle (surveillance, prevention, acute stroke, and rehabilitation) in 84 countries across World Health Organization regions and economic strata. The World Health Organization also conducted a survey of non-communicable diseases in 194 countries in 2019.Fewer surveillance activities (including presence of registries, presence of recent risk factors surveys, and participation in research) were reported in low-income countries than high-income countries. The overall global score for prevention was 40.2%. Stroke units were present in 91% of high-income countries in contrast to 18% of low-income countries (p < 0.001). Acute stroke treatments were offered in ∼ 60% of high-income countries compared to 26% of low-income countries (p = 0.009). Compared to high-income countries, LMICs provided less rehabilitation services including in-patient rehabilitation, home assessment, community rehabilitation, education, early hospital discharge program, and presence of rehabilitation protocol.There is an urgent need to improve access to stroke units and services globally especially in LMICs. Countries with less stroke services can adapt strategies from those with better services. This could include establishment of a framework for regular monitoring of stroke burden and services, implementation of integrated prevention activities and essential acute stroke care services, and provision of interdisciplinary care for stroke rehabilitation.

Stroke is the second leading cause of death worldwide. The burden of disability after a stroke is also large, and is increasing at a faster pace in low-income and middle-income countries than in high-income countries. Alarmingly, the incidence of stroke is increasing in young and middle-aged people (ie, age <55 years) globally. Should these trends continue, Sustainable Development Goal 3.4 (reducing the burden of stroke as part of the general target to reduce the burden of non-communicable diseases by a third by 2030) will not be met. In this Commission, we forecast the burden of stroke from 2020 to 2050. We project that stroke mortality will increase by 50%—from 6·6 million (95% uncertainty interval [UI] 6·0 million–7·1 million) in 2020, to 9·7 million (8·0 million–11·6 million) in 2050—with disability-adjusted life-years (DALYs) growing over the same period from 144·8 million (133·9 million–156·9 million) in 2020, to 189·3 million (161·8 million–224·9 million) in 2050. These projections prompted us to do a situational analysis across the four pillars of the stroke quadrangle: surveillance, prevention, acute care, and rehabilitation. We have also identified the barriers to, and facilitators for, the achievement of these four pillars. On the basis of our assessment, we have identified and prioritised several recommendations. For each of the four pillars (surveillance, prevention, acute care, and rehabilitation), we propose pragmatic solutions for the implementation of evidence-based interventions to reduce the global burden of stroke. The estimated direct (ie, treatment and rehabilitation) and indirect (considering productivity loss) costs of stroke globally are in excess of US$891 billion annually. The pragmatic solutions we put forwards for urgent implementation should help to mitigate these losses, reduce the global burden of stroke, and contribute to achievement of Sustainable Development Goal 3.4, the WHO Intersectoral Global Action Plan on epilepsy and other neurological disorders (2022–2031), and the WHO Global Action Plan for prevention and control of non-communicable diseases. Reduction of the global burden of stroke, particularly in low-income and middle-income countries, by implementing primary and secondary stroke prevention strategies and evidence-based acute care and rehabilitation services is urgently required. Measures to facilitate this goal include: the establishment of a framework to monitor and assess the burden of stroke (and its risk factors) and stroke services at a national level; the implementation of integrated population-level and individual-level prevention strategies for people at any increased risk of cerebrovascular disease, with emphasis on early detection and control of hypertension; planning and delivery of acute stroke care services, including the establishment of stroke units with access to reperfusion therapies for ischaemic stroke and workforce training and capacity building (and monitoring of quality indicators for these services nationally, regionally, and globally); the promotion of interdisciplinary stroke care services, training for caregivers, and capacity building for community health workers and other health-care providers working in stroke rehabilitation; and the creation of a stroke advocacy and implementation ecosystem that includes all relevant communities, organisations, and stakeholders.

&lt;i&gt;Background:&lt;/i&gt; Dysphagia is common after stroke. We aimed to study the prognosis of dysphagia (assessed clinically) over the first 3 months after acute stroke and to determine whether specific neurovascular-anatomical sites were associated with swallowing dysfunction. &lt;i&gt;Methods:&lt;/i&gt; We prospectively examined consecutive patients with acute first-ever stroke. The assessment of dysphagia was made using standardized clinical methods. The arterial territories involved were determined on CT/MRI. All patients were followed up for 3 months. &lt;i&gt;Results:&lt;/i&gt; 34.7% of 406 patients had dysphagia. Dysphagia was more frequent in patients with hemorrhagic stroke (31/63 vs. 110/343; p = 0.01). In patients with ischemic stroke, the involvement of the arterial territory of the total middle cerebral artery was more frequently associated with dysphagia (28.2 vs. 2.2%; p &lt; 0.0001). Multivariate analysis revealed that stroke mortality and disability were independently associated with dysphagia (p &lt; 0.0001). &lt;i&gt;Conclusions:&lt;/i&gt; The frequency of dysphagia was relatively high. Regarding anatomical-clinical correlation, the most important factor was the size rather than the location of the lesion. Dysphagia assessed clinically was a significant variable predicting death and disability at 90 days.

The widespread preference of anticoagulants over antiplatelets in patients with cervical artery dissection (CAD) is empirical rather than evidence-based. Summary of Review- This article summarizes pathophysiological considerations, clinical experiences, and the findings of a systematic metaanalysis about antithrombotic agents in CAD patients. As a result, there are several putative arguments in favor as well as against immediate anticoagulation in CAD patients.A randomized controlled trial comparing antiplatelets with anticoagulation is needed and ethically justified. However, attributable to the large sample size which is required to gather meaningful results, such a trial represents a huge venture. This comprehensive overview may be helpful for the design and the promotion of such a trial. In addition, it could be used to encourage both participation of centers and randomization of CAD patients. Alternatively, antithrombotic treatment decisions can be customized based on clinical and paraclinical characteristics of individual CAD patients. Stroke severity with National Institutes of Health Stroke Scale score > or =15, accompanying intracranial dissection, local compression syndromes without ischemic events, or concomitant diseases with increased bleeding risk are features in which antiplatelets seem preferable. In turn, in CAD patients with (pseudo)occlusion of the dissected artery, high intensity transient signals in transcranial ultrasound studies despite (dual) antiplatelets, multiple ischemic events in the same circulation, or with free-floating thrombus immediate anticoagulation is favored.

<h3>Objective:</h3> To examine whether risk factor profile, baseline features, and outcome of cervical artery dissection (CEAD) differ according to the dissection site. <h3>Methods:</h3> We analyzed 982 consecutive patients with CEAD included in the Cervical Artery Dissection and Ischemic Stroke Patients observational study (n = 619 with internal carotid artery dissection [ICAD], n = 327 with vertebral artery dissection [VAD], n = 36 with ICAD and VAD). <h3>Results:</h3> Patients with ICAD were older (<i>p</i> &lt; 0.0001), more often men (<i>p</i> = 0.006), more frequently had a recent infection (odds ratio [OR] = 1.59 [95% confidence interval (CI) 1.09–2.31]), and tended to report less often a minor neck trauma in the previous month (OR = 0.75 [0.56–1.007]) compared to patients with VAD. Clinically, patients with ICAD more often presented with headache at admission (OR = 1.36 [1.01–1.84]) but less frequently complained of cervical pain (OR = 0.36 [0.27–0.48]) or had cerebral ischemia (OR = 0.32 [0.21–0.49]) than patients with VAD. Among patients with CEAD who sustained an ischemic stroke, the NIH Stroke Scale (NIHSS) score at admission was higher in patients with ICAD than patients with VAD (OR = 1.17 [1.12–1.22]). Aneurysmal dilatation was more common (OR = 1.80 [1.13–2.87]) and bilateral dissection less frequent (OR = 0.63 [0.42–0.95]) in patients with ICAD. Multiple concomitant dissections tended to cluster on the same artery type rather than involving both a vertebral and carotid artery. Patients with ICAD had a less favorable 3-month functional outcome (modified Rankin Scale score &gt;2, OR = 3.99 [2.32–6.88]), but this was no longer significant after adjusting for baseline NIHSS score. <h3>Conclusion:</h3> In the largest published series of patients with CEAD, we observed significant differences between VAD and ICAD in terms of risk factors, baseline features, and functional outcome.

Antiplatelet therapy (APT) promotes bleeding; therefore, APT might worsen outcome in patients with intracerebral hemorrhage (ICH). We performed a systematic review and meta-analysis to address the hypothesis that pre-ICH APT use is associated with mortality and poor functional outcome following ICH.The Medline and Embase databases were searched in February 2008 using relevant key words, limited to human studies in the English language. Cohort studies of consecutive patients with ICH reporting mortality or functional outcome according to pre-ICH APT use were identified. Of 2,873 studies screened, 10 were judged to meet inclusion criteria by consensus of 2 authors. Additionally, we solicited unpublished data from all authors of cohort studies with >100 patients published within the last 10 years, and received data from 15 more studies. Univariate and multivariable-adjusted odds ratios (ORs) for mortality and poor functional outcome were abstracted as available and pooled using a random effects model.We obtained mortality data from 25 cohorts (15 unpublished) and functional outcome data from 21 cohorts (14 unpublished). Pre-ICH APT users had increased mortality in both univariate (OR 1.41, 95% confidence interval [CI] 1.21 to 1.64) and multivariable-adjusted (OR 1.27, 95% CI 1.10 to 1.47) pooled analyses. By contrast, the pooled OR for poor functional outcome was no longer significant when using multivariable-adjusted estimates (univariate OR 1.29, 95% CI 1.09 to 1.53; multivariable-adjusted OR 1.10, 95% CI 0.93 to 1.29).In cohort studies, APT use at the time of ICH compared to no APT use was independently associated with increased mortality but not with poor functional outcome.

To examine the import of prior cervical trauma (PCT) in patients with cervical artery dissection (CeAD).In this observational study, the presence of and the type of PCT were systematically ascertained in CeAD patients using 2 different populations for comparisons: 1) age- and sex-matched patients with ischemic stroke attributable to a cause other than CeAD (non-CeAD-IS), and 2) healthy subjects participating in the Cervical Artery Dissection and Ischemic Stroke Patients Study. The presence of PCT within 1 month was assessed using a standardized questionnaire. Crude odds ratios (ORs) with 95% confidence intervals (CIs) and ORs adjusted for age, sex, and center were calculated.We analyzed 1,897 participants (n = 966 with CeAD, n = 651 with non-CeAD-IS, n = 280 healthy subjects). CeAD patients had PCT in 40.5% (38.2%-44.5%) of cases, with 88% (344 of 392) classified as mild. PCT was more common in CeAD patients than in non-CeAD-IS patients (ORcrude 5.6 [95% CI 4.20-7.37], p < 0.001; ORadjusted 7.6 [95% CI 5.60-10.20], p < 0.001) or healthy subjects (ORcrude 2.8 [95% CI 2.03-3.68], p < 0.001; ORadjusted 3.7 [95% CI 2.40-5.56], p < 0.001). CeAD patients with PCT were younger and presented more often with neck pain and less often with stroke than CeAD patients without PCT. PCT was not associated with functional 3-month outcome after adjustment for age, sex, and stroke severity.PCT seems to be an important environmental determinant of CeAD, but was not an independent outcome predictor. Because of the characteristics of most PCTs, the term mechanical trigger event rather than trauma may be more appropriate.

Little is known about the risk factors for cervical artery dissection (CEAD), a major cause of ischemic stroke (IS) in young adults. Hypertension, diabetes mellitus, smoking, hypercholesterolemia, and obesity are important risk factors for IS. However, their specific role in CEAD is poorly investigated. Our aim was to compare the prevalence of vascular risk factors in CEAD patients versus referents and patients who suffered an IS of a cause other than CEAD (non-CEAD IS) in the multicenter Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study.The study sample comprised 690 CEAD patients (mean age, 44.2 ± 9.9 years; 43.9% women), 556 patients with a non-CEAD IS (44.7 ± 10.5 years; 39.9% women), and 1170 referents (45.9 ± 8.1 years; 44.1% women). We compared the prevalence of hypertension, diabetes mellitus, hypercholesterolemia, smoking, and obesity (body mass index ≥ 30 kg/m²) or overweightness (body mass index ≥ 25 kg/m² and <30 kg/m²) between the 3 groups using a multinomial logistic regression adjusted for country of inclusion, age, and gender. Compared with referents, CEAD patients had a lower prevalence of hypercholesterolemia (odds ratio 0.55; 95% confidence interval, 0.42 to 0.71; P<0.0001), obesity (odds ratio 0.37; 95% confidence interval, 0.26 to 0.52; P<0.0001), and overweightness (odds ratio 0.70; 95% confidence interval, 0.57 to 0.88; P=0.002) but were more frequently hypertensive (odds ratio 1.67; 95% confidence interval, 1.32 to 2.1; P<0.0001). All vascular risk factors were less frequent in CEAD patients compared with young patients with a non-CEAD IS. The latter were more frequently hypertensive, diabetic, and current smokers compared with referents.These results, from the largest series to date, suggest that hypertension, although less prevalent than in patients with a non-CEAD IS, could be a risk factor of CEAD, whereas hypercholesterolemia, obesity, and overweightness are inversely associated with CEAD.

Change in cognition is being increasingly recognized as an important outcome measure; however, the role of carotid revascularization on this issue remains to be determined. It is still under debate whether carotid artery stenting and carotid endarterectomy have the same influence on neuropsychological functions.This article systematically reviews recent literature in an attempt to clarify this issue. A total of 32 papers reporting on neurocognition after carotid endarterectomy (n=25), carotid artery stenting (n=4), or carotid artery stenting versus carotid endarterectomy (n=3) were identified. The studies were different for many methodological factors, eg, sample size, type of patients and control group, statistical measure, type of test, timing of assessment, and so on. There was a lack of consensus in defining the improvement or impairment after either carotid artery stenting or carotid endarterectomy. Furthermore, there were nonuneqivocal results regarding the same domain of assessment (memory, visuomotor, attention). Based on available evidence, it is probable that carotid endarterectomy as well as carotid artery stenting do not change neuropsychological function "per se."Assessment of cognition after carotid revascularization is probably influenced by many confounding factors such as learning effect, type of test, type of patients, and control group, which are often minimized in their importance. The role of carotid revascularization is to prevent stroke in patients with severe carotid stenosis as highlighted by previous large randomized trials. Although an effect of carotid revascularization on cognition could be missed as a consequence of underpowered studies included in this review, at this time, no prediction can be done regarding its repercussions on higher intellectual functions. Larger studies appropriately designed and powered to assess cognition after carotid revascularization might change this view.

Stroke remains a leading cause of death worldwide and the first cause of disability in the western world. Ischemic stroke (IS) accounts for almost 80% of the total cases of strokes and is a complex and multifactorial disease caused by the combination of vascular risk factors, environment and genetic factors. Investigations of the genetics of atherosclerosis and IS has greatly enhanced our knowledge of this complex multifactorial disease. In this article we sought to review common single-gene disorders relevant to IS, summarize candidate gene and genome-wide studies aimed at discovering genetic stroke risk factors and subclinical phenotypes, and to briefly discuss pharmacogenetics related to stroke treatments. Genetics of IS is, in fact, one of the most promising research frontiers and genetic testing may be helpful for novel drug discoveries as well as for appropriate drug and dose selection for treatment of patients with cerebrovascular disease.

HomeStrokeVol. 45, No. 3Neuroimaging in Intracerebral Hemorrhage Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBNeuroimaging in Intracerebral Hemorrhage Federica Macellari, MD, Maurizio Paciaroni, MD, Giancarlo Agnelli, MD and Valeria Caso, PhD, MD Federica MacellariFederica Macellari From the Stroke Unit and Division of Cardiovascular Medicine, University of Perugia, Perugia, Italy. Search for more papers by this author , Maurizio PaciaroniMaurizio Paciaroni From the Stroke Unit and Division of Cardiovascular Medicine, University of Perugia, Perugia, Italy. Search for more papers by this author , Giancarlo AgnelliGiancarlo Agnelli From the Stroke Unit and Division of Cardiovascular Medicine, University of Perugia, Perugia, Italy. Search for more papers by this author and Valeria CasoValeria Caso From the Stroke Unit and Division of Cardiovascular Medicine, University of Perugia, Perugia, Italy. Search for more papers by this author Originally published14 Jan 2014https://doi.org/10.1161/STROKEAHA.113.003701Stroke. 2014;45:903–908Other version(s) of this articleYou are viewing the most recent version of this article. Previous versions: January 1, 2014: Previous Version 1 IntroductionIntracerebral hemorrhage (ICH) is described as spontaneous extravasation of blood into the brain parenchyma. This clinical entity is present in 10% to 15% of all stroke cases1 in the Western population, with reported incidence rates higher in Asia.2–4 It is also associated with a higher mortality rate compared with either ischemic stroke (IS) or subarachnoid hemorrhage.5ICH is classified according to its primary (80% to 85%) or secondary (15% to 20%) causes. More than 50% of primary ICH events are directly correlated with hypertension as a risk factor, whereas ≈30% are known to be associated with cerebral amyloid angiopathy (CAA). The causes of secondary ICH include hemorrhage conversion of IS, amyloid angiopathy, stimulant drugs, vascular malformations (aneurysms, arterovenous malformations, venous angioma, cavernoma, dural arteriovenous fistula), coagulopathy (hereditary, acquired, induced by anticoagulants or antiplatelets), neoplasms, trauma, vasculitis, Moyamoya disease, or sinus venous thrombosis (Table 1).Table 1. Intracerebral Hemorrhage (ICH) Classification According to CausesPrimary CausesSecondary CausesHypertensionCerebral amyloid angiopathyHemorrhage conversion of ischemic strokeStimulant drugsVascular malformationAneurysmsArteriovenous malformationVenous angiomaCavernomaDural arteriovenous fistulaCoagulopathyHereditaryAcquiredIatrogenic (anticoagulants, antiplatelets)NeoplasmsTraumaVasculitisMoyamoya diseaseSinus venous thrombosisCurrently, ICH is classified as either primary or secondary according to only causes. However, this classification does not take into account the inherent differences of underlying vascular pathologies. Hence, a more systematic stratification based on new criteria is currently being developed.1 Specifically, Meretoja et al6 have proposed the SMASH-U classification, based on the underlying diseases of ICH: Structural lesions (cavernomas and arterovenous malformations), Medication (anticoagulation), Amyloid angiopathy, Systemic diseases (liver cirrhosis, thrombocytopenia, and various rare conditions), Hypertension, and Undetermined causes. This classification has proven to be feasible and is also associated with survival prognosis.6 Another classification used in clinical practice distinguishes between deep and lobar ICHs according to location. Deep ICHs are located in the basal ganglia, thalamus, internal capsule, cerebellum, or brain stem and are generally related to hypertension. Whereas, lobar ICHs usually require more extensive diagnostic testing because of their wider range of causes.7Regarding clinical outcome, ICH is commonly characterized by hematoma expansion and early neurological deterioration within the first few hours of onset.8 Thus, rapid management including diagnostic work-up needs to be performed.We reviewed the available neuroimaging tools for ICH, as well as the changes in ICH in response to blood breakdown products, seen on CT and MR at various stages (Table 2).9 Both catheter angiogram and CT angiography (CTA) methods were also analyzed and compared for their advantages in different clinical situations. The purpose of our neuroimaging review of ICHs was to provide a framework for choosing a rational diagnostic imaging plan, taking into account the clinical characteristics of the presenting patients. Because of the fact that a myriad of imaging modalities is available, it is important to understand the indications and limitations of each technique in order to select the most appropriate study for each patient.Table 2. Appearance of Intracerebral Hemorrhage on Noncontrast CT (NCCT) and MR by Stage9Phase of BloodNCCTT1-Weighted MRT2-Weighted MRT2*-Weighted MRHyperacuteOxyhemoglobinSmooth, hyperdenseHypointense or isointenseHyperintenseMarked hypointensityAcute (12–48 h)DeoxyhemoglobinHyperdense with fluid levelsIsointensity or slight hypointensity with thin hyperintense rim in the peripheryHypointense with hyperintense perilesional rimMarked hypointensityEarly subacute (72 h)Methemoglobin intracellularHypodense region of edema with mass effectHyperintensityHypointensityHypointensityLate subacute (3–20 d)Methemoglobin extracellularLess intense with ring-like profileHyperintensityHyperintensityHypointensityChronic (9 wk)Hemosiderin and ferritinIsodense or modest confined hypodensityHypointensityHypointensityHyperintense or isointense core surrounded by hypointense rimComputed TomographyContemporary CT, including noncontrast CT (NCCT), perfusion CT, and CTA, is generally used for hyperacute stroke imaging. In fact, NCCT is commonly used in an emergency room setting for acute stroke because of its convenience and its high sensitivity for detecting ICH, which is a contraindication to thrombolytic therapy.10 Moreover, NCCT allows to quantify hematoma volume and monitor hemorrhage evolution in ICH accurately.11 That is, ICH volume can be calculated by using the ABC/2 method,12 derived from an approximation, according to the formula for ellipsoids, where A is the greatest hemorrhage diameter; B, the diameter at 90° to A; and C, the approximate number of CT slices with hemorrhage multiplied by slice thicknesses13 (Figure 1). Nonetheless, some studies assessing the reliability of the ABC/2 method have shown that it produces a larger percentage of error compared with other measurement techniques, particularly for irregular-shaped objects.14 In fact, comparing the ABC/2 method with the manual planimetric method, the former consistently overestimated infarct volume by a median false increase of 7.33 cm3.15 Whereas, the Quantomo method for quantitative tomography has been reported to more reliably detect smaller changes in ICH volume compared with the ABC/2 method. This is because Quantomo method measures the geometry of individual hematoma volumes, whereas the ABC/2 method approximates all hematoma volumes such as ellipsoid.16 To this regard, Huttner et al12 reported an overestimation of 32.1% in hematoma volume calculations for irregular and dichotomized shapes of hematomas among ICH patients with a history of warfarin use. Both initial hematoma volume and hematoma growth are independent predictors of clinical outcome and mortality.8,17 To date, though the ABC/2 method is the most readily available assessment at bedside, protocols for accurate assessment of hematoma volume and its characteristics should be incorporated into the CT scanner consoles, because this can allow the operator to obtain such information accurately in a timely manner.14 CT scan is also able to determine the approximate age of hematomas, by evaluating for the density of the lesions measured in Houndsfield units, according to the value of x-ray attenuation corrected for the attenuation coefficient of water. The Houndsfield units for water is equal to 0, blood is between 30 and 45, gray substance is between 37 and 45, white substance is between 20 and 30, whereas bone is between 700 and 3000.18,19 At onset, hematoma is commonly seen as uniform and smooth hyperintense signals on CT. Over the course of the first 48 hours, large hematomas tend to show fluid levels, indicating that they are not solidified yet.20 To this regard, fluid blood levels have been defined as a horizontal interface between hypodense bloody serum layered above hyperdense settled blood. Fluid blood levels in acute ICH are moderately sensitive (59%) to the presence of coagulopathy (ie, abnormal prothrombin time and partial thromboplastin time) and highly specific (98%) for this condition.21 Blood/fluid levels are also frequent in thrombolysis-related ICH and associated with higher hemorrhage volumes.22 Over the first 72 hours, a hypodense region can be detected around lesions, as a result of the edema that surrounds the brain tissue; a noteworthy mass effect can be detected as well. Three to 20 days after onset, the lesion area tends to shrink and become less intense, losing ≈1.5 Houndsfield units per day. The periphery of the lesion tends to take on an uneven profile, which acquires a pseudoabscess (ring-like) appearance, as seen on contrast. Reductions in edema and mass effect can also occur up until the ninth week, when only a confined region of modest hypodensity can be observed on CT.23Download figureDownload PowerPointFigure 1. Intracerebral hemorrhage evidenced on CT (ABC/2 formula by CT).Contrast-enhanced CTA is able to identify patients at high risk of hemorrhage enlargement (HE), by revealing a spot sign, which is a contrast medium extravasation within the hematoma.24 Spot sign is highly predictive of HE and has been reported to have a positive predictive value of 73%, a negative predictive value of 84%, sensitivity of 63%, and specificity of 90%.25 HE usually occurs in 30% of patients with ICH <3 hours of symptom onset,26 and the frequency of spot sign is highest in patients presenting <3 hours, but its accuracy in predicting HE remains high, regardless of time from symptom onset.27 Furthermore, spot sign is associated with poor prognosis, high rates of early clinical deterioration, high mortality, more severe clinical presentation, and decompression of the hemorrhage into the intraventricular space.25,28–33 ICH volume ≥30 cm3 together with Glasgow Coma Scale score, presence of intraventricular blood, and age ≥80 years have been included as independent variables for 30-day mortality in the ICH score developed by Hemphill et al.34 The utility of detecting the spot sign on clinical decision making and outcome improvement remains questionable. So, patients with spot sign are amenable to other studies,35 with the purpose of demonstrating the feasibility of CTA in the hyperacute phase and the reliability of spot sign in emergency setting for guiding the therapy with factor VII or other prothrombotic to avoid HE and, therefore, a worse outcome.36CTAs performed <96 hours from symptom onset have a high accuracy for predicting underlying vascular anomalies, with sensitivities ≥95% and specificities approaching 100%. Positive and negative predictive values have also been reported to be in excess of 97%.37,38 Even so, CTA exposes patients to the risks of radiation, as well as risks associated with contrast-induced nephropathy (CIN) and allergic reaction, which can lead to death. Furthermore, the risk of contrast on blood–brain barrier permeability has unknown effects on bleeding risks and the worsening of vasogenic edema.39–43CIN is defined as a 25% elevation from baseline serum creatinine levels or an absolute increase of 0.5 mg/dL <48 to 72 hours of contrast administration.44 CIN is associated with 5-fold higher risks of prolonged hospitalization and mortality.45–47 In an emergency setting, it is neither feasible to adopt preventive measures such as prehydration with the addition of acetylcysteine48 nor possible to fully know patient history. However, the incidence of CIN, even in emergency settings, has been reported to be low (2%).49Magnetic ResonanceStroke MR protocols should include T1, T2, T2* or gradient echo (GE), fluid-attenuated inversion recovery, contrast-enhanced, diffusion-weighted, and perfusion-weighted images, as well as MR angiography.50 The appearance of ICH on MR is primarily affected by the age of hematoma, as well as the type of MR contrast used. The substrate responsible for early hemorrhage identification on MR scan is deoxyhemoglobin, a blood degradation product with paramagnetic properties, because of its unpaired electrons. On GE images, a few areas of hyperintensity can be detected in the lesion core, and of these, most are usually surrounded by hypointense boundaries. Hyperintense signals are commonly found bordering the central lesion on T2-weighted and GE images, whereas a hypointense signal is commonly observed on T1-weighted images, thereby indicating perifocal vasogenic edema.50 There is strong evidence supporting the diagnostic accuracy of MR in the hyperacute setting51,52 even after only 20 minutes of symptom onset.53 A randomized trial investigating the role of MR in detecting ICH54 has reported that hyperacute ICH is detectable with excellent accuracy even when the raters had only limited experience. Moreover, GE is as sensitive as NCCT in the detection of acute ICH, whereas a complete MR in patients with acute stroke has higher sensitivities for IS (diffusion-weighted imaging sequences) and chronic hemorrhage.55,56 However, in the case of minor bleeding, GE MR may not be sufficient to distinguish acute bleeding from chronic bleeding (ie, microbleeds [MBs]), and for this, NCCT should be performed.56 Furthermore, patient factors (ie, clinical instability, presence of pacemaker, claustrophobia) and hospital factors (availability of MR) may cause obtaining an MR impossible or impractical in the acute setting, and therefore, NCCT remains the neuroimaging modality of choice for the diagnosis of acute stroke.57,58MR is also a neuroradiological tool for distinguishing between hemorrhagic transformation and primary ICH. In fact, most HTs are smaller than their fields of ischemic infarct; thus, MR can provide information on nonhemorrhagic regions and evidence whether blood is within the larger ischemic infarct.59 A primary hematoma tends to be round and have a larger surrounding edema than would be seen on IS. Furthermore, hematomas do not necessarily respect vascular territories.59 In case of hemorrhagic transformation of IS, MR angiography can identify the location of vascular occlusion.MR has a high diagnostic rate for detecting underlying causes of secondary hemorrhages, including vascular malformations, tumors, and cerebral vein thrombosis, as well as a high diagnostic yield for young patients having lobar ICH and no history of hypertension.60 Thus, MR is the most sensitive tool for detecting cerebral venous thrombosis in the acute, subacute, and chronic phases.61 Contrast-enhanced MR venography is able to show the thrombosed segment of the venous sinus and is generally well correlated with conventional angiographic findings.62 It also assists in distinguishing anatomic variants, such as a hypoplastic sinus, from cerebral venous thrombosis.63MR is the most sensitive and specific neuroradiologic modality for detecting cavernomas, the abnormal capillary-like vessels with intermingled connective tissue whose rupture can lead to ICH.64 Cavernoma has a hyperintense popcorn ball–like appearance at T2-weighted imaging. The central component, hyperintense, indicates subrecent bleeding; the hypointense halo consists of hemosiderin and is the outcome of remote bleeding.With MR, it is possible to detect previously existing and clinically silent cerebral MBs that are not detectable on CT. MBs provide a lifetime history of hemorrhage. MBs are small dot-like lesions having a hypointense appearance on GE sequences and are usually smaller than 5 to 10 mm (Figure 2). Pathological studies have proven that MBs correspond to hemosiderin-laden macrophages adjacent to small vessels, suggesting previous extravasations of blood. MBs can have numerous types of mimics, such as the calcification of the basal ganglia, diffused axonal injury, metastatic melanoma, cavernous malformation, and small perforating arteries.65 MBs are considered markers of vascular pathology, including hypertensive vasculopathy and CAA, as identified from histopathologic analyses of the vessels surrounding MBs. Furthermore, MBs have been reported to be predictors of ICH in prospective observational studies on both ICH66,67 and IS.68,69 MBs can indicate bleeding-prone angiopathy and a high rate of hemorrhagic transformation in patients on anticoagulation, antithrombotic, or thrombolytic therapies.70 However, MBs are thought to be more than markers for minor episodes of cerebrovascular extravasation. In fact, a recent pathological study by Janaway et al71 has reported that a large putamen haemosiderin, correlated with more MBs, was significantly associated with putaminal indices of small-vessel ischemia (microinfarcts, arteriolosclerosis, perivascular attenuation), as well as lacunes in each examined brain region but neither with large-vessel disease nor whole-brain neurodegenerative pathologies. These findings suggest that basal ganglia MR MBs are a surrogate for ischemic small-vessel disease rather than exclusively a hemorrhagic diathesis.Download figureDownload PowerPointFigure 2. Intracerebral hemorrhage evidenced on gradient echo MR in patients with deep microbleeds (black arrows).Lobar localization of MBs and their associations with lobar ICH, especially in the elderly patients, render MBs possible indicators of CAA. To this regard, the Boston criteria for probable CAA specify that this diagnosis should not be made when MBs are located in the basal ganglia, thalamus, or brain stem, the regions atypical for CAA pathology.72Catheter AngiogramSubarachnoid hemorrhage, atypical (noncircular) hematoma configuration, edema out of proportion seen on CT at admission, unusual hemorrhage location, or the presence of other abnormal structures in the brain, including masses, are all distinctive radiological features of secondary causes of ICH.10 In these cases, a catheter angiogram is necessary to best reveal underlying conditions, including arteriovenous malformations, Moyamoya disease, tumors, vasculitis, reversible cerebral vasoconstriction syndrome, and cerebral vein thromboses.Angiography may also be indicated in patients with no obvious cause of bleeding. The angiographic yield has shown to be significantly high in young patients without pre-existing hypertension.73 Young age followed by the absence of hypertension and lobar hemorrhage have been proven to be the main factors influencing diagnostic choices in clinical practice.74 The presence of intraventricular hemorrhage in patients with acute spontaneous ICH is not associated with an increased risk of an underlying vascular lesion and should not be used to select patients for neurovascular evaluation.75 Timing of cerebral angiography should take into consideration the clinical state of the patient and the neurosurgeon’s judgment regarding urgency of surgery.76 There is a tendency to perform diagnostic investigations <1 or 2 days in younger patients.74 Delayed angiography can also show unexpected underlying structural lesions in patients without radiological suspicion of secondary causes of ICH,77 and therefore, a follow-up angiography should be considered for all patients with a first-negative angiogram, in the absence of a specific cause of hemorrhage.78MR angiogram/venogram along with CT angiogram/venogram are reliable tools for confirming secondary causes of hemorrhage. Thus, these are reliable substitutes for catheter angiogram, which is an invasive procedure that is not always readily available. In fact, catheter angiogram is associated with the risks of transient and permanent neurological deficits, 0.9% and 0.5%, respectively.79 It is expensive and time- and labor-intensive, as well as requires patient cooperation, a stable patient condition, and continuous monitoring. Radiation doses of catheter angiography (5 times higher than CTA)80 are delivered to both patients and operators. For this reason, CTA should be considered the better initial screening approach for identifying secondary vascular lesions, compared with catheter angiogram.81 Nonetheless, catheter angiogram remains the diagnostic tool of choice for the treatment of aneurysms and arteriovenous malformation (Figure 3).Download figureDownload PowerPointFigure 3. Catheter angiogram: Left temporal arteriovenous malformation before and after treatment (black arrows).ConclusionsAn optimal neuroradiological diagnosis and management of ICH requires more than defining the size, location, and presence of intraventricular blood. In fact, knowing the causes of ICH will allow us to better diagnose and treat ICH. Specifically, the pathogenesis provides more accurate information on predictive factors that can influence the clinical outcome and mortality: risk of hematoma expansion, presence of underlying diseases, and previous lesions such as MBs.Here, we propose a diagnostic flowchart that incorporates size, location, clinical risk factors, and pathogenesis that, when considered together, can lead to a more accurate diagnosis and, thus, a better management of ICH (Figure 4). Regarding those who may do without further imaging work-up, this decision, according to the authors, should be based on a careful assessment of age, functional outcome, life expectancy, as well as the will of the patient.Download figureDownload PowerPointFigure 4. Diagnostic work-up flowchart of intracerebral hemorrhage.DisclosuresDr Caso received honoraria as a member of the speaker bureau and advisory board of Boehringer Ingelheim. The other authors have no conflicts to report.FootnotesCorrespondence to Valeria Caso, PhD, MD, Stroke Unit and Division of Cardiovascular Medicine, University of Perugia, Santa Maria della Misericordia Hospital, Sant’ Andrea delle Fratte, 06126 Perugia, Italy. E-mail [email protected]References1. Steiner T, Petersson J, Al-Shahi Salman R, Christensen H, Cordonnier C, Csiba L, et al; European Research Network on Intracerebral Haemorrhage. European research priorities for intracerebral haemorrhage.Cerebrovasc Dis. 2011; 32:409–419.CrossrefMedlineGoogle Scholar2. Jiang B, Wang WZ, Chen H, Hong Z, Yang QD, Wu SP, et al. Incidence and trends of stroke and its subtypes in China: results from three large cities.Stroke. 2006; 37:63–68.LinkGoogle Scholar3. Feigin VL, Lawes CM, Bennett DA, Anderson CS. Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century.Lancet Neurol. 2003; 2:43–53.CrossrefMedlineGoogle Scholar4. Flaherty ML, Woo D, Broderick JP. The epidemiology of intracerebral hemorrhage., Carhuapoma JR, Mayer SA, Hanley DF, ed. In: Intracerebral Hemorrhage. 1st ed.New York, NY: Cambrigdge University Press; 2010:1–10.Google Scholar5. Dennis MS, Burn JP, Sandercock PA, Bamford JM, Wade DT, Warlow CP. Long-term survival after first-ever stroke: the Oxfordshire Community Stroke Project.Stroke. 1993; 24:796–800.LinkGoogle Scholar6. Meretoja A, Strbian D, Putaala J, Curtze S, Haapaniemi E, Mustanoja S, et al. SMASH-U: a proposal for etiologic classification of intracerebral hemorrhage.Stroke. 2012; 43:2592–2597.LinkGoogle Scholar7. Qureshi AI, Tuhrim S, Broderick JP, Batjer HH, Hondo H, Hanley DF. Spontaneous intracerebral hemorrhage.N Engl J Med. 2001; 344:1450–1460.CrossrefMedlineGoogle Scholar8. Davis SM, Broderick J, Hennerici M, Brun NC, Diringer MN, Mayer SA, et al; Recombinant Activated Factor VII Intracerebral Hemorrhage Trial Investigators. Hematoma growth is a determinant of mortality and poor outcome after intracerebral hemorrhage.Neurology. 2006; 66:1175–1181.CrossrefMedlineGoogle Scholar9. Kidwell CS, Wintermark M. Imaging of intracranial haemorrhage.Lancet Neurol. 2008; 7:256–267.CrossrefMedlineGoogle Scholar10. Morgenstern LB, Hemphill JC, Anderson C, Becker K, Broderick JP, Connolly ES, et al; American Heart Association Stroke Council and Council on Cardiovascular Nursing. Guidelines for the management of spontaneous intracerebral hemorrhage: a guideline for healthcare professionals from the American Heart Association/American Stroke Association.Stroke. 2010; 41:2108–2129.LinkGoogle Scholar11. Zimmerman RD, Maldjian JA, Brun NC, Horvath B, Skolnick BE. Radiologic estimation of hematoma volume in intracerebral hemorrhage trial by CT scan.AJNR Am J Neuroradiol. 2006; 27:666–670.MedlineGoogle Scholar12. Huttner HB, Steiner T, Hartmann M, Köhrmann M, Juettler E, Mueller S, et al. Comparison of ABC/2 estimation technique to computer-assisted planimetric analysis in warfarin-related intracerebral parenchymal hemorrhage.Stroke. 2006; 37:404–408.LinkGoogle Scholar13. Kothari RU, Brott T, Broderick JP, Barsan WG, Sauerbeck LR, Zuccarello M, et al. The ABCs of measuring intracerebral hemorrhage volumes.Stroke. 1996; 27:1304–1305.LinkGoogle Scholar14. Divani AA, Majidi S, Luo X, Souslian FG, Zhang J, Abosch A, et al. The ABCs of accurate volumetric measurement of cerebral hematoma.Stroke. 2011; 42:1569–1574.LinkGoogle Scholar15. Pedraza S, Puig J, Blasco G, Daunis-I-Estadella J, Boada I, Bardera A, et al. Reliability of the ABC/2 method in determining acute infarct volume.J Neuroimaging. 2012; 22:155–159.CrossrefMedlineGoogle Scholar16. Kosior JC, Idris S, Dowlatshahi D, Alzawahmah M, Eesa M, Sharma P, et al; PREDICT/Sunnybrook CTA ICH Study Investigators. Quantomo: validation of a computer-assisted methodology for the volumetric analysis of intracerebral haemorrhage.Int J Stroke. 2011; 6:302–305.CrossrefMedlineGoogle Scholar17. Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality.Stroke. 1993; 24:987–993.LinkGoogle Scholar18. Feeman TG. The Mathematics of Medical Imaging: A Beginner’s Guide. New York: Springer; 2010.CrossrefGoogle Scholar19. Mosby . Mosby’s Medical Dictionary. 9th ed.Elsevier; 2009.Google Scholar20. Zilkha A. Intraparenchymal fluid-blood level: a CT sign of recent intracerebral hemorrhage.J Comput Assist Tomogr. 1983; 7:301–305.CrossrefMedlineGoogle Scholar21. Pfleger MJ, Hardee EP, Contant CF, Hayman LA. Sensitivity and specificity of fluid-blood levels for coagulopathy in acute intracerebral hematomas.AJNR Am J Neuroradiol. 1994; 15:217–223.MedlineGoogle Scholar22. Gebel JM, Sila CA, Sloan MA, Granger CB, Mahaffey KW, Weisenberger J, et al. Thrombolysis-related intracranial hemorrhage: a radiographic analysis of 244 cases from the GUSTO-1 trial with clinical correlation. Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries.Stroke. 1998; 29:563–569.LinkGoogle Scholar23. Herold S, von Kummer R, Jaeger C. Follow-up of spontaneous intracerebral haemorrhage by computed tomography.J Neurol. 1982; 228:267–276.CrossrefMedlineGoogle Scholar24. Murai Y, Ikeda Y, Teramoto A, Goldstein JN, Greenberg SM, Smith EE, et al. Contrast extravasation on CT angiography predicts hematoma expansion in intracerebral hemorrhage.Neurology. 2007; 69:617, author reply 617.CrossrefGoogle Scholar25. Demchuk AM, Dowlatshahi D, Rodriguez-Luna D, Molina CA, Blas YS, Dzialowski I, et al; PREDICT/Sunnybrook ICH CTA Study Group. Prediction of haematoma growth and outcome in patients with intracerebral haemorrhage using the CT-angiography spot sign (PREDICT): a prospective observational study.Lancet Neurol. 2012; 11:307–314.CrossrefMedlineGoogle Scholar26. Brott T, Broderick J, Kothari R, Barsan W, Tomsick T, Sauerbeck L, et al. Early hemorrhage growth in patients with intracerebral hemorrhage.Stroke. 1997; 28:1–5.LinkGoogle Scholar27. Brouwers HB, Falcone GJ, McNamara KA, Ayres AM, Oleinik A, Schwab K, et al. CTA spot sign predicts hematoma expansion in patients with delayed presentation after intracerebral hemorrhage.Neurocrit Care. 2012; 17:421–428.CrossrefMedlineGoogle Scholar28. Becker KJ, Baxter AB, Bybee HM, Tirschwell DL, Abouelsaad T, Cohen WA. Extravasation of radiographic contrast is an independent predictor of death in primary intracerebral hemorrhage.Stroke. 1999; 30:2025–2032.LinkGoogle Scholar29. Li N, Wang Y, Wang W, Ma L, Xue J, Weissenborn K, et al. Contrast extravasation on computed tomography angiography predicts clinical outcome in primary intracerebral hemorrhage: a prospective study of 139 cases.Stroke. 2011; 42:3441–3446.LinkGoogle Scholar30. Wada R, Aviv RI, Fox AJ, Sahlas DJ, Gladstone DJ, Tomlinson G, et al. CT angiography “spot sign” predicts hematoma expansion in acute intracerebral hemorrhage.Stroke. 2007; 38:1257–1262.LinkGoogle Scholar31. Goldstein JN, Fazen LE, Snider R, Schwab K, Greenberg SM, Smith EE, et al. Contrast extravasation on CT angiography predicts hematoma expansion in intracerebral hemorrhage.Neurology. 2007; 68:889–894.CrossrefMedlineGoogle Scholar32. Kim J, Smith A, Hemphill JC, Smith WS, Lu Y, Dillon WP, et al. Contrast extravasation on CT predicts mortality in primary intracerebral hemorrhage.AJNR Am J Neuroradiol. 2008; 29:520–525.CrossrefMedlineGoogle Scholar33. Romero JM, Brouwers HB, Lu J, Delgado Almandoz JE, Kelly H, Heit J, et al. Prospective validation of the computed tomographic angiography spot sign score for intracerebral hemorrhage.Stroke. 2013; 44:3097–3102.LinkGoogle Scholar34. Hemphill JC, Bonovich DC, Besmertis L, Manley GT, Johnston SC. The ICH score: a simple, reliable grading scale for intracerebral hemor

The prevalence of stroke in women is predicted to increase rapidly in the near future. Yet, despite the presence of numerous female-specific risk factors for stroke, women remain under-represented in stroke clinical trials. Here, members of the Women Initiative for Stroke in Europe (WISE) group summarize new advances and future research priorities in the research of stroke in women. Stroke is the second largest cause of disability-adjusted life-years lost worldwide. The prevalence of stroke in women is predicted to rise rapidly, owing to the increasing average age of the global female population. Vascular risk factors differ between women and men in terms of prevalence, and evidence increasingly supports the clinical importance of sex differences in stroke. The influence of some risk factors for stroke — including diabetes mellitus and atrial fibrillation — are stronger in women, and hypertensive disorders of pregnancy also affect the risk of stroke decades after pregnancy. However, in an era of evidence-based medicine, women are notably under-represented in clinical trials — despite governmental actions highlighting the need to include both men and women in clinical trials — resulting in a reduced generalizability of study results to women. The aim of this Review is to highlight new insights into specificities of stroke in women, to plan future research priorities, and to influence public health policies to decrease the worldwide burden of stroke in women.

With the greater availability of treatments for acute ischaemic stroke, including advances in endovascular therapy, personalised assessment of patients before treatment is more important than ever. Women have a higher lifetime risk of stroke; therefore, reducing potential sex differences in the acute stroke setting is crucial for the provision of equitable and fast treatment. Evidence indicates sex differences in prevalence and types of non-traditional stroke symptoms or signs, prevalence of stroke mimics, and door-to-imaging times, but no substantial differences in use of emergency medical services, stroke knowledge, eligibility for or access to thrombolysis or thrombectomy, or outcomes after either therapy. Women presenting with stroke mimics or non-traditional stroke symptoms can be misdiagnosed, which can lead to inappropriate triage, and acute treatment delays. It is essential for health-care providers to recognise possible sex differences in stroke symptoms, signs, and mimics. Future studies focused on confounders that affect treatment and outcomes, such as age and pre-stroke function, are also needed.

Little is known about factors contributing to multiple rather than single cervical artery dissections (CeAD) and their associated prognosis.We compared the baseline characteristics and short-term outcome of patients with multiple to single CeAD included in the multicenter Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study.Among the 983 patients with CeAD, 149 (15.2%) presented with multiple CeAD. Multiple CeADs were more often associated with cervical pain at admission (odds ratio [OR], 1.59; 95% confidence interval [CI], 1.10-2.30), a remote history of head or neck surgery (OR, 1.87; 95% CI, 1.16-3.00), a recent infection (OR, 1.71; 95% CI, 1.12-2.61), and cervical manipulation (OR, 2.23; 95% CI, 1.26-3.95). On imaging, cervical fibromuscular dysplasia (OR, 3.97; 95% CI, 2.04-7.74) and the presence of a pseudoaneurysm (OR, 2.91; 95% CI, 1.86-4.57) were more often seen in patients with multiple CeAD. The presence of multiple rather than single CeAD had no effect on functional 3-month outcome (modified Rankin Scale score, ≥3; 12% in multiple CeAD versus 11.9% in single CeAD; OR, 1.20; 95% CI, 0.60-2.41).In the largest published series of patients with CeAD, we highlighted significant differences between multiple and single artery involvement. Features suggestive of an underlying vasculopathy (fibromuscular dysplasia) and environmental triggers (recent infection, cervical manipulation, and a remote history of head or neck surgery) were preferentially associated with multiple CeAD.

Background The optimal timing to administer non–vitamin K oral anticoagulants ( NOAC s) in patients with acute ischemic stroke and atrial fibrillation is unclear. This prospective observational multicenter study evaluated the rates of early recurrence and major bleeding (within 90 days) and their timing in patients with acute ischemic stroke and atrial fibrillation who received NOAC s for secondary prevention. Methods and Results Recurrence was defined as the composite of ischemic stroke, transient ischemic attack, and symptomatic systemic embolism, and major bleeding was defined as symptomatic cerebral and major extracranial bleeding. For the analysis, 1127 patients were eligible: 381 (33.8%) were treated with dabigatran, 366 (32.5%) with rivaroxaban, and 380 (33.7%) with apixaban. Patients who received dabigatran were younger and had lower admission National Institutes of Health Stroke Scale score and less commonly had a CHA 2 DS 2 ‐ VAS c score &gt;4 and less reduced renal function. Thirty‐two patients (2.8%) had early recurrence, and 27 (2.4%) had major bleeding. The rates of early recurrence and major bleeding were, respectively, 1.8% and 0.5% in patients receiving dabigatran, 1.6% and 2.5% in those receiving rivaroxaban, and 4.0% and 2.9% in those receiving apixaban. Patients who initiated NOAC s within 2 days after acute stroke had a composite rate of recurrence and major bleeding of 12.4%; composite rates were 2.1% for those who initiated NOACs between 3 and 14 days and 9.1% for those who initiated &gt;14 days after acute stroke. Conclusions In patients with acute ischemic stroke and atrial fibrillation, treatment with NOAC s was associated with a combined 5% rate of ischemic embolic recurrence and severe bleeding within 90 days.

<h3>Objective</h3> To assess the association of baseline imaging markers of cerebral small vessel disease (SVD) and brain frailty with clinical outcome after acute stroke in the Efficacy of Nitric Oxide in Stroke (ENOS) trial. <h3>Methods</h3> ENOS randomized 4,011 patients with acute stroke (&lt;48 hours of onset) to transdermal glyceryl trinitrate (GTN) or no GTN for 7 days. The primary outcome was functional outcome (modified Rankin Scale [mRS] score) at day 90. Cognition was assessed via telephone at day 90. Stroke syndrome was classified with the Oxfordshire Community Stroke Project classification. Brain imaging was adjudicated masked to clinical information and treatment and assessed SVD (leukoaraiosis, old lacunar infarcts/lacunes, atrophy) and brain frailty (leukoaraiosis, atrophy, old vascular lesions/infarcts). Analyses used ordinal logistic regression adjusted for prognostic variables. <h3>Results</h3> In all participants and those with lacunar syndrome (LACS; 1,397, 34.8%), baseline CT imaging features of SVD and brain frailty were common and independently associated with unfavorable shifts in mRS score at day 90 (all participants: SVD score odds ratio [OR] 1.15, 95% confidence interval [CI] 1.07–1.24; brain frailty score OR 1.25, 95% CI 1.17–1.34; those with LACS: SVD score OR 1.30, 95% CI 1.15–1.47, brain frailty score OR 1.28, 95% CI 1.14–1.44). Brain frailty was associated with worse cognitive scores at 90 days in all participants and in those with LACS. <h3>Conclusions</h3> Baseline imaging features of SVD and brain frailty were common in lacunar stroke and all stroke, predicted worse prognosis after all acute stroke with a stronger effect in lacunar stroke, and may aid future clinical decision-making. <h3>Identifier</h3> ISRCTN99414122.

The coronavirus disease 2019 (COVID-19) pandemic has been placing an overwhelming burden on health systems, thus threatening their ability to operate effectively for acute conditions in which treatments are highly time sensitive, such as cerebrovascular disorders and myocardial infarction. As part of an effort to reduce the consequences of this outbreak on health service delivery to stroke patients, the European Stroke Organisation has undertaken a survey aimed at collecting information on the provision of stroke care during the pandemic.Cross-sectional, web-based survey, conducted from 26 March through 1 April 2020 among stroke care providers, focused on reorganisation of health services, the delivery of acute and post-acute stroke care and the availability of personal protective equipment.A total of 426 stroke care providers from 55 countries completed the survey, most of whom worked in Europe (n = 375, 88%) and were stroke physicians/neurologists (n = 334, 78%). Among European respondents, 289 (77%) reported that not all stroke patients were receiving the usual care in their centres and 266 (71%) estimated that functional outcomes and recurrence rates of stroke patients would be negatively affected by the organisational changes caused by the pandemic. The areas considered as being most affected were acute care and rehabilitation. Most professionals had to adapt their activities and schedules and more than half reported shortage of protective equipment.Strategies to maintain availability of stroke care during the COVID-19 outbreak are crucial to prevent indirect mortality and disability due to suboptimal care.European Stroke Organisation proposes a set of targeted actions for decision makers facing this exceptional situation.

Background— We explored the safety of intravenous thrombolysis (IVT) or intra-arterial treatment (IAT) in patients with ischemic stroke on non-vitamin K antagonist oral anticoagulants (NOACs, last intake &lt;48 hours) in comparison with patients (1) taking vitamin K antagonists (VKAs) or (2) without previous anticoagulation (no-OAC). Methods and Results— This is a multicenter cohort pilot study. Primary outcome measures were (1) occurrence of intracranial hemorrhage (ICH) in 3 categories: any ICH (ICH any ), symptomatic ICH according to the criteria of the European Cooperative Acute Stroke Study II (ECASS-II) (sICH ECASS-II ) and the National Institute of Neurological Disorders and Stroke (NINDS) thrombolysis trial (sICH NINDS ); and (2) death (at 3 months). Cohorts were compared by using propensity score matching. Our NOAC cohort comprised 78 patients treated with IVT/IAT and the comparison groups of 441 VKA patients and 8938 no-OAC patients. The median time from last NOAC intake to IVT/IAT was 13 hours (interquartile range, 8–22 hours). In VKA patients, median pre-IVT/IAT international normalized ratio was 1.3 (interquartile range, 1.1–1.6). ICH any was observed in 18.4% NOAC patients versus 26.8% in VKA patients and 17.4% in no-OAC patients. sICH ECASS-II and sICH NINDS occurred in 2.6%/3.9% NOAC patients, in comparison with 6.5%/9.3% of VKA patients and 5.0%/7.2% of no-OAC patients, respectively. At 3 months, 23.0% of NOAC patients in comparison with 26.9% of VKA patients and 13.9% of no-OAC patients had died. Propensity score matching revealed no statistically significant differences. Conclusions— IVT/IAT in selected patients with ischemic stroke under NOAC treatment has a safety profile similar to both IVT/IAT in patients on subtherapeutic VKA treatment or in those without previous anticoagulation. However, further prospective studies are needed, including the impact of specific coagulation tests.

Objective We compared outcomes after treatment with direct oral anticoagulants (DOACs) and vitamin K antagonists (VKAs) in patients with atrial fibrillation (AF) and a recent cerebral ischemia. Methods We conducted an individual patient data analysis of seven prospective cohort studies. We included patients with AF and a recent cerebral ischemia (&lt;3 months before starting oral anticoagulation) and a minimum follow‐up of 3 months. We analyzed the association between type of anticoagulation (DOAC versus VKA) with the composite primary endpoint (recurrent ischemic stroke [AIS], intracerebral hemorrhage [ICH], or mortality) using mixed‐effects Cox proportional hazards regression models; we calculated adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs). Results We included 4,912 patients (median age, 78 years [interquartile range {IQR}, 71–84]; 2,331 [47.5%] women; median National Institute of Health Stroke Severity Scale at onset, 5 [IQR, 2–12]); 2,256 (45.9%) patients received VKAs and 2,656 (54.1%) DOACs. Median time from index event to starting oral anticoagulation was 5 days (IQR, 2–14) for VKAs and 5 days (IQR, 2–11) for DOACs ( p = 0.53). There were 262 acute ischemic strokes (AISs; 4.4%/year), 71 intracranial hemorrrhages (ICHs; 1.2%/year), and 439 deaths (7.4%/year) during the total follow‐up of 5,970 patient‐years. Compared to VKAs, DOAC treatment was associated with reduced risks of the composite endpoint (HR, 0.82; 95% CI, 0.67–1.00; p = 0.05) and ICH (HR, 0.42; 95% CI, 0.24–0.71; p &lt; 0.01); we found no differences for the risk of recurrent AIS (HR, 0.91; 95% CI, 0.70–1.19; p = 0.5) and mortality (HR, 0.83; 95% CI, 0.68–1.03; p = 0.09). Interpretation DOAC treatment commenced early after recent cerebral ischemia related to AF was associated with reduced risk of poor clinical outcomes compared to VKA, mainly attributed to lower risks of ICH. ANN NEUROL 2019;85:823–834.

The coronavirus 2019 (COVID-19) pandemic requires drastic changes in allocation of resources, which can affect the delivery of stroke care, and many providers are seeking guidance. As caregivers, we are guided by 3 distinct principles that will occasionally conflict during the pandemic: (1) we must ensure the best care for those stricken with COVID-19, (2) we must provide excellent care and advocacy for patients with cerebrovascular disease and their families, and (3) we must advocate for the safety of health care personnel managing patients with stroke, with particular attention to those most vulnerable, including trainees. This descriptive review by a diverse group of experts in stroke care aims to provide advice by specifically addressing the potential impact of this pandemic on (1) the quality of the stroke care delivered, (2) ethical considerations in stroke care, (3) safety and logistic issues for providers of patients with stroke, and (4) stroke research. Our recommendations on these issues represent our best opinions given the available information, but are subject to revision as the situation related to the COVID-19 pandemic continues to evolve. We expect that ongoing emergent research will offer additional insights that will provide evidence that could prompt the modification or removal of some of these recommendations.

The burden of stroke in low- and middle-income countries (LMICs) is large and increasing, challenging the already stretched health-care services.To determine the quality of existing stroke-care services in LMICs and to highlight indigenous, inexpensive, evidence-based implementable strategies being used in stroke-care.A detailed literature search was undertaken using PubMed and Google scholar from January 1966 to October 2015 using a range of search terms. Of 921 publications, 373 papers were shortlisted and 31 articles on existing stroke-services were included.We identified efficient models of ambulance transport and pre-notification. Stroke Units (SU) are available in some countries, but are relatively sparse and mostly provided by the private sector. Very few patients were thrombolysed; this could be increased with telemedicine and governmental subsidies. Adherence to secondary preventive drugs is affected by limited availability and affordability, emphasizing the importance of primary prevention. Training of paramedics, care-givers and nurses in post-stroke care is feasible.In this systematic review, we found several reports on evidence-based implementable stroke services in LMICs. Some strategies are economic, feasible and reproducible but remain untested. Data on their outcomes and sustainability is limited. Further research on implementation of locally and regionally adapted stroke-services and cost-effective secondary prevention programs should be a priority.

Background and Purpose- Despite treatment with oral anticoagulants, patients with nonvalvular atrial fibrillation (AF) may experience ischemic cerebrovascular events. The aims of this case-control study in patients with AF were to identify the pathogenesis of and the risk factors for cerebrovascular ischemic events occurring during non-vitamin K antagonist oral anticoagulants (NOACs) therapy for stroke prevention. Methods- Cases were consecutive patients with AF who had acute cerebrovascular ischemic events during NOAC treatment. Controls were consecutive patients with AF who did not have cerebrovascular events during NOACs treatment. Results- Overall, 713 cases (641 ischemic strokes and 72 transient ischemic attacks; median age, 80.0 years; interquartile range, 12; median National Institutes of Health Stroke Scale on admission, 6.0; interquartile range, 10) and 700 controls (median age, 72.0 years; interquartile range, 8) were included in the study. Recurrent stroke was classified as cardioembolic in 455 cases (63.9%) according to the A-S-C-O-D (A, atherosclerosis; S, small vessel disease; C, cardiac pathology; O, other causes; D, dissection) classification. On multivariable analysis, off-label low dose of NOACs (odds ratio [OR], 3.18; 95% CI, 1.95-5.85), atrial enlargement (OR, 6.64; 95% CI, 4.63-9.52), hyperlipidemia (OR, 2.40; 95% CI, 1.83-3.16), and CHA2DS2-VASc score (OR, 1.72 for each point increase; 95% CI, 1.58-1.88) were associated with ischemic events. Among the CHA2DS2-VASc components, age was older and presence of diabetes mellitus, congestive heart failure, and history of stroke or transient ischemic attack more common in patients who had acute cerebrovascular ischemic events. Paroxysmal AF was inversely associated with ischemic events (OR, 0.45; 95% CI, 0.33-0.61). Conclusions- In patients with AF treated with NOACs who had a cerebrovascular event, mostly but not exclusively of cardioembolic pathogenesis, off-label low dose, atrial enlargement, hyperlipidemia, and high CHA2DS2-VASc score were associated with increased risk of cerebrovascular events.

Background and Purpose- To date, there is still uncertainty about age and sex differences in access to stroke unit treatment and use of intravenous thrombolysis (IVT), while age and sex differences have not been investigated for the new treatment option of mechanical thrombectomy (MT). We, therefore, undertook a complete nationwide analysis of all hospitalized ischemic stroke patients in Germany from 2013 to 2017. Methods- We used the nationwide administrative database of the German Federal Statistical Office and investigated access to stroke unit treatment, IVT, MT, and in-hospital mortality. Patients were subdivided into 6 predefined age groups (20-44, 45-59, 60-69, 70-79, 80-89, and >90 years). Pooled overall and age group estimates were calculated using the random-effects model. To evaluate potential sex disparities, we estimated odds ratios (ORs) with 95% CIs. Results- A total of 1 112 570 patients were hospitalized for first or recurrent ischemic stroke from 2013 to 2017. Overall, stroke unit treatment increased significantly from 66.8% in 2013 to 73.5% in 2017, as did IVT (from 12.4% to 15.9%) and MT (from 2.4% to 5.8%; all P<0.001). Although the difference became smaller over time, patients ≥80 years of age still received significantly less often treatments. Men of all age groups had a significantly higher probability receiving stroke unit treatment (OR, 1.11; 95% CI, 1.09-1.12) and lower in-hospital mortality (OR, 0.91; 95% CI, 0.89-0.93). No disparity was observed in the use of IVT (OR, 1.00; 95% CI, 0.98-1.01), while women of all ages were treated more often with MT (OR, 1.26; 95% CI, 1.22-1.30). Conclusions- Access to stroke unit treatment has to be increased in both older patients and women of all ages. While there was no sex difference in IVT use, it is important to further investigate the significantly higher frequency of MT in women with ischemic stroke irrespective of age.

The present outbreak caused by SARS-CoV-2, an influenza virus with neurotropic potential, presents with neurological manifestations in a large proportion of the affected individuals. Disorders of the central and peripheral nervous system are all present, while stroke, ataxia, seizures, and depressed level of consciousness are more common in severely affected patients. People with these severe complications are most likely elderly with medical comorbidities, especially hypertension and other vascular risk factors. However, postinfectious complications are also expected. Neurological disorders as sequelae of influenza viruses have been repeatedly documented in the past and include symptoms, signs, and diseases occurring during the acute phase and, not rarely, during follow-up. Postinfectious neurological complications are the result of the activation of immune mechanisms and can explain the insurgence of immune-mediated diseases, including the Guillain-Barré syndrome and other diseases of the central and peripheral nervous system that in the past occurred as complications of viral infections and occasionally with vaccines. For these reasons, the present outbreak calls for the introduction of surveillance systems to monitor changes in the frequency of several immune-mediated neurological diseases. These changes will determine a reorganization of the measures apt to describe the interaction between the virus, the environment, and the host in areas of different dimensions, from local communities to regions with several millions of inhabitants. The public health system, mainly primary care, needs to be strengthened to ensure that research and development efforts are directed toward right needs and directions. To cope with the present pandemic, better collaboration is required between international organizations along with more research funding, and tools in order to detect, treat, and prevent future epidemics.

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.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.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]).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.

The "1-3-6-12-day rule" for starting direct oral anticoagulants (DOACs) in patients with nonvalvular atrial fibrillation after acute ischemic stroke or transient ischemic attack recommends timings that may be later than used in clinical practice. We investigated more practical optimal timing of DOAC initiation according to stroke severity.The combined data of prospective registries in Japan, Stroke Acute Management with Urgent Risk-factor Assessment and Improvement-nonvalvular atrial fibrillation (September 2011 to March 2014) and RELAXED (February 2014 to April 2016) were used. Patients were divided into transient ischemic attack and 3 stroke subgroups by the National Institutes of Health Stroke Scale score: mild (0-7), moderate (8-15), and severe (≥16). The early treatment group was defined as patients starting DOACs earlier than the median initiation day in each subgroup. Outcomes included a composite of recurrent stroke or systemic embolism, ischemic stroke, and severe bleeding within 90 days. Six European prospective registries were used for validation.In the 1797 derivation cohort patients, DOACs were started at median 2 days after transient ischemic attack and 3, 4, and 5 days after mild, moderate, and severe strokes, respectively. Stroke or systemic embolism was less common in Early Group (n=785)-initiating DOACS within 1, 2, 3, and 4 days, respectively-than Late Group (n=1012) (1.9% versus 3.9%; adjusted hazard ratio, 0.50 [95% CI, 0.27-0.89]), as was ischemic stroke (1.7% versus 3.2%, 0.54 [0.27-0.999]). Major bleeding was similarly common in the 2 groups (0.8% versus 1.0%). On validation, both ischemic stroke (2.4% versus 2.2%) and intracranial hemorrhage (0.2% versus 0.6%) were similarly common in Early (n=547) and Late (n=1483) Groups defined using derivation data.In Japanese and European populations, early DOAC initiation within 1, 2, 3, or 4 days according to stroke severity seemed to be feasible to decrease the risk of recurrent stroke or systemic embolism and no increase in major bleeding. These findings support ongoing randomized trials to better establish the optimal timing of DOAC initiation.

Pregnancy, postpartum and menopause are regarded as periods women are more vulnerable to ischaemic events. There are conflicting results regarding stroke risk and hormone replacement therapy (HRT) during menopause. Stroke in pregnancy is generally increasing with serious consequences for mother and child; therefore, recommendations for acute treatment with intravenous thrombolysis (IVT) and/or mechanical thrombectomy (MT) are needed. The aim of this guideline is to support and guide clinicians in treatment decisions in stroke in women. Following the "Grading of Recommendations and Assessment, Development and Evaluation (GRADE)" approach, the guidelines were developed according to the European Stroke Organisation (ESO) Standard Operating Procedure. Systematic reviews and metanalyses were performed. Based on available evidence, recommendations were provided. Where there was a lack of evidence, an expert consensus statement was given. Low quality of evidence was found to suggest against the use of HRT to reduce the risk of stroke (ischaemic and haemorrhagic) in postmenopausal women. No data was available on the outcome of women with stroke when treated with HRT. No sufficient evidence was found to provide recommendations for treatment with IVT or MT during pregnancy, postpartum and menstruation. The majority of members suggested that pregnant women can be treated with IVT after assessing the benefit/risk profile on an individual basis, all members suggested treatment with IVT during postpartum and menstruation. All members suggested treatment with MT during pregnancy. The guidelines highlight the need to identify evidence for stroke prevention and acute treatment in women in more vulnerable periods of their lifetime to generate reliable data for future guidelines.

Ischemic penumbra was first defined by Astrup in 1981 as perfused brain tissue at a level within the thresholds of functional impairment and morphological integrity, which has the capacity to recover if perfusion is improved. It exists, even for a short period of time in the center of ischemia, from which irreversible necrosis propagates to the neighboring tissues over time. Penumbra has become the focus of intense imaging research to differentiate it from infarction. Accurate detection of this ‘tissue at risk’ could be used to identify patients who would benefit most from acute treatment. Currently, recombinant tissue plasminogen activator (rtPA) is the only approved drug that has shown significant benefits in acute stroke patients when administered intravenously less than 4.5 h after stroke. However, its use is limited. Discrimination between infarct core and the surrounding potentially salvageable tissue is useful to better identify patients suitable for treatment. This can be achieved by positron emission tomography, single-photon-emission computed tomography, computed tomography perfusion scan and perfusion-weighted and diffusion-weighted magnetic resonance imaging. Identification of the penumbra might enable selective rtPA use in patients with large penumbras and small infarct cores, even beyond the 4.5-hour time window, where the penumbra may persist for more than 12 h. The purpose of this review was to describe neuroimaging modalities capable of identifying penumbra tissue so as to provide surrogate markers for new trials in acute ischemic stroke patients.

The role of anticoagulants for the prevention of venous thromboembolism in acute hemorrhagic stroke is uncertain. We performed an updated meta-analysis of studies to obtain the best estimates of the efficacy and safety of anticoagulants for the prevention of venous thromboembolism in patients with acute hemorrhagic stroke.Using electronic and manual searches of the literature, we identified randomized and non-randomized studies comparing anticoagulants (unfractionated heparin or low-molecular-weight heparin or heparinoids) with treatments other than anticoagulants (elastic stockings, intermittent pneumatic compression or placebo) in patients with acute hemorrhagic stroke. Study outcomes included symptomatic and asymptomatic deep venous thrombosis (DVT), symptomatic and asymptomatic pulmonary embolism (PE), any hematoma enlargement or death. Risk ratios (RRs) for individual outcomes were calculated for each study and data from all studies were pooled using the Mantel-Haenszel method.Four studies (two randomized) involving 1000 patients with acute hemorrhagic stroke met the criteria for inclusion in this meta-analysis. Compared with other treatments, anticoagulants were associated with a significant reduction in PE (1.7% vs. 2.9%; RR, 0.37; 95% CI, 0.17-0.80; P = 0.01), a DVT rate of 4.2% compared with 3.3% (RR, 0.77; 95% CI, 0.44-1.34; P = 0.36), an increase in any hematoma enlargement (8.0% vs. 4.0%; RR, 1.42; 95% CI, 0.57-3.53; P = 0.45), and a non-significant reduction in mortality (16.1% vs. 20.9%; RR, 0.76; 95% CI, 0.57-1.03; P = 0.07).Our findings indicate that in patients with hemorrhagic stroke, early anticoagulation is associated with a significant reduction in PE and a non-significant reduction in mortality, with the trade-off of a non-significant increase in hematoma enlargement. These results must be taken with caution and should encourage the assessment of the clinical benefit of antithrombotic prophylaxis in patients with cerebral bleeding by properly designed clinical trials.

Background and Purpose— The beneficial effect of intravenous thrombolytic therapy in patients with acute ischemic stroke attributable to internal carotid artery (ICA) occlusion remains unclear. The aim of this study was to evaluate the efficacy and safety of intravenous recombinant tissue-type plasminogen activator in these patients. Methods— ICARO was a case-control multicenter study on prospectively collected data. Patients with acute ischemic stroke and ICA occlusion treated with intravenous recombinant tissue-type plasminogen activator within 4.5 hours from symptom onset (cases) were compared to matched patients with acute stroke and ICA occlusion not treated with recombinant tissue-type plasminogen activator (controls). Cases and controls were matched for age, gender, and stroke severity. The efficacy outcome was disability at 90 days assessed by the modified Rankin Scale, dichotomized as favorable (score of 0–2) or unfavorable (score of 3–6). Safety outcomes were death and any intracranial bleeding. Results— Included in the analysis were 253 cases and 253 controls. Seventy-three cases (28.9%) had a favorable outcome as compared with 52 controls (20.6%; adjusted odds ratio (OR), 1.80; 95% confidence interval [CI], 1.03–3.15; P =0.037). A total of 104 patients died, 65 cases (25.7%) and 39 controls (15.4%; adjusted OR, 2.28; 95% CI, 1.36–3.22; P =0.001). There were more fatal bleedings (2.8% versus 0.4%; OR, 7.17; 95% CI, 0.87–58.71; P =0.068) in the cases than in the controls. Conclusions— In patients with stroke attributable to ICA occlusion, thrombolytic therapy results in a significant reduction in the proportion of patients dependent in activities of daily living. Increases in death and any intracranial bleeding were the trade-offs for this clinical benefit.

&lt;i&gt;Background:&lt;/i&gt; Hyperglycemia has been claimed to be associated with hemorrhagic transformation (HT) in patients with acute ischemic stroke treated with thrombolysis. The aim of this study was to assess whether the admission blood glucose level is related to HT in a prospective study in consecutive patients with acute ischemic stroke. &lt;i&gt;Methods:&lt;/i&gt; Consecutive patients admitted for ischemic stroke to 4 Italian hospitals were included in this prospective cohort study. &lt;i&gt;Results:&lt;/i&gt; Among 1,125 consecutive patients included in the analysis, 98 (8.7%) had HT: 62 (5.5%) had hemorrhagic infarction (HI) and 36 (3.2%) parenchymal hematoma (PH). A blood glucose level &gt;110 mg/dl was found in 42.4% of the patients, a level between 110 and 149 mg/dl in 25.2%, and a level &gt;150 mg/dl in 17.2%. At 3 months, 7 patients were lost at follow-up, 326 patients (29.2%) were disabled (modified Rankin score ≥3) and 129 died (11.5%). PH was associated with an increased risk of death or disability (OR 15.29, 95% CI 2.35–99.35). However, this was not the case for HT overall and HI. At logistic regression analysis, PH was predicted by high levels of admission blood glucose (OR 1.01, 95% CI 1.00–1.01 for 1 added mg/dl). The rate of PH was 2.1% in patients with &lt;110 mg/dl, 3.6% in patients with a level between 110 and 149 mg/dl and 6.4% in patients with a level &gt;150 mg/dl. The curve estimation regression model showed a significant linear increase in the risk of PH related to an increase in blood glucose levels (R&lt;sup&gt;2&lt;/sup&gt; = 0.007, p = 0.007). &lt;i&gt;Conclusions:&lt;/i&gt; Hyperglycemia during acute ischemic stroke predisposes to PH, which in turn determines a nonfavorable outcome at 3 months. This relationship seems to be linear.

<h3>Objective:</h3> Several small to medium-sized studies indicated a link between cervical artery dissection (CeAD) and migraine. Migrainous CeAD patients were suggested to have different clinical characteristics compared to nonmigraine CeAD patients. We tested these hypotheses in the large Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) population. <h3>Methods:</h3> A total of 968 CeAD patients and 653 patients with an ischemic stroke of a cause other than CeAD (non-CeAD IS) were recruited. CeAD patients with stroke (CeAD_stroke, n = 635) were compared with non-CeAD IS patients regarding migraine, clinical characteristics, and outcome. CeAD patients with and without migraine were compared in terms of clinical characteristics and outcome. <h3>Results:</h3> Migraine was more common among CeAD_stroke patients compared to non-CeAD IS patients (35.7 vs 27.4%, <i>p</i> = 0.003). The difference was mainly due to migraine without aura (20.2 vs 11.2%, <i>p</i> &lt; 0.001). There were no differences in prevalence of strokes, arterial distribution, or other clinical or prognostic features between migrainous and nonmigrainous CeAD patients. <h3>Conclusion:</h3> Migraine without aura is more common among CeAD_stroke patients compared to non-CeAD IS patients. The mechanisms and possible causative link remain to be proved. Although CeAD is often complicated by stroke, our data do not support increased risk of stroke in migrainous CeAD patients.

To examine whether thrombolysis for stroke attributable to cervical artery dissection (CeAD(Stroke) ) affects outcome and major haemorrhage rates.We used a multicentre CeAD(Stroke) database to compare CeAD(Stroke) patients treated with and without thrombolysis. Main outcome measures were favourable 3-month outcome (modified Rankin Scale 0-2) and 'major haemorrhage' [any intracranial haemorrhage (ICH) and major extracranial haemorrhage]. Adjusted odds ratios [OR (95% confidence intervals)] were calculated on the whole database and on propensity-matched groups.Among 616 CeAD(Stroke) patients, 68 (11.0%) received thrombolysis; which was used in 55 (81%) intravenously. Thrombolyzed patients had more severe strokes (median NIHSS score 16 vs. 3; P < 0.001) and more often occlusion of the dissected artery (66.2% vs. 39.4%; P < 0.001). After adjustment for stroke severity and vessel occlusion, the likelihood for favourable outcome did not differ between the treatment groups [OR(adjusted) 0.95 (95% CI 0.45-2.00)]. The propensity matching score model showed that the odds to recover favourably were virtually identical for 64 thrombolyzed and 64 non-thrombolyzed-matched CeAD(Stroke) patients [OR 1.00 (0.49-2.00)]. Haemorrhages occurred in 4 (5.9%) thrombolyzed patients, all being asymptomatic ICHs. In the non-thrombolysis group, 3 (0.6%) patients had major haemorrhages [asymptomatic ICH (n = 2) and major extracranial haemorrhage (n = 1)].As thrombolysis was neither independently associated with unfavourable outcome nor with an excess of symptomatic bleedings, our findings suggest thrombolysis should not be withheld in CeAD(Stroke) patients. However, the lack of any trend towards a benefit of thrombolysis may indicate the legitimacy to search for more efficient treatment options including mechanical revascularization strategies.

In a large series of patients with cervical artery dissection (CeAD), a major cause of ischemic stroke in young and middle-aged adults, we aimed to examine frequencies and correlates of family history of CeAD and of inherited connective tissue disorders.We combined data from 2 large international multicenter cohorts of consecutive patients with CeAD in 23 neurologic departments participating in the CADISP-plus consortium, following a standardized protocol. Frequency of reported family history of CeAD and of inherited connective tissue disorders was assessed. Putative risk factors, baseline features, and 3-month outcome were compared between groups.Among 1,934 consecutive patients with CeAD, 20 patients (1.0%, 95% confidence interval: 0.6%-1.5%) from 17 families (0.9%, 0.5%-1.3%) had a family history of CeAD. Family history of CeAD was significantly more frequent in patients with carotid location of the dissection and elevated cholesterol levels. Two patients without a family history of CeAD had vascular Ehlers-Danlos syndrome with a mutation in COL3A1. This diagnosis was suspected in 2 additional patients, but COL3A1 sequencing was negative. Two patients were diagnosed with classic and hypermobile Ehlers-Danlos syndrome, one patient with Marfan syndrome, and one with osteogenesis imperfecta, based on clinical criteria only.In this largest series of patients with CeAD to date, family history of symptomatic CeAD was rare and inherited connective tissue disorders seemed exceptional. This finding supports the notion that CeAD is a multifactorial disease in the vast majority of cases.

The risk of stroke recurrence in patients with Embolic Stroke of Undetermined Source (ESUS) is high, and the optimal antithrombotic strategy for secondary prevention is unclear. We investigated whether congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, and stroke or transient ischemic attack (TIA; CHADS2) and CHA2DS2-VASc scores can stratify the long-term risk of ischemic stroke/TIA recurrence and death in ESUS.We pooled data sets of 11 stroke registries from Europe and America. ESUS was defined according to the Cryptogenic Stroke/ESUS International Working Group. Cox regression analyses were performed to investigate if prestroke CHADS2 and congestive heart failure, hypertension, age ≥75 years, diabetes mellitus, stroke or TIA, vascular disease, age 65-74 years, sex category (CHA2DS2-VASc) scores were independently associated with the risk of ischemic stroke/TIA recurrence or death. The Kaplan-Meier product limit method was used to estimate the cumulative probability of ischemic stroke/TIA recurrence and death in different strata of the CHADS2 and CHA2DS2-VASc scores.One hundred fifty-nine (5.6% per year) ischemic stroke/TIA recurrences and 148 (5.2% per year) deaths occurred in 1095 patients (median age, 68 years) followed-up for a median of 31 months. Compared with CHADS2 score 0, patients with CHADS2 score 1 and CHADS2 score >1 had higher risk of ischemic stroke/TIA recurrence (hazard ratio [HR], 2.38; 95% confidence interval [CI], 1.41-4.00 and HR, 2.72; 95% CI, 1.68-4.40, respectively) and death (HR, 3.58; 95% CI, 1.80-7.12, and HR, 5.45; 95% CI, 2.86-10.40, respectively). Compared with low-risk CHA2DS2-VASc score, patients with high-risk CHA2DS2-VASc score had higher risk of ischemic stroke/TIA recurrence (HR, 3.35; 95% CI, 1.94-5.80) and death (HR, 13.0; 95% CI, 4.7-35.4).The risk of recurrent ischemic stroke/TIA and death in ESUS is reliably stratified by CHADS2 and CHA2DS2-VASc scores. Compared with the low-risk group, patients in the high-risk CHA2DS2-VASc group have much higher risk of ischemic stroke recurrence/TIA and death, approximately 3-fold and 13-fold, respectively.

HomeStrokeVol. 46, No. 6New Strategy to Reduce the Global Burden of Stroke Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissionsDownload Articles + Supplements ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toSupplemental MaterialFree AccessResearch ArticlePDF/EPUBNew Strategy to Reduce the Global Burden of Stroke Valery L. Feigin, MD, PhD, Rita Krishnamurthi, PhD, Rohit Bhattacharjee, MPH, Priya Parmar, MSc, Alice Theadom, PhD, Tasleem Hussein, BSc, Mitali Purohit, MBioEnt, Patria Hume, PhD, Max Abbott, PhD, Elaine Rush, PhD, Nikola Kasabov, PhD, Ineke Crezee, PhD, Stanley Frielick, PhD, Suzanne Barker-Collo, PhD, P. Alan Barber, MD, PhD, Bruce Arroll, MBChB, PhD, Richie Poulton, PhD, Yogini Ratnasabathy, MD, MSc, Martin Tobias, MBBCh, Norberto Cabral, MD, MSc, PhD, Sheila C.O. Martins, MD, PhD, Luis E.T.A. Furtado, MD, Patrice Lindsay, PhD, Gustavo Saposnik, MD, MSc, Maurice Giroud, MD, PhD, Yannick Béjot, MD, PhD, Werner Hacke, MD, PhD, Man Mohan Mehndiratta, MD, DM, Jeyaraj Durai Pandian, MD, DM, Sanjeev Gupta, MPT (MS), BPT, Vasantha Padma, MD, Dipes Kumar Mandal, MD, DM, Yoshihiro Kokubo, MD, PhD, Norlinah Mohamed Ibrahim, MBBCH, MRCP, Ramesh Sahathevan, PhD, Hua Fu, MB, PhD, Wenzhi Wang, PhD, Liping Liu, MD, Zeng-Guang Hou, PhD, António Freire Goncalves, MD, PhD, Manuel Correia, MD, Yury Varakin, MD, PhD, Michael Kravchenko, PhD, Michael Piradov, MD, PhD, Mohammed Saadah, MD, Amanda G. Thrift, PhD, Dominique Cadilhac, PhD, Stephen Davis, MD, PhD, Geoffrey Donnan, MD, PhD, Alan D. Lopez, PhD, Graeme J. Hankey, MD, PhD, Annick Maujean, PhD, Elizabeth Kendall, PhD, Michael Brainin, MD, Foad Abd-Allah, MD, Natan M. Bornstein, MD, Valeria Caso, MD, PhD, Juan Manuel Marquez-Romero, MD, MSc, Rufus O. Akinyemi, PhD, Nasser F. Bin Dhim, PhD, Bo Norrving, MD, Shireen Sindi, PhD, Miia Kivipelto, MD, PhD, Shanthi Mendis, PhD, M. Arfan Ikram, MD, PhD, Albert Hofman, MD, PhD, Saira Saeed Mirza, MD, MSc, Peter M. Rothwell, FMedSci, Peter Sandercock, MA, DM, Raad Shakir, MD, Ralph L. Sacco, MD, MS, Antonio Culebras, MD, Gregory A. Roth, MD, MPH, Maziar Moradi-Lakeh, MD, MPH, Christopher Murray, PhD, K.M. Venkat Narayan, MD, George A. Mensah, MD, David Wiebers, MD, PhD and Andrew E. Moran, MDRIBURST Study Collaboration Writing Group Valery L. FeiginValery L. Feigin From the National Institute for Stroke and Applied Neurosciences, School of Public Health and Psychosocial Studies (V.L.F., R.K., R.B., P.P., A.T.), Faculty of Health and Environmental Sciences (P.H., M.A., E.R.), Information Technology (T.H.), Research and Innovation Office (M.P.), Knowledge Engineering and Discovery Research Institute (N.K.), Translation and Interpreting Department (I.C.), and Centre for Learing and Teaching (S.F.), Auckland University of Technology, Auckland, New Zealand; School of Psychology, University of Auckland, Auckland, New Zealand (S.B.-C.); Department of Neurology, University of Auckland, Auckland, New Zealand (P.A.B.); School of Public Health, University of Auckland, Auckland, New Zealand (B.A.); Department of Preventive and Social Medicine, Otago University, Dunedin, New Zealand (R.P.); Older People Care, Waitemata DHB, Auckland, New Zealand (Y.R.); Health Intelligence, Ministry of Health, Wellington, New Zealand (M.T.); Joinville Stroke Register, University of Joinville Region, Joinville, Brazil (N.C.); Hospital de Clinicas de Porto Alegre, Hospital Moinhos de Vento, Ministry of Health, Brazil (S.C.O.M.); Department of Neurology, Universidade Federal do Ceará, Sobral-Ceará, Brazil (L.E.T.A.F.); Stroke Foundation of Canada, Ottawa, Canada (P.L.); Department of Medicine and Health Policy, Management and Evaluation University of Toronto, Toronto, Canada (G.S.); Dijon Stroke Registry, EA4184, University Hospital and Medical School of Dijon, University of Burgundy, Dijon, France (M.G., Y.B.); Department of Neurology, Ruprecht Karl University Heidelberg, Heidelberg, Germany (W.H.); Janakpuri Super Speciality Hospital, New Delhi, India (M.M.M.); Department of Neurology, Christian Medical College, Ludhiana, Punjab, India (J.D.P.); Banarsidas Chandiwala Institute of Physiotherapy, Kalkaji, New Delhi, India (S.G.); All India Institute of Medical Sciences, New Delhi, India (V.P.); Stroke Foundation of Bengal, Kolkata, West Bengal, India (D.K.M.); Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan (Y.K.); UKM Medical Center, Kuala Lumpur, Malaysia (N.M.I., R.S.); School of Public Health, Fudan University, Shanghai, China (H.F.); Beijing Neurosurgical Institute, Beijing, China (W.W.); Capital Medical University, Beijing, China (L.L.); Institute of Automation, Beijing, China (Z.-G.H.); University Hospital of Coimbra, Coimbra, Portugal (A.F.G.); Serviço de Neurologia, Hospital de Santo Antóni, Portugal (M.C.); Research Center of Neurology, Moscow, Russia (Y.V., M.K., M.P.); University of Emirates, Abu-Dhabi, United Arab Emirates (M.S.); Department of Medicine, Monash University, Clayton, Victoria, Australia (A.G.T., D.C.); The Royal Melbourne Hospital (S.D.), Florey Institute of Neuroscience and Mental Health (G.D.), and Public Health (A.D.L.), University of Melbourne, Parkville, Australia; School of Medicine and Pharmacology, University of Western Australia, Perth, Australia (G.J.H.); Griffith University, Brisbane, Australia (A.M., E.K.); Center for Clinical Neurosciences, Danube University, Vienna, Austria (M.B.); Cairo University, Cairo, Egypt (F.A.-A.); Tel Aviv Sourasky Medical Center, Neurology Department, Tel-Aviv University, Tel-Aviv, Israel (N.M.B.); Stroke Unit, Perugia, Perugia, Italy (V.C.); HGZ 2, IMSS Aguascalientes, Aguascalientes, Mexico (J.M.M.-R.); Federal Medical Centre Abeokuta, Abeokuta, Nigeria (R.O.A.); Health Informatics Department, Saudi Electronic University, Saudi Arabia (N.F.B.D.); Department of Neurology, Lund University, Lund, Sweden (B.N.); Department of Epidemiology (S.S.) and Aging Research Center, Center for Alzheimer Research (M.K.), Karolinska Institutet, Stockholm, Sweden; Noncommunicable Diseases, World Health Organization, Geneva, Switzerland (S.M.); Erasmus University Medical Center, Rotterdam, The Netherlands (M.A.I., A.H., S.S.M.); Nuffield Department of Neuroscience, Oxford University, Oxford, United Kingdom (P.M.R.); Western General Hospital, Edinburgh, United Kingdom (P.S.); Department of Neurology, Imperial College NHS Trust, London, United Kingdom (R.S.); Department of Neurology, Miller School of Medicine, University of Miami (R.L.S.); Department of Neurology, SUNY Upstate Medical University, Syracuse, NY (A.C.); Division of Cardiology, Department of Medicine (G.A.R.), Institute for Health Metrics and Evaluation (G.A.R., M.M.-L., C.M.), University of Washington, Seattle; Emory University, Atlanta, GA (K.M.V.N.); Center for Translation Research and Implementation Science, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (G.A.M.); Department of Neurology, Mayo Clinic, Rochester, MN (D.W.); and Division of General Medicine, Columbia University Medical Center, NY (A.E.M.). , Rita KrishnamurthiRita Krishnamurthi From the National Institute for Stroke and Applied Neurosciences, School of Public Health and Psychosocial Studies (V.L.F., R.K., R.B., P.P., A.T.), Faculty of Health and Environmental Sciences (P.H., M.A., E.R.), Information Technology (T.H.), Research and Innovation Office (M.P.), Knowledge Engineering and Discovery Research Institute (N.K.), Translation and Interpreting Department (I.C.), and Centre for Learing and Teaching (S.F.), Auckland University of Technology, Auckland, New Zealand; School of Psychology, University of Auckland, Auckland, New Zealand (S.B.-C.); Department of Neurology, University of Auckland, Auckland, New Zealand (P.A.B.); School of Public Health, University of Auckland, Auckland, New Zealand (B.A.); Department of Preventive and Social Medicine, Otago University, Dunedin, New Zealand (R.P.); Older People Care, Waitemata DHB, Auckland, New Zealand (Y.R.); Health Intelligence, Ministry of Health, Wellington, New Zealand (M.T.); Joinville Stroke Register, University of Joinville Region, Joinville, Brazil (N.C.); Hospital de Clinicas de Porto Alegre, Hospital Moinhos de Vento, Ministry of Health, Brazil (S.C.O.M.); Department of Neurology, Universidade Federal do Ceará, Sobral-Ceará, Brazil (L.E.T.A.F.); Stroke Foundation of Canada, Ottawa, Canada (P.L.); Department of Medicine and Health Policy, Management and Evaluation University of Toronto, Toronto, Canada (G.S.); Dijon Stroke Registry, EA4184, University Hospital and Medical School of Dijon, University of Burgundy, Dijon, France (M.G., Y.B.); Department of Neurology, Ruprecht Karl University Heidelberg, Heidelberg, Germany (W.H.); Janakpuri Super Speciality Hospital, New Delhi, India (M.M.M.); Department of Neurology, Christian Medical College, Ludhiana, Punjab, India (J.D.P.); Banarsidas Chandiwala Institute of Physiotherapy, Kalkaji, New Delhi, India (S.G.); All India Institute of Medical Sciences, New Delhi, India (V.P.); Stroke Foundation of Bengal, Kolkata, West Bengal, India (D.K.M.); Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan (Y.K.); UKM Medical Center, Kuala Lumpur, Malaysia (N.M.I., R.S.); School of Public Health, Fudan University, Shanghai, China (H.F.); Beijing Neurosurgical Institute, Beijing, China (W.W.); Capital Medical University, Beijing, China (L.L.); Institute of Automation, Beijing, China (Z.-G.H.); University Hospital of Coimbra, Coimbra, Portugal (A.F.G.); Serviço de Neurologia, Hospital de Santo Antóni, Portugal (M.C.); Research Center of Neurology, Moscow, Russia (Y.V., M.K., M.P.); University of Emirates, Abu-Dhabi, United Arab Emirates (M.S.); Department of Medicine, Monash University, Clayton, Victoria, Australia (A.G.T., D.C.); The Royal Melbourne Hospital (S.D.), Florey Institute of Neuroscience and Mental Health (G.D.), and Public Health (A.D.L.), University of Melbourne, Parkville, Australia; School of Medicine and Pharmacology, University of Western Australia, Perth, Australia (G.J.H.); Griffith University, Brisbane, Australia (A.M., E.K.); Center for Clinical Neurosciences, Danube University, Vienna, Austria (M.B.); Cairo University, Cairo, Egypt (F.A.-A.); Tel Aviv Sourasky Medical Center, Neurology Department, Tel-Aviv University, Tel-Aviv, Israel (N.M.B.); Stroke Unit, Perugia, Perugia, Italy (V.C.); HGZ 2, IMSS Aguascalientes, Aguascalientes, Mexico (J.M.M.-R.); Federal Medical Centre Abeokuta, Abeokuta, Nigeria (R.O.A.); Health Informatics Department, Saudi Electronic University, Saudi Arabia (N.F.B.D.); Department of Neurology, Lund University, Lund, Sweden (B.N.); Department of Epidemiology (S.S.) and Aging Research Center, Center for Alzheimer Research (M.K.), Karolinska Institutet, Stockholm, Sweden; Noncommunicable Diseases, World Health Organization, Geneva, Switzerland (S.M.); Erasmus University Medical Center, Rotterdam, The Netherlands (M.A.I., A.H., S.S.M.); Nuffield Department of Neuroscience, Oxford University, Oxford, United Kingdom (P.M.R.); Western General Hospital, Edinburgh, United Kingdom (P.S.); Department of Neurology, Imperial College NHS Trust, London, United Kingdom (R.S.); Department of Neurology, Miller School of Medicine, University of Miami (R.L.S.); Department of Neurology, SUNY Upstate Medical University, Syracuse, NY (A.C.); Division of Cardiology, Department of Medicine (G.A.R.), Institute for Health Metrics and Evaluation (G.A.R., M.M.-L., C.M.), University of Washington, Seattle; Emory University, Atlanta, GA (K.M.V.N.); Center for Translation Research and Implementation Science, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (G.A.M.); Department of Neurology, Mayo Clinic, Rochester, MN (D.W.); and Division of General Medicine, Columbia University Medical Center, NY (A.E.M.). , Rohit BhattacharjeeRohit Bhattacharjee From the National Institute for Stroke and Applied Neurosciences, School of Public Health and Psychosocial Studies (V.L.F., R.K., R.B., P.P., A.T.), Faculty of Health and Environmental Sciences (P.H., M.A., E.R.), Information Technology (T.H.), Research and Innovation Office (M.P.), Knowledge Engineering and Discovery Research Institute (N.K.), Translation and Interpreting Department (I.C.), and Centre for Learing and Teaching (S.F.), Auckland University of Technology, Auckland, New Zealand; School of Psychology, University of Auckland, Auckland, New Zealand (S.B.-C.); Department of Neurology, University of Auckland, Auckland, New Zealand (P.A.B.); School of Public Health, University of Auckland, Auckland, New Zealand (B.A.); Department of Preventive and Social Medicine, Otago University, Dunedin, New Zealand (R.P.); Older People Care, Waitemata DHB, Auckland, New Zealand (Y.R.); Health Intelligence, Ministry of Health, Wellington, New Zealand (M.T.); Joinville Stroke Register, University of Joinville Region, Joinville, Brazil (N.C.); Hospital de Clinicas de Porto Alegre, Hospital Moinhos de Vento, Ministry of Health, Brazil (S.C.O.M.); Department of Neurology, Universidade Federal do Ceará, Sobral-Ceará, Brazil (L.E.T.A.F.); Stroke Foundation of Canada, Ottawa, Canada (P.L.); Department of Medicine and Health Policy, Management and Evaluation University of Toronto, Toronto, Canada (G.S.); Dijon Stroke Registry, EA4184, University Hospital and Medical School of Dijon, University of Burgundy, Dijon, France (M.G., Y.B.); Department of Neurology, Ruprecht Karl University Heidelberg, Heidelberg, Germany (W.H.); Janakpuri Super Speciality Hospital, New Delhi, India (M.M.M.); Department of Neurology, Christian Medical College, Ludhiana, Punjab, India (J.D.P.); Banarsidas Chandiwala Institute of Physiotherapy, Kalkaji, New Delhi, India (S.G.); All India Institute of Medical Sciences, New Delhi, India (V.P.); Stroke Foundation of Bengal, Kolkata, West Bengal, India (D.K.M.); Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan (Y.K.); UKM Medical Center, Kuala Lumpur, Malaysia (N.M.I., R.S.); School of Public Health, Fudan University, Shanghai, China (H.F.); Beijing Neurosurgical Institute, Beijing, China (W.W.); Capital Medical University, Beijing, China (L.L.); Institute of Automation, Beijing, China (Z.-G.H.); University Hospital of Coimbra, Coimbra, Portugal (A.F.G.); Serviço de Neurologia, Hospital de Santo Antóni, Portugal (M.C.); Research Center of Neurology, Moscow, Russia (Y.V., M.K., M.P.); University of Emirates, Abu-Dhabi, United Arab Emirates (M.S.); Department of Medicine, Monash University, Clayton, Victoria, Australia (A.G.T., D.C.); The Royal Melbourne Hospital (S.D.), Florey Institute of Neuroscience and Mental Health (G.D.), and Public Health (A.D.L.), University of Melbourne, Parkville, Australia; School of Medicine and Pharmacology, University of Western Australia, Perth, Australia (G.J.H.); Griffith University, Brisbane, Australia (A.M., E.K.); Center for Clinical Neurosciences, Danube University, Vienna, Austria (M.B.); Cairo University, Cairo, Egypt (F.A.-A.); Tel Aviv Sourasky Medical Center, Neurology Department, Tel-Aviv University, Tel-Aviv, Israel (N.M.B.); Stroke Unit, Perugia, Perugia, Italy (V.C.); HGZ 2, IMSS Aguascalientes, Aguascalientes, Mexico (J.M.M.-R.); Federal Medical Centre Abeokuta, Abeokuta, Nigeria (R.O.A.); Health Informatics Department, Saudi Electronic University, Saudi Arabia (N.F.B.D.); Department of Neurology, Lund University, Lund, Sweden (B.N.); Department of Epidemiology (S.S.) and Aging Research Center, Center for Alzheimer Research (M.K.), Karolinska Institutet, Stockholm, Sweden; Noncommunicable Diseases, World Health Organization, Geneva, Switzerland (S.M.); Erasmus University Medical Center, Rotterdam, The Netherlands (M.A.I., A.H., S.S.M.); Nuffield Department of Neuroscience, Oxford University, Oxford, United Kingdom (P.M.R.); Western General Hospital, Edinburgh, United Kingdom (P.S.); Department of Neurology, Imperial College NHS Trust, London, United Kingdom (R.S.); Department of Neurology, Miller School of Medicine, University of Miami (R.L.S.); Department of Neurology, SUNY Upstate Medical University, Syracuse, NY (A.C.); Division of Cardiology, Department of Medicine (G.A.R.), Institute for Health Metrics and Evaluation (G.A.R., M.M.-L., C.M.), University of Washington, Seattle; Emory University, Atlanta, GA (K.M.V.N.); Center for Translation Research and Implementation Science, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (G.A.M.); Department of Neurology, Mayo Clinic, Rochester, MN (D.W.); and Division of General Medicine, Columbia University Medical Center, NY (A.E.M.). , Priya ParmarPriya Parmar From the National Institute for Stroke and Applied Neurosciences, School of Public Health and Psychosocial Studies (V.L.F., R.K., R.B., P.P., A.T.), Faculty of Health and Environmental Sciences (P.H., M.A., E.R.), Information Technology (T.H.), Research and Innovation Office (M.P.), Knowledge Engineering and Discovery Research Institute (N.K.), Translation and Interpreting Department (I.C.), and Centre for Learing and Teaching (S.F.), Auckland University of Technology, Auckland, New Zealand; School of Psychology, University of Auckland, Auckland, New Zealand (S.B.-C.); Department of Neurology, University of Auckland, Auckland, New Zealand (P.A.B.); School of Public Health, University of Auckland, Auckland, New Zealand (B.A.); Department of Preventive and Social Medicine, Otago University, Dunedin, New Zealand (R.P.); Older People Care, Waitemata DHB, Auckland, New Zealand (Y.R.); Health Intelligence, Ministry of Health, Wellington, New Zealand (M.T.); Joinville Stroke Register, University of Joinville Region, Joinville, Brazil (N.C.); Hospital de Clinicas de Porto Alegre, Hospital Moinhos de Vento, Ministry of Health, Brazil (S.C.O.M.); Department of Neurology, Universidade Federal do Ceará, Sobral-Ceará, Brazil (L.E.T.A.F.); Stroke Foundation of Canada, Ottawa, Canada (P.L.); Department of Medicine and Health Policy, Management and Evaluation University of Toronto, Toronto, Canada (G.S.); Dijon Stroke Registry, EA4184, University Hospital and Medical School of Dijon, University of Burgundy, Dijon, France (M.G., Y.B.); Department of Neurology, Ruprecht Karl University Heidelberg, Heidelberg, Germany (W.H.); Janakpuri Super Speciality Hospital, New Delhi, India (M.M.M.); Department of Neurology, Christian Medical College, Ludhiana, Punjab, India (J.D.P.); Banarsidas Chandiwala Institute of Physiotherapy, Kalkaji, New Delhi, India (S.G.); All India Institute of Medical Sciences, New Delhi, India (V.P.); Stroke Foundation of Bengal, Kolkata, West Bengal, India (D.K.M.); Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan (Y.K.); UKM Medical Center, Kuala Lumpur, Malaysia (N.M.I., R.S.); School of Public Health, Fudan University, Shanghai, China (H.F.); Beijing Neurosurgical Institute, Beijing, China (W.W.); Capital Medical University, Beijing, China (L.L.); Institute of Automation, Beijing, China (Z.-G.H.); University Hospital of Coimbra, Coimbra, Portugal (A.F.G.); Serviço de Neurologia, Hospital de Santo Antóni, Portugal (M.C.); Research Center of Neurology, Moscow, Russia (Y.V., M.K., M.P.); University of Emirates, Abu-Dhabi, United Arab Emirates (M.S.); Department of Medicine, Monash University, Clayton, Victoria, Australia (A.G.T., D.C.); The Royal Melbourne Hospital (S.D.), Florey Institute of Neuroscience and Mental Health (G.D.), and Public Health (A.D.L.), University of Melbourne, Parkville, Australia; School of Medicine and Pharmacology, University of Western Australia, Perth, Australia (G.J.H.); Griffith University, Brisbane, Australia (A.M., E.K.); Center for Clinical Neurosciences, Danube University, Vienna, Austria (M.B.); Cairo University, Cairo, Egypt (F.A.-A.); Tel Aviv Sourasky Medical Center, Neurology Department, Tel-Aviv University, Tel-Aviv, Israel (N.M.B.); Stroke Unit, Perugia, Perugia, Italy (V.C.); HGZ 2, IMSS Aguascalientes, Aguascalientes, Mexico (J.M.M.-R.); Federal Medical Centre Abeokuta, Abeokuta, Nigeria (R.O.A.); Health Informatics Department, Saudi Electronic University, Saudi Arabia (N.F.B.D.); Department of Neurology, Lund University, Lund, Sweden (B.N.); Department of Epidemiology (S.S.) and Aging Research Center, Center for Alzheimer Research (M.K.), Karolinska Institutet, Stockholm, Sweden; Noncommunicable Diseases, World Health Organization, Geneva, Switzerland (S.M.); Erasmus University Medical Center, Rotterdam, The Netherlands (M.A.I., A.H., S.S.M.); Nuffield Department of Neuroscience, Oxford University, Oxford, United Kingdom (P.M.R.); Western General Hospital, Edinburgh, United Kingdom (P.S.); Department of Neurology, Imperial College NHS Trust, London, United Kingdom (R.S.); Department of Neurology, Miller School of Medicine, University of Miami (R.L.S.); Department of Neurology, SUNY Upstate Medical University, Syracuse, NY (A.C.); Division of Cardiology, Department of Medicine (G.A.R.), Institute for Health Metrics and Evaluation (G.A.R., M.M.-L., C.M.), University of Washington, Seattle; Emory University, Atlanta, GA (K.M.V.N.); Center for Translation Research and Implementation Science, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (G.A.M.); Department of Neurology, Mayo Clinic, Rochester, MN (D.W.); and Division of General Medicine, Columbia University Medical Center, NY (A.E.M.). , Alice TheadomAlice Theadom From the National Institute for Stroke and Applied Neurosciences, School of Public Health and Psychosocial Studies (V.L.F., R.K., R.B., P.P., A.T.), Faculty of Health and Environmental Sciences (P.H., M.A., E.R.), Information Technology (T.H.), Research and Innovation Office (M.P.), Knowledge Engineering and Discovery Research Institute (N.K.), Translation and Interpreting Department (I.C.), and Centre for Learing and Teaching (S.F.), Auckland University of Technology, Auckland, New Zealand; School of Psychology, University of Auckland, Auckland, New Zealand (S.B.-C.); Department of Neurology, University of Auckland, Auckland, New Zealand (P.A.B.); School of Public Health, University of Auckland, Auckland, New Zealand (B.A.); Department of Preventive and Social Medicine, Otago University, Dunedin, New Zealand (R.P.); Older People Care, Waitemata DHB, Auckland, New Zealand (Y.R.); Health Intelligence, Ministry of Health, Wellington, New Zealand (M.T.); Joinville Stroke Register, University of Joinville Region, Joinville, Brazil (N.C.); Hospital de Clinicas de Porto Alegre, Hospital Moinhos de Vento, Ministry of Health, Brazil (S.C.O.M.); Department of Neurology, Universidade Federal do Ceará, Sobral-Ceará, Brazil (L.E.T.A.F.); Stroke Foundation of Canada, Ottawa, Canada (P.L.); Department of Medicine and Health Policy, Management and Evaluation University of Toronto, Toronto, Canada (G.S.); Dijon Stroke Registry, EA4184, University Hospital and Medical School of Dijon, University of Burgundy, Dijon, France (M.G., Y.B.); Department of Neurology, Ruprecht Karl University Heidelberg, Heidelberg, Germany (W.H.); Janakpuri Super Speciality Hospital, New Delhi, India (M.M.M.); Department of Neurology, Christian Medical College, Ludhiana, Punjab, India (J.D.P.); Banarsidas Chandiwala Institute of Physiotherapy, Kalkaji, New Delhi, India (S.G.); All India Institute of Medical Sciences, New Delhi, India (V.P.); Stroke Foundation of Bengal, Kolkata, West Bengal, India (D.K.M.); Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan (Y.K.); UKM Medical Center, Kuala Lumpur, Malaysia (N.M.I., R.S.); School of Public Health, Fudan University, Shanghai, China (H.F.); Beijing Neurosurgical Institute, Beijing, China (W.W.); Capital Medical University, Beijing, China (L.L.); Institute of Automation, Beijing, China (Z.-G.H.); University Hospital of Coimbra, Coimbra, Portugal (A.F.G.); Serviço de Neurologia, Hospital de Santo Antóni, Portugal (M.C.); Research Center of Neurology, Moscow, Russia (Y.V., M.K., M.P.); University of Emirates, Abu-Dhabi, United Arab Emirates (M.S.); Department of Medicine, Monash University, Clayton, Victoria, Australia (A.G.T., D.C.); The Royal Melbourne Hospital (S.D.), Florey Institute of Neuroscience and Mental Health (G.D.), and Public Health (A.D.L.), University of Melbourne, Parkville, Australia; School of Medicine and Pharmacology, University of Western Australia, Perth, Australia (G.J.H.); Griffith University, Brisbane, Australia (A.M., E.K.); Center for Clinical Neurosciences, Danube University, Vienna, Austria (M.B.); Cairo University, Cairo, Egypt (F.A.-A.); Tel Aviv Sourasky Medical Center, Neurology Department, Tel-Aviv University, Tel-Aviv, Israel (N.M.B.); Stroke Unit, Perugia, Perugia, Italy (V.C.); HGZ 2, IMSS Aguascalientes, Aguascalientes, Mexico (J.M.M.-R.); Federal Medical Centre Abeokuta, Abeokuta, Nigeria (R.O.A.); Health Informatics Department, Saudi Electronic University, Saudi Arabia (N.F.B.D.); Department of Neurology, Lund University, Lund, Sweden (B.N.); Department of Epidemiology (S.S.) and Aging Research Center, Center for Alzheimer Research (M.K.), Karolinska Institutet, Stockholm, Sweden; Noncommunicable Diseases, World Health Organization, Geneva, Switzerland (S.M.); Erasmus University Medical Center, Rotterdam, The Netherlands (M.A.I., A.H., S.S.M.); Nuffield Department of Neuroscience, Oxford University, Oxford, United Kingdom (P.M.R.); Western General Hospital, Edinburgh, United Kingdom (P.S.); Department of Neurology, Imperial College NHS Trust, London, United Kingdom (R.S.); Department of Neurology, Miller School of Medicine, University of Miami (R.L.S.); Department of Neurology, SUNY Upstate Medical University, Syracuse, NY (A.C.); Division of Cardiology, Department of Medicine (G.A.R.), Institute for Health Metrics and Evaluation (G.A.R., M.M.-L., C.M.), University of Washington, Seattle; Emory University, Atlanta, GA (K.M.V.N.); Center for Translation Research and Implementation Science, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD (G.A.M.); Department of Neurology, Mayo Clinic, Rochester, MN (D.W.); and Division of General Medicine, Columbia University Medical Center, NY (A.E.M.). , Tasleem HusseinTasleem Hussein From the National Institute for Stroke and Applied Neurosciences, School of Public Health and Psychosocial Studies (V.L.F., R.K., R.B., P.P., A.T.), Faculty of Health and Environmental Sciences (P.H., M.A., E.R.), Information Technology (T.H.), Research and Innovation Office (M.P.), Knowledge Engineering and Discovery Research Institute (N.K.), Translation and Interpreting Department (I.C.), and Centre for Learing and Teaching (S.F.), Auckland University of Technology, Auckland, New Zealand; School of Psychology, University of Auckland, Auckland, New Zealand (S.B.-C.); Department of Neurology, University of Auckland, Auckland, New Zealand (P.A.B.); School of Public Health, University of Auckland, Auckland, New Zealand (B.A.); Department of Preventive and Social Medicine, Otago University, Dunedin, New Zealand (R.P.); Older People Care, Waitemata DHB, Auckland, New Zealand (Y.R.); Health Intelligence, Ministry of Health, Wellington, New Zealand (M.T.); Joinville Stroke Register, University of Joinville Region, Joinville, Brazil (N.C.); Hospital de Clinicas de Porto Alegre, Hospital Moinhos de Vento, Ministry of Health, Brazil (S.C.O.M.); Department of Neurology, Universidade Federal do Ceará, Sobral-Ceará, Brazil (L.E.T.A.F.); Stroke Foundation of Canada, Ottawa, Canada (P.L.); Department of Medicine and Health Policy, Management and Evaluation University of Toronto, Toronto, Canada (G.S.); Dijon Stroke Registry, EA4184, University Hospital and Medical School of Dijon, University of Burgundy, Dijon, France (M.G., Y.B.); Department of Neurology, Ruprecht Karl University Heidelberg, Heidelberg, Germany (W.H.); Janakpuri Super Speciality Hospital, New Delhi, India (M.M.M.); Department of Neurology, Christian Medical College, Ludhiana, Punjab, India (J.D.P.); Banarsidas Chandiwala Institute of Physiotherapy, Kalkaji, New Delhi, India (S.G.); All India Institute of Medical Sciences, New Delhi, India (V.P.); Stroke Foundation of Bengal, Kolkata, West Bengal, India (D.K.M.); Department of Preventive Cardiology, National Cerebral and Cardiovascular Center, Osaka, Japan (Y.K.); UKM Medical Center, Kuala Lumpur, Malaysia (N.M.I., R.S.); School of Public Health, Fudan University, Shanghai, China (H.F.); Beijing Neurosurgical Institute, Beijing, China (W.W.); Capital Medical University, Beijing, China (L.L.); Institute of Automation, Beijing, China (Z.-G.H.); University Hospital of Coimbra, Coimbra, Portugal (A.F.G.); Serviço de Neurologia, Hospital de Santo Antóni, Portugal (M.C.); Research Center of Neurology, Moscow, Russia (Y.V., M.K., M.P.); University of Emirates, Abu-Dhabi, United Arab Emirates (M.S.); Department of Medicine, Monash University, Clayton, Victoria, Australia (A.G.T., D.C.); The Royal Melbourne Hospital (S.D.), Florey Institute of Neuroscience and Mental Health (G.D.), and Public Health (A.D.L.), University of Melbourne, Parkville, Australia; School of Medicine and Pharmacology, University of Western Australia, Perth, Australia (G.J.H.); Griffith University, Brisbane, Australia (A.M., E.K.); Center for Clinical Neurosciences, Danube University, Vienna, Austria (M.B.); Cairo University, Cairo, Egypt (F.A.-A.); Tel Aviv Sourasky Medical Center, Neurology Department, Tel-Aviv University, Tel-Aviv, Israel (N.M.B.); Stroke Unit, Perugia, Perugia, Italy (V.C.); HGZ 2, IMSS Aguascalientes, Aguascalientes, Mexico (J.M.M.-R.); Federal Medical Centre Abeokuta,

About the meeting: The purpose of the European Stroke Organisation (ESO)-Karolinska Stroke Update Conference is to provide updates on recent stroke therapy research and to give an opportunity for the participants to discuss how these results may be implemented into clinical routine. Several scientific sessions discussed in the meeting and each session produced consensus statements. The meeting started 20 years ago as Karolinska Stroke Update, but since 2014, it is a joint conference with ESO. Importantly, it provides a platform for discussion on the ESO guidelines process and on recommendations to the ESO guidelines committee on specific topics. By this, it adds a direct influence from stroke professionals otherwise not involved in committees and work groups on the guidelines procedure. The discussions at the conference may also inspire new guidelines when motivated. The topics raised at the meeting are selected by the scientific programme committee mainly based on recent important scientific publications. The ESO-Karolinska Stroke Update consensus statement and recommendations will be published every 2 years and it will work as implementation of ESO-guidelines Background This year’s ESO-Karolinska Stroke Update Meeting was held in Stockholm on 13–15 November 2016. There were 10 scientific sessions discussed in the meeting and each session produced a consensus statement ( Full version with background, issues, conclusions and references are published as web-material and at http://www.eso-karolinska.org/2016 and http://eso-stroke.org ) and recommendations which were prepared by a writing committee consisting of session chair(s), secretary and speakers and presented to the 312 participants of the meeting. In the open meeting, general participants commented on the consensus statement and recommendations and the final document were adjusted based on the discussion from the general participants. Recommendations (grade of evidence) were graded according to the 1998 Karolinska Stroke Update meeting with regard to the strength of evidence. Grade A Evidence: Strong support from randomised controlled trials and statistical reviews (at least one randomised controlled trial plus one statistical review). Grade B Evidence: Support from randomised controlled trials and statistical reviews (one randomised controlled trial or one statistical review). Grade C Evidence: No reasonable support from randomised controlled trials, recommendations based on small randomised and/or non-randomised controlled trials evidence.

<h3>Objective:</h3> To assess whether smoking cessation after an ischemic stroke or TIA improves outcomes compared to continued smoking. <h3>Methods:</h3> We conducted a prospective observational cohort study of 3,876 nondiabetic men and women enrolled in the Insulin Resistance Intervention After Stroke (IRIS) trial who were randomized to pioglitazone or placebo within 180 days of a qualifying stroke or TIA and followed up for a median of 4.8 years. A tobacco use history was obtained at baseline and updated during annual interviews. The primary outcome, which was not prespecified in the IRIS protocol, was recurrent stroke, myocardial infarction (MI), or death. Cox regression models were used to assess the differences in stroke, MI, and death after 4.8 years, with correction for adjustment variables prespecified in the IRIS trial: age, sex, stroke (vs TIA) as index event, history of stroke, history of hypertension, history of coronary artery disease, and systolic and diastolic blood pressures. <h3>Results:</h3> At the time of their index event, 1,072 (28%) patients were current smokers. By the time of randomization, 450 (42%) patients had quit smoking. Among quitters, the 5-year risk of stroke, MI, or death was 15.7% compared to 22.6% for patients who continued to smoke (adjusted hazard ratio 0.66, 95% confidence interval 0.48–0.90). <h3>Conclusion:</h3> Cessation of cigarette smoking after an ischemic stroke or TIA was associated with significant health benefits over 4.8 years in the IRIS trial cohort.

Ischaemic stroke patients with atrial fibrillation (AF) are at risk of early recurrent stroke (RS). However, antithrombotics commenced at the acute stage may exacerbate haemorrhagic transformation, provoking symptomatic intracerebral haemorrhage (SICH). The relevance of antithrombotics on the patterns and outcome of the cohort was investigated.A non-randomized cohort analysis was conducted using data obtained from VISTA (Virtual International Stroke Trials Archive). The associations of antithrombotics with the modified Rankin Scale (mRS) outcome and the occurrence of RS and SICH (each as a combined end-point of fatal and non-fatal events) at 90 days for post-stroke patients with AF were described. Dichotomized outcomes were also considered as a secondary end-point (i.e. mortality and good outcome measure at 90 days).In all, 1644 patients were identified; 1462 (89%) received antithrombotics, 157 (10%) had RS and 50 (3%) sustained SICH by day 90. Combined antithrombotic therapy (i.e. anticoagulants and antiplatelets), 782 (48%), was associated with favourable outcome on ordinal mRS and a significantly lower risk of RS, SICH and mortality by day 90, compared with the no antithrombotics group. The relative risk of RS and SICH appeared highest in the first 2 days post-stroke before attenuating to become constant over time.The risks and benefits of antithrombotics in recent stroke patients with AF appear to track together. Early introduction of anticoagulants (2-3 days post-stroke), and to a lesser extent antiplatelet agents, was associated with substantially fewer RS events over the following weeks but with no excess risk of SICH. More evidence is required to guide clinicians on this issue.

This study aimed to assess the evidence on the periprocedural (<30 days) risks of carotid intervention in relation to timing of procedure in patients with recently symptomatic carotid stenosis.A systematic literature review of studies published in the past 8 years reporting periprocedural stroke/death after carotid endarterectomy (CEA) and carotid stenting (CAS) related to the time between qualifying neurological symptoms and intervention was performed. Pooled estimates of periprocedural risk for patients treated within 0 to 48 hours, 0 to 7 days, and 0 to 15 days were derived with proportional meta-analyses and reported separately for patients with stroke and transient ischemic attack as index events.Of 47 studies included, 35 were on CEA, 7 on CAS, and 5 included both procedures. The pooled risk of periprocedural stroke was 3.4% (95% confidence interval [CI], 2.6-4.3) after CEA and 4.8% (95% CI, 2.5-7.8) after CAS performed <15 days; stroke/death rates were 3.8% and 6.9% after CEA and CAS, respectively. Pooled periprocedural stroke risk was 3.3% (95% CI, 2.1-4.6) after CEA and 4.8% (95% CI, 2.5-7.8) after CAS when performed within 0 to 7 days. In hyperacute surgery (<48 hours), periprocedural stroke risk after CEA was 5.3% (95% CI, 2.8-8.4) but with relevant risk differences among patients treated after transient ischemic attack (2.7%; 95% CI, 0.5-6.9) or stroke (8.0%; 95% CI, 4.6-12.2) as index.CEA within 15 days from stroke/transient ischemic attack can be performed with periprocedural stroke risk <3.5%. CAS within the same period may carry a stroke risk of 4.8%. Similar periprocedural risks occur after CEA and CAS performed earlier, within 0 to 7 days. Carotid revascularization can be safely performed within the first week (0-7 days) after symptom onset.

Background and purposeSex related differences in cardiovascular disease and stroke are issues of increasing interest. The aim of this study was to evaluate for sex differences in clinical presentation, severity of stroke and outcome in a population of patients admitted to 4 public and 1 private hospitals in three different regions of Italy.MethodsAll hospital admissions for ischemic and haemorrhagic stroke (ICD-IX code 434 and 431 respectively) between January 1st and December 31st, 2011 at five different hospitals located in three different regions of Italy: Milan (North), Rome and Perugia (Center), and Palermo (South) have been recorded and sex-differences have been evaluated.ResultsA total of 1272 stroke patients were included in the analysis: 1152 ischemic and 120 haemorrhagic strokes, 567 women and 705 men. Compared to men, women were significantly older (mean age 75.2 SD 13.7 vs 71.5 SD 12.5 years, P<0.001) and their stroke severities at onset, measured by NIHSS, were also compared to men (10 SD 8 vs 8 SD 7, P<0.001).Female sex was associated with a worse functional prognosis measured by modified Rankin Scale score (mRS≥3), as well as in-hospital mortality, without reaching statistical significance.There were no observed significant differences between sexes regarding the number of patients treated with thrombolytic therapy. Analysis of the distribution of risk factors between sexes showed a prevalence of atrial fibrillation in women (29% vs 21%, P=0.003).ConclusionsBoth stroke severity and functional outcome were worse in women.

Through a comprehensive analysis of Italy's estimates from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, we aimed to understand the patterns of health loss and response of the health-care system, and offer evidence-based policy indications in light of the demographic transition and government health spending in the country.Estimates for Italy were extracted from GBD 2017. Data on Italy are presented for 1990 and 2017, on prevalence, causes of death, years of life lost, years lived with disability, disability-adjusted life-years (DALYs), life expectancy at birth and at age 65 years, healthy life expectancy, and Healthcare Access and Quality (HAQ) Index. We compared the estimates for Italy with those of 15 other western European countries.The quality of the universal health system and healthy behaviours contribute to favourable overall health, even in comparison with other western European countries. In 2017, life expectancy and HAQ Index score in Italy were among the highest globally, with life expectancy at birth reaching 85·3 years for females and 80·8 for males in 2017, ranking Italy eighth globally for females and sixth for males, and an HAQ Index score of 94·9 in 2016 compared with 81·54 in 1990, keeping Italy ranked as ninth globally. Between 1990 and 2017 age-standardised death rates for cardiovascular diseases decreased by 53·7% (95% uncertainty interval -56·1 to -51·4), for neoplasms decreased by 28·2% (-32·3 to -24·6), and for transport injuries decreased by 62·1% (-64·6 to -59·2). However, population ageing is causing an increase in the burden of specific diseases, such as Alzheimer's disease and other dementias (DALYs increased by 77·9% [68·4 to 87·2]) and pancreatic (DALYs increased by 39·7% [28·4 to 51·7]) and uterine cancers (DALYs increased by 164·7% [129·7 to 202·5]). Behavioural risk factors, which are potentially modifiable, still have a strong effect, particularly on cardiovascular diseases and neoplasms. For instance, in 2017, 44 400 (41 200 to 47 800) cancer deaths were attributed to smoking, 12 000 (9600 to 14 800) to alcohol use, and 9500 (5400 to 14 200) to high body-mass index, while 47 000 (31 100 to 65 700) deaths due to cardiovascular diseases could be attributed to high LDL cholesterol, 28 700 (19 700 to 38 500) to diets low in whole grains, and 15 900 (8500 to 24 900) to low physical activity.Italy provides an interesting example of the results that can be achieved by a mix of relatively healthy lifestyles and a universal health system. Two main issues require attention, population ageing and gradual decrease of public health financing, which both pose several challenges to the future of Italy's health status. Our findings should be useful to Italy's policy makers and health system experts elsewhere.Bill & Melinda Gates Foundation.

Current guidelines do not provide firm directions on atrial fibrillation (AF) screening after ischemic stroke (IS). We sought to investigate the association of implantable cardiac monitoring (ICM) duration with the yield of AF detection in IS patients.We included studies reporting AF detection rates by ICM in IS patients with negative initial AF screening. We excluded studies reporting prolonged cardiac monitoring with devices other than ICM, not providing AF detection rates or monitoring duration, and reporting overlapping data for the same population. The random-effects model was used for all pooled estimates and meta-regression analyses.We included 28 studies (4,531 patients, mean age 65 years). In meta-regression analyses, the proportion of AF detection by ICM was independently associated with monitoring duration (coefficient=0.015; 95% confidence interval [CI], 0.005 to 0.024) and mean patient age (coefficient=0.009; 95% CI, 0.003 to 0.015). No associations were detected with other patient characteristics, including IS subtype (cryptogenic vs. embolic stroke of undetermined source) or time from IS onset to CM implantation. In subgroup analyses, significant differences (P<0.001) in the AF detection rates were found for ICM duration (<6 months: 5% [95% CI, 3% to 6%]; ≥6 and ≤12 months: 21% [95% CI, 16% to 25%]; >12 and ≤24 months: 26% [95% CI, 22% to 31%]; >24 months: 34% [95% CI, 29% to 39%]).s Extended duration of ICM monitoring and increased patient age are factors that substantially increase AF detection in IS patients with initial negative AF screening.

Background The study of sex differences on stroke incidence, prevalence and mortality is an emerging field of stroke epidemiology and care. Aims This study sought to determine the information available on stroke epidemiology in women worldwide and possible sex differences in stroke epidemiology, and, if so, describe the nature of these differences and whether they are consistent across countries/groups of countries. Summary We searched the available literature in English published between 1 January 2008 and 5 May 2015. Out of 17.789 papers only 56 peer-reviewed papers (29 community-based studies, 17 retrospective studies, 6 reviews, and 4 cross-sectional studies) have been included in the study. This review adopted the epidemiologic transition theory, which classifies countries into four stages according to their levels of industrialization and economy. For the first and second stages, reliable registries and health certification are lacking, and therefore our sought after data were very limited. In the third stage, specifically for Eastern Europe (post-socialist countries), the burden from stroke in women was on the rise, while in the fourth stage, despite an aging population, decreases in stroke incidence, prevalence and mortality have been observed, even in subjects older than 80 years for both sexes. However, regarding studies of US populations, these trends for women were less pronounced for African Americans, and Hispanics as well as Indians. This suggests a “gender-gap” regarding access to treatment and care. In conclusion, identifying the presence of differing global burden between the sexes will allow us to better understand how to prevent, treat, and manage both men and women.

Background The association between stroke and cancer is well-known but insufficiently investigated. Aim of this multicentre retrospective cohort study was to estimate the prevalence of cancer-associated ischemic stroke, describe clinical outcomes in patients with cancer-associated ischemic stroke and investigate independent factors associated with active cancer. Methods Consecutive adult patients admitted for acute ischemic stroke were included. Included patients were admitted in the Stroke Unit of the Hospital of Perugia, Italy, from March 2005 to March 2015, and in a medical unit of the Hospital of Varese, Italy, from January 2010 till December 2011. Clinical and laboratory data of patients with and without active cancer were collected. Multivariate logistic regression analysis was performed to identify independent factors associated with active cancer. Results A total of 2209 patients admitted with acute ischemic stroke were included with a median hospital stay of 9 days (interquartile range 5.75–14). Mean age was 72.7 years (standard deviation +/− 13); 55% patients were male and 4.4% had active cancer. Factors significantly associated with the presence of active cancer were age > 65 years (odds ratio [OR] 3.34; 95% confidence interval [CI] 1.64–6.81), occurrence of venous thromboembolism [VTE] (OR 2.84; 95% CI 1.12–7.19), low-density lipoprotein (LDL) cholesterol level < 70 mg/dL (OR 1.92; 95% CI 1.06–3.47), cryptogenic stroke subtype (OR 1.93; 95% CI 1.22–3.04). Overall mortality rate during hospital stay was greater in patients with active cancer (21.5% vs. 10% P < 0.05). Conclusions Older age, occurrence of VTE, low LDL level, and cryptogenic stroke subtype, are independently associated with active cancer. Overall, our findings suggest a possible prevalent role of hypercoagulability in the pathogenesis of cancer-associated ischemic stroke.

Sphenopalatine ganglion stimulation increased cerebral collateral blood flow, stabilised the blood-brain barrier, and reduced infarct size, in preclinical models of acute ischaemic stroke, and showed potential benefit in a pilot randomised trial in humans. The pivotal ImpACT-24B trial aimed to determine whether sphenopalatine ganglion stimulation 8-24 h after acute ischaemic stroke improved functional outcome.ImpACT-24B is a randomised, double-blind, sham-controlled, pivotal trial done at 73 centres in 18 countries. It included patients (men aged 40-80 years and women aged 40-85 years) with anterior-circulation acute ischaemic stroke, not undergoing reperfusion therapy. Enrolled patients were randomly assigned via web-based randomisation to receive active sphenopalatine ganglion stimulation (intervention group) or sham stimulation (sham-control group) 8-24 h after stroke onset. Patients, clinical care providers, and all outcome assessors were masked to treatment allocation. The primary efficacy endpoint was the difference between active and sham groups in the proportion of patients whose 3-month level of disability improved above expectations. This endpoint was evaluated in the modified intention-to-treat (mITT) population (defined as all patients who received one active or sham treatment session) and the population with confirmed cortical involvement (CCI) and was analysed using the Hochberg multi-step procedure (significance in both populations if p<0·05 in both, and in one population if p<0·025 in that one). Safety endpoints at 3 months were all serious adverse events (SAEs), SAEs related to implant placement or removal, SAEs related to stimulation, neurological deterioration, and mortality. All patients who underwent an attempted sphenopalatine ganglion stimulator or sham stimulator placement procedure were included in the safety analysis. This trial is registered with ClinicalTrials.gov, number NCT00826059.Between June 10, 2011, and March 7, 2018, 1078 patients were enrolled and randomly assigned to either the intervention or the sham-control group. 1000 patients received at least one session of sphenopalatine ganglion stimulation or sham stimulation and entered the mITT population (481 [48%] received sphenopalatine ganglion stimulation, 519 [52%] were sham controls), among whom 520 (52%) patients had CCI on imaging. The proportion of patients in the mITT population whose 3-month disability level was better than expected was 49% (234/481) in the intervention group versus 45% (236/519) in the sham-control group (odds ratio 1·14, 95% CI 0·89-1·46; p=0·31). In the CCI population, the proportion was 50% (121/244) in the intervention group versus 40% (110/276) in the sham-control group (1·48, 1·05-2·10; p=0·0258). There was an inverse U-shaped dose-response relationship between attained sphenopalatine ganglion stimulation intensity and the primary outcome in the CCI population: the proportion with favourable outcome increased from 40% to 70% at low-midrange intensity and decreased back to 40% at high intensity stimulation (p=0·0034). There were no differences in mortality or SAEs between the intervention group (n=536) and the sham-control group (n=519) in the safety population.Sphenopalatine ganglion stimulation is safe for patients with acute ischaemic stroke 8-24 h after onset, who are ineligible for thrombolytic therapy. Although not reaching significance, the trial's results support that, among patients with imaging evidence of cortical involvement at presentation, sphenopalatine ganglion stimulation is likely to improve functional outcome.BrainsGate Ltd.

An exhaustive and updated estimation of cardiovascular disease burden and vascular risk factors is still lacking in European countries. This study aims to fill this gap assessing the global Italian cardiovascular disease burden and its changes from 1990 to 2017 and comparing the Italian situation with European countries.All accessible data sources from the 2017 Global Burden of Disease study were used to estimate the cardiovascular disease prevalence, mortality and disability-adjusted life years and cardiovascular disease attributable risk factors burden in Italy from 1990 to 2017. Furthermore, we compared the cardiovascular disease burden within the 28 European Union countries.Since 1990, we observed a significant decrease of cardiovascular disease burden, particularly in the age-standardised prevalence (-12.7%), mortality rate (-53.8%), and disability-adjusted life years rate (-55.5%). Similar improvements were observed in the majority of European countries. However, we found an increase in all-ages prevalence of cardiovascular diseases from 5.75 m to 7.49 m Italian residents. Cardiovascular diseases still remain the first cause of death (34.8% of total mortality). More than 80% of the cardiovascular disease burden could be attributed to known modifiable risk factors such as high systolic blood pressure, dietary risks, high low density lipoprotein cholesterol, and impaired kidney function.Our study shows a decline in cardiovascular mortality and disability-adjusted life years, which reflects the success in reducing disability, premature death and early incidence of cardiovascular diseases. However, the burden of cardiovascular diseases is still high. An approach that includes the cooperation and coordination of all stakeholders of the Italian National Health System is required to further reduce this burden.

Objective There has been limited systematic evaluation of outcomes and drivers of inappropriate non-vitamin K antagonist oral anticoagulants (NOACs) dosing among patients with atrial fibrillation (AF). This review identified and systematically evaluated literature on clinical and economic outcomes of inappropriate NOAC dosing and associated patient characteristics. Methods MEDLINE, Embase, Cochrane Library, International Pharmaceutical Abstracts, Econlit, PubMed and NHS EEDs databases were searched for English language observational studies from all geographies published between 2008 and 2020, examining outcomes of, or factors associated with, inappropriate NOAC dosing in adult patients with AF. Results One hundred and six studies were included in the analysis. Meta-analysis showed that compared with recommended NOAC dosing, off-label underdosing was associated with a null effect on stroke outcomes (ischaemic stroke and stroke/transient ischaemic attack (TIA), stroke/systemic embolism (SE) and stroke/SE/TIA). Meta-analysis of 15 studies examining clinical outcomes of inappropriate NOAC dosing found a null effect of underdosing on bleeding outcomes (major bleeding HR=1.04, 95% CI 0.90 to 1.19; p=0.625) but an increased risk of all-cause mortality (HR=1.28, 95% CI 1.10 to 1.49; p=0.006). Overdosing was associated with an increased risk of major bleeding (HR=1.41, 95% CI 1.07 to 1.85; p=0.013). No studies were found examining economic outcomes of inappropriate NOAC dosing. Narrative synthesis of 12 studies examining drivers of inappropriate NOAC dosing found that increased age, history of minor bleeds, hypertension, congestive heart failure and low creatine clearance (CrCl) were associated with an increased risk of underdosing. There was insufficient evidence to assess drivers of overdosing. Conclusions Our analysis suggests that off-label underdosing of NOACs does not reduce bleeding outcomes. Patients prescribed off-label NOAC doses are at an increased risk of all-cause mortality. These data underscore the importance of prescriber adherence to NOAC dosing guidelines to achieve optimal clinical outcomes for patients with AF. PROSPERO registration number CRD42020219844.

We assessed best available data on access and delivery of acute stroke unit (SU) care, intravenous thrombolysis (IVT) and endovascular treatment (EVT) in the European region in 2019 and 2020.We compared national data per number of inhabitants and per 100 annual incident first-ever ischaemic strokes (AIIS) in 46 countries. Population estimates and ischaemic stroke incidence were based on United Nations data and the Global Burden of Disease Report 2019, respectively.The estimated mean number of acute SUs in 2019 was 3.68 (95% CI: 2.90-4.45) per one million inhabitants (MIH) with 7/44 countries having less than one SU per one MIH. The estimated mean annual number of IVTs was 21.03 (95% CI: 15.63-26.43) per 100,000 and 17.14% (95% CI: 12.98-21.30) of the AIIS in 2019, with highest country rates at 79.19 and 52.66%, respectively, and 15 countries delivering less than 10 IVT per 100,000. The estimated mean annual number of EVTs in 2019 was 7.87 (95% CI: 5.96-9.77) per 100,000 and 6.91% (95% CI: 5.15-8.67) of AIIS, with 11 countries delivering less than 1.5 EVT per 100,000. Rates of SUs, IVT and EVT were stable in 2020. There was an increase in mean rates of SUs, IVT and EVT compared to similar data from 2016.Although there was an increase in reperfusion treatment rates in many countries between 2016 and 2019, this was halted in 2020. There are persistent major inequalities in acute stroke treatment in the European region. Tailored strategies directed to the most vulnerable regions should be prioritised.

Background and Purpose —The pathogenesis of cervical artery dissection (CAD) remains unknown in most cases. Hyperhomocyst(e)inemia [hyperH(e)], an independent risk factor for cerebrovascular disease, induces damage in endothelial cells in animal cell culture. Consecutive patients with CAD and age-matched control subjects have been studied by serum levels of homocyst(e)ine and the genotype of 5,10-methylenetetrahydrofolate reductase ( MTHFR ). Methods —Twenty-six patients with CAD, admitted to our Stroke Unit (15 men and 11 women; 16 vertebral arteries, 10 internal carotid arteries), were compared with age-matched control subjects. All patients underwent duplex ultrasound, MR angiography, and/or conventional angiography. Results —Mean plasma homocyst(e)ine level was 17.88 μmol/L (range 5.95 to 40.0 μmol/L) for patients with CAD and 6.0±0.99 μmol/L for controls ( P &lt;0.001). The genetic analysis for the thermolabile form of MTHFR in CAD patients showed heterozygosity in 54% and homozygosity in 27%; comparable figures for controls were 40% ( P =0.4) and 10% ( P =0.1), respectively. Conclusions —Mild hyperH(e) might represent a risk factor for cervical artery dissection. The MTHFR mutation is not significantly associated with CAD. An interaction between different genetic and environmental factors probably takes place in the cascade of pathogenetic events leading to arterial wall damage.

&lt;i&gt;Background:&lt;/i&gt; The clinical outcome in patients with stroke associated with internal carotid artery (ICA) occlusion is poor, although a minority may recover without dependency. The purposes of this study were (1) to assess the predictive factors of adverse outcome in patients with stroke associated with an occlusion of the ICA and (2) to evaluate the rate of spontaneous recanalization of an occluded ICA. &lt;i&gt;Methods:&lt;/i&gt; A total of 177 consecutive patients with first-ever ischemic stroke associated with ICA occlusion were prospectively examined from the Perugia Stroke Registry. Mean age was 71.4 ± 14.3 years; 53% were males. Multiple regression models were used to analyze predictors of mortality, dependency and ipsilateral stroke recurrence. &lt;i&gt;Results:&lt;/i&gt; The most probable cause of occlusion was atherosclerosis in 65%, cardioembolism in 22%, dissection in 9% and other causes in 4%. Thirty percent of the patients died within 30 days. After a mean follow-up of 420 days (range 1–1,970 days), 45% of the patients had died and 75% had died or were disabled. Another 6% of the patients had a recurrent stroke ipsilateral to the occluded carotid artery. Age was the only predictor of 30-day mortality (77.7 ± 9.7 vs. 68.7 ± 15.2 years; p = 0.03) and of long-term mortality or disability (p &lt; 0.003). Hypertension (OR 0.42; 95% CI 0.17–1.00; p = 0.05) was associated with a better outcome within 30 days from stroke onset. Previous ipsilateral transient ischemic attack (OR 0.24; 95% CI 0.06–0.89; p = 0.03) and hyperlipidemia (OR 0.38; 95% CI 0.15–0.99; p = 0.049) were predictors of a better outcome with respect to long-term mortality or disability. No predictors of ipsilateral stroke recurrence were found. One hundred and five out of 177 patients had adequate follow-up ultrasound data. After a mean follow-up of 1.8 years, 10 patients had recanalization of the occluded ICA (2/71 atherosclerosis, 3/19 cardioembolism and 5/15 dissection). &lt;i&gt;Conclusions:&lt;/i&gt; After a mean follow-up of 1.2 years, 45% of the patients with stroke associated with ICA occlusion had died, while 75% had died or were functionally dependent. The presence of either previous ipsilateral transient ischemic attack, hypertension or hyperlipidemia was associated with a favorable outcome. Recanalization of an occluded ICA occurred in a minority of patients and it was associated with cardioembolism and with arterial dissection.

Background Cervical artery dissection (CAD) is a frequent cause of ischemic stroke, and occasionally death, in young adults. Several lines of evidence suggest a genetic predisposition to CAD. However, previous genetic studies have been inconclusive mainly due to insufficient numbers of patients. Our hypothesis is that CAD is a multifactorial disease caused by yet largely unidentified genetic variants and environmental factors, which may interact. Our aim is to identify genetic variants associated with an increased risk of CAD and possibly gene-environment interactions. Methods We organized a multinational European network, Cervical Artery Dissection and Ischemic Stroke Patients (CADISP), which aims at increasing our knowledge of the pathophysiological mechanisms of this disease in a large group of patients. Within this network, we are aiming to perform a de novo genetic association analysis using both a genome-wide and a candidate gene approach. For this purpose, DNA from approximately 1100 patients with CAD, and 2000 healthy controls is being collected. In addition, detailed clinical, laboratory, diagnostic, therapeutic, and outcome data are being collected from all participants applying predefined criteria and definitions in a standardized way. We are expecting to reach the above numbers of subjects by early 2009. Conclusions We present the strategy of a collaborative project searching for the genetic risk factors of CAD. The CADISP network will provide detailed and novel data on environmental risk factors and genetic susceptibility to CAD.

Perioperative stroke is an ischemic or hemorrhagic cerebrovascular accident that can arise intraoperatively or from 3 to 30 days after surgery. This relatively rare complication deserves attention because of its high mortality and serious disability, the latter of which can lead to prolonged hospital stay as well as discharge to long-term care facilities. The aim of this article was to review the literature on perioperative stroke in general surgery, excluding carotid and cardiac surgeries because these have already been thoroughly investigated in previous papers.A search strategy was designed to identify all relevant studies on perioperative stroke in the English language. This search was restricted to papers published up to December 5, 2011. Studies were initially identified from the Medline/PubMed database, EMBASE and the Cochrane Database using the search terms 'surgery', 'perioperative stroke', 'risk factors', 'anticoagulation treatment' and 'antiplatelet treatment'.The incidence of perioperative stroke among patients who undergo nonvascular surgery is reported to be about 0.08-0.7%. This depends on the type and complexity of the surgical procedure along with patient risk factors. The reported perioperative mortality is 18-26%. One of the main issues is the management of patients taking anticoagulant or antiplatelet drugs, as the risk of bleeding has to be counterbalanced with the risk of arterial thrombosis due to discontinuation. Additionally, the presence of symptomatic carotid stenosis should be taken into account in the risk evaluation.To date, current guidelines are incomplete regarding the management of patients with vascular disease undergoing nonvascular surgery. It is recommended to stop oral anticoagulation approximately 5 days before major surgery to adequately allow the INR to normalize, and at the same time subcutaneous low-molecular-weight heparin or intravenous unfractionated heparin should be started. Regarding new anticoagulants, dabigatran does not need to be withheld for minor procedures. Currently, there are no clear recommendations on the use of rivaroxaban and apixaban. Data concerning the management of patients undergoing antiplatelet therapy are lacking. To date, neurologists discourage the perioperative withdrawal of aspirin (acetylsalicylic acid, ASA) especially in patients in secondary prevention. The 'Antiplatelet Agents in the Perioperative Management of Patients Trial' is ongoing to assess the safety and determine the optimal use of ASA in the perioperative management of patients undergoing general and abdominal surgery. In the meantime an individualized, accurate, multidisciplinary (surgical, neurological, cardiological and anesthesiological) risk/benefit assessment remains the best basis for treatment decision.

In 2008, the recently founded European Stroke Organisation published its guidelines for the management of ischemic stroke and transient ischemic attack. This highly cited document was translated in several languages and was updated in 2009. Since then, the European Stroke Organisation has published guidelines for the management of intracranial aneurysms and subarachnoidal hemorrhage, for the establishment of stroke units and stroke centers, and recently for the management of intracerebral hemorrhage. In recent years, the methodology for the development of guidelines has evolved significantly. To keep pace with this progress and driven by the strong determination of the European Stroke Organisation to further promote stroke management, education, and research, the European Stroke Organisation decided to delineate a detailed standard operating procedure for its guidelines. There are two important cornerstones in this standard operating procedure: The first is the implementation of the Grading of Recommendations Assessment, Development, and Evaluation methodology for the development of its Guideline Documents. The second one is the decision of the European Stroke Organisation to move from the classical model of a single Guideline Document about a major topic (e.g. management of ischemic stroke) to focused modules (i.e. subdivisions of a major topic). This will enable the European Stroke Organisation to react faster when new developments in a specific stroke field occur and update its recommendations on the related module rather swiftly; with the previous approach of a single large Guideline Document, its entire revision had to be completed before an updated publication, delaying the production of up-to-date guidelines. After discussion within the European Stroke Organisation Guidelines Committee and significant input from European Stroke Organisation members as well as methodologists and analysts, this document presents the official standard operating procedure for the development of the Guideline Documents of the European Stroke Organisation.

Specific guidelines for management of cerebrovascular risk in women are currently lacking. This study aims to provide a consensus expert opinion to help make clinical decisions in women with carotid stenosis.Proposals for the use of carotid endarterectomy (CEA), carotid stenting (CAS), and medical therapy for stroke prevention in women with carotid stenosis were provided by a group of 9 international experts with consensus method.Symptomatic women with severe carotid stenosis can be managed by CEA provided that the perioperative risk of the operators is low (<4%). Periprocedural stroke risks may be increased in symptomatic women if revascularization is performed by CAS; however, the choice of CAS vs CEA can be tailored in subgroups best fit for each procedure (e.g., women with restenosis or severe coronary disease, best suited for CAS; women with tortuous vessels or old age, best suited for CEA). There is currently limited evidence to consider medical therapy alone as the best choice for women with neurologically severe asymptomatic carotid stenosis, who should be best managed within randomized trials including a medical arm. Medical management and cardiovascular risk factor control must be implemented in all women with carotid stenosis in periprocedural period and lifelong regardless of whether or not intervention is planned.The suggestions provided in this article may constitute a decision-making basis for planning treatment of carotid stenosis in women. Most recommendations are of limited strength; however, it is unlikely that new robust data will emerge soon to induce relevant changes.

To study the prognostic importance of Horner syndrome (HS) in patients with internal carotid artery dissection (ICAD) or vertebral artery dissection (VAD).In this observational study, characteristics and outcome of patients with ICAD or VAD from the CADISP (Cervical Artery Dissection and Ischemic Stroke Patients) database were analyzed. The presence of HS was systematically assessed using a standardized questionnaire. Patients with HS (HS+) were compared with HS- patients. Crude odds ratios (ORs) with 95% confidence intervals and ORs adjusted for age, sex, center, arterial occlusion, bilateral dissection, stroke severity, and type of antithrombotic treatment were calculated.We analyzed 765 patients (n = 496 with ICAD, n = 269 with VAD, n = 303 prospective, n = 462 retrospective). HS was present in 191 (38.5%) of the patients with ICAD and 36 (13.4%) of the patients with VAD (p < 0.001). HS+ ICAD patients presented less often with stroke or TIA (p < 0.001), less often had bilateral (p = 0.019) or occlusive (p = 0.001) dissections, and had fewer severe strokes (p = 0.041) than HS- ICAD patients. HS+ ICAD patients had a better functional 3-month outcome than those without HS (ORcrude = 4.0 [2.4-6.7]), and also after adjustment for outcome-relevant covariates (ORadjusted = 2.0 [1.1-4.0]). HS+ ICAD patients were less likely to have new strokes than HS- ICAD patients (p = 0.039). HS+ VAD patients more often had vessel occlusion (p = 0.014) than HS- patients but did not differ in any of the other aforementioned variables.In patients with ICAD, HS is an easily assessable marker that might indicate a more benign clinical course. HS had no prognostic meaning in patients with VAD.

Background Recent randomized controlled clinical trials have provided solid evidence that mechanical thrombectomy ( MT ) coupled with best medical therapy ( BMT ) improve functional outcomes of acute ischemic stroke patients with large vessel occlusion compared with BMT alone. However, they provided inconclusive evidence on the benefit of MT on mortality. Methods and Results We evaluated the association of MT + BMT compared with BMT with the risk of 3‐month mortality using aggregate data from all available randomized controlled clinical trials. We also sought to identify potential predictors on the mortality risk and performed univariate meta‐regression analyses. Our literature search identified 11 eligible randomized controlled clinical trials, including a total of 2460 patients. The pooled rates of 3‐month mortality were 15% (95% CI :12%–19%) and 19% (95% CI :16%–23%), respectively, in the MT + BMT and BMT groups. In the overall analysis MT + BMT was associated with a significantly lower risk for 3‐month mortality compared with BMT (risk ratio=0.83, 95% CI:0.69–0.99; P =0.04), without heterogeneity across included studies (I 2 =3%, P for Cochran Q=0.41). No evidence of publication bias was present in funnel plot inspection and Egger statistical test ( P =0.762). In meta‐regression analyses no moderating effect on the aforementioned association was detected with patient age ( P =0.254), sex ( P =0.702), admission systolic blood pressure ( P =0.601), admission glucose ( P =0.277), onset‐to‐groin puncture time ( P =0.985), administration of intravenous alteplase before MT ( P =0.804), MT under general anesthesia ( P =0.735), and successful reperfusion following MT ( P =0.663). Conclusions Our meta‐analysis provides evidence that MT + BMT reduces the risk of 3‐month mortality compared with BMT alone. This association appears not to be moderated by individual patient or procedural characteristics.

To investigate whether the correlation of age and sex with the risk of recurrence and death seen in patients with previous ischemic stroke is also evident in patients with embolic stroke of undetermined source (ESUS).We pooled datasets of 11 stroke registries from Europe and America. ESUS was defined according to the Cryptogenic Stroke/ESUS International Working Group. We performed Cox regression and Kaplan-Meier product limit analyses to investigate whether age (<60, 60-80, >80 years) and sex were independently associated with the risk for ischemic stroke/TIA recurrence or death.Ischemic stroke/TIA recurrences and deaths per 100 patient-years were 2.46 and 1.01 in patients <60 years old, 5.76 and 5.23 in patients 60 to 80 years old, 7.88 and 11.58 in those >80 years old, 3.53 and 3.48 in women, and 4.49 and 3.98 in men, respectively. Female sex was not associated with increased risk for recurrent ischemic stroke/TIA (hazard ratio [HR] 1.15, 95% confidence interval [CI] 0.84-1.58) or death (HR 1.35, 95% CI 0.97-1.86). Compared with the group <60 years old, the 60- to 80- and >80-year groups had higher 10-year cumulative probability of recurrent ischemic stroke/TIA (14.0%, 47.9%, and 37.0%, respectively, p < 0.001) and death (6.4%, 40.6%, and 100%, respectively, p < 0.001) and higher risk for recurrent ischemic stroke/TIA (HR 1.90, 95% CI 1.21-2.98 and HR 2.71, 95% CI 1.57-4.70, respectively) and death (HR 4.43, 95% CI 2.32-8.44 and HR 8.01, 95% CI 3.98-16.10, respectively).Age, but not sex, is a strong predictor of stroke recurrence and death in ESUS. The risk is ≈3- and 8-fold higher in patients >80 years compared with those <60 years of age, respectively. The age distribution in the ongoing ESUS trials may potentially influence their power to detect a significant treatment association.

Background Venous thromboembolism (VTE) including deep vein thrombosis (DVT) and pulmonary embolism is a frequent complication in immobile patients with acute ischemic stroke. This guideline document presents the European Stroke Organisation guidelines for the prophylaxis of VTE in immobile patients with acute ischaemic stroke. Guidelines for haemorrhagic stroke have already been published. Methods A multidisciplinary group identified related questions and developed its recommendations based on evidence from randomised controlled trials using the Grading of Recommendations Assessment, Development, and Evaluation approach. This guideline document was reviewed within the European Stroke Organisation and externally and was approved by the European Stroke Organisation Guidelines Committee and the European Stroke Organisation Executive Committee. Results We found mainly moderate quality evidence comprising randomised controlled trials and systematic reviews evaluating graduated compression stockings (GCS), intermittent pneumatic compression (IPC) and prophylactic anticoagulation with unfractionated (UFH) and low molecular weight heparins (LMWH) and heparinoids, but no randomised trials evaluating neuromuscular electrical stimulation (NES). We recommend that clinicians should use IPC in immobile patients, but that they should not use GCS. Prophylactic anticoagulation with UFH (5000U ×2, or ×3 daily) or LMWH or heparinoid should be considered in immobile patients with ischaemic stroke in whom the benefits of reducing the risk of VTE is high enough to offset the increased risks of intracranial and extracranial bleeding associated with their use. Where a judgement has been made that prophylactic anticoagulation is indicated LMWH or heparinoid should be considered instead of UFH because of its greater reduction in risk of DVT, the greater convenience, reduced staff costs and patient comfort associated single vs. multiple daily injections but these advantages should be weighed against the higher risk of extracranial bleeding, higher drug costs and risks in elderly patients with poor renal function associated with LMWH and heparinoids. Conclusions IPC, UFH or LMWH and heparinoids can reduce the risk of VTE in immobile patients with acute ischaemic stroke but further research is required to test whether NES is effective. The strongest evidence is for IPC. Better methods are needed to help stratify patients in the first few weeks after stroke onset, by their risk of VTE and their risk of bleeding on anticoagulants.

After the five positive randomized controlled trials showing the benefit of mechanical thrombectomy (MT) in the management of acute ischemic stroke (AIS) with emergent large vessel occlusion (ELVO), a multisociety meeting was organized during the 16th Congress of the World Federation of Interventional and Therapeutic Neuroradiology (WFITN), October 2015, Gold Coast (Australia). This meeting was dedicated to the training of physicians performing MT, and recommendations were published thereafter in multiple scientific journals.1 The same group of scientific societies decided to organize a similar meeting during the 17th WFITN Congress, October 2017, Budapest (Hungary). This multisociety meeting was dedicated to standards of practice in acute ischemic stroke intervention (AISI), aiming for a consensus on the minimum requirements for centers providing such treatment. In an ideal situation, all patients would be treated at a center offering a full spectrum of neuroendovascular care (a level 1 center). However, for geographical reasons, some patients are unable to reach such a center in a reasonable period of time. With this in mind, the group paid special attention to define recommendations on the prerequisites of organizing stroke centers providing MT for AIS, but not for other neurovascular diseases (a level 2 center). Finally, some centers will have a stroke unit and offer intravenous thrombolysis, but not any endovascular stroke therapy (a level 3 center). Together, these level 1, 2, and 3 centers form a complete stroke system of care. The requirements for these centers are summarized in table 1. View this table: Table 1 General summary of capabilities of level 1, 2, and 3 centers Due to the relatively short time elapsed since the evidence in favor of MT has been published, some organizational aspects still require scientific validation. However, considering the extremely fast growth of such activities around the world, the multisociety group considered it timely and rational to set-up recommendations and a framework for …

Current recommendations advocate that pretreatment with intravenous thrombolysis (IVT) should first be offered to all eligible patients with emergent large vessel occlusion (ELVO) before an endovascular thrombectomy (ET) procedure. However, there are observational data that question the safety and efficacy of IVT pretreatment in patients with ELVO.We performed a meta-analysis of the included subgroups from ET randomized controlled trials (RCTs) to evaluate the comparative efficacy between direct ET without IVT pretreatment and bridging therapy (IVT and ET) in patients with ELVO.We included a total of seven RCTs, including 1764 patients with ELVO (52.8% men). Patients receiving bridging therapy (IVT followed by ET) had lower rates (p = 0.041) of 90-day death/severe dependency (modified Rankin Scale-score of 5-6; 19.0%, 95% CI: 14.1-25.1%) compared with patients receiving only ET (31.0%, 95% CI: 21.2-42.9%). Moreover, patients receiving IVT and ET had a nonsignificant (p = 0.389) trend towards higher 90-day functional independence rates (51.4%, 95% CI: 42.5-60.1%) compared with patients undergoing only ET (41.7%, 95% CI: 24.1-61.7%). Finally, shift-analysis uncovered a nonsignificant trend towards functional improvement at 90 days for bridging therapy over ET (cOR = 1.28, 95% CI: 0.91-1.89; p = 0.155). It should be noted that patients included in the present meta-analysis were not randomized to receive IVT, and thus the two groups (bridging therapy versus ET monotherapy) may differ in terms of baseline characteristics and, in particular, in terms of onset to groin puncture time and thus the risk of confounding bias cannot be ruled out.Despite the limitations and the risk of confounding bias, our findings contradict the recent notion regarding potential equality between ET and bridging therapy in ELVO patients and suggest that IVT and ET are complementary therapies that should be pursued in a parallel and noncompeting fashion.

Background and purpose: Early neurological deterioration (END) after stroke onset may predict severe outcomes. Estimated rates of END after intravenous thrombolysis among small patient samples have been reported up to 29.8%. We studied the incidence and factors associated with END among patients following intravenous thrombolysis. Methods: We analyzed SITS-International Stroke Thrombolysis registry patients with known outcomes enrolled in 2010 to 2017. END was defined as an increase in National Institutes of Health Stroke Scale score ≥4 or death within 24 hours from baseline National Institutes of Health Stroke Scale. We determined the incidence of END and used logistic regression models to inspect its associated factors. We adjusted for variables found significant in univariate analyses ( P &lt;0.05). Main outcomes were incidence of END, associated predictors of END, ordinal day-90 mRS, and day-90 mortality. Results: We excluded 53 539 patients and included 50 726 patients. The incidence of END was 3415/50 726 (6.7% [95% CI, 6.5%–7.0%]). Factors independently associated with END on multivariate analysis were intracerebral hemorrhage (OR, 3.23 [95% CI, 2.96–3.54], P &lt;0.001), large vessel disease (LVD) with carotid stenosis (OR, 2.97 [95% CI, 2.45–3.61], P &lt;0.001), other LVD (OR, 2.41 [95% CI, 2.03–2.88], P &lt;0.001), and ischemic stroke versus transient ischemic attack (TIA)/stroke mimics (OR, 16.14 [95% CI, 3.99–65.3], P &lt;0.001). END was associated with worse outcome on ordinal mRS: adjusted OR 2.48 (95% CI, 2.39–2.57, P &lt;0.001) by day-90 compared with no END. The adjusted OR for day-90 mortality was 9.70 (95% CI, 8.36–11.26, P &lt;0.001). Conclusions: The routinely observed rate of END reflected by real-world data is low, but END greatly increases risk of disability and mortality. Readily identifiable factors predict END and may help with understanding causal mechanisms to assist prevention of END.

The rate of stroke-related death and disability is four times higher in low- and middle-income countries (LMICs) than in high-income countries (HICs), yet stroke units exist in only 18% of LMICs, compared with 91% of HICs. In order to ensure universal and equitable access to timely, guideline-recommended stroke care, multidisciplinary stroke-ready hospitals with coordinated teams of healthcare professionals and appropriate facilities are essential.Established in 2016, the Angels Initiative is an international, not-for-profit, public-private partnership. It is run in collaboration with the World Stroke Organization, European Stroke Organisation, and regional and national stroke societies in over 50 countries. The Angels Initiative aims to increase the global number of stroke-ready hospitals and to optimize the quality of existing stroke units. It does this through the work of dedicated consultants, who help to standardize care procedures and build coordinated, informed communities of stroke professionals. Angels consultants also establish quality monitoring frameworks using online audit platforms such as the Registry of Stroke Care Quality (RES-Q), which forms the basis of the Angels award system (gold/platinum/diamond) for all stroke-ready hospitals across the world.The Angels Initiative has supported over 1700 hospitals (>1000 in LMICs) that did not previously treat stroke patients to become "stroke ready." Since its inception in 2016, the Angels Initiative has impacted the health outcomes of an estimated 7.46 million stroke patients globally (including an estimated 4.68 million patients in LMICs). The Angels Initiative has increased the number of stroke-ready hospitals in many countries (e.g. in South Africa: 5 stroke-ready hospitals in 2015 vs 185 in 2021), reduced "door to treatment time" (e.g. in Egypt: 50% reduction vs baseline), and increased quality monitoring substantially.The focus of the work of the Angels Initiative has now expanded from the hyperacute phase of stroke treatment to the pre-hospital setting, as well as to the early post-acute setting. A continued and coordinated global effort is needed to achieve the target of the Angels Initiative of >10,000 stroke-ready hospitals by 2030, and >7500 of these in LMICs.

BackgroundThe safety and efficacy of oral anticoagulation for prevention of major adverse cardiovascular events in people with atrial fibrillation and spontaneous intracranial haemorrhage are uncertain. We planned to estimate the effects of starting versus avoiding oral anticoagulation in people with spontaneous intracranial haemorrhage and atrial fibrillation.MethodsIn this prospective meta-analysis, we searched bibliographic databases and trial registries using the strategies of a Cochrane systematic review (CD012144) on June 23, 2023. We included clinical trials if they were registered, randomised, and included participants with spontaneous intracranial haemorrhage and atrial fibrillation who were assigned to either start long-term use of any oral anticoagulant agent or avoid oral anticoagulation (ie, placebo, open control, another antithrombotic agent, or another intervention for the prevention of major adverse cardiovascular events). We assessed eligible trials using the Cochrane Risk of Bias tool. We sought data for individual participants who had not opted out of data sharing from chief investigators of completed trials, pending completion of ongoing trials in 2028. The primary outcome was any stroke or cardiovascular death. We used individual participant data to construct a Cox regression model of the time to the first occurrence of outcome events during follow-up in the intention-to-treat dataset supplied by each trial, followed by meta-analysis using a fixed-effect inverse-variance model to generate a pooled estimate of the hazard ratio (HR) with 95% CI. This study is registered with PROSPERO, CRD42021246133.FindingsWe identified four eligible trials; three were restricted to participants with atrial fibrillation and intracranial haemorrhage (SoSTART [NCT03153150], with 203 participants) or intracerebral haemorrhage (APACHE-AF [NCT02565693], with 101 participants, and NASPAF-ICH [NCT02998905], with 30 participants), and one included a subgroup of participants with previous intracranial haemorrhage (ELDERCARE-AF [NCT02801669], with 80 participants). After excluding two participants who opted out of data sharing, we included 412 participants (310 [75%] aged 75 years or older, 249 [60%] with CHA2DS2-VASc score ≤4, and 163 [40%] with CHA2DS2-VASc score >4). The intervention was a direct oral anticoagulant in 209 (99%) of 212 participants who were assigned to start oral anticoagulation, and the comparator was antiplatelet monotherapy in 67 (33%) of 200 participants assigned to avoid oral anticoagulation. The primary outcome of any stroke or cardiovascular death occurred in 29 (14%) of 212 participants who started oral anticoagulation versus 43 (22%) of 200 who avoided oral anticoagulation (pooled HR 0·68 [95% CI 0·42–1·10]; I2=0%). Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events (nine [4%] of 212 vs 38 [19%] of 200; pooled HR 0·27 [95% CI 0·13–0·56]; I2=0%). There was no significant increase in haemorrhagic major adverse cardiovascular events (15 [7%] of 212 vs nine [5%] of 200; pooled HR 1·80 [95% CI 0·77–4·21]; I2=0%), death from any cause (38 [18%] of 212 vs 29 [15%] of 200; 1·29 [0·78–2·11]; I2=50%), or death or dependence after 1 year (78 [53%] of 147 vs 74 [51%] of 145; pooled odds ratio 1·12 [95% CI 0·70–1·79]; I2=0%).InterpretationFor people with atrial fibrillation and intracranial haemorrhage, oral anticoagulation had uncertain effects on the risk of any stroke or cardiovascular death (both overall and in subgroups), haemorrhagic major adverse cardiovascular events, and functional outcome. Oral anticoagulation reduced the risk of ischaemic major adverse cardiovascular events, which can inform clinical practice. These findings should encourage recruitment to, and completion of, ongoing trials.FundingBritish Heart Foundation.

BACKGROUND: Endovascular treatment (EVT) for acute ischemic stroke (AIS) patients presenting with National Institutes of Health Stroke Scale score of 0 to 5 is common in clinical practice but has not yet been proven safe and effective. Our objective is to assess whether EVT on top of best medical treatment (BMT) in AIS patients with large-vessel occlusion of the anterior circulation presenting with mild symptoms is beneficial compared with BMT. METHODS: We searched MEDLINE, SCOPUS, and reference lists of retrieved articles published until December 28, 2022. A systematic literature search was conducted to identify clinical trials or observational cohort studies evaluating patients with AIS due to anterior circulation large-vessel occlusion and admission National Institutes of Health Stroke Scale score ≤5 treated with EVT versus BMT alone. The primary outcome was excellent functional outcome (modified Rankin Scale score 0–1) at 3 months. The protocol had been registered before data collection (PROSPERO). RESULTS: Eleven observational eligible studies were included in the meta-analysis, comprising a total of 2019 AIS patients with National Institutes of Health Stroke Scale score ≤5 treated with EVT versus 3171 patients treated with BMT. EVT was not associated with excellent functional outcome (risk ratio, 1.10 [95% CI, 0.93–1.31]). When stratified for different study design (per-protocol versus intention-to-treat), there were no significant subgroup differences. EVT was not associated with good functional outcome (modified Rankin Scale score 0–2; risk ratio, 1.01 [95% CI, 0.89–1.16]) or reduced disability at 3 months (common odds ratio, 0.92 [95% CI, 0.60–1.41]). Symptomatic intracranial hemorrhage was more common in the patients receiving EVT (risk ratio, 3.53 [95% CI, 2.35–5.31]). No correlation was found between EVT and mortality at 3 months (risk ratio, 1.34 [95% CI, 0.83–2.18]). The same overall associations were confirmed in the sensitivity analysis of studies that performed propensity score matching. CONCLUSIONS: EVT appears equivalent to BMT for patients with anterior circulation large-vessel occlusion AIS with low baseline National Institutes of Health Stroke Scale, despite the increased risk for symptomatic intracranial hemorrhage. REGISTRATION: URL: https://www.crd.york.ac.uk/PROSPERO/ ; Unique identifier: CRD42022334417.

Phase II trials of asundexian were underpowered to detect important differences in bleeding. The goal of this study was to obtain best estimates of effects of asundexian vs active control/placebo on major and clinically relevant nonmajor (CRNM) and all bleeding, describe most common sites of bleeding, and explore association between asundexian exposure and bleeding. We performed a pooled analysis of 3 phase II trials of asundexian in patients with atrial fibrillation (AF), recent acute myocardial infarction (AMI), or stroke. Bleeding was defined according to the International Society on Thrombosis and Hemostasis (ISTH) criteria. In patients with AF (n = 755), both asundexian 20 mg and 50 mg once daily vs apixaban had fewer major/CRNM events (3 of 249; incidence rate [IR] per 100 patient-years 5.47 vs 1 of 254 [IR: not calculable] vs 6 of 250 [IR: 11.10]) and all bleeding (12 of 249 [IR: 22.26] vs 10 of 254 [IR: 18.21] vs 26 of 250 [IR: 50.56]). In patients with recent AMI or stroke (n = 3,409), asundexian 10 mg, 20 mg, and 50 mg once daily compared with placebo had similar rates of major/CRNM events (44 of 840 [IR: 7.55] vs 42 of 843 [IR: 7.04] vs 56 of 845 [IR: 9.63] vs 41 of 851 [IR: 6.99]) and all bleeding (107 of 840 [IR: 19.57] vs 123 of 843 [IR: 22.45] vs 130 of 845 [IR: 24.19] vs 129 of 851 [IR: 23.84]). Most common sites of major/CRNM bleeding with asundexian were gastrointestinal, respiratory, urogenital, and skin. There was no significant association between asundexian exposure and major/CRNM bleeding. Analyses of phase II trials involving >500 bleeds highlight the potential for improved safety of asundexian compared with apixaban and similar safety compared with placebo. Further evidence on the efficacy of asundexian awaits the results of ongoing phase III trials.

<h2>Summary</h2> Atrial fibrillation is one of the most common cardiac arrhythmias and is a major cause of ischaemic stroke. Recent findings indicate the importance of atrial fibrillation burden (device-detected, subclinical, or paroxysmal and persistent or permanent) and whether atrial fibrillation was known before stroke onset or diagnosed after stroke for the risk of recurrence. Secondary prevention in patients with atrial fibrillation and stroke aims to reduce the risk of recurrent ischaemic stroke. Findings from randomised controlled trials assessing the optimal timing to introduce direct oral anticoagulant therapy after a stroke show that early start (ie, within 48 h for minor to moderate strokes and within 4–5 days for large strokes) seems safe and could reduce the risk of early recurrence. Other promising developments regarding early rhythm control, left atrial appendage occlusion, and novel factor XI inhibitor oral anticoagulants suggest that these therapies have the potential to further reduce the risk of stroke. Secondary prevention strategies in patients with atrial fibrillation who have a stroke despite oral anticoagulation therapy is an unmet medical need. Research advances suggest a heterogeneous spectrum of causes, and ongoing trials are investigating new approaches for secondary prevention in this vulnerable patient group. In patients with atrial fibrillation and a history of intracerebral haemorrhage, the latest data from randomised controlled trials on stroke prevention shows that oral anticoagulation reduces the risk of ischaemic stroke but more data are needed to define the safety profile.

A history of a minor precipitating event is frequently elicited in patients with a spontaneous dissection of the carotid or vertebral artery. Other precipitating events associated with hyperextension or rotation of the neck include practicing yoga, painting a ceiling, coughing, vomiting, sneezing, the receipt of anesthesia, and the act of resuscitation. Chiropractic manipulation of the neck has been associated with carotid artery dissection and, particularly, vertebral artery dissection. Another risk factor for spontaneous dissections seems to be a recent history of a respiratory tract infection. The possibility of an infectious trigger is supported by the finding of a seasonal variation in the incidence of spontaneous dissections, with a peak incidence in fall. A potential link with common risk factors for vascular disease, such as tobacco use, hypertension, and the use of oral contraceptives, has not been systematically evaluated, but atherosclerosis appears to be distinctly uncommon in patients with a dissection of the carotid or vertebral arteries. In conclusion, although any hypotheses on the pathogenic mechanisms linking environmental factors and dissection remain speculative at present, we believe that these hypotheses may contribute to better define the spectrum of pathogenic conditions predisposing a cervical artery to dissection and provide arguments to better investigate the single or combined effect of such susceptibility factors in future studies.

&lt;i&gt;Background:&lt;/i&gt; Intravenous (i.v.) thrombolysis with rt-PA within 3 h from symptom onset is the only approved treatment of pharmacological revascularization in acute ischemic stroke. However, little information exists on its use in elderly patients, in particular those aged &gt;80 years, who at present are excluded from treatment. &lt;i&gt;Methods:&lt;/i&gt; In a multicenter Italian study on i.v. thrombolysis, patients aged &gt;80 years (n = 41) were compared with those aged ≤80 years (n = 207) regarding the percentage of symptomatic (nonfatal and fatal) intracerebral hemorrhage (SICH), favorable 3-month functional outcome (modified Rankin Scale score 0–2) and poor outcome (death or dependence, i.e. modified Rankin Scale score 3–5). &lt;i&gt;Results:&lt;/i&gt; The percentage of SICH (nonfatal and fatal) was comparable between older (2.4%, 2.4%) and younger (2.4%, 2.4%) patient groups (p = 1.0). At 3 months, favorable outcome occurred in 44% and dependence in 22% of the older, and respectively in 58.5 and in 30.9% of the younger patients (p = 0.897). Patients aged &gt;80 years had a higher mortality (34.1%) as compared to those aged ≤80 years (10.6%) (p &lt; 0.001). Baseline National Institute of Health Stroke Scale score was the only statistically significant predictor of both mortality (OR = 1.26; 95% CI = 1.07–1.50) and poor outcome (OR = 1.39; 95% CI = 1.14–1.68) in the &gt;80-year-old group. &lt;i&gt;Conclusions:&lt;/i&gt; Acute ischemic stroke patients aged &gt;80 years treated with i.v. rt-PA have a higher mortality than younger patients, but there are no differences for SICH nor for favorable outcome. Our data suggest that thrombolytic therapy should not be a priori denied for appropriately selected &gt;80-year-old patients but randomized controlled clinical trials are necessary before definite recommendations can be given.

Stroke has a greater effect on women than men owing to the fact that women have more stroke events and are less likely to recover. Age-specific stroke rates are higher in men; however, because of women's longer life expectancy and the much higher incidence of stroke at older ages, women have more stroke events than men overall. The aims of this prospective study in consecutive patients were to assess whether there are gender differences in stroke risk factors, treatment or outcome. Consecutive patients with ischemic stroke were included in this prospective study at four study centers. Disability was assessed using a modified Rankin Scale score (>or=3 indicating disabling stroke) in both genders at 90 days. Outcomes and risk factors in both genders were compared using the chi(2) test. Multiple logistic regression analysis was used to identify any independent predictors of outcome. A total of 1136 patients were included in this study; of these, 494 (46%) were female. Women were statistically older compared with men: 76.02 (+/- 12.93) and 72.68 (+/- 13.27) median years of age, respectively. At admission, females had higher NIH Stroke Scale scores compared with males (9.4 [+/- 6.94] vs 7.6 [+/- 6.28] for men; p = 0.0018). Furthermore, females tended to have more cardioembolic strokes (153 [30%] vs 147 [23%] for men; p = 0.004). Males had lacunar and atherosclerotic strokes more often (146 [29%] vs 249 [39%] for men; p = 0.002, and 68 [13%] vs 123 [19%] for men; p = 0.01, respectively). The mean modified Rankin Scale score at 3 months was also significantly different between genders, at 2.5 (+/- 2.05) for women and 2.1 (+/- 2.02) for men (p = 0.003). However, at multivariate analysis, female gender was not an indicator for negative outcome. It was concluded that female gender was not an independent factor for negative outcome. In addition, both genders demonstrated different stroke pathophysiologies. These findings should be taken into account when diagnostic workup and treatment are being planned.

Stroke is the third most common cause of death in women and a major cause of disability. Stroke occurs in older age in women compared with men. High premenopausal estrogen concentrations in women are thought to be protective against stroke and cardiovascular disease. Estrogens are essential for normal reproductive function and they exert complex and diverse non reproductive actions on multiple tissues such as neuroprotective effects, vasodilatation, improved vascular reactivity, antithrombotic effects and lipid lowering effects. After menopause estrogen concentrations are depleted and in the past estrogen replacement therapy was considered as a potential protective agent against both cardiovascular disease and stroke. Although the use of hormone therapy was originally associated with a reduction in the risk of heart disease by about 50% in observational studies, the results regarding stroke have been less clear. In order to investigate the effect of hormone therapy on stroke risk, randomized controlled trials of cardio-and/or cerebrovascular- disease prevention in women with established heart disease have been designed. The Heart Estrogen- Progestin Replacement Study included stroke as secondary outcome. This study did not show any differences in myocardial infarction (MI) or coronary death (HR 0.99; 95%CI 0.80-1.22) and in stroke rate. In another study, the Women Estrogen Stroke Trial, 17 beta estradiol 1 mg/placebo was administered to women with previous ischemic stroke or transient ischaemic attack (TIA) having a mean age 71. No differences in stroke rate (RR 1.1; 95% CI 0.8-1.4) and in mortality rate (RR 1.2; 95% CI 0.8-1.8) were found, while a trend showing an increased rate of fatal strokes (RR 2.9; 95% CI 0.9-9.0) and for more severe non-fatal strokes (% patients with final National Institutes of Health Stroke Scale (NIHSS) 0-1: 19 % vs. 33%; p = 0.12) was observed. The Womens Health Initiative, a primary prevention study, where conjugated equine estrogen (CEE) plus medroxyprogesterone acetate/placebo was utilized, was stopped because of an excess in breast cancer and increased stroke rates (RR 1.4; 95% CI 1.1-1.8). Recently, a meta-analysis including 39,769 women participating in 28 trials has been published. Twelve studies were of secondary prevention and the overall stroke rate was 2%. In the hormone replacement therapy (HRT) arm there was a 29% increased rate of ischemic stroke (Number Needed to Harm, NNH:147). Furthermore, a 56% increased rate of death or dependency after stroke and a tendency of more fatal stroke were observed. Additionally, a higher stroke risk was reported in the first year of treatment. Conclusions: There seems to be no indication for hormone replacement therapy in the prevention of stroke in women. Further studies are needed to discover why estrogens have different effects on the heart and brain. Conventional risk-factors which could increase the risk of estrogen therapy need to be identified and as well as more restrictive inclusion and exclusion criteria such as coagulation parameters and intimal thickness should be adopted before new randomized trials are started. Keywords: Hormone replacement therapy, stroke, risk, menopause, clinical trials

ObjectivesIncreasing data suggest that statins can significantly decrease cardiovascular and cerebrovascular events due to a plaque stabilization effect. However, the benefit of statins in patients undergoing carotid angioplasty and stenting (CAS) for carotid stenosis is not well defined. The aim of this study was to investigate whether statins use was associated with decreased perioperative and late risks of stroke, mortality, and restenosis in patients undergoing CAS.MethodsAll patients undergoing CAS for primary carotid stenosis from 2004 to 2009 were reviewed. The independent association of statins and perioperative morbidity was assessed using multivariable analysis. Survival curves and Cox regression models were used to assess late morbidity and restenosis. Propensity score adjustment was employed.ResultsA total of 1083 consecutive CAS were performed (29% females, mean age 71.5 years; 24.7% symptomatic); 465 (43%) were on statins medication before treatment that was not discontinued at discharge. Statins use was associated with a reduction of perioperative stroke and death (odds ratio [OR] 0.327, 95% confidence interval [CI] 0.13-0.80, P = .016) according to multivariable analysis. Statins effect was more significant in reducing stroke and death in symptomatic patients (OR 0.13; P = .032) and in males (OR 0.27, P = .01). At 5 years, survival (87.2% vs 78.3%; P = .009) and ischemic stroke-free interval (88.9% vs 99.7%; P = .02) rates were higher in the statins group of patients. Adjusting for propensity score and covariates in Cox regression analyses, statins use was independently associated with reduced long-term mortality risk (HR 0.56, 95% CI 0.32-0.97; P = .039) and borderline associated with decreased late ischemic stroke risk (HR 0.14; 95% CI 0.018-1.08, P = .059). There was no effect on restenosis rates.ConclusionsThese data suggest that statins use is associated with decreased perioperative and late ischemic strokes risk and reduced mortality rates in patients undergoing CAS. Statins therapy should be considered part of the best medical treatment in current CAS practice. Increasing data suggest that statins can significantly decrease cardiovascular and cerebrovascular events due to a plaque stabilization effect. However, the benefit of statins in patients undergoing carotid angioplasty and stenting (CAS) for carotid stenosis is not well defined. The aim of this study was to investigate whether statins use was associated with decreased perioperative and late risks of stroke, mortality, and restenosis in patients undergoing CAS. All patients undergoing CAS for primary carotid stenosis from 2004 to 2009 were reviewed. The independent association of statins and perioperative morbidity was assessed using multivariable analysis. Survival curves and Cox regression models were used to assess late morbidity and restenosis. Propensity score adjustment was employed. A total of 1083 consecutive CAS were performed (29% females, mean age 71.5 years; 24.7% symptomatic); 465 (43%) were on statins medication before treatment that was not discontinued at discharge. Statins use was associated with a reduction of perioperative stroke and death (odds ratio [OR] 0.327, 95% confidence interval [CI] 0.13-0.80, P = .016) according to multivariable analysis. Statins effect was more significant in reducing stroke and death in symptomatic patients (OR 0.13; P = .032) and in males (OR 0.27, P = .01). At 5 years, survival (87.2% vs 78.3%; P = .009) and ischemic stroke-free interval (88.9% vs 99.7%; P = .02) rates were higher in the statins group of patients. Adjusting for propensity score and covariates in Cox regression analyses, statins use was independently associated with reduced long-term mortality risk (HR 0.56, 95% CI 0.32-0.97; P = .039) and borderline associated with decreased late ischemic stroke risk (HR 0.14; 95% CI 0.018-1.08, P = .059). There was no effect on restenosis rates. These data suggest that statins use is associated with decreased perioperative and late ischemic strokes risk and reduced mortality rates in patients undergoing CAS. Statins therapy should be considered part of the best medical treatment in current CAS practice.

The optimal management of patients with cryptogenic ischemic stroke found to have a patent foramen ovale (PFO) at diagnostic workup remains unclear. The aims of this observational multicenter study were to evaluate: (1) the risk of recurrent cerebrovascular events in patients with cryptogenic minor ischemic stroke or transient ischemic attack (TIA) and PFO who either underwent percutaneous PFO closure or received only medical treatment, and (2) the risk factors associated with recurrent events.Consecutive patients (aged 55 years or less) with first-ever cryptogenic minor ischemic stroke or TIA and PFO were recruited in 13 Italian hospitals between January 2006 and September 2007 and followed up for 2 years.238 patients were included in the study (mean age 42.2 ± 10.0 years; 118 males); 117 patients (49.2%) received only antithrombotic therapy while 121 patients underwent percutaneous PFO closure (50.8%). Stroke as the qualifying event was more common in the medical treatment group (p = 0.01). The presence of atrial septal aneurysm and evidence of 20 bubbles or more on transcranial Doppler were more common in the PFO closure group (p = 0.002 and 0.02). Eight patients (6.6%) experienced a nonfatal complication during PFO closure. At the 2-year follow-up, 17 recurrent events (TIA or stroke; 3.6% per year) were observed; 7 of these events (2.9% per year) occurred in the percutaneous PFO closure group and 10 events (4.2% per year) in the medical treatment group. The rate of recurrent stroke was 0.4% per year in patients who underwent percutaneous closure (1 event) and 3.4% per year in patients who received medical treatment (8 events). On multivariate analysis, percutaneous closure was not protective in preventing recurrent TIA or stroke (OR = 0.1, 95% CI = 0.02-1.5, p = 0.1), while it was barely protective in preventing recurrent stroke (OR = 0.1, 95% CI = 0.0-1.0, p = 0.053).The results of this observational, nonrandomized study suggest that PFO closure might be superior to medical therapy for the prevention of recurrent stroke. Periprocedural complications were the trade-off for this clinical benefit. Controlled randomized clinical trials comparing percutaneous closure with medical management are required.

Leukocytes are the first cells that arrive in the stroke region(s), and they increase in peripheral blood. The contribution or leukocytes in the early acute phase of cerebral ischemia has not yet been investigated.In consecutive first-ever acute ischemic stroke patients whose symptoms had started <12 hours earlier, we aimed to establish whether admission leukocyte count affects the short-term neurologic outcome, and whether there are differences between the various clinical syndromes of stroke. The National Institutes of Health Stroke Scale (NIHSS) was assessed at admission (NIHSS(0)) and after 72 hours (NIHSS(72)). Modified Rankin scale (mRS) scores were evaluated at discharge. The Spearman rank correlation was used for the correlation between leukocytes and outcome measures.Eight hundred and eleven patients were included (median age 77 years [range 68-82]; 418 [53%] were male; the median NIHSS(0) score was 7 [range 4-12], the median NIHSS(72) score was 6 [range 3-12], and the median mRS score was 2 [range 2-4]). The median leukocyte count at admission was 8100/mm(3) (range 6500-10300). Higher leukocyte levels predicted a worst clinical presentation and a poor functional outcome (NIHSS(0)P < .001; NIHSS(72)P < .001; mRS P < .001). The correlation between leukocyte count and outcome measures remained significant after multivariate analysis (NIHSS(0)P < .001; NIHSS(72)P < .001; mRS P < .008). Focusing on clinical syndromes, a higher leukocyte count predicted severe NIHSS(0) and NIHSS(72) scores in patients with total anterior cerebral stroke (P = .001), partial anterior cerebral stroke (P = .004), or posterior cerebral stroke (P = .026).An elevated leukocyte count in the acute phase of cerebral ischemia is a significant independent predictor of poor initial stroke severity, poor clinical outcome after 72 hours, and discharge disability. The involved underlying mechanism is still to determined.

The effect of obesity on the risk of intracerebral hemorrhage (ICH) may depend on the pathophysiology of vessel damage. To further address this issue, we investigated and quantified the correlations between obesity and obesity-related conditions in the causal pathways leading to ICH.A total of 777 ICH cases ≥ 55 years of age (287 lobar ICH and 490 deep ICH) were consecutively enrolled as part of the Multicenter Study on Cerebral Hemorrhage in Italy and compared with 2083 control subjects by a multivariate path analysis model. Separate analyses were conducted for deep and lobar ICH.Obesity was not independently associated with an increased risk of lobar ICH (odds ratio [OR], 0.76; 95% confidence interval [CI], 0.58-1.01) or deep ICH (OR, 1.18; 95% CI, 0.95-1.45) when compared with control subjects. The path analysis confirmed the nonsignificant total effect of obesity on the risk of lobar ICH (OR, 0.77; 95% CI, 0.58-1.02) but demonstrated a significant indirect effect on the risk of deep ICH (OR, 1.28; 95% CI, 1.03-1.57), mostly determined by hypertension (OR, 1.07; 95% CI, 1.04-1.11) and diabetes mellitus (OR, 1.04; 95% CI, 1.01-1.07). Obesity was also associated with an increased risk of deep ICH when compared with lobar ICH (OR, 1.62; 95% CI, 1.14-2.31).Obesity increases the risk of deep ICH, mostly through an indirect effect on hypertension and other intermediate obesity-related comorbidities, but has no major influence on the risk of lobar ICH. This supports the hypothesis of different, vessel-specific, biological mechanisms underlying the relationship between obesity and cerebral hemorrhage.

The caudate nucleus (CN) is composed of a head, body and tail. The head of the CN contributes to forming the floor of the lateral ventricle frontal horn. Moreover, the head, which is medially separated by the septum pellucidum extends beyond the anterior part of the thalamus, stroking the telencephalic cortex. The superior part of the head is covered by the knee of the corpus callosum, while the inferior part is below the thalamus and lenticular nucleus, which delimits the internal capsule. CN strokes are classified into hemorrhagic and ischemic. The clinical presentation of CN hemorrhage is often characterized by a clinical presentation mimicking subarachnoid hemorrhage, while clinical features of both ischemic and hemorrhagic strokes included behavioral abnormalities dysarthria, movement disorders, language disturbances and memory loss. Most studies to date that have examined vascular CN pathologies have evidenced good outcomes.

Summary In patients with acute stroke and atrial fibrillation (AF), the risk of early recurrence has been reported to range between 0.1% and 1.3% per day. Anticoagulants are the most effective therapy for the prevention of recurrent ischaemic stroke in these patients, but randomised clinical trials have failed to produce any evidence supporting the administration of heparin within 48 hours from stroke onset as it has been associated with a non-significant reduction in the recurrence of ischaemic stroke, no substantial reduction in death and disability, and an increase in intracranial bleeding. As early haemorrhagic transformation is a major concern in the acute phase of stroke patients with AF, determining the optimal time to start anticoagulant therapy is essential. This review which focuses on the epidemiology of recurrent ischaemic stroke and haemorrhagic transformation in patients with acute ischaemic stroke and AF, proposes a model for decision making on optimal timing for initiating anticoagulation, based on currently available evidence.

In a cohort of patients diagnosed with cervical artery dissection (CeAD), to determine the proportion of patients aged ≥60 years and compare the frequency of characteristics (presenting symptoms, risk factors, and outcome) in patients aged <60 vs ≥60 years.We combined data from 3 large cohorts of consecutive patients diagnosed with CeAD (i.e., Cervical Artery Dissection and Ischemic Stroke Patients-Plus consortium). We dichotomized cases into 2 groups, age ≥60 and <60 years, and compared clinical characteristics, risk factors, vascular features, and 3-month outcome between the groups. First, we performed a combined analysis of pooled individual patient data. Secondary analyses were done within each cohort and across cohorts. Crude and adjusted odds ratios (OR [95% confidence interval]) were calculated.Among 2,391 patients diagnosed with CeAD, we identified 177 patients (7.4%) aged ≥60 years. In this age group, cervical pain (ORadjusted 0.47 [0.33-0.66]), headache (ORadjusted 0.58 [0.42-0.79]), mechanical trigger events (ORadjusted 0.53 [0.36-0.77]), and migraine (ORadjusted 0.58 [0.39-0.85]) were less frequent than in younger patients. In turn, hypercholesterolemia (ORadjusted 1.52 [1.1-2.10]) and hypertension (ORadjusted 3.08 [2.25-4.22]) were more frequent in older patients. Key differences between age groups were confirmed in secondary analyses. In multivariable, adjusted analyses, favorable outcome (i.e., modified Rankin Scale score 0-2) was less frequent in the older age group (ORadjusted 0.45 [0.25, 0.83]).In our study population of patients diagnosed with CeAD, 1 in 14 was aged ≥60 years. In these patients, pain and mechanical triggers might be missing, rendering the diagnosis more challenging and increasing the risk of missed CeAD diagnosis in older patients.

Background and Purpose- There is clinical equipoise about the use of advanced imaging for selecting acute ischemic stroke patients eligible for mechanical thrombectomy (MT) during the first 6 hours from symptom onset. However, accumulating evidence indicates that advanced neuroimaging represents an invaluable and time-independent prognostic factor. Methods- We performed a systematic review and meta-analysis of available randomized clinical trials to evaluate the impact of patient selection with advanced neuroimaging on the 3-month: (1) functional independence (modified Rankin Scale score, 0-2), (2) favorable functional outcome (modified Rankin Scale scores, 0-1), (3) all-cause mortality, and (4) functional improvement (assessed with ordinal analysis of the modified Rankin Scale-scores). We compared patients with perfusion imaging documented penumbra to patients who did not have documented penumbra or perfusion imaging. Results- Among the 10 eligible randomized clinical trials (2227 total patients, mean age: 67 years), 5 studies reported the use of advanced imaging. Studies using advanced neuroimaging showed higher treatment effects of MT on 3-month functional independence (odds ratio [OR], 3.79; 95% CI, 2.71-5.28 versus OR, 1.89; 95% CI, 1.52-2.35; P for subgroup differences <0.001), favorable functional outcome (OR, 3.16; 95% CI, 1.94-5.14 versus OR, 1.75; 95% CI, 1.30-2.34; P for subgroup differences=0.04), and functional improvement (common OR, 2.66; 95% CI, 1.95-3.63 versus common OR, 1.60; 95% CI, 1.32-1.95; P for subgroup differences=0.007) compared with studies using conventional neuroimaging. The pooled rate of successful reperfusion after MT was higher in studies with advanced neuroimaging ( P for subgroup differences=0.003). No difference in the mortality and symptomatic intracranial hemorrhage rates was found between the 2 groups. No evidence of heterogeneity was documented in all reported analyses. Conclusions- The present indirect comparisons indicate that acute ischemic stroke patient selection for MT using advanced neuroimaging appears to be associated with improved clinical outcomes. The use of advanced neuroimaging for both the selection and prediction of prognosis for MT candidates should not depend on the elapsed time from symptom onset.

Intracranial hemorrhage (ICH) is the most feared complication in patients treated with oral anticoagulants due to non-valvular atrial fibrillation. Non-vitamin K oral anticoagulants (NOACs) reduce the risk of ICH compared with vitamin K antagonists (VKAs). We performed a systematic review and meta-analysis to evaluate the risk of fatal NOAC-related ICH compared with VKA-related ICH.We calculated the corresponding risk ratios (RRs) in each included study to express the relative risk of fatal ICH amongst all patients receiving oral anticoagulation with either NOACs or VKAs. We additionally evaluated the mortality rates in NOAC-related ICH in patients treated with and without NOAC-specific reversal agents (idarucizumab and factor Xa inhibitors antidote). Case fatality was evaluated at 30-90 days following symptom onset.Our literature search identified six eligible studies (four randomized controlled trials and two open-label trials of NOAC-specific reversal agents). In pairwise analyses, NOACs were found to have a lower risk of fatal ICH compared with VKAs [RR, 0.46; 95% confidence interval (CI), 0.36-0.58] with no heterogeneity (I2 = 0%) across included randomized controlled trials. However, the case fatality rate was similar in NOAC-related and VKA-related (RR, 1.00; 95% CI, 0.84-1.19) ICH with no evidence of heterogeneity (I2 = 0%). In the indirect analysis, the case fatality rate of NOAC-related ICH in patients treated with specific reversal agents was lower compared with the remainder of the patients [17% (95% CI, 11-24%) vs. 41% (95% CI, 34-49%); P < 0.001].Non-vitamin K oral anticoagulants halve the risk of fatal ICH in patients with non-valvular atrial fibrillation compared with VKAs, whereas indirect comparisons indicate that NOAC-specific reversal agents may be associated with a lower case fatality rate in NOAC-related ICH.

Background and Purpose— The Efficacy of Nitric Oxide in Stroke (ENOS) trial found that transdermal glyceryl trinitrate (GTN, a nitric oxide donor) lowered blood pressure but did not improve functional outcome in patients with acute stroke. However, GTN was associated with improved outcome if patients were randomized within 6 hours of stroke onset. Methods— In this prespecified subgroup analysis, the effect of GTN (5 mg/d for 7 days) versus no GTN was studied in 629 patients with intracerebral hemorrhage presenting within 48 hours and with systolic blood pressure ≥140 mm Hg. The primary outcome was the modified Rankin Scale at 90 days. Results— Mean blood pressure at baseline was 172/93 mm Hg and significantly lower (difference −7.5/−4.2 mm Hg; both P ≤0.05) on day 1 in 310 patients allocated to GTN when compared with 319 randomized to no GTN. No difference in the modified Rankin Scale was observed between those receiving GTN versus no GTN (adjusted odds ratio for worse outcome with GTN, 1.04; 95% confidence interval, 0.78–1.37; P =0.84). In the subgroup of 61 patients randomized within 6 hours, GTN improved functional outcome with a shift in the modified Rankin Scale (odds ratio, 0.22; 95% confidence interval, 0.07–0.69; P =0.001). There was no significant difference in the rates of serious adverse events between GTN and no GTN. Conclusions— In patients with intracerebral hemorrhage within 48 hours of onset, GTN lowered blood pressure was safe but did not improve functional outcome. Very early treatment might be beneficial but needs assessment in further studies. Clinical Trial Registration— URL: http://www.isrctn.com/ISRCTN99414122 . Unique identifier: 99414122.

Background and Purposes— This study was designed to derive and validate a score to predict early ischemic events and major bleedings after an acute ischemic stroke in patients with atrial fibrillation. Methods— The derivation cohort consisted of 854 patients with acute ischemic stroke and atrial fibrillation included in prospective series between January 2012 and March 2014. Older age (hazard ratio 1.06 for each additional year; 95% confidence interval, 1.00–1.11) and severe atrial enlargement (hazard ratio, 2.05; 95% confidence interval, 1.08–2.87) were predictors for ischemic outcome events (stroke, transient ischemic attack, and systemic embolism) at 90 days from acute stroke. Small lesions (≤1.5 cm) were inversely correlated with both major bleeding (hazard ratio, 0.39; P =0.03) and ischemic outcome events (hazard ratio, 0.55; 95% confidence interval, 0.30–1.00). We assigned to age ≥80 years 2 points and between 70 and 79 years 1 point; ischemic index lesion &gt;1.5 cm, 1 point; severe atrial enlargement, 1 point (ALESSA score). A logistic regression with the receiver-operating characteristic graph procedure (C statistic) showed an area under the curve of 0.697 (0.632–0.763; P =0.0001) for ischemic outcome events and 0.585 (0.493–0.678; P =0.10) for major bleedings. Results— The validation cohort consisted of 994 patients included in prospective series between April 2014 and June 2016. Logistic regression with the receiver-operating characteristic graph procedure showed an area under the curve of 0.646 (0.529–0.763; P =0.009) for ischemic outcome events and 0.407 (0.275–0.540; P =0.14) for hemorrhagic outcome events. Conclusions— In acute stroke patients with atrial fibrillation, high ALESSA scores were associated with a high risk of ischemic events but not of major bleedings.

Background and Purpose— Bridging therapy with low-molecular-weight heparin reportedly leads to a worse outcome for acute cardioembolic stroke patients because of a higher incidence of intracerebral bleeding. However, this practice is common in clinical settings. This observational study aimed to compare (1) the clinical profiles of patients receiving and not receiving bridging therapy, (2) overall group outcomes, and (3) outcomes according to the type of anticoagulant prescribed. Methods— We analyzed data of patients from the prospective RAF and RAF-NOACs studies. The primary outcome was defined as the composite of ischemic stroke, transient ischemic attack, systemic embolism, symptomatic cerebral bleeding, and major extracerebral bleeding observed at 90 days after the acute stroke. Results— Of 1810 patients who initiated oral anticoagulant therapy, 371 (20%) underwent bridging therapy with full-dose low-molecular-weight heparin. Older age and the presence of leukoaraiosis were inversely correlated with the use of bridging therapy. Forty-two bridged patients (11.3%) reached the combined outcome versus 72 (5.0%) of the nonbridged patients ( P =0.0001). At multivariable analysis, bridging therapy was associated with the composite end point (odds ratio, 2.3; 95% CI, 1.4–3.7; P &lt;0.0001), as well as ischemic (odds ratio, 2.2; 95% CI, 1.3–3.9; P =0.005) and hemorrhagic (odds ratio, 2.4; 95% CI, 1.2–4.9; P =0.01) end points separately. Conclusions— Our findings suggest that patients receiving low-molecular-weight heparin have a higher risk of early ischemic recurrence and hemorrhagic transformation compared with nonbridged patients.

To assess the utility of IV thrombolysis (IVT) treatment in patients with acute ischemic stroke (AIS) with unclear symptom onset time or outside the 4.5-hour time window selected by advanced neuroimaging.We performed random-effects meta-analyses on the unadjusted and adjusted for potential confounders associations of IVT (alteplase 0.9 mg/kg) with the following outcomes: 3-month favorable functional outcome (FFO; modified Rankin Scale [mRS] scores 0-1), 3-month functional independence (FI; mRS scores 0-2), 3-month mortality, 3-month functional improvement (assessed with ordinal analysis on the mRS scores), symptomatic intracranial hemorrhage (sICH), and complete recanalization (CR).We identified 4 eligible randomized clinical trials (859 total patients). In unadjusted analyses, IVT was associated with a higher likelihood of 3-month FFO (odds ratio [OR] 1.48, 95% confidence interval [CI] 1.12-1.96), FI (OR 1.42, 95% CI 1.07-1.90), sICH (OR 5.28, 95% CI 1.35-20.68), and CR (OR 3.29, 95% CI 1.90-5.69), with no significant difference in the odds of all-cause mortality risk at 3 months (OR 1.75, 95% CI 0.93-3.29). In the adjusted analyses, IVT was also associated with higher odds of 3-month FFO (adjusted OR [ORadj] 1.62, 95% CI 1.20-2.20), functional improvement (ORadj 1.42, 95% CI 1.11-1.81), and sICH (ORadj 6.22, 95% CI 1.37-28.26). There was no association between IVT and FI (ORadj 1.61, 95% CI 0.94-2.75) or all-cause mortality (ORadj 1.75, 95% CI 0.93-3.29) at 3 months. No evidence of heterogeneity was evident in any of the analyses (I2 = 0).IVT in patients with AIS with unknown symptom onset time or elapsed time from symptom onset >4.5 hours selected with advanced neuroimaging results in a higher likelihood of CR and functional improvement at 3 months despite the increased risk of sICH.