Impact of Cerebral Microbleeds in Stroke Patients with Atrial Fibrillation.

OBJECTIVES: Cerebral microbleeds are associated with the risks of ischemic stroke and intracranial hemorrhage, causing clinical dilemmas for antithrombotic treatment decisions. We aimed to evaluate the risks of intracranial hemorrhage and ischemic stroke associated with microbleeds in patients with atrial fibrillation treated with vitamin K antagonists, direct oral anticoagulants, antiplatelets, and combination therapy (i.e. concurrent oral anticoagulant and antiplatelet). METHODS: We included patients with documented atrial fibrillation from the pooled individual patient data analysis by the Microbleeds International Collaborative Network. Risks of subsequent intracranial hemorrhage and ischemic stroke were compared between patients with and without microbleeds, stratified by antithrombotic use. RESULTS: A total of 7,839 patients were included. The presence of microbleeds was associated with an increased relative risk of intracranial hemorrhage (adjusted hazard ratio [aHR] = 2.74, 95% confidence interval = 1.76-4.26) and ischemic stroke (aHR = 1.29, 95% confidence interval = 1.04-1.59). For the entire cohort, the absolute incidence of ischemic stroke was higher than intracranial hemorrhage regardless of microbleed burden. However, for the subgroup of patients taking combination of anticoagulant and antiplatelet therapy, the absolute risk of intracranial hemorrhage exceeded that of ischemic stroke in those with 2 to 4 microbleeds (25 vs 12 per 1,000 patient-years) and ≥ 11 microbleeds (94 vs 48 per 1,000 patient-years). INTERPRETATION: Patients with atrial fibrillation and high burden of microbleeds receiving combination therapy have a tendency of higher rate of intracranial hemorrhage than ischemic stroke, with potential for net harm. Further studies are needed to help optimize stroke preventive strategies in this high-risk group. ANN NEUROL 2023;94:61-74.

MRI-Guided Thrombolysis for Stroke with Unknown Time of Onset.

BACKGROUND: Under current guidelines, intravenous thrombolysis is used to treat acute stroke only if it can be ascertained that the time since the onset of symptoms was less than 4.5 hours. We sought to determine whether patients with stroke with an unknown time of onset and features suggesting recent cerebral infarction on magnetic resonance imaging (MRI) would benefit from thrombolysis with the use of intravenous alteplase. METHODS: In a multicenter trial, we randomly assigned patients who had an unknown time of onset of stroke to receive either intravenous alteplase or placebo. All the patients had an ischemic lesion that was visible on MRI diffusion-weighted imaging but no parenchymal hyperintensity on fluid-attenuated inversion recovery (FLAIR), which indicated that the stroke had occurred approximately within the previous 4.5 hours. We excluded patients for whom thrombectomy was planned. The primary end point was favorable outcome, as defined by a score of 0 or 1 on the modified Rankin scale of neurologic disability (which ranges from 0 [no symptoms] to 6 [death]) at 90 days. A secondary outcome was the likelihood that alteplase would lead to lower ordinal scores on the modified Rankin scale than would placebo (shift analysis). RESULTS: The trial was stopped early owing to cessation of funding after the enrollment of 503 of an anticipated 800 patients. Of these patients, 254 were randomly assigned to receive alteplase and 249 to receive placebo. A favorable outcome at 90 days was reported in 131 of 246 patients (53.3%) in the alteplase group and in 102 of 244 patients (41.8%) in the placebo group (adjusted odds ratio, 1.61; 95% confidence interval [CI], 1.09 to 2.36; P=0.02). The median score on the modified Rankin scale at 90 days was 1 in the alteplase group and 2 in the placebo group (adjusted common odds ratio, 1.62; 95% CI, 1.17 to 2.23; P=0.003). There were 10 deaths (4.1%) in the alteplase group and 3 (1.2%) in the placebo group (odds ratio, 3.38; 95% CI, 0.92 to 12.52; P=0.07). The rate of symptomatic intracranial hemorrhage was 2.0% in the alteplase group and 0.4% in the placebo group (odds ratio, 4.95; 95% CI, 0.57 to 42.87; P=0.15). CONCLUSIONS: In patients with acute stroke with an unknown time of onset, intravenous alteplase guided by a mismatch between diffusion-weighted imaging and FLAIR in the region of ischemia resulted in a significantly better functional outcome and numerically more intracranial hemorrhages than placebo at 90 days. (Funded by the European Union Seventh Framework Program; WAKE-UP ClinicalTrials.gov number, NCT01525290; and EudraCT number, 2011-005906-32 .).

Five-Year Risk of Stroke after TIA or Minor Ischemic Stroke.

BACKGROUND: After a transient ischemic attack (TIA) or minor stroke, the long-term risk of stroke and other vascular events is not well known. In this follow-up to a report on 1-year outcomes from a registry of TIA clinics in 21 countries that enrolled 4789 patients with a TIA or minor ischemic stroke from 2009 through 2011, we examined the 5-year risk of stroke and vascular events. METHODS: We evaluated patients who had had a TIA or minor stroke within 7 days before enrollment in the registry. Among 61 sites that participated in the 1-year outcome study, we selected 42 sites that had follow-up data on more than 50% of their enrolled patients at 5 years. The primary outcome was a composite of stroke, acute coronary syndrome, or death from cardiovascular causes (whichever occurred first), with an emphasis on events that occurred in the second through fifth years. In calculating the cumulative incidence of the primary outcome and secondary outcomes (except death from any cause), we treated death as a competing risk. RESULTS: A total of 3847 patients were included in the 5-year follow-up study; the median percentage of patients with 5-year follow-up data per center was 92.3% (interquartile range, 83.4 to 97.8). The composite primary outcome occurred in 469 patients (estimated cumulative rate, 12.9%; 95% confidence interval [CI], 11.8 to 14.1), with 235 events (50.1%) occurring in the second through fifth years. At 5 years, strokes had occurred in 345 patients (estimated cumulative rate, 9.5%; 95% CI, 8.5 to 10.5), with 149 of these patients (43.2%) having had a stroke during the second through fifth years. Rates of death from any cause, death from cardiovascular causes, intracranial hemorrhage, and major bleeding were 10.6%, 2.7%, 1.1%, and 1.5%, respectively, at 5 years. In multivariable analyses, ipsilateral large-artery atherosclerosis, cardioembolism, and a baseline ABCD2 score for the risk of stroke (range, 0 to 7, with higher scores indicating greater risk) of 4 or more were each associated with an increased risk of subsequent stroke. CONCLUSIONS: In a follow-up to a 1-year study involving patients who had a TIA or minor stroke, the rate of cardiovascular events including stroke in a selected cohort was 6.4% in the first year and 6.4% in the second through fifth years. (Funded by AstraZeneca and others.).

Stroke Care during the COVID-19 Pandemic: International Expert Panel Review.

BACKGROUND: Coronavirus disease 2019 (COVID-19) has placed a tremendous strain on healthcare services. This study, prepared by a large international panel of stroke experts, assesses the rapidly growing research and personal experience with COVID-19 stroke and offers recommendations for stroke management in this challenging new setting: modifications needed for prehospital emergency rescue and hyperacute care; inpatient intensive or stroke units; posthospitalization rehabilitation; follow-up including at-risk family and community; and multispecialty departmental developments in the allied professions. SUMMARY: The severe acute respiratory syndrome coronavirus 2 uses spike proteins binding to tissue angiotensin-converting enzyme (ACE)-2 receptors, most often through the respiratory system by virus inhalation and thence to other susceptible organ systems, leading to COVID-19. Clinicians facing the many etiologies for stroke have been sobered by the unusual incidence of combined etiologies and presentations, prominent among them are vasculitis, cardiomyopathy, hypercoagulable state, and endothelial dysfunction. International standards of acute stroke management remain in force, but COVID-19 adds the burdens of personal protections for the patient, rescue, and hospital staff and for some even into the postdischarge phase. For pending COVID-19 determination and also for those shown to be COVID-19 affected, strict infection control is needed at all times to reduce spread of infection and to protect healthcare staff, using the wealth of well-described methods. For COVID-19 patients with stroke, thrombolysis and thrombectomy should be continued, and the usual early management of hypertension applies, save that recent work suggests continuing ACE inhibitors and ARBs. Prothrombotic states, some acute and severe, encourage prophylactic LMWH unless bleeding risk is high. COVID-19-related cardiomyopathy adds risk of cardioembolic stroke, where heparin or warfarin may be preferable, with experience accumulating with DOACs. As ever, arteritis can prove a difficult diagnosis, especially if not obvious on the acute angiogram done for clot extraction. This field is under rapid development and may generate management recommendations which are as yet unsettled, even undiscovered. Beyond the acute management phase, COVID-19-related stroke also forces rehabilitation services to use protective precautions. As with all stroke patients, health workers should be aware of symptoms of depression, anxiety, insomnia, and/or distress developing in their patients and caregivers. Postdischarge outpatient care currently includes continued secondary prevention measures. Although hoping a COVID-19 stroke patient can be considered cured of the virus, those concerned for contact safety can take comfort in the increasing use of telemedicine, which is itself a growing source of patient-physician contacts. Many online resources are available to patients and physicians. Like prior challenges, stroke care teams will also overcome this one. Key Messages: Evidence-based stroke management should continue to be provided throughout the patient care journey, while strict infection control measures are enforced.

Global Burden of Small Vessel Disease-Related Brain Changes on MRI Predicts Cognitive and Functional Decline.

Background and Purpose- Cerebral small vessel disease is characterized by a wide range of focal and global brain changes. We used a magnetic resonance imaging segmentation tool to quantify multiple types of small vessel disease-related brain changes and examined their individual and combined predictive value on cognitive and functional abilities. Methods- Magnetic resonance imaging scans of 560 older individuals from LADIS (Leukoaraiosis and Disability Study) were analyzed using automated atlas- and convolutional neural network-based segmentation methods yielding volumetric measures of white matter hyperintensities, lacunes, enlarged perivascular spaces, chronic cortical infarcts, and global and regional brain atrophy. The subjects were followed up with annual neuropsychological examinations for 3 years and evaluation of instrumental activities of daily living for 7 years. Results- The strongest predictors of cognitive performance and functional outcome over time were the total volumes of white matter hyperintensities, gray matter, and hippocampi (P<0.001 for global cognitive function, processing speed, executive functions, and memory and P<0.001 for poor functional outcome). Volumes of lacunes, enlarged perivascular spaces, and cortical infarcts were significantly associated with part of the outcome measures, but their contribution was weaker. In a multivariable linear mixed model, volumes of white matter hyperintensities, lacunes, gray matter, and hippocampi remained as independent predictors of cognitive impairment. A combined measure of these markers based on Z scores strongly predicted cognitive and functional outcomes (P<0.001) even above the contribution of the individual brain changes. Conclusions- Global burden of small vessel disease-related brain changes as quantified by an image segmentation tool is a powerful predictor of long-term cognitive decline and functional disability. A combined measure of white matter hyperintensities, lacunar, gray matter, and hippocampal volumes could be used as an imaging marker associated with vascular cognitive impairment.

One-Year Risk of Stroke after Transient Ischemic Attack or Minor Stroke.

BACKGROUND: Previous studies conducted between 1997 and 2003 estimated that the risk of stroke or an acute coronary syndrome was 12 to 20% during the first 3 months after a transient ischemic attack (TIA) or minor stroke. The TIAregistry.org project was designed to describe the contemporary profile, etiologic factors, and outcomes in patients with a TIA or minor ischemic stroke who receive care in health systems that now offer urgent evaluation by stroke specialists. METHODS: We recruited patients who had had a TIA or minor stroke within the previous 7 days. Sites were selected if they had systems dedicated to urgent evaluation of patients with TIA. We estimated the 1-year risk of stroke and of the composite outcome of stroke, an acute coronary syndrome, or death from cardiovascular causes. We also examined the association of the ABCD(2) score for the risk of stroke (range, 0 [lowest risk] to 7 [highest risk]), findings on brain imaging, and cause of TIA or minor stroke with the risk of recurrent stroke over a period of 1 year. RESULTS: From 2009 through 2011, we enrolled 4789 patients at 61 sites in 21 countries. A total of 78.4% of the patients were evaluated by stroke specialists within 24 hours after symptom onset. A total of 33.4% of the patients had an acute brain infarction, 23.2% had at least one extracranial or intracranial stenosis of 50% or more, and 10.4% had atrial fibrillation. The Kaplan-Meier estimate of the 1-year event rate of the composite cardiovascular outcome was 6.2% (95% confidence interval, 5.5 to 7.0). Kaplan-Meier estimates of the stroke rate at days 2, 7, 30, 90, and 365 were 1.5%, 2.1%, 2.8%, 3.7%, and 5.1%, respectively. In multivariable analyses, multiple infarctions on brain imaging, large-artery atherosclerosis, and an ABCD(2) score of 6 or 7 were each associated with more than a doubling of the risk of stroke. CONCLUSIONS: We observed a lower risk of cardiovascular events after TIA than previously reported. The ABCD(2) score, findings on brain imaging, and status with respect to large-artery atherosclerosis helped stratify the risk of recurrent stroke within 1 year after a TIA or minor stroke. (Funded by Sanofi and Bristol-Myers Squibb.).

Arterial Spin Labeling Cerebral Perfusion Magnetic Resonance Imaging in Migraine Aura: An Observational Study.

BACKGROUND: Changes in cerebral perfusion during migraine with aura (MA) have been assessed mainly using dynamic susceptibility contrast (DSC) magnetic resonance perfusion imaging. A contrast agent-free method to assess these changes would be desirable. We assessed changes in cerebral perfusion during MA using arterial spin labeling (ASL) perfusion magnetic resonance imaging. METHODS: We investigated 4 patients with a standardized protocol including ASL perfusion imaging during MA (n = 2) or early headache phase (n = 2) and asymptomatic follow-up. Semiquantitative evaluation was done using a region of interest (ROI) within hypoperfused or hyperperfused areas and corresponding ROIs in the contralateral hemisphere. Relative ratios of mean perfusion in the corresponding ROIs were calculated. DSC imaging was done at initial time points and compared visually with ASL findings. RESULTS: In all patients, regional perfusion changes were detected in the acute phase. These abnormalities did not respect the boundaries of major cerebral vascular territories but overlapped onto adjoining regions. During MA, adjacent hypoperfused and hyperperfused areas were found, whereas during headache, regional hyperperfusion only was observed. Perfusion abnormalities normalized on follow-up. CONCLUSIONS: ASL perfusion imaging is a contrast agent-free method suitable for assessment of reversible perfusion changes during or immediately after MA.

Patent Foramen Ovale and Cryptogenic Strokes in the Stroke in Young Fabry Patients Study.

BACKGROUND AND PURPOSE: A patent foramen ovale (PFO) is disproportionately prevalent in patients with cryptogenic stroke. Without alternative explanations, it is frequently considered to be causative. A detailed stratification of these patients may improve the identification of incidental PFO. METHODS: We investigated the PFO prevalence in 3497 transient ischemic attack and ischemic stroke patients aged 18 to 55 years in the prospective multicenter SIFAP1 study (Stroke in Young Fabry Patients 1) using the ASCO classification. Patients without an obvious cause for transient ischemic attack/stroke (ASCO 0) were divided into subgroups with and without vascular risk factors (ASCO 0+ and 0-). In addition, we looked for PFO-related magnetic resonance imaging lesion patterns. RESULTS: PFO was identified in 25% of patients. Twenty percent of patients with a definite or probable cause of transient ischemic attack/stroke (≥1 grade 1 or 2 ASCO criterion; n=1769) had a PFO compared with 29% of cryptogenic stroke patients (ASCO 0 and 3; n=1728; P<0,001); subdivision of cryptogenic strokes revealed a PFO in 24% of 978 ASCO 3 patients (n.s. versus ASCO 1 and 2) and a higher prevalence of 36% in 750 ASCO 0 cases (P<0.001 versus ASCO 3 and versus ASCO 1 and 2). PFO was more commonly observed in ASCO 0- (n=271) than in ASCO 0+ patients (n=479; 48 versus 29%; P<0.001). There was no PFO-associated magnetic resonance imaging lesion pattern. CONCLUSIONS: Cryptogenic stroke patients demonstrate a heterogeneous PFO prevalence. Even in case of less conclusive diseases like nonstenotic arteriosclerosis, patients should preferentially be considered to have a non-PFO-mediated stroke. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00414583.

Symptomatic Patients Remain at Substantial Risk of Arterial Disease Complications Before and After Endarterectomy or Stenting.

BACKGROUND AND PURPOSE: After carotid endarterectomy (CEA) or carotid artery stenting (CAS) in patients with transient ischemic attack or minor ischemic stroke, recurrent stroke risk falls to a low rate on modern medical treatment. METHODS: We used data from 4583 patients with recent transient ischemic attack or minor stroke enrolled in the TIAregistry.org to perform a nested case-control analysis to evaluate pre- and post-CEA/CAS risk. Cases were defined as patients with a CEA/CAS during the 1-year follow-up period. For each case, 2 controls with a follow-up time greater than the time from qualifying event to CEA/CAS were randomly selected, matched by age and sex. Primary outcome was defined as major vascular events (MVE, including stroke, cardiovascular death, and myocardial infarction). RESULTS: The median delay from symptom onset of qualifying event to CEA/CAS was 11 days (interquartile range, 6-23). Overall, patients with CEA/CAS had a higher 1-year risk of MVE than other patients (14.8% versus 5.8%; adjusted hazard ratio, 2.40; 95% confidence interval, 1.61-3.60; P<0.001). During the matched preprocedural period, MVE occurred in 14 (7.5%) cases and in 13 (3.5%) controls, with an adjusted odds ratio =2.46 (95% confidence interval, 1.07-5.64; P=0.03). In the postprocedural period, the risk of MVE was also higher in cases than in controls (adjusted P<0.03). CONCLUSIONS: Patients with CEA/CAS had a higher 12-month risk of MVE, as well as during pre- and postprocedural periods. These results suggest that patients in whom CEA/CAS is anticipated are likely to be an informative population for inclusion in studies testing new antithrombotic strategies started soon after symptom onset.

Differences in Characteristics and Outcomes Between Asian and Non-Asian Patients in the TIAregistry.org.

BACKGROUND AND PURPOSE: This study provides the contemporary causes and prognosis of transient ischemic attack (TIA) and minor stroke in Asians and the direct comparisons with non-Asians. METHODS: The TIAregistry.org enrolled 4789 patients (1149 Asians and 3640 non-Asians) with a TIA or minor ischemic stroke within 7 days of onset. Every participating facility had systems dedicated to urgent intervention of TIA/stroke patients by specialists. The primary outcome was a composite of cardiovascular death, nonfatal stroke, and nonfatal acute coronary syndrome. RESULTS: Approximately 80% of patients were evaluated within 24 hours of symptom onset. At 1 year, there were no differences in the rates of composite cardiovascular events (6.8% versus 6.0%; P=0.38) and stroke (6.0% versus 4.8%; P=0.11) between Asians and non-Asians. Asians had a lower risk of cerebrovascular disease (stroke or TIA) than non-Asians (adjusted hazard ratio, 0.79; 95% confidence interval, 0.63-0.98; P=0.03); the difference was primarily driven by a lower rate of TIA in Asians (4.2% versus 8.3%; P<0.001). Moderately severe bleeding was more frequent in Asians (0.8% versus 0.3%; P=0.02). In multivariable analysis, multiple acute infarcts (P=0.005) and alcohol consumption (P=0.02) were independent predictors of stroke recurrence in Asians, whereas intracranial stenosis (P<0.001), ABCD2 score (P<0.001), atrial fibrillation (P=0.008), extracranial stenosis (P=0.03), and previous stroke or TIA (P=0.03) were independent predictors in non-Asians. CONCLUSIONS: The short-term stroke risk after a TIA or minor stroke was lower than expected when urgent evidence-based care was delivered, irrespective of race/ethnicity or region. However, the predictors of stroke were different for Asians and non-Asians.

Posterior versus Anterior Circulation Stroke in Young Adults: A Comparative Study of Stroke Aetiologies and Risk Factors in Stroke among Young Fabry Patients (sifap1).

BACKGROUND: Although 20-30% of all strokes occur in the posterior circulation, few studies have explored the characteristics of patients with strokes in the posterior compared to the anterior circulation so far. Especially data on young patients is missing. METHODS: In this secondary analysis of data of the prospective multi-centre European sifap1 study that investigated stroke and transient ischemic attack (TIA) patients aged 18-55 years, we compared vascular risk factors, stroke aetiology, presence of white matter hyperintensities (WMH) and cerebral microbleeds (CMB) between patients with ischaemic posterior circulation stroke (PCS) and those having suffered from anterior circulation stroke (ACS) based on cerebral MRI. RESULTS: We diagnosed PCS in 612 patients (29.1%, 407 men, 205 women) and ACS in 1,489 patients (70.9%). Their age (median 46 vs. 47 years, p = 0.205) and stroke severity (modified Rankin Scale: both 2, p = 0.375, Barthel Index 90 vs. 85, p = 0.412) were similar. PCS was found to be more frequent among the male gender (66.5 vs. 60.1% with ACS, p = 0.003). Vertebral artery (VA) dissection was more often the cause of PCS (16.8%) than was carotid artery dissection of ACS (7.9%, p < 0.001). Likewise, small vessel disease (Trial of Org 10172 in Acute Stroke Treatment [TOAST] = 3, PCS: 14.7%, ACS: 11.8%) and stroke of other determined aetiology (TOAST = 4, PCS: 24.5%, ACS: 16.0%) were more frequent in those with PCS. Furthermore, patent foramen ovale (PFO; PCS: 31.1%, ACS: 25.4%, p = 0.029) was more often detected in patients with PCS. In contrast, large-artery atherosclerosis (TOAST = 1, PCS: 15.4%, ACS: 22.2%) and cardio-embolic stroke (TOAST = 2, PCS: 15.6%, ACS: 18.0%) were less frequent in those with PCS (p < 0.001) as were preceding cerebrovascular events (10.1 vs. 14.1%, p = 0.014), TIA (4.8 vs. 7.7%, p = 0.016) and smoking (53.2 vs. 61.0%, p = 0.001). The presence, extent, and location of WMH and CMB did not differ between the 2 groups. CONCLUSIONS: Our data suggested a different pattern of aetiology and risk factors in young patients with PCS compared to those with ACS. These findings especially call for a higher awareness of VA dissection and potentially for more weight of a PFO as a risk factor in young patients with PCS. Clinical trial registration-URL: http://www.clinicaltrials.gov; NCT00414583.

The Intracranial-B2LEED3S Score and the Risk of Intracranial Hemorrhage in Ischemic Stroke Patients Under Antiplatelet Treatment.

BACKGROUND: Chronic antiplatelet therapy in the post-acute phase of non-cardioembolic ischemic stroke is limited by the risk of intracranial hemorrhage (ICH) complications. METHODS: We developed an ICH risk score based on the PERFORM trial cohort (n = 19,100), which included patients with a non-cardioembolic ischemic stroke or transient ischemic attack, and externally validated this score in one contemporary trial of very similar size and inclusion criteria, the PRoFESS trial (n = 20,332 patients). Outcome was ICH over 2 years. A Cox proportional-hazard regression analysis identified risk factors. Discrimination was quantified with c-statistics and calibration was assessed by comparing predicted and observed ICH risk in PERFORM and PRoFESS. RESULTS: ICH occurred within 2 years in 263 (1.4%) patients in PERFORM trial and in 246 (1.2%) patients in PRoFESS trial. A 13-point score based on 9 items (Intracranial-B2LEED3S score - low body mass index, blood pressure, lacune, elderly, Asian ethnicity, coronary artery or cerebrovascular disease history, dual antithrombotic agent or oral anticoagulant, gender) was derived from the PERFORM trial. In PERFORM, the observed 2-year ICH risk varied from 0.75% in low-risk (score ≤2) to 2.44% in high-risk patients (score ≥5) with an acceptable calibration but a low discrimination both in PERFORM (c-statistic 0.64, 95% CI 0.61-0.68) and on external validation in PRoFESS (0.58, 95% CI 0.55-0.62). CONCLUSION: The Intracranial-B2LEED3S score helps identify patients who are at a high risk of bleeding. However, other variables need to be identified to improve the score (e.g., microbleeds) (Clinical Trial Registration Information ISRCTN66157730). URL: http://www.isrctn.com/ISRCTN66157730?totalResults=5&pageSize=10&page=1&searchType=basic-search&offset=3&q=&filters=conditionCategory%3ACirculatory+System%2CrecruitmentCountry%3ATaiwan%2CrecruitmentCountry%3AAustria&sort=.

Specificities of Ischemic Stroke Risk Factors in Arab-Speaking Countries.

BACKGROUND: Stroke is largely preventable, and therefore, a better understanding of risk factors is an essential step in reducing the population stroke rate and resulting disease burden in Arab countries. SUMMARY: We performed 2 separate analyses in 2 similar populations of patients with noncardioembolic ischemic stroke. This first involved 3,635 patients in the Outcomes in Patients with TIA and Cerebrovascular disease (OPTIC) registry (followed for 2 years), with baseline collection of the usual risk factors and 5 socioeconomic variables (unemployment status, residence in rural area, living in fully serviced accommodation, no health-insurance coverage, and low educational level). The second involved patients in the PERFORM trial (n = 19,100 followed up for 2 years), with baseline collection of the usual risk factors and 1 socioeconomic variable (low educational level). The primary outcome was a composite of nonfatal stroke, nonfatal myocardial infarction, or cardiovascular death. Stroke risk factors were more prevalent in patients in Arab countries. The incidence of major cardiovascular events (MACE; age- and gender-adjusted) was higher in Arab countries (OPTIC, 18.5 vs. 13.3%; PERFORM, 18.4 vs. 9.7%; both p ≤ 0.0001). These results remained significant after adjustment on risk factors and were attenuated in OPTIC after further adjustment on socioeconomic variables (hazard ratio 1.24; 95% CI 0.98-1.55; p = 0.07). Key Messages: Patients with ischemic stroke living in Arab countries had a lower mean socioeconomic status, a much higher prevalence of diabetes mellitus, and a higher rate of MACE compared with patients from non-Arab countries. This finding is partly explained by a higher prevalence of risk factors and also by a high prevalence of poverty and low educational level.

Does being physically active prevent future disability in older people? Attenuated effects when taking time-dependent confounders into account.

BACKGROUND: Causal experimental evidence that physical activity prevents disability in older people is sparse. Being physically active has nonetheless been shown to be associated with disability-free survival in observational studies. Observational studies are, however, prone to bias introduced by time-dependent confounding. Time-dependent confounding occurs when an exposure (e.g. being physically active at some time-point) potentially affects the future status of a confounder (such as depression sometime later), and both variables have an effect on latter outcome (i.e. disability). "Conventional" analysis with e.g. Cox-regression is the mainstay when analyzing longitudinal observational studies. Unfortunately, it does not provide unbiased estimates in the presence of time-dependent confounding. Marginal structural models (MSM) - a relatively new class of causal models - have the potential to adequately account for time-dependent confounding. Here we analyze the effect of older people being physically active on disability, in a large long-term observational study. We address time-dependent confounding by using marginal structural models and provide a non-technical practical demonstration of how to implement this type of modeling. METHODS: Data is from 639 elderly individuals ascertained in the European multi-center Leukoaraiosis and Disability study (LADIS), followed-up yearly over a period of three years. We estimated the effect of self-reported physical activity on the probability to transit to instrumental disability in the presence of a large set of potential confounders. We compare the results of "conventional" modeling approaches to those estimated using marginal structural models, highlighting discrepancies. RESULTS: A "conventional" Cox-regression-like adjustment for salient baseline confounders signals a significant risk reduction under physical activity for later instrumental disability (OR 0.62, 95% CI 0.44-0.90). However, given MSM estimation, the effect is attenuated towards null (OR 1.00, 95% CI 0.57-1.76). CONCLUSIONS: Contrary to most reports, we did not find that physical activity in older people prevents future instrumental disability, when taking time-dependent confounding into account. This result may be due to the characteristics our particular study population. It is, however, also conceivable that previous evidence neglected the effect of this type of bias. We suggest that analysts of longitudinal observational studies consider marginal structural models as a further modeling approach.

Diagnostic and Prognostic Relevance of Magnetic Resonance Imaging and Electrophysiological Findings in Acute Spinal Ischemia.

OBJECTIVE: Our purpose was to classify the rare entity of spontaneous spinal ischemia with clinical, magnetic resonance-tomographic, and electrophysiological parameters to determine criteria for outcome prediction. METHODS: We analyzed the stroke registry database of the University Hospital Mannheim, Germany, from 2004 to 2010 for patients with a diagnosis of vascular spinal cord ischemia. RESULTS: Ten patients were identified (mean age 65 years [range 50-83], 5 women). In 5 patients an etiology was found. Spinal diffusion-weighted magnetic resonance imaging revealed acute ischemia in 7 patients at initial imaging and this diagnosis was confirmed during the first week in the remaining 3 patients. Electrophysiological studies showed abnormal motor evoked potentials (MEPs) in 8 patients and abnormal somatosensory evoked potentials (SSEPs) in 7 patients. After rehabilitation, 5 patients had regained walking ability, whereas 5 patients stayed wheelchair bound. All patients with unfavorable outcome (American Spinal Injury Association (ASIA) Impairment score [AIS] score of ≤C) showed severe pyramidal tract lesions in MEPs during the first week. All patients with normal MEPs had an excellent outcome (AIS of E, P < .05). CONCLUSIONS: Diffusion-weighted imaging (DWI) is a useful tool to confirm acute spinal ischemia suspected in patients within the first days after symptom onset. Poor outcome was associated with severe electrophysiological abnormalities in MEPs and SSEPs. Normal MEPs were significantly predictive of an excellent prognosis. A multimodal diagnostic approach combining DWI and electrophysiological evaluation facilitates the prediction of the individual clinical outcome.

Prediction of Early Reperfusion From Repeated Arterial Spin Labeling Perfusion Magnetic Resonance Imaging During Intravenous Thrombolysis.

BACKGROUND AND PURPOSE: There are few in vivo data on the pathophysiology of reperfusion during systemic thrombolysis. We monitored the time course of cerebral perfusion changes in patients during thrombolysis with repeated arterial spin labeling perfusion magnetic resonance imaging. METHODS: Ten patients with proximal arterial occlusion within 4.5 hours after symptom onset were prospectively enrolled. All patients received intravenous thrombolysis during the magnetic resonance imaging examination. Repeated arterial spin labeling perfusion images were acquired during the 60-minute therapy and at follow-up after 24 to 72 hours. Clinical data, magnetic resonance imaging features, and cerebral perfusion changes were analyzed. RESULTS: Before thrombolysis, arterial spin labeling hypoperfusion and fluid-attenuation inversion recovery vascular hyperintensity in the territory of the occluded arteries were observed in all patients. In 5 patients, extensive arterial transit artifacts (ATA) developed in the hypoperfused area. The ATA corresponded with fluid-attenuation inversion recovery vascular hyperintensities. All 5 patients who developed extensive ATA in the hypoperfused area had complete reperfusion after thrombolysis, whereas the 5 without extensive ATA showed no or only partial reperfusion (P<0.01). The development of ATA preceded the normalization of tissue perfusion. CONCLUSIONS: The development of ATA during thrombolysis is associated with early reperfusion after thrombolysis. arterial spin labeling assessment during intravenous thrombolysis has the potential to guide subsequent therapeutic strategies in patients with acute stroke.

Paracetamol, Ibuprofen, and Recurrent Major Cardiovascular and Major Bleeding Events in 19 120 Patients With Recent Ischemic Stroke.

BACKGROUND AND PURPOSE: The presumed safety of paracetamol in high-cardiovascular risk patients has been questioned. We determined whether paracetamol or ibuprofen use is associated with major cardiovascular events (MACE) or major bleeding in 19 120 patients with recent ischemic stroke or transient ischemic attack of mainly atherothrombotic origin included in the Prevention of cerebrovascular and cardiovascular events of ischemic origin with terutroban in patients with a history of ischemic stroke or transient ischemic attack (PERFORM) trial. METHODS: We performed 2 nested case-control analysis (2153 cases with MACE during trial follow-up and 4306 controls matched on Essen stroke risk score; 809 cases with major bleeding matched with 1616 controls) and a separate time-varying analysis. RESULTS: 12.3% were prescribed paracetamol and 2.5% ibuprofen. Median duration of treatment was 14 (interquartile range 5-145) days for paracetamol and 9 (5-30) days for ibuprofen. Paracetamol, but not ibuprofen, was associated with increased risk of MACE (odds ratio 1.21, 95% confidence interval [CI] 1.04-1.42) or a major bleeding (odds ratio 1.60, 95% CI 1.26-2.03), with no impact of daily dose and duration of paracetamol treatment. Time-varying analysis found an increased risk of MACE with both paracetamol (hazard ratio 1.22, 95% CI 1.05-1.43) and ibuprofen (hazard ratio 1.47, 95% CI 1.06-2.03) and of major bleeding with paracetamol (hazard ratio 1.95, 95% CI 1.45-2.62). CONCLUSIONS: There was a weak and inconsistent signal for association between paracetamol or ibuprofen and MACE or major bleeding, which may be related to either a genuine but modest effect of these drugs or to residual confounding. CLINICAL TRIAL REGISTRATION: http://www.isrctn.com. Unique identifier: ISRCTN66157730.

Safety of Endovascular Thrombectomy in Patients Receiving Non-Vitamin K Antagonist Oral Anticoagulants.

BACKGROUND AND PURPOSE: Prospective data on the safety of endovascular thrombectomy in acute stroke patients on non-vitamin K antagonist oral anticoagulants are lacking. METHODS: Prospective multicenter observational study. Patients with ischemic stroke undergoing thrombectomy with or without preceding thrombolysis were enrolled into the Registry of Acute Ischemic Stroke Under New Oral Anticoagulants. Baseline characteristics and functional outcome at 3 months were assessed. Hemorrhagic transformation and symptomatic intracranial hemorrhage were analyzed. Reperfusion was graded using the modified Thrombolysis in Cerebral Infarction score. RESULTS: Of 28 patients treated with thrombectomy, 5 had received also systemic thrombolysis (18%). Intracranial hemorrhage was observed in 46%, but symptomatic intracranial hemorrhage occurred only in 1 patient. Successful reperfusion (Thrombolysis in Cerebral Infarction score, 2b-3) was achieved in 59%. At 3 months, 19% had a modified Rankin Scale score of 0 to 2, and mortality was 26%. CONCLUSIONS: Thrombectomy in non-vitamin K antagonist oral anticoagulant patients seems safe although a comparatively high rate of asymptomatic hemorrhagic transformation was noted. Confirmation in larger prospective controlled cohorts is necessary. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT01850797.

Heterogeneity of acute multiple sclerosis lesions on sodium (23Na) MRI.

BACKGROUND: Advanced magnetic resonance imaging (MRI) techniques provide a window into pathological processes in multiple sclerosis (MS). Nevertheless, to date only few studies have performed sodium MRI in MS. OBJECTIVES: We analysed total sodium concentration (TSC) in hyperacute, acute and chronic lesions in MS with (23)Na MRI. METHODS: (23)Na MRI and (1)H MRI were performed in 65 MS patients and 10 healthy controls (HC). Mean TSC was quantified in all MS lesions with a diameter of >5 mm and in the normal appearing white and grey matter (NAWM, NAGM). RESULTS: TSC in the NAWM and the NAGM of MS patients was significantly higher compared to HC (WM: 37.51 ± 2.65 mM versus 35.17 ± 3.40 mM; GM: 43.64 ± 2.75 mM versus 40.09 ± 4.64 mM). Acute and chronic MS lesions showed elevated TSC levels of different extent (contrast-enhancing lesions (49.07 ± 6.99 mM), T1 hypointense lesions (45.06 ± 6.26 mM) and remaining T1 isointense lesions (39.88 ± 5.54 mM)). However, non-enhancing hyperacute lesions with a reduced apparent diffusion coefficient showed a TSC comparable to the NAWM (37.22 ± 4.62 mM). CONCLUSIONS: TSC is not only a sensitive marker of the severity of chronic tissue abnormalities in MS but is also highly sensitive to opening of the blood-brain barrier and vasogenic tissue oedema in contrast-enhancing lesions.

Body weight gain in patients with bilateral deep brain stimulation for dystonia.

In patients with Parkinson's disease, significant weight gain following chronic deep brain stimulation (DBS) has been reported. Recently, relevant weight gain could be demonstrated also following subthalamic nucleus DBS in patients with primary cervical dystonia. Prospective analyses of body weight changes following DBS in patients with dystonia, however, have not been published so far. We aimed to analyse the changes of body weight following DBS in patients with dystonia. The body mass index (BMI) of 17 consecutive patients with segmental or generalised dystonia (mean age 54.6 ± 16.1 years) treated with bilateral DBS of the globus pallidus internus (GPi) (n = 14) or the thalamic ventral intermediate nucleus (n = 3) was measured preoperatively (pre-OP) and at three follow-up (FU) time points post-DBS surgery (FU1 = 7 months, FU2 = 17 months, FU3 = 72 months). All patients benefited from marked improvement in their dystonia. The mean BMI pre-OP (SD) was 22.5 (±3.7) kg/m(2) and increased stepwise to 24.0 (±3.3) kg/m(2) at FU1, 24.4 (±3.7) kg/m(2) at FU2 and 24.9 (±3.7) kg/m(2) at FU3 (p < 0.05 at all three FUs compared to pre-OP). Relative BMI increase and improvement of dystonia were correlated (p = 0.025). Chronic bilateral GPi DBS in patients with dystonia is associated with significant body weight gain, in particular during the first 6 months post-OP. This probably is a result of improvement of dystonic motor symptoms and recovery of eating dysfunction rather than a target-specific phenomenon.