Statin Therapy for Secondary Prevention in Ischemic Stroke Patients With Cerebral Microbleeds.

BACKGROUND AND OBJECTIVES: The association between statin use and the risk of intracranial hemorrhage (ICrH) following ischemic stroke (IS) or transient ischemic attack (TIA) in patients with cerebral microbleeds (CMBs) remains uncertain. This study investigated the risk of recurrent IS and ICrH in patients receiving statins based on the presence of CMBs. METHODS: We conducted a pooled analysis of individual patient data from the Microbleeds International Collaborative Network, comprising 32 hospital-based prospective studies fulfilling the following criteria: adult patients with IS or TIA, availability of appropriate baseline MRI for CMB quantification and distribution, registration of statin use after the index stroke, and collection of stroke event data during a follow-up period of ≥3 months. The primary endpoint was the occurrence of recurrent symptomatic stroke (IS or ICrH), while secondary endpoints included IS alone or ICrH alone. We calculated incidence rates and performed Cox regression analyses adjusting for age, sex, hypertension, atrial fibrillation, previous stroke, and use of antiplatelet or anticoagulant drugs to explore the association between statin use and stroke events during follow-up in patients with CMBs. RESULTS: In total, 16,373 patients were included (mean age 70.5 ± 12.8 years; 42.5% female). Among them, 10,812 received statins at discharge, and 4,668 had 1 or more CMBs. The median follow-up duration was 1.34 years (interquartile range: 0.32-2.44). In patients with CMBs, statin users were compared with nonusers. Compared with nonusers, statin therapy was associated with a reduced risk of any stroke (incidence rate [IR] 53 vs 79 per 1,000 patient-years, adjusted hazard ratio [aHR] 0.68 [95% CI 0.56-0.84]), a reduced risk of IS (IR 39 vs 65 per 1,000 patient-years, aHR 0.65 [95% CI 0.51-0.82]), and no association with the risk of ICrH (IR 11 vs 16 per 1,000 patient-years, aHR 0.73 [95% CI 0.46-1.15]). The results in aHR remained consistent when considering anatomical distribution and high burden (≥5) of CMBs. DISCUSSION: These observational data suggest that secondary stroke prevention with statins in patients with IS or TIA and CMBs is associated with a lower risk of any stroke or IS without an increased risk of ICrH. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that for patients with IS or TIA and CMBs, statins lower the risk of any stroke or IS without increasing the risk of ICrH.

Clinical Associations and Prognostic Value of MRI-Visible Perivascular Spaces in Patients With Ischemic Stroke or TIA: A Pooled Analysis

BACKGROUND AND OBJECTIVES: Visible perivascular spaces are an MRI marker of cerebral small vessel disease and might predict future stroke. However, results from existing studies vary. We aimed to clarify this through a large collaborative multicenter analysis. METHODS: We pooled individual patient data from a consortium of prospective cohort studies. Participants had recent ischemic stroke or transient ischemic attack (TIA), underwent baseline MRI, and were followed up for ischemic stroke and symptomatic intracranial hemorrhage (ICH). Perivascular spaces in the basal ganglia (BGPVS) and perivascular spaces in the centrum semiovale (CSOPVS) were rated locally using a validated visual scale. We investigated clinical and radiologic associations cross-sectionally using multinomial logistic regression and prospective associations with ischemic stroke and ICH using Cox regression. RESULTS: We included 7,778 participants (mean age 70.6 years; 42.7% female) from 16 studies, followed up for a median of 1.44 years. Eighty ICH and 424 ischemic strokes occurred. BGPVS were associated with increasing age, hypertension, previous ischemic stroke, previous ICH, lacunes, cerebral microbleeds, and white matter hyperintensities. CSOPVS showed consistently weaker associations. Prospectively, after adjusting for potential confounders including cerebral microbleeds, increasing BGPVS burden was independently associated with future ischemic stroke (versus 0-10 BGPVS, 11-20 BGPVS: HR 1.19, 95% CI 0.93-1.53; 21+ BGPVS: HR 1.50, 95% CI 1.10-2.06; p = 0.040). Higher BGPVS burden was associated with increased ICH risk in univariable analysis, but not in adjusted analyses. CSOPVS were not significantly associated with either outcome. DISCUSSION: In patients with ischemic stroke or TIA, increasing BGPVS burden is associated with more severe cerebral small vessel disease and higher ischemic stroke risk. Neither BGPVS nor CSOPVS were independently associated with future ICH.

Domain-specific neuropsychological investigation of CAA with and without intracerebral haemorrhage.

BACKGROUND: Cerebral amyloid angiopathy (CAA) is associated with cognitive impairment, but the contributions of lobar intracerebral haemorrhage (ICH), underlying diffuse vasculopathy, and neurodegeneration, remain uncertain. We investigated the domain-specific neuropsychological profile of CAA with and without ICH, and their associations with structural neuroimaging features. METHODS: Data were collected from patients with possible or probable CAA attending a specialist outpatient clinic. Patients completed standardised neuropsychological assessment covering seven domains. MRI scans were scored for markers of cerebral small vessel disease and neurodegeneration. Patients were grouped into those with and without a macro-haemorrhage (CAA-ICH and CAA-non-ICH). RESULTS: We included 77 participants (mean age 72, 65% male). 26/32 (81%) CAA-non-ICH patients and 41/45 (91%) CAA-ICH patients were impaired in at least one cognitive domain. Verbal IQ and non-verbal IQ were the most frequently impaired, followed by executive functions and processing speed. We found no significant differences in the frequency of impairment across domains between the two groups. Medial temporal atrophy was the imaging feature most consistently associated with cognitive impairment (both overall and in individual domains) in both univariable and multivariable analyses. DISCUSSION: Cognitive impairment is common in CAA, even in the absence of ICH, suggesting a key role for diffuse processes related to small vessel disease and/or neurodegeneration. Our findings indicate that neurodegeneration, possibly due to co-existing Alzheimer's disease pathology, may be the most important contributor. The observation that general intelligence is the most frequently affected domain suggests that CAA has a generalised rather than focal cognitive impact.

Associations of renal function with cerebral small vessel disease and functional outcome in acute intracerebral haemorrhage: A hospital-based prospective cohort study.

BACKGROUND: Intracerebral haemorrhage (ICH) is a severe clinical consequence of cerebral small vessel disease (SVD), but associations between renal impairment and SVD in patients with ICH have not been fully characterised. METHODS: Using data from the CROMIS-2 ICH observational study, we compared SVD neuroimaging markers and total burden (score 0-3) identified using CT brain imaging in patients with and without renal impairment (estimated glomerular filtration rate, eGFR<60). We assessed functional outcome at 6-month follow-up using the modified Rankin scale. RESULTS: 1027 participants were included (mean age 72.8, 57.1% male); 274 with and 753 without renal impairment. 18.7% of the eGFR<60 group had moderate-to-severe SVD burden (score 2-3), compared with 14.0% of those with eGFR>60 (p = 0.039). SVD burden was associated with renal impairment after adjusting for hypertension (OR 1.36, 95% CI 1.04-1.77, p = 0.023), but not after adjusting for age. Cerebral atrophy was more prevalent in patients with eGFR<60 (81.2% vs. 72.0%, p = 0.002), as were WMH (45.6% vs. 36.6%, p = 0.026). Neither was associated with renal function after adjusting for age and vascular risk factors. Renal impairment was associated with functional outcome (OR 0.65, 95% CI 0.47-0.89, p = 0.007), but not after adjusting for age, pre-morbid function and comorbidities (OR 0.95, 95% CI 0.65-1.38, p = 0.774). CONCLUSION: In acute ICH, renal impairment is associated with a higher cerebral SVD burden independent of hypertension, but not age. Reduced eGFR is associated with worse functional outcome, but not independent of age and comorbidities. Since CT has limited sensitivity to detect SVD severity and distribution, further studies including MRI are needed.

Sex Differences in Poststroke Cognitive Impairment: A Multicenter Study in 2343 Patients With Acute Ischemic Stroke.

BACKGROUND: Poststroke cognitive impairment (PSCI) occurs in about half of stroke survivors. Cumulative evidence indicates that functional outcomes of stroke are worse in women than men. Yet it is unknown whether the occurrence and characteristics of PSCI differ between men and women. METHODS: Individual patient data from 9 cohorts of patients with ischemic stroke were harmonized and pooled through the Meta-VCI-Map consortium (n=2343, 38% women). We included patients with visible symptomatic infarcts on computed tomography/magnetic resonance imaging and cognitive assessment within 15 months after stroke. PSCI was defined as impairment in ≥1 cognitive domains on neuropsychological assessment. Logistic regression analyses were performed to compare men to women, adjusted for study cohort, to obtain odds ratios for PSCI and individual cognitive domains. We also explored sensitivity and specificity of cognitive screening tools for detecting PSCI, according to sex (Mini-Mental State Examination, 4 cohorts, n=1814; Montreal Cognitive Assessment, 3 cohorts, n=278). RESULTS: PSCI was found in 51% of both women and men. Men had a lower risk of impairment of attention and executive functioning (men: odds ratio, 0.76 [95% CI, 0.61-0.96]), and language (men: odds ratio, 0.67 [95% CI, 0.45-0.85]), but a higher risk of verbal memory impairment (men: odds ratio, 1.43 [95% CI, 1.17-1.75]). The sensitivity of Mini-Mental State Examination (<25) for PSCI was higher for women (0.53) than for men (0.27; P=0.02), with a lower specificity for women (0.80) than men (0.96; P=0.01). Sensitivity and specificity of Montreal Cognitive Assessment (<26.) for PSCI was comparable between women and men (0.91 versus 0.86; P=0.62 and 0.29 versus 0.28; P=0.86, respectively). CONCLUSIONS: Sex was not associated with PSCI occurrence but affected domains differed between men and women. The latter may explain why sensitivity of the Mini-Mental State Examination for detecting PSCI was higher in women with a lower specificity compared with men. These sex differences need to be considered when screening for and diagnosing PSCI in clinical practice.

Immunisation with Transgenic L. tarentolae Expressing Gamma Glutamyl Cysteine Synthetase from Pathogenic Leishmania Species Protected against L. major and L. donovani Infection in a Murine Model.

Leishmaniasis is a protozoan disease responsible for significant morbidity and mortality. There is no recommended vaccine to protect against infection. In this study, transgenic Leishmania tarentolae expressing gamma glutamyl cysteine synthetase (γGCS) from three pathogenic species were produced and their ability to protect against infection determined using models of cutaneous and visceral leishmaniasis. The ability of IL-2-producing PODS® to act as an adjuvant was also determined in L. donovani studies. Two doses of the live vaccine caused a significant reduction in L. major (p < 0.001) and L. donovani (p < 0.05) parasite burdens compared to their respective controls. In contrast, immunisation with wild type L. tarentolae, using the same immunisation protocol, had no effect on parasite burdens compared to infection controls. Joint treatment with IL-2-producing PODS® enhanced the protective effect of the live vaccine in L. donovani studies. Protection was associated with a Th1 response in L. major and a mixed Th1/Th2 response in L. donovani, based on specific IgG1 and IgG2a antibody and cytokine production from in vitro proliferation assays using antigen-stimulated splenocytes. The results of this study provide further proof that γGCS should be considered a candidate vaccine for leishmaniasis.

Cerebral small vessel disease and intracranial bleeding risk: Prognostic and practical significance.

Balancing the risks of recurrent ischemia and antithrombotic-associated bleeding, particularly intracranial hemorrhage (ICH), is a key challenge in the secondary prevention of ischemic stroke and transient ischemic attack. In hyperacute ischemic stroke, the use of acute reperfusion therapies is determined by the balance of anticipated benefit and the risk of ICH. Cerebral small vessel disease (CSVD) causes most spontaneous ICH. Here, we review the evidence linking neuroimaging markers of CSVD to antithrombotic and thrombolytic-associated ICH, with emphasis on cerebral microbleeds (CMB). We discuss their role in the prediction of ICH, and practical implications for clinical decision making. Although current observational data suggest CMB presence should not preclude antithrombotic therapy in patients with ischemic stroke or TIA, they are useful for improving ICH risk prediction with potential relevance for determining the optimal secondary prevention strategy, including the use of left atrial appendage occlusion. Following ICH, recommencing antiplatelets is probably safe in most patients, while the inconclusive results of recent randomized controlled trials of anticoagulant use makes recruitment to ongoing trials (including those testing left atrial appendage occlusion) in this area a high priority. Concern regarding CSVD and ICH risk after hyperacute stroke treatment appears to be unjustified in most patients, though some uncertainty remains regarding patients with very high CMB burden and other risk factors for ICH. We encourage careful phenotyping for underlying CSVD in future trials, with the potential to enhance precision medicine in stroke.

Stroke Risk and Antithrombotic Treatment During Follow-up of Patients With Ischemic Stroke and Cortical Superficial Siderosis.

BACKGROUND AND OBJECTIVES: In patients with ischemic stroke (IS) or transient ischemic attack (TIA) and cortical superficial siderosis (cSS), there are few data regarding the risk of future cerebrovascular events and also about the benefits and safety of antithrombotic drugs for secondary prevention. We investigated the associations of cSS and stroke risk in patients with recent IS or TIA. METHODS: We retrospectively analyzed the Microbleeds International Collaborative Network (MICON) database. We selected patients with IS or TIA from cohorts who had MRI-assessed cSS, available data on antithrombotic treatments, recurrent cerebrovascular events (intracranial hemorrhage [ICrH], IS, or any stroke [ICrH or IS]), and mortality. We calculated incidence rates (IRs) and performed univariable and multivariable Cox regression analyses. RESULTS: Of 12,669 patients (mean age 70.4 ± 12.3 years, 57.3% men), cSS was detected in 273 (2.2%) patients. During a mean follow-up of 24 ± 17 months, IS was more frequent than ICrH in both cSS (IR 57.1 vs 14.6 per 1,000 patient-years) and non-cSS (33.7 vs 6.3 per 1,000 patient-years) groups. Compared with the non-cSS group, cSS was associated with any stroke on multivariable analysis {IR 83 vs 42 per 1,000 patient-years, adjusted hazard ratio [HR] for cSS 1.62 (95% CI: 1.14-2.28; p = 0.006)}. This association was not significant in subgroups of patients treated with antiplatelet drugs (n = 6,554) or with anticoagulants (n = 4,044). Patients with cSS who were treated with both antiplatelet drugs and anticoagulants (n = 1,569) had a higher incidence of ICrH (IR 107.5 vs 4.9 per 1,000 patient-years, adjusted HR 13.26; 95% CI: 2.90-60.63; p = 0.001) and of any stroke (IR 198.8 vs 34.7 per 1,000 patient-years, adjusted HR 5.03; 95% CI: 2.03-12.44; p < 0.001) compared with the non-cSS group. DISCUSSION: Patients with IS or TIA with cSS are at increased risk of stroke (ICrH or IS) during follow-up; the risk of IS exceeds that of ICrH for patients receiving antiplatelet or anticoagulant treatment alone, but the risk of ICrH exceeds that of IS in patients receiving both treatments. The findings suggest that either antiplatelet or anticoagulant treatment alone should not be avoided in patients with cSS, but combined antithrombotic therapy might be hazardous. Our findings need to be confirmed by randomized clinical trials.

Targeted, actionable and fair: Reviewer reports as feedback and its effect on ECR career choices.

Previous studies of the use of peer review for the allocation of competitive funding agencies have concentrated on questions of efficiency and how to make the 'best' decision, by ensuring that successful applicants are also the more productive or visible in the long term. This paper examines the components of feedback received from an unsuccessful grant application, is associated with motivating applicants career decisions to persist (reapply for funding at T1), or to switch (not to reapply, or else leave academia). This study combined data from interviews with unsuccessful ECR applicants (n = 19) to The Wellcome Trust 2009-19, and manual coding of reviewer comments received by applicants (n = 81). All applicants received feedback on their application at T0 with a large proportion of unsuccessful applicants reapplying for funding at T1. Here, peer-review-comments-as-feedback sends signals to applicants to encourage them to persist (continue) or switch (not continue) even when the initial application has failed. Feedback associated by unsuccessful applicants as motivating their decision to resubmit had three characteristics: actionable; targeted; and fair. The results lead to identification of standards of feedback for funding agencies and peer-reviewers to promote when providing reviewer feedback to applicants as part of their peer review process. The provision of quality reviewer-reports-as-feedback to applicants, ensures that peer review acts as a participatory research governance tool focused on supporting the development of individuals and their future research plans.

Antithrombotic dilemmas in stroke medicine: new data, unsolved challenges.

Antithrombotic therapy is a key element of secondary prevention in patients who have had an ischaemic stroke or transient ischaemic attack. However, its use in clinical practice is not always straightforward. This review provides an update on certain difficult scenarios in antithrombotic management, with a focus on recent clinical trials and large observational studies. We discuss the approach to patients with an indication for antithrombotic treatment who also have clinical or radiological evidence of previous intracranial bleeding, patients with indications for both anticoagulant and antiplatelet treatment, and patients in whom antithrombotic treatment fails to prevent stroke. We also review the timing of anticoagulation initiation after cardioembolic stroke, and the use of antithrombotics in patients with asymptomatic cerebrovascular disease. Despite a wealth of new evidence, numerous uncertainties remain and we highlight ongoing trials addressing these.

Network impact score is an independent predictor of post-stroke cognitive impairment: A multicenter cohort study in 2341 patients with acute ischemic stroke.

BACKGROUND: Post-stroke cognitive impairment (PSCI) is a common consequence of stroke. Accurate prediction of PSCI risk is challenging. The recently developed network impact score, which integrates information on infarct location and size with brain network topology, may improve PSCI risk prediction. AIMS: To determine if the network impact score is an independent predictor of PSCI, and of cognitive recovery or decline. METHODS: We pooled data from patients with acute ischemic stroke from 12 cohorts through the Meta VCI Map consortium. PSCI was defined as impairment in ≥ 1 cognitive domain on neuropsychological examination, or abnormal Montreal Cognitive Assessment. Cognitive recovery was defined as conversion from PSCI < 3 months post-stroke to no PSCI at follow-up, and cognitive decline as conversion from no PSCI to PSCI. The network impact score was related to serial measures of PSCI using Generalized Estimating Equations (GEE) models, and to PSCI stratified according to post-stroke interval (<3, 3-12, 12-24, >24 months) and cognitive recovery or decline using logistic regression. Models were adjusted for age, sex, education, prior stroke, infarct volume, and study site. RESULTS: We included 2341 patients with 4657 cognitive assessments. PSCI was present in 398/844 patients (47%) <3 months, 709/1640 (43%) at 3-12 months, 243/853 (28%) at 12-24 months, and 208/522 (40%) >24 months. Cognitive recovery occurred in 64/181 (35%) patients and cognitive decline in 26/287 (9%). The network impact score predicted PSCI in the univariable (OR 1.50, 95%CI 1.34-1.68) and multivariable (OR 1.27, 95%CI 1.10-1.46) GEE model, with similar ORs in the logistic regression models for specified post-stroke intervals. The network impact score was not associated with cognitive recovery or decline. CONCLUSIONS: The network impact score is an independent predictor of PSCI. As such, the network impact score may contribute to a more precise and individualized cognitive prognostication in patients with ischemic stroke. Future studies should address if multimodal prediction models, combining the network impact score with demographics, clinical characteristics and other advanced brain imaging biomarkers, will provide accurate individualized prediction of PSCI. A tool for calculating the network impact score is freely available at https://metavcimap.org/features/software-tools/lsm-viewer/.

Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS): Protocol for a randomized controlled trial.

RATIONALE: Atrial fibrillation causes one-fifth of ischemic strokes, with a high risk of early recurrence. Although long-term anticoagulation is highly effective for stroke prevention in atrial fibrillation, initiation after stroke is usually delayed by concerns over intracranial hemorrhage risk. Direct oral anticoagulants offer a significantly lower risk of intracranial hemorrhage than other anticoagulants, potentially allowing earlier anticoagulation and prevention of recurrence, but the safety and efficacy of this approach has not been established. AIM: Optimal timing of anticoagulation after acute ischemic stroke with atrial fibrillation (OPTIMAS) will investigate whether early treatment with a direct oral anticoagulant, within four days of stroke onset, is as effective or better than delayed initiation, 7 to 14 days from onset, in atrial fibrillation patients with acute ischemic stroke. METHODS AND DESIGN: OPTIMAS is a multicenter randomized controlled trial with blinded outcome adjudication. Participants with acute ischemic stroke and atrial fibrillation eligible for anticoagulation with a direct oral anticoagulant are randomized 1:1 to early or delayed initiation. As of December 2021, 88 centers in the United Kingdom have opened. STUDY OUTCOMES: The primary outcome is a composite of recurrent stroke (ischemic stroke or symptomatic intracranial hemorrhage) and systemic arterial embolism within 90 days. Secondary outcomes include major bleeding, functional status, anticoagulant adherence, quality of life, health and social care resource use, and length of hospital stay. SAMPLE SIZE TARGET: A total of 3478 participants assuming event rates of 11.5% in the control arm and 8% in the intervention arm, 90% power and 5% alpha. We will follow a non-inferiority gatekeeper analysis approach with a non-inferiority margin of 2 percentage points. DISCUSSION: OPTIMAS aims to provide high-quality evidence on the safety and efficacy of early direct oral anticoagulant initiation after atrial fibrillation-associated ischemic stroke.Trial registrations: ISRCTN: 17896007; ClinicalTrials.gov: NCT03759938.

Strategic infarct locations for post-stroke cognitive impairment: a pooled analysis of individual patient data from 12 acute ischaemic stroke cohorts.

BACKGROUND: Post-stroke cognitive impairment (PSCI) occurs in approximately half of people in the first year after stroke. Infarct location is a potential determinant of PSCI, but a comprehensive map of strategic infarct locations predictive of PSCI is unavailable. We aimed to identify infarct locations most strongly predictive of PSCI after acute ischaemic stroke and use this information to develop a prediction model. METHODS: In this large-scale multicohort lesion-symptom mapping study, we pooled and harmonised individual patient data from 12 cohorts through the Meta-analyses on Strategic Lesion Locations for Vascular Cognitive Impairment using Lesion-Symptom Mapping (Meta VCI Map) consortium. The identified cohorts (as of Jan 1, 2019) comprised patients with acute symptomatic infarcts on CT or MRI (with available infarct segmentations) and a cognitive assessment up to 15 months after acute ischaemic stroke onset. PSCI was defined as performance lower than the fifth percentile of local normative data, on at least one cognitive domain on a multidomain neuropsychological assessment or on the Montreal Cognitive Assessment. Voxel-based lesion-symptom mapping (VLSM) was used to calculate voxel-wise odds ratios (ORs) for PSCI that were mapped onto a three-dimensional brain template to visualise PSCI risk per location. For the prediction model of PSCI risk, a location impact score on a 5-point scale was derived from the VLSM results on the basis of the mean voxel-wise coefficient (ln[OR]) within each patient's infarct. We did combined internal-external validation by leave-one-cohort-out cross-validation for all 12 cohorts using logistic regression. Predictive performance of a univariable model with only the location impact score was compared with a multivariable model with addition of other clinical PSCI predictors (age, sex, education, time interval between stroke onset and cognitive assessment, history of stroke, and total infarct volume). Testing of visual ratings was done by three clinicians, and accuracy, inter-rater reliability, and intra-rater reliability were assessed with Cohen's weighted kappa. FINDINGS: In our sample of 2950 patients (mean age 66·8 years [SD 11·6]; 1157 [39·2%] women), 1286 (43·6%) had PSCI. We achieved high lesion coverage of the brain in our analyses (86·9%). Infarcts in the left frontotemporal lobes, left thalamus, and right parietal lobe were strongly associated with PSCI (after false discovery rate correction, q<0·01; voxel-wise ORs >20). On cross-validation, the location impact score showed good correspondence, based on visual assessment of goodness of fit, between predicted and observed risk of PSCI across cohorts after adjusting for cohort-specific PSCI occurrence. Cross-validations showed that the location impact score by itself had similar performance to the combined model with other PSCI predictors, while allowing for easy visual assessment. Therefore the univariable model with only the location impact score was selected as the final model. Correspondence between visual ratings and actual location impact score (Cohen's weighted kappa: range 0·88-0·92), inter-rater agreement (0·85-0·87), and intra-rater agreement (for a single rater, 0·95) were all high. INTERPRETATION: To the best of our knowledge, this study provides the first comprehensive map of strategic infarct locations associated with risk of PSCI. A location impact score was derived from this map that robustly predicted PSCI across cohorts. Furthermore, we developed a quick and reliable visual rating scale that might in the future be applied by clinicians to identify individual patients at risk of PSCI. FUNDING: The Netherlands Organisation for Health Research and Development.

Development of imaging-based risk scores for prediction of intracranial haemorrhage and ischaemic stroke in patients taking antithrombotic therapy after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies.

BACKGROUND: Balancing the risks of recurrent ischaemic stroke and intracranial haemorrhage is important for patients treated with antithrombotic therapy after ischaemic stroke or transient ischaemic attack. However, existing predictive models offer insufficient performance, particularly for assessing the risk of intracranial haemorrhage. We aimed to develop new risk scores incorporating clinical variables and cerebral microbleeds, an MRI biomarker of intracranial haemorrhage and ischaemic stroke risk. METHODS: We did a pooled analysis of individual-patient data from the Microbleeds International Collaborative Network (MICON), which includes 38 hospital-based prospective cohort studies from 18 countries. All studies recruited participants with previous ischaemic stroke or transient ischaemic attack, acquired baseline MRI allowing quantification of cerebral microbleeds, and followed-up participants for ischaemic stroke and intracranial haemorrhage. Participants not taking antithrombotic drugs were excluded. We developed Cox regression models to predict the 5-year risks of intracranial haemorrhage and ischaemic stroke, selecting candidate predictors on biological relevance and simplifying models using backward elimination. We derived integer risk scores for clinical use. We assessed model performance in internal validation, adjusted for optimism using bootstrapping. The study is registered on PROSPERO, CRD42016036602. FINDINGS: The included studies recruited participants between Aug 28, 2001, and Feb 4, 2018. 15 766 participants had follow-up for intracranial haemorrhage, and 15 784 for ischaemic stroke. Over a median follow-up of 2 years, 184 intracranial haemorrhages and 1048 ischaemic strokes were reported. The risk models we developed included cerebral microbleed burden and simple clinical variables. Optimism-adjusted c indices were 0·73 (95% CI 0·69-0·77) with a calibration slope of 0·94 (0·81-1·06) for the intracranial haemorrhage model and 0·63 (0·62-0·65) with a calibration slope of 0·97 (0·87-1·07) for the ischaemic stroke model. There was good agreement between predicted and observed risk for both models. INTERPRETATION: The MICON risk scores, incorporating clinical variables and cerebral microbleeds, offer predictive value for the long-term risks of intracranial haemorrhage and ischaemic stroke in patients prescribed antithrombotic therapy for secondary stroke prevention; external validation is warranted. FUNDING: British Heart Foundation and Stroke Association.

Association of enlarged perivascular spaces and anticoagulant-related intracranial hemorrhage.

OBJECTIVE: To investigate whether enlarged perivascular spaces (PVS) within the basal ganglia or deep cerebral white matter are risk factors for intracranial hemorrhage in patients taking oral anticoagulants (OACs), independent of established clinical and radiologic risk factors, we conducted a post hoc analysis of Clinical Relevance of Microbleeds in Stroke (CROMIS-2) (atrial fibrillation [AF]), a prospective inception cohort study. METHODS: Patients with atrial fibrillation and recent TIA or ischemic stroke underwent standardized MRI prior to starting OAC. We rated basal ganglia PVS (BGPVS) and centrum semiovale PVS (CSOPVS), cerebral microbleeds (CMBs), white matter hyperintensities, and lacunes. We dichotomized the PVS rating using a threshold of >10 PVS in the relevant region of either cerebral hemisphere. The primary outcome was symptomatic intracranial hemorrhage (sICH). We identified risk factors for sICH using Cox regression. RESULTS: A total of 1,386 participants with available clinical and imaging variables were followed up for a mean of 2.34 years; 14 sICH occurred (11 intracerebral). In univariable analysis, diabetes, CMB presence, lacune presence, and >10 BGPVS, but not CSOPVS, were associated with sICH. In a multivariable model incorporating all variables with significant associations in univariable analysis, >10 BGPVS (hazard ratio [HR] 8.96, 95% [CI] 2.41-33.4, p = 0.001) and diabetes (HR 3.91, 95% CI 1.34-11.4) remained significant risk factors for sICH. CONCLUSION: Enlarged BGPVS might be a novel risk factor for OAC-related ICH. The strength of this association and potential use in predicting ICH in clinical practice should be investigated in larger cohorts.

Proportion of intracerebral haemorrhage due to cerebral amyloid angiopathy in the East and West: Comparison between single hospital centres in Japan and the United Kingdom.

PURPOSE: We investigated whether the proportion of intracerebral haemorrhage (ICH) due to cerebral amyloid angiopathy (CAA) differs between patients admitted to hospitals in the East and the West. METHODS: This international cross-sectional study included consecutive spontaneous ICH patients admitted to one stroke centre in the United Kingdom (Western centre origin) and one in Japan (Eastern centre origin) during the same period. We classified spontaneous ICH into "CAA-related" or "other" using the Edinburgh CT-based diagnostic criteria. We used multivariable logistic regression analyses to assess the relationship between CAA-related ICH and geographical location or ethnicity (White vs. East Asian or other ethnicities). Sensitivity analyses were performed using the modified Boston MRI-based diagnostic criteria for CAA-related ICH. RESULTS: Of 433 patients (median age, 72 years; Western centre origin, 55%), 15% were classified as CAA-related ICH. In the multivariable logistic regression model, Eastern centre and ethnicity had a lower proportion of CAA-related ICH (odds ratio [OR] vs Western centre origin 0.55, 95%CI 0.31-0.98; OR [vs. White] 0.47, 95%CI 0.25-0.87); these findings remained robust in sensitivity analyses. The estimated incidence of "other" (non-CAA) ICH (attributed to hypertensive arteriopathy) was 2.5-fold higher in East Asian populations. CONCLUSIONS: The proportion CAA-related ICH is lower in an Eastern compared to a Western hospital ICH population; this might be explained by a higher incidence of ICH related to hypertensive arteriopathy in East Asian populations, suggesting that optimal ICH prevention strategies might differ between the East and West.

Atrial fibrillation and stroke: a practical guide.

Neurologists and stroke physicians will be familiar with atrial fibrillation as a major cause of ischaemic stroke, and the role of anticoagulation in preventing cardioembolic stroke. However, making decisions about anticoagulation for individual patients remains a difficult area of clinical practice, balancing the serious risk of ischaemic stroke against that of major bleeding, particularly intracranial haemorrhage. Atrial fibrillation management requires interdisciplinary collaboration with colleagues in cardiology and haematology. Recent advances, especially the now-widespread availability of direct oral anticoagulants, have brought opportunities to improve stroke care while posing new challenges. This article gives an overview of the contemporary diagnosis and management of atrial fibrillation, and the associated evidence base. Where there is uncertainty, we describe our own approach to these areas, while highlighting ongoing research that will likely guide future practice.

Hippocampal Functional Dynamics Are Clinically Implicated in Autoimmune Encephalitis With Faciobrachial Dystonic Seizures.

This is the first study to investigate functional brain activity in patients affected by autoimmune encephalitis with faciobrancial dystonic seizures (FBDS). Multimodal 3T MRI scans, including structural neuroimaging (T1-weighted, diffusion weighted) and functional neuroimaging (scene-encoding task known to activate hippocampal regions), were performed. This case series analysis included eight patients treated for autoimmune encephalitis with FBDS, scanned during the convalescent phase of their condition (median 1.1 years post-onset), and eight healthy volunteers. Compared to controls, 50% of patients showed abnormal hippocampal activity during scene-encoding relative to familiar scene-viewing. Higher peak FBDS frequency was significantly related to lower hippocampal activity during scene-encoding (p = 0.02), though not to markers of hippocampal microstructure (mean diffusivity, p = 0.3) or atrophy (normalized volume, p = 0.4). During scene-encoding, stronger within-medial temporal lobe (MTL) functional connectivity correlated with poorer Addenbrooke's Cognitive Examination-Revised memory score (p = 0.03). These findings suggest that in autoimmune encephalitis, frequent seizures may have a long-term impact on hippocampal activity, beyond that of structural damage. These observations also suggest a potential approach to determine on-going MTL performance in this condition to guide long-term management and future clinical trials.

Post-mortem magnetic resonance imaging in patients with suspected prion disease: Pathological confirmation, sensitivity, specificity and observer reliability. A national registry.

The relationship between magnetic resonance imaging (MRI) and clinical variables in patients suspected to have Creutzfeldt-Jakob Disease (CJD) is uncertain. We aimed to determine which MRI features of CJD (positive or negative), previously described in vivo, accurately identify CJD, are most reliably detected, vary with disease duration, and whether combined clinical and imaging features increase diagnostic accuracy for CJD. Prospective patients suspected of having CJD were referred to the National CJD Research and Surveillance Unit between 1994-2004; post-mortem, brains were sent for MRI and histopathology. Two neuroradiologists independently assessed MRI for atrophy, white matter hyperintensities, and caudate, lentiform and pulvinar signals, blind to histopathological diagnosis and clinical details. We examined differences in variable frequencies using Fisher's exact tests, and associations between variables and CJD in logistic regression models. Amongst 200 cases, 118 (59%) with a histopathological diagnosis of CJD and 82 (41%) with histopathological diagnoses other than CJD, a logistic regression model including age, disease duration at death, atrophy, white matter hyperintensities, bright or possibly bright caudate, and present pulvinar sign correctly classified 81% of cases as CJD versus not CJD. Pulvinar sign alone was not independently associated with an increased likelihood of histopathologically-confirmed CJD (of any subtype) or sporadic CJD after adjustment for age at death, disease duration, atrophy, white matter hyperintensities or caudate signal; despite the large sample, data sparsity precluded investigation of the association of pulvinar sign with variant CJD. No imaging feature varied significantly with disease duration. Of the positive CJD signs, neuroradiologists most frequently agreed on the presence or absence of atrophy (agreements in 169/200 cases [84.5%]). Combining patient age, and disease duration, with absence of atrophy and white matter hyperintensities and presence of increased caudate signal and pulvinar sign predicts CJD with good accuracy. Autopsy remains essential.

Goalkeepers' Reputations Bias Shot Placement in Soccer Penalties.

Research has demonstrated that in addition to minor changes in goalkeepers' position or height, goalkeeper reputation seems to influence penalty takers' shot placement. However, this evidence is based on correlative designs. Here, the authors experimentally manipulated both height and reputation to examine their causal impact on actual shot placement. Penalty takers performed kicks facing goalkeepers of different height (tall vs. short) and reputation (high vs. low) projected on a life-size screen. Results showed that tall goalkeepers were judged as taller than short goalkeepers. Likewise, high-reputation goalkeepers were judged as taller than low-reputation goalkeepers. An important finding was that reputation also influenced shot placement. When facing high-reputation goalkeepers, penalty takers aimed farther away from the goalkeeper and missed the goal more often. It follows that reputation affects both height estimates of goalkeepers and, most important, shot placement. Consequently, manipulating perceived reputation of goalkeepers provides an avenue for sport professionals to subtly influence shot placement of penalty takers.