Sex Differences in Frequency, Severity, and Distribution of Cerebral Microbleeds.

Importance: Cerebral small vessel disease (SVD) is associated with various cerebrovascular outcomes, but data on sex differences in SVD are scarce. Objective: To investigate whether the frequency, severity, and distribution of cerebral microbleeds (CMB), other SVD markers on magnetic resonance imaging (MRI), and outcomes differ by sex. Design, Setting, and Participants: This cohort study used pooled individual patient data from the Microbleeds International Collaborative Network, including patients from 38 prospective cohort studies in 18 countries between 2000 and 2018, with clinical follow-up of at least 3 months (up to 5 years). Participants included patients with acute ischemic stroke or transient ischemic attack with available brain MRI. Data were analyzed from April to December 2023. Main Outcomes and Measures: Outcomes of interest were presence of CMB, lacunes, and severe white matter hyperintensities determined on MRI. Additionally, mortality, recurrent ischemic stroke, and intracranial hemorrhage during follow-up were assessed. Multivariable random-effects logistic regression models, Cox regression, and competing risk regression models were used to investigate sex differences in individual SVD markers, risk of recurrent cerebrovascular events, and death. Results: A total of 20 314 patients (mean [SD] age, 70.1 [12.7] years; 11 721 [57.7%] male) were included, of whom 5649 (27.8%) had CMB. CMB were more frequent in male patients, and this was consistent throughout different age groups, locations, and in multivariable models (female vs male adjusted odds ratio [aOR], 0.86; 95% CI, 0.80-0.92; P < .001). Female patients had fewer lacunes (aOR, 0.82; 95% CI, 0.74-0.90; P < .001) but a higher prevalence of severe white matter hyperintensities (aOR, 1.10; 95% CI, 1.01-1.20; P = .04) compared with male patients. A total of 2419 patients (11.9%) died during a median (IQR) follow-up of 1.4 (0.7-2.5) years. CMB presence was associated with a higher risk of mortality in female patients (hazard ratio, 1.15; 95% CI, 1.02-1.31), but not male patients (hazard ratio, 0.95; 95% CI, 0.84-1.07) (P for interaction = .01). A total of 1113 patients (5.5%) had recurrent ischemic stroke, and 189 patients (0.9%) had recurrent intracranial hemorrhage, with no sex differences. Conclusions and Relevance: This cohort study using pooled individual patient data found varying frequencies of individual SVD markers between female and male patients, indicating potential pathophysiological differences in manifestation and severity of SVD. Further research addressing differences in pathomechanisms and outcomes of SVD between female and male patients is required.

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.

Does Chronic Kidney Disease Have an Impact on the Use of Oral Anticoagulants after Stroke? An Observational Follow-Up Study.

INTRODUCTION: Chronic kidney disease is common in patients with acute ischemic stroke. We investigated whether chronic kidney disease has an impact on anticoagulation treatment recommendations after ischemic stroke or transient ischemic attack (TIA) related with atrial fibrillation (AF). MATERIALS AND METHODS: We extracted treatment-related data concerning stroke/TIA patients with AF and available estimated glomerular filtration rates (eGFR) from a monocentric prospective German stroke registry. Chronic kidney disease was defined as eGFR <60 mL/min/1.73 m2. Using uni- and multivariate logistic regression analyses, we investigated whether chronic kidney disease was associated with a lower probability to be treated with anticoagulation early after stroke. RESULTS: A total of 273 patients entered the analysis. In 242 AF patients (88.6%), oral anticoagulation was recommended after stroke. In multivariate logistic regression analysis, chronic kidney disease was not identified as an independent factor for the decision against anticoagulation (OR 1.63, 95% CI: 0.50-5.31, p = 0.421); only increasing age (OR 1.10, 95% CI: 1.00-1.21, p = 0.061) and a modified Rankin Scale >3 at discharge (OR 3.41, 95% CI: 0.88-13.24, p = 0.077) showed a nonsignificant trend for the decision to omit anticoagulation. A total of 155 of 167 patients (92.8%) were still anticoagulated at follow-up. A total of 44 patients with chronic kidney disease completed follow-up, and of those, 37 were still anticoagulated (84%). In patients without chronic kidney disease, 118/167 (70.7%) had continued anticoagulation (p = 0.310). CONCLUSION: Our results show that chronic kidney disease was not the main factor in the decision to withhold oral anticoagulation in patients with recent stroke/TIA and AF.

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.

[Aquaporin-4 and Myelin Oligodendrocyte Glycoprotein Antibody-Associated Optic Neuritis: Diagnosis and Treatment]. / Aquaporin-4- und Myelin-Oligodendrozyten-Glykoprotein-Antikörper-assoziierte Optikusneuritis: Diagnose und Therapie.

Optic neuritis (ON) is a frequent manifestation of aquaporin-4 (AQP4) antibody-mediated neuromyelitis optica spectrum disorders (NMOSD) and myelin oligodendrocyte glycoprotein antibody-associated encephalomyelitis (MOG-EM; also termed MOG antibody-associated disorders, MOGAD). The past few years have seen major advances in the diagnosis and treatment of these two relatively new entities: international diagnostic criteria for NMOSD and MOG-EM have been proposed, improved antibody assays developed, and consensus recommendations on the indications and methodology of serological testing published. Very recently, the results of four phase III trials assessing new treatment options for NMOSD have been presented. With eculizumab, a monoclonal antibody inhibiting complement factor C5, for the first time a relapse-preventing long-term treatment for NMOSD - which has so far mostly been treated off-label with rituximab, azathioprine, and other immunosuppressants - has been approved. Data from recent retrospective studies evaluating treatment responses in MOG-ON suggest that rituximab and other immunosuppressants are effective also in this entity. By contrast, many drugs approved for the treatment of multiple sclerosis (MS) have been found to be either ineffective or to cause disease exacerbation (e.g., interferon-ß). Recent studies have shown that not only NMOSD-ON but also MOG-ON usually follows a relapsing course. If left untreated, both disorders can result in severe visual deficiency or blindness, though MOG-ON seems to have a better prognosis overall. Acute attacks are treated with high-dose intravenous methylprednisolone and, in many cases, plasma exchange (PEX) or immunoadsorption (IA). Early use of PEX/IA may prevent persisting visual loss and improve the long-term outcome. Especially MOG-ON has been found to be frequently associated with flare-ups, if steroids are not tapered, and to underlie many cases of "chronic relapsing inflammatory optic neuropathy" (CRION). Both NMOSD-ON and MOG-ON are often associated with simultaneous or consecutive attacks of myelitis and brainstem encephalitis; in contrast to earlier assumptions, supratentorial MRI brain lesions are a common finding and do not preclude the diagnosis. In this article, we review the current knowledge on the clinical presentation, epidemiology, diagnosis, and treatment of these two rare yet important differential diagnoses of both MS-associated ON und idiopathic autoimmune ON.

Cerebral microbleeds and stroke risk after ischaemic stroke or transient ischaemic attack: a pooled analysis of individual patient data from cohort studies.

BACKGROUND: Cerebral microbleeds are a neuroimaging biomarker of stroke risk. A crucial clinical question is whether cerebral microbleeds indicate patients with recent ischaemic stroke or transient ischaemic attack in whom the rate of future intracranial haemorrhage is likely to exceed that of recurrent ischaemic stroke when treated with antithrombotic drugs. We therefore aimed to establish whether a large burden of cerebral microbleeds or particular anatomical patterns of cerebral microbleeds can identify ischaemic stroke or transient ischaemic attack patients at higher absolute risk of intracranial haemorrhage than ischaemic stroke. METHODS: We did a pooled analysis of individual patient data from cohort studies in adults with recent ischaemic stroke or transient ischaemic attack. Cohorts were eligible for inclusion if they prospectively recruited adult participants with ischaemic stroke or transient ischaemic attack; included at least 50 participants; collected data on stroke events over at least 3 months follow-up; used an appropriate MRI sequence that is sensitive to magnetic susceptibility; and documented the number and anatomical distribution of cerebral microbleeds reliably using consensus criteria and validated scales. Our prespecified primary outcomes were a composite of any symptomatic intracranial haemorrhage or ischaemic stroke, symptomatic intracranial haemorrhage, and symptomatic ischaemic stroke. We registered this study with the PROSPERO international prospective register of systematic reviews, number CRD42016036602. FINDINGS: Between Jan 1, 1996, and Dec 1, 2018, we identified 344 studies. After exclusions for ineligibility or declined requests for inclusion, 20 322 patients from 38 cohorts (over 35 225 patient-years of follow-up; median 1·34 years [IQR 0·19-2·44]) were included in our analyses. The adjusted hazard ratio [aHR] comparing patients with cerebral microbleeds to those without was 1·35 (95% CI 1·20-1·50) for the composite outcome of intracranial haemorrhage and ischaemic stroke; 2·45 (1·82-3·29) for intracranial haemorrhage and 1·23 (1·08-1·40) for ischaemic stroke. The aHR increased with increasing cerebral microbleed burden for intracranial haemorrhage but this effect was less marked for ischaemic stroke (for five or more cerebral microbleeds, aHR 4·55 [95% CI 3·08-6·72] for intracranial haemorrhage vs 1·47 [1·19-1·80] for ischaemic stroke; for ten or more cerebral microbleeds, aHR 5·52 [3·36-9·05] vs 1·43 [1·07-1·91]; and for ≥20 cerebral microbleeds, aHR 8·61 [4·69-15·81] vs 1·86 [1·23-1·82]). However, irrespective of cerebral microbleed anatomical distribution or burden, the rate of ischaemic stroke exceeded that of intracranial haemorrhage (for ten or more cerebral microbleeds, 64 ischaemic strokes [95% CI 48-84] per 1000 patient-years vs 27 intracranial haemorrhages [17-41] per 1000 patient-years; and for ≥20 cerebral microbleeds, 73 ischaemic strokes [46-108] per 1000 patient-years vs 39 intracranial haemorrhages [21-67] per 1000 patient-years). INTERPRETATION: In patients with recent ischaemic stroke or transient ischaemic attack, cerebral microbleeds are associated with a greater relative hazard (aHR) for subsequent intracranial haemorrhage than for ischaemic stroke, but the absolute risk of ischaemic stroke is higher than that of intracranial haemorrhage, regardless of cerebral microbleed presence, antomical distribution, or burden. FUNDING: British Heart Foundation and UK Stroke Association.

Clinical significance of cerebral microbleeds on MRI: A comprehensive meta-analysis of risk of intracerebral hemorrhage, ischemic stroke, mortality, and dementia in cohort studies (v1).

Background Cerebral microbleeds can confer a high risk of intracerebral hemorrhage, ischemic stroke, death and dementia, but estimated risks remain imprecise and often conflicting. We investigated the association between cerebral microbleeds presence and these outcomes in a large meta-analysis of all published cohorts including: ischemic stroke/TIA, memory clinic, "high risk" elderly populations, and healthy individuals in population-based studies. Methods Cohorts (with > 100 participants) that assessed cerebral microbleeds presence on MRI, with subsequent follow-up (≥3 months) were identified. The association between cerebral microbleeds and each of the outcomes (ischemic stroke, intracerebral hemorrhage, death, and dementia) was quantified using random effects models of (a) unadjusted crude odds ratios and (b) covariate-adjusted hazard rations. Results We identified 31 cohorts ( n = 20,368): 19 ischemic stroke/TIA ( n = 7672), 4 memory clinic ( n = 1957), 3 high risk elderly ( n = 1458) and 5 population-based cohorts ( n = 11,722). Cerebral microbleeds were associated with an increased risk of ischemic stroke (OR: 2.14; 95% CI: 1.58-2.89 and adj-HR: 2.09; 95% CI: 1.71-2.57), but the relative increase in future intracerebral hemorrhage risk was greater (OR: 4.65; 95% CI: 2.68-8.08 and adj-HR: 3.93; 95% CI: 2.71-5.69). Cerebral microbleeds were an independent predictor of all-cause mortality (adj-HR: 1.36; 95% CI: 1.24-1.48). In three population-based studies, cerebral microbleeds were independently associated with incident dementia (adj-HR: 1.35; 95% CI: 1.00-1.82). Results were overall consistent in analyses stratified by different populations, but with different degrees of heterogeneity. Conclusions Our meta-analysis shows that cerebral microbleeds predict an increased risk of stroke, death, and dementia and provides up-to-date effect sizes across different clinical settings. These pooled estimates can inform clinical decisions and trials, further supporting cerebral microbleeds role as biomarkers of underlying subclinical brain pathology in research and clinical settings.

Brain microbleeds, anticoagulation, and hemorrhage risk: Meta-analysis in stroke patients with AF.

OBJECTIVES: To assess the association between cerebral microbleeds (CMBs) and future spontaneous intracerebral hemorrhage (ICH) risk in ischemic stroke patients with nonvalvular atrial fibrillation (AF) taking oral anticoagulants. METHODS: This was a meta-analysis of cohort studies with >50 patients with recent ischemic stroke and documented AF, brain MRI at baseline, long-term oral anticoagulation treatment, and ≥6 months of follow-up. Authors provided summary-level data on stroke outcomes stratified by CMB status. We estimated pooled annualized ICH and ischemic stroke rates from Poisson regression. We calculated odds ratios (ORs) of ICH by CMB presence/absence, ≥5 CMBs, and CMB topography (strictly lobar, mixed, and strictly deep) using random-effects models. RESULTS: We established an international collaboration and pooled data from 8 centers including 1,552 patients. The crude CMB prevalence was 30% and 7% for ≥5 CMBs. Baseline CMB presence (vs no CMB) was associated with ICH during follow-up (OR 2.68, 95% confidence interval [CI] 1.19-6.01, p = 0.017). Presence of ≥5 CMB was related to higher future ICH risk (OR 5.50, 95% CI 2.07-14.66, p = 0.001). The pooled annual ICH incidence increased from 0.30% (95% CI 0.04-0.55) among CMB-negative patients to 0.81% (95% CI 0.17-1.45) in CMB-positive patients (p = 0.01) and 2.48% (95% CI 1.2-6.2) in patients with ≥5 CMBs (p = 0.001). There was no association between CMBs and recurrent ischemic stroke. CONCLUSIONS: The presence of CMB on MRI and the dichotomized cutoff of ≥5 CMBs might identify subgroups of ischemic stroke patients with AF with high ICH risk and after further validation could help in risk stratification, in anticoagulation decisions, and in guiding randomized trials and ongoing large observational studies.

Recurrent stroke risk and cerebral microbleed burden in ischemic stroke and TIA: A meta-analysis.

OBJECTIVE: To determine associations between cerebral microbleed (CMB) burden with recurrent ischemic stroke (IS) and intracerebral hemorrhage (ICH) risk after IS or TIA. METHODS: We identified prospective studies of patients with IS or TIA that investigated CMBs and stroke (ICH and IS) risk during ≥3 months follow-up. Authors provided aggregate summary-level data on stroke outcomes, with CMBs categorized according to burden (single, 2-4, and ≥5 CMBs) and distribution. We calculated absolute event rates and pooled risk ratios (RR) using random-effects meta-analysis. RESULTS: We included 5,068 patients from 15 studies. There were 115/1,284 (9.6%) recurrent IS events in patients with CMBs vs 212/3,781 (5.6%) in patients without CMBs (pooled RR 1.8 for CMBs vs no CMBs; 95% confidence interval [CI] 1.4-2.5). There were 49/1,142 (4.3%) ICH events in those with CMBs vs 17/2,912 (0.58%) in those without CMBs (pooled RR 6.3 for CMBs vs no CMBs; 95% CI 3.5-11.4). Increasing CMB burden increased the risk of IS (pooled RR [95% CI] 1.8 [1.0-3.1], 2.4 [1.3-4.4], and 2.7 [1.5-4.9] for 1 CMB, 2-4 CMBs, and ≥5 CMBs, respectively) and ICH (pooled RR [95% CI] 4.6 [1.9-10.7], 5.6 [2.4-13.3], and 14.1 [6.9-29.0] for 1 CMB, 2-4 CMBs, and ≥5 CMBs, respectively). CONCLUSIONS: CMBs are associated with increased stroke risk after IS or TIA. With increasing CMB burden (compared to no CMBs), the risk of ICH increases more steeply than that of IS. However, IS absolute event rates remain higher than ICH absolute event rates in all CMB burden categories.

Preexisting Heart Disease Underlies Newly Diagnosed Atrial Fibrillation After Acute Ischemic Stroke.

BACKGROUND AND PURPOSE: Whether newly diagnosed atrial fibrillation (nAF) after stroke reflects underlying heart disease and represents an increased risk of cardioembolic stroke, or whether it is triggered by neurogenic mechanisms remains uncertain. We investigated, whether cardiovascular risk factors and echocardiographic parameters in patients with nAF are similar to patients with known AF (kAF) and differ from patients without AF. METHODS: Consecutive acute ischemic stroke patients were enrolled into a prospective stroke database. All patients with echocardiography were included and univariable and multivariable testing was applied to compare clinical characteristics and echocardiographic findings among patients with nAF, kAF, and no AF. RESULTS: A total of 1397 patients were included (male, 62.3%; median age, 71 years). AF was present in 320 (22.9%) patients. Of those, nAF was present in 36.2% (116/320) and kAF in 63.8% (204/320). No clinical or echocardiographic factor was independently associated with detection of nAF compared with kAF but a trend toward larger left atrial diameters in patients with kAF was observed (P=0.070). In contrast, patients with nAF were more often female (P<0.001), older (P<0.001) and had a larger left atrial diameters (P<0.001) compared with patients without AF. While stroke severity in patients with nAF and kAF was similar, patients without AF had less severe strokes. CONCLUSIONS: Stroke patients with nAF and with kAF share common cardiovascular risk factors, have similar echocardiographic findings and suffer equally severe strokes. We conclude that preexisting heart disease is the major cause of AF that is first diagnosed after stroke.

Renal dysfunction is associated with deep cerebral microbleeds but not white matter hyperintensities in patients with acute intracerebral hemorrhage.

Kidney disease is a risk factor for cerebral microangiopathy and spontaneous intracerebral hemorrhage (ICH). We aimed to determine the association of renal dysfunction (RD) with MRI correlates of different patterns of cerebral microangiopathies including cerebral microbleeds (CMB) and white matter lesions (WML) in patients with ICH. In a prospectively collected, single-center cohort of ICH patients, glomerular filtration rate (eGFR) was estimated using the Modification of Diet in Renal Disease equation. We classified the renal function in five categories: category 1 (eGFR ≥ 90 mL/min/1.73 m(2)), category 2 (eGFR 60-89), category 3 (eGFR 30-59), category 4 (eGFR 15-29), and category 5 (eGFR <15) and dichotomized at an eGFR of 60. Number, location, and extent of CMB and WML were measured on MRI. ICH and CMB locations were classified as lobar or deep. 97 ICH patients with MRI (mean age 65.9 ± 13.9 years) were included. Intracerebral hemorrhage was lobar in 52.6 %. Median eGFR was 85.8 mL/min/1.73 m(2) (IQR 34.3). Renal dysfunction was present in 12.4 % of the patients. At least one CMB was present in 57.7 % of patients, WML were even more frequent (97.7 %). Age and impaired renal function were factors independently associated with the presence of CMB. The presence of CMB was independently associated with the number and extent of WML. RD is a frequent comorbidity in patients with ICH. Associations of RD with hypertension and with CMB in deep location suggest a predominant impact of RD on deep rather than on lobar microangiopathy.

Cognitive impairment is not a predictor of failure to adhere to anticoagulation of stroke patients with atrial fibrillation.

BACKGROUND: Oral anticoagulation (OAC) with vitamin K antagonists (VKA) or direct oral anticoagulants (DOAC) is an effective strategy that is used for stroke prevention in patients with atrial fibrillation (AF). However, OAC is underused particularly in elderly patients, who are often physically disabled or cognitively impaired. We aimed at evaluating the effect of cognitive status and disability on OAC adherence 1 year after stroke or TIA. METHODS: In this prospective, single-center, observational study patients with ischemic stroke or TIA were consecutively included between 3/2011 and 9/2012. The detailed medical history, basic demographic variables, cardiovascular risk factors, stroke severity according to the National Institutes of Health Stroke Scale (NIHSS), medication including OAC were all recorded. Cognitive performance was measured using the Montreal Cognitive Assessment (MoCA) score at baseline. The functional status was assessed by recording activities and instrumental activities of daily living, respectively (ADL, IADL). After 12 months, patients had a follow-up visit to reassess the cognitive and functional status (MoCA, ADL and IADL) and to document the current use of OAC. RESULTS: In total, 12 months after the ischemic stroke or TIA AF had been diagnosed in 160/586 (27.3%). Of these, 151 patients (94.4%) were treated with OAC. OAC was performed using VKA in 79/151 (52.3%) and DOACs in 72/151 (47.7%). Cognitive impairment at 12 months follow-up was not associated with the absence of OAC treatment. However, regression analysis revealed that patients with AF with physical (ADL) and functional disability (IADL) were less likely to be treated with OAC (p = 0.08 and p = 0.04, respectively) 12 months after a stroke. None of these two factors, however, was independently associated with nonadherence to OAC 12 months after stroke. Although cognitive performance was similar in patients receiving VKA and direct anticoagulants (DOAC), adherence to VKA tended to be lower (82.6 vs. 94.6%, p = 0.12). CONCLUSIONS: In stroke and TIA patients with AF, the multifactorial medical and functional constellation rather than cognitive impairment specifically can be an obstacle for long-term OAC.

Reversal strategies for vitamin K antagonists in acute intracerebral hemorrhage.

OBJECTIVE: There is little evidence to guide treatment strategies for intracerebral hemorrhage on vitamin K antagonists (VKA-ICH). Treatments utilized in clinical practice include fresh frozen plasma (FFP) and prothrombin complex concentrate (PCC). Our aim was to compare case fatality with different reversal strategies. METHODS: We pooled individual ICH patient data from 16 stroke registries in 9 countries (n = 10 282), of whom 1,797 (17%) were on VKA. After excluding 250 patients with international normalized ratio < 1.3 and/or missing data required for analysis, we compared all-cause 30-day case fatality using Cox regression. RESULTS: We included 1,547 patients treated with FFP (n = 377, 24%), PCC (n = 585, 38%), both (n = 131, 9%), or neither (n = 454, 29%). The crude case fatality and adjusted hazard ratio (HR) were highest with no reversal (61.7%, HR = 2.540, 95% confidence interval [CI] = 1.784-3.616, p < 0.001), followed by FFP alone (45.6%, HR = 1.344, 95% CI = 0.934-1.934, p = 0.112), then PCC alone (37.3%, HR = 1.445, 95% CI = 1.014-2.058, p = 0.041), compared to reversal with both FFP and PCC (27.8%, reference). Outcomes with PCC versus FFP were similar (HR = 1.075, 95% CI = 0.874-1.323, p = 0.492); 4-factor PCC (n = 441) was associated with higher case fatality compared to 3-factor PCC (n = 144, HR = 1.441, 95% CI = 1.041-1.995, p = 0.027). INTERPRETATION: The combination of FFP and PCC might be associated with the lowest case fatality in reversal of VKA-ICH, and FFP may be equivalent to PCC. Randomized controlled trials with functional outcomes are needed to establish the most effective treatment.

Reasons underlying non-adherence to and discontinuation of anticoagulation in secondary stroke prevention among patients with atrial fibrillation.

BACKGROUND: Although long-term oral anticoagulation (OAC) with vitamin K antagonists for secondary stroke prevention in atrial fibrillation (AF) is highly effective, it is frequently not started or discontinued in clinical practice. We analyzed the reasons for stroke patients' and physician's nonadherence. METHODS: In this prospective, observational, single-center cohort study, consecutive patients diagnosed with acute ischemic stroke or transient ischemic attack (TIA) and AF presenting during a nine-month period were included. Adherence to OAC was evaluated at 15 ± 1 months after the event using a semi-structured telephone interview. In patients without anticoagulation, the primary care physician (PCP) was contacted to explore the reason. Associations between nonadherence to OAC therapy at follow-up and potential predictors were assessed by logistic regression analysis. RESULTS: Of the 1,049 presenting stroke/TIA patients, 139 with a first (n = 101) or a continued recommendation (n = 38) of OAC were analyzed. After 15 months, 54 patients (39% of 85 patients with OAC at follow-up) were nonadherent. The main reasons for patients' nonadherence were fear of side effects (e.g., bleeding) and inconvenience of regular international normalized ratio measurements. In two-thirds (36/54) of cases, OAC was not prescribed by the PCP; the most important reasons were a putative high risk of falling and dementia. Risk factors for nonadherence were dementia, living in a nursing home, and the noninitiation of OAC during in-hospital stay. Treatment was temporarily discontinued in 21 (25%) of patients on OAC at follow-up. CONCLUSION: Nonadherence to OAC in stroke patients results from fear of potential complications or inconvenience and physicians' concerns regarding functional status. OAC should be initiated wherever possible during the in-hospital stay.

Treatment of intracerebral hemorrhage associated with new oral anticoagulant use: the neurologist's view.

Intracerebral hemorrhage (ICH) associated with the use of oral anticoagulants (OAC-ICH) results in particularly severe strokes. A key target for the treatment of OAC-ICH is rapid restoration of effective coagulation. In patients receiving vitamin K antagonists, hemostatic factors such as prothrombin complex concentrate (PCC), fresh frozen plasma, and recombinant activated factor VII, in addition to vitamin K, can be used for anticoagulation reversal. However, emergency management of ICH during treatment with the new direct OACs (NOACs) is a major challenge. In the absence of specific antidotes, PCCs are recommended for NOAC reversal, mainly based on preclinical data.

Atrial fibrillation and prestroke cognitive impairment in stroke.

Dementia and atrial fibrillation (AF) are common comorbidities in stroke patients. The potential role of AF in cognitive impairment prior to a first stroke has yet not been characterized. The aim of our study was to evaluate the prevalence of prestroke cognitive impairment in stroke patients, and to identify whether AF is associated with prestroke cognitive impairment. In this prospective, single-center, explorative, observational study, consecutive patients with first ever transient ischemic attack (TIA), ischemic (IS) or hemorrhagic stroke (ICH) were included. For each patient cardiovascular risk factors and the National Institutes of Health Stroke Scale were recorded. Cognitive status prior to the stroke/TIA was assessed using the informant questionnaire on cognitive decline in the elderly (IQCODE). AF was diagnosed according to a standardised procedure that included the documented medical history, ECG upon admission, 24-h Holter-ECG, continuos ECG monitoring, and was categorized into paroxysmal and persistent. Logistic regression analysis was used to evaluate association of AF and prestroke cognitive impairment. A total of 788 patients were enrolled in our study. Of these, 548 (69.5 %) had an IS, TIA was present in 168 (21.3 %) and ICH in 72 (9.1 %) patients. Mean IQCODE was 3.1 (SD 0.4). Prestroke cognitive impairment (IQCODE ≥3.44) was detected in 96 (12.5 %) patients. Of these, 33 patients (4.3 %) were demented before the actual stroke event. AF was independently associated with prestroke cognitive impairment. Patients with an acute stroke frequently show a history of cognitive impairment before the event. AF is independently associated with prestroke cognitive impairment.

Left atrial appendage occlusion in atrial fibrillation after intracranial hemorrhage.

OBJECTIVE: To evaluate the safety and feasibility of percutaneous left atrial appendage occlusion (LAAO) in patients with atrial fibrillation (AF) and previous intracranial hemorrhage (ICH). METHODS: In an explorative, prospective, single-center, observational study, LAAO was performed in patients with previous ICH and AF using the Amplatzer Cardiac Plug device. Risks of ischemic strokes and hemorrhagic complications were estimated using the CHA2DS2Vasc score and the HAS-BLED score. Before and 1, 6, 12, and 24 months after the procedure, clinical status and complications were recorded. Major complications were predefined as periprocedural stroke, death, pericardial effusion, and device embolism. RESULTS: LAAO was performed in 20 patients. Based on CHA2DS2Vasc score (mean 4.5 ± 1.4) and HAS-BLED score (mean 4.7 ± 1.0), annual risks of stroke and hemorrhagic complications were 4.0%-6.7% and 8.7%-12.5%, respectively. No patient had a procedure-related complication. Minor postprocedural complications were observed in 4/20 patients (2 inguinal hematoma, 1 self-limiting asystole, and 1 thrombus formation on device). No ischemic or hemorrhagic stroke occurred during a mean follow-up of 13.6 ± 8.2 months. CONCLUSIONS: In this first study of LAAO in patients with previous ICH, LAAO appears feasible and safe. A larger, controlled trial is needed to assess the efficacy and safety of the procedure compared to other preventive measures. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that in patients with a history of previous ICH and AF, percutaneous LAAO is safe and feasible.

Intracerebral bleeding in patients on antithrombotic agents.

Patients treated with oral anticoagulants (OAC) carry a 7- to 10-fold higher risk of intracerebral hemorrhage (ICH) than patients without OAC. ICH related to oral anticoagulation (OAC-ICH) is a particularly severe form of stroke. The overall incidence of OAC-ICH ranges between 2 and 9 per 100,000 population/year and is expected to increase as the number of patients treated with OAC rises. Besides common risk factors of ICH such as age and hypertension, the intensity of anticoagulation, previous ischemic stroke, and the presence of cerebral vasculopathies (e.g., amyloid angiopathy, subcortical hypertensive arteriopathy) are associated with a greater risk of OAC-ICH. Mortality rates in OAC-ICH of 52 to 67% considerably exceed those of ICH in nonanticoagulated patients. Factors that mediate worse outcome in OAC-ICH are more frequent and prolonged secondary hematoma enlargement and intraventricular hemorrhage, The current concept of emergency treatment in OAC-ICH is rapid restoration of effective coagulation using hemostatic factors such as prothrombin complex concentrate, fresh frozen plasma, factor IX concentrates, and recombinant factor VIIa in addition to vitamin K. Emergency management of ICH under treatment with the new direct OAC is a major challenge. In the absence of specific antidotes, prothrombin concentrates are recommended mainly on the basis of preclinical data.

Spot signs in intracerebral hemorrhage: useful for identifying patients at risk for hematoma enlargement?

BACKGROUND: Prognostic signs for the identification of patients with acute spontaneous intracerebral hemorrhage (SICH) prone to hematoma expansion are limited. Contrast extravasation (spot signs, SpS) on computed tomographic angiography (CTA) may be a promising method to predict hematoma expansion in acute SICH. However, prospective data on the predictive value of the SpS on hematoma expansion and clinical outcome are still limited. We aimed to investigate associations between the presence of SpS, hematoma expansion, and clinical outcome in acute SICH. METHODS: A prospective observational study was performed between 08/2008 and 08/2011. Patients with SICH presenting within 6 h of symptom onset were included. Patients with secondary hematomas, purely intraventricular hematomas, incomplete CT evaluation, hematoma evacuation prior to follow-up brain imaging, and incomplete follow-up data and those who refused to give consent for data analysis were excluded. CT and CTA brain imaging were carried out in all patients at baseline. After 24 h, follow-up brain imaging was performed. Hematoma location, hematoma volume, and substantial hematoma expansion were documented. CTA images were evaluated by two investigators for the presence of SpS. In all positive SpS cases, images were additionally reviewed by a third rater to achieve consensus for interpretating contrast extravasation. Clinical outcome was measured by the modified Rankin Scale (mRS) at discharge and at 3 months. RESULTS: In total, 101 patients [median age 73 years (interquartile range 60-79); male 61.4%] were included in the analysis. Median time from onset to CTA was 128 min (interquartile range 90-209 min); median initial National Institute of Health Stroke Scale score was 16 (8-21). SpS were detected in 27 patients (26.7%). Cohen's kappa for the presence of SpS was 0.606, indicating moderate agreement. SpS patients had significantly higher initial hematoma volumes than patients without SpS (36.0 vs. 14.39 ml, p = 0.005). Hematoma expansion was significantly more frequent in SpS patients (59.3 vs. 21.6%, p < 0.001) and associated with the presence of SpS in the univariate analysis (OR 5.273; 95% CI 2.047-13.584, p = 0.001) and in multivariable analysis adjusted for the initial hematoma volume (OR 4.678, 95% CI 1.781-12.288, p = 0.002). Sensitivity of SpS to predict hematoma expansion was 0.5, specificity was 0.84. The positive likelihood ratio for SpS to predict hematoma expansion was 3.136 (95% CI 1.649-5.967), the negative likelihood ratio was 0.595 (95% CI 0.414-0.854). No difference in 3-month clinical outcome was observed between patients with and without SpS (median mRS score 4 and 4, p = 0.457). CONCLUSIONS: The clinical value of SpS needs to be further explored. Future studies should particularly focus on structured training procedures to identify SpS and measure the time needed to precisely assess the presence of SpS and on the prevalence of SpS in consecutive intracerebral hemorrhage populations.