Defining Minor Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: The minor stroke concept has not been analyzed in intracerebral hemorrhage (ICH) patients. Our purpose was to determine the optimal cut point on the NIH Stroke Scale (NIHSS) for defining a minor ICH (mICH) in patients with primary ICH. METHODS: An ICH was considered minor if associated with a favorable 3-month outcome (modified Rankin Scale score ≤2). For supratentorial ICH, the discovery cohort consisted of 478 patients prospectively admitted at University Hospital del Mar. Association between NIHSS at admission and 3-month outcome was evaluated with area under the curve-receiver operating characteristics (AUC-ROC) and Youden's index to identify the optimal NIHSS cutoff point to define mICH. External validation was performed in a cohort of 242 supratentorial ICH patients from University Hospital Sant Pau. For infratentorial location, patients from both hospitals (n = 85) were analyzed together. RESULTS: The best -NIHSS cutoff point defining supratentorial-mICH was 6 (AUC-ROC = 0.815 [0.774-0.857] in the discovery cohort and AUC-ROC = 0.819 [0.756-0.882] in the external validation cohort). For infratentorial ICH, the best cutoff point was 4 (AUC-ROC = 0.771 [0.664-0.877]). Using these cutoff points, 40.5% of all primary ICH cases were mICH. Of these, 70.2% were living independently at 3-month follow-up (72% for supratentorial ICH and 56.1% for infratentorial ICH) and 6.5% had died (5.3% for supratentorial ICH, and 14.6% for infratentorial ICH). For patients identified as non-mICH, good 3-month outcome was observed in 11.3% of cases; mortality was 51%. CONCLUSIONS: The definition of mICH using the NIHSS cutoff point of 6 for supratentorial ICH and 4 for infratentorial ICH is useful to identify good outcome in ICH patients.

Biological age is a novel biomarker to predict stroke recurrence.

BACKGROUND: Stroke recurrence (SR) after an ischemic stroke is an important cause of death and disability. We conducted a hospital-based study to evaluate the role of biological age (b-Age: age-related DNA-methylation changes) as a risk factor for SR. METHODS: We included 587 patients in the acute phase of stroke, assessed at one tertiary stroke center (Hospital del Mar: Barcelona, Spain). B-Age was estimated with 5 different methods based on DNA methylation, and Hannum's method was the one that better performed. We analyzed the relationships between b-Age, chronological age, sex, vascular risk factors, coronary and peripheral arterial disease, atrial fibrillation, initial neurological severity assessed by National Institutes of Health Stroke Scale (NIHSS), transient ischemic attack (TIA) in the 7 days preceding the index stroke, and symptomatic atherosclerosis. Stroke recurrence definition include: new symptoms that suggest a new ischemic event had occurred within 3 months after stroke onset and worsening by four points in the initial neurological severity (measured by National Institutes of Health Stroke Scale (NIHSS) score). RESULTS: Logistic regression analysis associated b-Age with SR [p = 0.003; OR = 1.06 (95% CI: 1.02-1.09)], independently of chronological age [p = 0.022; OR = 0.96 (95% CI 0.94-1.00)], symptomatic atherosclerosis (stenosis > 50% in the symptomatic territory), transient ischemic attack (TIA) in the 7 days preceding the index stroke, and initial NIHSS. The b-Age of patients with SR was 2.7 years older than patients without SR. CONCLUSIONS: Patients with SR were biologically older than those without SR. B-Age was independently associated with high risk of developing SR.

Influence of time to admission to a comprehensive stroke centre on the outcome of patients with intracerebral haemorrhage.

INTRODUCTION: In patients with spontaneous intracerebral haemorrhage, it is uncertain if diagnostic and therapeutic measures are time-sensitive on their impact on the outcome. We sought to determine the influence of the time to admission to a comprehensive stroke centre on the outcome of patients with acute intracerebral haemorrhage. PATIENTS AND METHODS: We studied a prospective database of consecutive patients with intracerebral haemorrhage attended at two comprehensive stroke centres (2005-2017). We excluded patients with an unwitnessed time of onset of the intracerebral haemorrhage, or previous modified Rankin Scale >3 or in those in whom withdrawal of life-sustaining interventions were decided <24 h from admission. We recorded the time from the intracerebral haemorrhage onset to admission, demographic, clinical, radiological data, the functional outcome (favourable when modified Rankin Scale ≤3) and mortality at 90 days. We conducted a propensity score-matching analysis to evaluate functional outcome and mortality. RESULTS: We included 487 patients (mean age 72.3 ± 13.9 years), and 53.2% were men. Compared to patients with an admission >110 min, patients who were admitted ≤110 min were significantly younger, and had higher National Institutes of Health Stroke Scale scores. Moreover, patients admitted ≤110 min were more likely to have basal ganglia intracerebral haemorrhage, and to show neurological deterioration. The propensity score groups were well matched. We did not find an association between time to admission and the favourable outcome (OR: 1.42 (95% CI: 0.93-2.16)) or mortality (OR: 0.64 (0.41-0.99)) at 90 days. CONCLUSIONS: Our results suggest that in patients with intracerebral haemorrhage and known symptom onset who are admitted to a comprehensive stroke centre, an early admission (≤110 min) does not influence the outcome at 90 days.

Identification of 20 novel loci associated with ischaemic stroke. Epigenome-wide association study.

DNA methylation is dynamic, varies throughout the life course, and its levels are influenced by lifestyle and environmental factors, as well as by genetic variation. The leading genetic variants at stroke risk loci identified to date explain roughly 1-2% of stroke heritability. Most of these single nucleotide polymorphisms are situated within a regulatory sequence marked by DNase I hypersensitivity sites, which would indicate involvement of an epigenetic mechanism. To detect epigenetic variants associated with stroke occurrence and stroke subtypes. A two-stage case-control epigenome-wide association study was designed. The discovery sample with 401 samples included 218 ischaemic stroke (IS) patients, assessed at Hospital del Mar (Barcelona, Spain) and 183 controls from the REGICOR cohort. In two independent samples (N = 226 and N = 166), we replicated 22 CpG sites differentially methylated in IS in 21 loci, including 2 CpGs in locus ZFHX3, which includes known genetic variants associated with stroke. The pathways associated with these loci are inflammation and angiogenesis. The meta-analysis identified 384 differentially methylated CpGs, including loci of known stroke and vascular risk genetic variants, enriched by loci involved in lipid metabolism, adipogenesis, circadian clock, and glycolysis pathways. We identified a set of 22 CpGs in 21 loci associated with IS. Our analysis suggests that DNA methylation changes may contribute to orchestrating gene expression that contributes to IS.

Association of residential air pollution, noise, and greenspace with initial ischemic stroke severity.

BACKGROUND AND PURPOSE: A number of environmental risk factors of acute ischemic stroke have been identified, but few studies have evaluated the influence of the outdoor environment on stroke severity. We assessed the association of residential ambient fine particulate matter air pollution (PM2.5), noise, and surrounding greenspace with initial stroke severity. METHODS: We obtained data on patients hospitalized with acute ischemic stroke from a hospital-based prospective stroke register (2005-2014) in Barcelona. We estimated residential PM2.5 based on an established land use regression model, greenspace as the average satellite-based Normalized Difference Vegetation Index (NDVI) within a 300 m buffer of the residence, and daily (Lday), evening (Levening), night (Lnight) and average noise (Lden) level at the street nearest to the residential address using municipal noise models. Stroke severity was assessed at the time of hospital presentation using the National Institute of Health Stroke Scale (NIHSS).We used logistic regression and binomial models to evaluate the associations of PM2.5, greenspace, and noise with initial stroke severity adjusting for potential confounders. RESULTS: Among 2761 patients, higher residential surrounding greenspace was associated with lower risk of severe stroke (OR for NIHSS>5, 0.75; 95% CI: 0.60-0.95), while, living in areas with higher Lden was associated with a higher risk of severe stroke (OR, 1.30; 95% CI: 1.02-1.65). PM2.5 was not associated with initial stroke severity. CONCLUSIONS: In an urban setting, surrounding greenspace and traffic noise at home are associated with initial stroke severity, suggesting an important influence of the built environment on the global burden of ischemic stroke.

Underdiagnosis of Unilateral Spatial Neglect in stroke unit.

OBJECTIVES: Unilateral spatial neglect (USN) is the incapacity to respond to stimuli presented opposite to a dysfunctional cerebral hemisphere. It is usually caused by non-dominant hemisphere lesions, leads to poorer prognosis and might be underdiagnosed. The objectives of the study were to ascertain the presence of USN in acute stroke patients and analyze the possible degree of underdiagnosis in a Stroke Unit. MATERIALS AND METHODS: Prospective study of consecutive non-dominant hemisphere stroke patients within a period of 21 months. "Line Bisection" and "Triangles Cancellation" tests were used for USN screening and "Circle Gap Detection Task" to confirm the USN. The results were compared with routine Stroke Unit assessment using the NIHSS to determine the possible degree of underdiagnosis. RESULTS: A total of 62 subjects, 38 women (61.29%), mean age of 74.05 (SD 10.5) years, were included. USN was diagnosed in 25 cases (40.3%) but 56% of them were not detected in routine evaluation using the NIHSS. CONCLUSIONS: Unilateral spatial neglect, a common cognitive deficit after acute stroke, is greatly underdiagnosed in routine Stroke Unit assessment. The use of simple USN-specific screening tools would improve diagnosis and therefore the possibility of implementing appropriate rehabilitation strategies.

Biological age is better than chronological as predictor of 3-month outcome in ischemic stroke.

OBJECTIVE: To analyze the effect of age-related DNA methylation changes in multiple cytosine-phosphate-guanine (CpG) sites (biological age [b-age]) on patient outcomes at 3 months after an ischemic stroke. METHODS: We included 511 patients with first-ever acute ischemic stroke assessed at Hospital del Mar (Barcelona, Spain) as the discovery cohort. Demographic and clinical data, including chronological age (c-age), vascular risk factors, initial stroke severity, recanalization treatment, and previous and 3-month modified Rankin Scale (p-mRS and 3-mRS, respectively) were registered. B-age was estimated with an algorithm, based on DNA methylation in 71 CpGs. Bivariate analysis determined variables associated with 3-mRS for inclusion in ordinal multivariate analysis. RESULTS: After ordinal regressions for 3-month ischemic stroke outcome (3-mRS), b-age was associated with outcome (odds ratio 1.04 [95% confidence interval 1.01-1.07]), nullifying c-age. Stepwise regression kept b-age, basal NIH Stroke Scale, sex, p-mRS, and recanalization treatment as better explanatory variables, instead of c-age. These results were successfully replicated in an independent cohort. CONCLUSIONS: B-age, estimated by DNA methylation, is an independent predictor of ischemic stroke outcome regardless of chronological years.

Risk factors are different for deep and lobar remote hemorrhages after intravenous thrombolysis.

BACKGROUND AND PURPOSE: Remote parenchymal haemorrhage (rPH) after intravenous thrombolysis is defined as hemorrhages that appear in brain regions without visible ischemic damage, remote from the area of ischemia causing the initial stroke symptom. The pathophysiology of rPH is not clear and may be explained by different underlying mechanisms. We hypothesized that rPH may have different risk factors according to the bleeding location. We report the variables that we found associated with deep and lobar rPH after intravenous thrombolysis. METHODS: This is a descriptive study of patients with ischemic stroke who were treated with intravenous thrombolysis. These patients were included in a multicenter prospective registry. We collected demographic, clinical and radiological data. We evaluated the number and distribution of cerebral microbleeds (CMB) from Magnetic Resonance Imaging. We excluded patients treated endovascularly, patients with parenchymal hemorrhage without concomitant rPH and stroke mimics. We compared the variables from patients with deep or lobar rPH with those with no intracranial hemorrhage. RESULTS: We studied 934 patients (mean age 73.9±12.6 years) and 52.8% were men. We observed rPH in 34 patients (3.6%); 9 (0.9%) were deep and 25 (2.7%) lobar. No hemorrhage was observed in 900 (96.6%) patients. Deep rPH were associated with hypertensive episodes within first 24 hours after intravenous thrombolysis (77.7% vs 23.3%, p<0.001). Lobar rPH were associated with the presence of CMB (53.8% vs 7.9%, p<0.001), multiple (>1) CMB (30.7% vs 4.4%, p = 0.003), lobar CMB (53.8% vs 3.0%, p<0.001) and severe leukoaraiosis (76.9% vs 42%, p = 0.02). CONCLUSIONS: A high blood pressure within the first 24 hours after intravenous thrombolysis is associated with deep rPH, whereas lobar rPH are associated with imaging markers of amyloid deposition. Thus, our results suggest that deep and lobar rPH after intravenous thrombolysis may have different mechanisms.

Antithrombotic pretreatment increases very-early mortality in primary intracerebral hemorrhage.

OBJECTIVE: To analyze the effect of previous antiplatelet (AP) and vitamin K antagonist (VKA) treatments on outcome in patients with primary intracerebral hemorrhage (ICH). METHODS: In this prospective observational study, we analyzed 529 patients according to antithrombotic pretreatment: none, AP, or VKA. Very-early (24-hour) death, 3-month mortality, and functional independence were analyzed. RESULTS: Of 236 (44.6%) pretreated patients, 147 (27.8%) patients were taking AP and 89 (16.8%) VKA. Very-early death was observed in 13.4% and was increased in pretreated patients: 19.0% for AP and 27.0% for VKA treatment, compared to 6.5% in non-pretreated patients, p < 0.0001. Three-month mortality was 40.8% overall (49.7% for AP pretreated, 58.4% for VKA pretreated, and 31.1% for non-pretreated patients, p < 0.0001). The adjusted odds of very-early and 3-month mortality were 2.55 (p = 0.004) and 1.56 (p = 0.046) for AP-pretreated patients and 4.24 (p < 0.0001) and 2.34 (p = 0.01) for VKA-pretreated patients, respectively, compared with non-pretreated patients. The effect of antithrombotic pretreatment on mortality from 24 hours to 3 months was nonsignificant. At 3-month follow-up, 28.5% of patients remained functionally independent: 22.4% of AP-pretreated, 15.7% of VKA-pretreated, and 35.5% of non-pretreated patients (p < 0.0001). CONCLUSIONS: A high percentage of patients with ICH preventively treated with VKA or AP died during the first 24 hours after admission. Both treatments were predictors of very-early mortality. The final effect of antithrombotics on 3-month mortality remains significant through its strong effect on very-early mortality. Safety concerns about starting chronic antithrombotic treatment should be considered not only when VKA treatment is planned but also for AP treatment.

Remote Intracerebral Hemorrhage After Intravenous Thrombolysis: Results From a Multicenter Study.

BACKGROUND AND PURPOSE: Remote parenchymal hemorrhage (rPH) after intravenous thrombolysis with recombinant tissue-type plasminogen activator may be associated with cerebral amyloid angiopathy, although supportive data are limited. We aimed to investigate risk factors of rPH after intravenous thrombolysis with recombinant tissue-type plasminogen activator. METHODS: This is an observational study of patients with ischemic stroke who were treated with intravenous thrombolysis with recombinant tissue-type plasminogen activator and were included in a multicenter prospective registry. rPH was defined as any extraischemic hemorrhage detected in the follow-up computed tomography. We collected demographic, clinical, laboratory, radiological, and outcome variables. In the subset of patients who underwent a magnetic resonance imaging examination, we evaluated the distribution and burden of cerebral microbleeds, cortical superficial siderosis, leukoaraiosis, and recent silent ischemia in regions anatomically unrelated to the ischemic lesion that caused the initial symptoms. We compared patients with rPH with those without rPH or parenchymal hemorrhage. Independent risk factors for rPH were obtained by multivariable logistic regression analyses. RESULTS: We evaluated 992 patients (mean age, 74.0±12.6 years; 52.9% were men), and 408 (41%) of them underwent a magnetic resonance imaging. Twenty-six patients (2.6%) had a rPH, 8 (0.8%) had both rPH and PH, 58 (5.8%) had PH, and 900 (90.7%) had no bleeding complication. Lobar cerebral microbleeds (odds ratio, 8.0; 95% confidence interval, 2.3-27.2) and recent silent ischemia (odds ratio, 4.8; 95% confidence interval, 1.6-14.1) increased the risk of rPH. CONCLUSIONS: The occurrence of rPH after intravenous thrombolysis with recombinant tissue-type plasminogen activator in patients with ischemic stroke is associated with lobar cerebral microbleeds and multiple ischemic lesions in different regions.

New-Onset Paroxysmal Atrial Fibrillation Diagnosis in Ischemic Stroke Patients.

INTRODUCTION: The aims of this study are to describe the incidence of paroxysmal atrial fibrillation (pAF) in patients with ischemic stroke (IS) or transient ischemic attack (TIA), and to create a risk prediction model, using immediately available clinical data associated with new pAF diagnosis. METHODS: We analyzed data from the BASICMAR stroke register, with 5 inclusion criteria: (1) diagnosis of IS/TIA; (2) no history of AF or structural cardiopathy; (3) stroke unit (SU) monitoring after normal electrocardiogram in the emergency room; (4) complete etiologic study; and (5) 3-month follow-up. We investigated clinical predictors of pAF detection; we analyzed newly diagnosed pAF according to 4 cardiac monitoring screening methods and created a pAF-risk prediction model. RESULTS: The final cohort included 1,240 patients. pAF was diagnosed in 139 patients (11.2%), the majority at the SU (54.7%). Multivariate predictors of new-pAF diagnosis during 3-month follow-up after ischemic event were age 75 years, female gender, history of congestive heart failure, and initial National Institute of Health Stroke Scale 15, with a predicted AF risk of 64%. CONCLUSIONS: This risk prediction model can be helpful to estimate the risk of an underlying pAF within 3 months after suffering an IS/TIA, contributing to increased AF detection efforts, thereby starting the correct secondary prevention treatment.