Association of Retinal Biomarkers With the Subtypes of Ischemic Stroke and an Automated Classification Model.

Purpose: Retinal microvascular changes are associated with ischemic stroke, and optical coherence tomography angiography (OCTA) is a potential tool to reveal the retinal microvasculature. We investigated the feasibility of using the OCTA image to automatically identify ischemic stroke and its subtypes (i.e. lacunar and non-lacunar stroke), and exploited the association of retinal biomarkers with the subtypes of ischemic stroke. Methods: Two cohorts were included in this study and a total of 1730 eyes from 865 participants were studied. A deep learning model was developed to discriminate the subjects with ischemic stroke from healthy controls and to distinguish the subtypes of ischemic stroke. We also extracted geometric parameters of the retinal microvasculature at different retinal layers to investigate the correlations. Results: Superficial vascular plexus (SVP) yielded the highest areas under the receiver operating characteristic curve (AUCs) of 0.922 and 0.871 for the ischemic stroke detection and stroke subtypes classification, respectively. For external data validation, our model achieved an AUC of 0.822 and 0.766 for the ischemic stroke detection and stroke subtypes classification, respectively. When parameterizing the OCTA images, we showed individuals with ischemic strokes had increased SVP tortuosity (B = 0.085, 95% confidence interval [CI] = 0.005-0.166, P = 0.038) and reduced FAZ circularity (B = -0.212, 95% CI = -0.42 to -0.005, P = 0.045); non-lacunar stroke had reduced SVP FAZ circularity (P = 0.027) compared to lacunar stroke. Conclusions: Our study demonstrates the applicability of artificial intelligence (AI)-enhanced OCTA image analysis for ischemic stroke detection and its subtypes classification. Biomarkers from retinal OCTA images can provide useful information for clinical decision-making and diagnosis of ischemic stroke and its subtypes.

Added Value of a Blinded Outcome Adjudication Committee in an Open-Label Randomized Stroke Trial.

BACKGROUND AND PURPOSE: Blinded outcome assessment in trials with prospective randomized open blinded end point design is challenging. Unblinding can result in misclassified outcomes and biased treatment effect estimates. An outcome adjudication committee assures blinded outcome assessment, but the added value for trials with prospective randomized open blinded end point design and subjective outcomes is unknown. We aimed to assess the degree of misclassification of modified Rankin Scale (mRS) scores by a central assessor and its impact on treatment effect estimates in a stroke trial with prospective randomized open blinded end point design. METHODS: We used data from the MR CLEAN (Multicenter Randomized Clinical Trial of Endovascular Treatment for Acute Ischemic Stroke in the Netherlands). The primary outcome was the mRS at 90 days. Standardized, algorithm-based telephone interviews to assess the mRS were conducted from a central location by an experienced research nurse, unaware but not formally blinded to treatment allocation (central assessor). Masked reports of these interviews were adjudicated by a blinded outcome committee. Misclassification was defined as an incorrect classification of the mRS by the central assessor. The effect of endovascular treatment on the mRS was assessed with multivariable ordinal logistic regression. RESULTS: In MR CLEAN, 53/500 (10.6%) of the mRS scores were misclassified. The degree and direction of misclassification did not differ between treatment arms (P=0.59). Benefit of endovascular treatment was shown on the mRS when scored by the central assessor (adjusted common odds ratio, 1.60 [95% CI, 1.16-2.21]) and the outcome adjudication committee (adjusted common odds ratio, 1.67 [95% CI, 1.21-2.20]). CONCLUSIONS: Misclassification by the central assessor was small, randomly distributed over treatment arms, and did not affect treatment effect estimates. This study suggests that the added value of a blinded outcome adjudication committee is limited in a stroke trial with prospective randomized open blinded end point design applying standardized, algorithm-based outcome assessment by a central assessor, who is unaware but not formally blinded to treatment allocation. Registration: URL: https://www.isrctn.com; Unique identifier: ISRCTN10888758.

Variations of risk factors for ischemic stroke and its subtypes in Chinese patients in Taiwan.

Chinese have a higher stroke incidence and a different distribution of ischemic stroke (IS) subtypes as compared with Caucasians. Herein we aimed to investigate the prevalence and associations of major risk factors in IS and its subtypes in Chinese patients. From 2006 to 2011, we included 4953 acute IS patients consecutively recruited in National Taiwan University Hospital Stroke Registry (mean age 68 years; male 59%). For each risk factor, we accessed the proportion in all IS patients, and calculated odds ratios for each main IS subtype versus other subtypes. Multiple logistic regression models were used to adjust for confounders, and to examine the associations of risk factors with IS subtypes. Compared with other ischemic subtypes, large artery atherosclerotic and lacunar strokes were associated with hypertension, diabetes, and hyperlipidaemia, while cardioembolic strokes were associated with ischemic heart disease. Furthermore, the associations with hypertension and diabetes became stronger in lacunar strokes after adjusting for confounders, but not in other ischemic subtypes. Here we report the variable effects of risk factors on different IS subtypes in Chinese patients in Taiwan. Our findings could help shed light on different mechanisms of IS subtypes and provide targets to make more effective strategies for IS prevention.

Tissue-Based Stroke Definition Impacts Stroke Incidence but not Ethnic Differences.

OBJECTIVES: We explored how the new, tissue-based stroke definition impacted incidence estimates, including an ethnic comparison, in a population-based study. METHODS: Stroke patients, May, 2014-May, 2016 in Nueces County, Texas were ascertained and validated using source documentation. Overall, ethnic-specific and age-specific Poisson regression models were used to compare first-ever ischemic stroke and intracerebral hemorrhage (ICH) incidence between old and new stroke definitions, adjusting for age, ethnicity, sex, and National Institutes of Health Stroke Scale score. RESULTS: Among 1308 subjects, 1245 (95%) were defined as stroke by the old definition and 63 additional cases (5%) according to the new. There were 12 cases of parenchymal hematoma (PH1 or PH2) that were reclassified from ischemic stroke to ICH. Overall, incidence of ischemic stroke was slightly higher under the new compared to the old definition (RR 1.07; 95% CI 0.99-1.16); similarly higher in both Mexican Americans (RR 1.06; 95% CI 1.00-1.12) and Non Hispanic whites (RR 1.09, 95% CI 0.97-1.22), p(ethnic difference)=0.36. Overall, incidence of ICH was higher under the new definition compared to old definition (RR 1.16; 95% CI 1.05-1.29), similarly higher among both Mexican Americans (RR 1.14; 95% CI 1.06-1.23) and Non Hispanic whites (RR 1.20, 95% CI 1.03-1.39), p(ethnic difference)=0.25. CONCLUSION: Modest increases in ischemic stroke and ICH incidence occurred using the new compared with old stroke definition. There were no differences between Mexican Americans and non Hispanic whites. These estimates provide stroke burden estimates for public health planning.

[Embolic stroke of undetermined source (ESUS) - Classification of a new stroke entity]. / Embolischer Schlaganfall mit ungeklärter Emboliequelle (ESUS) ­ Klassifikation einer neuen Schlaganfallentität.

Embolic stroke of undetermined source (ESUS) represents a subpopulation of cryptogenic strokes defined by its embolic stroke pattern on imaging and if after a carefully performed diagnostic evaluation, a specific, well recognized cause of stroke has not been identified. This review article analyses the basics of the ESUS concept and provides an overview of the evidence from recent cohort studies. The definition, aetiology and diagnosis of ESUS are reassessed. Targeted diagnostics in ESUS patients can reduce the number of cryptogenic strokes by making a specific diagnosis.

Clinical features and disease course of patients with acute ischaemic stroke just before the Italian index case: Was COVID-19 already there?

Since the end of February 2020, Italy has suffered one of the most severe outbreaks of coronavirus disease 2019 (COVID-19). However, what happened just before the Italian index case has not yet been investigated. To answer this question, we evaluated the potential impact of COVID-19 on the clinical features of a cohort of neurological inpatients admitted right before the Italian index case, as compared to the same period of the previous year. Demographic, clinical, treatment and laboratory data were extracted from medical records. The data collected included all inpatients who had been admitted to the Neurology and Stroke Units of the Ospedale Maggiore Policlinico, Milan, Italy, from December 15, 2018 to February 20, 2019 and from December 15, 2019 to February 20, 2020. Of the 248 patients, 97 subjects (39.1%) were admitted for an acute cerebrovascular event: 46 in the 2018/2019 period (mean [SD] age, 72.3 [15.6] years; 22 men [47.8%]), and 51 in the 2019/2020 interval (mean [SD] age, 72.8 [12.4] years; 24 men [47.1%]). The number of cryptogenic strokes has increased during the 2019-2020 year, as compared to the previous year (30 [58.8%] vs. 18 [39.1%], p = 0.05). These patients had a longer hospitalization (mean [SD] day, 15.7 [10.5] days vs. mean [SD] day, 11.7 [7.2] days, p = 0.03) and more frequent cerebrovascular complications (9 [30.0%] vs. 2 [11.1%]), but presented a lower incidence of cardiocerebral risk factors (18 [60.0%] vs. 14 [77.8%]). Right before the Italian index case, an increase in cryptogenic strokes has occurred, possibly due to the concomitant COVID-19.

Factors Associated with Stroke Coding Quality: A Comparison of Registry and Administrative Data.

BACKGROUND: The International Statistical Classification of Diseases and Related Health Problems, 10th Revision, Australian Modification (ICD-10-AM) codes are commonly used to identify patients with diseases or clinical conditions for epidemiological research. We aimed to determine the diagnostic agreement and factors associated with a clinician-assigned stroke diagnosis in a national registry and the ICD-10-AM codes recorded in government-held administrative data. MATERIALS AND METHODS: Data from 39 hospitals (2009-2013) participating in the Australian Stroke Clinical Registry (AuSCR) were linked and merged with person-level administrative data. The AuSCR clinician-assigned stroke diagnosis was the reference standard. Concordance was defined as agreement between the clinician-assigned diagnosis and the ICD-10-AM codes for acute stroke or transient ischemic attack (TIA) (ICD-10-AM codes: I61-I64, G45.9). Multivariable logistic regression was undertaken to assess factors associated with coded diagnostic concordance. RESULTS: A total of 14,716 patient admissions were included (46% female, 63% ischemic, 14% intracerebral hemorrhage [ICH], 18% TIA and 5% unspecified stroke based on the reference standard). Principal ICD-10-AM code concordance was ICH: 76.7%; ischemic stroke: 72.2%; TIA: 80.2%; unspecified stroke: 50.8%. Factors associated with a greater odds of ischemic stroke concordance included: treatment in a stroke unit (adjusted Odds Ratio, aOR:1.58; 95% confidence interval (CI) 1.37, 1.82); length of stay >4 days (aOR:1.30; 95% CI 1.17, 1.45); and discharge destination other than home (Residential care aOR:1.57; 95% CI 1.24, 1.96; Inpatient rehabilitation aOR:1.63; 95% CI 1.43, 1.86). CONCLUSIONS: Diagnostic concordance varied based on stroke type. Future research to improve the quality of coding for stroke should focus on patients not treated in stroke units or with shorter lengths of stay where documentation in medical records may be limited.

Five-Year Risk of Acute Myocardial Infarction After Acute Ischemic Stroke in Korea.

Background The long-term incidence of acute myocardial infarction (AMI) in patients with acute ischemic stroke (AIS) has not been well defined in large cohort studies of various race-ethnic groups. Methods and Results A prospective cohort of patients with AIS who were registered in a multicenter nationwide stroke registry (CRCS-K [Clinical Research Collaboration for Stroke in Korea] registry) was followed up for the occurrence of AMI through a linkage with the National Health Insurance Service claims database. The 5-year cumulative incidence and annual risk were estimated according to predefined demographic subgroups, stroke subtypes, a history of coronary heart disease (CHD), and known risk factors of CHD. A total of 11 720 patients with AIS were studied. The 5-year cumulative incidence of AMI was 2.0%. The annual risk was highest in the first year after the index event (1.1%), followed by a much lower annual risk in the second to fifth years (between 0.16% and 0.27%). Among subgroups, annual risk in the first year was highest in those with a history of CHD (4.1%) compared with those without a history of CHD (0.8%). The small-vessel occlusion subtype had a much lower incidence (0.8%) compared with large-vessel occlusion (2.2%) or cardioembolism (2.4%) subtypes. In the multivariable analysis, history of CHD (hazard ratio, 2.84; 95% CI, 2.01-3.93) was the strongest independent predictor of AMI after AIS. Conclusions The incidence of AMI after AIS in South Korea was relatively low and unexpectedly highest during the first year after stroke. CHD was the most substantial risk factor for AMI after stroke and conferred an approximate 5-fold greater risk.

Inconsistent centralised versus non-centralised ischaemic stroke aetiology.

BACKGROUND AND PURPOSE: The Trial of Org 10 172 in Acute Stroke Treatment (TOAST) system is the most widely used aetiological categorisation system in clinical practice and research. Limited studies have validated the accuracy of routine aetiological diagnosis of patients with ischaemic stroke according to the TOAST criteria when the reported subtype is assumed to be correct. We investigated the agreement between centralised and non-centralised (site-reported, at discharge) stroke subtypes in the Third China National Stroke Registry (CNSR-III), and analysed the influence of classification consistency on evaluation during hospitalisation and for secondary prevention strategy. METHODS: All patients with ischaemic stroke from the CNSR-III study with complete diffusion-weighted imaging data were included. We used multivariable Cox proportional-hazard regression models to evaluate the factors associated with consistency between centralised and non-centralised stroke subtypes. Sensitivity analyses were conducted of the subgroup of patients with complete information. RESULTS: This study included 12 180 patients (mean age, 62.3 years; and women, 31.4%). Agreement between centralised and non-centralised subtype was the highest for the large-artery atherosclerosis subtype stroke (77.4% of centralised patients), followed by the small-vessel occlusion subtype (40.6% of centralised patients). Agreements for cardioembolism and stroke of other determined aetiology subtypes were 38.7% and 12.2%, respectively. Patient-level and hospital-level factors were associated with the inconsistency between centralised/non-centralised aetiological subtyping. This inconsistency was related to differences in secondary prevention strategies. Only 15.3% of the newly diagnosed patients with cardioembolism underwent centralised subtyping with indications to receive oral anticoagulants at discharge. In comparison, 51.3% of the consistent cardioembolism group and 42.0% of the centrally reassigned cardioembolism group with anticoagulation indications were prescribed oral anticoagulants. CONCLUSIONS: Substantial inconsistency exists between centralised and non-centralised subtyping in China. Inaccurate aetiological subtyping could lead to inadequate secondary prevention, especially in patients with cardioembolic stroke.

CIMT as a risk factor for stroke subtype: A systematic review.

INTRODUCTION: An increase in the common carotid artery intima-media thickness (CCA-IMT) is generally considered an early marker of atherosclerosis and is a well-established predictor of cardiovascular disease (CVD). An association between changes in CCA-IMT and risk of stroke has been reported but has conflicting findings. OBJECTIVE: The present meta-analysis was aimed to clarify the association between CCA-IMT with the risk of stroke and its subtype by estimating pooled analysis of published literature. METHODS: Comprehensive search for all published articles was performed in electronic databases including PubMed, Embase, Cochrane Library, Trip Databases, Worldwide Science, CINAHL and Google Scholar from 01 January 1950 to 30 April 2020. RESULTS: In our meta-analysis, a total of 19 studies, of which sixteen studies involving 3475 ischaemic stroke (IS) cases and 11 826 controls; six studies with 902 large vessel disease (LVD) and 548 small vessel disease (SVD) of IS subtypes; five studies with 228 intracerebral haemorrhage (ICH) and 1032 IS cases, were included. Our findings suggest a strong association between increased CCA-IMT with risk of IS as compared to control subjects [SMD = 1.46, 95% CI = 0.90-2.02]. However, there is an increased risk of LVD as compared to the SVD subtype of IS [SMD = 0.36, 95% CI = 0.19-0.52] and more chance of occurrence of IS rather than ICH [SMD = 0.71, 95% CI = 0.28-1.41]. CONCLUSIONS: Carotid intima thickness measurements are found to be associated with the risk of stroke along with its subtypes and may be used as a diagnostic marker for predicting the risk of stroke events.

Proposal for Updated Nomenclature and Classification of Potential Causative Mechanism in Patent Foramen Ovale-Associated Stroke.

Importance: Recent epidemiologic and therapeutic advances have transformed understanding of the role of and therapeutic approach to patent foramen ovale (PFO) in ischemic stroke. Patent foramen ovale is likely responsible for approximately 5% of all ischemic strokes and 10% of those occurring in young and middle-aged adults. Observations: Randomized clinical trials have demonstrated that, to prevent recurrent ischemic stroke in patients with PFO and an otherwise-cryptogenic index ischemic stroke, PFO closure is superior to antiplatelet medical therapy alone; these trials have provided some evidence that, among medical therapy options, anticoagulants may be more effective than antiplatelet agents. Conclusions and Relevance: These new data indicate a need to update classification schemes of causative mechanisms in stroke, developed in an era in which an association between PFO and stroke was viewed as uncertain. We propose a revised general nomenclature and classification framework for PFO-associated stroke and detailed revisions for the 3 major stroke subtyping algorithms in wide use.

EMR-Based Phenotyping of Ischemic Stroke Using Supervised Machine Learning and Text Mining Techniques.

Ischemic stroke is a major cause of death and disability in adulthood worldwide. Because it has highly heterogeneous phenotypes, phenotyping of ischemic stroke is an essential task for medical research and clinical prognostication. However, this task is not a trivial one when the study population is large. Phenotyping of ischemic stroke depends primarily on manual annotation of medical records in previous studies. This article evaluated various strategies for automated phenotyping of ischemic stroke into the four subtypes of the Oxfordshire Community Stroke Project classification based on structured and unstructured data from electronical medical records (EMRs). A total of 4640 adult patients who were hospitalized for acute ischemic stroke in a teaching hospital were included. In addition to the structured items in the National Institutes of Health Stroke Scale, unstructured clinical narratives were preprocessed using MetaMap to identify medical concepts, which were then encoded into feature vectors. Various supervised machine learning algorithms were used to build classifiers. The study results indicate that textual information from EMRs could facilitate phenotyping of ischemic stroke when this information was combined with structured information. Furthermore, decomposition of this multi-class problem into binary classification tasks followed by aggregation of classification results could improve the performance.

Ischaemic stroke etiological classification system: the agreement analysis of CISS, SPARKLE and TOAST.

BACKGROUND AND PURPOSE: The ideal stroke classification system needs to have validity, high reliability and applicability among different stroke research settings. The Chinese Ischemic Stroke Subclassification (CISS) and the Subtypes of Ischemic Stroke Classification System (SPARKLE) have emerged recently but have not been tested using agreement analysis. As a result, the objective of this study is to investigate the level of agreement among stroke subtype classifications using CISS, SPARKLE and Trial of Org 10172 in Acute Stroke Treatment (TOAST). We also analyse the inter-rater reliability of CISS. METHODS: The data include 623 inpatients who have had an ischaemic stroke, accrued from Beijing Tiantan Hospital between 1 October 2015 and 19 April 2016. According to the diagnostic standards of the three subtype classification systems, 299 inpatients who satisfied the requirements of our study were independently classified with etiological subtypes, and we compared the three subclassifications. RESULTS: There was substantial overall agreement among the three classification systems: CISS versus SPARKLE (kappa value=0.684, p<0.001), CISS versus TOAST (kappa value=0.615, p<0.001) and SPARKLE versus TOAST (kappa value=0.675, p<0.001). The inter-rater reliability of CISS was excellent (kappa value=0.857, p<0.001). Furthermore, among the three subtype classification systems, the variance analysis results of the etiological subtypes were not uniform. CONCLUSION: There were generally substantial agreements among three ischaemic stroke etiological classification systems. CISS is a valid and reliable classification system, with which different stroke research centres can apply and compare data.

Phenotypic ASCOD characterisations of ischaemic stroke in the young at an urban tertiary care centre.

BACKGROUND AND PURPOSE: Stroke in young individuals is a serious public health burden. This study aimed to characterise the various phenotypes of ischaemic stroke in a young urban population (≤50 years old) using the ASCOD classification system, which assigns a score to five stroke categories: atherosclerosis, small vessel disease (SVD), cardioembolism, other and dissection. Within each category, a numerical score represents the degree of causality attributed to the stroke. METHODS: This retrospective study cohort was composed of patients from an urban tertiary care academic centre. Cases were selected by searching Get With the Guidelines database for adults ≤50 years old with ischaemic stroke. The study sample included 175 ischaemic strokes in 157 patients, with 16 subjects re-infarcting. Using retrospective chart review, each stroke was scored according to the ASCOD classification system. Multivariable logistic regression analyses were performed to explore each ASCOD category's association with causal risk factors. RESULTS: Of possible causal mechanisms, defined as receiving a grade 1 or 2, a cardiovascular aetiology was most prevalent (25.7%), followed by SVD (22.3%), and closely by atherosclerosis (21.1%). Of general phenotypes, defined as receiving a grade 1 or 2 or 3, atherosclerosis was the most prevalent (51.4%), followed by SVD (47.4%), cardioembolism (42.3%) and other (35.4%). 31.6% of all strokes were of unclear aetiology. Subjects between 45 and 50 years old were more likely to develop a cardioembolic or SVD stroke when compared with subjects <45 years old. CONCLUSION: This study took a novel approach to ASCOD phenotyping, allowing several observations: (1) In patients with advanced atherosclerosis receiving the score A1, the vast majority had systemic atherosclerosis in multiple vascular territories; (2) the cardiac score C2(6), defined as a radiographic pattern highly suggestive of a central embolic source, may overestimate the prevalence of true cardiac disease; (3) incidental laboratory findings may detect some underlying pathology, but causality to the stroke is unlikely.