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      Three-dimensional simulations of embolic stroke and an equation for sizing emboli from imaging

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          Abstract

          Stroke simulations are needed to run in-silico trials, develop hypotheses for clinical studies and to interpret ultrasound monitoring and radiological imaging. We describe proof-of-concept three-dimensional stroke simulations, carrying out in silico trials to relate lesion volume to embolus diameter and calculate probabilistic lesion overlap maps, building on our previous Monte Carlo method. Simulated emboli were released into an in silico vasculature to simulate 1000 s of strokes. Infarct volume distributions and probabilistic lesion overlap maps were determined. Computer-generated lesions were assessed by clinicians and compared with radiological images. The key result of this study is development of a three-dimensional simulation for embolic stroke and its application to an in silico clinical trial. Probabilistic lesion overlap maps showed that the lesions from small emboli are homogeneously distributed throughout the cerebral vasculature. Mid-sized emboli were preferentially found in posterior cerebral artery (PCA) and posterior region of the middle cerebral artery (MCA) territories. For large emboli, MCA, PCA and anterior cerebral artery (ACA) lesions were comparable to clinical observations, with MCA, PCA then ACA territories identified as the most to least probable regions for lesions to occur. A power law relationship between lesion volume and embolus diameter was found. In conclusion, this article showed proof-of-concept for large in silico trials of embolic stroke including 3D information, identifying that embolus diameter could be determined from infarct volume and that embolus size is critically important to the resting place of emboli. We anticipate this work will form the basis of clinical applications including intraoperative monitoring, determining stroke origins, and in silico trials for complex situations such as multiple embolisation.

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          Most cited references37

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          Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment.

          The etiology of ischemic stroke affects prognosis, outcome, and management. Trials of therapies for patients with acute stroke should include measurements of responses as influenced by subtype of ischemic stroke. A system for categorization of subtypes of ischemic stroke mainly based on etiology has been developed for the Trial of Org 10172 in Acute Stroke Treatment (TOAST). A classification of subtypes was prepared using clinical features and the results of ancillary diagnostic studies. "Possible" and "probable" diagnoses can be made based on the physician's certainty of diagnosis. The usefulness and interrater agreement of the classification were tested by two neurologists who had not participated in the writing of the criteria. The neurologists independently used the TOAST classification system in their bedside evaluation of 20 patients, first based only on clinical features and then after reviewing the results of diagnostic tests. The TOAST classification denotes five subtypes of ischemic stroke: 1) large-artery atherosclerosis, 2) cardioembolism, 3) small-vessel occlusion, 4) stroke of other determined etiology, and 5) stroke of undetermined etiology. Using this rating system, interphysician agreement was very high. The two physicians disagreed in only one patient. They were both able to reach a specific etiologic diagnosis in 11 patients, whereas the cause of stroke was not determined in nine. The TOAST stroke subtype classification system is easy to use and has good interobserver agreement. This system should allow investigators to report responses to treatment among important subgroups of patients with ischemic stroke. Clinical trials testing treatments for acute ischemic stroke should include similar methods to diagnose subtypes of stroke.
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            Embolic Stroke of Undetermined Source: A Systematic Review and Clinical Update.

            Embolic stroke of undetermined source (ESUS) designates patients with nonlacunar cryptogenic ischemic strokes in whom embolism is the likely stroke mechanism. It has been hypothesized that anticoagulation is more efficacious than antiplatelet therapy for secondary stroke prevention in ESUS patients. We review available information about ESUS.
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              Cardioembolic Stroke.

              Cardiac embolism accounts for an increasing proportion of ischemic strokes and might multiply several-fold during the next decades. However, research points to several potential strategies to stem this expected rise in cardioembolic stroke. First, although one-third of strokes are of unclear cause, it is increasingly accepted that many of these cryptogenic strokes arise from a distant embolism rather than in situ cerebrovascular disease, leading to the recent formulation of embolic stroke of undetermined source as a distinct target for investigation. Second, recent clinical trials have indicated that embolic stroke of undetermined source may often stem from subclinical atrial fibrillation, which can be diagnosed with prolonged heart rhythm monitoring. Third, emerging evidence indicates that a thrombogenic atrial substrate can lead to atrial thromboembolism even in the absence of atrial fibrillation. Such an atrial cardiomyopathy may explain many cases of embolic stroke of undetermined source, and oral anticoagulant drugs may prove to reduce stroke risk from atrial cardiomyopathy given its parallels to atrial fibrillation. Non-vitamin K antagonist oral anticoagulant drugs have recently expanded therapeutic options for preventing cardioembolic stroke and are currently being tested for stroke prevention in patients with embolic stroke of undetermined source, including specifically those with atrial cardiomyopathy. Fourth, increasing appreciation of thrombogenic atrial substrate and the common coexistence of cardiac and extracardiac stroke risk factors suggest benefits from global vascular risk factor management in addition to anticoagulation. Finally, improved imaging of ventricular thrombus plus the availability of non-vitamin K antagonist oral anticoagulant drugs may lead to better prevention of stroke from acute myocardial infarction and heart failure.
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                Author and article information

                Contributors
                Jim.Hague@open.ac.uk
                Journal
                Sci Rep
                Sci Rep
                Scientific Reports
                Nature Publishing Group UK (London )
                2045-2322
                21 February 2023
                21 February 2023
                2023
                : 13
                : 3021
                Affiliations
                [1 ]GRID grid.10837.3d, ISNI 0000 0000 9606 9301, School of Physical Sciences, , The Open University, ; Walton Hall, Milton Keynes, MK7 6AA UK
                [2 ]GRID grid.9918.9, ISNI 0000 0004 1936 8411, Department of Cardiovascular Sciences, , University of Leicester, ; Leicester, LE1 7RH UK
                [3 ]GRID grid.269014.8, ISNI 0000 0001 0435 9078, Department of Radiology, , University Hospitals of Leicester NHS Trust, ; Leicester, LE1 5WW UK
                [4 ]GRID grid.511501.1, NIHR Leicester Biomedical Research Centre, , British Heart Foundation Cardiovascular Research Centre, ; Leicester, LE3 9QP UK
                [5 ]GRID grid.269014.8, ISNI 0000 0001 0435 9078, Department of Medical Physics, Leicester Royal Infirmary, , University Hospitals of Leicester NHS Trust, ; Leicester, LE1 5WW UK
                [6 ]GRID grid.13097.3c, ISNI 0000 0001 2322 6764, School of Life Course and Population Sciences, , King’s College London, Guy’s Campus, ; London, SE1 1UL UK
                Article
                29974
                10.1038/s41598-023-29974-2
                9944911
                36810427
                5dfc8d2d-5a44-470b-9b40-7de3443c4030
                © The Author(s) 2023

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 13 May 2022
                : 14 February 2023
                Funding
                Funded by: EPSRC
                Award ID: EP/P505046/1
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000377, Dunhill Medical Trust;
                Award ID: RTF1806\27
                Award Recipient :
                Categories
                Article
                Custom metadata
                © The Author(s) 2023

                Uncategorized
                computational biophysics,embolism,cerebrovascular disorders,biological physics,medical imaging

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