Relationship Between Leukocyte Counts and Large Vessel Occlusion in Acute Ischemic Stroke

Relationship Between Leukocyte Counts and Large Vessel Occlusion in Acute Ischemic Stroke | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research article Relationship Between Leukocyte Counts and Large Vessel Occlusion in Acute Ischemic Stroke Gábor Tárkányi, Zsófia Nozomi Karádi, Zsófia Szabó, István Szegedi, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-76213/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Dec, 2020 Read the published version in BMC Neurology → Version 1 posted 10 You are reading this latest preprint version Abstract Background: Neuroinflammation plays an important role in the pathogenesis of acute ischemic stroke (AIS) and peripheral leukocyte counts have proved to be independent predictors of stroke severity and outcomes. Clinical significance of large vessel occlusion (LVO) in AIS is increasing, as these patients are potential candidates for endovascular thrombectomy and likely to have worse outcomes if not treated urgently. The aim of our study was to assess the relationship between on admission leukocyte counts and the presence of LVO in the early phase of AIS. Methods: We have conducted a cross-sectional, observational study based on a registry of consecutive AIS patients admitted up to 4.5 hours after stroke onset. Blood samples were taken at admission and leukocyte counts were measured immediately. The presence of LVO was verified based on the computed tomography angiography scan on admission. Results: Total white blood cell (WBC) and neutrophil counts were significantly higher in patients with LVO than those without LVO (P<0.001 respectively). After adjustment for potential confounders total WBC counts (adjusted OR: 1.405 per 1x10 9 /L increase, 95% CI: 1.209 to 1.632) and neutrophil counts (adjusted OR: 1.344 per 1x10 9 /L increase, 95% CI: 1.155 to 1.564) were found to have the strongest associations with the presence of LVO. Total WBC and neutrophil counts had moderate ability to discriminate an LVO in AIS (AUC: 0.667 and 0.655 respectively). No differences were recorded in leukocyte counts according to the size of the occluded vessel and the status of collateral circulation in the anterior vascular territory. However, total WBC and neutrophil counts tended to be higher in patients with LVO in the posterior circulation (p= 0.005 and 0.010 respectively). Conclusion: Higher admission total WBC and neutrophil counts are strongly associated with the presence of LVO and has moderate ability to discriminate an LVO in AIS. Detailed evaluation of stroke-evoked inflammatory mechanisms and changes according to the presence of LVO demands further investigation. Neurology ischemic stroke large vessel occlusion leukocytes neutrophils neuroinflammation Figures Figure 1 Figure 2 Background Secondary neuroinflammation plays an important role in the pathogenesis of acute ischemic stroke (AIS). Ischemic brain damage elicits systematic inflammatory response and cause a time-dependent activation of peripheral immune cells [ 1 ]. Leukocyte counts and ratios (such as neutrophil-to-lymphocyte ratio) in peripheral blood proved to have good prognostic value to predict outcomes and post-stroke complications [ 2 , 3 ]. Higher leukocyte counts, especially neutrophil elevation is also associated with increasing severity and larger infarct volumes in AIS [ 4 , 5 ]. Approximately 20–40% of AIS cases are caused by large vessel occlusion (LVO), early detection of which is crucial because these patients are potential candidates for endovascular thrombectomy (EVT) and have worse outcomes if not treated urgently [ 6 , 7 ]. Large vessel occlusion tends to cause more severe strokes and place large cerebral territories at ischemic risk [ 8 ]. Therefore, the magnitude of peripheral inflammatory response may be related to the presence of LVO, however previous studies did not investigate this context. The aim of our study was to examine the relationship between on admission total and differential leukocyte counts and the presence of LVO in the early phase of AIS. Methods Study population We have conducted a cross-sectional, observational study based on a prospectively collected registry of consecutive AIS patients admitted up to 4.5 hours after symptom onset to the comprehensive stroke centres (CSC) of two university hospitals between October 2017 and October 2019. Blood samples were collected on admission. Total and differential leukocyte counts were measured immediately with an automated hemocytometer (Sysmex XN-1000; Sysmex, Kobe, Japan). We have recorded demographic data, vascular risk factors, baseline clinical variables, baseline laboratory values, medications at stroke onset and times from onset to sample collection for each patient. On admission stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS). Our outcome of interest was the presence of LVO on the on admission computed tomography angiography (CTA) scan. According to Rennert et al. [9] unilateral, acute occlusion of the internal carotid artery (ICA), M1, M2 and M3 segments of the middle cerebral artery (MCA), A1 and A2 segments of the anterior cerebral artery (ACA), vertebral artery (VA), basilar artery (BA), P1 and P2 segments of the posterior cerebral artery (PCA) and tandem occlusions were considered. Collateral circulation in the anterior vascular territory was evaluated using the multiphase CTA (mCTA) collateral score. Patients were dichotomized into two groups according to good (mCTA 4-5 points) and poor (mCTA 0-3 points) collateral circulation. Evaluation of CTA scan and mCTA collateral score was done by trained neuroradiologist as a standard of care who were blinded to clinical data. Patients without CTA assessment or whose laboratory results were missing due to sampling or measurement errors were excluded. We have also excluded patients who had infection or surgery within 2 weeks prior to the stroke, those who had relevant neurological events (transient ischemic attack [TIA] before or seizures after stroke onset), those who take immunomodulatory medications and those with haematological malignancies, as these conditions could influence peripheral leukocyte counts. Statistical analysis Data analysis was performed using SPSS (version 26.0, IBM, New York). Continuous variables were presented as mean and standard deviation (SD) or as median and interquartile range (IQR) where appropriate. Categorical variables were presented as counts and percentages. In the univariate analysis the comparison of continuous variables was performed using t test or Mann-Whitney U test. Normality was assessed using the Shapiro-Wilk test and visually, based on Q-Q plots and histograms. Categorical data were compared using the Pearson X 2 test or the Fischer exact test when expected values in any cell was below 5. Univariable and multivariable binary logistic regression analysis was performed to assess the associations between leukocyte counts and the presence of LVO, variables with P value ≤0.1 in the univariable analysis were included in the multivariable model. Total white blood cell (WBC) count, each leukocyte subtype counts and neutrophil-to-lymphocyte ratio (NLR) were entered in a separate model because of multicollinearity. The ability of leukocyte counts to discriminate the presence of LVO was assessed using the receiver operating characteristic analysis, area under the curve (AUC) was calculated for each variable. Odds ratios (OR) and 95% confidence intervals (CI) were presented where appropriate, P<0.05 was considered as statistical significance. Results During the study period 514 patients were screened, after exclusions the data of 419 patients were analysed (Fig. 1 ). The main age of the study cohort was 67.7 ± 12.2 years (43.9% female), 167 patients had LVO (39.9%). Demography and baseline characteristics of the cohort are presented in Table 1 . Univariable associations between baseline variables and the presence of LVO are presented in Table S1 of the Supplementary material. Table 1 Demography and clinical characteristics of the cohort according to the presence of LVO LVO present (N = 167) LVO absent (N = 252) P value Demographic characteristics Age, years, median (IQR) 68 (61–79) 69 (59–77) 0.258 Gender, female, % (n) 52.1 (87) 38.5 (97) 0.006 Elapsed times Onset-to-sample time, min, median (IQR) 83 (55–124) 88 (59–139) 0.313 Sample-to-CTA time, min, median (IQR) 16 (6–25) 12 (5–28) 0.684 Parameters on admission NIHSS score on admission, median (IQR) 12 (7–17) 6 (4–8) < 0.001 On admission SBP, mmHg, median (IQR) 158 (140–177) 167 (145–180) 0.004 On admission DBP, mmHg, median (IQR) 85 (78–96) 90 (80–100) 0.004 Body temperature, o C, median (IQR) 36.4 (36.1–36.5) 36.4 (36.2–36.6) 0.069 Blood glucose, mmol/L, median (IQR) 6.89 (5.90–8.10) 6.43 (5.61–8.35) 0.120 INR, ratio, median (IQR) 1.02 (0.95–1.08) 0.99 (0.94–1.04) 0.003 Vascular risk factors Smoking, % (n), 60 missing 39.1 (52) 31.4 (71) 0.139 Hypertension, % (n), 13 missing 81.6 (133) 77.8 (189) 0.352 Diabetes mellitus, % (n), 19 missing 21.4 (34) 30.3 (73) 0.049 Hyperlipidaemia, % (n), 36 missing 50.7 (76) 53.6 (125) 0.568 Atrial fibrillation, % (n), 23 missing 32.9 (52) 17.2 (41) < 0.001 Coronary artery disease, % (n), 33 missing 27.7 (43) 23.4 (54) 0.332 Chronic heart failure, % (n), 23 missing 15.0 (24) 7.6 (18) 0.019 Previous stroke/TIA, % (n), 22 missing 17.6 (28) 25.2 (60) 0.074 Malignancy, % (n), 31 missing 16.4 (25) 9.3 (22) 0.036 Therapy at stroke onset Antiplatelet, % (n), 23 missing 40.3 (62) 36.0 (87) 0.388 Anticoagulant, % (n), 28 missing 17.6 (27) 9.7 (23) 0.021 Lipid lowering, % (n), 23 missing 27.7 (43) 22.4 (54) 0.228 Antihypertensive, % (n), 24 missing 72.9 (113) 66.7 (160) 0.190 Antidiabetic, % (n), 24 missing 16.4 (25) 24.0 (58) 0.070 Abbreviation: LVO, large vessel occlusion; NIHSS, National Institutes of Health Stroke Scale; SBP, systolic blood pressure; DBP, diastolic blood pressure; IQR, interquartile range; INR, International Normalized Ratio; TIA, transient ischemic attack. Higher total WBC counts were recorded in LVO patients than those without LVO (9.27 × 10 9 /L vs. 7.61 × 10 9 /L; P < 0.001). Regarding major leukocyte subtypes, median neutrophil counts were significantly higher in the LVO group (6.05 × 10 9 /L vs. 4.69 × 10 9 /L; P < 0.001). In contrast, no significant difference was recorded between the groups for the other subtypes (Fig. 2 ). Neutrophil-to-lymphocyte ratio values was slightly higher in patients with LVO (2.83 versus 2.56; P = 0.034). Increasing onset to sample times correlated with higher neutrophil counts (Spearman r , 0.175; P < 0.001), lower lymphocyte counts (Spearman r , -0.229; P < 0.001) and increasing NLR values (Spearman r , 0.275; P < 0.001). On admission total WBC, neutrophil, lymphocyte, monocyte and basophil counts were associated with the presence of LVO in the univariable binary logistic regression analysis. Independent associations were found between total WBC, neutrophil, lymphocyte and basophil counts and the presence of LVO after adjustment for potential confounders (Table 2 ). There was a trend between increasing NLR values and the presence of LVO in the univariable analysis (OR: 1.079 per 1-point increase, 95% CI: 1.001 to 1.164; P = 0.048), but this trend was not present after adjustment for confounders (OR: 1.022 per 1-point increase, 95% CI: 0.924 to 1.131; P = 0.672). Table 2 Associations between leukocyte counts and the presence of large vessel occlusion in acute ischemic stroke Crude OR (95% CI) P value Adjusted OR (95% CI) P value Total WBC (1 × 10 9 /L increase) 1.292 (1.187 to 1.405) < 0.001 1.405 (1.209 to 1.632) < 0.001 Neutrophil (1 × 10 9 /L increase) 1.296 (1.181 to 1.421) < 0.001 1.344 (1.155 to 1.564) < 0.001 Lymphocyte (1 × 10 9 /L increase) 1.321 (1.064 to 1.641) 0.012 1.631 (1.106 to 2.407) 0.014 Monocyte (0.1 × 10 9 /L increase) 1.112 (1.018 to 1.214) 0.018 1.048 (0.903 to 1.217) 0.535 Eosinophil (0.1 × 10 9 /L increase) 0.955 (0.807 to 1.131) 0.596 1.043 (0.799 to 1.363) 0.755 Basophil (0.01 × 10 9 /L increase) 1.106 (1.024 to 1.194) 0.010 1.296 (1.119 to 1.501) < 0.001 Abbreviation: OR, odds ratio; CI, confidence interval; WBC, white blood cell; L, litre. Receiver operating characteristic analyses demonstrated moderate ability of total WBC (AUC: 0.667, 95% CI: 0.613 to 0.721; P < 0.001) and neutrophil counts (AUC: 0.655, 95% CI: 0.600 to 0.710; P < 0.001) to discriminate the presence of LVO. Marginally significant ability was detected for NLR values (AUC: 0.563, 95% CI: 0.505 to 0.621; P = 0.030), and the abilities of other leukocyte subtypes to discriminate an LVO were not significant ( Figure S1 in the Supplementary material). Out of 167 LVO patients 147 (88.0%) had occlusion in the anterior circulation (ICA, M1, M2 and M3 segments of MCA, A1 and A2 segments of ACA). Proximal occlusions (defined as occlusion of ICA or M1 segment of MCA) were found at 105 patients (71.4%). These patients had more severe strokes (median NIHSS score 15 vs. 8; P < 0.001) compared to those with more distal occlusions (M2 and M3 segment of MCA, A1 and A2 segments of ACA), but no significant differences were recorded in leukocyte counts ( Table S2 in the Supplementary material). Data on collateral status was available for 145 patients (98.6%). Good collateral circulation was found in 86 patients (59.3%). Patients with poor collateral circulation had higher NIHSS median scores on admission than those with good collaterals (16 vs. 11; P < 0.001), but no significant differences in leukocyte counts were found between the two groups ( Table S3 in the Supplementary material). Twenty patients (12.0%) had LVO in the posterior circulation (VA, BA, P1 and P2 segments of PCA). These patients tended to be younger and had milder strokes than patients with LVO in the anterior circulation. Median admission total WBC and neutrophil counts were significantly higher in patients with posterior LVO. Lymphocyte and monocyte counts were slightly higher in posterior LVO patients; however, differences did not reach the significance level ( Table S4 in the Supplementary material). Discussion The main finding of our study is that leukocyte counts (especially total WBC and neutrophil) are associated with the presence of LVO in the acute phase of ischemic stroke. Higher total WBC and neutrophil counts could be detected in LVO patients compared to those without LVO, already in the first hours after stroke onset. This highlights the rapid response of systematic inflammatory mechanisms after ischemic brain injury, the extent of which may differ among leukocyte subtypes according to the presence of LVO. Proinflammatory factors and pathways are activated within minutes after ischemic onset [ 10 ]. Neutrophils are the first leukocyte subtype to be upregulated and subsequently infiltrate the ischemic brain tissue [ 11 ]. A previous study has reported that neutrophilia is associated with the volume of ischemic tissue in AIS [ 5 ]. The presence of LVO can cause blood supply disturbances in large vascular territories and places substantial cerebral areas under ischemic risk, thereby probably increase the magnitude of proinflammatory response. This may explain why higher total WBC counts (mainly due to the increase in neutrophil counts) can be detected in LVO patients compared to those without LVO in AIS. Our results are consistent with previous studies highlighting the longitudinal changes in leukocyte activation: elevation of neutrophil and decrease in lymphocyte counts over time [ 12 , 13 ]. It should be noted that lymphocytes are recruited in the later stages of ischemic brain injury [ 14 ]. In our study no differences were found in baseline lymphocyte counts between LVO and non LVO patients, which may be because lymphocytes have not yet been extensively activated at this early stage of AIS. This may also be the reason why NLR, which is well established in stroke prognosis prediction [ 3 , 12 , 13 ], hardly differed between the two groups. Independent associations between increasing counts of neutrophils, lymphocytes and basophils and higher odds of LVO may represent a broad, bi-directional crosstalk between the ischemic brain and the peripheral immune system, which likely affects almost all participants of the immune response quite early after stroke onset. Interestingly in addition to the strong association between neutrophil counts and LVO, the association was also quite strong for basophil counts. Basophil leukocytes have unique role in allergic reactions, parasite infections and autoimmune diseases, however, their role in brain injury is currently unclear [ 15 ]. Raising the suspicion of LVO in AIS early on is crucial to ensure appropriate imaging methods and early transportation of patients to an EVT capable CSC. Hence reliable blood-based biomarkers would be valuable to detect patients with LVO early on. Our results demonstrated that the ability of leukocyte counts to discriminate the presence of LVO are limited on their own. This may be because changes in peripheral leukocyte counts are not specific for brain damage and can be influenced by many other confounding factors. Interestingly leukocytes did not associate with the size of the occluded vessel and with the status of collateral circulation in the anterior vascular territory. These findings are partly consistent with the result of a previous study by Semerano et al. , reporting no significant differences in admission leukocyte counts according to the status of collateral circulation [ 12 ]. The interplay between the size of occluded vascular territory and the quality of collateral circulation supplemented by other metabolic and genetic factors are highly related to the size and the core and the penumbra within ischemic brain lesions [ 16 , 17 ]. A study by Buck et al. suggests that early changes in peripheral counts are related to the size of bioenergetically compromised brain tissue [ 5 ]. Based on our results the magnitude of early peripheral inflammatory response after LVO may not related to the collateral circulation or the size of occluded artery separately. However, the interaction between these factors may affect the size of ischemic core and penumbra, and thus probably the extent of neuroinflammation as well. The etiology of LVO in the posterior circulation and the composition of such thrombi (including the proportion of leukocytes) are different from those of the anterior circulation LVO [ 18 , 19 ]. In our study higher median neutrophil and slightly higher lymphocyte and monocyte counts in the posterior LVO group may be related to these conditions. It should also be noted, that the structure of the brain is slightly different in the posterior territory, with a higher proportion of white matter and with different distribution of glia and neuronal cells [ 20 ], which may also influence the extent of inflammation. Our result may be useful for primary stroke-centres without CTA imaging facilities to consider LVO in AIS patients with very high total WBC or neutrophil counts. However, peripheral leukocyte counts in AIS should be interpreted cautiously, considering that a variety of factors can influence their elevation. The rapidly evolving, new options in the treatment of AIS due to LVO facilitate the need for better understanding the nature of this type of stroke. Our result may warrant further investigation to explore the relationship between LVO and neuroinflammation in details. The scope of further studies could be the interplay between LVO and well-established inflammatory markers such as acute phase proteins, cytokines, cell adhesion molecules, matrix metalloproteinases, damage-associated molecular patterns, markers of oxidative stress, markers of the complement pathway and annexins [ 1 , 21 – 24 ]. Inflammatory markers may also be good candidates to find suitable blood-based biomarkers for early LVO detection [ 25 ]. Further, larger scale studies are also needed to examine alterations in neuroinflammation according to the location and the volume of cerebral infarction and ischemic penumbra. As previously discussed, the changes in peripheral leukocyte counts may be epiphenomenal to brain damage. However, previous studies have revealed that higher leukocyte counts in healthy patients are also associated with the increased risk of ischemic stroke events [ 2 , 26 ]. Further investigation may clarify how peripheral leukocyte counts are related to the risk of suffering an LVO is AIS, or how it may affect the composition of the thrombi. The main strength of our study is the thorough investigation of multiple leukocyte subtypes in a reasonable number of patients from two university centres. However, our study also has some limitations. The observational, cross-sectional design did not allow to assess cause-effect relationship. No assessment of ischemic lesion volume or of the size of ischemic core and penumbra was made on admission. Although we attempted to exclude patients whose leukocyte counts may be affected by other conditions, we cannot be sure that all such patients have been excluded. There is a chance of other, unknown confounding factors that were not considered in this study. No CTA was performed in almost 8% of screened cases (mainly due to minor symptoms or contraindications), which might lead to selection bias. The small number of patients with posterior LVO resulted a probably underpowered subanalysis. Finally, automated analysis of leukocyte subtypes with very low number of cells (eosinophil and basophil counts) might be slightly inaccurate. Conclusion Our study demonstrates that higher on admission total WBC and neutrophil counts are strongly associated with the presence of LVO and has moderate ability to discriminate an LVO in AIS. Further studies are needed to ensure these findings in larger cohorts and to explore the detailed mechanisms of changes in inflammatory pathways after AIS according to the presence of LVO. List of Abbreviations AIS acute ischemic stroke LVO large vessel occlusion EVT endovascular thrombectomy CSC comprehensive stroke centre NIHSS National Institutes of Health Stroke Scale CTA computed tomography angiography ICA internal carotid artery MCA middle cerebral artery ACA anterior cerebral artery VA vertebral artery BA basilar artery PCA posterior cerebral artery mCTA multiphase computed tomography angiography TIA transient ischemic attack SD standard deviation IQR interquartile range WBC white blood cell NLR neutrophil-to-lymphocyte ratio AUC area under the curve OR odds ratio CI confidence interval Declarations Ethical approval and consent to participate The study protocol was approved by the Hungarian Medical Research Council (35403-2/2017/EKU). Written informed consent was obtained from each patient according to the Good Clinical Practice (GCP) guidelines. Consent for publication Not applicable. Availability of data and materials The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. Competing interest The authors declare no conflict of interest. Funding In this study we used data from the STAY ALIVE Acute Stroke Registry, the operation of which was funded by the Economic Development and Innovation Operative Programme Grant (GINOP 2.3.2-15-2016-00048). None of the authors received personalized funding for this work. Authors’ contribution GT designed the study, performed literature search, data acquisition and analysis, statistical analysis and wrote the manuscript. ZNK performed data acquisition, data analysis and reviewed the manuscript. ZS performed data acquisition, data analysis and reviewed the manuscript. IS performed literature search, data acquisition and reviewed the manuscript. LC designed the concepts of the study, interpreted the data, reviewed and approved the manuscript. 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BMC Neurol. 2013;13:7 Supplementary Files Supplement.docx Cite Share Download PDF Status: Published Journal Publication published 04 Dec, 2020 Read the published version in BMC Neurology → Version 1 posted Editorial decision: Major revision 20 Oct, 2020 Review # 2 received at journal 15 Oct, 2020 Review # 1 received at journal 14 Oct, 2020 Reviewer # 1 agreed at journal 24 Sep, 2020 Reviewer # 2 agreed at journal 24 Sep, 2020 Reviewers invited by journal 23 Sep, 2020 Editor assigned by journal 14 Sep, 2020 Submission checks completed at journal 13 Sep, 2020 Editor invited by journal 13 Sep, 2020 First submitted to journal 10 Sep, 2020 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-76213","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":2539974,"identity":"caeccbf0-ee95-41c2-aa1f-6e319ee6af4f","order_by":0,"name":"Gábor Tárkányi","email":"","orcid":"","institution":"University of Pécs Clinical Center: Pecsi Tudomanyegyetem Klinikai Kozpont","correspondingAuthor":false,"prefix":"","firstName":"Gábor","middleName":"","lastName":"Tárkányi","suffix":""},{"id":2539975,"identity":"482b9b8f-2a45-40e6-9558-0fbe6bd201d9","order_by":1,"name":"Zsófia Nozomi Karádi","email":"","orcid":"","institution":"University of Pécs Clinical Center: Pecsi Tudomanyegyetem Klinikai Kozpont","correspondingAuthor":false,"prefix":"","firstName":"Zsófia","middleName":"Nozomi","lastName":"Karádi","suffix":""},{"id":2539976,"identity":"268f10c5-e9a2-44c1-8f0d-0b32d27aeeb9","order_by":2,"name":"Zsófia Szabó","email":"","orcid":"","institution":"University of Debrecen Clinical Centre: Debreceni Egyetem Klinikai Kozpont","correspondingAuthor":false,"prefix":"","firstName":"Zsófia","middleName":"","lastName":"Szabó","suffix":""},{"id":2539977,"identity":"de8dc0a1-a957-4820-aa68-e9c6f66a8f10","order_by":3,"name":"István Szegedi","email":"","orcid":"","institution":"University of Debrecen Clinical Centre: Debreceni Egyetem Klinikai Kozpont","correspondingAuthor":false,"prefix":"","firstName":"István","middleName":"","lastName":"Szegedi","suffix":""},{"id":2539978,"identity":"f87b4038-fae9-4b71-bffe-7cc6eef19541","order_by":4,"name":"László Csiba","email":"","orcid":"","institution":"University of Debrecen Clinical Centre: Debreceni Egyetem Klinikai Kozpont","correspondingAuthor":false,"prefix":"","firstName":"László","middleName":"","lastName":"Csiba","suffix":""},{"id":2539979,"identity":"1702d5e5-27ca-467b-becc-084e5e18d808","order_by":5,"name":"László Szapáry","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA1UlEQVRIiWNgGAWjYBADAwb2BhBlQYRaNiA+ANLCcwCkRYIULRIJIC4RWszlmw9//rjHxphf8vnVDT8KJBj427sT8GqxbGNLkzjwLM1McnZO2c0eoMMkzpzdgFeLwTEeM4YDBw7bGNzOSbvBA9RiIJFLSAv/5w8gLfY3z6Td/EOcFh4GCaAWMwMJ9mO3ibLFsi3NTOLMgTRjiTM5bLdlDCR4CPrFnPnw4w8VB2wM+9uPP7v55o+NHH97LwGHIZg8YDYPXuVoWtgfEFQ9CkbBKBgFIxMAAMaGSPxUpgpRAAAAAElFTkSuQmCC","orcid":"","institution":"University of Pécs Clinical Center: Pecsi Tudomanyegyetem Klinikai Kozpont","correspondingAuthor":true,"prefix":"","firstName":"László","middleName":"","lastName":"Szapáry","suffix":""}],"badges":[],"createdAt":"2020-09-11 11:14:33","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-76213/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-76213/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12883-020-02017-3","type":"published","date":"2020-12-04T15:01:03+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":2536858,"identity":"d35bb56d-bd36-4d30-b471-cb97bbde7fed","added_by":"auto","created_at":"2020-09-22 15:22:07","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":634009,"visible":true,"origin":"","legend":"Patient exclusion flowchart.","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-76213/v1/Figure1.jpg"},{"id":2536859,"identity":"fc558f89-b6b8-4e87-835e-6991a690d106","added_by":"auto","created_at":"2020-09-22 15:22:07","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":706046,"visible":true,"origin":"","legend":"Comparison of admission total white blood cell (WBC) counts, leukocyte subtype counts and neutrophil-to-lymphocyte ratio (NLR) values in acute ischemic stroke according to the presence of large vessel occlusion (LVO). Boxes, 25% to 75% interquartile range; central horizontal bars, median; outer horizontal bars, minimum and maximum values. Statistics: Mann-Whitney U test.","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-76213/v1/Figure2.jpg"},{"id":13594614,"identity":"2e58e40a-e3b7-4b15-88be-463386e3ed13","added_by":"auto","created_at":"2021-09-17 05:21:08","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":395501,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-76213/v1/a2a420fa-4f68-4022-9510-cdd60ba1cedd.pdf"},{"id":2536861,"identity":"51064ec5-8c2b-467d-b1e1-75ace126cff2","added_by":"auto","created_at":"2020-09-22 15:22:08","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":237846,"visible":true,"origin":"","legend":"","description":"","filename":"Supplement.docx","url":"https://assets-eu.researchsquare.com/files/rs-76213/v1/Supplement.docx"}],"financialInterests":"","formattedTitle":"\u003cp\u003eRelationship Between Leukocyte Counts and Large Vessel Occlusion in Acute Ischemic Stroke\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eSecondary neuroinflammation plays an important role in the pathogenesis of acute ischemic stroke (AIS). Ischemic brain damage elicits systematic inflammatory response and cause a time-dependent activation of peripheral immune cells [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Leukocyte counts and ratios (such as neutrophil-to-lymphocyte ratio) in peripheral blood proved to have good prognostic value to predict outcomes and post-stroke complications [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e]. Higher leukocyte counts, especially neutrophil elevation is also associated with increasing severity and larger infarct volumes in AIS [\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eApproximately 20\u0026ndash;40% of AIS cases are caused by large vessel occlusion (LVO), early detection of which is crucial because these patients are potential candidates for endovascular thrombectomy (EVT) and have worse outcomes if not treated urgently [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. Large vessel occlusion tends to cause more severe strokes and place large cerebral territories at ischemic risk [\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e]. Therefore, the magnitude of peripheral inflammatory response may be related to the presence of LVO, however previous studies did not investigate this context. The aim of our study was to examine the relationship between on admission total and differential leukocyte counts and the presence of LVO in the early phase of AIS.\u003c/p\u003e "},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eStudy population\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe have conducted a cross-sectional, observational study based on a prospectively collected registry of consecutive AIS patients admitted up to 4.5 hours after symptom onset to the comprehensive stroke centres (CSC) of two university hospitals between October 2017 and October 2019. Blood samples were collected on admission. Total and differential leukocyte counts were measured immediately with an automated hemocytometer (Sysmex XN-1000; Sysmex, Kobe, Japan). We have recorded demographic data, vascular risk factors, baseline clinical variables, baseline laboratory values, medications at stroke onset and times from onset to sample collection for each patient. On admission stroke severity was assessed using the National Institutes of Health Stroke Scale (NIHSS).\u003c/p\u003e\n\u003cp\u003eOur outcome of interest was the presence of LVO on the on admission computed tomography angiography (CTA) scan. According to \u003cem\u003eRennert et al. \u003c/em\u003e[9] unilateral, acute occlusion of the internal carotid artery (ICA), M1, M2 and M3 segments of the middle cerebral artery (MCA), A1 and A2 segments of the anterior cerebral artery (ACA), vertebral artery (VA), basilar artery (BA), P1 and P2 segments of the posterior cerebral artery (PCA) and tandem occlusions were considered. Collateral circulation in the anterior vascular territory was evaluated using the multiphase CTA (mCTA) collateral score. Patients were dichotomized into two groups according to good (mCTA 4-5 points) and poor (mCTA 0-3 points) collateral circulation. Evaluation of CTA scan and mCTA collateral score was done by trained neuroradiologist as a standard of care who were blinded to clinical data.\u003c/p\u003e\n\u003cp\u003ePatients without CTA assessment or whose laboratory results were missing due to sampling or measurement errors were excluded. We have also excluded patients who had infection or surgery within 2 weeks prior to the stroke, those who had relevant neurological events (transient ischemic attack [TIA] before or seizures after stroke onset), those who take immunomodulatory medications and those with haematological malignancies, as these conditions could influence peripheral leukocyte counts.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistical analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData analysis was performed using SPSS (version 26.0, IBM, New York). Continuous variables were presented as mean and standard deviation (SD) or as median and interquartile range (IQR) where appropriate. Categorical variables were presented as counts and percentages. In the univariate analysis the comparison of continuous variables was performed using \u003cem\u003et \u003c/em\u003etest or \u003cem\u003eMann-Whitney U\u003c/em\u003e test. Normality was assessed using the \u003cem\u003eShapiro-Wilk\u003c/em\u003e test and visually, based on Q-Q plots and histograms. Categorical data were compared using the \u003cem\u003ePearson X\u003csup\u003e2\u003c/sup\u003e\u003c/em\u003e test or the \u003cem\u003eFischer\u003c/em\u003e exact test when expected values in any cell was below 5. Univariable and multivariable binary logistic regression analysis was performed to assess the associations between leukocyte counts and the presence of LVO, variables with P value \u0026le;0.1 in the univariable analysis were included in the multivariable model. Total white blood cell (WBC) count, each leukocyte subtype counts and neutrophil-to-lymphocyte ratio (NLR) were entered in a separate model because of multicollinearity. The ability of leukocyte counts to discriminate the presence of LVO was assessed using the receiver operating characteristic analysis, area under the curve (AUC) was calculated for each variable. Odds ratios (OR) and 95% confidence intervals (CI) were presented where appropriate, P\u0026lt;0.05 was considered as statistical significance.\u003c/p\u003e"},{"header":"Results","content":" \u003cp\u003eDuring the study period 514 patients were screened, after exclusions the data of 419 patients were analysed (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). The main age of the study cohort was 67.7\u0026thinsp;\u0026plusmn;\u0026thinsp;12.2\u0026nbsp;years (43.9% female), 167 patients had LVO (39.9%). Demography and baseline characteristics of the cohort are presented in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Univariable associations between baseline variables and the presence of LVO are presented in \u003cb\u003eTable S1\u003c/b\u003e of the Supplementary material.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eDemography and clinical characteristics of the cohort according to the presence of LVO\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eLVO present\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;167)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eLVO absent\u003c/p\u003e \u003cp\u003e(N\u0026thinsp;=\u0026thinsp;252)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eDemographic characteristics\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAge, years, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e68 (61\u0026ndash;79)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e69 (59\u0026ndash;77)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.258\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGender, female, % (n)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e52.1 (87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e38.5 (97)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.006\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eElapsed times\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOnset-to-sample time, min, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e83 (55\u0026ndash;124)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e88 (59\u0026ndash;139)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.313\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSample-to-CTA time, min, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16 (6\u0026ndash;25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12 (5\u0026ndash;28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.684\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eParameters on admission\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNIHSS score on admission, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e12 (7\u0026ndash;17)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6 (4\u0026ndash;8)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOn admission SBP, mmHg, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e158 (140\u0026ndash;177)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e167 (145\u0026ndash;180)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.004\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eOn admission DBP, mmHg, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e85 (78\u0026ndash;96)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90 (80\u0026ndash;100)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.004\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBody temperature, \u003csup\u003eo\u003c/sup\u003eC, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36.4 (36.1\u0026ndash;36.5)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.4 (36.2\u0026ndash;36.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.069\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBlood glucose, mmol/L, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6.89 (5.90\u0026ndash;8.10)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6.43 (5.61\u0026ndash;8.35)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.120\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eINR, ratio, median (IQR)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.02 (0.95\u0026ndash;1.08)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e0.99 (0.94\u0026ndash;1.04)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eVascular risk factors\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eSmoking, % (n), 60 missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e39.1 (52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e31.4 (71)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.139\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHypertension, % (n), 13 missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e81.6 (133)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e77.8 (189)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.352\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eDiabetes mellitus, % (n), 19 missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e21.4 (34)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e30.3 (73)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.049\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eHyperlipidaemia, % (n), 36 missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.7 (76)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53.6 (125)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.568\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAtrial fibrillation, % (n), 23 missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e32.9 (52)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17.2 (41)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eCoronary artery disease, % (n), 33 missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.7 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e23.4 (54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.332\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eChronic heart failure, % (n), 23 missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15.0 (24)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.6 (18)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.019\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003ePrevious stroke/TIA, % (n), 22 missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17.6 (28)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.2 (60)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.074\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMalignancy, % (n), 31 missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.4 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.3 (22)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.036\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eTherapy at stroke onset\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntiplatelet, % (n), 23 missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e40.3 (62)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e36.0 (87)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.388\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAnticoagulant, % (n), 28 missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e17.6 (27)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e9.7 (23)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e\u003cb\u003e0.021\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLipid lowering, % (n), 23 missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e27.7 (43)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22.4 (54)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.228\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntihypertensive, % (n), 24 missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e72.9 (113)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e66.7 (160)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.190\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAntidiabetic, % (n), 24 missing\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e16.4 (25)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e24.0 (58)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e \u003cp\u003e0.070\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eAbbreviation: LVO, large vessel occlusion; NIHSS, National Institutes of Health Stroke Scale; SBP, systolic blood pressure; DBP, diastolic blood pressure; IQR, interquartile range; INR, International Normalized Ratio; TIA, transient ischemic attack.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eHigher total WBC counts were recorded in LVO patients than those without LVO (9.27\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L vs. 7.61\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Regarding major leukocyte subtypes, median neutrophil counts were significantly higher in the LVO group (6.05\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L vs. 4.69\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In contrast, no significant difference was recorded between the groups for the other subtypes (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). Neutrophil-to-lymphocyte ratio values was slightly higher in patients with LVO (2.83 versus 2.56; P\u0026thinsp;=\u0026thinsp;0.034). Increasing onset to sample times correlated with higher neutrophil counts (Spearman \u003cem\u003er\u003c/em\u003e, 0.175; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), lower lymphocyte counts (Spearman \u003cem\u003er\u003c/em\u003e, -0.229; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and increasing NLR values (Spearman \u003cem\u003er\u003c/em\u003e, 0.275; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003eOn admission total WBC, neutrophil, lymphocyte, monocyte and basophil counts were associated with the presence of LVO in the univariable binary logistic regression analysis. Independent associations were found between total WBC, neutrophil, lymphocyte and basophil counts and the presence of LVO after adjustment for potential confounders (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). There was a trend between increasing NLR values and the presence of LVO in the univariable analysis (OR: 1.079 per 1-point increase, 95% CI: 1.001 to 1.164; P\u0026thinsp;=\u0026thinsp;0.048), but this trend was not present after adjustment for confounders (OR: 1.022 per 1-point increase, 95% CI: 0.924 to 1.131; P\u0026thinsp;=\u0026thinsp;0.672).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003eAssociations between leukocyte counts and the presence of large vessel occlusion in acute ischemic stroke\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eCrude OR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003eAdjusted OR (95% CI)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eTotal WBC (1\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L increase)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.292 (1.187 to 1.405)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.405 (1.209 to 1.632)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eNeutrophil (1\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L increase)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.296 (1.181 to 1.421)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.344 (1.155 to 1.564)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eLymphocyte (1\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L increase)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.321 (1.064 to 1.641)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.012\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.631 (1.106 to 2.407)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e0.014\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eMonocyte (0.1\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L increase)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.112 (1.018 to 1.214)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.018\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.048 (0.903 to 1.217)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.535\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eEosinophil (0.1\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L increase)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e0.955 (0.807 to 1.131)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e0.596\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.043 (0.799 to 1.363)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.755\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eBasophil (0.01\u0026thinsp;\u0026times;\u0026thinsp;10\u003csup\u003e9\u003c/sup\u003e/L increase)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e1.106 (1.024 to 1.194)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e \u003cp\u003e\u003cb\u003e0.010\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.296 (1.119 to 1.501)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;0.001\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAbbreviation: OR, odds ratio; CI, confidence interval; WBC, white blood cell; L, litre.\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eReceiver operating characteristic analyses demonstrated moderate ability of total WBC (AUC: 0.667, 95% CI: 0.613 to 0.721; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and neutrophil counts (AUC: 0.655, 95% CI: 0.600 to 0.710; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) to discriminate the presence of LVO. Marginally significant ability was detected for NLR values (AUC: 0.563, 95% CI: 0.505 to 0.621; P\u0026thinsp;=\u0026thinsp;0.030), and the abilities of other leukocyte subtypes to discriminate an LVO were not significant (\u003cb\u003eFigure S1\u003c/b\u003e in the Supplementary material).\u003c/p\u003e \u003cp\u003eOut of 167 LVO patients 147 (88.0%) had occlusion in the anterior circulation (ICA, M1, M2 and M3 segments of MCA, A1 and A2 segments of ACA). Proximal occlusions (defined as occlusion of ICA or M1 segment of MCA) were found at 105 patients (71.4%). These patients had more severe strokes (median NIHSS score 15 vs. 8; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001) compared to those with more distal occlusions (M2 and M3 segment of MCA, A1 and A2 segments of ACA), but no significant differences were recorded in leukocyte counts (\u003cb\u003eTable S2\u003c/b\u003e in the Supplementary material). Data on collateral status was available for 145 patients (98.6%). Good collateral circulation was found in 86 patients (59.3%). Patients with poor collateral circulation had higher NIHSS median scores on admission than those with good collaterals (16 vs. 11; P\u0026thinsp;\u0026lt;\u0026thinsp;0.001), but no significant differences in leukocyte counts were found between the two groups (\u003cb\u003eTable S3\u003c/b\u003e in the Supplementary material).\u003c/p\u003e \u003cp\u003eTwenty patients (12.0%) had LVO in the posterior circulation (VA, BA, P1 and P2 segments of PCA). These patients tended to be younger and had milder strokes than patients with LVO in the anterior circulation. Median admission total WBC and neutrophil counts were significantly higher in patients with posterior LVO. Lymphocyte and monocyte counts were slightly higher in posterior LVO patients; however, differences did not reach the significance level (\u003cb\u003eTable S4\u003c/b\u003e in the Supplementary material).\u003c/p\u003e "},{"header":"Discussion","content":" \u003cp\u003eThe main finding of our study is that leukocyte counts (especially total WBC and neutrophil) are associated with the presence of LVO in the acute phase of ischemic stroke. Higher total WBC and neutrophil counts could be detected in LVO patients compared to those without LVO, already in the first hours after stroke onset. This highlights the rapid response of systematic inflammatory mechanisms after ischemic brain injury, the extent of which may differ among leukocyte subtypes according to the presence of LVO.\u003c/p\u003e \u003cp\u003eProinflammatory factors and pathways are activated within minutes after ischemic onset [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Neutrophils are the first leukocyte subtype to be upregulated and subsequently infiltrate the ischemic brain tissue [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. A previous study has reported that neutrophilia is associated with the volume of ischemic tissue in AIS [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. The presence of LVO can cause blood supply disturbances in large vascular territories and places substantial cerebral areas under ischemic risk, thereby probably increase the magnitude of proinflammatory response. This may explain why higher total WBC counts (mainly due to the increase in neutrophil counts) can be detected in LVO patients compared to those without LVO in AIS.\u003c/p\u003e \u003cp\u003eOur results are consistent with previous studies highlighting the longitudinal changes in leukocyte activation: elevation of neutrophil and decrease in lymphocyte counts over time [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. It should be noted that lymphocytes are recruited in the later stages of ischemic brain injury [\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e]. In our study no differences were found in baseline lymphocyte counts between LVO and non LVO patients, which may be because lymphocytes have not yet been extensively activated at this early stage of AIS. This may also be the reason why NLR, which is well established in stroke prognosis prediction [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e], hardly differed between the two groups.\u003c/p\u003e \u003cp\u003eIndependent associations between increasing counts of neutrophils, lymphocytes and basophils and higher odds of LVO may represent a broad, bi-directional crosstalk between the ischemic brain and the peripheral immune system, which likely affects almost all participants of the immune response quite early after stroke onset. Interestingly in addition to the strong association between neutrophil counts and LVO, the association was also quite strong for basophil counts. Basophil leukocytes have unique role in allergic reactions, parasite infections and autoimmune diseases, however, their role in brain injury is currently unclear [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRaising the suspicion of LVO in AIS early on is crucial to ensure appropriate imaging methods and early transportation of patients to an EVT capable CSC. Hence reliable blood-based biomarkers would be valuable to detect patients with LVO early on. Our results demonstrated that the ability of leukocyte counts to discriminate the presence of LVO are limited on their own. This may be because changes in peripheral leukocyte counts are not specific for brain damage and can be influenced by many other confounding factors.\u003c/p\u003e \u003cp\u003eInterestingly leukocytes did not associate with the size of the occluded vessel and with the status of collateral circulation in the anterior vascular territory. These findings are partly consistent with the result of a previous study by \u003cem\u003eSemerano et al.\u003c/em\u003e, reporting no significant differences in admission leukocyte counts according to the status of collateral circulation [\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. The interplay between the size of occluded vascular territory and the quality of collateral circulation supplemented by other metabolic and genetic factors are highly related to the size and the core and the penumbra within ischemic brain lesions [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. A study by \u003cem\u003eBuck et al.\u003c/em\u003e suggests that early changes in peripheral counts are related to the size of bioenergetically compromised brain tissue [\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. Based on our results the magnitude of early peripheral inflammatory response after LVO may not related to the collateral circulation or the size of occluded artery separately. However, the interaction between these factors may affect the size of ischemic core and penumbra, and thus probably the extent of neuroinflammation as well.\u003c/p\u003e \u003cp\u003eThe etiology of LVO in the posterior circulation and the composition of such thrombi (including the proportion of leukocytes) are different from those of the anterior circulation LVO [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. In our study higher median neutrophil and slightly higher lymphocyte and monocyte counts in the posterior LVO group may be related to these conditions. It should also be noted, that the structure of the brain is slightly different in the posterior territory, with a higher proportion of white matter and with different distribution of glia and neuronal cells [\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], which may also influence the extent of inflammation.\u003c/p\u003e \u003cp\u003eOur result may be useful for primary stroke-centres without CTA imaging facilities to consider LVO in AIS patients with very high total WBC or neutrophil counts. However, peripheral leukocyte counts in AIS should be interpreted cautiously, considering that a variety of factors can influence their elevation.\u003c/p\u003e \u003cp\u003eThe rapidly evolving, new options in the treatment of AIS due to LVO facilitate the need for better understanding the nature of this type of stroke. Our result may warrant further investigation to explore the relationship between LVO and neuroinflammation in details. The scope of further studies could be the interplay between LVO and well-established inflammatory markers such as acute phase proteins, cytokines, cell adhesion molecules, matrix metalloproteinases, damage-associated molecular patterns, markers of oxidative stress, markers of the complement pathway and annexins [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan additionalcitationids=\"CR22 CR23\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e]. Inflammatory markers may also be good candidates to find suitable blood-based biomarkers for early LVO detection [\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Further, larger scale studies are also needed to examine alterations in neuroinflammation according to the location and the volume of cerebral infarction and ischemic penumbra. As previously discussed, the changes in peripheral leukocyte counts may be epiphenomenal to brain damage. However, previous studies have revealed that higher leukocyte counts in healthy patients are also associated with the increased risk of ischemic stroke events [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. Further investigation may clarify how peripheral leukocyte counts are related to the risk of suffering an LVO is AIS, or how it may affect the composition of the thrombi.\u003c/p\u003e \u003cp\u003eThe main strength of our study is the thorough investigation of multiple leukocyte subtypes in a reasonable number of patients from two university centres. However, our study also has some limitations. The observational, cross-sectional design did not allow to assess cause-effect relationship. No assessment of ischemic lesion volume or of the size of ischemic core and penumbra was made on admission. Although we attempted to exclude patients whose leukocyte counts may be affected by other conditions, we cannot be sure that all such patients have been excluded. There is a chance of other, unknown confounding factors that were not considered in this study. No CTA was performed in almost 8% of screened cases (mainly due to minor symptoms or contraindications), which might lead to selection bias. The small number of patients with posterior LVO resulted a probably underpowered subanalysis. Finally, automated analysis of leukocyte subtypes with very low number of cells (eosinophil and basophil counts) might be slightly inaccurate.\u003c/p\u003e "},{"header":"Conclusion","content":" \u003cp\u003eOur study demonstrates that higher on admission total WBC and neutrophil counts are strongly associated with the presence of LVO and has moderate ability to discriminate an LVO in AIS. Further studies are needed to ensure these findings in larger cohorts and to explore the detailed mechanisms of changes in inflammatory pathways after AIS according to the presence of LVO.\u003c/p\u003e "},{"header":"List of Abbreviations","content":"\u003cp\u003eAIS acute ischemic stroke\u003c/p\u003e \u003cp\u003eLVO large vessel occlusion\u003c/p\u003e \u003cp\u003eEVT endovascular thrombectomy\u003c/p\u003e \u003cp\u003eCSC comprehensive stroke centre\u003c/p\u003e \u003cp\u003eNIHSS National Institutes of Health Stroke Scale\u003c/p\u003e \u003cp\u003eCTA computed tomography angiography\u003c/p\u003e \u003cp\u003eICA internal carotid artery\u003c/p\u003e \u003cp\u003eMCA middle cerebral artery\u003c/p\u003e \u003cp\u003eACA anterior cerebral artery\u003c/p\u003e \u003cp\u003eVA vertebral artery\u003c/p\u003e \u003cp\u003eBA basilar artery\u003c/p\u003e \u003cp\u003ePCA posterior cerebral artery\u003c/p\u003e \u003cp\u003emCTA multiphase computed tomography angiography\u003c/p\u003e \u003cp\u003eTIA transient ischemic attack\u003c/p\u003e \u003cp\u003eSD standard deviation\u003c/p\u003e \u003cp\u003eIQR interquartile range\u003c/p\u003e \u003cp\u003eWBC white blood cell\u003c/p\u003e \u003cp\u003eNLR neutrophil-to-lymphocyte ratio\u003c/p\u003e \u003cp\u003eAUC area under the curve\u003c/p\u003e \u003cp\u003eOR odds ratio\u003c/p\u003e \u003cp\u003eCI confidence interval\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Hungarian Medical Research Council (35403-2/2017/EKU). Written informed consent was obtained from each patient according to the Good Clinical Practice (GCP) guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare no conflict of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn this study we used data from the STAY ALIVE Acute Stroke Registry, the operation of which was funded by the Economic Development and Innovation Operative Programme Grant (GINOP 2.3.2-15-2016-00048). None of the authors received personalized funding for this work.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contribution \u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eGT designed the study, performed literature search, data acquisition and analysis, statistical analysis and wrote the manuscript. ZNK performed data acquisition, data analysis and reviewed the manuscript. ZS performed data acquisition, data analysis and reviewed the manuscript. IS performed literature search, data acquisition and reviewed the manuscript. LC designed the concepts of the study, interpreted the data, reviewed and approved the manuscript. LS is the guarantor and designed the concepts of the study, interpreted the data, reviewed and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eJayaraj RL, Azimullah S, Beiram R, Jalal FY, Rosenberg GA. Neuroinflammation: friend and foe for ischemic stroke. J Neuroinflammation. 2019;16:142.\u003c/li\u003e\n\u003cli\u003eSong SY, Zhao XX, Rajah G, Hua C, Kang R, Han Y, et al. Clinical significance of baseline neutrophil-to-lymphocyte ratio in patients with ischemic stroke or hemorrhagic stroke: an updated meta-analysis. Front Neurol. 2019;10:1032.\u003c/li\u003e\n\u003cli\u003eLiu H, Wang R, Shi J, Zhang Y, Huang Z, You S, et al. Baseline neutrophil counts and neutrophil ratio may predict a poor clinical outcome in minor stroke patients with intravenous thrombolysis. 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J Stroke Cerebrovasc Dis. 2016;25:2055-2060.\u003c/li\u003e\n\u003cli\u003eF\u0026uuml;st G, Munthe-Fog L, Illes Z, Sz\u0026eacute;plaki G, Molnar T, Pusch G, et al. Low ficolin-3 levels in early follow-up serum samples are associated with the severity and unfavorable outcome of acute ischemic stroke. J Neuroinflammation. 2011;8:185.\u003c/li\u003e\n\u003cli\u003eMolnar T, Papp V, Banati M, Szereday L, Pusch G, Szapary L, et al. Relationship between C-reactive protein and early activation of leukocytes indicated by leukocyte antisedimentation rate (LAR) in patients with acute cerebrovascular events. Clin Hemorheol and Microcirc, 2010, 44:183-192\u003c/li\u003e\n\u003cli\u003eRamiro L, Simats A, Garc\u0026iacute;a-Berrocoso T, Montaner J. Inflammatory molecules might become both biomarkers and therapeutic targets for stroke management. Ther Adv Neurol Disord. 2018;11:1-24.\u003c/li\u003e\n\u003cli\u003eWu T, Chien K, Lin H, Hsu H, Su T, Chen M, et al. Total white blood cell count or neutrophil count predict ischemic stroke events among adult Taiwanese: report from a community-based cohort study. BMC Neurol. 2013;13:7\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"ischemic stroke, large vessel occlusion, leukocytes, neutrophils, neuroinflammation","lastPublishedDoi":"10.21203/rs.3.rs-76213/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-76213/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground: \u003c/strong\u003eNeuroinflammation plays an important role in the pathogenesis of acute ischemic stroke (AIS) and peripheral leukocyte counts have proved to be independent predictors of stroke severity and outcomes. Clinical significance of large vessel occlusion (LVO) in AIS is increasing, as these patients are potential candidates for endovascular thrombectomy and likely to have worse outcomes if not treated urgently. The aim of our study was to assess the relationship between on admission leukocyte counts and the presence of LVO in the early phase of AIS.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods: \u003c/strong\u003eWe have conducted a cross-sectional, observational study based on a registry of consecutive AIS patients admitted up to 4.5 hours after stroke onset. Blood samples were taken at admission and leukocyte counts were measured immediately. The presence of LVO was verified based on the computed tomography angiography scan on admission.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults: \u003c/strong\u003eTotal white blood cell (WBC) and neutrophil counts were significantly higher in patients with LVO than those without LVO (P\u0026lt;0.001 respectively). After adjustment for potential confounders total WBC counts (adjusted OR: 1.405 per 1x10\u003csup\u003e9\u003c/sup\u003e/L increase, 95% CI: 1.209 to 1.632) and neutrophil counts (adjusted OR: 1.344 per 1x10\u003csup\u003e9\u003c/sup\u003e/L increase, 95% CI: 1.155 to 1.564) were found to have the strongest associations with the presence of LVO. Total WBC and neutrophil counts had moderate ability to discriminate an LVO in AIS (AUC: 0.667 and 0.655 respectively). No differences were recorded in leukocyte counts according to the size of the occluded vessel and the status of collateral circulation in the anterior vascular territory. However, total WBC and neutrophil counts tended to be higher in patients with LVO in the posterior circulation (p= 0.005 and 0.010 respectively).\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion: \u003c/strong\u003eHigher admission total WBC and neutrophil counts are strongly associated with the presence of LVO and has moderate ability to discriminate an LVO in AIS. Detailed evaluation of stroke-evoked inflammatory mechanisms and changes according to the presence of LVO demands further investigation.\u003c/p\u003e","manuscriptTitle":"Relationship Between Leukocyte Counts and Large Vessel Occlusion in Acute Ischemic Stroke","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-09-22 15:22:05","doi":"10.21203/rs.3.rs-76213/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Major revision","date":"2020-10-20T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2020-10-15T12:00:00+00:00","index":2,"fulltext":"Recommendation: Accept after minor essential revisions\nForm responses:\n---\n\nComments to Author:\n---\nGeneral comment.\n\nThe authors conducted a cross- sectional, observational study of consecutive patients presented in the 4.5h time window after the onset of stroke. Blood markers (WBC, leucocyte subtypes and neutrophil-to-lymphocyte ratio) were examined and a logistic regression and ROC analysis were conducted for a possible association between leucocyte counts and presence of a large vessel occlusion. The study showed that elevated leucocyte counts are detected in LVO patients and ROC analysis showed a moderate ability to discriminate an LVO in acute ischemic stroke patients.\n\nThe study is well written and adds to the current literature regarding the elevated inflammation markers observed during the acute phase (see also Weisenburger-Lille et al Neurol Neuroimmunol Neuroinflamm 2019;6:e571.). Interesting finding that there was no difference of the observed markers according to the size of the vessel and the collateral status.\n\nThe proposal \"Our result may be useful for primary stroke-centres without CTA imaging facilities to consider LVO in AIS patients with very high total WBC or neutrophil counts.\" is not highly supported by the findings as ROC analysis was marginally indicative (possibly due to low specificity??). I would kindly suggest to modify. \n\nLine 83 \"on the on…\". Please make the appropriate correction.\n\nPlease add bibliography in the mCTA collateral score.\n\nLine 132 Please add (either in the main text or in the logistic regression table) the confounders used for the adjustments.\n\nLine 201 \"and the core…\". Please make the appropriate correction.\n\nIt would be of interest to provide any significant differences among the measured markers between patients with or without subsequent stroke-associated infections (notably aspiration pneumonia) or patients with or without IS risk factors (such as hypertension, diabetes, and hyperlipidemia) in order to clearly attribute the WBC elevation solely to the IS.\n\nComplementary to the ROC curves can you please also provide us with the table of sensitivity, specificity, positive predictive value, negative predictive value and AUC.\n* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **Yes**\n* Declaration of competing interests: **No competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please publish my name with my report.**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"editorInvitedReview","content":"","date":"2020-10-14T12:00:00+00:00","index":1,"fulltext":"Recommendation: Accept after minor essential revisions\nForm responses:\n---\n\nComments to Author:\n---\nThe authors have conducted a cross sectional observational study on the peripheral white blood cell counts and their association with the angiographic and clinical findings in patients submitted to the hospital within 4,5 hours post stroke ictus. Statistical analysis is performed and a p\u003c0,05 is considered of having statistical significance.\n\nIt is noted in line 121 up to line 124 that \"higher total WBC counts were recorded in LVO patients\" and that \"median neutrophil counts were significantly higher in the LVO group (p\u003c0,01)\" while \"no significant difference was recorded between the group of the other subtypes\" of white blood cells. ROC (line 137) demonstrated the ability of the neutrophils and the total WBC counts to discriminate the presence of LVO with p\u003c0,001 for both parameters but failed to demonstrate significance of the \"other leukocyte subtypes\". This seems to come in contrast with line 186-187 where the authors state that even \"the association was also quite strong for basophils\". It would be appreciated to be provided with more details regarding the results of the basophils and their statistical association to LVO presence as well as a more accurate citation. Citation 15 seems to be focused on spinal cord injury in wild type vs. basophil‐deficient mice and has limited relations to AIS and the general role of the basophils in brain injury thus limited relation to the topic that the authors examine.\n\nThe authors refer to patients with stroke in the posterior circulation as having the tendency to have \"milder strokes\" (line 155). It would be important to receive further explanation regarding the method used to access the severity of the stroke symptoms as posterior circulation stroke severity can be underestimated because of the limited ability of the National Institutes of Health Stroke scale (NIHSS) to determine the non-focal symptomatology thus being classified with lower NIHSS points.\n\nIn line 212 the authors suggest that the posterior territory has a higher proportion of white matter. It would be valuable to provide further references and details\n\nThe paper would also benefit from information about the number and the percentage of the patients that were diagnosed with an infection shortly after admission.\n\nLastly I would like to stress that leukocyte counts rise and their relation to the acute diagnosis regarding presence or not of LVO is still not crystal clear. In the data provided it is noted that the total WBC count is 9.27x109 /L for patients presenting with AIS secondary to LVO in comparison to 7.61x109 /L with patients without LVO (line 121-122). According to the authors the usage of the results of the study could be to \"consider LVO in AIS patients with very high total WBC or neutrophil counts\" (215) according to the discussion section of the article. The normal value of WBC ranges from 4,5x109 /L to 11,0x109 /L which suggests that the median values calculated in this article are not suggestive for \"very high total\" count. This raises the suspicion that the authors suggestions could be falsely interpreted and lead to confusion about the management of the patient presenting with an acute stroke within the therapeutic window for endovascular treatment with thrombectomy.* Publons Reviewer Recognition. Springer Nature can send verification of this review directly to Publons (a subsidiary of Clarivate Analytics). If you would like to take advantage of this service, please click on the “Yes” option below. Your name, email address, title of the reviewed manuscript, name of the journal, and date of your review submission (the “Review Data”) will then be transmitted to Publons upon publication of the manuscript. If you have already registered at Publons, they will notify you of the receipt of this review and update your profile as per your settings and their policy. If you are not registered with Publons, you will receive an email from them asking you to register in order for them to be able to recognize your review on your new profile page. Publons may use the Review Data to generate derivative metadata for the benefit of Publons and you as a reviewer, carefully considering the sensitivity of such information. For example, Publons may verify your record as a reviewer by updating your profile published on its webservice if you have registered for such service or help editors to identify candidate reviewers. Please find the details of processing in Publons’ privacy policy https://publons.com/about/terms: **No**\n* Declaration of competing interests: **I declare that I have no competing interests**\n* Reviewer Publication Consent. I agree for my report to be made available under an Open Access Creative Commons CC-BY License (http://creativecommons.org/licenses/by/4.0) if this manuscript is accepted for publication. Any comments that I do not wish to be included in the published report have been included as confidential comments to the editor, which will not be published.: **I agree to the terms of the CC-BY 4.0 license; please do not publish my name with my report. (default)**\n* Is the study design appropriate to answer the research question (including the use of appropriate controls), and are the conclusions supported by the evidence presented?: **Yes**\n* Are the methods sufficiently described to allow the study to be repeated?: **Yes**\n* Is the use of statistics and treatment of uncertainties appropriate?: **Yes**\n* Is the presentation of the work clear?: **Yes**\n* Are the images in this manuscript (including electrophoretic gels and blots) free from apparent manipulation?: **Yes**\n"},{"type":"reviewerAgreed","content":"","date":"2020-09-24T12:00:00+00:00","index":1,"fulltext":""},{"type":"reviewerAgreed","content":"","date":"2020-09-24T12:00:00+00:00","index":2,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2020-09-23T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-09-14T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-09-13T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-09-13T12:00:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"","date":"2020-09-10T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"0ed45e42-35ed-4554-b38d-4b77feae6dc5","owner":[],"postedDate":"September 22nd, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":578470,"name":"Neurology"}],"tags":[],"updatedAt":"2020-12-06T15:02:45+00:00","versionOfRecord":{"articleIdentity":"rs-76213","link":"https://doi.org/10.1186/s12883-020-02017-3","journal":{"identity":"bmc-neurology","isVorOnly":false,"title":"BMC Neurology"},"publishedOn":"2020-12-04 15:01:03","publishedOnDateReadable":"December 4th, 2020"},"versionCreatedAt":"2020-09-22 15:22:05","video":"","vorDoi":"10.1186/s12883-020-02017-3","vorDoiUrl":"https://doi.org/10.1186/s12883-020-02017-3","workflowStages":[]},"version":"v1","identity":"rs-76213","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-76213","identity":"rs-76213","version":["v1"]},"buildId":"_2-kVJe1T_tPrBINL-cwx","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}