key: cord-0933461-6mfrzg5n authors: Shahjouei, S.; Tsivgoulis, G.; Arora, R.; Harirchian, M. H.; Rahimian, N.; Borhani-Haghighi, A.; Mondello, S.; Kia, A.; Vafaei Sadr, A.; Mowla, A.; Avula, V.; Ansari, S.; Zand, R.; Abedi, V.; Farahmand, G.; Koza, E.; Punter, M.; Ranta, A.; Cernigliaro, A.; Vaghefi Far, A.; Li, J.; Olulana, O.; Chaudhary, D. title: SARS-CoV-2 and Stroke Characteristics: A Report from the Multinational COVID-19 Stroke Study Group date: 2020-08-07 journal: nan DOI: 10.1101/2020.08.05.20169169 sha: f19a1abb407ac9b3a33494d6e360ab6382d67a1e doc_id: 933461 cord_uid: 6mfrzg5n Background: Stroke is reported as a consequence of SARS-CoV-2 infection. However, there is a lack of regarding comprehensive stroke phenotype and characteristics Methods: We conducted a multinational observational study on features of consecutive acute ischemic stroke (AIS), intracranial hemorrhage (ICH), and cerebral venous or sinus thrombosis (CVST) among SARS-CoV-2 infected patients. We further investigated the association of demographics, clinical data, geographical regions, and countrie's health expenditure among AIS patients with the risk of large vessel occlusion (LVO), stroke severity as measured by National Institute of Health stroke scale (NIHSS), and stroke subtype as measured by the TOAST criteria. Additionally, we applied unsupervised machine learning algorithms to uncover possible similarities among stroke patients. Results: Among the 136 tertiary centers of 32 countries who participated in this study, 71 centers from 17 countries had at least one eligible stroke patient. Out of 432 patients included, 323(74.8%) had AIS, 91(21.1%) ICH, and 18(4.2%) CVST. Among 23 patients with subarachnoid hemorrhage, 16(69.5%) had no evidence of aneurysm. A total of 183(42.4%) patients were women, 104(24.1%) patients were younger than 55 years, and 105(24.4%) patients had no identifiable vascular risk factors. Among 380 patients who had known interval onset of the SARS-CoV-2 and stroke, 144(37.8%) presented to the hospital with chief complaints of stroke-related symptoms, with asymptomatic or undiagnosed SARS-CoV-2 infection. Among AIS patients 44.5% had LVO; 10% had small artery occlusion according to the TOAST criteria. We observed a lower median NIHSS (8[3-17], versus 11[5-17]; p=0.02) and higher rate of mechanical thrombectomy (12.4% versus 2%; p<0.001) in countries with middle to high-health expenditure when compared to countries with lower health expenditure. The unsupervised machine learning identified 4 subgroups, with a relatively large group with no or limited comorbidities. Conclusions: We observed a relatively high number of young, and asymptomatic SARS-CoV-2 infections among stroke patients. Traditional vascular risk factors were absent among a relatively large cohort of patients. Among hospitalized patients, the stroke severity was lower and rate of mechanical thrombectomy was higher among countries with middle to high-health expenditure. algorithms to uncover the possible similarities among these patients. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 7, 2020. . https://doi.org/10.1101/2020.08.05.20169169 doi: medRxiv preprint infection, those who had a stroke while being hospitalized for SARS-CoV-2 infection, or patients with stroke-related 23 admission who had confirmed prior diagnosis of SARS-CoV-2 were included in this study. We excluded patients with 24 stroke incidents prior to the SARS-CoV-2 infection onset. The onset of SARS-CoV-2 was considered as either the 25 symptoms onset or positive test, whichever was first. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 7, 2020. . https://doi.org/10.1101/2020.08.05.20169169 doi: medRxiv preprint like symptoms and obscure viral infection versus those who presented the symptoms or were diagnosed by SARSpatients with >2 comorbidities. The above processes were repeated for the laboratory findings (data not shown); 23 however, no patterns or significant differences among the subgroups were observed. The clustering was not performed 24 for patients with SAH and CVST due to limited sample size. Statistical Analysis and Modeling 26 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 7, 2020. . We used descriptive statistics to summarize the data. Demographic data, comorbidities, laboratory findings, and 1 neurological investigations were reported as medians and interquartile range (IQR), mean and standard deviations 2 (SD), and under stratified categories when possible. The equality of the variances was assessed by Leven's test. Categorical variables were reported as absolute frequencies and percentages. The comparisons between categorical 4 variables were conducted with the Pearson chi-square test, while the differences among continuous variables were 5 assessed by independent t-test and analysis of variance (ANOVA). A post-hoc z-test on the adjusted residuals, and comparison of means, while post-hoc comparison of medians was conducted by Dunn-Bonferroni approach to 8 compare subgroups. All tests were performed using IBM SPSS Statistics version 26 [42] , and p<0.05 was considered 9 statistically significant. Bonferroni correction was used for adjusting all p values in multiple comparisons. We used unsupervised ML algorithms to cluster the patients based on the comorbidities and laboratory findings. The laboratory values were scaled to 1-100 range and underwent Log 10 transformation prior to the clustering. We applied 12 hierarchical (complete linkage method) and k-means (Hartigan-Wong algorithm) clustering, and spectral 13 clustering,[43] to produce 2 to 5 clusters. We used the contingency matrix (a.k.a contingency table)[44] to present the 14 clusters of each model versus other models. The similarity of the models was calculated as follows: ; where i is the number of columns and k is the total number of cells in the 16 contingency matrix. Similarities among the models were considered to be mild (50%-65%), moderate (65%-80%), . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) The copyright holder for this preprint this version posted August 7, 2020. . The mean age for the entire cohort was 65.7±15.7 years. Out of 432 patients, majority were men--249(57.6%), 1 p<0.001. Among 380 patients who had known interval onset of the SARS-CoV-2 and stroke, 144(37.8%) presented 2 to the hospital with chief complaints of stroke-related symptoms, with asymptomatic or undiagnosed SARS-CoV-2 3 infection. In total, 105(24.4%) out of the 430 patients with complete comorbidity profiles had no identifiable vascular 4 risk factor at the time of stroke incidence. Details of patient phenotype and demographic characteristics under each 5 stroke subtype are presented in Table 1 . AIS was diagnosed in 323(74.8%) patients ( Table 6 ). Patients with LVO were different from those without LVO in terms of NIHSS, imaging patterns, TOAST . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 7, 2020. . criteria, and prevalence of intravenous thrombolysis, mechanical thrombectomy, and ischemic heart disease. (Table 1 3, Supplemental Table 7 ). Supplemental Tables 8 and 9 also present the difference among subgroups in terms of cluster demonstrates 4 subgroups, with a relatively large group with no or limited comorbidities. Figure 2B 1 demonstrates comorbidities among IPH patients. Hypertension and diabetes were the most repeated and overlapped and a low rate of small artery occlusion and lacunar infarcts. We also noted significant differences regarding the 23 TOAST criteria in both regional and health-expenditure subgroups as well as higher NIHSS among countries with 24 lower health-expenditure. About one third of IPH patients did not have vascular risk factors but presented with higher 25 ICH scores. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 7, 2020. . https://doi.org/10.1101/2020.08.05.20169169 doi: medRxiv preprint Although the definition of young stroke is debatable, the majority of the studies considered 50 or 55 years as the cut-1 off. [40] We considered both 55 and 65 years-old as the cut-off and realized that younger patients had fewer LVOs and IVT were almost the same in various regions, we observed a significant difference among the regions in 27 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 7, 2020. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 7, 2020. . https://doi.org/10.1101/2020.08.05.20169169 doi: medRxiv preprint Cerebrovascular DisordErs) are required to shed light on changes in stroke care protocols and hospitalization rate 1 during the pandemic. [84] with stroke as the first and only symptom, but difficulty in measuring all symptoms related to COVID-19 (such as 23 fatigue, anosmia, and ageusia) should be taken into consideration. Due to the small sample and heterogeneity of the 24 patients with subclasses of SAH or CVST, we did not apply the machine learning on this subgroup for further 25 exploration. Although attempts were made to minimize the selection bias by including patients from different 26 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 7, 2020. . https://doi.org/10.1101/2020.08.05.20169169 doi: medRxiv preprint ethnicities, ecological conditions, and health care systems, this study may suffer from selection bias and low power in 1 some subgroups. Further studies that include a control population are warranted. In conclusion, we observed a relatively high number of young, and asymptomatic SARS-CoV-2 infections among 3 stroke patients. Traditional vascular risk factors were absent among a relatively large cohort of patients. Among 4 hospitalized patients, the stroke severity was lower and rate of mechanical thrombectomy was higher among countries 5 with middle to high-health expenditure 6 Acknowledgement: We appreciate the efforts of all other health care providers and administrators who contributed 7 data for this study. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 7, 2020. . https://doi.org/10.1101/2020.08.05.20169169 doi: medRxiv preprint common carotid artery thrombosis during a severe COVID-19 infection. J Neuroradiol 2020. is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 7, 2020. 10 11 . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 7, 2020. CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 7, 2020. . https://doi.org/10.1101/2020.08.05.20169169 doi: medRxiv preprint . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 7, 2020. . https://doi.org/10.1101/2020.08.05.20169169 doi: medRxiv preprint . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 7, 2020. . CC-BY-ND 4.0 International license It is made available under a is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The copyright holder for this preprint this version posted August 7, 2020. . https://doi.org/10.1101/2020.08.05.20169169 doi: medRxiv preprint Neurologic Manifestations of Hospitalized Patients With Outcomes from ischemic stroke subtypes classified by the Oxfordshire Community Epidemiology of Ischemic Stroke Cerebral venous sinus thrombosis (CVST) secondary to Cerebral venous 1 thrombosis: clinical features, risk factors, and long-term outcome in a Tunisian cohort