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December 15, 2020; 95 (24) Article

Stroke risk, phenotypes, and death in COVID-19

Systematic review and newly reported cases

View ORCID ProfileSebastian Fridman, Maria Bres Bullrich, View ORCID ProfileAmado Jimenez-Ruiz, Pablo Costantini, Palak Shah, Caroline Just, View ORCID ProfileDaniel Vela-Duarte, Italo Linfante, View ORCID ProfileAthena Sharifi-Razavi, Narges Karimi, View ORCID ProfileRodrigo Bagur, Derek B. Debicki, Teneille E. Gofton, View ORCID ProfileDavid A. Steven, View ORCID ProfileLuciano A. Sposato
First published September 15, 2020, DOI: https://doi.org/10.1212/WNL.0000000000010851
Sebastian Fridman
From the Department of Clinical Neurological Sciences (S.F., M.B.B., P.S., C.J., D.B.D., T.E.G., D.A.S., L.A.S.), Department of Medicine (R.B.), Division of Cardiology, Department of Anatomy and Cell Biology (L.A.S.), and Department of Epidemiology and Biostatistics (R.B., D.A.S., L.A.S.), Schulich School of Medicine and Dentistry, Heart & Brain Laboratory (A.J.-R., L.A.S.), and Robarts Research Institute (L.A.S.), Western University, London, Ontario, Canada; Instituto de Neurología y Neurocirugía de Neuquén (P.C.), Argentina; Miami Cardiac & Vascular Institute (D.V.-D., I.L.), Baptist Hospital Neuroscience Center, FL; Clinical Research Development Unit of Bou Ali Sina Hospital (A.S.-R.) and Immunogenetics Research Center (N.K.), Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari, Iran; and Lawson Health Research Institute (L.A.S.), London, Ontario, Canada.
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Maria Bres Bullrich
From the Department of Clinical Neurological Sciences (S.F., M.B.B., P.S., C.J., D.B.D., T.E.G., D.A.S., L.A.S.), Department of Medicine (R.B.), Division of Cardiology, Department of Anatomy and Cell Biology (L.A.S.), and Department of Epidemiology and Biostatistics (R.B., D.A.S., L.A.S.), Schulich School of Medicine and Dentistry, Heart & Brain Laboratory (A.J.-R., L.A.S.), and Robarts Research Institute (L.A.S.), Western University, London, Ontario, Canada; Instituto de Neurología y Neurocirugía de Neuquén (P.C.), Argentina; Miami Cardiac & Vascular Institute (D.V.-D., I.L.), Baptist Hospital Neuroscience Center, FL; Clinical Research Development Unit of Bou Ali Sina Hospital (A.S.-R.) and Immunogenetics Research Center (N.K.), Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari, Iran; and Lawson Health Research Institute (L.A.S.), London, Ontario, Canada.
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Amado Jimenez-Ruiz
From the Department of Clinical Neurological Sciences (S.F., M.B.B., P.S., C.J., D.B.D., T.E.G., D.A.S., L.A.S.), Department of Medicine (R.B.), Division of Cardiology, Department of Anatomy and Cell Biology (L.A.S.), and Department of Epidemiology and Biostatistics (R.B., D.A.S., L.A.S.), Schulich School of Medicine and Dentistry, Heart & Brain Laboratory (A.J.-R., L.A.S.), and Robarts Research Institute (L.A.S.), Western University, London, Ontario, Canada; Instituto de Neurología y Neurocirugía de Neuquén (P.C.), Argentina; Miami Cardiac & Vascular Institute (D.V.-D., I.L.), Baptist Hospital Neuroscience Center, FL; Clinical Research Development Unit of Bou Ali Sina Hospital (A.S.-R.) and Immunogenetics Research Center (N.K.), Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari, Iran; and Lawson Health Research Institute (L.A.S.), London, Ontario, Canada.
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Pablo Costantini
From the Department of Clinical Neurological Sciences (S.F., M.B.B., P.S., C.J., D.B.D., T.E.G., D.A.S., L.A.S.), Department of Medicine (R.B.), Division of Cardiology, Department of Anatomy and Cell Biology (L.A.S.), and Department of Epidemiology and Biostatistics (R.B., D.A.S., L.A.S.), Schulich School of Medicine and Dentistry, Heart & Brain Laboratory (A.J.-R., L.A.S.), and Robarts Research Institute (L.A.S.), Western University, London, Ontario, Canada; Instituto de Neurología y Neurocirugía de Neuquén (P.C.), Argentina; Miami Cardiac & Vascular Institute (D.V.-D., I.L.), Baptist Hospital Neuroscience Center, FL; Clinical Research Development Unit of Bou Ali Sina Hospital (A.S.-R.) and Immunogenetics Research Center (N.K.), Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari, Iran; and Lawson Health Research Institute (L.A.S.), London, Ontario, Canada.
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Palak Shah
From the Department of Clinical Neurological Sciences (S.F., M.B.B., P.S., C.J., D.B.D., T.E.G., D.A.S., L.A.S.), Department of Medicine (R.B.), Division of Cardiology, Department of Anatomy and Cell Biology (L.A.S.), and Department of Epidemiology and Biostatistics (R.B., D.A.S., L.A.S.), Schulich School of Medicine and Dentistry, Heart & Brain Laboratory (A.J.-R., L.A.S.), and Robarts Research Institute (L.A.S.), Western University, London, Ontario, Canada; Instituto de Neurología y Neurocirugía de Neuquén (P.C.), Argentina; Miami Cardiac & Vascular Institute (D.V.-D., I.L.), Baptist Hospital Neuroscience Center, FL; Clinical Research Development Unit of Bou Ali Sina Hospital (A.S.-R.) and Immunogenetics Research Center (N.K.), Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari, Iran; and Lawson Health Research Institute (L.A.S.), London, Ontario, Canada.
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Caroline Just
From the Department of Clinical Neurological Sciences (S.F., M.B.B., P.S., C.J., D.B.D., T.E.G., D.A.S., L.A.S.), Department of Medicine (R.B.), Division of Cardiology, Department of Anatomy and Cell Biology (L.A.S.), and Department of Epidemiology and Biostatistics (R.B., D.A.S., L.A.S.), Schulich School of Medicine and Dentistry, Heart & Brain Laboratory (A.J.-R., L.A.S.), and Robarts Research Institute (L.A.S.), Western University, London, Ontario, Canada; Instituto de Neurología y Neurocirugía de Neuquén (P.C.), Argentina; Miami Cardiac & Vascular Institute (D.V.-D., I.L.), Baptist Hospital Neuroscience Center, FL; Clinical Research Development Unit of Bou Ali Sina Hospital (A.S.-R.) and Immunogenetics Research Center (N.K.), Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari, Iran; and Lawson Health Research Institute (L.A.S.), London, Ontario, Canada.
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Daniel Vela-Duarte
From the Department of Clinical Neurological Sciences (S.F., M.B.B., P.S., C.J., D.B.D., T.E.G., D.A.S., L.A.S.), Department of Medicine (R.B.), Division of Cardiology, Department of Anatomy and Cell Biology (L.A.S.), and Department of Epidemiology and Biostatistics (R.B., D.A.S., L.A.S.), Schulich School of Medicine and Dentistry, Heart & Brain Laboratory (A.J.-R., L.A.S.), and Robarts Research Institute (L.A.S.), Western University, London, Ontario, Canada; Instituto de Neurología y Neurocirugía de Neuquén (P.C.), Argentina; Miami Cardiac & Vascular Institute (D.V.-D., I.L.), Baptist Hospital Neuroscience Center, FL; Clinical Research Development Unit of Bou Ali Sina Hospital (A.S.-R.) and Immunogenetics Research Center (N.K.), Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari, Iran; and Lawson Health Research Institute (L.A.S.), London, Ontario, Canada.
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Italo Linfante
From the Department of Clinical Neurological Sciences (S.F., M.B.B., P.S., C.J., D.B.D., T.E.G., D.A.S., L.A.S.), Department of Medicine (R.B.), Division of Cardiology, Department of Anatomy and Cell Biology (L.A.S.), and Department of Epidemiology and Biostatistics (R.B., D.A.S., L.A.S.), Schulich School of Medicine and Dentistry, Heart & Brain Laboratory (A.J.-R., L.A.S.), and Robarts Research Institute (L.A.S.), Western University, London, Ontario, Canada; Instituto de Neurología y Neurocirugía de Neuquén (P.C.), Argentina; Miami Cardiac & Vascular Institute (D.V.-D., I.L.), Baptist Hospital Neuroscience Center, FL; Clinical Research Development Unit of Bou Ali Sina Hospital (A.S.-R.) and Immunogenetics Research Center (N.K.), Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari, Iran; and Lawson Health Research Institute (L.A.S.), London, Ontario, Canada.
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Athena Sharifi-Razavi
From the Department of Clinical Neurological Sciences (S.F., M.B.B., P.S., C.J., D.B.D., T.E.G., D.A.S., L.A.S.), Department of Medicine (R.B.), Division of Cardiology, Department of Anatomy and Cell Biology (L.A.S.), and Department of Epidemiology and Biostatistics (R.B., D.A.S., L.A.S.), Schulich School of Medicine and Dentistry, Heart & Brain Laboratory (A.J.-R., L.A.S.), and Robarts Research Institute (L.A.S.), Western University, London, Ontario, Canada; Instituto de Neurología y Neurocirugía de Neuquén (P.C.), Argentina; Miami Cardiac & Vascular Institute (D.V.-D., I.L.), Baptist Hospital Neuroscience Center, FL; Clinical Research Development Unit of Bou Ali Sina Hospital (A.S.-R.) and Immunogenetics Research Center (N.K.), Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari, Iran; and Lawson Health Research Institute (L.A.S.), London, Ontario, Canada.
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Narges Karimi
From the Department of Clinical Neurological Sciences (S.F., M.B.B., P.S., C.J., D.B.D., T.E.G., D.A.S., L.A.S.), Department of Medicine (R.B.), Division of Cardiology, Department of Anatomy and Cell Biology (L.A.S.), and Department of Epidemiology and Biostatistics (R.B., D.A.S., L.A.S.), Schulich School of Medicine and Dentistry, Heart & Brain Laboratory (A.J.-R., L.A.S.), and Robarts Research Institute (L.A.S.), Western University, London, Ontario, Canada; Instituto de Neurología y Neurocirugía de Neuquén (P.C.), Argentina; Miami Cardiac & Vascular Institute (D.V.-D., I.L.), Baptist Hospital Neuroscience Center, FL; Clinical Research Development Unit of Bou Ali Sina Hospital (A.S.-R.) and Immunogenetics Research Center (N.K.), Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari, Iran; and Lawson Health Research Institute (L.A.S.), London, Ontario, Canada.
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Rodrigo Bagur
From the Department of Clinical Neurological Sciences (S.F., M.B.B., P.S., C.J., D.B.D., T.E.G., D.A.S., L.A.S.), Department of Medicine (R.B.), Division of Cardiology, Department of Anatomy and Cell Biology (L.A.S.), and Department of Epidemiology and Biostatistics (R.B., D.A.S., L.A.S.), Schulich School of Medicine and Dentistry, Heart & Brain Laboratory (A.J.-R., L.A.S.), and Robarts Research Institute (L.A.S.), Western University, London, Ontario, Canada; Instituto de Neurología y Neurocirugía de Neuquén (P.C.), Argentina; Miami Cardiac & Vascular Institute (D.V.-D., I.L.), Baptist Hospital Neuroscience Center, FL; Clinical Research Development Unit of Bou Ali Sina Hospital (A.S.-R.) and Immunogenetics Research Center (N.K.), Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari, Iran; and Lawson Health Research Institute (L.A.S.), London, Ontario, Canada.
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Derek B. Debicki
From the Department of Clinical Neurological Sciences (S.F., M.B.B., P.S., C.J., D.B.D., T.E.G., D.A.S., L.A.S.), Department of Medicine (R.B.), Division of Cardiology, Department of Anatomy and Cell Biology (L.A.S.), and Department of Epidemiology and Biostatistics (R.B., D.A.S., L.A.S.), Schulich School of Medicine and Dentistry, Heart & Brain Laboratory (A.J.-R., L.A.S.), and Robarts Research Institute (L.A.S.), Western University, London, Ontario, Canada; Instituto de Neurología y Neurocirugía de Neuquén (P.C.), Argentina; Miami Cardiac & Vascular Institute (D.V.-D., I.L.), Baptist Hospital Neuroscience Center, FL; Clinical Research Development Unit of Bou Ali Sina Hospital (A.S.-R.) and Immunogenetics Research Center (N.K.), Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari, Iran; and Lawson Health Research Institute (L.A.S.), London, Ontario, Canada.
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Teneille E. Gofton
From the Department of Clinical Neurological Sciences (S.F., M.B.B., P.S., C.J., D.B.D., T.E.G., D.A.S., L.A.S.), Department of Medicine (R.B.), Division of Cardiology, Department of Anatomy and Cell Biology (L.A.S.), and Department of Epidemiology and Biostatistics (R.B., D.A.S., L.A.S.), Schulich School of Medicine and Dentistry, Heart & Brain Laboratory (A.J.-R., L.A.S.), and Robarts Research Institute (L.A.S.), Western University, London, Ontario, Canada; Instituto de Neurología y Neurocirugía de Neuquén (P.C.), Argentina; Miami Cardiac & Vascular Institute (D.V.-D., I.L.), Baptist Hospital Neuroscience Center, FL; Clinical Research Development Unit of Bou Ali Sina Hospital (A.S.-R.) and Immunogenetics Research Center (N.K.), Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari, Iran; and Lawson Health Research Institute (L.A.S.), London, Ontario, Canada.
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David A. Steven
From the Department of Clinical Neurological Sciences (S.F., M.B.B., P.S., C.J., D.B.D., T.E.G., D.A.S., L.A.S.), Department of Medicine (R.B.), Division of Cardiology, Department of Anatomy and Cell Biology (L.A.S.), and Department of Epidemiology and Biostatistics (R.B., D.A.S., L.A.S.), Schulich School of Medicine and Dentistry, Heart & Brain Laboratory (A.J.-R., L.A.S.), and Robarts Research Institute (L.A.S.), Western University, London, Ontario, Canada; Instituto de Neurología y Neurocirugía de Neuquén (P.C.), Argentina; Miami Cardiac & Vascular Institute (D.V.-D., I.L.), Baptist Hospital Neuroscience Center, FL; Clinical Research Development Unit of Bou Ali Sina Hospital (A.S.-R.) and Immunogenetics Research Center (N.K.), Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari, Iran; and Lawson Health Research Institute (L.A.S.), London, Ontario, Canada.
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Luciano A. Sposato
From the Department of Clinical Neurological Sciences (S.F., M.B.B., P.S., C.J., D.B.D., T.E.G., D.A.S., L.A.S.), Department of Medicine (R.B.), Division of Cardiology, Department of Anatomy and Cell Biology (L.A.S.), and Department of Epidemiology and Biostatistics (R.B., D.A.S., L.A.S.), Schulich School of Medicine and Dentistry, Heart & Brain Laboratory (A.J.-R., L.A.S.), and Robarts Research Institute (L.A.S.), Western University, London, Ontario, Canada; Instituto de Neurología y Neurocirugía de Neuquén (P.C.), Argentina; Miami Cardiac & Vascular Institute (D.V.-D., I.L.), Baptist Hospital Neuroscience Center, FL; Clinical Research Development Unit of Bou Ali Sina Hospital (A.S.-R.) and Immunogenetics Research Center (N.K.), Toxoplasmosis Research Center, Mazandaran University of Medical Sciences, Sari, Iran; and Lawson Health Research Institute (L.A.S.), London, Ontario, Canada.
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Citation
Stroke risk, phenotypes, and death in COVID-19
Systematic review and newly reported cases
Sebastian Fridman, Maria Bres Bullrich, Amado Jimenez-Ruiz, Pablo Costantini, Palak Shah, Caroline Just, Daniel Vela-Duarte, Italo Linfante, Athena Sharifi-Razavi, Narges Karimi, Rodrigo Bagur, Derek B. Debicki, Teneille E. Gofton, David A. Steven, Luciano A. Sposato
Neurology Dec 2020, 95 (24) e3373-e3385; DOI: 10.1212/WNL.0000000000010851

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Abstract

Objectives To investigate the hypothesis that strokes occurring in patients with coronavirus disease 2019 (COVID-19) have distinctive features, we investigated stroke risk, clinical phenotypes, and outcomes in this population.

Methods We performed a systematic search resulting in 10 studies reporting stroke frequency among patients with COVID-19, which were pooled with 1 unpublished series from Canada. We applied random-effects meta-analyses to estimate the proportion of stroke among COVID-19. We performed an additional systematic search for cases series of stroke in patients with COVID-19 (n = 125), and we pooled these data with 35 unpublished cases from Canada, the United States, and Iran. We analyzed clinical characteristics and in-hospital mortality stratified into age groups (<50, 50–70, >70 years). We applied cluster analyses to identify specific clinical phenotypes and their relationship with death.

Results The proportions of patients with COVID-19 with stroke (1.8%, 95% confidence interval [CI] 0.9%–3.7%) and in-hospital mortality (34.4%, 95% CI 27.2%–42.4%) were exceedingly high. Mortality was 67% lower in patients <50 years of age relative to those >70 years of age (odds ratio [OR] 0.33, 95% CI 0.12–0.94, p = 0.039). Large vessel occlusion was twice as frequent (46.9%) as previously reported and was high across all age groups, even in the absence of risk factors or comorbid conditions. A clinical phenotype characterized by older age, a higher burden of comorbid conditions, and severe COVID-19 respiratory symptoms was associated with the highest in-hospital mortality (58.6%) and a 3 times higher risk of death than the rest of the cohort (OR 3.52, 95% CI 1.53–8.09, p = 0.003).

Conclusions Stroke is relatively frequent among patients with COVID-19 and has devastating consequences across all ages. The interplay of older age, comorbid conditions, and severity of COVID-19 respiratory symptoms is associated with an extremely elevated mortality.

Glossary

CI=
confidence interval;
COVID-19=
coronavirus disease 2019;
CVT=
cerebral venous thrombosis;
ICH=
intracerebral hemorrhage;
LVO=
large vessel occlusion;
OR=
odds ratio;
SAH=
subarachnoid hemorrhage;
SARS-CoV=
severe acute respiratory syndrome coronavirus;
uOR=
unadjusted OR

Footnotes

  • Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • NPub.org/COVID19

  • Received June 9, 2020.
  • Accepted in final form August 25, 2020.
  • © 2020 American Academy of Neurology
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