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Frequency of Neurologic Manifestations in COVID-19: A Systematic Review and Meta-analysis

Misra S 1 , Kolappa K 1 , Prasad M 1 , Radhakrishnan D 1 , Thakur KT 1 , Solomon T 1 Show all authors , Michael BD 1 , Winkler AS 1 , Beghi E 1 , Guekht A 1 , Pardo CA 1 , Wood GK 1 , Hsiang-Yi Chou S 1 , Fink EL 1 , Schmutzhard E 1 , Kheradmand A 1 , Hoo FK 1 , Kumar A 1 , Das A 1 , Srivastava AK 1 , Agarwal A 1 , Dua T 1 , Prasad K 2

Affiliations 

  • 1 From the Department of Neurology (S.M., D.R., A.K., A.D., A.K.S., A.A.), All India Institute of Medical Sciences, New Delhi, India; Brain Health Unit (K.K., T.D.), World Health Organization, Geneva, Switzerland; Department of Clinical Research and Epidemiology (M.P.), Institute of Liver and Biliary Sciences, New Delhi, India; Columbia University Irving Medical Center-New York Presbyterian Hospital (K.T.T.), NY; Institute of Infection, Veterinary and Ecological Sciences (T.S., B.D.M., G.K.W.), University of Liverpool; Department of Neurology (T.S., B.D.M.), Walton Centre NHS Foundation Trust; NIHR Health Protection Research Unit for Emerging and Zoonotic Infection (B.D.M.), Liverpool, UK; Center for Global Health (A.S.W.), Department of Neurology, Technical University of Munich, Germany; Centre for Global Health (A.S.W.), Institute of Health and Society, University of Oslo, Norway; Istituto di Ricerche Farmacologiche Mario Negri IRCCS (E.B.), Milan, Italy; Moscow Research and Clinical Center for Neuropsychiatry and Pirogov Russian National Research Medical University (A.G.), Russia; Departments of Neurology and Pathology (C.A.P.), Johns Hopkins University School of Medicine, Baltimore, MD; University of Pittsburgh School of Medicine (S.H.-Y.C.); Department of Critical Care Medicine (E.L.F.), UPMC Children's Hospital of Pittsburgh, PA; Department of Neurology (E.S.), Medical University Innsbruck, Austria; Departments of Neurology and Otolaryngology-Head & Neck Surgery (A.K.), The Johns Hopkins Hospital, Baltimore, MD; Department of Neurology (F.K.H.), Faculty of Medicine and Health Sciences, University Putra Malaysia, Seri Kembangan; and Rajendra Institute of Medical Sciences (K.P.), Ranchi, Jharkhand, India
  • 2 From the Department of Neurology (S.M., D.R., A.K., A.D., A.K.S., A.A.), All India Institute of Medical Sciences, New Delhi, India; Brain Health Unit (K.K., T.D.), World Health Organization, Geneva, Switzerland; Department of Clinical Research and Epidemiology (M.P.), Institute of Liver and Biliary Sciences, New Delhi, India; Columbia University Irving Medical Center-New York Presbyterian Hospital (K.T.T.), NY; Institute of Infection, Veterinary and Ecological Sciences (T.S., B.D.M., G.K.W.), University of Liverpool; Department of Neurology (T.S., B.D.M.), Walton Centre NHS Foundation Trust; NIHR Health Protection Research Unit for Emerging and Zoonotic Infection (B.D.M.), Liverpool, UK; Center for Global Health (A.S.W.), Department of Neurology, Technical University of Munich, Germany; Centre for Global Health (A.S.W.), Institute of Health and Society, University of Oslo, Norway; Istituto di Ricerche Farmacologiche Mario Negri IRCCS (E.B.), Milan, Italy; Moscow Research and Clinical Center for Neuropsychiatry and Pirogov Russian National Research Medical University (A.G.), Russia; Departments of Neurology and Pathology (C.A.P.), Johns Hopkins University School of Medicine, Baltimore, MD; University of Pittsburgh School of Medicine (S.H.-Y.C.); Department of Critical Care Medicine (E.L.F.), UPMC Children's Hospital of Pittsburgh, PA; Department of Neurology (E.S.), Medical University Innsbruck, Austria; Departments of Neurology and Otolaryngology-Head & Neck Surgery (A.K.), The Johns Hopkins Hospital, Baltimore, MD; Department of Neurology (F.K.H.), Faculty of Medicine and Health Sciences, University Putra Malaysia, Seri Kembangan; and Rajendra Institute of Medical Sciences (K.P.), Ranchi, Jharkhand, India. [email protected]
Neurology, 2021 Dec 07;97(23):e2269-e2281.
PMID: 34635561 DOI: 10.1212/WNL.0000000000012930

Abstract

BACKGROUND AND OBJECTIVES: One year after the onset of the coronavirus disease 2019 (COVID-19) pandemic, we aimed to summarize the frequency of neurologic manifestations reported in patients with COVID-19 and to investigate the association of these manifestations with disease severity and mortality.

METHODS: We searched PubMed, Medline, Cochrane library, ClinicalTrials.gov, and EMBASE for studies from December 31, 2019, to December 15, 2020, enrolling consecutive patients with COVID-19 presenting with neurologic manifestations. Risk of bias was examined with the Joanna Briggs Institute scale. A random-effects meta-analysis was performed, and pooled prevalence and 95% confidence intervals (CIs) were calculated for neurologic manifestations. Odds ratio (ORs) and 95% CIs were calculated to determine the association of neurologic manifestations with disease severity and mortality. Presence of heterogeneity was assessed with I 2, meta-regression, and subgroup analyses. Statistical analyses were conducted in R version 3.6.2.

RESULTS: Of 2,455 citations, 350 studies were included in this review, providing data on 145,721 patients with COVID-19, 89% of whom were hospitalized. Forty-one neurologic manifestations (24 symptoms and 17 diagnoses) were identified. Pooled prevalence of the most common neurologic symptoms included fatigue (32%), myalgia (20%), taste impairment (21%), smell impairment (19%), and headache (13%). A low risk of bias was observed in 85% of studies; studies with higher risk of bias yielded higher prevalence estimates. Stroke was the most common neurologic diagnosis (pooled prevalence 2%). In patients with COVID-19 ≥60 years of age, the pooled prevalence of acute confusion/delirium was 34%, and the presence of any neurologic manifestations in this age group was associated with mortality (OR 1.80, 95% CI 1.11-2.91).

DISCUSSION: Up to one-third of patients with COVID-19 analyzed in this review experienced at least 1 neurologic manifestation. One in 50 patients experienced stroke. In those >60 years of age, more than one-third had acute confusion/delirium; the presence of neurologic manifestations in this group was associated with nearly a doubling of mortality. Results must be interpreted with the limitations of observational studies and associated bias in mind.

SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42020181867.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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