Prevalence and Risk Factors of Neurologic Manifestations in Hospitalized Children Diagnosed with Acute SARS-CoV-2 or MIS-C

doi:10.1016/j.pediatrneurol.2021.12.010

Multicenter Study

. 2022 Mar:128:33-44.

doi: 10.1016/j.pediatrneurol.2021.12.010. Epub 2021 Dec 28.

Prevalence and Risk Factors of Neurologic Manifestations in Hospitalized Children Diagnosed with Acute SARS-CoV-2 or MIS-C

Ericka L Fink¹, Courtney L Robertson², Mark S Wainwright³, Juan D Roa⁴, Marlina E Lovett⁵, Casey Stulce⁶, Mais Yacoub⁷, Renee M Potera⁸, Elizabeth Zivick⁹, Adrian Holloway¹⁰, Ashish Nagpal¹¹, Kari Wellnitz¹², Theresa Czech¹³, Katelyn M Even¹⁴, Werther Brunow de Carvalho¹⁵, Isadora Souza Rodriguez¹⁵, Stephanie P Schwartz¹⁶, Tracie C Walker¹⁶, Santiago Campos-Miño¹⁷, Leslie A Dervan¹⁸, Andrew S Geneslaw¹⁹, Taylor B Sewell¹⁹, Patrice Pryce²⁰, Wendy G Silver²¹, Jieru Egeria Lin²¹, Wendy S Vargas²¹, Alexis Topjian²², Alicia M Alcamo²², Jennifer L McGuire²³, Jesus Angel Domínguez Rojas²⁴, Jaime Tasayco Muñoz²⁴, Sue J Hong²⁵, William J Muller²⁵, Matthew Doerfler²⁵, Cydni N Williams²⁶, Kurt Drury²⁷, Dhristie Bhagat²⁸, Aaron Nelson²⁸, Dana Price²⁸, Heda Dapul²⁹, Laura Santos²⁹, Robert Kahoud³⁰, Conall Francoeur³¹, Brian Appavu³², Kristin P Guilliams³³, Shannon C Agner³³, Karen H Walson³⁴, Lindsey Rasmussen³⁵, Anna Janas³⁵, Peter Ferrazzano³⁶, Raquel Farias-Moeller³⁷, Kellie C Snooks³⁸, Chung-Chou H Chang³⁹, James Yun³⁹, Michelle E Schober⁴⁰; Global Consortium Study of Neurologic Dysfunction in COVID-19 (GCS-NeuroCOVID) Investigators

Affiliations

¹ Division of Pediatric Critical Care Medicine, Department of Critical Care Medicine, Pittsburgh, Pennsylvania; Safar Center for Resuscitation Research, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: finkel@ccm.upmc.edu.
² Departments of Anesthesiology and Critical Care Medicine, and Pediatrics of The Johns Hopkins University SOM, Baltimore, Maryland.
³ Division of Pediatric Neurology, University of Washington, Seattle Children's Hospital, Seattle, Washington.
⁴ Department of Pediatrics, Universidad Nacional de Colombia and Fundación Universitaria de Ciencias de la Salud, Bogotá, Colombia.
⁵ Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio.
⁶ Department of Pediatrics, University of Chicago, Chicago, Illinois.
⁷ Division of Critical Care, Department of Pediatrics, UMC Children's Hospital, Las Vegas, Nevada.
⁸ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
⁹ Division of Pediatric Critical Care Medicine, Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina.
¹⁰ Division of Critical Care, Department of Pediatrics, University of Maryland Medical Center, Baltimore, Maryland.
¹¹ Department of Pediatrics, Section of Critical Care Medicine, Oklahoma Children's Hospital at OU health, Oklahoma University College of Medicine, Oklahoma City, Oklahoma.
¹² Division of Pediatric Critical Care, Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa.
¹³ Division of Pediatric Neurology, Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa.
¹⁴ Division of Pediatric Critical Care Medicine, Penn State College of Medicine, Hershey, Pennsylvania.
¹⁵ Department of Pediatrics, University of São Paulo, São Paulo, Brazil.
¹⁶ Department of Pediatrics, University of North Carolina at Chapel Hill Hospitals, Chapel Hill, North Carolina.
¹⁷ Pediatric Intensive Care Unit, Hospital Metropolitano, Quito, Ecuador.
¹⁸ Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington.
¹⁹ Division of Pediatric Critical Care and Hospital Medicine, Department of Pediatrics, Columbia University Irving Medical Center, New York, New York.
²⁰ Division of Pediatric Critical Care and Hospital Medicine, Department of Pediatrics, Columbia University Irving Medical Center, Morgan Stanley Children's Hospital New York-Presbyterian Hospital, New York, New York.
²¹ Division of Child Neurology, Department of Neurology, Columbia University Irving Medical Center, New York, New York.
²² Division of Critical Care Medicine at The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Departments of Anesthesiology and Critical Care Medicine and Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
²³ Division of Neurology at The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Departments of Neurology and Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
²⁴ Division of Pediatric Critical Care, Department of Pediatrics, Hospital de Emergencia Villa El Salvador, Lima, Peru.
²⁵ Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago and Northwestern University Feinberg School of Medicine, Chicago, Illinois.
²⁶ Division of Pediatric Critical Care, Department of Pediatrics Pediatric Critical Care and Neurotrauma Recovery Program Portland, Oregon Health & Science University, Oregon.
²⁷ Division of Pediatric Critical Care, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon.
²⁸ Department of Neurology, NYU Langone Health, New York, New York.
²⁹ Division of Pediatric Critical Care, Department of Pediatrics, Hassenfeld Children's Hospital at NYU Langone Health, New York, New York.
³⁰ Division of Pediatric Critical Care Medicine, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota.
³¹ Department of Pediatrics, CHU de Québec - Université Laval Research Center, Quebec City, Quebec, Canada.
³² Division of Neurology, Barrow Neurological Institute at Phoenix Children's Hospital, University of Arizona, College of Medicine, Phoenix, Arizona.
³³ Departments of Neurology, Pediatrics, and Radiology, Washington University in St. Louis, St. Louis, Missouri.
³⁴ Department of Pediatric Critical Care Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia.
³⁵ Pediatric Critical Care Medicine, Lucile Packard Children's Hospital, Stanford University, Stanford, California.
³⁶ Department of Pediatrics, University of Wisconsin, Madison, Wisconsin.
³⁷ Division Child Neurology, Department of Neurology, Medical College of Wisconsin, Children's Wisconsin, Milwaukee, Wisconsin.
³⁸ Department of Pediatrics, Medical College of Wisconsin, Children's Wisconsin, Milwaukee, Wisconsin.
³⁹ Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
⁴⁰ Division of Critical Care of the University of Utah, Department of Pediatrics, Salt Lake City, Utah.

PMID: 35066369
PMCID: PMC8713420
DOI: 10.1016/j.pediatrneurol.2021.12.010

Multicenter Study

Prevalence and Risk Factors of Neurologic Manifestations in Hospitalized Children Diagnosed with Acute SARS-CoV-2 or MIS-C

Ericka L Fink et al. Pediatr Neurol. 2022 Mar.

. 2022 Mar:128:33-44.

doi: 10.1016/j.pediatrneurol.2021.12.010. Epub 2021 Dec 28.

Authors

Affiliations

¹ Division of Pediatric Critical Care Medicine, Department of Critical Care Medicine, Pittsburgh, Pennsylvania; Safar Center for Resuscitation Research, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania. Electronic address: finkel@ccm.upmc.edu.
² Departments of Anesthesiology and Critical Care Medicine, and Pediatrics of The Johns Hopkins University SOM, Baltimore, Maryland.
³ Division of Pediatric Neurology, University of Washington, Seattle Children's Hospital, Seattle, Washington.
⁴ Department of Pediatrics, Universidad Nacional de Colombia and Fundación Universitaria de Ciencias de la Salud, Bogotá, Colombia.
⁵ Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio.
⁶ Department of Pediatrics, University of Chicago, Chicago, Illinois.
⁷ Division of Critical Care, Department of Pediatrics, UMC Children's Hospital, Las Vegas, Nevada.
⁸ Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas.
⁹ Division of Pediatric Critical Care Medicine, Department of Pediatrics, Medical University of South Carolina, Charleston, South Carolina.
¹⁰ Division of Critical Care, Department of Pediatrics, University of Maryland Medical Center, Baltimore, Maryland.
¹¹ Department of Pediatrics, Section of Critical Care Medicine, Oklahoma Children's Hospital at OU health, Oklahoma University College of Medicine, Oklahoma City, Oklahoma.
¹² Division of Pediatric Critical Care, Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa.
¹³ Division of Pediatric Neurology, Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa.
¹⁴ Division of Pediatric Critical Care Medicine, Penn State College of Medicine, Hershey, Pennsylvania.
¹⁵ Department of Pediatrics, University of São Paulo, São Paulo, Brazil.
¹⁶ Department of Pediatrics, University of North Carolina at Chapel Hill Hospitals, Chapel Hill, North Carolina.
¹⁷ Pediatric Intensive Care Unit, Hospital Metropolitano, Quito, Ecuador.
¹⁸ Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Washington School of Medicine, Seattle, Washington.
¹⁹ Division of Pediatric Critical Care and Hospital Medicine, Department of Pediatrics, Columbia University Irving Medical Center, New York, New York.
²⁰ Division of Pediatric Critical Care and Hospital Medicine, Department of Pediatrics, Columbia University Irving Medical Center, Morgan Stanley Children's Hospital New York-Presbyterian Hospital, New York, New York.
²¹ Division of Child Neurology, Department of Neurology, Columbia University Irving Medical Center, New York, New York.
²² Division of Critical Care Medicine at The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Departments of Anesthesiology and Critical Care Medicine and Pediatrics, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania.
²³ Division of Neurology at The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; Departments of Neurology and Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania.
²⁴ Division of Pediatric Critical Care, Department of Pediatrics, Hospital de Emergencia Villa El Salvador, Lima, Peru.
²⁵ Department of Pediatrics, Ann & Robert H. Lurie Children's Hospital of Chicago and Northwestern University Feinberg School of Medicine, Chicago, Illinois.
²⁶ Division of Pediatric Critical Care, Department of Pediatrics Pediatric Critical Care and Neurotrauma Recovery Program Portland, Oregon Health & Science University, Oregon.
²⁷ Division of Pediatric Critical Care, Department of Pediatrics, Oregon Health & Science University, Portland, Oregon.
²⁸ Department of Neurology, NYU Langone Health, New York, New York.
²⁹ Division of Pediatric Critical Care, Department of Pediatrics, Hassenfeld Children's Hospital at NYU Langone Health, New York, New York.
³⁰ Division of Pediatric Critical Care Medicine, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota.
³¹ Department of Pediatrics, CHU de Québec - Université Laval Research Center, Quebec City, Quebec, Canada.
³² Division of Neurology, Barrow Neurological Institute at Phoenix Children's Hospital, University of Arizona, College of Medicine, Phoenix, Arizona.
³³ Departments of Neurology, Pediatrics, and Radiology, Washington University in St. Louis, St. Louis, Missouri.
³⁴ Department of Pediatric Critical Care Medicine, Children's Healthcare of Atlanta, Atlanta, Georgia.
³⁵ Pediatric Critical Care Medicine, Lucile Packard Children's Hospital, Stanford University, Stanford, California.
³⁶ Department of Pediatrics, University of Wisconsin, Madison, Wisconsin.
³⁷ Division Child Neurology, Department of Neurology, Medical College of Wisconsin, Children's Wisconsin, Milwaukee, Wisconsin.
³⁸ Department of Pediatrics, Medical College of Wisconsin, Children's Wisconsin, Milwaukee, Wisconsin.
³⁹ Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania.
⁴⁰ Division of Critical Care of the University of Utah, Department of Pediatrics, Salt Lake City, Utah.

PMID: 35066369
PMCID: PMC8713420
DOI: 10.1016/j.pediatrneurol.2021.12.010

Abstract

Background: Our objective was to characterize the frequency, early impact, and risk factors for neurological manifestations in hospitalized children with acute severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or multisystem inflammatory syndrome in children (MIS-C).

Methods: Multicenter, cross-sectional study of neurological manifestations in children aged <18 years hospitalized with positive SARS-CoV-2 test or clinical diagnosis of a SARS-CoV-2-related condition between January 2020 and April 2021. Multivariable logistic regression to identify risk factors for neurological manifestations was performed.

Results: Of 1493 children, 1278 (86%) were diagnosed with acute SARS-CoV-2 and 215 (14%) with MIS-C. Overall, 44% of the cohort (40% acute SARS-CoV-2 and 66% MIS-C) had at least one neurological manifestation. The most common neurological findings in children with acute SARS-CoV-2 and MIS-C diagnosis were headache (16% and 47%) and acute encephalopathy (15% and 22%), both P < 0.05. Children with neurological manifestations were more likely to require intensive care unit (ICU) care (51% vs 22%), P < 0.001. In multivariable logistic regression, children with neurological manifestations were older (odds ratio [OR] 1.1 and 95% confidence interval [CI] 1.07 to 1.13) and more likely to have MIS-C versus acute SARS-CoV-2 (OR 2.16, 95% CI 1.45 to 3.24), pre-existing neurological and metabolic conditions (OR 3.48, 95% CI 2.37 to 5.15; and OR 1.65, 95% CI 1.04 to 2.66, respectively), and pharyngeal (OR 1.74, 95% CI 1.16 to 2.64) or abdominal pain (OR 1.43, 95% CI 1.03 to 2.00); all P < 0.05.

Conclusions: In this multicenter study, 44% of children hospitalized with SARS-CoV-2-related conditions experienced neurological manifestations, which were associated with ICU admission and pre-existing neurological condition. Posthospital assessment for, and support of, functional impairment and neuroprotective strategies are vitally needed.

Keywords: Child development; Neurological manifestations; Pediatrics; SARS-CoV-2.

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Figures

**FIGURE 1**
Cumulative number of neurological manifestations by overall, and grouped by acute SARS-CoV-2 versus MIS-C. MIS-C, multisystem inflammatory syndrome in children; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

**FIGURE 2**
Median days to neurological manifestation by overall and acute SARS-CoV-2 and MIS-C groups. Day 0 is the day of hospitalization; thus, negative days represent days leading up to hospitalization. MIS-C, multisystem inflammatory syndrome in children; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

**FIGURE 3**
Median days to nonneurological manifestation by overall and acute SARS-CoV-2 and MIS-C groups. Day 0 is the day of hospitalization; thus, negative days represent days leading up to hospitalization. MIS-C, multisystem inflammatory syndrome in children; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.

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References

1. Mao L., Jin H., Wang M., et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77:683–690. - PMC - PubMed
1. Chou S.H., Beghi E., Helbok R., et al. Global incidence of neurological manifestations among patients hospitalized with COVID-19-a report for the GCS-NeuroCOVID consortium and the ENERGY consortium. JAMA Netw Open. 2021;4 - PMC - PubMed
1. Abdel-Mannan O., Eyre M., Löbel U., et al. Neurologic and radiographic findings associated with COVID-19 infection in children. JAMA Neurol. 2020;77:1440–1445. - PMC - PubMed
1. Lin J., Lawson E.C., Verma S., Peterson R.B., Sidhu R. Cytotoxic lesion of the corpus callosum in an adolescent with multisystem inflammatory syndrome and SARS-CoV-2 infection. AJNR Am J Neuroradiol. 2020;41:2017–2019. - PMC - PubMed
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[1] Mao L., Jin H., Wang M., et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77:683–690. - PMC - PubMed

[2] Mao L., Jin H., Wang M., et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China. JAMA Neurol. 2020;77:683–690. - PMC - PubMed

[3] Chou S.H., Beghi E., Helbok R., et al. Global incidence of neurological manifestations among patients hospitalized with COVID-19-a report for the GCS-NeuroCOVID consortium and the ENERGY consortium. JAMA Netw Open. 2021;4 - PMC - PubMed

[4] Chou S.H., Beghi E., Helbok R., et al. Global incidence of neurological manifestations among patients hospitalized with COVID-19-a report for the GCS-NeuroCOVID consortium and the ENERGY consortium. JAMA Netw Open. 2021;4 - PMC - PubMed

[5] Abdel-Mannan O., Eyre M., Löbel U., et al. Neurologic and radiographic findings associated with COVID-19 infection in children. JAMA Neurol. 2020;77:1440–1445. - PMC - PubMed

[6] Abdel-Mannan O., Eyre M., Löbel U., et al. Neurologic and radiographic findings associated with COVID-19 infection in children. JAMA Neurol. 2020;77:1440–1445. - PMC - PubMed

[7] Lin J., Lawson E.C., Verma S., Peterson R.B., Sidhu R. Cytotoxic lesion of the corpus callosum in an adolescent with multisystem inflammatory syndrome and SARS-CoV-2 infection. AJNR Am J Neuroradiol. 2020;41:2017–2019. - PMC - PubMed

[8] Lin J., Lawson E.C., Verma S., Peterson R.B., Sidhu R. Cytotoxic lesion of the corpus callosum in an adolescent with multisystem inflammatory syndrome and SARS-CoV-2 infection. AJNR Am J Neuroradiol. 2020;41:2017–2019. - PMC - PubMed

[9] Frank C.H.M., Almeida T.V.R., Marques E.A., et al. Guillain-barré syndrome associated with SARS-CoV-2 infection in a pediatric patient. J Trop Pediatr. 2020;67:fmaa044. - PMC - PubMed

[10] Frank C.H.M., Almeida T.V.R., Marques E.A., et al. Guillain-barré syndrome associated with SARS-CoV-2 infection in a pediatric patient. J Trop Pediatr. 2020;67:fmaa044. - PMC - PubMed

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Prevalence and Risk Factors of Neurologic Manifestations in Hospitalized Children Diagnosed with Acute SARS-CoV-2 or MIS-C

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Prevalence and Risk Factors of Neurologic Manifestations in Hospitalized Children Diagnosed with Acute SARS-CoV-2 or MIS-C

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