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Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome

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Key Points

Question  What is the extent of neurologic involvement in US hospitalized children and adolescents with coronavirus disease 2019 (COVID-19)?

Findings  In this study of 1695 patients 21 years or younger hospitalized for acute COVID-19 or multisystem inflammatory syndrome, 365 (22%) had neurologic involvement. Forty-three patients (12%) developed COVID-19–related life-threatening neurologic disorders, 11 (26%) died, and 17 (40%) survived with new neurologic sequelae.

Meaning  In this study, COVID-19–related neurologic involvement was common in hospitalized children and adolescents and mostly transient.

Abstract

Importance  Coronavirus disease 2019 (COVID-19) affects the nervous system in adult patients. The spectrum of neurologic involvement in children and adolescents is unclear.

Objective  To understand the range and severity of neurologic involvement among children and adolescents associated with COVID-19.

Setting, Design, and Participants  Case series of patients (age <21 years) hospitalized between March 15, 2020, and December 15, 2020, with positive severe acute respiratory syndrome coronavirus 2 test result (reverse transcriptase-polymerase chain reaction and/or antibody) at 61 US hospitals in the Overcoming COVID-19 public health registry, including 616 (36%) meeting criteria for multisystem inflammatory syndrome in children. Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening involvement was adjudicated by experts based on clinical and/or neuroradiologic features.

Exposures  Severe acute respiratory syndrome coronavirus 2.

Main Outcomes and Measures  Type and severity of neurologic involvement, laboratory and imaging data, and outcomes (death or survival with new neurologic deficits) at hospital discharge.

Results  Of 1695 patients (909 [54%] male; median [interquartile range] age, 9.1 [2.4-15.3] years), 365 (22%) from 52 sites had documented neurologic involvement. Patients with neurologic involvement were more likely to have underlying neurologic disorders (81 of 365 [22%]) compared with those without (113 of 1330 [8%]), but a similar number were previously healthy (195 [53%] vs 723 [54%]) and met criteria for multisystem inflammatory syndrome in children (126 [35%] vs 490 [37%]). Among those with neurologic involvement, 322 (88%) had transient symptoms and survived, and 43 (12%) developed life-threatening conditions clinically adjudicated to be associated with COVID-19, including severe encephalopathy (n = 15; 5 with splenial lesions), stroke (n = 12), central nervous system infection/demyelination (n = 8), Guillain-Barré syndrome/variants (n = 4), and acute fulminant cerebral edema (n = 4). Compared with those without life-threatening conditions (n = 322), those with life-threatening neurologic conditions had higher neutrophil-to-lymphocyte ratios (median, 12.2 vs 4.4) and higher reported frequency of D-dimer greater than 3 μg/mL fibrinogen equivalent units (21 [49%] vs 72 [22%]). Of 43 patients who developed COVID-19–related life-threatening neurologic involvement, 17 survivors (40%) had new neurologic deficits at hospital discharge, and 11 patients (26%) died.

Conclusions and Relevance  In this study, many children and adolescents hospitalized for COVID-19 or multisystem inflammatory syndrome in children had neurologic involvement, mostly transient symptoms. A range of life-threatening and fatal neurologic conditions associated with COVID-19 infrequently occurred. Effects on long-term neurodevelopmental outcomes are unknown.

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Article Information

Corresponding Author: Adrienne G. Randolph, MD, Boston Children’s Hospital, 300 Longwood Ave, Bader 634, Boston, MA 02115 (adrienne.randolph@childrens.harvard.edu).

Accepted for Publication: February 12, 2021.

Published Online: March 5, 2021. doi:10.1001/jamaneurol.2021.0504

Author Contributions: Dr Randolph had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs LaRovere, Riggs, and Poussaint contributed equally. Drs Patel and Randolph contributed equally.

Concept and design: LaRovere, Walker, Hobbs, Feldstein, Doymaz, Spinella, Patel, Randolph.

Acquisition, analysis, or interpretation of data: LaRovere, Riggs, Poussaint, Young, Newhams, Maamari, Singh, Dapul, Hobbs, McLaughlin, Son, Maddux, Clouser, Rowan, McGuire, Fitzgerald, Gertz, Shein, Coronado Munoz, Thomas, Irby, Levy, Staat, Tenforde, Halasa, Giuliano, Hall, Kong, Carroll, Schuster, Loftis, Tarquinio, Babbitt, Nofziger, Kleinman, Keenaghan, Cvijanovich, Spinella, Hume, Wellnitz, Mack, Michelson, Flori, Patel, Randolph.

Drafting of the manuscript: LaRovere, Riggs, Poussaint, Hobbs, Kong, Spinella, Randolph.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: LaRovere, Giuliano, Randolph.

Obtained funding: Randolph.

Administrative, technical, or material support: Poussaint, Newhams, Maamari, Singh, Hobbs, McLaughlin, Son, Rowan, Fitzgerald, Gertz, Shein, Coronado Munoz, Levy, Tenforde, Feldstein, Hall, Kong, Carroll, Schuster, Doymaz, Loftis, Babbitt, Nofziger, Cvijanovich, Spinella, Hume, Wellnitz, Michelson, Flori, Patel, Randolph.

Supervision: Newhams, Walker, Singh, Hobbs, McLaughlin, Thomas, Irby, Staat, Kong, Schuster, Loftis, Nofziger, Cvijanovich, Spinella, Hume, Patel, Randolph.

Conflict of Interest Disclosures: Dr Riggs reported grants from the US Centers for Disease Control and Prevention (CDC) funding through Boston Children's Hospital during the conduct of the study. Dr Newhams reported grants from the CDC during the conduct of the study. Dr Maamari reported other support from the CDC during the conduct of the study. Dr McLaughlin reported grants from Boston Children's Hospital and the CDC during the conduct of the study. Dr Maddux reported grants from the National Institutes of Health (NIH)/Eunice Kennedy Shriver National Institute of Child Health and Human Development during the conduct of the study. Dr Rowan reported grants from the CDC during the conduct of the study and from the NIH outside the submitted work. Dr McGuire reported grants from the CDC during the conduct of the study. Dr Fitzgerald reported grants from the CDC during the conduct of the study and from the NIH outside the submitted work. Dr Gertz reported grants from Boston Children’s Hospital as a passthrough for the CDC during the conduct of the study. Dr Shein reported grants from the CDC during the conduct of the study. Dr Coronado Munoz reported grants from the CDC during the conduct of the study. Dr Levy reported grants from the CDC during the conduct of the study and from the National Institute of Allergy and Infectious Diseases outside the submitted work. Dr Staat reported other support from Boston Children's Hospital during the conduct of the study. Dr Halasa reported grants from the CDC during the conduct of the study; grants from Sanofi and Quidel; and personal fees from Genentech outside the submitted work. Dr Hall reported grants from the CDC during the conduct of the study and personal fees from LaJolla Pharmaceuticals outside the submitted work. Dr Schuster reported other from the CDC during the conduct of the study; other support from Merck; and grants from the CDC outside the submitted work. Dr Doymaz reported grants from the CDC during the conduct of the study. Dr Tarquinio reported grants from the CDC during the conduct of the study. Dr Nofziger reported other from the CDC during the conduct of the study. Dr Kleinman reported grants from Boston Children's Hospital during the conduct of the study and grants from Health Services Research Administration and NICHD outside the submitted work. Dr Cvijanovich reported grants from the CDC during the conduct of the study and grants from Cincinnati Children’s Medical Center and Boston Children's Hospital outside the submitted work. Dr Hume reported grants from the CDC during the conduct of the study. Dr Wellnitz reported other support from the CDC and NIH during the conduct of the study. Dr Michelson reported grants from the CDC during the conduct of the study and grants National Palliative Care Research Center and the National Institutes of Health outside the submitted work. Dr Randolph reported grants from the CDC during the conduct of the study and other support from UpToDate outside the submitted work. Dr Poussaint reported receiving grants from the National Institutes of Health and royalties from Springer Publishing outside of the submitted work. No other disclosures were reported.

Funding/Support: This study was funded by the US Centers for Disease Control and Prevention under a contract to Boston Children’s Hospital.

Role of the Funder/Sponsor: The US Centers for Disease Control and Prevention designed and conducted the study; collected, managed, analyzed, and interpreted the data; prepared, reviewed, and approved the manuscript; had a role in the decision to submit the manuscript for publication and journal choice; and had the right to veto publication.

Disclaimer: The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention.

Group Information: The Overcoming COVID-19 Investigators are listed in Supplement 2.

Additional Contributions: We appreciate and thank the many research coordinators at the Overcoming COVID-19 hospitals who assisted in data collection for this study. We thank the leadership of the Pediatric Acute Lung Injury and Sepsis Investigator’s (PALISI) Network for their ongoing support.

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