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Changes in Distribution of Severe Neurologic Involvement in US Pediatric Inpatients With COVID-19 or Multisystem Inflammatory Syndrome in Children in 2021 vs 2020

Educational Objective
To identify the key insights or developments described in this article
1 Credit CME
Key Points

Question  What was the spectrum of SARS-CoV-2–related pediatric severe neurologic involvement in 2021?

Findings  In this case series of 2168 US patients younger than 21 years hospitalized for acute COVID-19 (34%) or multisystem inflammatory syndrome in children (66%), 476 (22%) had neurologic involvement. Of these, 42 (9%) had life-threatening conditions, with 23 (55%) having acute central nervous system (CNS) infections/demyelination; 18 of 42 (43%) died or had new neurologic deficits; and most vaccine-eligible patients were unvaccinated.

Meaning  In 2021, SARS-CoV-2–related severe neurologic involvement in US hospitalized children and adolescents showed a potential increase in diagnoses of acute CNS infections/demyelination.


Importance  In 2020 during the COVID-19 pandemic, neurologic involvement was common in children and adolescents hospitalized in the United States for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–related complications.

Objective  To provide an update on the spectrum of SARS-CoV-2–related neurologic involvement among children and adolescents in 2021.

Design, Setting, and Participants  Case series investigation of patients reported to public health surveillance hospitalized with SARS-CoV-2–related illness between December 15, 2020, and December 31, 2021, in 55 US hospitals in 31 states with follow-up at hospital discharge. A total of 2253 patients were enrolled during the investigation period. Patients suspected of having multisystem inflammatory syndrome in children (MIS-C) who did not meet criteria (n = 85) were excluded. Patients (<21 years) with positive SARS-CoV-2 test results (reverse transcriptase–polymerase chain reaction and/or antibody) meeting criteria for MIS-C or acute COVID-19 were included in the analysis.

Exposure  SARS-CoV-2 infection.

Main Outcomes and Measures  Patients with neurologic involvement had acute neurologic signs, symptoms, or diseases on presentation or during hospitalization. Life-threatening neurologic involvement was adjudicated by experts based on clinical and/or neuroradiological features. Type and severity of neurologic involvement, laboratory and imaging data, vaccination status, and hospital discharge outcomes (death or survival with new neurologic deficits).

Results  Of 2168 patients included (58% male; median age, 10.3 years), 1435 (66%) met criteria for MIS-C, and 476 (22%) had documented neurologic involvement. Patients with neurologic involvement vs without were older (median age, 12 vs 10 years) and more frequently had underlying neurologic disorders (107 of 476 [22%] vs 240 of 1692 [14%]). Among those with neurologic involvement, 42 (9%) developed acute SARS-CoV-2–related life-threatening conditions, including central nervous system infection/demyelination (n = 23; 15 with possible/confirmed encephalitis, 6 meningitis, 1 transverse myelitis, 1 nonhemorrhagic leukoencephalopathy), stroke (n = 11), severe encephalopathy (n = 5), acute fulminant cerebral edema (n = 2), and Guillain-Barré syndrome (n = 1). Ten of 42 (24%) survived with new neurologic deficits at discharge and 8 (19%) died. Among patients with life-threatening neurologic conditions, 15 of 16 vaccine-eligible patients (94%) were unvaccinated.

Conclusions and Relevance  SARS-CoV-2–related neurologic involvement persisted in US children and adolescents hospitalized for COVID-19 or MIS-C in 2021 and was again mostly transient. Central nervous system infection/demyelination accounted for a higher proportion of life-threatening conditions, and most vaccine-eligible patients were unvaccinated. COVID-19 vaccination may prevent some SARS-CoV-2–related neurologic complications and merits further study.

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Article Information

Accepted for Publication: September 2, 2022.

Published Online: November 7, 2022. doi:10.1001/jamaneurol.2022.3881

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2022 LaRovere KL et al. JAMA Neurology.

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

Author Contributions: Dr Randolph had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: LaRovere, Poussaint, Young, Walker, Fitzgerald, Hobbs, Schwarz, Zambrano, Randolph.

Acquisition, analysis, or interpretation of data: LaRovere, Poussaint, Young, Newhams, Kucukak, Irby, Kong, Schwartz, Bembea, Wellnitz, Havlin, Cvijanovich, Hall, Fitzgerald, Schuster, Hobbs, Halasa, Singh, Mack, Bradford, Gertz, Typpo, Loftis, Giuliano, Horwitz, Biagas, Clouser, Rowan, Maddux, Soma, Babbitt, Aguiar, Kolmar, Heidemann, Harvey, Campbell, Randolph.

Drafting of the manuscript: LaRovere, Poussaint, Hobbs.

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

Statistical analysis: Young.

Obtained funding: Zambrano, Randolph.

Administrative, technical, or material support: Poussaint, Newhams, Kucukak, Kong, Hall, Fitzgerald, Hobbs, Singh, Mack, Bradford, Typpo, Loftis, Babbitt, Kolmar, Zambrano, Campbell, Randolph.

Supervision: LaRovere, Schuster, Hobbs, Singh, Schwarz, Campbell, Randolph.

Conflict of Interest Disclosures: Dr Poussaint reported grants from the National Institutes of Health (NIH) for the PBTC Neuroimaging Center and personal fees from Springer Publishing outside the submitted work. Dr Bembea reported grants from the NIH, National Institute of Neurological Disorders and Stroke, and Grifols outside the submitted work. Dr Hall reported personal fees for serving on data and safety monitoring boards from AbbVie and La Jolla Pharmaceutical, personal fees from the American Board of Pediatrics Service for subboard service outside the submitted work, and patents for WO 2020/168250 and WO 2020/168254, both licensed to Kiadis. Dr Schuster reported grants from Merck outside the submitted work. Dr Hobbs reported consulting fees from Biomerieux and dynamed.com outside the submitted work. Dr Halasa reported grants from Sanofi and Quidel outside the submitted work. Dr Rowan reported grants from the National Heart, Lung, and Blood Institute outside the submitted work. Dr Randolph reported royalties from UpToDate and grants from the NIH outside the submitted work. No other disclosures were reported.

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

Role of the Funder/Sponsor: The funder participated in the design and conduct of the study; collection, management, analysis, and interpretation of the data; and preparation, review, and approval of the manuscript; had a role in the decision to submit the manuscript for publication and the choice of journal; and had the right to veto publication.

Group Information: Additional members of the Overcoming COVID-19 Investigators are listed in Supplement 2.

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

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

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