Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome | Adolescent Medicine | JAMA Neurology | JAMA Network
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    3 Comments for this article
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    SARS CoV-2 and Neurological complications-our experience and views
    Khichar Shubhakaran, MD()Med, (D.M.) Neurology | Senior Professor and head of department of Neurology, M D M Hospital, Dr. S.N Medical College, Jodhpur (Rajasthan) India-342001
    We are also seeing various complications like GBS, pseudotumorcerebri, precipitation of stroke, seizures etc, but do not have the access to antiganglioside antibodies, all those who can afford to get it done we should try for that and get it documented for academic and research purpose in this pandemic of modern time of advanced technology. The gangliosides are particularly abundant in the brain and in the nervous system; they participate in maintenance and repair of neuronal cells, memory formation and synaptic transmission (1). So we have to be watchful in this regard towards impairment of these neurological functions i.e. new autoimmune disorder like GBS, multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMO-SD), chronic inflammatory demyelinating neuropathy (CIDP), etc. and precipitation of neurodegenerative and cognitive disorders in acute, convalescent and post recovery follow up. Of course the pediatric population is less affected, but as in the case of neurons, the SARS-CoV-2 may affect the growth and development of pediatric population.
    Just as Intravenous immunoglobulins (IVIg) and plasmapharesis are useful in the treatment of GBS with antiganglioside antibodies, the trial of IVIg and monoclonal antibodies in other neurological complications with SARS-CoV-2 along with monitoring of antiganglioside antibodies may prove to be a game changer, as it has been claimed to be effective in general treatment of COVID-19 (2).
    References-
    1. Cutillo G, Saariaho A-H, Meri S. Physiology of gangliosides and the role of antiganglioside antibodies in human diseases. Cell Mol Immunol 2020;17:313–22.doi:10.1038/s41423-020-0388-9
    2. Alan A. Nguyen, Saddiq B. Habiballah, Craig D. Platt, Raif S. Geha, Janet S. Chou, and Douglas R. McDonald. Immunoglobulins in the treatment of COVID-19 infection: Proceed with caution! Clin Immunol. 2020 Jul; 216: 108459. doi: 10.1016/j.clim.2020.108459
    CONFLICT OF INTEREST: None Reported
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    Hyper-inflammatory state in Covid-19 might induce cells to abandon mitochondrial oxidative phosphorylation in favor of cytosolic aerobic gly
    Calixto Machado, MD, PhD, FAAN | Institute of Neurology and Neurosurgery, Havana, Cuba
    I read with interest the paper by LaRovere et al. to comprehend the variety and severity of neurologic involvement among children and adolescents with COVID-19 (1).
    Several papers of life-threatening neurologic involvement have appeared about children and adolescent patients developing multisystem inflammatory syndrome (MIS-C), which is a fairly infrequent, hyperinflammatory, severe disease, temporally linked with SARS-CoV-2 infection, apparently post-infectious (2). 
    These authors concluded that COVID-19 or MIS-C had neurologic involvement, although mostly transient symptoms. Though brain infarcts were found in MRI studies, these authors found, in several patients, T2 hyperintensity, leptomeningeal enhancement, and reduced diffusivity within the bilateral frontal lobes,
    basal ganglia, and thalami, with no focal lesions (1).
    This publication appears when several authors have also reported reversible encephalopathy bilateral thalamic lesions after SARS-CoV-2 infection. the most characteristic MRI feature included symmetric, multifocal lesions with invariable thalamic involvement, showing T2-weighted fluid-attenuated inversion recovery hyperintense signal, and reduced diffusivity (3).
    I have recently discussed that the hyper-inflammatory state of immune cells during the cytokine storm in Covid-19 might cause a dramatic change in metabolism, inducing cells to abandon mitochondrial oxidative phosphorylation for ATP production, in favor of cytosolic aerobic glycolysis, which is an inefficient way to generate ATP. This might explain disturbances in water diffusion within tissue, detected by MRI-ADC, due to a cytotoxic edema. Afterwards, improvement of the patient’s inflammatory syndrome surely helped to recover mitochondrial oxidative phosphorylation, explaining reversible and transient symptoms. Whether it was indeed the hyper-inflammatory state that led to abandonment of mitochondrial oxidative phosphorylation, needs further research on this topic (4).  
    The pathogenesis of MIS-C is unknown, and a postinfectious immunological etiology has been hypothesized but not proven. SARS–CoV-2 antibodies arise in the second week after infection, but their presence does not indicate resolution of infection. Therefore, current treatment guidelines recommend use of intravenous immunoglobulin and high-dose corticosteroids as first-line treatment (1,3).
    Nonetheless, virus invasion into the central nervous system through olfactory nerve invasion, cellular invasion, and trans-synaptic transmission, provide the routes for SARS-CoV-2 to vastly invade infratentorial and supratentorial structures. Viral dissemination through neural pathways, retrograde or antegrade, is facilitated by proteins called dinein and kinesin, which can be targets of viruses, hence, possible direct virus infection can also be an important pathogenic contributing factor (4).  
    REFERENCES
    1. LaRovere K, Riggs B, Poussaint T. Neurologic Involvement in Children and Adolescents Hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome. JAMA Neurol. JAMA Neurol. Published online March 05, 2021. doi:10.1001/jamaneurol.2021.0504.
    2. Abdel-Haq N, Asmar BI, Deza Leon MP, et al. SARS-CoV-2-associated multisystem inflammatory syndrome in children: clinical manifestations and the role of infliximab treatment. Eur J Pediatr. 2021, doi: 10.1007/s00431-021-03935-1.
    3. Princiotta Cariddi L, Tabaee Damavandi P, Carimati F, et al. Reversible Encephalopathy Syndrome (PRES) in a COVID-19 patient. J Neurol. 2020, doi: 10.1007/s00415-020-10001-7.
    4. Machado C. Reader response: Encephalopathy and bil
    CONFLICT OF INTEREST: None Reported
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    More Confirmation of Possible MEEN.
    Gary Ordog, MD, DABEM, DABMT | County of Los Angeles, Department of Health Services, (retired)
    Interesting study confirming a significant prevalence of neurological complications of post COVID-19 neuropathology. This may also support the syndrome of MEEN (Mass Epidemic Encephalopathic Nightmare). This also justifies further research, and promotes the more urgent need to vaccine the population, instead of herd immunity for COVID. Thank you, and stay safe, Gary Joseph Ordog, MD.
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    March 5, 2021

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

    Author Affiliations
    • 1Department of Neurology, Boston Children’s Hospital, Boston, Massachusetts
    • 2Division of Pediatric Anesthesiology and Critical Care Medicine, Department of Anesthesiology and Critical Care Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland
    • 3Department of Radiology, Boston Children’s Hospital, Boston, Massachusetts
    • 4Division of Critical Care Medicine, Department of Anesthesiology, Critical Care and Pain Medicine, Boston Children’s Hospital, Boston, Massachusetts
    • 5Division of Critical Care Medicine, Department of Pediatrics, University of Texas Southwestern, Children’s Health Medical Center Dallas
    • 6Department of Pediatrics, University of North Carolina at Chapel Hill Children's Hospital, Chapel Hill
    • 7Pediatric Critical Care Division, Maria Fareri Children's Hospital at Westchester Medical Center and New York Medical College, Valhalla
    • 8Division of Pediatric Critical Care Medicine, Department of Pediatrics, New York University Grossman School of Medicine, New York
    • 9Division of Infectious Diseases, Department of Pediatrics, Department of Microbiology, University of Mississippi Medical Center, Jackson
    • 10Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Miami Miller School of Medicine, Miami, Florida
    • 11Division of Immunology, Department of Pediatrics, Boston Children’s Hospital, Boston, Massachusetts
    • 12Section of Critical Care Medicine, Department of Pediatrics, University of Colorado School of Medicine and Children’s Hospital Colorado, Aurora
    • 13Department of Pediatrics, Joseph M. Sanzari Children’s Hospital at Hackensack University Medical Center, Hackensack, New Jersey
    • 14Division of Pediatric Critical Care Medicine, Department of Pediatrics, Indiana University School of Medicine, Riley Hospital for Children, Indianapolis
    • 15Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Washington, Seattle
    • 16Division of Critical Care, Department of Anesthesiology and Critical Care, University of Pennsylvania Perelman School of Medicine, Philadelphia
    • 17Division of Pediatric Critical Care, Department of Pediatrics, Saint Barnabas Medical Center, Livingston, New Jersey
    • 18Division of Pediatric Critical Care Medicine, Rainbow Babies and Children’s Hospital, Cleveland, Ohio
    • 19Pediatric Critical Care Division, Department of Pediatrics, University of Texas Health Science Center at Houston, Houston
    • 20Department of Pediatrics, Penn State Hershey Children’s Hospital, Pennsylvania State University College of Medicine, Hershey
    • 21Section of Pediatric Critical Care, Department of Pediatrics, Arkansas Children's Hospital, Little Rock
    • 22Divisions of Pediatric Infectious Diseases and Pediatric Critical Care Medicine, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, Minnesota
    • 23Department of Pediatrics, University of Cincinnati, Division of Infectious Diseases, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio
    • 24COVID-19 Response, Centers for Disease Control and Prevention, Atlanta, Georgia
    • 25Influenza Division, Centers for Disease Control and Prevention, Atlanta, Georgia
    • 26Division of Pediatric Infectious Diseases, Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee
    • 27Division of Critical Care, Yale University School of Medicine, New Haven, Connecticut
    • 28Division of Critical Care Medicine, Department of Pediatrics, Nationwide Children’s Hospital, Columbus, Ohio
    • 29Division of Pediatric Critical Care Medicine, Department of Pediatrics, University of Alabama at Birmingham
    • 30Division of Critical Care, Connecticut Children’s, Hartford, Connecticut
    • 31Division of Pediatric Infectious Diseases, Department of Pediatrics, Children’s Mercy Kansas City, Kansas City, Missouri
    • 32Division of Pediatric Critical Care, Department of Pediatrics, State University of New York Downstate Health Sciences University, Brooklyn
    • 33Section of Critical Care Medicine, Department of Pediatrics, Texas Children’s Hospital, Houston
    • 34Division of Critical Care Medicine, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
    • 35Miller Children’s and Women’s Hospital of Long Beach, Long Beach, California
    • 36Division of Critical Care Medicine, Akron Children’s Hospital, Akron, Ohio
    • 37Division of Population Health, Quality, and Implementation Sciences (PopQuIS), Department of Pediatrics, Rutgers Robert Wood Johnson Medical School, New Brunswick, New Jersey
    • 38Pediatric Critical Care, New York City Health and Hospitals, Kings County Hospital, Brooklyn, New York
    • 39Division of Critical Care Medicine, University of California, San Francisco, Benioff Children's Hospital, Oakland
    • 40Division of Critical Care, Department of Pediatrics, Washington University School of Medicine in St Louis, St Louis, Missouri
    • 41Division of Pediatric Critical Care, University of Minnesota Masonic Children’s Hospital, Minneapolis
    • 42Division of Pediatric Critical Care, Stead Family Department of Pediatrics, University of Iowa Carver College of Medicine, Iowa City, Iowa
    • 43Division of Pediatric Critical Care Medicine, Medical University of South Carolina, Charleston
    • 44Division of Critical Care Medicine, Department of Pediatrics, Northwestern University Feinberg School of Medicine, Ann and Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois
    • 45Division of Pediatric Critical Care Medicine, Department of Pediatrics, Mott Children’s Hospital and University of Michigan, Ann Arbor
    • 46Departments of Anaesthesia and Pediatrics, Harvard Medical School, Boston, Massachusetts
    JAMA Neurol. Published online March 5, 2021. doi:10.1001/jamaneurol.2021.0504
    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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