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Figure.  Neuroimaging Findings in Association With Coronavirus Disease 2019 in Children
Neuroimaging Findings in Association With Coronavirus Disease 2019 in Children

A, Computed tomography image of patient 1 on day 5 (top), during intensive care admission, showing hypodensity of the splenium of the corpus collosum (SCC). Coronal fluid-attenuated inversion recovery performed on day 12 (bottom) shows resolution of the changes previously seen on computed tomography, with persistent signal changes in the genu and SCC without restricted diffusion (not shown). B, Axial T2 magnetic resonance image of patient 2 on day 1, showing signal changes of the genu and SCC (top) and bilateral centrum semiovale with restricted diffusion (bottom). Repeated imaging on day 6 (not shown) demonstrated resolution of the restricted diffusion, with minimal signal changes remaining on T2-weighted imaging. C, Axial T2 magnetic resonance imaging of patient 3 on day 21, showing hyperintensities (top) with restricted diffusion (bottom) in the SCC and bilateral centrum semiovale (not shown). D, Axial T2 magnetic resonance imaging of patient 4 on day 5 (top), showing signal change in the SCC with mild restricted diffusion (bottom).

Table 1.  Patient Demographics and Neurological Characteristics
Patient Demographics and Neurological Characteristics
Table 2.  Comorbidities and Systemic Involvements
Comorbidities and Systemic Involvements
1.
Ludvigsson  JF.  Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults.   Acta Paediatr. 2020;109(6):1088-1095. doi:10.1111/apa.15270 PubMedGoogle ScholarCrossref
2.
Riphagen  S, Gomez  X, Gonzalez-Martinez  C, Wilkinson  N, Theocharis  P.  Hyperinflammatory shock in children during COVID-19 pandemic.   Lancet. 2020;395(10237):1607-1608. doi:10.1016/S0140-6736(20)31094-1PubMedGoogle ScholarCrossref
3.
Verdoni  L, Mazza  A, Gervasoni  A,  et al.  An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.   Lancet. 2020;395(10239):1771-1778. doi:10.1016/S0140-6736(20)31103-X PubMedGoogle ScholarCrossref
4.
Baig  AM, Khaleeq  A, Ali  U, Syeda  H.  Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms.   ACS Chem Neurosci. 2020;11(7):995-998. doi:10.1021/acschemneuro.0c00122 PubMedGoogle ScholarCrossref
5.
Gutiérrez-Ortiz  C, Méndez  A, Rodrigo-Rey  S,  et al.  Miller Fisher syndrome and polyneuritis cranialis in COVID-19.   Neurology. 2020;10.1212/WNL.0000000000009619. doi:10.1212/WNL.0000000000009619 PubMedGoogle Scholar
6.
Pilotto  A, Odolini  S, Stefano Masciocchi  S,  et al  Steroid-responsive encephalitis in COVID-19 disease.   Ann Neurol. Published online May 17, 2020. doi:10.1002/ana.25783Google Scholar
7.
Mao  L, Jin  H, Wang  M,  et al.  Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.   JAMA Neurol. 2020. doi:10.1001/jamaneurol.2020.1127 PubMedGoogle Scholar
8.
Tada  H, Takanashi  J, Barkovich  AJ,  et al.  Clinically mild encephalitis/encephalopathy with a reversible splenial lesion.   Neurology. 2004;63(10):1854-1858. doi:10.1212/01.WNL.0000144274.12174.CB PubMedGoogle ScholarCrossref
9.
Doherty  MJ, Jayadev  S, Watson  NF, Konchada  RS, Hallam  DK.  Clinical implications of splenium magnetic resonance imaging signal changes.   Arch Neurol. 2005;62(3):433-437. doi:10.1001/archneur.62.3.433 PubMedGoogle ScholarCrossref
10.
Kontzialis  M, Soares  BP, Huisman  TAGM.  Lesions in the splenium of the corpus callosum on MRI in children: a review.   J Neuroimaging. 2017;27(6):549-561. doi:10.1111/jon.12455 PubMedGoogle ScholarCrossref
11.
Sejvar  JJ, Uyeki  TM.  Neurologic complications of 2009 influenza A (H1N1): heightened attention on an ongoing question.   Neurology. 2010;74(13):1020-1021. doi:10.1212/WNL.0b013e3181d6b869 PubMedGoogle ScholarCrossref
12.
Wells  E, Hacohen  Y, Waldman  A,  et al; attendees of the International Neuroimmune Meeting.  Neuroimmune disorders of the central nervous system in children in the molecular era.   Nat Rev Neurol. 2018;14(7):433-445. doi:10.1038/s41582-018-0024-9 PubMedGoogle ScholarCrossref
13.
Varga  Z, Flammer  AJ, Steiger  P,  et al.  Endothelial cell infection and endotheliitis in COVID-19.   Lancet. 2020;395(10234):1417-1418. doi:10.1016/S0140-6736(20)30937-5 PubMedGoogle ScholarCrossref
14.
Horne  A, Trottestam  H, Aricò  M,  et al; Histiocyte Society.  Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis.   Br J Haematol. 2008;140(3):327-335. doi:10.1111/j.1365-2141.2007.06922.x PubMedGoogle ScholarCrossref
15.
Benson  LA, Li  H, Henderson  LA,  et al.  Pediatric CNS-isolated hemophagocytic lymphohistiocytosis.   Neurol Neuroimmunol Neuroinflamm. 2019;6(3):e560. doi:10.1212/NXI.0000000000000560 PubMedGoogle Scholar
16.
Gofshteyn  JS, Shaw  PA, Teachey  DT,  et al.  Neurotoxicity after CTL019 in a pediatric and young adult cohort.   Ann Neurol. 2018;84(4):537-546. doi:10.1002/ana.25315 PubMedGoogle ScholarCrossref
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    EXPAND ALL
    Neurological Manifestations in COVID-19-related Pediatric Multisystem Inflammatory Syndrome
    Tai-Heng Chen, MD | Department of Pediatrics, Division of Pediatric Emergency, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
    We read with interest the article regarding neurological involvement of multisystem inflammatory syndrome in children (MIS-C) by Abdel-Mannan et al. While reviewing the similar four case-series of MIS-C enrolling 82 children, we surprisingly found an even higher prevalence (37%) of neurological involvement (1-4). Among these MIS-C cases, positive nasal swab of COVID-19 reverse transcription-polymerase chain reaction (RT-PCR) and serum antibodies (IgG and/or IgM) were reported in 38% and 86% of patients, respectively. This finding implied that most children might not have active COVID-19 infection when MIS-C developed. Among different neurological manifestations, positive meningeal signs (meningism) and/or altered mental status accounted for the most. However, even though their presenting signs highly suggested a diagnosis of meningoencephalitis, only eight cases had received cerebrospinal fluid (CSF) study, including one with computed tomography (CT). Of the results of CSF, five children had non-specific pleocytosis, which suggested aseptic meningitis, but no SARS-CoV-2 was detected through RT-PCR. Collectively, the laboratory and neurological features of MIS-C patients highly suggested a post-infectious immunological response, similar to the mechanism of COVID-19-related autoimmune meningoencephalitis, which was recently reported in adult COVID-19 patients (5) As autoimmune meningoencephalitis may occur at all ages, it is imperative to look into whether children might have a similar neuropathological mechanism related to COVID-19. Indeed, children with MIS-C always showed increased inflammatory acute-phase reactants in sera, including C-reactive protein, procalcitonin, ferritin, or interleukins 6, which implied an aberrant immune response.

    The pathomechanism of COVID-19-associated encephalopathy is not fully understood but may be related to edema secondary to neuroinflammatory injury. The immune-mediated neuronal injury might be attributed to the cytokine storms with increased levels of inflammatory cytokines and activation of T lymphocytes, and macrophages. Treatments with intravenous immunoglobulins (IVIG) or plasma exchange might benefit such neuroinflammatory crises. However, the procedure of plasmapheresis could be more complicated, especially in children due to a higher risk of hemodynamic instability and irritability. Notably, all MIS-C cases treated with Kawasaki disease-targeted regimens, IVIG, and steroids (methylprednisolone) recovered uneventfully without neurological sequelae. This favorable outcome suggests IVIG and steroid are efficicacious in treating children with meningoencephalitis complicated by COVID-19-related MIS-C but further studies, including essential assessment of brain MRI, on the pediatric COVID-19 population are encouraged to verify this hypothesis.

    References
    1. Belhadjer et al. Circulation. 2020. doi:10.1161/CIRCULATIONAHA.120.048360
    2. Pouletty et al. Ann Rheum Dis. 2020. doi:10.1136/annrheumdis-2020-217960
    3. Toubiana et al. BMJ. 2020;369:m2094.
    4. Verdoni et al. Lancet. 2020;395(10239):1771-1778.
    5. Dogan et al. Brain Behav Immun. 2020;87:155-158.
    CONFLICT OF INTEREST: None Reported
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    Brief Report
    July 1, 2020

    Neurologic and Radiographic Findings Associated With COVID-19 Infection in Children

    Author Affiliations
    • 1Department of Neurology, Great Ormond Street Hospital for Children, London, United Kingdom
    • 2Department of Neuroradiology, Great Ormond Street Hospital for Children, London, United Kingdom
    • 3UCL Great Ormond Street Institute of Child Health, Department of Infectious Disease, Great Ormond Street Hospital for Children, London, United Kingdom
    • 4UCL Great Ormond Street Institute of Child Health, Department of Neurology, Great Ormond Street Hospital for Children, London, United Kingdom
    • 5Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, London, United Kingdom
    JAMA Neurol. Published online July 1, 2020. doi:10.1001/jamaneurol.2020.2687
    Key Points

    Question  What are the neurological manifestations of coronavirus disease 2019 (COVID-19) in children?

    Findings  In a case series of 4 children with COVID-19 and neurological symptoms, all 4 patients had signal changes in the splenium of the corpus callosum on neuroimaging and required intensive care admission for the treatment of COVID-19 pediatric multisystem inflammatory syndrome.

    Meaning  Children with COVID-19 may present with new neurological symptoms involving both the central and peripheral nervous system and splenial changes on imaging, in the absence of respiratory symptoms; this diagnosis should be considered within the differential diagnosis of splenial lesions.

    Abstract

    Importance  Neurological manifestations have been reported in adults with coronavirus disease 2019 (COVID-19), which is caused by the highly pathogenic virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

    Objective  To report the neurological manifestations of children with COVID-19.

    Design, Setting, and Participants  In this case-series study, patients younger than 18 years who presented with SARS-CoV-2 infection and neurological symptoms to Great Ormond Street Hospital for Children (London, UK) between March 1, 2020, and May 8, 2020, were included after infection was confirmed by either a quantitative reverse transcription–polymerase chain reaction assay by nasopharyngeal swab or a positive test result for IgG antibodies against SARS-CoV-2 in serum.

    Main Outcomes and Measures  Clinical and paraclinical features were retrieved from electronic patient records.

    Results  Of the 27 children with COVID-19 pediatric multisystem inflammatory syndrome, 4 patients (14.8%) who were previously healthy had new-onset neurological symptoms. Symptoms included encephalopathy, headaches, brainstem and cerebellar signs, muscle weakness, and reduced reflexes. All 4 patients required intensive care unit admission for the treatment of COVID-19 pediatric multisystem inflammatory syndrome. Splenium signal changes were seen in all 4 patients on magnetic resonance imaging of the brain. In the 2 patients whose cerebrospinal fluid was tested, samples were acellular, with no evidence of infection on polymerase chain reaction or culture (including negative SARS-CoV-2 polymerase chain reaction results) and negative oligoclonal band test results. In all 3 patients who underwent electroencephalography, a mild excess of slow activity was found. Tests for N-methyl-d-aspartate receptor, myelin oligodendrocyte glycoprotein, and aquaporin-4 autoantibodies had negative results in all patients. In all 3 patients who underwent nerve conduction studies and electromyography, mild myopathic and neuropathic changes were seen. Neurological improvement was seen in all patients, with 2 making a complete recovery by the end of the study.

    Conclusions and Relevance  In this case-series study, children with COVID-19 presented with new neurological symptoms involving both the central and peripheral nervous systems and splenial changes on imaging, in the absence of respiratory symptoms. Additional research is needed to assess the association of neurological symptoms with immune-mediated changes among children with COVID-19.

    Introduction

    Coronavirus disease 2019 (COVID-19), which is caused by the highly pathogenic virus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), was first detected in Wuhan, China, in December 2019 and has since become a worldwide pandemic infecting more than 9 million people (as of mid-June 2020). In adults, COVID-19 ranges from an asymptomatic infection to severe respiratory failure. Data so far suggest that children and young adults are less likely to become severely ill than older adults.1 Increasing reports of children developing systemic inflammatory response requiring intensive care (labeled pediatric multisystem inflammatory syndrome temporally associated with COVID-192) and a further group of children with a far less severe, Kawasaki-like disease, who respond to a variety of immunomodulatory treatments,3 suggest that despite the typically mild acute infection, children may be at high risk of a secondary inflammatory syndrome.

    Laboratory studies have revealed that the main host-cell receptor of SARS-CoV-2 is angiotensin-converting enzyme 2 (ACE2)4; given that ACE2 is expressed in both neurons and glial cells, direct viral invasion of the central nervous system (CNS) is a possible mechanism for neurological manifestations of COVID-19. More recently, an immune-mediated neurological syndrome was proposed in adult patients presenting with Miller-Fisher syndrome and polyneuritis cranialis5 or steroid-responsive encephalitis.6 Here, we report a case series of 4 children who presented with new-onset neurological symptoms in association with SARS-CoV-2.

    Methods

    Patients younger than 18 years who presented with new-onset neurological symptoms to Great Ormond Street Hospital for Children (London, UK) between March 1, 2020, and May 8, 2020, were included from a cohort of children with SARS-CoV-2 infection (confirmed by either quantitative reverse transcription–polymerase chain reaction [PCR] assay by nasopharyngeal swab or a positive SARS-CoV-2 IgG test result in serum). Data on demographics, comorbidities, neurological symptoms, relevant investigations (of cerebrospinal fluid, neuroimaging, and neurophysiology), treatments, and outcomes were retrieved from the electronic patient records. Because the data analysis was retrospective and no additional data were collected beyond those required for standard medical care, a full ethics review under the terms of the Governance Arrangements of Research Ethics Committees in the UK was not required. Written informed consent was obtained from the parents of all of the patients.

    Results

    Fifty children presented with SARS-CoV-2 infection during the study time frame. Of these, 27 had features consistent with COVID-19 pediatric multisystem inflammatory syndrome. A total of 4 patients (14.8%) with multisystem inflammatory syndrome had neurological involvement. The median age at onset of symptoms was 12 (range, 8-15) years. A summary of the clinical and paraclinical features is provided in Table 1, Table 2, and the Figure. Neurological symptoms included encephalopathy (n = 4), headache (n = 3), brainstem signs with dysarthria or dysphagia (n = 2), meningism (n = 1), and cerebellar ataxia (n = 1). Peripheral nervous system involvement was seen in all patients, with global proximal muscle weakness (n = 4) and reduced reflexes (n = 2). Neurological symptoms were part of the initial presentation in 2 patients.

    Systemic manifestations included fever (n = 4), cardiovascular shock (n = 4), rash (n = 4), and dyspnea (n = 2). All patients required mechanical ventilation and intensive care admission for cardiovascular shock (n = 4) and/or respiratory decompensation (n = 1). The intensive care unit stay was for a median 6.5 (range, 2-14) days, and mechanical ventilation duration was for a median of 5 (range, 1-7) days.

    A comprehensive screening of all 4 patients for other infective causative mechanisms had negative results. In the 2 patients who had lumbar punctures, cerebrospinal fluid samples were acellular with normal protein and glucose levels, negative results for oligoclonal bands, and negative results for bacterial cultures and viral and bacterial PCR (including negative SARS-CoV-2 PCR). Tests for N-methyl-d-aspartate receptor, myelin oligodendrocyte glycoprotein, and aquaporin-4 autoantibodies had negative results in all patients.

    Signal changes in the splenium of the corpus callosum (SCC) were seen in all 4 patients; T2-hyperintense lesions associated with restricted diffusion were seen in 3 children. The fourth patient presented with a splenial lesion on computed tomography, but on subsequent magnetic resonance imaging, no restricted diffusion was evident, although the signal change remained. The genu was involved in 2 patients and the bilateral centrum semiovale in 2 patients (Figure). No spinal cord involvement or pathological enhancement was observed. Patient 2 had a repeated magnetic resonance image on day 5 that showed resolution of diffusion restriction in the SCC and centrum semiovale.

    Electroencephalography showed a mild excess of slow activity in the 3 patients tested. Nerve conduction studies and electromyography showed mild myopathic and neuropathic changes in all 3 patients tested.

    Three patients received immunomodulatory therapies as part of COVID-19 pediatric multisystem inflammatory syndrome management (Table 1); these were intravenous methylprednisolone (n = 2), dexamethasone (n = 2), intravenous immunoglobulin (n = 2), anakinra (n = 2), and rituximab (n = 1). No patients required antiviral treatment. After a median follow-up of 18 (range, 11-32) days, patients 2 and 4 fully recovered and were discharged from hospital after 11 and 18 days respectively, fully ambulating. The remaining 2 patients have been discharged from the intensive care unit and remain inpatients. Both are improving clinically but currently wheelchair bound (as a result of proximal lower-limb muscle weakness).

    Discussion

    In this case series, we describe 4 children with confirmed COVID-19 who presented with a distinct neurological syndrome associated with lesions of the SCC on neuroimaging. In an adult cohort7 in Wuhan, China, 78 of 214 patients (36.4%) had neurological manifestations, which included dizziness (n = 36), headache (n = 28), impaired consciousness (n = 16), acute cerebrovascular disease (n = 6), ataxia (n = 1), and seizures (n = 1). In comparison with patients with nonsevere infection, those with severe infection had more neurological presentations, including acute cerebrovascular diseases (5 [5.7%] vs 1 [0.8%]) and impaired consciousness (13 [14.8%] vs 3 [2.4%]). Neuroimaging, cerebrospinal fluid, or neurophysiology tests were not performed in this cohort7 to reduce the risk of cross-infection.

    A key observation in this cohort was the acute splenial lesions seen on neuroimaging in all 4 patients. Reversible lesions of the SCC are rare but have been previously reported in patients with encephalopathies and are thought to represent focal intramyelin edema secondary to inflammation. In a multicenter study from Japan of 15 adult patients, a variety of viral prodromes were reported in 5 patients; these were influenza A (n = 1), mumps (n = 2), adenovirus (n = 1), and varicella-zoster virus (n = 1).8 Other differential diagnoses of splenial lesions include ischemia, posterior reversible encephalopathy syndrome, severe electrolyte disturbances, and lymphoma.9 Interestingly, a typical, transient, oval-shaped lesion in the median aspect of the SCC, either in isolation or with more extensive brain involvement, has also been reported10 in children with Kawasaki disease.

    Similar to the previous 2009 influenza A (H1N1) virus pandemic, the neurological symptom findings have not demonstrated neurotropism, and the pathobiology has been considered secondary to an immune-mediated causative mechanisms.11 A number of neuroimmune disorders are known to occur in close timing to viral infection; examples are in children who develop anti–N-methyl-d-aspartate receptor encephalitis after recovery from herpes simplex virus encephalitis and those who develop a primary CNS vasculitis after varicella-zoster virus infection.12 The phenotype of our cohort raises the possibility of a virus-specific immunological syndrome. A plausible mechanism would be exposure of the immune system to new CNS antigens as a result of blood-brain barrier damage from SARS-CoV-2, which causes endotheliopathy13 and leads to an immune-directed attack on the CNS.

    Alternatively, the neurological symptoms may be part of the systemic autoinflammatory disease in keeping with the raised systemic inflammatory markers seen in our cohort (Table 1). The combinations of both CNS and peripheral nervous system symptom profiles are rare in pediatrics but can be seen in children with hemophagocytic lymphohistiocytosis.14 This condition, which can be either genetic or acquired, is traditionally characterized by a cytokine storm with multiorgan dysfunction. More recently, isolated CNS presentations have also been reported.15 Similarly, neurological symptoms secondary to cytokines storms were reported in 23 of 51 pediatric and young adult patients (45.1%) receiving chimeric antigen receptor–modified T-cell therapy.16

    Limitations

    The key limitation of this study is the small sample size. Further studies are now required to confirm our observation and evaluate the mechanism of disease in this distinct syndrome.

    Conclusions

    In conclusion, we describe 4 children with COVID-19 who have a clinical phenotype involving both the CNS and the peripheral nervous system and lesions of the SCC. The negative cerebrospinal fluid results, the response to immunosuppression, and the clinical overlap with hemophagocytic lymphohistiocytosis suggest that this is likely to be immune mediated. Although the imaging finding is not specific to SARS-CoV-2, in that it has been previously seen with other viral infections, clinicians should be adding SARS-CoV-2 to their differential diagnosis for children presenting with new neurologic symptoms and this imaging finding while still exploring other possible causes. Furthermore, because respiratory symptoms were uncommon in this cohort and, when present, were mild and easily missed, and because reports are growing of children carrying COVID-19 infection without symptoms (with this condition likely presenting late), SARS-CoV-2 should also be considered in pediatric patients presenting with primary neurologic symptoms without systemic involvement. Close neurodevelopmental surveillance is required to assess the neurological and cognitive outcomes in these patients.

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    Article Information

    Accepted for Publication: June 17, 2020.

    Corresponding Author: Yael Hacohen, MD, PhD, Queen Square Multiple Sclerosis Centre, UCL Institute of Neurology, Faculty of Brain Sciences, University College London, 10-12 Russell Square, London WC1B 5EH, United Kingdom (y.hacohen@ucl.ac.uk).

    Published Online: July 1, 2020. doi:10.1001/jamaneurol.2020.2687

    Author Contributions: Dr Hacohen 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: Abdel-Mannan, Eyre, Hemingway, Hacohen.

    Acquisition, analysis, or interpretation of data: Abdel-Mannan, Eyre, Löbel, Bamford, Eltze, Hameed, Hacohen.

    Drafting of the manuscript: Abdel-Mannan, Hemingway, Hacohen.

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

    Statistical analysis: Abdel-Mannan.

    Administrative, technical, or material support: Eyre.

    Supervision: Hameed, Hemingway, Hacohen.

    Other—figure images and description: Löbel.

    Conflict of Interest Disclosures: Dr Hemingway has received educational and travel grants from Merck Serono and Bayer and Biogen. Dr Eyre reported personal fees from Terumo BCT outside the submitted work. No other disclosures were reported.

    Additional Contributions: We would like to acknowledge the following people for their input into the clinical care of the patients described in this series: Vijeya Ganesan, MD, Robert Robinson, PhD, Lucinda Carr, MD, Marios Kaliakatsos, PhD, Sophia Varadkar, PhD, Katherine Hassell, MD, Noelle Enright, MD, and Anoushka Alwis, MD, Department of Neurology, Great Ormond Street Hospital for Children; Nailia Ismayilova, PhD, Children and Adolescent Services, Chelsea and Westminster NHS Foundation Trust; Kshitij Mankad, MD, Felice D’Arco, MD, Sniya Sudhakar, MD, Department of Neuroradiology, Great Ormond Street Hospital for Children; Krishna Das, MD, Friederike Moeller, MD, Department of Neurophysiology, Great Ormond Street Hospital for Children; Gerald Coorey, MD, Delane Shingadia, MD, Karyn Moshal, MD, Louis Grandjean, PhD, and Nele Alders, MD, Department of Infectious Diseases, Great Ormond Street Hospital for Children. These individuals were not compensated for their contributions. We also thank the parents of the patients for granting permission to publish this information.

    References
    1.
    Ludvigsson  JF.  Systematic review of COVID-19 in children shows milder cases and a better prognosis than adults.   Acta Paediatr. 2020;109(6):1088-1095. doi:10.1111/apa.15270 PubMedGoogle ScholarCrossref
    2.
    Riphagen  S, Gomez  X, Gonzalez-Martinez  C, Wilkinson  N, Theocharis  P.  Hyperinflammatory shock in children during COVID-19 pandemic.   Lancet. 2020;395(10237):1607-1608. doi:10.1016/S0140-6736(20)31094-1PubMedGoogle ScholarCrossref
    3.
    Verdoni  L, Mazza  A, Gervasoni  A,  et al.  An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.   Lancet. 2020;395(10239):1771-1778. doi:10.1016/S0140-6736(20)31103-X PubMedGoogle ScholarCrossref
    4.
    Baig  AM, Khaleeq  A, Ali  U, Syeda  H.  Evidence of the COVID-19 virus targeting the CNS: tissue distribution, host-virus interaction, and proposed neurotropic mechanisms.   ACS Chem Neurosci. 2020;11(7):995-998. doi:10.1021/acschemneuro.0c00122 PubMedGoogle ScholarCrossref
    5.
    Gutiérrez-Ortiz  C, Méndez  A, Rodrigo-Rey  S,  et al.  Miller Fisher syndrome and polyneuritis cranialis in COVID-19.   Neurology. 2020;10.1212/WNL.0000000000009619. doi:10.1212/WNL.0000000000009619 PubMedGoogle Scholar
    6.
    Pilotto  A, Odolini  S, Stefano Masciocchi  S,  et al  Steroid-responsive encephalitis in COVID-19 disease.   Ann Neurol. Published online May 17, 2020. doi:10.1002/ana.25783Google Scholar
    7.
    Mao  L, Jin  H, Wang  M,  et al.  Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.   JAMA Neurol. 2020. doi:10.1001/jamaneurol.2020.1127 PubMedGoogle Scholar
    8.
    Tada  H, Takanashi  J, Barkovich  AJ,  et al.  Clinically mild encephalitis/encephalopathy with a reversible splenial lesion.   Neurology. 2004;63(10):1854-1858. doi:10.1212/01.WNL.0000144274.12174.CB PubMedGoogle ScholarCrossref
    9.
    Doherty  MJ, Jayadev  S, Watson  NF, Konchada  RS, Hallam  DK.  Clinical implications of splenium magnetic resonance imaging signal changes.   Arch Neurol. 2005;62(3):433-437. doi:10.1001/archneur.62.3.433 PubMedGoogle ScholarCrossref
    10.
    Kontzialis  M, Soares  BP, Huisman  TAGM.  Lesions in the splenium of the corpus callosum on MRI in children: a review.   J Neuroimaging. 2017;27(6):549-561. doi:10.1111/jon.12455 PubMedGoogle ScholarCrossref
    11.
    Sejvar  JJ, Uyeki  TM.  Neurologic complications of 2009 influenza A (H1N1): heightened attention on an ongoing question.   Neurology. 2010;74(13):1020-1021. doi:10.1212/WNL.0b013e3181d6b869 PubMedGoogle ScholarCrossref
    12.
    Wells  E, Hacohen  Y, Waldman  A,  et al; attendees of the International Neuroimmune Meeting.  Neuroimmune disorders of the central nervous system in children in the molecular era.   Nat Rev Neurol. 2018;14(7):433-445. doi:10.1038/s41582-018-0024-9 PubMedGoogle ScholarCrossref
    13.
    Varga  Z, Flammer  AJ, Steiger  P,  et al.  Endothelial cell infection and endotheliitis in COVID-19.   Lancet. 2020;395(10234):1417-1418. doi:10.1016/S0140-6736(20)30937-5 PubMedGoogle ScholarCrossref
    14.
    Horne  A, Trottestam  H, Aricò  M,  et al; Histiocyte Society.  Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis.   Br J Haematol. 2008;140(3):327-335. doi:10.1111/j.1365-2141.2007.06922.x PubMedGoogle ScholarCrossref
    15.
    Benson  LA, Li  H, Henderson  LA,  et al.  Pediatric CNS-isolated hemophagocytic lymphohistiocytosis.   Neurol Neuroimmunol Neuroinflamm. 2019;6(3):e560. doi:10.1212/NXI.0000000000000560 PubMedGoogle Scholar
    16.
    Gofshteyn  JS, Shaw  PA, Teachey  DT,  et al.  Neurotoxicity after CTL019 in a pediatric and young adult cohort.   Ann Neurol. 2018;84(4):537-546. doi:10.1002/ana.25315 PubMedGoogle ScholarCrossref
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