Abstract Coronavirus disease 2019 (COVID-19) has become a worldwide pandemic and can occur at any age, including children. Children with COVID-19 can develop the clinical symptoms of multiple systems, among which symptoms of the nervous system have been reported increasingly, and thus it is particularly important to understand COVID-19-associated neurological damage in children. This article reviews the mechanisms and types of COVID-19-associated neurological damage in children.
World Health Organization. WHO coronavirus disease (COVID-19) dashboard[DB/OL].[2020-12-19]. https://covid19.who.int/.
[2]
Choi SH, Kim HW, Kang JM, et al. Epidemiology and clinical features of coronavirus disease 2019 in children[J]. Clin Exp Pediatr, 2020, 63(4):125-132.
[3]
Garazzino S, Montagnani C, Donà D, et al. Multicentre Italian study of SARS-CoV-2 infection in children and adolescents, preliminary data as at 10 April 2020[J]. Euro Surveill, 2020, 25(18):2000600.
[4]
Viner RM, Mytton OT, Bonell C, et al. Susceptibility to SARS-CoV-2 infection among children and adolescents compared with adults:a systematic review and meta-analysis[J]. JAMA Pediatr, 2021, 175(2):143-156.
[5]
Mao L, Jin HJ, Wang MD, et al. Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China[J]. JAMA Neurol, 2020, 77(6):683-690.
[6]
Cagnazzo F, Arquizan C, Derraz I, et al. Neurological manifestations of patients infected with the SARS-CoV-2:a systematic review of the literature[J]. J Neurol, 2020. DOI:10.1007/s00415-020-10285-9. Epub ahead of print.
[7]
Panda PK, Sharawat IK, Panda P, et al. Neurological complications of SARS-CoV-2 infection in children:a systematic review and meta-analysis[J]. J Trop Pediatr, 2020. DOI:10.1093/tropej/fmaa070. Epub ahead of print.
[8]
Bhatta S, Sayed A, Ranabhat B, et al. New-onset seizure as the only presentation in a child with COVID-19[J]. Cureus, 2020, 12(6):e8820.
[9]
Mak PQ, Chung KS, Wong JS, et al. Anosmia and ageusia:not an uncommon presentation of COVID-19 infection in children and adolescents[J]. Pediatr Infect Dis J, 2020, 39(8):e199-e200.
[10]
Mirzaee SMM, Gonçalves FG, Mohammadifard M, et al. Focal cerebral arteriopathy in a COVID-19[J]. Radiology, 2020, 297(2):E274-E275.
[11]
Butowt R, Bilinska K. SARS-CoV-2:olfaction, brain infection, and the urgent need for clinical samples allowing earlier virus detection[J]. ACS Chem Neurosci, 2020, 11(9):1200-1203.
[12]
Morgello S. Coronaviruses and the central nervous system[J]. J Neurovirol, 2020, 26(4):459-473.
[13]
Netland J, Meyerholz DK, Moore S, et al. Severe acute respiratory syndrome coronavirus infection causes neuronal death in the absence of encephalitis in mice transgenic for human ACE2[J]. J Virol, 2008, 82(15):7264-7275.
[14]
Saraiva LR, Ibarra-Soria X, Khan M, et al. Hierarchical deconstruction of mouse olfactory sensory neurons:from whole mucosa to single-cell RNA-seq[J]. Sci Rep, 2015, 5:18178.
[15]
Kanageswaran N, Demond M, Nagel M, et al. Deep sequencing of the murine olfactory receptor neuron transcriptome[J]. PLoS One, 2015, 10(1):e0113170.
[16]
Debuc B, Smadja DM. Is COVID-19 a new hematologic disease?[J]. Stem Cell Rev Rep, 2021, 17(1):4-8.
[17]
Allan SM, Rothwell NJ. Cytokines and acute neurodegenera-tion[J]. Nat Rev Neurosci, 2001, 2(10):734-744.
[18]
Aghagoli G, Gallo Marin B, Katchur NJ, et al. Neurological involvement in COVID-19 and potential mechanisms:a review[J]. Neurocrit Care, 2020. DOI:10.1007/s12028-020-01049-4. Epub ahead of print.
[19]
Hamming I, Timens W, Bulthuis ML, et al. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis[J]. J Pathol, 2004, 203(2):631-637.
Wang J, Hajizadeh N, Moore EE, et al. Tissue plasminogen activator (tPA) treatment for COVID-19 associated acute respiratory distress syndrome (ARDS):a case series[J]. J Thromb Haemost, 2020, 18(7):1752-1755.
[22]
Oxley TJ, Mocco J, Majidi S, et al. Large-vessel stroke as a presenting feature of COVID-19 in the young[J]. N Engl J Med, 2020, 382(20):e60.
[23]
Levi M, van der Poll T. Inflammation and coagulation[J]. Crit Care Med, 2010, 38(2 Suppl):S26-S34.
[24]
Ahmad I, Rathore FA. Neurological manifestations and complications of COVID-19:a literature review[J]. J Clin Neurosci, 2020, 77:8-12.
[25]
Fan HY, Tang XJ, Song YX, et al. Influence of COVID-19 on cerebrovascular disease and its possible mechanism[J]. Neuropsychiatr Dis Treat, 2020, 16:1359-1367.
[26]
Christy A. COVID-19:a review for the pediatric neurologist[J]. J Child Neurol, 2020, 35(13):934-939.
[27]
Luethgen M, Eggeling J, Heyckendorf J, et al. Changes in taste and smell as an early marker for COVID-19[J]. Int J Infect Dis, 2020, 99:8-9.
[28]
Qiu CH, Cui C, Hautefort C, et al. Olfactory and gustatory dysfunction as an early identifier of COVID-19 in adults and children:an international multicenter study[J]. Otolaryngol Head Neck Surg, 2020, 163(4):714-721.
[29]
Cazzolla AP, Lovero R, Lo Muzio L, et al. Taste and smell disorders in COVID-19 patients:role of interleukin-6[J]. ACS Chem Neurosci, 2020, 11(17):2774-2781.
[30]
Henkin RI, Schmidt L, Velicu I. Interleukin 6 in hyposmia[J]. JAMA Otolaryngol Head Neck Surg, 2013, 139(7):728-734.
[31]
Gaborieau L, Delestrain C, Bensaid P, et al. Epidemiology and clinical presentation of children hospitalized with SARS-CoV-2 infection in suburbs of Paris[J]. J Clin Med, 2020, 9(7):2227.
[32]
Alyu F, Dikmen M. Inflammatory aspects of epileptogenesis:contribution of molecular inflammatory mechanisms[J]. Acta Neuropsychiatr, 2017, 29(1):1-16.
[33]
Rana A, Musto AE. The role of inflammation in the development of epilepsy[J]. J Neuroinflammation, 2018, 15(1):144.
[34]
Postnikova TY, Zubareva OE, Kovalenko AA, et al. Status epilepticus impairs synaptic plasticity in rat hippocampus and is followed by changes in expression of NMDA receptors[J]. Biochemistry (Mosc), 2017, 82(3):282-290.
[35]
García-Howard M, Herranz-Aguirre M, Moreno-Galarraga L, et al. Case report:benign infantile seizures temporally associated with COVID-19[J]. Front Pediatr, 2020, 8:507.
[36]
Gulko E, Overby P, Ali S, et al. Vessel wall enhancement and focal cerebral arteriopathy in a pediatric patient with acute infarct and COVID-19 infection[J]. AJNR Am J Neuroradiol, 2020, 41(12):2348-2350.
[37]
Arango Ferreira C, Correa-Roda M. Acute meningoencephalitis as initial presentation of SARS-CoV-2 infection in pediatrics[J]. Pediatr Infect Dis J, 2020, 39(11):e386-e387.
[38]
McAbee GN, Brosgol Y, Pavlakis S, et al. Encephalitis associated with COVID-19 infection in an 11-year-old child[J]. Pediatr Neurol, 2020, 109:94.
[39]
McClelland S, Dubé CM, Yang J, et al. Epileptogenesis after prolonged febrile seizures:mechanisms, biomarkers and therapeutic opportunities[J]. Neurosci Lett, 2011, 497(3):155-162.
[40]
Dugue R, Cay-Martínez KC, Thakur KT, et al. Neurologic manifestations in an infant with COVID-19[J]. Neurology, 2020, 94(24):1100-1102.
[41]
Tan YP, Tan BY, Pan J, et al. Epidemiologic and clinical characteristics of 10 children with coronavirus disease 2019 in Changsha, China[J]. J Clin Virol, 2020, 127:104353.
[42]
Francis JR, Richmond P, Robins C, et al. An observational study of febrile seizures:the importance of viral infection and immunization[J]. BMC Pediatr, 2016, 16(1):202.
[43]
Carman KB, Calik M, Karal Y, et al. Viral etiological causes of febrile seizures for respiratory pathogens (EFES Study)[J]. Hum Vaccin Immunother, 2019, 15(2):496-502.
[44]
Xia W, Shao JB, Guo Y, et al. Clinical and CT features in pediatric patients with COVID-19 infection:different points from adults[J]. Pediatr Pulmonol, 2020, 55(5):1169-1174.
[45]
Tsai LK, Hsieh ST, Chao CC, et al. Neuromuscular disorders in severe acute respiratory syndrome[J]. Arch Neurol, 2004, 61(11):1669-1673.
[46]
Frank CHM, Almeida TVR, Marques EA, et al. Guillain-Barré syndrome associated with SARS-CoV-2 infection in a pediatric patient[J]. J Trop Pediatr, 2020. DOI:10.1093/tropej/fmaa044. Epub ahead of print.
[47]
Khalifa M, Zakaria F, Ragab Y, et al. Guillain-Barré syndrome associated with severe acute respiratory syndrome coronavirus 2 detection and coronavirus disease 2019 in a child[J]. J Pediatric Infect Dis Soc, 2020, 9(4):510-513.
[48]
Caress JB, Castoro RJ, Simmons Z, et al. COVID-19-associated Guillain-Barré syndrome:the early pandemic experience[J]. Muscle Nerve, 2020, 62(4):485-491.
[49]
Fantini J, Di Scala C, Chahinian H, et al. Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection[J]. Int J Antimicrob Agents, 2020, 55(5):105960.
[50]
Yousefi K, Poorbarat S, Abasi Z, et al. Viral meningitis associated with COVID-19 in a 9-year-old child:a case report[J]. Pediatr Infect Dis J, 2021, 40(2):e87-e98.
[51]
Ellul MA, Benjamin L, Singh B, et al. Neurological associations of COVID-19[J]. Lancet Neurol, 2020, 19(9):767-783.
[52]
Winter PM, Dung NM, Loan HT, et al. Proinflammatory cytokines and chemokines in humans with Japanese encephalitis[J]. J Infect Dis, 2004, 190(9):1618-1626.
[53]
Li YY, Li HP, Fan RY, et al. Coronavirus infections in the central nervous system and respiratory tract show distinct features in hospitalized children[J]. Intervirology, 2016, 59(3):163-169.
[54]
Li HP, Li YY, Wen B, et al. Dengue virus and Japanese encephalitis virus infection of the central nervous system share similar profiles of cytokine accumulation in cerebrospinal fluid[J]. Cent Eur J Immunol, 2017, 42(2):218-222.
[55]
Conto-Palomino NM, Cabrera-Bueno ML, Vargas-Ponce KG, et al. Encephalitis associated with COVID-19 in a 13-year-old girl:a case report[J]. Medwave, 2020, 20(7):e7984.
[56]
Wintermark M, Hills NK, Deveber GA, et al. Clinical and imaging characteristics of arteriopathy subtypes in children with arterial ischemic stroke:results of the VIPS study[J]. AJNR Am J Neuroradiol, 2017, 38(11):2172-2179.
[57]
Fullerton HJ, Stence N, Hills NK, et al. Focal cerebral arteriopathy of childhood:novel severity score and natural history[J]. Stroke, 2018, 49(11):2590-2596.
[58]
Lanthier S, Armstrong D, Domi T, et al. Post-varicella arteriopathy of childhood:natural history of vascular stenosis[J]. Neurology, 2005, 64(4):660-663.
[59]
Woo D. Infection, vaccination, and childhood arterial ischemic stroke[J]. Neurology, 2015, 85(17):e134.
[60]
Grau AJ, Urbanek C, Palm F. Common infections and the risk of stroke[J]. Nat Rev Neurol, 2010, 6(12):681-694.
[61]
Liuba P, Persson J, Luoma J, et al. Acute infections in children are accompanied by oxidative modification of LDL and decrease of HDL cholesterol, and are followed by thickening of carotid intima-media[J]. Eur Heart J, 2003, 24(6):515-521.
[62]
Steinlin M, Bigi S, Stojanovski B, et al. Focal cerebral arteriopathy:do steroids improve outcome?[J]. Stroke, 2017, 48(9):2375-2382.
[63]
Abrams JY, Godfred-Cato SE, Oster ME, et al. Multisystem inflammatory syndrome in children associated with severe acute respiratory syndrome coronavirus 2:a systematic review[J]. J Pediatr, 2020, 226:45-54.e1.
[64]
Abdel-Mannan O, Eyre M, Löbel U, et al. Neurologic and radiographic findings associated with COVID-19 infection in children[J]. JAMA Neurol, 2020, 77(11):1-6.
[65]
De Paulis M, Oliveira DBL, Vieira RP, et al. Multisystem inflammatory syndrome associated with COVID-19 with neurologic manifestations in a child:a brief report[J]. Pediatr Infect Dis J, 2020, 39(10):e321-e324.
[66]
Schupper AJ, Yaeger KA, Morgenstern PF. Neurological manifestations of pediatric multi-system inflammatory syndrome potentially associated with COVID-19[J]. Childs Nerv Syst, 2020, 36(8):1579-1580.
[67]
Saeed A, Shorafa E. Status epilepticus as a first presentation of COVID-19 infection in a 3 years old boy; Case report and review the literature[J]. IDCases, 2020, 22:e00942.
[68]
Abel D, Shen MY, Abid Z, et al. Encephalopathy and bilateral thalamic lesions in a child with MIS-C associated with COVID-19[J]. Neurology, 2020, 95(16):745-748.
[69]
Nakra NA, Blumberg DA, Herrera-Guerra A, et al. Multi-system inflammatory syndrome in children (MIS-C) following SARS-CoV-2 infection:review of clinical presentation, hypothetical pathogenesis, and proposed management[J]. Children (Basel), 2020, 7(7):69.
[70]
Vella L, Giles JR, Baxter AE, et al. Deep immune profiling of MIS-C demonstrates marked but transient immune activation compared to adult and pediatric COVID-19[J]. medRxiv, 2020. DOI:10.1101/2020.09.25.20201863. Epub ahead of print.
[71]
Gruber CN, Patel RS, Trachman R, et al. Mapping systemic inflammation and antibody responses in multisystem inflammatory syndrome in children (MIS-C)[J]. Cell, 2020, 183(4):982-995.E14.
[72]
Mudd JC, Panigrahi S, Kyi B, et al. Inflammatory function of CX3CR1+ CD8+ T cells in treated HIV infection is modulated by platelet interactions[J]. J Infect Dis, 2016, 214(12):1808-1816.
[73]
Motaghinejad M, Gholami M. Possible neurological and mental outcomes of COVID-19 infection:a hypothetical role of ACE-2\Mas\BDNF signaling pathway[J]. Int J Prev Med, 2020, 11:84.
[74]
Bathina S, Das UN. Brain-derived neurotrophic factor and its clinical implications[J]. Arch Med Sci, 2015, 11(6):1164-1178.