Abstract
Apart from the typical respiratory symptoms, coronavirus disease 2019 (COVID-19) also affects the central nervous system, leading to central disorders such as encephalopathy and encephalitis. However, knowledge of pediatric COVID-19-associated encephalopathy is limited, particularly regarding specific subtypes of encephalopathy. This study aimed to assess the features of COVID-19-associated encephalopathy/encephalitis in children. We retrospectively analyzed a single cohort of 13 hospitalized children with COVID-19-associated encephalopathy. The primary outcome was the descriptive analysis of the clinical characteristics, magnetic resonance imaging and electroencephalography findings, treatment progression, and outcomes. Thirteen children among a total of 275 (5%) children with confirmed COVID-19 developed associated encephalopathy/encephalitis (median age, 35 months; range, 3–138 months). Autoimmune encephalitis was present in six patients, acute necrotizing encephalopathy in three, epilepsy in three, and central nervous system small-vessel vasculitis in one patient. Eight (62%) children presented with seizures. Six (46%) children exhibited elevated blood inflammatory indicators, cerebrospinal fluid inflammatory indicators, or both. Two (15%) critically ill children presented with multi-organ damage. The magnetic resonance imaging findings varied according to the type of encephalopathy/encephalitis. Electroencephalography revealed a slow background rhythm in all 13 children, often accompanied by epileptic discharges. Three (23%) children with acute necrotizing encephalopathy had poor prognoses despite immunotherapy and other treatments. Ten (77%) children demonstrated good functional recovery without relapse. This study highlights COVID-19 as a new trigger of encephalopathy/encephalitis in children. Autoimmune encephalitis is common, while acute necrotizing encephalopathy can induce poor outcomes. These findings provide valuable insights into the impact of COVID-19 on children’s brains.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Data availability
Data will be made available on request.
References
Antoon JW, Hall M, Howard LM, Herndon A, Freundlich KL, Grijalva CG, Williams DJ (2022) COVID-19 and Acute neurologic complications in children. Pediatrics 150. https://doi.org/10.1542/peds.2022-058167
Arino H, Heartshorne R, Michael BD, Nicholson TR, Vincent A, Pollak TA, Vogrig A (2022) Neuroimmune disorders in COVID-19. J Neurol 269:2827–2839. https://doi.org/10.1007/s00415-022-11050-w
Davies NG, Klepac P, Liu Y, Prem K, Jit M, group, CC-w, Eggo RM (2020) Age-dependent effects in the transmission and control of COVID-19 epidemics. Nat Med 26: 1205–1211. https://doi.org/10.1038/s41591-020-0962-9
Durovic E, Bien C, Bien CG, Isenmann S (2021) MOG antibody-associated encephalitis secondary to Covid-19: case report. BMC Neurol 21:414. https://doi.org/10.1186/s12883-021-02449-5
Feldstein LR, Rose EB, Horwitz SM, Collins JP, Newhams MM, Son MBF, Newburger JW, Kleinman LC, Heidemann SM, Martin AA, Singh AR, Li S, Tarquinio KM, Jaggi P, Oster ME, Zackai SP, Gillen J, Ratner AJ, Walsh RF, Fitzgerald JC, Keenaghan MA, Alharash H, Doymaz S, Clouser KN, Giuliano JS Jr., Gupta A, Parker RM, Maddux AB, Havalad V, Ramsingh S, Bukulmez H, Bradford TT, Smith LS, Tenforde MW, Carroll CL, Riggs BJ, Gertz SJ, Daube A, Lansell A, Coronado Munoz A, Hobbs CV, Marohn KL, Halasa NB, Patel MM, Randolph AG, Overcoming C-I, Team CC-R (2020) Multisystem inflammatory syndrome in U.S. children and adolescents. N Engl J Med 383:334–346. https://doi.org/10.1056/NEJMoa2021680
Garg RK, Paliwal VK, Gupta A (2021) Encephalopathy in patients with COVID-19: a review. J Med Virol 93:206–222. https://doi.org/10.1002/jmv.26207
Geng C, Zhao W, Wang Z, Wu J, Jiang D, Jiang N, Liu M, Yao M, Guan H (2023) Acute necrotizing encephalopathy associated with COVID-19: case series and systematic review. J Neurol 270:5171–5181. https://doi.org/10.1007/s00415-023-11915-8
Gotzinger F, Santiago-Garcia B, Noguera-Julian A, Lanaspa M, Lancella L, Calo Carducci FI, Gabrovska N, Velizarova S, Prunk P, Osterman V, Krivec U, Lo Vecchio A, Shingadia D, Soriano-Arandes A, Melendo S, Lanari M, Pierantoni L, Wagner N, L’Huillier AG, Heininger U, Ritz N, Bandi S, Krajcar N, Roglic S, Santos M, Christiaens C, Creuven M, Buonsenso D, Welch SB, Bogyi M, Brinkmann F, Tebruegge M, ptbnet C-SG (2020) COVID-19 in children and adolescents in Europe: a multinational, multicentre cohort study. Lancet Child Adolesc Health 4:653–661. https://doi.org/10.1016/S2352-4642(20)30177-2
Graus F, Titulaer MJ, Balu R, Benseler S, Bien CG, Cellucci T, Cortese I, Dale RC, Gelfand JM, Geschwind M, Glaser CA, Honnorat J, Hoftberger R, Iizuka T, Irani SR, Lancaster E, Leypoldt F, Pruss H, Rae-Grant A, Reindl M, Rosenfeld MR, Rostasy K, Saiz A, Venkatesan A, Vincent A, Wandinger KP, Waters P, Dalmau J (2016) A clinical approach to diagnosis of autoimmune encephalitis. Lancet Neurol 15:391–404. https://doi.org/10.1016/S1474-4422(15)00401-9
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B (2020) Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 395:497–506. https://doi.org/10.1016/S0140-6736(20)30183-5
Kurd M, Hashavya S, Benenson S, Gilboa T (2021) Seizures as the main presenting manifestation of acute SARS-CoV-2 infection in children. Seizure 92:89–93. https://doi.org/10.1016/j.seizure.2021.08.017
LaRovere KL, Riggs BJ, Poussaint TY, Young CC, Newhams MM, Maamari M, Walker TC, Singh AR, Dapul H, Hobbs CV, McLaughlin GE, Son MBF, Maddux AB, Clouser KN, Rowan CM, McGuire JK, Fitzgerald JC, Gertz SJ, Shein SL, Munoz AC, Thomas NJ, Irby K, Levy ER, Staat MA, Tenforde MW, Feldstein LR, Halasa NB, Giuliano JS Jr., Hall MW, Kong M, Carroll CL, Schuster JE, Doymaz S, Loftis LL, Tarquinio KM, Babbitt CJ, Nofziger RA, Kleinman LC, Keenaghan MA, Cvijanovich NZ, Spinella PC, Hume JR, Wellnitz K, Mack EH, Michelson KN, Flori HR, Patel MM, Randolph AG, Overcoming C-I (2021) Neurologic involvement in children and adolescents hospitalized in the United States for COVID-19 or Multisystem Inflammatory Syndrome. JAMA Neurol 78:536–547. https://doi.org/10.1001/jamaneurol.2021.0504
Lin X, Wang Y, Li X, Abdalla M, Zhang F, Dong C, Lu W, Liu X, Zhang J, Ma K, Ma X, Jiang Q (2023) Acute necrotizing encephalopathy in children with COVID-19: a retrospective study of 12 cases. Front Neurol 14:1184864. https://doi.org/10.3389/fneur.2023.1184864
Lindan CE, Mankad K, Ram D, Kociolek LK, Silvera VM, Boddaert N, Stivaros SM, Palasis S, Group APC (2021) Neuroimaging manifestations in children with SARS-CoV-2 infection: a multinational, multicentre collaborative study. Lancet Child Adolesc Health 5:167–177. https://doi.org/10.1016/S2352-4642(20)30362-X
Magro C, Mulvey JJ, Berlin D, Nuovo G, Salvatore S, Harp J, Baxter-Stoltzfus A, Laurence J (2020) Complement associated microvascular injury and thrombosis in the pathogenesis of severe COVID-19 infection: a report of five cases. Transl Res 220:1–13. https://doi.org/10.1016/j.trsl.2020.04.007
Mansueto G, Lanza G, Fisicaro F, Alaouieh D, Hong E, Girolami S, Montella M, Feola A, Di Napoli M (2022) Central and Peripheral Nervous System complications of Vasculitis syndromes from Pathology to Bedside: part 1-Central Nervous System. Curr Neurol Neurosci Rep 22:47–69. https://doi.org/10.1007/s11910-022-01172-z
Paniz-Mondolfi A, Bryce C, Grimes Z, Gordon RE, Reidy J, Lednicky J, Sordillo EM, Fowkes M (2020) Central nervous system involvement by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). J Med Virol 92:699–702. https://doi.org/10.1002/jmv.25915
Paterson RW, Brown RL, Benjamin L, Nortley R, Wiethoff S, Bharucha T, Jayaseelan DL, Kumar G, Raftopoulos RE, Zambreanu L, Vivekanandam V, Khoo A, Geraldes R, Chinthapalli K, Boyd E, Tuzlali H, Price G, Christofi G, Morrow J, McNamara P, McLoughlin B, Lim ST, Mehta PR, Levee V, Keddie S, Yong W, Trip SA, Foulkes AJM, Hotton G, Miller TD, Everitt AD, Carswell C, Davies NWS, Yoong M, Attwell D, Sreedharan J, Silber E, Schott JM, Chandratheva A, Perry RJ, Simister R, Checkley A, Longley N, Farmer SF, Carletti F, Houlihan C, Thom M, Lunn MP, Spillane J, Howard R, Vincent A, Werring DJ, Hoskote C, Jager HR, Manji H, Zandi MS (2020) The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings. Brain 143:3104–3120. https://doi.org/10.1093/brain/awaa240
Payus AO, Jeffree MS, Ohn MH, Tan HJ, Ibrahim A, Chia YK, Raymond AA (2022) Immune-mediated neurological syndrome in SARS-CoV-2 infection: a review of literature on autoimmune encephalitis in COVID-19. Neurol Sci 43:1533–1547. https://doi.org/10.1007/s10072-021-05785-z
Peters J, Alhasan S, Vogels CBF, Grubaugh ND, Farhadian S, Longbrake EE (2021) MOG-associated encephalitis following SARS-COV-2 infection. Mult Scler Relat Disord 50:102857. https://doi.org/10.1016/j.msard.2021.102857
Pinto AA, Carroll LS, Nar V, Varatharaj A, Galea I (2020) CNS inflammatory vasculopathy with antimyelin oligodendrocyte glycoprotein antibodies in COVID-19. Neurol Neuroimmunol Neuroinflamm 7. https://doi.org/10.1212/NXI.0000000000000813
Poyiadji N, Shahin G, Noujaim D, Stone M, Patel S, Griffith B (2020) COVID-19-associated Acute Hemorrhagic Necrotizing Encephalopathy: imaging features. Radiology 296:E119–E120. https://doi.org/10.1148/radiol.2020201187
Sharma S, Ruparelia J, Bhaskar S, Tiwari S, Nag VL, Panda S (2021) Acute fulminant cerebellitis in children with COVID-19 infection: a Rare but Treatable Complication. Pediatr Neurol 119:45–47. https://doi.org/10.1016/j.pediatrneurol.2021.03.004
Siow I, Lee KS, Zhang JJY, Saffari SE, Ng A (2021) Encephalitis as a neurological complication of COVID-19: a systematic review and meta-analysis of incidence, outcomes, and predictors. Eur J Neurol 28:3491–3502. https://doi.org/10.1111/ene.14913
Song E, Bartley CM, Chow RD, Ngo TT, Jiang R, Zamecnik CR, Dandekar R, Loudermilk RP, Dai Y, Liu F, Sunshine S, Liu J, Wu W, Hawes IA, Alvarenga BD, Huynh T, McAlpine L, Rahman NT, Geng B, Chiarella J, Goldman-Israelow B, Vogels CBF, Grubaugh ND, Casanovas-Massana A, Phinney BS, Salemi M, Alexander JR, Gallego JA, Lencz T, Walsh H, Wapniarski AE, Mohanty S, Lucas C, Klein J, Mao T, Oh J, Ring A, Spudich S, Ko AI, Kleinstein SH, Pak J, DeRisi JL, Iwasaki A, Pleasure SJ, Wilson MR, Farhadian SF (2021) Divergent and self-reactive immune responses in the CNS of COVID-19 patients with neurological symptoms. Cell Rep Med 2:100288. https://doi.org/10.1016/j.xcrm.2021.100288
Uginet M, Breville G, Assal F, Lovblad KO, Vargas MI, Pugin J, Serratrice J, Herrmann FR, Lalive PH, Allali G (2021) COVID-19 encephalopathy: clinical and neurobiological features. J Med Virol 93:4374–4381. https://doi.org/10.1002/jmv.26973
Valencia Sanchez C, Theel E, Binnicker M, Toledano M, McKeon A (2021) Autoimmune Encephalitis after SARS-CoV-2 infection: case frequency, findings, and outcomes. Neurology 97:e2262–e2268. https://doi.org/10.1212/WNL.0000000000012931
Vasilevska V, Guest PC, Bernstein HG, Schroeter ML, Geis C, Steiner J (2021) Molecular mimicry of NMDA receptors may contribute to neuropsychiatric symptoms in severe COVID-19 cases. J Neuroinflammation 18:245. https://doi.org/10.1186/s12974-021-02293-x
Vohora D, Jain S, Tripathi M, Potschka H (2020) COVID-19 and seizures: is there a link? Epilepsia 61:1840–1853. https://doi.org/10.1111/epi.16656
Wan D, Du T, Hong W, Chen L, Que H, Lu S, Peng X (2021) Neurological complications and infection mechanism of SARS-COV-2. Signal Transduct Target Ther 6:406. https://doi.org/10.1038/s41392-021-00818-7
Wong AM, Simon EM, Zimmerman RA, Wang HS, Toh CH, Ng SH (2006) Acute necrotizing encephalopathy of childhood: correlation of MR findings and clinical outcome. AJNR Am J Neuroradiol 27:1919–1923
Acknowledgements
We would like to thank Editage (www.editage.cn) for English language editing. A special thank you to all the children and their families whose data contributed to this study.
Funding
This study was funded by the Natural Science Foundation of Hunan Province, China (Grant No. 2023JJ60276) and the Scientific Research Project of Hunan Provincial Health Commission, China (Grant No. 202209013520).
Author information
Authors and Affiliations
Contributions
Li Li: Writing– original draft, Conceptualization, Methodology, Formal analysis, Project administration, Investigation, Funding acquisition. Hongmei Liao: Supervision, Conceptualization, Funding acquisition. Xiaojun Kuang: Data curation. Ke Jin: Conceptualization, Methodology, Formal analysis, Conceptualization, Methodology, Formal analysis, Validation, Supervision. All authors reviewed the manuscript.
Corresponding authors
Ethics declarations
Ethical approval
The Institutional Review Board of Hunan Children’s Hospital approved this study (KS2023-114). The requirement for informed consent was waived because of the study’s retrospective design and because all procedures were part of standard care.
Conflict of interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
Competing interests
The authors declare no competing interests.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.
About this article
Cite this article
Li, L., Liao, H., Kuang, X. et al. Clinical characteristics and outcomes of COVID-19-associated encephalopathy in children. J. Neurovirol. (2024). https://doi.org/10.1007/s13365-024-01202-1
Received:
Revised:
Accepted:
Published:
DOI: https://doi.org/10.1007/s13365-024-01202-1