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03-04-2024 | Encephalitis

Clinical characteristics and outcomes of COVID-19-associated encephalopathy in children

Authors: Li Li, Hongmei Liao, Xiaojun Kuang, Ke Jin

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.

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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-wCrossRefPubMedPubMedCentral

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/s12883-021-02449-5CrossRefPubMedPubMedCentral

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/NEJMoa2021680CrossRefPubMed

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.26207CrossRefPubMed

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/s00415-023-11915-8CrossRefPubMed

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)30177-2CrossRefPubMedPubMedCentral

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)00401-9CrossRefPubMedPubMedCentral

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)30183-5CrossRefPubMedPubMedCentral

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.2021.08.017CrossRefPubMedPubMedCentral

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.2021.0504CrossRefPubMed

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.2023.1184864CrossRefPubMedPubMedCentral

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-XCrossRefPubMed

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.2020.04.007CrossRefPubMedPubMedCentral

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-zCrossRefPubMedPubMedCentral

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.25915CrossRefPubMedPubMedCentral

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/awaa240CrossRefPubMedPubMedCentral

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-zCrossRefPubMed

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.2021.102857CrossRefPubMedPubMedCentral

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.2020201187CrossRefPubMed

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.2021.03.004CrossRefPubMedPubMedCentral

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.14913CrossRefPubMedPubMedCentral

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.2021.100288CrossRefPubMedPubMedCentral

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.26973CrossRefPubMedPubMedCentral

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.0000000000012931CrossRefPubMedPubMedCentral

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-xCrossRefPubMedPubMedCentral

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.16656CrossRefPubMedPubMedCentral

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/s41392-021-00818-7CrossRefPubMedPubMedCentral

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 27:1919–1923PubMedPubMedCentral

Title: Clinical characteristics and outcomes of COVID-19-associated encephalopathy in children
Authors: Li Li
Hongmei Liao
Xiaojun Kuang
Ke Jin
Publication date: 03-04-2024
Publisher: Springer International Publishing
Keywords: Encephalitis
COVID-19
Encephalopathy
Autoimmune Encephalitis
Electroencephalography
Magnetic Resonance Imaging
Magnetic Resonance Imaging
Epilepsy
Published in: Journal of NeuroVirology
Print ISSN: 1355-0284
Electronic ISSN: 1538-2443
DOI: https://doi.org/10.1007/s13365-024-01202-1

At a glance: The STEP trials

Springer Medicine

Clinical characteristics and outcomes of COVID-19-associated encephalopathy in children

Abstract

At a glance: The STEP trials

Springer Medicine

Abstract

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