Modern infectious and immune-mediated causes of acute encephalitis in children
DOI:
https://doi.org/10.15574/SP.2025.8(152).7078Keywords:
acute encephalitis, etiology, children, SARS-CoV-2Abstract
Acute encephalitis in children is a heterogeneous clinical syndrome with diverse infectious and immune-mediated causes. Despite the availability of diagnostic criteria proposed by the International Encephalitis Consortium, establishing the etiology remains challenging in many cases, as clinical manifestations often overlap across different etiological groups. Recent epidemiological changes, including the emergence of SARS-CoV-2 and the rise in recognized autoimmune encephalitides, have further expanded the spectrum of potential triggers in pediatric populations.
Aim - to summarize current evidence on the etiological structure of acute encephalitis in children and analyze the contribution of infectious, autoimmune, and post-infectious mechanisms over the past decade.
A structured literature review was conducted using publications from 2015-2025, focusing on epidemiology, pathogen distribution, diagnostic approaches, and the evolving role of advanced molecular technologies in etiology determination. Despite comprehensive diagnostic work-up, the etiological agent can be identified in only about half of pediatric encephalitis cases. Viral pathogens, particularly HSV-1, enteroviruses, HHV-6, influenza, and emerging infections such as SARS-CoV-2, remain the leading causes. However, autoimmune encephalitides, including anti-NMDAR, MOG-associated disease, and AQP4-IgG-positive neuromyelitis optica spectrum disorders, are increasingly recognized, accounting for a substantial proportion of previously unexplained cases. Novel diagnostic tools such as metagenomic next-generation sequencing, phage immunoprecipitation sequencing (PhIP-Seq), and rapid multiplex PCR panels significantly improve detection rates. The growing number of reported co-infections and virus-triggered immune dysregulation highlights the importance of considering both infectious and immune-mediated etiologies in every child with acute encephalitis.
Conclusions. The etiological landscape of pediatric acute encephalitis is dynamic and continues to evolve in response to emerging pathogens and expanding diagnostic capabilities. Integrating modern molecular methods with standardized clinical and immunologic assessment is essential to increase the proportion of etiologically confirmed cases. The development and implementation of a unified, stepwise diagnostic algorithm will facilitate the earlier identification of the underlying cause, the timely initiation of targeted therapy, and improved outcomes in affected children.
The authors declare no conflict of interest.
References
Abe Y, Ohno T, Matsumoto H et al. (2021). HPeV3-associated acute encephalitis/encephalopathy among Japanese infants. Brain Dev. 43(4): 528-537. https://doi.org/10.1016/j.braindev.2020.12.010; PMid:33423809
Benninger F, Steiner I. (2021). Non-infectious mechanisms of neurological damage due to infection. J Neurol Sci. 431: 120057. https://doi.org/10.1016/j.jns.2021.120057; PMid:34800841
Biyani AM, Sharath V, Varma TS. (2024). Effect of Pediatric Rehabilitation on Children With Viral Encephalitis: A CaseReport. Cureus. 16(3): e57239. https://doi.org/10.7759/cureus.57239
Boyarchuk O, Perestiuk V, Kosovska T et al. (2024). Coagulation profile in hospitalized children with COVID-19: pediatric age dependency and its impact on long COVID development. Front Immunol. 15: 1363410. https://doi.org/10.3389/fimmu.2024.1363410; PMid:38510249 PMCid:PMC10950941
Boyarchuk O, Volianska L. (2023). Autoimmunity and long COVID in children. Reumatologia. 61(6): 492-501. https://doi.org/10.5114/reum/176464; PMid:38322108 PMCid:PMC10839920
Boyarchuk O, Mudryk U, Volyanska L. (2021). Hyperkalemia in newborn: case report. Pharmacologyonline, archives. 2: 73-79.
Cheng H, Chen D, Peng X et. al. (2020). Clinical characteristics of Epstein-Barr virus infection in the pediatric nervous system. BMC Infect Dis. 20(1): 886. https://doi.org/10.1186/s12879-020-05623-1; PMid:33238935 PMCid:PMC7691062
Cleaver J, Jeffery K, Klenerman P et al. (2024). Lim M, Handunnetthi L, Irani SR, Handel A. The immunobiology of herpes simplex virus encephalitis and post-viral autoimmunity. Brain. 147(4): 1130-1148. https://doi.org/10.1093/brain/awad419; PMid:38092513 PMCid:PMC10994539
Dale RC, Mohammad SS. (2024). Movement disorders associated with pediatric encephalitis. Handbook of Clin Neurol. 200: 229-238. https://doi.org/10.1016/B978-0-12-823912-4.00018-9
Dehghan A, Saleh R, Rahimi H et. al. (2023). Acute neurological symptoms in multisystem inflammatory syndrome in children: A case series. Heliyon. 9(8): e18566. https://doi.org/10.1016/j.heliyon.2023.e18566; PMid:37576195 PMCid:PMC10412987
Dwibedi B, Satapathy AK, Jain A et.al. (2024). Prevalence and clinical come of autoimmune encephalitis versus viral encephalitis in children with acute encephalitis syndrome: A prospective observational study. Indian J MedRes. 160(2): 217-225. https://doi.org/10.25259/ijmr_2332_23; PMid:39513204 PMCid:PMC11544577
Gonzalez G, Carr MJ, Kobayashi M et.al. (2019). Enterovirus-Associated Hand-Foot and Mouth Disease and Neurological Complications in Japan and the Rest of the World. Int J Mol Sci. 20(20): 5201. https://doi.org/10.3390/ijms20205201; PMid:31635198 PMCid:PMC6834195
Guo Y, Jiang L. (2019). Cytomegalovirus encephalitis in immunocompetent infants: A 15-year retrospective study at a single center. Int J Infect Dis. 82: 106-110. https://doi.org/10.1016/j.ijid.2019.02.045; PMid:30844517
Hansen MA, Hasbun R. (2022). US Hospitalizations and 60-Day Readmission Rates Associated With Herpes Simplex Virus Encephalitis: Analysis of All Cause Readmissions and Encephalopathy Associated Readmissions. Clin Infect Dis. 74(7): 1174-1182. https://doi.org/10.1093/cid/ciab613; PMid:34240104 PMCid:PMC9633713
Han SJ, Chen SH, Dai BW et al. (2024). Epidemiological characteristic of viral encephalitis in children and adolescents in Henan Province, 2012-2023. Zhonghua Liu Xing Bing Xue Za Zhi. 45(6): 852-856.
Huang S, Chen J, Li F et al. (2025). Clinical characteristics and outcomes of COVID-19-Associated acute encephalopathy in pediatric patients during the Omicron wave in beijing: a single-center prospective study. BMC Pediatr. 25(1): 688. https://doi.org/10.1186/s12887-025-05970-5; PMid:40993593 PMCid:PMC12462391
Huang CW, Lin JJ, Kuo CY et. al. (2023). Risk factors of Omicron variant associated acute encephalitis/encephalopathy in children. J Microbiol Immunol Infect. 56(6): 1169-1177. https://doi.org/10.1016/j.jmii.2023.08.010; PMid:37709632
Islam KA, Akhter S, Podder KM. (2022, Oct). Encephalitis in Children: Viruses and Beyond. Mymensingh Med J. 31(4): 1212-1221. PMID: 36189575.
Jindal N, Mishra BB, Kanak KR et al. (2025). A comparative analysis of Japanese Encephalitis Virus (JEV) in Asia: patterns of transmission, clinical diagnosis, and control strategies, Clinical Microbiology Newsletter. 53: 14-19. https://doi.org/10.1016/j.clinmicnews.2025.09.004
Kalita D, Debbarma BG. (2025). Clinical and Etiological Profile of Acute Encephalitis Syndrome among Pediatric Age Group in a Tertiary Care Centre- An observational study. European Journal of Cardiovascular Medicine. 15(1): 324-329.
Ketelaar M, Bogossian A, Saini M et. al. (2017). Assessment of the family environment in pediatric neurodisability: a state-of-the-artreview. Dev Med Child Neurol. 59(3): 259-269. https://doi.org/10.1111/dmcn.13287; PMid:27696390
Khalili M, Rahimi Hajiabadi H, Akbari M et. al. (2022). Viral aetiology of acute central nervous system infections in children, Iran. J Med Microbiol. 71(10). https://doi.org/10.1099/jmm.0.001602
Korgenski EK, Blaschke AJ, Holmberg KM et. al. (2018). Retrospective Evaluation of Infants Aged 1 to 60 Days with Residual Cerebrospinal Fluid (CSF) Tested Using the FilmArray Meningitis/Encephalitis (ME) Panel. J. Clin. Microbiol. 56(7): e00277-18. https://doi.org/10.1128/JCM.00277-18; PMid:29669791 PMCid:PMC6018345
Krawczuk K, Czupryna P, Pancewicz S et.al. (2020). Comparison of tick-borne encephalitis between children and adults-analysis of 669 patients. J Neurovirol. 26(4): 565-571. https://doi.org/10.1007/s13365-020-00856-x; PMid:32524423 PMCid:PMC7438291
Kumar G, Sharma V, Kumar A. (2022). Clinical Profile of Pediatric Neurology Disorders: A Study From a Semi-Urban Medical College in Northwestern India. Cureus. 16; 14(10): e30359. https://doi.org/10.7759/cureus.30359
Lemmon ME, Barks MC, Bernstein S et. al. (2022). Prognostic Discussion for Infants with Neurologic Conditions: Qualitative Analysis of Family Conferences. Ann Neurol. 92(4): 699-709. https://doi.org/10.1002/ana.26457; PMid:35866708 PMCid:PMC9600061
Leruez-Ville M, Chatzakis C, Lilleri D et. al. (2024). Consensus recommendation for prenatal, neonatal and postnatal management of congenital cytomegalovirus infection from the European congenital infection initiative (ECCI). Lancet Reg Health Eur. 40: 100892. https://doi.org/10.1016/j.lanepe.2024.100892; PMid:38590940 PMCid:PMC10999471
Levesque ZA, Walsh MG, Webb CE et. al. (2024). A scoping review of evidence of naturally occurring Japanese encephalitis infection in vertebrate animals other than humans, ardeid birds and pigs. PLoS Negl Trop Dis. 18(10): e0012510. https://doi.org/10.1371/journal.pntd.0012510; PMid:39365832 PMCid:PMC11482687
Lindan CE, Mankad K, Ram D et at. (2021). Neuroimaging manifestations in children with SARS-CoV-2 infection: a multinational, multicentre collaborative study. Lancet Child Adolesc Health. 5(3): 167-177.
Lin X, Wang Y, Li X et. al. (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; PMid:37602239 PMCid:PMC10433176
Li Q, Wang R, Xu H et. al. (2023). Epidemiology and Disease Burden of Hospitalized Children With Viral Central Nervous System Infections in China, 2016 to 2020. Pediatr Neurol. 138: 38-44. https://doi.org/10.1016/j.pediatrneurol.2022.09.003; PMid:36356470
Liu JJ, Teng LP, Hua CZ et. al. (2022). Etiological Analysis of Viral Encephalitis in Children in Zhejiang Province from 2018 to 2019. Diagnostics (Basel). 12(8): 1964. https://doi.org/10.3390/diagnostics12081964; PMid:36010314 PMCid:PMC9407060
Mangat R, Louie T. (2023). Arbovirus Encephalitides. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. PMID: 32809701.
Mansfield KL, Parekh I, Rasmussen TB et.al. (2025). European Preparedness for Japanese Encephalitis Virus Through Alignment of Animal Health Laboratory Diagnosis. Transbound Emerg Dis. 2025: 5516160. https://doi.org/10.1155/tbed/5516160; PMid:40529624 PMCid:PMC12173556
Marvik Å, Ravn LM, Randby H et. al. (2023). Tick-borne encephalitis in children. Tidsskr Nor Laegeforen. 143(14). https://doi.org/10.4045/tidsskr.23.0222
Messacar K, Fischer M, Dominguez SR et. al. (2018). Encephalitis in US Children. Infect Dis Clin North Am. 32(1): 145-162. https://doi.org/10.1016/j.idc.2017.10.007; PMid:29224854 PMCid:PMC5801071
Page MJ, McKenzie JE, Bossuyt PM et. al. (2021). The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 372: n71. https://doi.org/10.1136/bmj.n71; PMid:33782057 PMCid:PMC8005924
Park J-Y, Lee H-M. (2025). Managing Japanese Encephalitis Virus as a Veterinary Infectious Disease Through Animal Surveillance and One Health Control Strategies. Life. 15: 1260. https://doi.org/10.3390/life15081260; PMid:40868908 PMCid:PMC12387159
Perestiuk V, Kosovska T, Volianska L et. al. (2025). Prevalence and duration of clinical symptoms of pediatric long COVID: findings from a one-year prospective study. Front Pediatr. 13: 1645228. https://doi.org/10.3389/fped.2025.1645228; PMid:41059474 PMCid:PMC12499359
Quade A, Rostasy K, Wickström R et al. (2023). Autoimmune Encephalitis with Autoantibodies to NMDAR1 following Herpes Encephalitis in Children and Adolescents. Neuropediatrics. 54(1): 14-19. https://doi.org/10.1055/s-0042-1757706; PMid:36543183
Rozenberg F. (2020). Herpes simplex virus and central nervous system infections: encephalitis, meningitis, myelitis. Virologie (Montrouge). 24(5): 283-294. https://doi.org/10.1684/vir.2020.0862; PMid:33111702
Safavi M, Taghipour S, Vasei M. (2022). Evaluation of human bocavirus as well as other well-known viral etiologic agents by PCR in the cerebrospinal fluid of children with clinical impression of viral meningoencephalitis referred to the Children's Medical Center in Tehran, Iran, from 2019 to 2020. J MedVirol. 94(10): 4944-4949. https://doi.org/10.1002/jmv.27930; PMid:35689362
Sakuma H, Takanashi JI, Muramatsu K et al. (2023). Japanese Pediatric Neuro-COVID-19 Study Group. Severe pediatric acute encephalopathy syndromes related to SARS-CoV-2. Front Neurosci. 17: 1085082. https://doi.org/10.3389/fnins.2023.1085082; PMid:36922927 PMCid:PMC10008884
Sharma KB, Vrati S, Kalia M. (2021). Pathobiology of Japanese encephalitis virus infection. Mol Aspects Med. 81: 100994. https://doi.org/10.1016/j.mam.2021.100994; PMid:34274157
Sharma P, Parmar K, Datta A et al. (2025). Recent progress and challenges of acute encephalitis syndrome: an update on pathogenesis and interventional approaches. Brain Disorders. 19: 100267. https://doi.org/10.1016/j.dscb.2025.100267
Sun Z, Shi C, Jin L. (2024). Mechanisms by Which SARS-CoV-2 Invades and Damages the Central Nervous System: Apart from the Immune Response and Inflammatory Storm, What Else Do We Know? Viruses. 16(5): 663. https://doi.org/10.3390/v16050663; PMid:38793545 PMCid:PMC11125732
Takanashi J-I. (2025). Acute Encephalopathy in Childhood Associated With COVID-19, Journal of Tokyo Women's Medical University. 95(4): 103-108.
Valle DAD, Santos MLSF, Giamberardino HIG. (2020). Acute Childhood Viral Encephalitis in Southern Brazil. Pediatr Infect Dis J. 39(10): 894-898. https://doi.org/10.1097/INF.0000000000002709; PMid:32936599
Vannice KS, Hills SL, Schwartz LM et al. (2021). Japanese encephalitis vaccination experts panel. The future of Japanese encephalitis vaccination: expert recommendations for achieving and maintaining optimal JE control. NPJ Vaccines. 6(1): 82. https://doi.org/10.1038/s41541-021-00338-z; PMid:34131150 PMCid:PMC8206071
Vaysman T, Melkonyan A, Liu A. (2020). New onset of Bell's palsy in a patient with West Nile Encephalitis. Clin Case Rep. 8(10): 1895-1899. https://doi.org/10.1002/ccr3.3009; PMid:33088514 PMCid:PMC7562893
Venkatesan A, Michael BD, Probasco JC. et al. (2019). Acute encephalitis in immunocompetent adults. Lancet. 393(10172): 702-716. https://doi.org/10.1016/S0140-6736(18)32526-1; PMid:30782344
Venkatesan A, Tunkel AR, Bloch KC et al. (2013). International Encephalitis Consortium. Case definitions, diagnostic algorithms, and priorities in encephalitis: consensus statement of the international encephalitis consortium. Clin Infect Dis. 57(8): 1114-1128.
Vikse R, Paulsen KM, Edgar KS et al. (2020). Geographical distribution and prevalence of tick-borne encephalitis virus in questing Ixodes ricinus ticks and phylogeographic structure of the Ixodes ricinus vector in Norway. Zoonoses Public Health. 67(4): 370-381. https://doi.org/10.1111/zph.12696; PMid:32112526
Volianska LA, Burbela EI, Bugel LV et al. (2024). Acute necrotizing encephalitis caused by a viral duet. Modern Pediatrics. Ukraine. 4(140): 126-130. https://doi.org/10.15574/SP.2024.140.126
Wan Natrah WY, Lili HY, Maryam MZ. (2022). Child with cytomegalovirus associated acute demyelinating encephalomyelitis: a case report. Bangladesh Journal of Medical Science. 21(3): 749-753. https://doi.org/10.3329/bjms.v21i3.59594
Yang M, Yi L, Jia F et al. (2024). Characteristics and outcome of influenza-associated encephalopathy/encephalitis among children in China. Clinics (Sao Paulo). 79: 100475. https://doi.org/10.1016/j.clinsp.2024.100475; PMid:39096859 PMCid:PMC11345302
Zhao C, Wang Yu, Hou J et al. (2025). Mortality and Neurological Sequelae Among Children with COVID-19-associated Encephalopathy/encephalitis: A Multi-center, Retrospective Cohort Study with Long-term Follow-up. Pediatric Neurology. URL: https://www.pedneur.com/article/S0887-8994(25)00325-X/abstract. https://doi.org/10.1016/j.pediatrneurol.2025.10.024
Downloads
Published
Issue
Section
License
Copyright (c) 2025 Modern pediatrics. Ukraine

This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
The policy of the Journal “MODERN PEDIATRICS. UKRAINE” is compatible with the vast majority of funders' of open access and self-archiving policies. The journal provides immediate open access route being convinced that everyone – not only scientists - can benefit from research results, and publishes articles exclusively under open access distribution, with a Creative Commons Attribution-Noncommercial 4.0 international license (СС BY-NC).
Authors transfer the copyright to the Journal “MODERN PEDIATRICS. UKRAINE” when the manuscript is accepted for publication. Authors declare that this manuscript has not been published nor is under simultaneous consideration for publication elsewhere. After publication, the articles become freely available on-line to the public.
Readers have the right to use, distribute, and reproduce articles in any medium, provided the articles and the journal are properly cited.
The use of published materials for commercial purposes is strongly prohibited.