Beyond The Usual – Infection Triggered Encephalopathy Syndromes (ITES) In Children
Main Article Content
Abstract
Infections of the central nervous system have significant long-term morbidity and mortality in the paediatric population in both developing and developed countries. One of the dreaded presentations seen in children is that of acute febrile encephalopathy that is triggered by infectious or non-infectious agents. The COVID 19/SARS-CoV pandemic gave us newer insights into the role of immune dysregulation that is triggered by an antecedent infection. Since then, multiple new terminologies have been defined based on imaging characteristics in children presenting with acute encephalopathy. This is now collectively termed as infection triggered encephalopathy syndrome (ITES). This review looks at the expanding spectrum of infective conditions of the CNS in children and how early differentiation of the various conditions can impact the management and overall clinical outcome.
Keywords:
Central nervous system, infections, artificial intelligence, MRI patterns, ITES
Article Details
How to Cite
CHOUDHURY, Prerna.
Beyond The Usual – Infection Triggered Encephalopathy Syndromes (ITES) In Children.
Medical Research Archives, [S.l.], v. 13, n. 7, july 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6828>. Date accessed: 05 dec. 2025.
doi: https://doi.org/10.18103/mra.v13i7.6828.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
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29. Takanashi J, Imamura A, Hayakawa F, Terada H. Differences in the time course of splenial and white matter lesions in clinically mild encephalitis/ encephalopathy with a reversible splenial lesion (MERS). J Neurol Sci. 2010 May 15;292(1-2):24-7. doi: 10.1016/j.jns.2010.02.013. Epub 2010 Mar 16. PMID: 20236662.
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31. Shein SL, Ferguson NM, et al. Effectiveness of Pharmacological Therapies for Intracranial Hypertension in Children with Severe Traumatic Brain Injury--Results From an Automated Data Collection System Time-Synched to Drug Administration. Pediatr Crit Care Med. 2016 Mar;17(3):236-45. doi: 10.1097/PCC.0000000000000610. PMID: 26673840; PMCID: PMC4779724.
32. Horino A, Kuki I, et al. Intrathecal dexamethasone therapy for febrile infection-related epilepsy syndrome. Ann Clin Transl Neurol. 2021 Mar;8(3):645-655. doi: 10.1002/acn3.51308. Epub 2021 Feb 5. PMID: 33547757; PMCID: PMC7951105.
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36. Angel A S, Roshan H, Alicia G M, et al. Anakinra and tocilizumab in the chronic phase of febrile infection-related epilepsy syndrome (FIRES): Effectiveness and safety from a case-series,Seizure: European Journal of Epilepsy,Volume 100,2022,Pages 51-55,ISSN 1059-1311. https://doi.org/10.1016/j.seizure.2022.06.012.
37. Imataka G, Fujita Y, Kikuchi J, et al. Brain Hypothermia Therapy and Targeted Temperature Management for Acute Encephalopathy in Children: Status and Prospects. Journal of Clinical Medicine. 2023; 12(6):2095. https://doi.org/10.3390/jcm12062095
38. Fujita, Y.; Imataka, G.; Kikuchi, J.; Yoshihara, S. Successful mild brain hypothermia therapy followed by targeted temperature management for pediatric hemorrhagic shock and encephalopathy syndrome. Eur. Rev. Med. Pharm. Sci.2021,25, 3002–3006. [Google Scholar]
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40. Gombolay GY, Gopalan N, Bernasconi A, et al. Review of Machine Learning and Artificial Intelligence (ML/AI) for the Pediatric Neurologist. Pediatr Neurol. 2023 Apr;141:42-51. doi: 10.1016/j.pediatrneurol.2023.01.004. Epub 2023 Jan 13. PMID: 36773406; PMCID: PMC10040433.
41. Peng J, Kim DD, Patel JB, et al. Deep learning-based automatic tumor burden assessment of pediatric high-grade gliomas, medulloblastomas, and other leptomeningeal seeding tumors. Neuro Oncol. 2022;24(2):289–299
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2. Erkkinen MG, Berkowitz AL. A Clinical Approach to Diagnosing Encephalopathy. Am J Med. 2019 Oct;132(10):1142-1147. doi: 10.1016/j.amjmed.2019.07.001. Epub 2019 Jul 19. PMID: 31330129. –
3. Imataka G, Kuwashima S, Yoshihara S. A Comprehensive Review of Pediatric Acute Encephalopathy. J Clin Med. 2022 Oct 7;11(19):5921. doi: 10.3390/jcm11195921. PMID: 36233788; PMCID: PMC9570744.
4. Rossor T, Lim M. Immune-mediated encephalitis. Dev Med Child Neurol. 2024 Mar;66(3):307-316. doi: 10.1111/dmcn.15694. Epub 2023 Jul 12. PMID: 37438863.
5. Wunrow, Han Yong et al. Global, regional, and national burden of meningitis and its aetiologies, 1990–2019: a systematic analysis for the Global Burden of Disease Study 2019, The Lancet Neurology, Volume 22, Issue 8, 685 – 711
6. Bokade C, Gulhane R, Bagul A, Thakre S. Acute febrile encephalopathy in children and predictors of mortality. J Clin Diagn Res. 2014 Aug;8(8):PC09-11. doi: 10.7860/JCDR/2014/9115.4686. Epub 2014 Aug 20. PMID: 25302241; PMCID: PMC4190766.
7. Damodar T, Singh B, Prabhu N, Marate S, et al. Association of Scrub Typhus in Children with Acute Encephalitis Syndrome and Meningoencephalitis, Southern India. Emerg Infect Dis. 2023 Apr;29(4):711-722. doi: 10.3201/eid2904.221157. PMID: 36957990; PMCID: PMC10045701.
8. Choudhury P, Mohanty S, Reddy Y, Reddy N. A Rare Case of Listeria Meningitis with Spinal Involvement. Pediatr Infect Dis J. 2023 Dec 1;42(12):e498-e499. doi: 10.1097/INF.0000000000004100. Epub 2023 Oct 11. PMID: 37851965.
9. Susanna E, Giovanni A, Alberto A, et al. Autoimmune encephalitis after herpes simplex encephalitis: A still undefined condition, Autoimmunity Reviews, Volume 21, Issue 12, 2022, 103187, ISSN 1568-9972, https://doi.org/10.1016/j.autrev.2022.103187.
10. Sakuma H, Thomas T, Debinski C, et al. International consensus definitions for infection-triggered encephalopathy syndromes. Dev Med Child Neurol. 2025 Feb;67(2):195-207. doi: 10.1111/dmcn.16067. Epub 2024 Aug 14. PMID: 39143740; PMCID: PMC11695768.
11. Masashi M, Takashi I, George I, et al. Guidelines for the diagnosis and treatment of acute encephalopathy in childhood, Brain and Development, Volume 43, Issue 1,2021,Pages 2-31, ISSN 0387-7604, https://doi.org/10.1016/j.braindev.2020.08.001.
12. Barron S, Han V, Gupta J, et al. Dengue-Associated Acute Necrotizing Encephalopathy Is an Acute Necrotizing Encephalopathy Variant Rather than a Mimic: Evidence From a Systematic Review, Pediatric Neurology, Volume 161, 2024, Pages 208-215, ISSN 0887- 994. https://doi.org/10.1016/j.pediatrneurol.2024.09.021.
13. Levine JM, Ahsan N, Ho E, Santoro JD. Genetic Acute Necrotizing Encephalopathy Associated with RANBP2: Clinical and Therapeutic Implications in Pediatrics. Mult Scler Relat Disord. 2020 Aug;43:102194. doi: 10.1016/j.msard.2020.102194. Epub 2020 May 15. PMID: 32426208; PMCID: PMC7228726.
14. Kurahashi, H., Azuma, Y., Masuda, A., Okuno, T., Nakahara, E., Imamura, T., et al. (2018). MYRF is associated with encephalopathy with reversible myelin vacuolization. Ann. Neurol. 83, 98–106. doi: 10.1002/ana.25125.
15. Gaudenzi G, Kumbakumba E, Rasti R, et al. Point-of-Care Approaches for Meningitis Diagnosis in a Low-Resource Setting (Southwestern Uganda): Observational Cohort Study Protocol of the "PI-POC" Trial. JMIR Res Protoc. 2020 Nov 4;9(11):e21430. doi: 10.2196/21430. PMID: 33146628; PMCID: PMC7690656.
16. Rasti, R., Kumbakumba, E., Nanjebe, D. et al. Clinical utility of the FilmArray® meningitis/encephalitis panel in children with suspected central nervous system infection in a low-resource setting – a prospective study in Southwestern Uganda. BMC Infect Dis 25, 396 (2025). https://doi.org/10.1186/s12879-025-10732-w
17. O’Brien, Matthew P, et al. Impact of Cerebrospinal Fluid Multiplex Assay on Diagnosis and Outcomes of Central Nervous System Infections in Children: A Before and After Cohort Study. The Pediatric Infectious Disease Journal 37(9):p 868-871, September 2018. | Doi: 10.1097/INF.0000000000001936
18. He, S., Xiong, Y., Tu, T. et al. Diagnostic performance of metagenomic next-generation sequencing for the detection of pathogens in cerebrospinal fluid in pediatric patients with central nervous system infection: a systematic review and meta-analysis. BMC Infect Dis 24, 103 (2024). https://doi.org/10.1186/s12879-024-09010-y
19. Li X, Yang L, Li D et al.Diagnosis of Neurological Infections in Pediatric Patients from Cell-Free DNA Specimens by Using Metagenomic Next-Generation Sequencing. Microbiol Spectr11 2023: e02530-22. https://doi.org/10.1128/spectrum.02530-22
20. Yuan, L., Zhu, X.Y., Lai, L.M. et al. Clinical application and evaluation of metagenomic next-generation sequencing in pathogen detection for suspected central nervous system infections. Sci Rep 14, 16961 (2024). https://doi.org/10.1038/s41598-024-68034-1
21. Uematsu K, Matsumoto H, Zaha K, et al. Prediction and assessment of acute encephalopathy syndromes immediately after febrile status epilepticus. Brain Dev. 2023 Feb;45(2):93-101. doi: 10.1016/j.braindev.2022.10.004. Epub 2022 Oct 31. PMID: 36328834.
22. Tada H, Takanashi J, Okuno H, et al. Predictive score for early diagnosis of acute encephalopathy with biphasic seizures and late reduced diffusion (AESD), Journal of the Neurological Sciences, Volume 358, Issues 1–2, 2015, Pages 62-65, ISSN 0022-510X, https://doi.org/10.1016/j.jns.2015.08.016.
23. Takanashi J, Tada H, Maeda M, et al. Encephalopathy with a reversible splenial lesion is associated with hyponatremia. Brain Dev 2009;31:217–20
24. Tomioka K, Nishiyama M, Tokumoto S, et al. Time course of serum cytokine level changes within 72 h after onset in children with acute encephalopathy and febrile seizures. BMC Neurol. 2023 Jan 7;23(1):7. doi: 10.1186/s12883-022-03048-8. PMID: 36609211; PMCID: PMC9824967.
25. Dale RC, Thomas T, Patel S, et al. CSF neopterin and quinolinic acid are biomarkers of neuroinflammation and neurotoxicity in FIRES and other infection-triggered encephalopathy syndromes. Ann Clin Transl Neurol. 2023 Aug;10(8):1417-1432. doi: 10.1002/acn3.51832. Epub 2023 Jun 20. PMID: 37340737; PMCID: PMC10424664.
26. Triulzi, F., Doneda, C., & Parazzini, C. Neuroimaging of pediatric brain infections. Expert Review of Anti-infective Therapy. 2011; 9. https://doi.org/10.1586/eri.11.38.
27. . Maheswarappa RP, Agarwal C, Bansal J. Tuberculoma versus neurocysticercosis: can Magnetic resonance Spectroscopy and Diffusion Weighted Imaging solve the diagnostic conundrum? Original article. Journal of Clinical and Diagnostic Research. 2019 Jun, Vol-13(6): TC01-TC06 doi: 10.7860/JCDR/2019/41334.12957
28. Kamate M. Acute Leukoencephalopathy with Restricted Diffusion. Indian J Crit Care Med. 2018 Jul;22(7):519-523. doi: 10.4103/ijccm.IJCCM_ 139_18. PMID: 30111927; PMCID: PMC6069315.
29. Takanashi J, Imamura A, Hayakawa F, Terada H. Differences in the time course of splenial and white matter lesions in clinically mild encephalitis/ encephalopathy with a reversible splenial lesion (MERS). J Neurol Sci. 2010 May 15;292(1-2):24-7. doi: 10.1016/j.jns.2010.02.013. Epub 2010 Mar 16. PMID: 20236662.
30. Rameshkumar R, Bansal A, Singhi S, et al. Randomized Clinical Trial of 20% Mannitol Versus 3% Hypertonic Saline in Children With Raised Intracranial Pressure Due to Acute CNS Infections. Pediatr Crit Care Med. 2020 Dec;21(12):1071-1080. doi: 10.1097/PCC. 0000000000002557. PMID: 33003179.
31. Shein SL, Ferguson NM, et al. Effectiveness of Pharmacological Therapies for Intracranial Hypertension in Children with Severe Traumatic Brain Injury--Results From an Automated Data Collection System Time-Synched to Drug Administration. Pediatr Crit Care Med. 2016 Mar;17(3):236-45. doi: 10.1097/PCC.0000000000000610. PMID: 26673840; PMCID: PMC4779724.
32. Horino A, Kuki I, et al. Intrathecal dexamethasone therapy for febrile infection-related epilepsy syndrome. Ann Clin Transl Neurol. 2021 Mar;8(3):645-655. doi: 10.1002/acn3.51308. Epub 2021 Feb 5. PMID: 33547757; PMCID: PMC7951105.
33. Wagner, J.N., Leibetseder, A., Troescher, A. et al. Efficacy and safety of intravenous immunoglobulins for the treatment of viral encephalitis: a systematic literature review. J Neurol 269, 712–724 (2022). https://doi.org/10.1007/s00415-021-10494-w
34. Lee WJ, Lee ST, Moon J,et al. Tocilizumab in Autoimmune Encephalitis Refractory to Rituximab: An Institutional Cohort Study. Neurotherapeutics. 2016 Oct;13(4):824-832. doi: 10.1007/s13311-016-0442-6. PMID: 27215218; PMCID: PMC5081109.
35. Lai YC, Muscal E, Wells E, et al. Anakinra usage in febrile infection related epilepsy syndrome: an international cohort. Ann Clin Transl Neurol. 2020 Dec;7(12):2467-2474. doi: 10.1002/acn3.51229. Epub 2020 Dec 4. PMID: 33506622; PMCID: PMC7732241.
36. Angel A S, Roshan H, Alicia G M, et al. Anakinra and tocilizumab in the chronic phase of febrile infection-related epilepsy syndrome (FIRES): Effectiveness and safety from a case-series,Seizure: European Journal of Epilepsy,Volume 100,2022,Pages 51-55,ISSN 1059-1311. https://doi.org/10.1016/j.seizure.2022.06.012.
37. Imataka G, Fujita Y, Kikuchi J, et al. Brain Hypothermia Therapy and Targeted Temperature Management for Acute Encephalopathy in Children: Status and Prospects. Journal of Clinical Medicine. 2023; 12(6):2095. https://doi.org/10.3390/jcm12062095
38. Fujita, Y.; Imataka, G.; Kikuchi, J.; Yoshihara, S. Successful mild brain hypothermia therapy followed by targeted temperature management for pediatric hemorrhagic shock and encephalopathy syndrome. Eur. Rev. Med. Pharm. Sci.2021,25, 3002–3006. [Google Scholar]
39. Kessi M, Liu F, Zhan Y et al (2020) Efficacy of different treatment modalities for acute and chronic phases of the febrile infection-related epilepsy syndrome: a systematic review. Seizure 79:61–68
40. Gombolay GY, Gopalan N, Bernasconi A, et al. Review of Machine Learning and Artificial Intelligence (ML/AI) for the Pediatric Neurologist. Pediatr Neurol. 2023 Apr;141:42-51. doi: 10.1016/j.pediatrneurol.2023.01.004. Epub 2023 Jan 13. PMID: 36773406; PMCID: PMC10040433.
41. Peng J, Kim DD, Patel JB, et al. Deep learning-based automatic tumor burden assessment of pediatric high-grade gliomas, medulloblastomas, and other leptomeningeal seeding tumors. Neuro Oncol. 2022;24(2):289–299
42. Yildiz I, Garner R, Lai M, Duncan D. Unsupervised seizure identification on EEG. Comput Methods Programs Biomed. 2022;215:106604.
43. Megerian JT, Dey S, Melmed RD, et al. Evaluation of an artificial intelligence-based medical device for diagnosis of autism spectrum disorder. NPJ Digit Med. 2022;5(1):57.