A case series of acute necrotizing encephalitis in children

A case series of acute necrotizing encephalitis in children | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report A case series of acute necrotizing encephalitis in children Grace Gombolay, Madeleine Hebert McLaughlin, Varun Kannan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6323005/v2 This work is licensed under a CC BY 4.0 License Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Abstract Acute necrotizing encephalitis (ANE) is a condition that can cause encephalopathy and seizures. ANE can occur in the presence of infection, especially influenza, or related to genetic causes, such as RANBP2 mutations. Characteristic radiographic features are symmetric cytotoxic lesions in thalamus and basal ganglia, with potential cavitation, necrosis, and hemorrhaged. ANE is associated with high mortality and poor neurological outcomes and disability. Here we present a case series of ANE at a single pediatric hospital to describe clinical features and outcomes. Critical Care & Emergency Medicine acute necrotizing encephalitis influenza acute disseminated encephalomyelitis Introduction Acute necrotizing encephalitis (ANE) is a condition that can cause encephalopathy and seizures. ANE can occur in the presence of infection, especially influenza, or related to genetic causes, such as RANBP2 mutations. Characteristic radiographic features are symmetric cytotoxic lesions in thalamia and basal ganglia, with potential cavitation, necrosis, and hemorrhaged. ANE is associated with high mortality and poor neurological outcomes and disability. Here we present a case series of ANE at a single pediatric hospital to describe clinical features and outcomes. Methods A retrospective chart review was performed at a single children’s hospital. Children who presented with ANE between October 1, 2022 to May 1, 2025 were included in the study. We report on demographic and ancillary test features, including whether the children had influenza or suspected influenza and genetic test results. Consent was waived for this study, but IRB approval was obtained. Results Three children were diagnosed with ANE and had confirmed influenza at the time of presentation. They were 16 months, 12 years and 16 years old at time of onset. All patients had fevers and seizures. Lab abnormalities are noted in Table 2, but only one patient had CSF pleocytosis. Genetic testing was unrevealing. Brain MRI features included multifocal bilateral T2 hyperintense and diffusion restricting lesions. Enhancement was noted in two of three patients (Table 3). EEG features included slowing, epileptiform discharges – both focal and generalized, and electrographic seizures (Table 3). Treatments included steroids, IVIG, and plasmapheresis (Table 4). At time of the last follow up, two had mild spasticity and improved language, whereas one patient still had severe spasticity and poor communication skills (Table 5). Discussion ANE can be a devastating neurological condition, often associated with influenza or genetic etiologies, although sometimes the cause is unknown. Some proposed cases include systemic inflammation and cytokine storming in response to infection. 1 Rates of encephalopathy/encephalitis has been noted in 18/513 (3.5%) of children hospitalized with influenza, though only 3/513 (0.6%) developed ANE. 2 In a multicenter study in France from 2010–2018, 41 children were diagnosed with influenza associated encephalopathy/encephalitis, with one-third having ANE. Treatments were variable with 49% of patients receiving steroids. 17% died during hospitalization and by time of hospital discharge, 49% had neurological deficits and 27% had severe outcomes, as defined by a modified Rankin Score 4 or greater. 3 Higher rates of hemorrhage are noted in influenza positive patients, and more likely to have diffusion restriction. 4 ALT was also noted to be elevated in those with encephalopathy. 5 While rare, ANE can have severe neurological outcomes. Clinicians and the community should be aware about ANE, its association with influenza, and appropriate testing and management. Declarations Conflicts of interest: MHM and VK: none GG: part time salary support from the CDC for acute flaccid myelitis case review References Shukla P, Mandalla A, Elrick MJ, Venkatesan A (2021) Clinical Manifestations and Pathogenesis of Acute Necrotizing Encephalopathy: The Interface Between Systemic Infection and Neurologic Injury. Front Neurol 12:628811. 10.3389/fneur.2021.628811 Fang Y, Gao Q, Jin W et al (2023) Clinical characteristics and prognostic analysis of acute necrotizing encephalopathy of childhood: a retrospective study at a single center in China over 3 years. Front Neurol 14:1308044. 10.3389/fneur.2023.1308044 Cleuziou P, Renaldo F, Renolleau S et al (2021) Mortality and Neurologic Sequelae in Influenza-Associated Encephalopathy: Retrospective Multicenter PICU Cohort in France. Pediatr Crit Care Med Nov 1(11):e582–e587. 10.1097/PCC.0000000000002750 Chatur N, Yea C, Ertl-Wagner B, Yeh EA (2022) Outcomes in influenza and RANBP2 mutation-associated acute necrotizing encephalopathy of childhood. Dev Med Child Neurol Aug 64(8):1008–1016. 10.1111/dmcn.15165 Zhang R, Wen J, Wu K et al (2023) Influenza-associated neurologic complications in children from an H3N2 outbreak in Shenzhen, China during COVID-19 lockdown. Int J Infect Dis Sep 134:91–94. 10.1016/j.ijid.2023.05.064 Tables Tables are available in the supplementary files. Additional Declarations The authors declare no competing interests. Supplementary Files Tables.docx Cite Share Download PDF Status: Posted Version 2 posted You are reading this latest preprint version Show more versions Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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ANE can occur in the presence of infection, especially influenza, or related to genetic causes, such as RANBP2 mutations. Characteristic radiographic features are symmetric cytotoxic lesions in thalamia and basal ganglia, with potential cavitation, necrosis, and hemorrhaged. ANE is associated with high mortality and poor neurological outcomes and disability. Here we present a case series of ANE at a single pediatric hospital to describe clinical features and outcomes.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eA retrospective chart review was performed at a single children\u0026rsquo;s hospital. Children who presented with ANE between October 1, 2022 to May 1, 2025 were included in the study. We report on demographic and ancillary test features, including whether the children had influenza or suspected influenza and genetic test results. Consent was waived for this study, but IRB approval was obtained.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eThree children were diagnosed with ANE and had confirmed influenza at the time of presentation. They were 16 months, 12 years and 16 years old at time of onset. All patients had fevers and seizures. Lab abnormalities are noted in Table 2, but only one patient had CSF pleocytosis. Genetic testing was unrevealing.\u003c/p\u003e\n\u003cp\u003eBrain MRI features included multifocal bilateral T2 hyperintense and diffusion restricting lesions. Enhancement was noted in two of three patients (Table 3). EEG features included slowing, epileptiform discharges – both focal and generalized, and electrographic seizures (Table 3). Treatments included steroids, IVIG, and plasmapheresis (Table 4). At time of the last follow up, two had mild spasticity and improved language, whereas one patient still had severe spasticity and poor communication skills (Table 5).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eANE can be a devastating neurological condition, often associated with influenza or genetic etiologies, although sometimes the cause is unknown. Some proposed cases include systemic inflammation and cytokine storming in response to infection.\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e Rates of encephalopathy/encephalitis has been noted in 18/513 (3.5%) of children hospitalized with influenza, though only 3/513 (0.6%) developed ANE.\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eIn a multicenter study in France from 2010\u0026ndash;2018, 41 children were diagnosed with influenza associated encephalopathy/encephalitis, with one-third having ANE. Treatments were variable with 49% of patients receiving steroids. 17% died during hospitalization and by time of hospital discharge, 49% had neurological deficits and 27% had severe outcomes, as defined by a modified Rankin Score 4 or greater.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Higher rates of hemorrhage are noted in influenza positive patients, and more likely to have diffusion restriction.\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e ALT was also noted to be elevated in those with encephalopathy.\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e \u003cp\u003eWhile rare, ANE can have severe neurological outcomes. Clinicians and the community should be aware about ANE, its association with influenza, and appropriate testing and management.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e \u003ch2\u003eConflicts of interest:\u003c/h2\u003e \u003cp\u003eMHM and VK: none\u003c/p\u003e\n\u003cp\u003eGG: part time salary support from the CDC for acute flaccid myelitis case review\n\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eShukla P, Mandalla A, Elrick MJ, Venkatesan A (2021) Clinical Manifestations and Pathogenesis of Acute Necrotizing Encephalopathy: The Interface Between Systemic Infection and Neurologic Injury. Front Neurol 12:628811. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fneur.2021.628811\u003c/span\u003e\u003cspan address=\"10.3389/fneur.2021.628811\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eFang Y, Gao Q, Jin W et al (2023) Clinical characteristics and prognostic analysis of acute necrotizing encephalopathy of childhood: a retrospective study at a single center in China over 3 years. Front Neurol 14:1308044. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.3389/fneur.2023.1308044\u003c/span\u003e\u003cspan address=\"10.3389/fneur.2023.1308044\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCleuziou P, Renaldo F, Renolleau S et al (2021) Mortality and Neurologic Sequelae in Influenza-Associated Encephalopathy: Retrospective Multicenter PICU Cohort in France. Pediatr Crit Care Med Nov 1(11):e582\u0026ndash;e587. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1097/PCC.0000000000002750\u003c/span\u003e\u003cspan address=\"10.1097/PCC.0000000000002750\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eChatur N, Yea C, Ertl-Wagner B, Yeh EA (2022) Outcomes in influenza and RANBP2 mutation-associated acute necrotizing encephalopathy of childhood. Dev Med Child Neurol Aug 64(8):1008\u0026ndash;1016. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1111/dmcn.15165\u003c/span\u003e\u003cspan address=\"10.1111/dmcn.15165\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eZhang R, Wen J, Wu K et al (2023) Influenza-associated neurologic complications in children from an H3N2 outbreak in Shenzhen, China during COVID-19 lockdown. Int J Infect Dis Sep 134:91\u0026ndash;94. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003e10.1016/j.ijid.2023.05.064\u003c/span\u003e\u003cspan address=\"10.1016/j.ijid.2023.05.064\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables are available in the supplementary files.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Emory University School of Medicine","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"acute necrotizing encephalitis, influenza, acute disseminated encephalomyelitis","lastPublishedDoi":"10.21203/rs.3.rs-6323005/v2","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6323005/v2","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eAcute necrotizing encephalitis (ANE) is a condition that can cause encephalopathy and seizures. ANE can occur in the presence of infection, especially influenza, or related to genetic causes, such as RANBP2 mutations. Characteristic radiographic features are symmetric cytotoxic lesions in thalamus and basal ganglia, with potential cavitation, necrosis, and hemorrhaged. ANE is associated with high mortality and poor neurological outcomes and disability. Here we present a case series of ANE at a single pediatric hospital to describe clinical features and outcomes.\u003c/p\u003e","manuscriptTitle":"A case series of acute necrotizing encephalitis in children","msid":"","msnumber":"","nonDraftVersions":[{"code":2,"date":"2025-06-03 15:44:02","doi":"10.21203/rs.3.rs-6323005/v2","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}},{"code":1,"date":"2025-03-28 08:08:40","doi":"10.21203/rs.3.rs-6323005/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"ad93c6a1-2c71-4697-96e3-56271429ebd0","owner":[],"postedDate":"June 3rd, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":46342610,"name":"Critical Care \u0026 Emergency Medicine"}],"tags":[],"updatedAt":"2025-03-28T08:08:40+00:00","versionOfRecord":[],"versionCreatedAt":"2025-06-03 15:44:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v2","identity":"rs-6323005","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6323005","identity":"rs-6323005","version":["v2"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}