Varicella Zoster Virus as a trigger for Multiple Sclerosis

Varicella Zoster Virus as a trigger for Multiple Sclerosis | 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 Case Report Varicella Zoster Virus as a trigger for Multiple Sclerosis Ece Onel, Yusuf Kenan Cetinoglu, Unsal Yılmaz This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8841242/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 5 You are reading this latest preprint version Abstract Multiple sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system, with environmental factors potentially triggering disease in susceptible individuals. Although a link between varicella-zoster virus (VZV) and MS onset has been suggested, the association remains inconclusive. We report a previously healthy 17-year-old girl who presented with mild headache and a three-day history of vesicular lesions consistent with varicella. Initial neurological examination and brain MRI were normal. Due to persistent headache and development of hand numbness, follow-up brain and spinal MRI two months later revealed multiple demyelinating lesions in the periventricular and pericallosal white matter, optic nerve, and cervical and thoracic spinal cord, with gadolinium enhancement. Cerebrospinal fluid analysis demonstrated type 2 oligoclonal bands and elevated IgG index (0.67). Serum VZV serology showed positive IgG and elevated IgM (42.6 AU/mL), consistent with recent infection or reactivation. The patient fulfilled the revised 2024 McDonald criteria and was diagnosed with MS. She received intravenous methylprednisolone, achieved complete clinical recovery, and was started on dimethyl fumarate. This case supports a potential role of VZV as a trigger for MS onset. Multiple sclerosis demyelinating varicella zoster virus varicella immune-mediated multiple sclerosis triggers Figures Figure 1 Figure 2 INTRODUCTION Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system (CNS), characterized by focal lymphocytic infiltration leading to demyelination, axonal injury, and a wide spectrum of neurological deficits.(Compston & Coles, 2008 ) Although the precise etiopathogenesis of MS is not fully understood, increasing evidence suggests that disease onset involves interactions between genetic susceptibility and environmental factors resulting in immune dysregulation and chronic neuroinflammation within the CNS.(Ascherio, 2013 ) Viral infections have been suggested as potential environmental triggers of MS, possibly through immune-mediated mechanisms such as molecular mimicry and bystander activation. Varicella-zoster virus (VZV) is a highly neurotropic herpesvirus capable of establishing latency within sensory ganglia and inducing both direct neuronal injury and sustained immune activation.(Sotelo, 2007 ) Although VZV has not been proven to cause MS, several case reports describe a temporal association between VZV infection and MS onset, suggesting a possible triggering role in susceptible individuals.(Shiba et al., 2018 )(Rosener et al., 1995 ) (Wurdack et al., 2024 )Here, we report a pediatric MS case with a close temporal relationship to VZV infection, supporting a possible triggering role of VZV in childhood MS. CASE PRESENTATION A previously well 17-year-old girl presented with a mild-intensity, non-migrainous headache (NRS 2–3/10) without focal neurological symptoms. She had a three-day history of varicella, characterized by successive crops of pruritic vesicular lesions involving the skin and mucous membranes, accompanied by mild fever and malaise. (Fig. 1 ) Neurological examination and vital signs were normal for age. There was no relevant family history, and development was age appropriate. Brain MRI performed at the onset of neurological symptoms was unremarkable. (Fig. 2 A) Due to persistent headache and the development of hand numbness, brain and spinal MRI were repeated two months later. Brain MRI demonstrated multiple supratentorial FLAIR-hyperintense lesions in a periventricular and pericallosal distribution, perpendicular to the lateral ventricles. The largest lesion measured 7 mm, with an additional millimetric lesion adjacent to the left temporal horn. A 7 mm T2-hyperintense lesion was identified in the intraorbital segment of the left optic nerve (Fig. 2 B). Post-contrast images showed focal gadolinium enhancement in the bilateral peritrigonal white matter. Spinal MRI revealed multiple scattered short-segment T2-hyperintense lesions across the cervical, thoracic, and lumbar spinal cord (Fig. 2 C–D), including enhancing lesions at C2–C3 (7 mm, mild cord expansion) and T9–T10 (15 mm). Complete blood count and serum biochemistry were within normal limits, with no evidence of active infection, metabolic disturbance, or systemic autoimmune disease. Cerebrospinal fluid (CSF) analysis showed mild lymphocytic pleocytosis (17 lymphocytes/µL) with normal protein levels (25.6 mg/dL). CSF culture and multiplex polymerase chain reaction testing for bacterial and viral pathogens, including HSV-1/2, enterovirus, CMV, HHV-6, and VZV, were negative. Oligoclonal band analysis by isoelectric focusing demonstrated type 2 positivity, with an elevated IgG index (0.67; reference range 0.2–0.6). Serum anti–myelin oligodendrocyte glycoprotein antibodies and Borrelia burgdorferi IgM/IgG were negative. In contrast, serum varicella-zoster virus serology showed positive IgG with markedly elevated IgM levels (42.6 AU/mL; reference < 9 AU/mL), consistent with recent infection or reactivation. The patient met the revised 2024 McDonald criteria and was diagnosed with multiple sclerosis. She was treated with intravenous methylprednisolone (1 g/day for five days), with complete clinical recovery within one week, followed by initiation of dimethyl fumarate for maintenance therapy. VZV vaccination was not administered due to naturally acquired immunity. DISCUSSION Varicella-zoster virus (VZV) is a human-specific neurotropic alpha-herpesvirus responsible for varicella, predominantly observed in unvaccinated children.(Kennedy & Gershon, 2018 ) Such typical infection can, in rare cases, precede neurological complications, as illustrated here. The patient developed demyelinating lesions within two months following varicella infection, accompanied by positive serum VZV IgM and IgG but negative cerebrospinal fluid (CSF) VZV DNA. This pattern favors an immune-mediated mechanism rather than direct viral invasion of the CNS.(Min et al., 2016 ) Current pathogen-related hypotheses largely focus on molecular mimicry, whereby T-cell clones reactive to myelin basic protein (MBP 85–99) also recognize viral or bacterial peptides, potentially initiating or amplifying autoimmune responses against myelin.(Wucherpfennig & Strominger, 1995 ) Sustained CNS inflammation, mediated by epitope spreading, altered cytokine milieus, microglia and macrophage activation, complement-mediated injury, and ectopic B-cell follicle formation, ultimately leads to axonal loss, demyelination, gliosis, and neurodegeneration, underlying irreversible disability in MS.(Sedighi et al., 2023 ) Modifications of viral vaccines to remove specific T-cell epitopes have been proposed to reduce future MS risk.(Wucherpfennig & Strominger, 1995 ) Our patient, born in 2007, had not received the VZV vaccine, which was introduced into Turkey’s national immunization program in 2013. (Dinleyici et al., 2015 ) Several large population-based cohort studies have reported a significant coexistence of VZV exposure and MS, with higher VZV-IgG rates observed in regions where varicella is endemic and MS prevalence is relatively low, similar to the epidemiological context in our country.(Rice et al., 2021 ) In line with these findings, a large population study of over 300,000 herpes zoster cases reported an increased risk of MS development within one year following VZV reactivation.(Kang et al., 2011 ) Other cohort study has also demonstrated higher rates of primary varicella infection and increased serum VZV-IgG positivity in MS patients.(Manouchehrinia et al., 2017 ) In addition to population-level observations, individual case reports further support a temporal association between VZV exposure and MS onset. Perez-Cesari et al. described six patients aged 14–35 years who developed MS shortly after varicella infection or vaccination.(Perez-Cesari et al., 2005 ) An immunocompetent 10-year-old girl developed optic neuritis and MS within 10 weeks of prolonged VZV reactivation affecting the trigeminal nerve, while a 27-year-old male experienced a severe MS relapse shortly after varicella infection.(Shiba et al., 2018 )(Rosener et al., 1995 ) Another report describes a patient who sequentially developed VZV encephalitis, limbic autoimmune encephalitis, and multiple sclerosis, highlighting a possible continuum from viral infection to autoimmune CNS pathology and the importance of timely recognition for appropriate treatment. (Wurdack et al., 2024 ) Taken together, population-based studies, the single additional cohort, and individual case reports suggest that VZV may act a trigger for MS, consistent with the temporal sequence seen in our patient. This case highlights that VZV-induced immune activation can precipitate MS in susceptible individuals and underscores shared pathways linking viral infection to autoimmune demyelination. Declarations DECLARATION OF PATIENT CONSENT The authors certify that they have obtained all appropriate patient consent forms. In the form the patient and her parents have given her consent for her images and other clinical information to be reported in the journal. The patient and her parents understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. ACKNOWLEDGMENTS No financial support was received for this study. CONFLICT OF INTEREST None declared. Author Contribution E.O. and U.Y. wrote the main manuscript text and Y.K.C. prepared figures 1-2. All authors reviewed the manuscript. References Ascherio, A. (2013). Environmental factors in multiple sclerosis. Expert Review of Neurotherapeutics , 13 (sup2), 3–9. https://doi.org/10.1586/14737175.2013.865866 Compston, A., & Coles, A. (2008). Multiple sclerosis. The Lancet , 372 (9648), 1502–1517. https://doi.org/10.1016/S0140-6736(08)61620-7 Dinleyici, E. C., Kurugol, Z., Kara, A., Tezer, H., Tas, M. A., Guler, E., Yasa, O., Devrim, I., Ciftci, E., Ozdemir, H., Somer, A., Ozen, M., Sensoy, G., Dalgic, N., & Alhan, E. (2015). Children with breakthrough varicella infection requiring hospitalization in Turkey (VARICOMP Study 2008–2013). Vaccine , 33 (32), 3983–3987. https://doi.org/10.1016/j.vaccine.2015.06.029 Kang, J.-H., Sheu, J.-J., Kao, S., & Lin, H.-C. (2011). Increased Risk of Multiple Sclerosis Following Herpes Zoster: A Nationwide, Population-Based Study. The Journal of Infectious Diseases , 204 (2), 188–192. https://doi.org/10.1093/infdis/jir239 Kennedy, P. G. E., & Gershon, A. A. (2018). Clinical Features of Varicella-Zoster Virus Infection. Viruses , 10 (11), 609. https://doi.org/10.3390/v10110609 Manouchehrinia, A., Tanasescu, R., Kareem, H., Jerca, O. P., Jabeen, F., Shafei, R., Breuer, J., Neal, K., Irving, W., & Constantinescu, C. S. (2017). Prevalence of a history of prior varicella/herpes zoster infection in multiple sclerosis. Journal of NeuroVirology , 23 (6), 839–844. https://doi.org/10.1007/s13365-017-0569-1 Min, S.-W., Kim, Y. S., Nahm, F. S., Yoo, D. H., Choi, E., Lee, P.-B., Choo, H., Park, Z.-Y., & Yang, C. S. (2016). The positive duration of varicella zoster immunoglobulin M antibody test in herpes zoster. Medicine , 95 (33), e4616. https://doi.org/10.1097/MD.0000000000004616 Perez-Cesari, C., Saniger, M. M., & Sotelo, J. (2005). Frequent association of multiple sclerosis with varicella and zoster. Acta Neurologica Scandinavica , 112 (6), 417–419. https://doi.org/10.1111/j.1600-0404.2005.00491.x Rice, E. M., Thakolwiboon, S., & Avila, M. (2021). Geographic heterogeneity in the association of varicella-zoster virus seropositivity and multiple sclerosis: A systematic review and meta-analysis. Multiple Sclerosis and Related Disorders , 53 , 103024. https://doi.org/10.1016/j.msard.2021.103024 Rosener, M., Dichgans, J., Martin, R., & Harms, F. (1995). Chickenpox and multiple sclerosis: a case report. Journal of Neurology, Neurosurgery & Psychiatry , 58 (5), 637–638. https://doi.org/10.1136/jnnp.58.5.637-a Sedighi, S., Gholizadeh, O., Yasamineh, S., Akbarzadeh, S., Amini, P., Favakehi, P., Afkhami, H., Firouzi-Amandi, A., Pahlevan, D., Eslami, M., Yousefi, B., Poortahmasebi, V., & Dadashpour, M. (2023). Comprehensive Investigations Relationship Between Viral Infections and Multiple Sclerosis Pathogenesis. Current Microbiology , 80 (1), 15. https://doi.org/10.1007/s00284-022-03112-z Shiba, N., Inaba, Y., Motobayashi, M., Nishioka, M., Kawasaki, Y., Noda, S., Matsuura, H., Kobayashi, N., Matsuoka, T., Nakamura, A., & Nakazawa, Y. (2018). A Pediatric Case of Relapsing‐Remitting Multiple Sclerosis Onset following Varicella Zoster Ophthalmicus with Optic Neuritis. Case Reports in Pediatrics , 2018 (1). https://doi.org/10.1155/2018/6931206 Sotelo, J. (2007). On the viral hypothesis of multiple sclerosis: Participation of varicella-zoster virus. Journal of the Neurological Sciences , 262 (1–2), 113–116. https://doi.org/10.1016/j.jns.2007.07.001 Wucherpfennig, K. W., & Strominger, J. L. (1995). Molecular mimicry in T cell-mediated autoimmunity: Viral peptides activate human T cell clones specific for myelin basic protein. Cell , 80 (5), 695–705. https://doi.org/10.1016/0092-8674(95)90348-8 Wurdack, K., Prüss, H., & Finke, C. (2024). Evolution from viral encephalitis to autoimmune encephalitis to multiple sclerosis: a case report. Journal of Neurology , 271 (10), 7035–7038. https://doi.org/10.1007/s00415-024-12659-9 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Reviewers agreed at journal 12 Feb, 2026 Reviewers invited by journal 12 Feb, 2026 Editor assigned by journal 11 Feb, 2026 Submission checks completed at journal 11 Feb, 2026 First submitted to journal 10 Feb, 2026 You are reading this latest preprint version 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. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8841242","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Case Report","associatedPublications":[],"authors":[{"id":592369795,"identity":"71b131bb-636d-4b0d-b24a-b4606a368f84","order_by":0,"name":"Ece Onel","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA3ElEQVRIiWNgGAWjYDCCA2BSAoiZQUwJGVK0sCWAGDzEagEBHgMwSVAH3+3DBz98qLHI45995vOrGzUWPAzsh49uwKdF8lxasuSMYxLFEudyt1nnHAM6jCct7QY+LQZneMyYeRskEhvO8G4zzmEDapHgMSOghf8b81+glvlneJ4Z5/wjSgsPGzMjUMuGMzzMj3PbiNAieYbNWLLnmETixjNsZsy5fRI8bIT8wneG+eGHHzV1ifPOMD/+nPOtTo6f/fAxvFqQAZsEmCRWOQgwfyBF9SgYBaNgFIwcAAAGFEWP0Q3nvAAAAABJRU5ErkJggg==","orcid":"","institution":"University of Health Sciences, Dr. Behcet Uz Children’s Hospital, Department of Pediatric Neurology","correspondingAuthor":true,"prefix":"","firstName":"Ece","middleName":"","lastName":"Onel","suffix":""},{"id":592369796,"identity":"0d614cd9-70de-43a1-8421-2b3854d2cb28","order_by":1,"name":"Yusuf Kenan Cetinoglu","email":"","orcid":"","institution":"University of Health Sciences Turkey, Dr. Behcet Uz Children’s Hospital, Department of Radiology","correspondingAuthor":false,"prefix":"","firstName":"Yusuf","middleName":"Kenan","lastName":"Cetinoglu","suffix":""},{"id":592369797,"identity":"2d448ee2-9993-4a96-bf73-163aa46ce279","order_by":2,"name":"Unsal Yılmaz","email":"","orcid":"","institution":"University of Health Sciences, Dr. Behcet Uz Children’s Hospital, Department of Pediatric Neurology","correspondingAuthor":false,"prefix":"","firstName":"Unsal","middleName":"","lastName":"Yılmaz","suffix":""}],"badges":[],"createdAt":"2026-02-10 12:53:46","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8841242/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8841242/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":102910140,"identity":"61cdc050-dbbe-445a-bbe7-2c26a6c194c3","added_by":"auto","created_at":"2026-02-18 09:57:35","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":1421752,"visible":true,"origin":"","legend":"\u003cp\u003eThe typical skin rash of varicella-zoster virus (VZV) infection, consisting of pruritic, vesicular, and pustular lesions at various stages of evolution localized to the mandibular, periauricular, and malar regions.\u003c/p\u003e","description":"","filename":"Figure1.png","url":"https://assets-eu.researchsquare.com/files/rs-8841242/v1/6113a0d6ba02ccc2419341fb.png"},{"id":102910151,"identity":"5761428d-5b5f-41c4-83f5-7ffa43502437","added_by":"auto","created_at":"2026-02-18 09:57:39","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":3136051,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003e(A)\u003c/strong\u003eBrain magnetic resonance imaging (MRI), performed at the onset of her neurological symptoms, was completely unremarkable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(B)\u003c/strong\u003e At the two-month follow-up, brain MRI demonstrates the development of bilateral, patchy periventricular hyperintense lesions.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(C-D) \u003c/strong\u003eSagittal and axial T2-weighted cervical spinal MRI images show multiple short-segment, predominantly paramedian T2-hyperintense plaque-like lesions.\u003c/p\u003e","description":"","filename":"Figure2.png","url":"https://assets-eu.researchsquare.com/files/rs-8841242/v1/dde7ed3142f8e2c150657143.png"},{"id":102910246,"identity":"b15bb63b-d4c9-4a99-b565-24d33c52c506","added_by":"auto","created_at":"2026-02-18 09:58:04","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":8476313,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8841242/v1/930437b7-1390-4b36-abac-b9081806b536.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Varicella Zoster Virus as a trigger for Multiple Sclerosis","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eMultiple sclerosis (MS) is an immune-mediated inflammatory disease of the central nervous system (CNS), characterized by focal lymphocytic infiltration leading to demyelination, axonal injury, and a wide spectrum of neurological deficits.(Compston \u0026amp; Coles, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2008\u003c/span\u003e) Although the precise etiopathogenesis of MS is not fully understood, increasing evidence suggests that disease onset involves interactions between genetic susceptibility and environmental factors resulting in immune dysregulation and chronic neuroinflammation within the CNS.(Ascherio, \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2013\u003c/span\u003e) Viral infections have been suggested as potential environmental triggers of MS, possibly through immune-mediated mechanisms such as molecular mimicry and bystander activation. Varicella-zoster virus (VZV) is a highly neurotropic herpesvirus capable of establishing latency within sensory ganglia and inducing both direct neuronal injury and sustained immune activation.(Sotelo, \u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e2007\u003c/span\u003e) Although VZV has not been proven to cause MS, several case reports describe a temporal association between VZV infection and MS onset, suggesting a possible triggering role in susceptible individuals.(Shiba et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2018\u003c/span\u003e)(Rosener et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e1995\u003c/span\u003e) (Wurdack et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2024\u003c/span\u003e)Here, we report a pediatric MS case with a close temporal relationship to VZV infection, supporting a possible triggering role of VZV in childhood MS.\u003c/p\u003e"},{"header":"CASE PRESENTATION","content":"\u003cp\u003eA previously well 17-year-old girl presented with a mild-intensity, non-migrainous headache (NRS 2\u0026ndash;3/10) without focal neurological symptoms. She had a three-day history of varicella, characterized by successive crops of pruritic vesicular lesions involving the skin and mucous membranes, accompanied by mild fever and malaise. (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e) Neurological examination and vital signs were normal for age. There was no relevant family history, and development was age appropriate. Brain MRI performed at the onset of neurological symptoms was unremarkable. (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eA)\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDue to persistent headache and the development of hand numbness, brain and spinal MRI were repeated two months later. Brain MRI demonstrated multiple supratentorial FLAIR-hyperintense lesions in a periventricular and pericallosal distribution, perpendicular to the lateral ventricles. The largest lesion measured 7 mm, with an additional millimetric lesion adjacent to the left temporal horn. A 7 mm T2-hyperintense lesion was identified in the intraorbital segment of the left optic nerve (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eB). Post-contrast images showed focal gadolinium enhancement in the bilateral peritrigonal white matter. Spinal MRI revealed multiple scattered short-segment T2-hyperintense lesions across the cervical, thoracic, and lumbar spinal cord (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003eC\u0026ndash;D), including enhancing lesions at C2\u0026ndash;C3 (7 mm, mild cord expansion) and T9\u0026ndash;T10 (15 mm). Complete blood count and serum biochemistry were within normal limits, with no evidence of active infection, metabolic disturbance, or systemic autoimmune disease. Cerebrospinal fluid (CSF) analysis showed mild lymphocytic pleocytosis (17 lymphocytes/\u0026micro;L) with normal protein levels (25.6 mg/dL). CSF culture and multiplex polymerase chain reaction testing for bacterial and viral pathogens, including HSV-1/2, enterovirus, CMV, HHV-6, and VZV, were negative. Oligoclonal band analysis by isoelectric focusing demonstrated type 2 positivity, with an elevated IgG index (0.67; reference range 0.2\u0026ndash;0.6). Serum anti\u0026ndash;myelin oligodendrocyte glycoprotein antibodies and Borrelia burgdorferi IgM/IgG were negative. In contrast, serum varicella-zoster virus serology showed positive IgG with markedly elevated IgM levels (42.6 AU/mL; reference\u0026thinsp;\u0026lt;\u0026thinsp;9 AU/mL), consistent with recent infection or reactivation. The patient met the revised 2024 McDonald criteria and was diagnosed with multiple sclerosis. She was treated with intravenous methylprednisolone (1 g/day for five days), with complete clinical recovery within one week, followed by initiation of dimethyl fumarate for maintenance therapy. VZV vaccination was not administered due to naturally acquired immunity.\u003c/p\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eVaricella-zoster virus (VZV) is a human-specific neurotropic alpha-herpesvirus responsible for varicella, predominantly observed in unvaccinated children.(Kennedy \u0026amp; Gershon, \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2018\u003c/span\u003e) Such typical infection can, in rare cases, precede neurological complications, as illustrated here. The patient developed demyelinating lesions within two months following varicella infection, accompanied by positive serum VZV IgM and IgG but negative cerebrospinal fluid (CSF) VZV DNA. This pattern favors an immune-mediated mechanism rather than direct viral invasion of the CNS.(Min et al., \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e2016\u003c/span\u003e) Current pathogen-related hypotheses largely focus on molecular mimicry, whereby T-cell clones reactive to myelin basic protein (MBP 85\u0026ndash;99) also recognize viral or bacterial peptides, potentially initiating or amplifying autoimmune responses against myelin.(Wucherpfennig \u0026amp; Strominger, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e1995\u003c/span\u003e) Sustained CNS inflammation, mediated by epitope spreading, altered cytokine milieus, microglia and macrophage activation, complement-mediated injury, and ectopic B-cell follicle formation, ultimately leads to axonal loss, demyelination, gliosis, and neurodegeneration, underlying irreversible disability in MS.(Sedighi et al., \u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e2023\u003c/span\u003e) Modifications of viral vaccines to remove specific T-cell epitopes have been proposed to reduce future MS risk.(Wucherpfennig \u0026amp; Strominger, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e1995\u003c/span\u003e) Our patient, born in 2007, had not received the VZV vaccine, which was introduced into Turkey\u0026rsquo;s national immunization program in 2013. (Dinleyici et al., \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e2015\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eSeveral large population-based cohort studies have reported a significant coexistence of VZV exposure and MS, with higher VZV-IgG rates observed in regions where varicella is endemic and MS prevalence is relatively low, similar to the epidemiological context in our country.(Rice et al., \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2021\u003c/span\u003e) In line with these findings, a large population study of over 300,000 herpes zoster cases reported an increased risk of MS development within one year following VZV reactivation.(Kang et al., \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e2011\u003c/span\u003e) Other cohort study has also demonstrated higher rates of primary varicella infection and increased serum VZV-IgG positivity in MS patients.(Manouchehrinia et al., \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2017\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eIn addition to population-level observations, individual case reports further support a temporal association between VZV exposure and MS onset. Perez-Cesari et al. described six patients aged 14\u0026ndash;35 years who developed MS shortly after varicella infection or vaccination.(Perez-Cesari et al., \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2005\u003c/span\u003e) An immunocompetent 10-year-old girl developed optic neuritis and MS within 10 weeks of prolonged VZV reactivation affecting the trigeminal nerve, while a 27-year-old male experienced a severe MS relapse shortly after varicella infection.(Shiba et al., \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2018\u003c/span\u003e)(Rosener et al., \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e1995\u003c/span\u003e) Another report describes a patient who sequentially developed VZV encephalitis, limbic autoimmune encephalitis, and multiple sclerosis, highlighting a possible continuum from viral infection to autoimmune CNS pathology and the importance of timely recognition for appropriate treatment. (Wurdack et al., \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2024\u003c/span\u003e)\u003c/p\u003e \u003cp\u003eTaken together, population-based studies, the single additional cohort, and individual case reports suggest that VZV may act a trigger for MS, consistent with the temporal sequence seen in our patient. This case highlights that VZV-induced immune activation can precipitate MS in susceptible individuals and underscores shared pathways linking viral infection to autoimmune demyelination.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eDECLARATION OF PATIENT CONSENT\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors certify that they have obtained all appropriate patient consent forms. In the form the patient and her parents have given her consent for her images and other clinical information to be reported in the journal. The patient and her parents understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eACKNOWLEDGMENTS\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNo financial support was received for this study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCONFLICT OF INTEREST\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNone declared.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eE.O. and U.Y. wrote the main manuscript text and Y.K.C. prepared figures 1-2. All authors reviewed the manuscript.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eAscherio, A. (2013). Environmental factors in multiple sclerosis. \u003cem\u003eExpert Review of Neurotherapeutics\u003c/em\u003e, \u003cem\u003e13\u003c/em\u003e(sup2), 3\u0026ndash;9. https://doi.org/10.1586/14737175.2013.865866\u003c/li\u003e\n\u003cli\u003eCompston, A., \u0026amp; Coles, A. (2008). Multiple sclerosis. \u003cem\u003eThe Lancet\u003c/em\u003e, \u003cem\u003e372\u003c/em\u003e(9648), 1502\u0026ndash;1517. https://doi.org/10.1016/S0140-6736(08)61620-7\u003c/li\u003e\n\u003cli\u003eDinleyici, E. C., Kurugol, Z., Kara, A., Tezer, H., Tas, M. A., Guler, E., Yasa, O., Devrim, I., Ciftci, E., Ozdemir, H., Somer, A., Ozen, M., Sensoy, G., Dalgic, N., \u0026amp; Alhan, E. (2015). Children with breakthrough varicella infection requiring hospitalization in Turkey (VARICOMP Study 2008\u0026ndash;2013). \u003cem\u003eVaccine\u003c/em\u003e, \u003cem\u003e33\u003c/em\u003e(32), 3983\u0026ndash;3987. https://doi.org/10.1016/j.vaccine.2015.06.029\u003c/li\u003e\n\u003cli\u003eKang, J.-H., Sheu, J.-J., Kao, S., \u0026amp; Lin, H.-C. (2011). Increased Risk of Multiple Sclerosis Following Herpes Zoster: A Nationwide, Population-Based Study. \u003cem\u003eThe Journal of Infectious Diseases\u003c/em\u003e, \u003cem\u003e204\u003c/em\u003e(2), 188\u0026ndash;192. https://doi.org/10.1093/infdis/jir239\u003c/li\u003e\n\u003cli\u003eKennedy, P. G. E., \u0026amp; Gershon, A. A. (2018). Clinical Features of Varicella-Zoster Virus Infection. \u003cem\u003eViruses\u003c/em\u003e, \u003cem\u003e10\u003c/em\u003e(11), 609. https://doi.org/10.3390/v10110609\u003c/li\u003e\n\u003cli\u003eManouchehrinia, A., Tanasescu, R., Kareem, H., Jerca, O. P., Jabeen, F., Shafei, R., Breuer, J., Neal, K., Irving, W., \u0026amp; Constantinescu, C. S. (2017). Prevalence of a history of prior varicella/herpes zoster infection in multiple sclerosis. \u003cem\u003eJournal of NeuroVirology\u003c/em\u003e, \u003cem\u003e23\u003c/em\u003e(6), 839\u0026ndash;844. https://doi.org/10.1007/s13365-017-0569-1\u003c/li\u003e\n\u003cli\u003eMin, S.-W., Kim, Y. S., Nahm, F. S., Yoo, D. H., Choi, E., Lee, P.-B., Choo, H., Park, Z.-Y., \u0026amp; Yang, C. S. (2016). The positive duration of varicella zoster immunoglobulin M antibody test in herpes zoster. \u003cem\u003eMedicine\u003c/em\u003e, \u003cem\u003e95\u003c/em\u003e(33), e4616. https://doi.org/10.1097/MD.0000000000004616\u003c/li\u003e\n\u003cli\u003ePerez-Cesari, C., Saniger, M. M., \u0026amp; Sotelo, J. (2005). Frequent association of multiple sclerosis with varicella and zoster. \u003cem\u003eActa Neurologica Scandinavica\u003c/em\u003e, \u003cem\u003e112\u003c/em\u003e(6), 417\u0026ndash;419. https://doi.org/10.1111/j.1600-0404.2005.00491.x\u003c/li\u003e\n\u003cli\u003eRice, E. M., Thakolwiboon, S., \u0026amp; Avila, M. (2021). Geographic heterogeneity in the association of varicella-zoster virus seropositivity and multiple sclerosis: A systematic review and meta-analysis. \u003cem\u003eMultiple Sclerosis and Related Disorders\u003c/em\u003e, \u003cem\u003e53\u003c/em\u003e, 103024. https://doi.org/10.1016/j.msard.2021.103024\u003c/li\u003e\n\u003cli\u003eRosener, M., Dichgans, J., Martin, R., \u0026amp; Harms, F. (1995). Chickenpox and multiple sclerosis: a case report. \u003cem\u003eJournal of Neurology, Neurosurgery \u0026amp; Psychiatry\u003c/em\u003e, \u003cem\u003e58\u003c/em\u003e(5), 637\u0026ndash;638. https://doi.org/10.1136/jnnp.58.5.637-a\u003c/li\u003e\n\u003cli\u003eSedighi, S., Gholizadeh, O., Yasamineh, S., Akbarzadeh, S., Amini, P., Favakehi, P., Afkhami, H., Firouzi-Amandi, A., Pahlevan, D., Eslami, M., Yousefi, B., Poortahmasebi, V., \u0026amp; Dadashpour, M. (2023). Comprehensive Investigations Relationship Between Viral Infections and Multiple Sclerosis Pathogenesis. \u003cem\u003eCurrent Microbiology\u003c/em\u003e, \u003cem\u003e80\u003c/em\u003e(1), 15. https://doi.org/10.1007/s00284-022-03112-z\u003c/li\u003e\n\u003cli\u003eShiba, N., Inaba, Y., Motobayashi, M., Nishioka, M., Kawasaki, Y., Noda, S., Matsuura, H., Kobayashi, N., Matsuoka, T., Nakamura, A., \u0026amp; Nakazawa, Y. (2018). A Pediatric Case of Relapsing‐Remitting Multiple Sclerosis Onset following Varicella Zoster Ophthalmicus with Optic Neuritis. \u003cem\u003eCase Reports in Pediatrics\u003c/em\u003e, \u003cem\u003e2018\u003c/em\u003e(1). https://doi.org/10.1155/2018/6931206\u003c/li\u003e\n\u003cli\u003eSotelo, J. (2007). On the viral hypothesis of multiple sclerosis: Participation of varicella-zoster virus. \u003cem\u003eJournal of the Neurological Sciences\u003c/em\u003e, \u003cem\u003e262\u003c/em\u003e(1\u0026ndash;2), 113\u0026ndash;116. https://doi.org/10.1016/j.jns.2007.07.001\u003c/li\u003e\n\u003cli\u003eWucherpfennig, K. W., \u0026amp; Strominger, J. L. (1995). Molecular mimicry in T cell-mediated autoimmunity: Viral peptides activate human T cell clones specific for myelin basic protein. \u003cem\u003eCell\u003c/em\u003e, \u003cem\u003e80\u003c/em\u003e(5), 695\u0026ndash;705. https://doi.org/10.1016/0092-8674(95)90348-8\u003c/li\u003e\n\u003cli\u003eWurdack, K., Pr\u0026uuml;ss, H., \u0026amp; Finke, C. (2024). Evolution from viral encephalitis to autoimmune encephalitis to multiple sclerosis: a case report. \u003cem\u003eJournal of Neurology\u003c/em\u003e, \u003cem\u003e271\u003c/em\u003e(10), 7035\u0026ndash;7038. https://doi.org/10.1007/s00415-024-12659-9\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-neurovirology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"njiv","sideBox":"Learn more about [Journal of NeuroVirology](http://link.springer.com/journal/13365)","snPcode":"13365","submissionUrl":"https://submission.nature.com/new-submission/13365/3","title":"Journal of NeuroVirology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Multiple sclerosis, demyelinating, varicella zoster virus, varicella, immune-mediated, multiple sclerosis triggers","lastPublishedDoi":"10.21203/rs.3.rs-8841242/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8841242/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMultiple sclerosis (MS) is an immune-mediated demyelinating disorder of the central nervous system, with environmental factors potentially triggering disease in susceptible individuals. Although a link between varicella-zoster virus (VZV) and MS onset has been suggested, the association remains inconclusive. We report a previously healthy 17-year-old girl who presented with mild headache and a three-day history of vesicular lesions consistent with varicella. Initial neurological examination and brain MRI were normal. Due to persistent headache and development of hand numbness, follow-up brain and spinal MRI two months later revealed multiple demyelinating lesions in the periventricular and pericallosal white matter, optic nerve, and cervical and thoracic spinal cord, with gadolinium enhancement. Cerebrospinal fluid analysis demonstrated type 2 oligoclonal bands and elevated IgG index (0.67). Serum VZV serology showed positive IgG and elevated IgM (42.6 AU/mL), consistent with recent infection or reactivation. The patient fulfilled the revised 2024 McDonald criteria and was diagnosed with MS. She received intravenous methylprednisolone, achieved complete clinical recovery, and was started on dimethyl fumarate. This case supports a potential role of VZV as a trigger for MS onset.\u003c/p\u003e","manuscriptTitle":"Varicella Zoster Virus as a trigger for Multiple Sclerosis","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-18 09:55:40","doi":"10.21203/rs.3.rs-8841242/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"288992653918334498469838455461191709510","date":"2026-02-12T21:33:41+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-02-12T21:27:40+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-02-11T23:57:25+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-02-11T23:57:14+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of NeuroVirology","date":"2026-02-10T11:56:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-neurovirology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"njiv","sideBox":"Learn more about [Journal of NeuroVirology](http://link.springer.com/journal/13365)","snPcode":"13365","submissionUrl":"https://submission.nature.com/new-submission/13365/3","title":"Journal of NeuroVirology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"6776ea57-0479-4554-9833-6106341a8c62","owner":[],"postedDate":"February 18th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-02-18T09:55:40+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-18 09:55:40","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8841242","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8841242","identity":"rs-8841242","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}