Treatment Options for Epstein-Barr Virus-Related Disorders of the Central Nervous System

References

• Epstein MA, Achong BG, Barr YM. Virus particles in cultured lymphoblasts from Burkitt’s lymphoma. Lancet. 1964;15:702–703. doi:10.1016/S0140-6736(64)91524-7
   Web of Science ®Google Scholar
• Young LS, Yap LF, Murray PG. Epstein-Barr virus: more than 50 years old and still providing surprises. Nat Rev Cancer. 2016;16(12):789–802. doi:10.1038/nrc.2016.92
   PubMed Web of Science ®Google Scholar
• Gerber P, Kalter SS, Schidlovsky G, Peterson WD Jr, Daniel MD. Biologic and antigenic characteristics of Epstein-Barr virus-related Herpesviruses of chimpanzees and baboons. Int J Cancer. 1977;20(3):448–459. doi:10.1002/ijc.2910200318
   PubMed Web of Science ®Google Scholar
• Dunmire SK, Hogquist KA, Balfour HH. Infectious mononucleosis. Curr Top Microbiol Immunol. 2015;390(Pt 1):211–240. doi:10.1007/978-3-319-22822-8_9
   PubMedGoogle Scholar
• Thorley-Lawson DA. EBV persistence–introducing the virus. Curr Top Microbiol Immunol. 2015;390(Pt 1):151–209. doi:10.1007/978-3-319-22822-8_8
   PubMed Web of Science ®Google Scholar
• Menet A, Speth C, Larcher C, et al. Epstein-Barr virus infection of human astrocyte cell lines. J Virol. 1999;73(9):7722–7733. doi:10.1128/JVI.73.9.7722-7733.1999
   PubMed Web of Science ®Google Scholar
• Jones K, Rivera C, Sgadari C, et al. Infection of human endothelial cells with Epstein-Barr virus. J Exp Med. 1995;182(5):1213–1221. doi:10.1084/jem.182.5.1213
   PubMed Web of Science ®Google Scholar
• Bjornevik K, Cortese M, Healy BC, et al. Longitudinal analysis reveals high prevalence of Epstein-Barr virus associated with multiple sclerosis. Science. 2022;375(6578):296–301. doi:10.1126/science.abj8222
   PubMed Web of Science ®Google Scholar
• Demissie A, Svmyr A. Age distribution of antibodies to EB virus in Swedish females as studied by indirect immunofluorescence on Burkitt cells. Acta Pathol Microbiol Scand. 1969;75(3):457–465.
   PubMedGoogle Scholar
• Sixbey JW, Nedrud JG, Raab-Traub N, Hanes RA, Pagano JS. Epstein- Barr virus replication in oropharyngeal epithelial cells. N Engl J Med. 1984;310(19):1225–1230. doi:10.1056/NEJM198405103101905
   PubMed Web of Science ®Google Scholar
• Sixbey JW, Lemon SM, Pagano JS. A second site for Epstein-Barr virus shedding: the uterine cervix. Lancet. 1986;328(8516):1122–1124. doi:10.1016/S0140-6736(86)90531-3
   Google Scholar
• Young LS, Arrand JR, Murray PG. EBV gene expression and regulation. In: Arvin A, Campadelli-Fiume G, Mocarski E, editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007: Chapter 27.
   Google Scholar
• Skalsky RL, Cullen BR. EBV Noncoding RNAs. Curr Top Microbiol Immunol. 2015;391:181–217. doi:10.1007/978-3-319-22834-1_6
   PubMed Web of Science ®Google Scholar
• Zimber U, Adldinger HK, Lenoir GM, et al. Geographical prevalence of two types of Epstein-Barr virus. Virology. 1986;154(1):56–66. doi:10.1016/0042-6822(86)90429-0
   PubMed Web of Science ®Google Scholar
• Shannon-Lowe C, Rowe M. Epstein Barr virus entry; kissing and conjugation. Curr Opin Virol. 2013;4:78–84. doi:10.1016/j.coviro.2013.12.001
   Web of Science ®Google Scholar
• Haan KM, Longnecker R. Coreceptor restriction within the HLA-DQ locus for Epstein-Barr virus infection. Proc Natl Acad Sci U S A. 2000;97(16):9252–9257. doi:10.1073/pnas.160171697
   PubMed Web of Science ®Google Scholar
• Ogembo JG, Kannan L, Ghiran I, et al. Human complement receptor type 1/CD35 is an Epstein-Barr Virus receptor. Cell Rep. 2013;3(2):371–385. doi:10.1016/j.celrep.2013.01.023
   PubMed Web of Science ®Google Scholar
• Tierney RJ, Steven N, Young LS, Rickinson AB. Epstein-Barr virus latency in blood mononuclear cells: analysis of viral gene transcription during primary infection and in the carrier state. J Virol. 1994;68(11):7374–7385. doi:10.1128/jvi.68.11.7374-7385.1994
   PubMed Web of Science ®Google Scholar
• Kanda T. EBV-ENCODED LATENT GENES. Adv Exp Med Biol. 2018;1045:377–394.
   PubMed Web of Science ®Google Scholar
• Chen F, Zou JZ, Di Renzo L, et al. A subpopulation of normal B cells latently infected with Epstein-Barr virus resembles Burkitt lymphoma cells in expressing EBNA-1 but not EBNA-2 or LMP1. J Virol. 1995;69(6):3752–3758. doi:10.1128/jvi.69.6.3752-3758.1995
   PubMed Web of Science ®Google Scholar
• Leight ER, Sugden B. EBNA-1: a protein pivotal to latent infection by Epstein-Barr virus. Rev Med Virol. 2000;10(2):83–100. doi:10.1002/(SICI)1099-1654(200003/04)10:2<83::AID-RMV262>3.0.CO;2-T
   PubMed Web of Science ®Google Scholar
• Howe JG, Steitz JA. Localization of Epstein-Barr virus-encoded small RNAs by in situ hybridization. Proc Natl Acad Sci U S A. 1986;83(23):9006–9010. doi:10.1073/pnas.83.23.9006
   PubMed Web of Science ®Google Scholar
• Klein G, Ernberg I. Effects on apoptosis, cell cycle and transformation, and comparative aspects of EBV with other known DNA tumor viruses. In: Arvin A, Campadelli-Fiume G, Mocarski E, et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007: Chapter 29.
   Google Scholar
• Levitskaya J, Coram M, Levitsky V, et al. Inhibition of antigen processing by the internal repeat region of the Epstein-Barr virus nuclear antigen-1. Nature. 1995;375(6533):685–688. doi:10.1038/375685a0
   PubMed Web of Science ®Google Scholar
• Ressing ME, van Gent M, Gram AM, Hooykaas MJ, Piersma SJ, Wiertz EJ. Immune evasion by Epstein-Barr virus. Curr Top Microbiol Immunol. 2015;391:355–381. doi:10.1007/978-3-319-22834-1_12
   PubMed Web of Science ®Google Scholar
• Hennessy K, Kieff E. A second nuclear protein is encoded by Epstein-Barr virus in latent infection. Science. 1985;227(4691):1238–1240. doi:10.1126/science.2983420
   PubMed Web of Science ®Google Scholar
• Rickinson AB, Young LS, Rowe M. Influence of the Epstein-Barr virus nuclear antigen EBNA 2 on the growth phenotype of virus-transformed B cells. J Virol. 1987;61(5):1310–1317. doi:10.1128/jvi.61.5.1310-1317.1987
   PubMed Web of Science ®Google Scholar
• Ling PD, Hsieh JJ, Ruf IK, Rawlins DR, Hayward SD. EBNA-2 upregulation of Epstein-Barr virus latency promoters and the cellular CD23 promoter utilizes a common targeting intermediate, CBF1. J Virol. 1994;68(9):5375–5383. doi:10.1128/jvi.68.9.5375-5383.1994
   PubMed Web of Science ®Google Scholar
• Styles CT, Paschos K, White RE, Farrell PJ. The cooperative functions of the EBNA3 proteins are central to EBV persistence and latency. Pathogens. 2018;7(1):31. doi:10.3390/pathogens7010031
   PubMed Web of Science ®Google Scholar
• Lo AK, Dawson CW, Lung HL, Wong KL, Young LS. The role of EBV-encoded LMP1 in the NPC tumor microenvironment: from function to therapy. Front Oncol. 2021;11:640207. doi:10.3389/fonc.2021.640207
   PubMed Web of Science ®Google Scholar
• Longnecker R. Epstein-Barr virus latency: LMP2, a regulator or means for Epstein- Barr virus persistence? Adv Cancer Res. 2000;79:175–200.
   PubMed Web of Science ®Google Scholar
• Nanbo A, Takada K. The role of Epstein-Barr virus-encoded small RNAs (EBERs) in oncogenesis. Rev Med Virol. 2002;12(5):321–326. doi:10.1002/rmv.363
   PubMed Web of Science ®Google Scholar
• Sadler RH, Raab-Traub N. Structural analyses of the Epstein-Barr virus BamHI A transcripts. J Virol. 1995;69(2):1132–1141. doi:10.1128/jvi.69.2.1132-1141.1995
   PubMed Web of Science ®Google Scholar
• McKenzie J, El-Guindy A. Epstein-Barr virus lytic cycle reactivation. Curr Top Microbiol Immunol. 2015;391:237–261. doi:10.1007/978-3-319-22834-1_8
   PubMed Web of Science ®Google Scholar
• Evans AS, Niederman JC, McCollum RW. Seroepidemiologic studies of infectious mononucleosis with EB virus. N Engl J Med. 1968;279(21):1121–1127. doi:10.1056/NEJM196811212792101
   PubMed Web of Science ®Google Scholar
• Niller HH, Bauer G. Epstein-Barr Virus: clinical diagnostics. Methods Mol Biol. 2017;1532:33–55.
   PubMedGoogle Scholar
• McAulay KA, Higgins CD, Macsween KF, et al. HLA class I polymorphisms are associated with development of infectious mononucleosis upon primary EBV infection. J Clin Invest. 2007;117:3042–3048. doi:10.1172/JCI32377
   PubMed Web of Science ®Google Scholar
• Agostini S, Mancuso R, Guerini FR, et al. HLA alleles modulate EBV viral load in multiple sclerosis. J Transl Med. 2018;16:80. doi:10.1186/s12967-018-1450-6
   PubMed Web of Science ®Google Scholar
• Svedmyr E, Ernberg I, Seeley J, et al. Virologic, immunologic, and clinical observations on a patient during the incubation, acute, and convalescent phases of infectious mononucleosis. Clin Immunol Immunopathol. 1984;30(3):437–450. doi:10.1016/0090-1229(84)90029-1
   PubMedGoogle Scholar
• Rickinson AB, Fox CP. Epstein-Barr virus and infectious mononucleosis: what students can teach us. J Infect Dis. 2013;207(1):6–8. doi:10.1093/infdis/jis647
   PubMed Web of Science ®Google Scholar
• Lee SP, Thomas WA, Murray RJ, et al. HLA A2.1-restricted cytotoxic T cells recognizing a range of Epstein-Barr virus isolates through a defined epitope in latent membrane protein LMP2. J Virol. 1993;67(12):7428–7435. doi:10.1128/jvi.67.12.7428-7435.1993
   PubMed Web of Science ®Google Scholar
• Svedmyr E, Jondal M. Cytotoxic effector cells specific for B cell lines transformed by Epstein-Barr virus are present in patients with infectious mononucleosis. Proc Natl Acad Sci U S A. 1975;72(4):1622–1626. doi:10.1073/pnas.72.4.1622
   PubMed Web of Science ®Google Scholar
• Callan MF, Tan L, Annels N, et al. Direct visualization of antigen- specific CD8+ T cells during the primary immune response to Epstein-Barr virus in vivo. J Exp Med. 1998;187(9):1395–1402. doi:10.1084/jem.187.9.1395
   PubMed Web of Science ®Google Scholar
• Hislop AD, Annels NE, Gudgeon NH, Leese AM, Rickinson AB. Epitope-specific evolution of human CD8+ T cell responses from primary to persistent phases of Epstein-Barr virus infection. J Exp Med. 2002;195(7):893–905. doi:10.1084/jem.20011692
   PubMed Web of Science ®Google Scholar
• Fujiwara S, Nakamura H. Chronic active Epstein–Barr virus infection: is it immunodeficiency, malignancy, or both? Cancers. 2020;12(11):3202. doi:10.3390/cancers12113202
   PubMed Web of Science ®Google Scholar
• Jakhmola S, Jha HC. Glial cell response to Epstein-Barr virus infection: a plausible contribution to virus-associated inflammatory reactions in the brain. Virology. 2021;559:182–195. doi:10.1016/j.virol.2021.04.005
   PubMed Web of Science ®Google Scholar
• Jha HC, Mehta D, Lu J, et al. Gammaherpesvirus infection of human neuronal cells. mBio. 2015;6(6):e01844–e01915. doi:10.1128/mBio.01844-15
   PubMed Web of Science ®Google Scholar
• Casiraghi C, Dorovini-Zis K, Horwitz M. Epstein-Barr virus infection of human brain microvessel endothelial cells: a novel role in multiple sclerosis. J Neuroimmunol. 2011;230(1–2):173–177. doi:10.1016/j.jneuroim.2010.08.003
   PubMed Web of Science ®Google Scholar
• Lehrnbecher T, Chittka B, Nanan R, et al. Activated T lymphocytes in the cerebrospinal fluid of a patient with Epstein-Barr virus-associated meningoencephalitis. Pediatr Infect Dis J. 1996;15(7):631–633. doi:10.1097/00006454-199607000-00016
   PubMed Web of Science ®Google Scholar
• Jakhmola S, Sk MF, Chatterjee A, et al. A plausible contributor to multiple sclerosis; presentation of antigenic myelin protein epitopes by major histocompatibility complexes. Comput Biol Med. 2022;148:105856. doi:10.1016/j.compbiomed.2022.105856
   PubMed Web of Science ®Google Scholar
• Fan Y, Sanyal S, Bruzzone R. Breaking bad: how viruses subvert the cell cycle. Front Cell Infect Microbiol. 2018;8:396. doi:10.3389/fcimb.2018.00396
   PubMed Web of Science ®Google Scholar
• Tiwari D, Mittal N, Chandra Jha H. Unraveling the links between neurodegeneration and Epstein-Barr virus-mediated cell cycle dysregulation. Curr Res Neurobiol. 2022;3:100046. doi:10.1016/j.crneur.2022.100046
   PubMedGoogle Scholar
• Grillo E, da Silva RJM, Barbato Filho JH. Epstein-Barr virus acute encephalomyelitis in a 13-year-old boy. Eur J Paediatr Neurol. 2008;12(5):417–420. doi:10.1016/j.ejpn.2007.10.016
   PubMed Web of Science ®Google Scholar
• Dyachenko P, Smiianova O, Kurhanskaya V, Oleshko A, Dyachenko A. Epstein-Barr virus-associated encephalitis in a case-series of more than 40 patients. Wiad Lek. 2018;71(6):1224–1230.
   PubMedGoogle Scholar
• Cheng H, Chen D, Peng X, et al. Clinical characteristics of Epstein–Barr virus infection in the pediatric nervous system. BMC Infect Dis. 2020;20(1):886. doi:10.1186/s12879-020-05623-1
   PubMed Web of Science ®Google Scholar
• Weinberg A, Li S, Palmer M, Tyler KL. Quantitative CSF PCR in Epstein-Barr virus infections of the central nervous system. Ann Neurol. 2002;52(5):543–548. doi:10.1002/ana.10321
   PubMed Web of Science ®Google Scholar
• Abul-Kasim K, Palm L, Maly P, Sundgren PC. The neuroanatomic localization of Epstein-Barr virus encephalitis may be a predictive factor for its clinical outcome: a case report and review of 100 cases in 28 reports. J Child Neurol. 2009;24(6):720–726. doi:10.1177/0883073808327842
   PubMed Web of Science ®Google Scholar
• Doja A, Bitnun A, Jones ELF, et al. Pediatric Epstein-Barr virus—associated encephalitis: 10-year review. J Child Neurol. 2006;21(5):384–391. doi:10.1177/08830738060210051101
   PubMed Web of Science ®Google Scholar
• Tselis A, Duman R, Storch GA, Lisak RP. Epstein-Barr virus encephalomyelitis diagnosed by polymerase chain reaction: detection of the genome in the CSF. Neurology. 1997;48(5):1351–1355. doi:10.1212/WNL.48.5.1351
   PubMed Web of Science ®Google Scholar
• Bauer J, Bien CG, Lassmann H. Rasmussenʼs encephalitis: a role for autoimmune cytotoxic T lymphocytes. Curr Opin Neurol. 2002;15(2):197–200. doi:10.1097/00019052-200204000-00012
   PubMed Web of Science ®Google Scholar
• Liu D, Wang X, Wang Y, et al. Detection of EBV and HHV6 in the brain tissue of patients with Rasmussen’s encephalitis. Virol Sin. 2018;33(5):402–409. doi:10.1007/s12250-018-0063-9
   PubMed Web of Science ®Google Scholar
• Leake JAD, Albani S, Kao AS, et al. Acute disseminated encephalomyelitis in childhood: epidemiologic, clinical and laboratory features. Pediatr Infect Dis J. 2004;23(8):756–764. doi:10.1097/01.inf.0000133048.75452.dd
   PubMed Web of Science ®Google Scholar
• Shen J, Lin D, Jiang T, Gao F, Jiang K. Clinical characteristics and associated factors of pediatric acute disseminated encephalomyelitis patients with MOG antibodies: a retrospective study in Hangzhou, China. BMC Neurol. 2022;22(1):418. doi:10.1186/s12883-022-02963-0
   PubMed Web of Science ®Google Scholar
• Hennes E-M, Baumann M, Schanda K, et al. Prognostic relevance of MOG antibodies in children with an acquired demyelinating syndrome. Neurology. 2017;89(9):900–908. doi:10.1212/WNL.0000000000004312
   PubMed Web of Science ®Google Scholar
• Prineas J, McDonald WI, Franklin R. Demyelinating diseases. In: Graham D, Lantos P, editors. Greenfield’s Neuropathology. 7th ed. London: Arnold; 2002:471–550.
   Google Scholar
• Kakalacheva K, Regenass S, Wiesmayr S, et al. Infectious mononucleosis triggers generation of IgG auto-antibodies against native myelin oligodendrocyte glycoprotein. Viruses. 2016;8(2):51. doi:10.3390/v8020051
   PubMed Web of Science ®Google Scholar
• Peschl P, Bradl M, Höftberger R, et al. Myelin oligodendrocyte glycoprotein: deciphering a target in inflammatory demyelinating diseases. Front Immunol. 2017;8:529. doi:10.3389/fimmu.2017.00529
   PubMed Web of Science ®Google Scholar
• Hennes E-M, Baumann M, Lechner C, Rostasy K. MOG spectrum disorders and role of MOG-Antibodies in clinical practice. Neuropediatrics. 2018;49(01):3–11. doi:10.1055/s-0037-1604404
   PubMedGoogle Scholar
• Wingerchuk DM. The clinical course of acute disseminated encephalomyelitis. Neurol Res. 2006;28(3):341–347. doi:10.1179/016164106X98251
   PubMed Web of Science ®Google Scholar
• Davis DP, Marino A. Acute cerebellar ataxia in a toddler: case report and literature review. J Emerg Med. 2003;24(3):281–284. doi:10.1016/S0736-4679(02)00746-1
   PubMed Web of Science ®Google Scholar
• Nussinovitch M, Prais D, Volovitz B, Shapiro R, Amir J. Post-infectious acute cerebellar ataxia in children. Clin Pediatr. 2003;42(7):581–584. doi:10.1177/000992280304200702
   PubMed Web of Science ®Google Scholar
• Al-Shokri SD, Karumannil SA, Mohammed SS, Sadek MS. Post-Epstein-Barr virus acute cerebellitis in an adult. Am J Case Rep. 2020;21:e918567. doi:10.12659/AJCR.918567
   PubMed Web of Science ®Google Scholar
• Ali K, Lawthom C. Epstein-Barr virus-associated cerebellar ataxia. BMJ Case Rep. 2013;2013(apr22 1):bcr2013009171. doi:10.1136/bcr-2013-009171
   PubMedGoogle Scholar
• Uchibori A, Sakuta M, Kusunoki S, Chiba A. Autoantibodies in postinfectious acute cerebellar ataxia. Neurology. 2005;65(7):1114–1116. doi:10.1212/01.wnl.0000178802.38268.1e
   PubMed Web of Science ®Google Scholar
• Paydas S. Primary central nervous system lymphoma: essential points in diagnosis and management. Med Oncol. 2017;34(4):61. doi:10.1007/s12032-017-0920-7
   PubMed Web of Science ®Google Scholar
• Enblad G, Martinsson G, Baecklund E, et al. Population-based experience on primary central nervous system lymphoma 2000–2012: the incidence is increasing. Acta Oncol. 2017;56(4):599–607. doi:10.1080/0284186X.2016.1270465
   PubMed Web of Science ®Google Scholar
• Kleinschmidt-DeMasters BK, Damek DM, Lillehei KO, Dogan A, Giannini C. Epstein Barr virus-associated primary CNS lymphomas in elderly patients on immunosuppressive medications. J Neuropathol Exp Neurol. 2008;67(11):1103–1111. doi:10.1097/NEN.0b013e31818beaea
   PubMed Web of Science ®Google Scholar
• Bataille B, Delwail V, Menet E, et al. Primary intracerebral malignant lymphoma: report of 248 cases. J Neurosurg. 2000;92(2):261–266. doi:10.3171/jns.2000.92.2.0261
   PubMed Web of Science ®Google Scholar
• Grommes C, DeAngelis LM. Primary CNS lymphoma. J Clin Oncol. 2017;35(21):2410–2418. doi:10.1200/JCO.2017.72.7602
   PubMed Web of Science ®Google Scholar
• Venetz D, Ponzoni M, Schiraldi M, et al. Perivascular expression of CXCL9 and CXCL12 in primary central nervous system lymphoma: t-cell infiltration and positioning of malignant B cells. Int J Cancer. 2010;127(10):2300–2312. doi:10.1002/ijc.25236
   PubMed Web of Science ®Google Scholar
• Rubenstein JL, Fridlyand J, Shen A, et al. Gene expression and angiotropism in primary CNS lymphoma. Blood. 2006;107(9):3716–3723. doi:10.1182/blood-2005-03-0897
   PubMed Web of Science ®Google Scholar
• Sugita Y, Terasaki M, Niino D, et al. Epstein–Barr virus-associated primary central nervous system lymphomas in immunocompetent elderly patients: analysis for latent membrane protein-1 oncogene deletion and EBNA-2 strain typing. J Neuro Oncol. 2010;100(2):271–279. doi:10.1007/s11060-010-0191-z
   PubMed Web of Science ®Google Scholar
• Lublin FD, Reingold SC. Defining the clinical course of multiple sclerosis: results of an international survey. National multiple sclerosis society (USA) advisory committee on clinical trials of new agents in multiple sclerosis. Neurology. 1996;46(4):907–911. doi:10.1212/WNL.46.4.907
   PubMed Web of Science ®Google Scholar
• Ascherio A, Munger KL. Epstein–Barr virus infection and multiple sclerosis: a review. J Neuroimmune Pharmacol. 2010;5(3):271–277. doi:10.1007/s11481-010-9201-3
   PubMed Web of Science ®Google Scholar
• Levin LI, Munger K, Rubertone MV, et al. Temporal relationship between elevation of Epstein-Barr virus antibody titers and initial onset of neurological symptoms in multiple sclerosis. JAMA. 2005;293(20):2493–2500. doi:10.1001/jama.293.20.2496
   Web of Science ®Google Scholar
• Sundström P, Juto P, Wadell G, et al. An altered immune response to Epstein-Barr virus in multiple sclerosis: a prospective study. Neurology. 2004;62(12):2277–2282. doi:10.1212/01.WNL.0000130496.51156.D7
   PubMed Web of Science ®Google Scholar
• Moreno MA, Or-Geva N, Aftab BT, et al. Molecular signature of Epstein-Barr virus infection in MS brain lesions. Neurol Neuroimmunol Neuroinflamm. 2018;5(4):e466. doi:10.1212/NXI.0000000000000466
   PubMed Web of Science ®Google Scholar
• Veroni C, Serafini B, Rosicarelli B, et al. Transcriptional profile and Epstein-Barr virus infection status of laser-cut immune infiltrates from the brain of patients with progressive multiple sclerosis. J Neuroinflammation. 2018;15(1):18. doi:10.1186/s12974-017-1049-5
   PubMedGoogle Scholar
• Magliozzi R, Howell O, Vora A, et al. Meningeal B-cell follicles in secondary progressive multiple sclerosis associate with early onset of disease and severe cortical pathology. Brain. 2006;130(4):1089–1104. doi:10.1093/brain/awm038
   Google Scholar
• Serafini B, Rosicarelli B, Magliozzi R, Stigliano E, Aloisi F. Detection of ectopic B-cell follicles with germinal centers in the meninges of patients with secondary progressive multiple sclerosis. Brain Pathol. 2004;14(2):164–174. doi:10.1111/j.1750-3639.2004.tb00049.x
   PubMed Web of Science ®Google Scholar
• Nociti V, Frisullo G, Marti A, et al. Epstein-Barr virus antibodies in serum and cerebrospinal fluid from multiple sclerosis, chronic inflammatory demyelinating polyradiculoneuropathy and amyotrophic lateral sclerosis. J Neuroimmunol. 2010;225(1–2):149–152. doi:10.1016/j.jneuroim.2010.04.007
   PubMed Web of Science ®Google Scholar
• Lünemann JD, Edwards N, Muraro PA, et al. Increased frequency and broadened specificity of latent EBV nuclear antigen-1-specific T cells in multiple sclerosis. Brain. 2006;129(6):1493–1506. doi:10.1093/brain/awl067
   PubMedGoogle Scholar
• Lynemann JD, Jelcic I, Roberts S, et al. EBNA1-specific T cells from patients with multiple sclerosis cross react with myelin antigens and co-produce IFN-γ and IL-2. J Exp Med. 2008;205(8):1763–1773. doi:10.1084/jem.20072397
   PubMed Web of Science ®Google Scholar
• Sawcer S, Hellenthal G, Pirinen M, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476:214–219.
   PubMed Web of Science ®Google Scholar
• Bjornevik K, Münz C, Cohen JI, Ascherio A. Epstein–Barr virus as a leading cause of multiple sclerosis: mechanisms and implications. Nat Rev Neurol. 2023;19(3):160–171. doi:10.1038/s41582-023-00775-5
   PubMed Web of Science ®Google Scholar
• Peferoen LAN, Lamers F, Lodder LNR, et al. Epstein Barr virus is not a characteristic feature in the central nervous system in established multiple sclerosis. Brain. 2010;133(5):e137. doi:10.1093/brain/awp296
   PubMedGoogle Scholar
• Balfour, Jr. HH Jr, Holman CJ, Hokanson KM, et al. A prospective clinical study of Epstein-Barr virus and host interactions during acute infectious mononucleosis. J Infect Dis. 2005;192(9):1505–1512. doi:10.1086/491740
   PubMed Web of Science ®Google Scholar
• Macsween KF, Higgins CD, McAulay KA, et al. Infectious mononucleosis in university students in the United Kingdom: evaluation of the clinical features and consequences of the disease. Clin Infect Dis. 2010;50(5):699–706. doi:10.1086/650456
   PubMed Web of Science ®Google Scholar
• Luzuriaga K, Sullivan JL. Infectious mononucleosis. N Engl J Med. 2010;362(21):1993–2000. doi:10.1056/NEJMcp1001116
   PubMed Web of Science ®Google Scholar
• Martelius T, Lappalainen M, Palomaki M, Anttila VJ. Clinical characteristics of patients with Epstein Barr virus in cerebrospinal fluid. BMC Infect Dis. 2011;11:281. doi:10.1186/1471-2334-11-281
   PubMed Web of Science ®Google Scholar
• Hjalgrim H, Smedby KE, Rostgaard K, et al. Infectious mononucleosis, childhood social environment, and risk of Hodgkin lymphoma. Cancer Res. 2007;67(5):2382–2388. doi:10.1158/0008-5472.CAN-06-3566
   PubMed Web of Science ®Google Scholar
• Andersson J, Sköldenberg B, Henle W, et al. Acyclovir treatment in infectious mononucleosis: a clinical and virological study. Infection. 1987;15(Suppl 1):S14–S20. doi:10.1007/BF01650106
   PubMed Web of Science ®Google Scholar
• Tengvall K, Huang J, Hellström C, et al. Molecular mimicry between anoctamin 2 and Epstein-Barr virus nuclear antigen 1 associates with multiple sclerosis risk. Proc Natl Acad Sci U S A. 2019;116(34):16955–16960. doi:10.1073/pnas.1902623116
   PubMed Web of Science ®Google Scholar
• Tynell E, Aurelius E, Brandell A, et al. Acyclovir and prednisolone treatment of acute infectious mononucleosis: a multicenter, double-blind, placebo-controlled study. J Infect Dis. 1996;174:324–331. doi:10.1093/infdis/174.2.324
   PubMed Web of Science ®Google Scholar
• De Paor M, O’Brien K, Fahey T, Smith SM. Antiviral agents for infectious mononucleosis (glandular fever). Cochrane Database Syst Rev. 2016;12(12):CD011487. doi:10.1002/14651858.CD011487.pub2
   PubMedGoogle Scholar
• Hu H, Deng H, Bi J, et al. Clinical characteristics and effectiveness of antiviral agents in hospitalized children with infectious mononucleosis in China: A multicenter retrospective study. Pediatr Investig. 2021;5(3):188–194.
   PubMedGoogle Scholar
• Silveira EL, Fogg MH, Leskowitz RM, et al. Therapeutic vaccination against the rhesus lymphocryptovirus EBNA-1 homologue, rhEBNA-1, elicits T cell responses to novel epitopes in rhesus macaques. J Virol. 2013;87(24):13904–13910. doi:10.1128/JVI.01947-13
   PubMed Web of Science ®Google Scholar
• Ruiss R, Jochum S, Wanner G, et al. A virus-like particle-based Epstein-Barr virus vaccine. J Virol. 2011;85(24):13105–13113. doi:10.1128/JVI.05598-11
   PubMed Web of Science ®Google Scholar
• Cui X, Snapper CM. Epstein Barr virus: development of vaccines and immune cell therapy for EBV-associated diseases. Front Immunol. 2021;12:734471. doi:10.3389/fimmu.2021.734471
   PubMed Web of Science ®Google Scholar
• Gu SY, Huang TM, Ruan L, et al. First EBV vaccine trial in humans using recombinant vaccinia virus expressing the major membrane antigen. Dev Biol Stand. 1995;84:171–177.
   PubMedGoogle Scholar
• Cui X, Cao Z, Chen Q, et al. Rabbits immunized with Epstein-Barr virus Gh/gL or gB recombinant proteins elicit higher serum virus neutralizing activity than Gp350. Vaccine. 2016;34(34):4050–4055. doi:10.1016/j.vaccine.2016.06.021
   PubMed Web of Science ®Google Scholar
• Sun C, Chen XC, Kang YF, Zeng MS. The status and prospects of Epstein-Barr virus prophylactic vaccine development. Front Immunol. 2021;12:677027. doi:10.3389/fimmu.2021.677027
   PubMed Web of Science ®Google Scholar
• Rees L, Tizard EJ, Morgan AJ, et al. A phase I trial of Epstein-Barr virus gp350 vaccine for children with chronic kidney disease awaiting transplantation. Transplantation. 2009;88(8):1025–1029. doi:10.1097/TP.0b013e3181b9d918
   PubMed Web of Science ®Google Scholar
• Sokal EM, Hoppenbrouwers K, Vandermeulen C, et al. Recombinant gp350 vaccine for infectious mononucleosis: a Phase 2, randomized, double-blind, placebo-controlled trial to evaluate the safety, immunogenicity, and efficacy of an Epstein-Barr virus vaccine in healthy young adults. J Infect Dis. 2007;196(12):1749–1753. doi:10.1086/523813
   PubMed Web of Science ®Google Scholar
• Cui X, Cao Z, Sen G, et al. A novel tetrameric gp350 1–470 as a potential Epstein-Barr virus vaccine. Vaccine. 2013;31(30):3039–3045. doi:10.1016/j.vaccine.2013.04.071
   PubMed Web of Science ®Google Scholar
• Bharadwaj M, Burows SR, Burrows JM, et al. Longitudinal dynamics of antigen-specific CD8+ cytotoxic T lymphocytes following primary Epstein-Barr virus infection. Blood. 2001;98:2588–2589. doi:10.1182/blood.V98.8.2588
   PubMed Web of Science ®Google Scholar
• Elliott SL, Suhrbier A, Miles JJ, et al. Phase I trial of a CD8+ T-cell peptide epitope-based vaccine for infectious mononucleosis. J Virol. 2008;82(3):1448–1457. doi:10.1128/JVI.01409-07
   PubMed Web of Science ®Google Scholar
• Internetbased information. Available from: http://clinicaltrials.gov/ct2/show/NCT05164094. Accessed February 14, 2023.
   Google Scholar
• Tsuruyama Y, Mori N, Yoshida S, Hayashi T. Epstein-Barr virus-related encephalitis in a young woman: a case-report. J Infect Chemother. 2020;26:741–744. doi:10.1016/j.jiac.2020.02.005
   PubMed Web of Science ®Google Scholar
• Hayton E, Wakerley B, Bowler IC, et al. Successful outcome of Epstein-Barr virus encephalitis managed with bilateral craniectomy, corticosteroids and aciclovir. Pract Neurol. 2012;12:234–237. doi:10.1136/practneurol-2012-000234
   PubMedGoogle Scholar
• Hussain RS, Hussain NA. Ataxia and encephalitis in a young adult with EBV mononucleosis: a case report. Case Rep Neurol Med. 2013;2013:516325. doi:10.1155/2013/516325
   PubMedGoogle Scholar
• Gaudioso CM, Mar S, Casper TC, et al. MOG and AQP4 antibodies among children with multiple sclerosis and controls. Ann Neurol. 2023;93:271–284. doi:10.1002/ana.26502
   PubMed Web of Science ®Google Scholar
• Murasawa E, Masazumi M, Koichi I, et al. Adult-onset acute disseminated encephalomyelitis with Epstein-Barr virus infection. Case Rep Radiol. 2022;2022:6149501. doi:10.1155/2022/6149501
   PubMedGoogle Scholar
• Deeba A, Cardos B, Gorur Y, et al. A rare case of adult acute disseminated encephalomyelitis associated with primary Epstein-Barr virus infection. Eur J Cas Rep Intern Med. 2019;6:001094.
   PubMedGoogle Scholar
• Mohsen H, Zeinah GFA, Elsotouhy AH, Mohamed K. Acute disseminated encephalomyelitis following infectious mononucleosis in a toddler. BMJ Case Rep. 2013;2013:bcr2013010048. doi:10.1136/bcr-2013-010048
   PubMedGoogle Scholar
• Pangprasertkul S, Sanguansermsri C, Sudjaituk T. Epstein-Barr virus meningoencephalitis in a young immunocompetent child: a case report. Heliyon. 2022;8:e11150. doi:10.1016/j.heliyon.2022.e11150
   PubMed Web of Science ®Google Scholar
• Koning MT, Brik T, Hagenbeek R, et al. A case of fulminant Epstein-Barr virus encephalitis in an immune-competent adult. J Neurovirol. 2019;25(3):422–425. doi:10.1007/s13365-018-0718-1
   PubMed Web of Science ®Google Scholar
• Celik T, Celik U, Tolunay O, et al. Epstein-Barr virus encephalitis with substantia nigra involvement. J Pediatr Neurosci. 2015;10(4):401–403. doi:10.4103/1817-1745.174436
   PubMedGoogle Scholar
• Zhang S, Feng J, Shi Y. Transient widespread cortical and splenial lesions in acute encephalitis/encephalopathy associated with primary Epstein-Barr virus infection. Int J Infect Dis. 2016;42:7–10. doi:10.1016/j.ijid.2015.11.009
   PubMed Web of Science ®Google Scholar
• Muscat K, Galea R, Vella M. An adult case of acute EBV cerebellitis. Eur J Case Rep Intern Med. 2017;4(1):000519. doi:10.12890/2016_000519
   PubMedGoogle Scholar
• Samkar AV, Poulsen MNF, Beinfait HP, Van Leeuwen RB. Acute cerebellitis in adults: a case report and review of the literature. BMC Res Notes. 2017;10:610. doi:10.1186/s13104-017-2935-8
   PubMedGoogle Scholar
• Wang Y, Dong Q, Chen Y, et al. Intracranial Epstein-Barr virus infection appearing as an unusual case of meningitis in an immunocompetent woman: a case report. J Int Med Res. 2020;48:300060520903215. doi:10.1177/0300060520903215
   PubMed Web of Science ®Google Scholar
• Crocchiolo R, Ciccolini J, El-Cheikh J, et al. Successful treatment of post-transplant Epstein-Barr virus-related meningoencephalitis by intravenous rituximab monotherapy. Leuk Lymphoma. 2012;53(10):2063–2065. doi:10.3109/10428194.2012.670232
   PubMed Web of Science ®Google Scholar
• Nakamura J, Yanagida M, Saito K, et al. Epstein-Barr virus encephalitis in a patient with rheumatoid arthritis. Mod Rheumatol Case Rep. 2022;6:160–162. doi:10.1093/mrcr/rxab045
   PubMedGoogle Scholar
• Ueda M, Tateishi T, Shigeto H, et al. A case of acute disseminated encephalomyelitis associated with Epstein-Barr virus reactivation during infliximab therapy. Rinsho Shinkeigaku. 2010;50:461–466. doi:10.5692/clinicalneurol.50.461
   PubMedGoogle Scholar
• Caucheteux N, Maarouf A, Daelman L, et al. Acute disseminated encephalomyelitis in two renal transplant patients: is there a role for Epstein-Barr virus reactivation? Mult Scler. 2013;19(9):1222–1225. doi:10.1177/1352458513478674
   PubMed Web of Science ®Google Scholar
• Rodrigo-Armenteros P, Kapetanovic-Garcia S, Anton-Mendez L, et al. Akinetic mutism and status epilepticus due to Epstein Barr virus encephalitis. Clin Neurol Neurosurg. 2019;185:105492. doi:10.1016/j.clineuro.2019.105492
   PubMed Web of Science ®Google Scholar
• Görander S, Andersen O, Leiram B, et al. Multiphasic encephalomyelitis in a patient with recurrent herpes simplex type 2 meningitis. Scand J Infec Dis. 2006;38:942. doi:10.1080/00365540600606499
   PubMed Web of Science ®Google Scholar
• Nakamura Y, Nakajima H, Tani H, et al. Anti-MOG antibody-positive ADEM following infectious mononucleosis due to a primary EBV infection: a case report. BMC Neurol. 2017;17(1):76. doi:10.1186/s12883-017-0858-6
   PubMed Web of Science ®Google Scholar
• Hampe CS, Mitoma H. A breakdown of immune tolerance in the cerebellum. Brain Sci. 2022;12(3):328. doi:10.3390/brainsci12030328
   PubMed Web of Science ®Google Scholar
• D’Ambrosio E, Khalighinejad F, Ionete C. Intravenous immunoglobulins in an adult case of post-EBV cerebellitis. BMJ Case Rep. 2020;13(2). doi:10.1136/bcr-2019-231661
   PubMedGoogle Scholar
• Sanefuji M, Ohga S, Kira R, et al. Epstein-Barr virus-associated meningoencephalomyelitis: intrathecal reactivation of the virus in an immunocompetent child. J Child Neurol. 2008;23(9):1072–1077. doi:10.1177/0883073808315414
   PubMed Web of Science ®Google Scholar
• Fortin Ensign SP, Gathers D, Wiedmeier JE, Mrugala MM. Central nervous system lymphoma: novel therapies. Curr Treat Options Oncol. 2022;23(1):117–136. doi:10.1007/s11864-021-00921-5
   PubMed Web of Science ®Google Scholar
• Law SC, Hoang T, O’Rourke K, et al. Successful treatment of Epstein-Barr virus-associated primary central nervous system lymphoma due to post-transplantation lymphoproliferative disorder, with ibrutinib and third-party Epstein-Barr virus-specific T cells. Am J Transplant. 2021;21:3465–3471. doi:10.1111/ajt.16628
   PubMed Web of Science ®Google Scholar
• Wang M, Gu B, Chen X, et al. The function and therapeutic potential of Epstein-Barr virus-encoded microRNAs in cancer. Mol Ther Nucleic Acids. 2019;17:657–668. doi:10.1016/j.omtn.2019.07.002
   PubMedGoogle Scholar
• Kaulen LD, Karschnia P, Dietrich J, Baehring JM. Autoimmune disease-related CNS lymphoma: systematic review and meta-analysis. J Neurooncol. 2020;149:153–159. doi:10.1007/s11060-020-03583-9
   PubMed Web of Science ®Google Scholar
• Kappos L, Bar-Or A, Cree BAC, et al. Siponimod versus placebo in secondary progressive multiple sclerosis (EXPAND): a double-blind, randomised, Phase 3 study. Lancet. 2018;391(10127):1263–1273. doi:10.1016/S0140-6736(18)30475-6
   PubMed Web of Science ®Google Scholar
• Lycke J, Svennerholm B, Hjelmquist E, et al. Acyclovir treatment of relapsing-remitting multiple sclerosis. A randomized, placebo-controlled, double-blind study. J Neurol. 1996;243(3):214–224. doi:10.1007/BF00868517
   PubMed Web of Science ®Google Scholar
• Bech E, Lycke J, Gadeberg P, et al. A randomized, double-blind, placebo-controlled MRI study of anti-herpes virus therapy in MS. Neurology. 2002;58(1):31–36. doi:10.1212/WNL.58.1.31
   PubMed Web of Science ®Google Scholar
• Friedman JE, Zabriskie JB, Plank C, et al. A randomized clinical trial of valacyclovir in multiple sclerosis. Mult Scler. 2005;11(3):286–295. doi:10.1191/1352458505ms1185oa
   PubMedGoogle Scholar
• Pender MP, Csurhes PA, Smith C, et al. Epstein-Barr virus-specific T cell therapy for progressive multiple sclerosis. JCI Insight. 2020;5(20). doi:10.1172/jci.insight.144624
   PubMed Web of Science ®Google Scholar
• Ioannides ZA, Csurhes PA, Douglas NL, et al. Sustained clinical improvement in a subset of patients with progressive multiple sclerosis treated with Epstein-Barr virus-specific T cell therapy. Front Neurol. 2021;12:652811. doi:10.3389/fneur.2021.652811
   PubMed Web of Science ®Google Scholar
• Svenningsson A, Frisell T, Burman J, et al. Safety and efficacy of rituximab versus dimethyl fumarate in patients with relapsing-remitting multiple sclerosis or clinically isolated syndrome in Sweden: a rater-blinded, phase 3- randomisex controlled trial. Lancet Neurol. 2022;21:693–703. doi:10.1016/S1474-4422(22)00209-5
   PubMed Web of Science ®Google Scholar
• Jons D, Persson Berg L, Sundstrom P, et al. Follow-up after infectious mononucleosis in search of serological similarities with presymptomatic multiple sclerosis. Mult Scler Relat Disord. 2021;56. doi:10.1016/j.msard.2021.103288
   PubMed Web of Science ®Google Scholar
• Maple PA, Ascherio A, Cohen JI, et al. The potential for EBV vaccines to prevent multiple sclerosis. Front Neurol. 2022;13:887794. doi:10.3389/fneur.2022.887794
   PubMed Web of Science ®Google Scholar
• Engdahl E, Gustafsson R, Huang J, et al. Increased serological response against human herpesvirus 6A is associated with risk for multiple sclerosis. Front Immunol. 2019;10:2715. doi:10.3389/fimmu.2019.02715
   PubMed Web of Science ®Google Scholar
• Gentili V, Turrin G, Marchetti P, et al. Synthesis and biological evaluation of novel rhodanine-based structures with antiviral activity towards HHV-6 virus. Bioorg Chem. 2022;119:105518. doi:10.1016/j.bioorg.2021.105518
   PubMed Web of Science ®Google Scholar