Intrathecal Antibody Production Against Epstein-Barr, Herpes Simplex, and Other Neurotropic Viruses in Autoimmune Encephalitis

Background and Objectives Neurotropic viruses are suspected to play a role in the pathogenesis of autoimmune diseases of the CNS such as the association between the Epstein-Barr virus (EBV) and multiple sclerosis (MS). A group of autoimmune encephalitis (AE) is linked to antibodies against neuronal cell surface proteins. Because CNS infection with the herpes simplex virus can trigger anti–NMDA receptor (NMDAR) encephalitis, a similar mechanism for EBV and other neurotropic viruses could be postulated. To investigate for previous viral infections of the CNS, intrathecally produced virus-specific antibody synthesis was determined in patients with AE. Methods Antibody-specific indices (AIs) against EBV and measles, rubella, varicella zoster, herpes simplex virus, and cytomegalovirus were determined in 27 patients having AE (anti-NMDAR encephalitis, n = 21, and LGI1 encephalitis, n = 6) and in 2 control groups comprising of 30 patients with MS and 21 patients with noninflammatory CNS diseases (NIND), which were sex and age matched. Results An intrathecal synthesis of antibodies against EBV was found in 5/27 (19%) patients with AE and 2/30 (7%) of the patients with MS. All these patients had also at least 1 additional elevated virus-specific AI. In contrast, in none of the patients with NIND, an elevated virus-specific AI was detected. Discussion Intrathecally produced antibodies against EBV can be found in patients with AE and MS but only together with antibodies against different neurotropic viruses. Evidence of these antibodies is the result of a polyspecific immune response similar yet distinct from MS response rather than an elapsed infection of the CNS.

[1]  F. Paul,et al.  Complete Epstein-Barr virus seropositivity in a large cohort of patients with early multiple sclerosis , 2020, Journal of Neurology, Neurosurgery, and Psychiatry.

[2]  C. Yalçınkaya,et al.  Co-existence of multiple sclerosis and anti-NMDA receptor encephalitis: A case report and review of literature. , 2020, Multiple sclerosis and related disorders.

[3]  C. Geis,et al.  An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: mechanisms and models , 2019, The Lancet Neurology.

[4]  M. Sprengers,et al.  EBV-NMDA double positive encephalitis in an immunocompromised patient , 2019, Journal of the Neurological Sciences.

[5]  H. Butzkueven,et al.  Prognosis in autoimmune encephalitis: Database , 2018, Data in brief.

[6]  J. Dalmau,et al.  Antibody-Mediated Encephalitis. , 2018, The New England journal of medicine.

[7]  J. Kass,et al.  Anti-NMDAR encephalitis with concomitant varicella zoster virus detection and nonteratomatous malignancy , 2018, Neurology: Neuroimmunology & Neuroinflammation.

[8]  K. Ruprecht,et al.  Low intrathecal antibody production despite high seroprevalence of Epstein–Barr virus in multiple sclerosis: a review of the literature , 2018, Journal of Neurology.

[9]  A. Frigo,et al.  Herpes simplex virus‐induced anti‐N‐methyl‐d‐aspartate receptor encephalitis: a systematic literature review with analysis of 43 cases , 2017, Developmental medicine and child neurology.

[10]  C. Geis,et al.  Autoantibodies to Synaptic Receptors and Neuronal Cell Surface Proteins in Autoimmune Diseases of the Central Nervous System. , 2017, Physiological reviews.

[11]  K. Ruprecht,et al.  Antibody producing B lineage cells invade the central nervous system predominantly at the time of and triggered by acute Epstein-Barr virus infection: A hypothesis on the origin of intrathecal immunoglobulin synthesis in multiple sclerosis. , 2016, Medical hypotheses.

[12]  C. Klein,et al.  CSF herpes virus and autoantibody profiles in the evaluation of encephalitis , 2016, Neurology: Neuroimmunology & Neuroinflammation.

[13]  A. Venkatesan,et al.  A clinical approach to diagnosis of autoimmune encephalitis , 2016, The Lancet Neurology.

[14]  G. Akman-Demir,et al.  The MRZ reaction as a highly specific marker of multiple sclerosis: re-evaluation and structured review of the literature , 2016, Journal of Neurology.

[15]  F. Paul,et al.  Association of serum Epstein–Barr nuclear antigen-1 antibodies and intrathecal immunoglobulin synthesis in early multiple sclerosis , 2015, Journal of Neuroimmunology.

[16]  E. Granieri,et al.  Epstein-Barr virus-specific intrathecal oligoclonal IgG production in relapsing-remitting multiple sclerosis is limited to a subset of patients and is composed of low-affinity antibodies , 2014, Journal of Neuroinflammation.

[17]  J. Dalmau,et al.  Autoimmune encephalitis as differential diagnosis of infectious encephalitis. , 2014, Current opinion in neurology.

[18]  A. Vincent,et al.  N‐methyl‐D‐aspartate receptor antibodies in post–herpes simplex virus encephalitis neurological relapse , 2014, Movement disorders : official journal of the Movement Disorder Society.

[19]  G. Giovannoni,et al.  The risk of developing multiple sclerosis in individuals seronegative for Epstein-Barr virus: a meta-analysis , 2013, Multiple sclerosis.

[20]  K. Ruprecht,et al.  Measles IgG Antibody Index Correlates with T2 Lesion Load on MRI in Patients with Early Multiple Sclerosis , 2012, PloS one.

[21]  J. Carrillo,et al.  Low intrathecal immune response of anti-EBNA-1 antibodies and EBV DNA from multiple sclerosis patients. , 2011, Diagnostic microbiology and infectious disease.

[22]  B. Gärtner,et al.  Intrathecal EBV antibodies are part of the polyspecific immune response in multiple sclerosis , 2011, Neurology.

[23]  E. Granieri,et al.  Epstein-Barr virus-specific antibody response in cerebrospinal fluid and serum of patients with multiple sclerosis , 2010, Multiple sclerosis.

[24]  A. Ludolph,et al.  IgG Antibodies against Measles, Rubella, and Varicella Zoster Virus Predict Conversion to Multiple Sclerosis in Clinically Isolated Syndrome , 2009, PloS one.

[25]  F. Hanefeld,et al.  Intrathecal antibody production against Epstein-Barr and other neurotropic viruses in pediatric and adult onset multiple sclerosis , 2009, Journal of Neurology.

[26]  H. Reiber,et al.  Quantitation of intrathecal antibodies in cerebrospinal fluid of subacute sclerosing panencephalitis, herpes simplex encephalitis and multiple sclerosis: Discrimination between microorganism-driven and polyspecific immune response , 2007, Journal of Neuroimmunology.

[27]  A. Ascherio,et al.  Environmental risk factors for multiple sclerosis. Part I: The role of infection , 2007, Annals of neurology.

[28]  R. Whitley.  Herpes simplex encephalitis: adolescents and adults. , 2006, Antiviral research.

[29]  D Spiegelman,et al.  Epstein-Barr virus antibodies and risk of multiple sclerosis: a prospective study. , 2001, JAMA.

[30]  Hansotto Reiber,et al.  Cerebrospinal fluid analysis: disease-related data patterns and evaluation programs , 2001, Journal of the Neurological Sciences.

[31]  K. Heilman,et al.  Epstein–Barr virus nuclear antigen-1 (EBNA-1) associated oligoclonal bands in patients with multiple sclerosis , 2000, Journal of the Neurological Sciences.

[32]  H. Reiber.  Cerebrospinal fluid - physiology, analysis and interpretation of protein patterns for diagnosis of neurological diseases , 1998, Multiple sclerosis.

[33]  H. Reiber,et al.  Quantification of virus-specific antibodies in cerebrospinal fluid and serum: sensitive and specific detection of antibody synthesis in brain. , 1991, Clinical chemistry.