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

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Intrathecal Antibody Production Against Epstein-Barr, Herpes Simplex, and Other Neurotropic Viruses in Autoimmune Encephalitis ARTICLE OPEN ACCESS Intrathecal Antibody Production Against Epstein-Barr, Herpes Simplex, and Other Neurotropic Viruses in Autoimmune Encephalitis Philipp Schwenkenbecher, MD, Thomas Skripuletz, MD, Peter Lange, Marc Durr,¨ MD, Felix F. Konen, MD, Correspondence Nora Mohn,¨ MD, Marius Ringelstein, MD, Til Menge, MD, Manuel A. Friese, MD, Nico Melzer, MD, Dr. Schwenkenbecher schwenkenbecher.philipp@ ¨ Michael P. Malter, MD, Martin Hausler, MD, Franziska S. Thaler, MD, Martin Stangel, MD, Jan Lewerenz, MD, mh-hannover.de and Kurt-Wolfram Suhs,¨ MD, on behalf of the German Network for Research on Autoimmune Encephalitis Neurol Neuroimmunol Neuroinflamm 2021;8:e1062. doi:10.1212/NXI.0000000000001062 Abstract 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-specificAI 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. From the Department of Neurology (P.S., T.S., F.F.K., Nora Mohn,¨ M.S., K.-W.S.), Hannover Medical School; Department of Neurology (P.L.), Georg August University Gottingen;¨ Department of Neurology (M.D., J.L.), Ulm University; Department of Neurology (M.R.), Medical Faculty, Heinrich-Heine-University Dusseldorf;¨ Department of Neurology (M.R., T.M.), Centre for Neurology and Neuropsychiatry, LVR-Klinikum, Heinrich-Heine-University Dusseldorf;¨ Institute of Neuroimmunology and Multiple Sclerosis (M.A.F.), University Medical Center Hamburg-Eppendorf; Department of Neurology with Institute of Translational Neurology (Nico Melzer), University Hospital Muenster; Department of Neurology (M.P.M.), University Hospital Cologne; Division of Neuropediatrics and Social Pediatrics (M.H.), Department of Pediatrics, Medical Faculty, RWTH Aachen University; and Institute of Clinical Neuroimmunology (F.S.T.), University Hospital and Biomedical Center, Ludwig-Maximilians University Munich, Germany. Go to Neurology.org/NN for full disclosures. Funding information is provided at the end of the article. German Network for Research on Autoimmune Encephalitis (GENERATE) coinvestigators are listed in Appendix 2 at links.lww.com/NXI/A541. The Article Processing Charge was funded by Hannover Medical School. This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially without permission from the journal. Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology. 1 Glossary AE = autoimmune encephalitis; AI = antibody-specific index; CMV = cytomegalovirus; EBNA-1 = EBV-encoded nuclear antigen-I; EBV = Epstein-Barr virus; EBV-VCA = EBV-virus capsid antigen; HSV = herpes simplex virus; LGI1 = leucine-rich, glioma-inactivated 1; mRS = modified Rankin Scale; MRZ = measles, rubella, varicella zoster; MS = multiple sclerosis; NIND = noninflammatory neurologic disease; NMDAR = NMDA receptor; NPH = normal pressure hydrocephalus; IIH = idiopathic intracranial hypertension; OCB = oligoclonal band; QAlb = CSF/serum albumin ratio; VZV = varicella zoster virus. Autoimmune encephalitis (AE) is a group of inflammatory were recruited by the German Network for Research on CNS diseases associated with antibodies against neural Autoimmune Encephalitis (GENERATE; generate.net) antigens.1 These antibodies can either be directed against with detection of anti-NMDAR or anti-LGI1 antibodies intracellular antigens or against cell surface antigens caus- enrolled until 2016 were identified, and clinical and labo- ing neuronal dysfunction.2 The most common AE is asso- ratory data were extracted from the GENERATE database. ciated with antibodies against the cell surface antigen Only adult patients aged 18 years or older who fulfilled the NMDA receptor (NMDAR).1 The second most common recently suggested diagnostic criteria for definitive AE one is associated with antibodies against leucine-rich, (with detection of antibodies against cell surface).10 with a glioma-inactivated 1 (LGI1).1 A clinical association be- sufficient clinical documentation and a complete CSF tween herpes simplex virus (HSV) encephalitis and anti- workup without evidence of any other inflammatory dis- NMDAR encephalitis has been described.3 It is hypothe- ease of the CNS were included. Part of the results of 20 of sized that the HSV, and possibly other neurotropic viruses, these (14 patients with anti-NMDAR encephalitis and 6 can trigger the production of antibodies against the with anti-LGI1 encephalitis) including the AIs for measles, NMDAR and other neuronal cell surface proteins.1 One rubella, and varicella zoster virus (VZV) is described in mechanism could be that these viruses may lyse neurons, more detail in the accompanying article (D¨urr et al., 2021, releasing antigens that sensitize antibodies to the NMDAR submitted). and initiate autoimmune reactivity.4 Epstein-Barr virus (EBV), another member of the herpes virus family, might The modified Rankin Scale (mRS) score, which indicates the act in a similar way as it is known to be a potential trigger for extent of functional impairment due to the neurologic disease, a wide range of autoimmune disorders.5 was extracted from the medical records for all patients with AE. The peak mRS score during the hospital stay and the mRS An association between multiple sclerosis (MS) and EBV score at discharge were evaluated. infections has been described in several articles.6 In par- ticular, the almost universal EBV seroprevalence in pa- The control group of NIND consisted of patients with normal tients with MS and the extremely low MS risk in EBV- pressure hydrocephalus (NPH) and patients with idiopathic seronegative patients have been emphasized.7-9 Of in- intracranial hypertension (IIH). Prodromal symptoms in- terest, the frequency of intrathecally produced antibodies cluded fever and signs of upper respiratory or gastrointestinal to EBV in patients with MS is paradoxically low compared infection, which occurred within 4 weeks before onset of with that of other common viruses.6 In comparison with neurologic symptoms. MS, little is known about the association between EBV and AE. Another control group comprised patients with MS di- agnosed according to the McDonald criteria of 2010. Patients In this study, we investigated the frequency and titer of in the control groups were admitted to Hannover Medical intrathecal synthesis of antibodies against EBV and HSV, School between 2016 and 2018 and sex and age matched. and other neurotropic viruses measles, rubella, varicella zoster (MRZ), and cytomegalovirus (CMV), in patients Analytical Procedures with AE in comparison to control groups consisting of CSF and paired serum samples were collected as part of fl routine diagnostic workup. A leukocyte count in CSF samples patients with MS and nonin ammatory neurologic diseases μ fi ff (NIND). >4 cells/ L was de ned as pleocytosis. The cuto for total CSF protein levels was set to >500 mg/L. Concentrations of albumin, IgG, IgA, and IgM were measured nephelometri- Methods cally, and the CSF/serum ratios of albumin, IgG, IgA, and IgM were calculated. The age-dependent upper reference limit for Patients the CSF/serum ratio of albumin (QAlb), as an indicator for Medical records of patients admitted to the Department of the CSF/blood barrier, was calculated according to the for- 11 Neurology at Hannover Medical School between 2014 and mula QAlbumin = 4 + (age in y/15). The intrathecally pro- 2019 were screened for the diagnosis of AE with detection duced fraction of IgG, IgA, and IgM was determined by of NMDAR or LG1 antibodies. In addition, patients who plotting the CSF/serum ratio vs QAlb according to the 2 Neurology: Neuroimmunology & Neuroinflammation | Volume 8, Number 6 | November 2021 Neurology.org/NN Table 1 CSF Characteristics of Patients With AE (Anti-NMDAR and LGI1) in Comparison to Control Groups (MS and NIND) AE Controls Total (n = 27) Anti-NMDAR (n =
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