Akrivou, Sofia

Alexopoulos, Harry

Chalmoukou, Konstantina

Dalakas, Marinos C.

Reindl, Markus

Stathopoulos, Panos

Neurology: Neuroimmunology & Neuroinflammation

English

PubMed

Konstantina Chalmoukou

Harry Alexopoulos

Sofia Akrivou

Panos Stathopoulos

Markus Reindl

Marinos C. Dalakas

Crossref

Neurology Neuroimmunology & Neuroinflammation

Anti-MOG antibodies are frequently associated with steroid-sensitive recurrent optic neuritis

Jefferson Digital Commons

Thomas Jefferson UniversityJefferson Digital CommonsDepartment of Neurology Faculty Papers Department of Neurology8-1-2015Anti-MOG antibodies are frequently associatedwith steroid-sensitive recurrent optic neuritis.Konstantina ChalmoukouNational Kapodistrian University of AthensHarry AlexopoulosNational Kapodistrian University of AthensSofia AkrivouNational Kapodistrian University of AthensPanos StathopoulosNational Kapodistrian University of AthensMarkus ReindlNational Kapodistrian University of AthensSee next page for additional authorsLet us know how access to this document benefits youFollow this and additional works at: https://jdc.jefferson.edu/neurologyfpPart of the Neurology CommonsThis Article is brought to you for free and open access by the Jefferson Digital Commons. The Jefferson Digital Commons is a service of ThomasJefferson University's Center for Teaching and Learning (CTL). The Commons is a showcase for Jefferson books and journals, peer-reviewed scholarlypublications, unique historical collections from the University archives, and teaching tools. The Jefferson Digital Commons allows researchers andinterested readers anywhere in the world to learn about and keep up to date with Jefferson scholarship. This article has been accepted for inclusion inDepartment of Neurology Faculty Papers by an authorized administrator of the Jefferson Digital Commons. For more information, please contact:JeffersonDigitalCommons@jefferson.edu.Recommended CitationChalmoukou, Konstantina; Alexopoulos, Harry; Akrivou, Sofia; Stathopoulos, Panos; Reindl,Markus; and Dalakas, Marinos C., "Anti-MOG antibodies are frequently associated with steroid-sensitive recurrent optic neuritis." (2015). Department of Neurology Faculty Papers. Paper 134.https://jdc.jefferson.edu/neurologyfp/134AuthorsKonstantina Chalmoukou, Harry Alexopoulos, Sofia Akrivou, Panos Stathopoulos, Markus Reindl, andMarinos C. DalakasThis article is available at Jefferson Digital Commons: https://jdc.jefferson.edu/neurologyfp/134Clinical/ScientificNotesKonstantinaChalmoukou, MD*Harry Alexopoulos,DPhil*Sofia Akrivou, BScPanos Stathopoulos, MD,PhDMarkus Reindl, PhDMarinos C. Dalakas, MDNeurol NeuroimmunolNeuroinflamm2015;2:e131; doi: 10.1212/NXI.0000000000000131Supplemental data atNeurology.org/nnANTI-MOG ANTIBODIES ARE FREQUENTLYASSOCIATED WITH STEROID-SENSITIVERECURRENT OPTIC NEURITISOptic neuritis (ON) is an inflammatory disease of theoptic nerve characterized by pain and visual loss andoften associated with multiple sclerosis (MS) or neu-romyelitis optica spectrum disorders (NMOSD).Recent evidence suggests that certain forms of ONare associated with anti–myelin oligodendrocyte gly-coprotein (MOG) antibodies.1–4A distinct clinical subset of ON is characterized bymultiple episodes that involve one or both optic nerves,occur within months or weeks, and do not involve anyother associated clinical or radiologic findings. Thisentity, defined as either recurrent optic neuritis(rON) or chronic relapsing inflammatory optic neuritis(CRION),5 is typically corticosteroid-responsive andcorticosteroid-dependent, often requiring immuno-suppressive therapy for corticosteroid-sparing effect.Our aim was to determine whether aquaporin-4(AQP4)-negative patients with ON harbor antibodiesto MOG and whether anti-MOG antibodies are clin-ically relevant.Methods. We examined sera from 111 patients ini-tially referred to our diagnostic service for AQP4 test-ing. These patients had at least one episode ofunilateral or bilateral ON, as reported by their referringphysicians. All 111 patients were APQ4-negative.Twelve patients with primary progressive MS and 30patients with relapsing-remitting MS (RRMS) wereused as disease controls. The Ethics Committee ofthe University of Athens granted ethical approval.Anti-MOG screening was performed using a cell-based-assay (CBA). Patient sera (1:60 dilution) wereapplied on live human embryonic kidney 293T cellsand transiently transfected with full-length MOGenhanced green fluorescent protein followed by a goatanti-human secondary antibody (Alexa Fluor 568).Positive samples were retested and titrated in ablinded fashion by M.R.To investigate optic nerve specificity, anti-MOG–positive sera were applied onto 10 mm nonfixed or2% paraformaldehyde-fixed sections of fresh frozenhuman optic nerves (Netherlands Brain Bank,Amsterdam). A commercial monoclonal anti-MOGantibody was used as a positive control (Millipore,Billerica, MA; clone 8–18C5).Results. Anti-MOG antibodies were detected byCBA in 8/111 AQP4-seronegative patients and in0/42 MS disease controls (figure 1, B–D). All 8MOG-positive patients had at least one episode ofON, and 5 of them fulfilled the criteria for rON/CRION (defined as $3 episodes of ON within aperiod of a few months to a year). Fifteen of 30patients with RRMS had at least one episode ofON, and 10 of the 15 had a relapsing ON course.The 5 patients with rON/CRION (followed byM.C.D. for 2–11 years) had recurrent disease con-fined to optic nerves, often associated with or pre-ceded by pain. Brain/orbital MRI or CSF analyseswere normal except for optic nerve enhancement in2 patients. Spinal MRI depicted one small subclinicalchronic lesion in the cervical spine in one of thepatients who never developed any clinical symptomsof myelitis. Antibody titers did not correlate withdisease severity or number of relapses (figure 1A).All received IV steroids during the early attacks, butthey were subsequently maintained on a low-dose oralregimen. In 2 patients, the attacks occurred very fre-quently when the oral corticosteroid dose was loweredbelow 15–20 mg every other day, necessitating theconcurrent administration of an immunosuppressantsuch as mycophenolate mofetil. One patient withmultiple episodes over many years who eventuallydeveloped optic atrophy in one eye also received rit-uximab without success; relative stability (only 1 or 2episodes yearly) was induced by bimonthly plasma-pheresis (figure e-1 at Neurology.org/nn).As human MOG antibodies do not recognizeparaffin-fixed denaturated epitopes,6 we used fresh-frozen, nonfixed, or lightly fixed human optic nervetissue as substrate. No specific binding of the patients’sera or IgG was observed (figure e-2A).Discussion. We have characterized and longitudi-nally followed up 5/8 patients with anti-MOG–positive rON/CRION without spinal cord or brainsymptomatology These patients do not fall within therubric of NMOSD, and our follow-up revealed thatrelapses were confined to the optic nerves andwere highly sensitive to even low doses of oralNeurology.org/nn © 2015 American Academy of Neurology 1corticosteroids. Our results confirm recentobservations3,4 that anti-MOG antibodies arefrequently associated with recurrent forms of ON.Anti-MOG antibodies have also been associatedwith pediatric inflammatory demyelinating diseases,including acute disseminated encephalomyelitis.7 Acomparative epitope mapping of MOG antibodiesfrom different syndromes identified a dominantMOG epitope but failed to elucidate a causative rela-tionship or define distinct clinical phenotypes.6 Nobinding of patients’ sera was observed in our opticnerve preparations, in which native epitopes are pre-served. Whether the rON-associated anti-MOG anti-bodies are pathogenic, causing conduction block inthe optic nerve, demyelination, or edema, remainsunclear.Our observations suggest that anti-MOG antibod-ies are frequently associated with the rON/CRIONphenotype, which is a highly steroid-responsive disor-der. Although the rON series is small, the finding issupported by the observation that all of the RRMScontrol patients with ON were MOG-seronegative.*These authors contributed equally to this work.From the Neuroimmunology Unit (K.C., H.A., S.A., P.S., M.C.D.),Department of Pathophysiology, Faculty of Medicine, National andKapodistrian University of Athens, Greece; Clinical Department ofNeurology (M.R.), Medical University of Innsbruck, Austria; andDepartment of Neurology (M.C.D.), Thomas Jefferson University,Philadelphia, PA.Author contributions: Dr. Alexopoulos and Dr. Dalakas: study con-cept and design. Dr. Chalmoukou, Dr. Alexopoulos, Ms. Akrivou,Dr. Reindl, and Dr. Dalakas: acquisition of data. Dr. Chalmoukou,Dr. Alexopoulos, and Dr. Stathopoulos: data analysis and interpre-tation. Dr. Alexopoulos, Dr. Reindl, and Dr. Dalakas: drafting andcritical revision of the manuscript.Study funding: No targeted funding reported.Disclosure: K. Chalmoukou, H. Alexopoulos, and S. Akrivou reportno disclosures. P. Stathopoulos received research support from YaleFigure 1 Clinical characteristics and antibody profile of patients(A) Clinical characteristics of myelin oligodendrocyte glycoprotein (MOG)-positive patients with recurrent optic neuritis (rON). (B–D) Cell-based assay of arepresentative patient. (B) MOG– enhanced green fluorescent protein (EGFP) transfected human embryonic kidney 293T cells. (C) Immunostaining withserum of a representative patient with rON on live non-permeabilized MOG-EGFP transfected cells. (D) Merged immunofluorescence image that showscolocalization. Scale bar 5 100 mm. CS 5 corticosteroids; IVIg 5 IV immunoglobulin; ON 5 optic neuritis; PE 5 plasma exchange.2 Neurology: Neuroimmunology & Neuroinflammationand Hellenic Neurological Society. M. Reindl is an academic editorfor PLOS ONE; is on the editorial board for Current MedicinalChemistry and Autoimmune Diseases; and received research sup-port from Austrian Science Fund and Austrian Federal Ministry ofScience. M. Reindl and Medical University of Innsbruck receivepayments for antibody assays (AQP4 and antineuronal antibodies)and for AQP4 antibody validation experiments organized byEuroimmun. M.C. Dalakas is on the scientific advisory board forNovartis; received travel funding and/or speaker honoraria fromBaxter, CSL, Servier, Novartis, Hoffman LaRoche, and Merck-Serono; is on the editorial board for Neurology, Acta Myologica,and Acta Neurologica Scandinavica; is a section editor for BMCNeurology; is an associate editor for Therapeutic Advances inNeurology; has consulted for Therapath, Grifols, Novartis, Baxter,Octapharma, Hoffman LaRoche, Servier, and CSL; and receivedinstitutional support to Thomas Jefferson University or Universityof Athens Medical School from Merck-Serono, Genzyme, Novartis,CSL, Biogen, Genesis, TEVA, and Newfactor. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge waspaid by the Institute of Autoimmune, Systemic and NeurologicalDisorders.This is an open access article distributed under the terms of theCreative Commons Attribution-NonCommercial-NoDerivativesLicense 4.0 (CC BY-NC-ND), which permits downloading andsharing the work provided it is properly cited. The work cannot bechanged in any way or used commercially.Received February 24, 2015. Accepted in final form May 21, 2015.Correspondence to Dr. Dalakas: mdalakas@med.uoa.gr1. Kitley J, Woodhall M, Waters P, et al. Myelin-oligodendrocyteglycoprotein antibodies in adults with a neuromyelitis opticaphenotype. Neurology 2012;79:1273–1277.2. Rostásy K, Mader S, Hennes EM, et al. Persisting myelinoligodendrocyte glycoprotein antibodies in aquaporin-4antibody negative pediatric neuromyelitis optica. Mult Scler2013;19:1052–1059.3. Ramanathan S, Reddel SW, Henderson A, et al. Antibodiesto myelin oligodendrocyte glycoprotein in bilateral and recur-rent optic neuritis. Neurol Neuroimmunol Neuroinflamm2014;1:e40; doi: 10.1212/NXI.0000000000000040.4. Martinez-Hernandez E, Sepulveda M, Rostásy K, et al. Anti-bodies to aquaporin 4, myelin-oligodendrocyte glycoprotein,and the glycine receptor a1 subunit in patients with isolatedoptic neuritis. JAMA Neurol 2015;72:187–193.5. Kidd D, Burton B, Plant GT, Graham EM. Chronic relaps-ing inflammatory optic neuropathy (CRION). Brain 2003;126:276–284.6. Mayer MC, Breithaupt C, Reindl M, et al. Distinction andtemporal stability of conformational epitopes on myelin oli-godendrocyte glycoprotein recognized by patients with dif-ferent inflammatory central nervous system diseases.J Immunol 2013;191:3594–3604.7. Reindl M, Di Pauli F, Rostásy K, Berger T. The spectrumof MOG autoantibody-associated demyelinating diseases.Nat Rev Neurol 2013;9:455–461.Neurology: Neuroimmunology & Neuroinflammation 3

Anti-MOG antibodies are frequently associated with steroid-sensitive recurrent optic neuritis.

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Anti-MOG antibodies are frequently associated with steroid-sensitive recurrent optic neuritis.

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