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Status of diagnostic approaches to AQP4-IgG seronegative NMO and NMO/MS overlap syndromes

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Abstract

Distinguishing aquaporin-4 IgG(AQP4-IgG)-negative neuromyelitis optica spectrum disorders (NMOSD) from opticospinal predominant multiple sclerosis (MS) is a clinical challenge with important treatment implications. The objective of the study was to examine whether expert clinicians diagnose and treat NMO/MS overlapping patients in a similar way. 12 AQP4-IgG-negative patients were selected to cover the range of clinical scenarios encountered in an NMO clinic. 27 NMO and MS experts reviewed their clinical vignettes, including relevant imaging and laboratory tests. Diagnoses were categorized into four groups (NMO, MS, indeterminate, other) and management into three groups (MS drugs, immunosuppression, no treatment). The mean proportion of agreement for the diagnosis was low (p o = 0.51) and ranged from 0.25 to 0.73 for individual patients. The majority opinion was divided between NMOSD versus: MS (nine cases), monophasic longitudinally extensive transverse myelitis (LETM) (1), acute disseminated encephalomyelitis (ADEM) (1) and recurrent isolated optic neuritis (RION) (1). Typical NMO features (e.g., LETM) influenced the diagnosis more than features more consistent with MS (e.g., short TM). Agreement on the treatment of patients was higher (p o = 0.64) than that on the diagnosis with immunosuppression being the most common choice not only in patients with the diagnosis of NMO (98 %) but also in those indeterminate between NMO and MS (74 %). The diagnosis in AQP4-IgG-negative NMO/MS overlap syndromes is challenging and diverse. The classification of such patients currently requires new diagnostic categories, which incorporate lesser degrees of diagnostic confidence. Long-term follow-up may identify early features or biomarkers, which can more accurately distinguish the underlying disorder.

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References

  1. Wingerchuk DM, Lennon V, Lucchinetti CF et al (2007) The spectrum of neuromyelitis optica. Lancet Neurol 6:805–815. doi:10.1016/S1474-4422(07)70216-8

    Article  CAS  PubMed  Google Scholar 

  2. Lennon VA, Wingerchuk DM, Kryzer TJ et al (2004) A serum autoantibody marker of neuromyelitis optica: Lancet 364:2106–2112

    CAS  PubMed  Google Scholar 

  3. Lennon VA, Kryzer TJ, Pittock SJ et al (2005) IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 202:473–477. doi:10.1084/jem.20050304

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  4. Palace J, Leite MI, Leite I, Jacob A (2012) A practical guide to the treatment of neuromyelitis optica. Pract Neurol 12:209–214. doi:10.1136/practneurol-2012-000237

    Article  PubMed  Google Scholar 

  5. Juryńczyk M, Craner M, Palace J (2015) Overlapping CNS inflammatory diseases: differentiating features of NMO and MS. J Neurol Neurosurg Psychiatry 86:20–25. doi:10.1136/jnnp-2014-308984

    Article  PubMed  Google Scholar 

  6. Matthews L, Marasco R, Jenkinson M et al (2013) Distinction of seropositive NMO spectrum disorder and MS brain lesion distribution. Neurology 80:1330–1337. doi:10.1212/01.wnl.0000436079.95856.1f

    Article  PubMed Central  PubMed  Google Scholar 

  7. Palace J, Leite MI, Nairne A, Vincent A (2010) Interferon Beta treatment in neuromyelitis optica: increase in relapses and aquaporin 4 antibody titers. Arch Neurol 67:1016–1017. doi:10.1001/archneurol.2010.188

    Article  PubMed  Google Scholar 

  8. Kleiter I, Hellwig K, Berthele A et al (2012) Failure of Natalizumab to Prevent Relapses in Neuromyelitis Optica. Arch Neurol 69:239–245. doi:10.1001/archneurol.2011.216

    Article  PubMed  Google Scholar 

  9. Jacob A, Kelly S, Ali R, Optica N (2012) Does Natalizumab Therapy Worsen Neuromyelitis Optica? Neurology 79:1065–1069

    Article  PubMed  Google Scholar 

  10. Juryńczyk M, Zaleski K, Selmaj K (2013) Natalizumab and the development of extensive brain lesions in neuromyelitis optica. J Neurol 260:1919–1921. doi:10.1007/s00415-013-6965-4

    Article  PubMed  Google Scholar 

  11. Min J-H, Kim BJ, Lee KH (2012) Development of extensive brain lesions following fingolimod (FTY720) treatment in a patient with neuromyelitis optica spectrum disorder. Mult Scler J 18:113–115. doi:10.1177/1352458511431973

    Article  CAS  Google Scholar 

  12. Kitley J, Woodhall M, Waters P et al (2012) Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology 79:1273–1277. doi:10.1212/WNL.0b013e31826aac4e

    Article  CAS  PubMed  Google Scholar 

  13. Kitley J, Waters P, Woodhall M et al (2014) Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol. doi:10.1001/jamaneurol.2013.5857

    Google Scholar 

  14. Sato DK, Callegaro D, Lana-Peixoto MA et al (2014) Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology 82:474–481. doi:10.1212/WNL.0000000000000101

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Fleiss JL (1971) Measuring nominal scale agreement among many raters. Psychol Bull 76:378–382

    Article  Google Scholar 

  16. Landis JR, Koch GG (1977) The measurement of observer agreement for categorical data. Biometrics 33:159–174

    Article  CAS  PubMed  Google Scholar 

  17. Koch-Henriksen N, Sørensen PS (2010) The changing demographic pattern of multiple sclerosis epidemiology. Lancet Neurol 9:520–532. doi:10.1016/S1474-4422(10)70064-8

    Article  PubMed  Google Scholar 

  18. Tackley G, Kuker W, Palace J (2014) Magnetic resonance imaging in neuromyelitis optica. Mult Scler. doi:10.1177/1352458514531087

    PubMed  Google Scholar 

  19. Kim HJ, Paul F, Lana-Peixoto MA et al (2015) MRI characteristics of neuromyelitis optica spectrum disorder: an international update. Neurology 84:1165–1173. doi:10.1212/WNL.0000000000001367

    Article  PubMed Central  PubMed  Google Scholar 

  20. Wingerchuk DM, Lennon VA, Pittock SJ et al (2006) Revised diagnostic criteria for neuromyelitis optica. Neurology 66:1485–1489. doi:10.1212/01.wnl.0000216139.44259.74

    Article  CAS  PubMed  Google Scholar 

  21. Wingerchuk DM, Banwell B, Bennett JL et al (2015) International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 85:177–189. doi:10.1212/WNL.0000000000001729

    Article  PubMed Central  PubMed  Google Scholar 

  22. Kitley JL, Leite MI, George JS, Palace J (2012) The differential diagnosis of longitudinally extensive transverse myelitis. Mult Scler 18:271–285. doi:10.1177/1352458511406165

    Article  CAS  PubMed  Google Scholar 

  23. Kitley J, Leite MI, Küker W et al (2013) Longitudinally extensive transverse myelitis with and without aquaporin 4 antibodies. JAMA Neurol 70:1375–1381. doi:10.1001/jamaneurol.2013.3890

    Article  PubMed  Google Scholar 

  24. Flanagan EP, Weinshenker BG, Krecke KN et al (2015) Short myelitis lesions in aquaporin-4-IgG-positive neuromyelitis optica spectrum disorders. JAMA Neurol 72:81–87. doi:10.1001/jamaneurol.2014.2137

    Article  PubMed Central  PubMed  Google Scholar 

  25. Kidd D, Burton B, Plant GT, Graham EM (2003) Chronic relapsing inflammatory optic neuropathy (CRION). Brain 126:276–284

    Article  CAS  PubMed  Google Scholar 

  26. Petzold A, Plant GT (2014) Chronic relapsing inflammatory optic neuropathy: a systematic review of 122 cases reported. J Neurol 261:17–26. doi:10.1007/s00415-013-6957-4

    Article  PubMed  Google Scholar 

  27. Paty DW, Oger JJ, Kastrukoff LF et al (1988) MRI in the diagnosis of MS: a prospective study with comparison of clinical evaluation, evoked potentials, oligoclonal banding, and CT. Neurology 38:180–185

    Article  CAS  PubMed  Google Scholar 

  28. Papeix C, Vidal J-S, de Seze J et al (2007) Immunosuppressive therapy is more effective than interferon in neuromyelitis optica. Mult Scler 13:256–259. doi:10.1177/1352458506070732

    Article  CAS  PubMed  Google Scholar 

  29. Matsuoka T, Matsushita T, Kawano Y et al (2007) Heterogeneity of aquaporin-4 autoimmunity and spinal cord lesions in multiple sclerosis in Japanese. Brain 130:1206–1223. doi:10.1093/brain/awm027

    Article  PubMed  Google Scholar 

  30. Kira J, Itoyama Y, Kikuchi S et al (2014) Fingolimod (FTY720) therapy in Japanese patients with relapsing multiple sclerosis over 12 months: results of a phase 2 observational extension. BMC Neurol 14:21. doi:10.1186/1471-2377-14-21

    Article  PubMed Central  PubMed  Google Scholar 

  31. Palace J, Rothwell P (1997) New treatments and azathioprine in multiple sclerosis. Lancet 350:261. doi:10.1016/S0140-6736(97)24030-4

    Article  CAS  PubMed  Google Scholar 

  32. Michel L, Vukusic S, De Seze J et al (2014) Mycophenolate mofetil in multiple sclerosis: a multicentre retrospective study on 344 patients. J Neurol Neurosurg Psychiatry 85:279–283. doi:10.1136/jnnp-2013-305298

    Article  CAS  PubMed  Google Scholar 

  33. Goodkin DE, Rudick RA, VanderBrug Medendorp S et al (1995) Low-dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol 37:30–40. doi:10.1002/ana.410370108

    Article  CAS  PubMed  Google Scholar 

  34. Hauser SL, Waubant E, Arnold DL et al (2008) B-cell depletion with rituximab in relapsing-remitting multiple sclerosis. N Engl J Med 358:676–688. doi:10.1056/NEJMoa0706383

    Article  CAS  PubMed  Google Scholar 

  35. Peabody JW, Luck J, Glassman P et al (2004) Measuring the quality of physician practice by using clinical vignettes: a prospective validation study. Ann Intern Med 141:771–780

    Article  PubMed  Google Scholar 

  36. Waters P, Woodhall M, O’Connor KC et al (2015) MOG cell-based assay detects non-MS patients with inflammatory neurologic disease. Neurol Neuroimmunol Neuroinflam 2:e89

    Article  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Nuffield Department of Clinical Neurosciences, Level 3, West Wing, John Radcliffe Hospital, University of Oxford, Headley Way, Headington, Oxford, OX3 9DU, UK

    Maciej Juryńczyk, Isabel Leite & Jacqueline Palace

  2. Department of Neurology, Mayo Clinic, 200 First Street SW, Rochester, 55905, MN, USA

    Brian Weinshenker

  3. Department of Neurology, School of Medicine, Istanbul Bilim University, Istanbul, Turkey

    Gulsen Akman-Demir

  4. Department of Neurology, Vejle Hospital and Neurobiology, Institute of Molecular Medicine, University of Southern Denmark, Odense, Denmark

    Nasrin Asgari

  5. Department of Neurology, Atkinson Morley’s Wing, St George’s Hospital, London, UK

    David Barnes & Damian Wren

  6. The Townsville Hospital, 100 Angus Smith Drive, Douglas Qld 4814, Douglas, Townsville, Australia

    Mike Boggild

  7. Department of Neurology, Queens Hospital Rom Valley Way, Romford, RM7 0AG, UK

    Abhijit Chaudhuri

  8. Department of Neurology, University Hospital Brussel, Vrije Universiteit Brussel, Brussels, Belgium

    Marie D’hooghe

  9. Division of Clinical Neuroscience, Queens Medical Center, University of Nottingham, Derby Road, Nottingham, NG7 2UH, UK

    Nikos Evangelou & Radu Tanasescu

  10. Neuroscience Department, Santa Maria Hospital, University of Lisbon, Lisbon, Portugal

    Ruth Geraldes

  11. Department of Neurology, Institute of Clinical Research, Odense, Odense University Hospital, University of Southern Denmark, Odense, Denmark

    Zsolt Illes

  12. NMO Clinical Service, The Walton Centre, Liverpool, UK

    Anu Jacob

  13. Department of Neurology, National Cancer Center, Seoul, South Korea

    Ho Jin Kim

  14. Department of Neurology, St. Josef-Hospital, Ruhr-University Bochum, Bochum, Germany

    Ingo Kleiter

  15. Neuromyelitis Optica Clinic, John Hopkins University, 1800 E. Orleans St., Baltimore, MD, 21287, USA

    Michael Levy

  16. Service de Neurologie A, Hopital Neurologique Pierre Wertheimer, Hospices Civils de Lyon, 69677, Lyon, France

    Romain Marignier & Sandra Vukusic

  17. University College Dublin, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland

    Christopher McGuigan

  18. Anne Rowling Regenerative Neurology Clinic, University of Edinburgh, Chancellor’s Building, Edinburgh, EH16 4SB, UK

    Katy Murray

  19. Department of Neurology, Tohoku University School of Medicine, Sendai, 980-8574, Japan

    Ichiro Nakashima

  20. Nitte University, Mangalore, 575018, Karnataka, India

    Lekha Pandit

  21. Department of Neurology, NeuroCure Clinical Research Center and Clinical and Experimental Multiple Sclerosis Research Center, Charité-Universitätsmedizin Berlin, Berlin, Germany

    Friedemann Paul

  22. Department of Neurology and Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Sean Pittock

  23. Department of Neurology, Medical University of Lodz, Lodz, Poland

    Maciej Juryńczyk & Krzysztof Selmaj

  24. Neurology Service, University Hospital of Strasbourg, Strasbourg, France

    Jérôme de Sèze

  25. Department of Neurology, Cerrahpasa School of Medicine, Istanbul University, Istanbul, Turkey

    Aksel Siva

  26. Department of Neurology, Neurosurgery and Psychiatry, University of Medicine and Pharmacy Carol Davila, Bucharest, Romania

    Radu Tanasescu

  27. Mayo Clinic Division of Multiple Sclerosis and Autoimmune Neurology, Mayo Clinic, 13400 E Shea BLVD, Scottsdale, 85259, AZ, USA

    Dean Wingerchuk

Authors
  1. Maciej Juryńczyk
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  2. Brian Weinshenker
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  3. Gulsen Akman-Demir
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  4. Nasrin Asgari
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  5. David Barnes
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  6. Mike Boggild
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  7. Abhijit Chaudhuri
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  8. Marie D’hooghe
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  9. Nikos Evangelou
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  10. Ruth Geraldes
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  11. Zsolt Illes
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  12. Anu Jacob
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  13. Ho Jin Kim
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  14. Ingo Kleiter
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  15. Michael Levy
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  16. Romain Marignier
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  17. Christopher McGuigan
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  18. Katy Murray
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  19. Ichiro Nakashima
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  20. Lekha Pandit
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  21. Friedemann Paul
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  22. Sean Pittock
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  23. Krzysztof Selmaj
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  24. Jérôme de Sèze
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  27. Sandra Vukusic
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  28. Dean Wingerchuk
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  29. Damian Wren
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  30. Isabel Leite
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  31. Jacqueline Palace
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Corresponding authors

Correspondence to Maciej Juryńczyk or Jacqueline Palace.

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Conflicts of interest

Dr. Jurynczyk received research fellowship from the Polish Ministry of Science and Higher Education programme Mobliność Plus (1070/MOB/2013/0). Dr. Weinshenker is a member of data safety monitoring boards: Novartis, Biogen Idec and Mitsubishi; Adjudication panel member: MedImmune. Consultant: Elan, GlaxoSmithKline, Ono, CHORD Therapeutics, and Chugai. Editorial board membership: Neurology, the Canadian Journal of Neurological Sciences, and the Turkish Journal of Neurology. Research support: Guthy-Jackson Charitable Foundation. Royalties and patent: RSR Ltd. and Oxford University for a patent regarding AQP4-associated antibodies for diagnosis of neuromyelitis optica. Dr. Akman-Demir reports no disclosures. Dr Asgari reports no disclosures. Dr. Barnes reports no disclosures. Dr. Boggild reports no disclosures. Dr Chaudhuri received travel grants, sponsorship for attending medical congresses, speaker fees and honoraria from: Novartis, Biogen Idec, Bayer-Schering, UCB, Eisai, Terumo BCT and Genzyme. Dr. D’hooghe reports no disclosures. Dr. Evangelou reports no disclosures. Dr. Geraldes reports no disclosures. Dr. Illes reports no disclosures. Dr. Jacob reports no disclosures. Dr. Kim reports no disclosures. Dr. Kleiter reports no disclosures. Dr. Levy reports no disclosures. Dr Marignier was supported by the European research project on rare diseases ERA-Net E-RARE-2 in the frame of the Eugene Devic European Network (EDEN) and Association pour la Recherche contre la Sclerose en Plaques(ARSEP) Foundation. Dr McGuigan has received research funding from Biogen Idec, Novartis, Bayer and Genzyme and honoraria for advisory boards from Biogen Idec, Novartis and Genzyme. Dr. Murray reports no disclosures. Dr. Nakashima reports no disclosures. Dr. Pandit reports no disclosures. Dr Paul was supported by the German Research Foundation (DFG Exc 257), the German Ministry for Education and Research (KKNMS Competence Network Multiple Sclerosis) and the Guthy-Jackson Charitable Foundation. Dr. Pittock reports no disclosures. Dr. Selmaj reports no disclosures. Dr. de Sèze reports no disclosures. Dr. Siva reports no disclosures. Dr. Tanasescu reports no disclosures. Dr. Vukusic reports no disclosures. Dr. Wingerchuk reports no disclosures. Dr. Wren reports no disclosures. Dr. Leite reports no disclosures. Dr. Palace reports no disclosures.

Ethical standards

This study has been performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki.

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All patients gave their informed consent to include their anonymised clinical data in the manuscript.

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415_2015_7952_MOESM4_ESM.pdf

The number of MS diagnoses per one expert depending on MS prevalence in the country where the expert practices. (PDF 30 kb)

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Juryńczyk, M., Weinshenker, B., Akman-Demir, G. et al. Status of diagnostic approaches to AQP4-IgG seronegative NMO and NMO/MS overlap syndromes. J Neurol 263, 140–149 (2016). https://doi.org/10.1007/s00415-015-7952-8

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  • DOI: https://doi.org/10.1007/s00415-015-7952-8

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