Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination

doi:10.1136/jnnp-2017-316880

. 2018 Feb;89(2):127-137.

doi: 10.1136/jnnp-2017-316880. Epub 2017 Nov 15.

Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination

Sudarshini Ramanathan^{1

2

3}, Shekeeb Mohammad^{1

2

4}, Esther Tantsis^{1

2

5}, Tina Kim Nguyen^{1

2}, Vera Merheb^{1

2}, Victor S C Fung^{3

6}, Owen Bruce White^{7

8}, Simon Broadley^{9

10}, Jeannette Lechner-Scott^{11

12}, Steve Vucic^{3

6}, Andrew P D Henderson^{3

6

13}, Michael Harry Barnett¹⁴, Stephen W Reddel¹⁴, Fabienne Brilot^{1

2

14}, Russell C Dale^{4

14}; Australasian and New Zealand MOG Study Group

Collaborators, Affiliations

Collaborators

Australasian and New Zealand MOG Study Group:
Pi Andrews, Jl Barton, Jnc Burrow, H Butzkueven, Ag Cairns, S Calvert, P Caruana, S Chelakkadan, D Clark, Cl Fraser, Jl Freeman, D Gill, Pj Grattan-Smith, S Gupta, Ta Hardy, K Kothur, Sr Ling, Ja Lopez, S Malone, Mp Marriott, M Nosadini, Gl O'grady, Cf Orr, R Ouvrier, J Parratt, E Patrick, D Pilli, Ds Riminton, K Riney, V Rodriguez-Casero, Mm Ryan, Ie Scheffer, Uh Shah, N Shuey, Cg Spooner, Gm Subramanian, F Tea, T Thomas, J Thompson, C Troedson, Tl Ware, Ri Webster, C Yiannikas, Em Yiu, A Zou

Affiliations

¹ Brain Autoimmunity Group, Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children's Hospital, Westmead, New South Wales, Australia.
² Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
³ Department of Neurology, Westmead Hospital, Westmead, New South Wales, Australia.
⁴ TY Nelson Department of Neurology and Neurosurgery, Children's Hospital, Westmead, New South Wales, Australia.
⁵ Department of Clinical Medicine, Macquarie University, Sydney, New South Wales, Australia.
⁶ University of Sydney, Sydney, New South Wales, Australia.
⁷ Ocular Motor Research Laboratory, University of Melbourne, Melbourne, Victoria, Australia.
⁸ Department of Neurology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
⁹ School of Medicine, Griffith University, Gold Coast, Queensland, Australia.
¹⁰ Department of Neurology, Gold Coast University Hospital, Gold Coast, Queensland, Australia.
¹¹ Department of Neurology, John Hunter Hospital, Newcastle, New South Wales, Australia.
¹² Faculty of Medicine and Public Health, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
¹³ Department of Ophthalmology, Westmead Hospital, Sydney, New South Wales, Australia.
¹⁴ Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.

PMID: 29142145
PMCID: PMC5800335
DOI: 10.1136/jnnp-2017-316880

Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination

Sudarshini Ramanathan et al. J Neurol Neurosurg Psychiatry. 2018 Feb.

. 2018 Feb;89(2):127-137.

doi: 10.1136/jnnp-2017-316880. Epub 2017 Nov 15.

Authors

Collaborators

Australasian and New Zealand MOG Study Group:
Pi Andrews, Jl Barton, Jnc Burrow, H Butzkueven, Ag Cairns, S Calvert, P Caruana, S Chelakkadan, D Clark, Cl Fraser, Jl Freeman, D Gill, Pj Grattan-Smith, S Gupta, Ta Hardy, K Kothur, Sr Ling, Ja Lopez, S Malone, Mp Marriott, M Nosadini, Gl O'grady, Cf Orr, R Ouvrier, J Parratt, E Patrick, D Pilli, Ds Riminton, K Riney, V Rodriguez-Casero, Mm Ryan, Ie Scheffer, Uh Shah, N Shuey, Cg Spooner, Gm Subramanian, F Tea, T Thomas, J Thompson, C Troedson, Tl Ware, Ri Webster, C Yiannikas, Em Yiu, A Zou

Affiliations

¹ Brain Autoimmunity Group, Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children's Hospital, Westmead, New South Wales, Australia.
² Sydney Medical School, University of Sydney, Sydney, New South Wales, Australia.
³ Department of Neurology, Westmead Hospital, Westmead, New South Wales, Australia.
⁴ TY Nelson Department of Neurology and Neurosurgery, Children's Hospital, Westmead, New South Wales, Australia.
⁵ Department of Clinical Medicine, Macquarie University, Sydney, New South Wales, Australia.
⁶ University of Sydney, Sydney, New South Wales, Australia.
⁷ Ocular Motor Research Laboratory, University of Melbourne, Melbourne, Victoria, Australia.
⁸ Department of Neurology, Royal Melbourne Hospital, Parkville, Victoria, Australia.
⁹ School of Medicine, Griffith University, Gold Coast, Queensland, Australia.
¹⁰ Department of Neurology, Gold Coast University Hospital, Gold Coast, Queensland, Australia.
¹¹ Department of Neurology, John Hunter Hospital, Newcastle, New South Wales, Australia.
¹² Faculty of Medicine and Public Health, Hunter Medical Research Institute, University of Newcastle, Newcastle, New South Wales, Australia.
¹³ Department of Ophthalmology, Westmead Hospital, Sydney, New South Wales, Australia.
¹⁴ Brain and Mind Centre, University of Sydney, Sydney, New South Wales, Australia.

PMID: 29142145
PMCID: PMC5800335
DOI: 10.1136/jnnp-2017-316880

Abstract

Objective: We characterised the clinical course, treatment and outcomes in 59 patients with relapsing myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination.

Methods: We evaluated clinical phenotypes, annualised relapse rates (ARR) prior and on immunotherapy and Expanded Disability Status Scale (EDSS), in 218 demyelinating episodes from 33 paediatric and 26 adult patients.

Results: The most common initial presentation in the cohort was optic neuritis (ON) in 54% (bilateral (BON) 32%, unilateral (UON) 22%), followed by acute disseminated encephalomyelitis (ADEM) (20%), which occurred exclusively in children. ON was the dominant phenotype (UON 35%, BON 19%) of all clinical episodes. 109/226 (48%) MRIs had no brain lesions. Patients were steroid responsive, but 70% of episodes treated with oral prednisone relapsed, particularly at doses <10 mg daily or within 2 months of cessation. Immunotherapy, including maintenance prednisone (P=0.0004), intravenous immunoglobulin, rituximab and mycophenolate, all reduced median ARRs on-treatment. Treatment failure rates were lower in patients on maintenance steroids (5%) compared with non-steroidal maintenance immunotherapy (38%) (P=0.016). 58% of patients experienced residual disability (average follow-up 61 months, visual loss in 24%). Patients with ON were less likely to have sustained disability defined by a final EDSS of ≥2 (OR 0.15, P=0.032), while those who had any myelitis were more likely to have sustained residual deficits (OR 3.56, P=0.077).

Conclusion: Relapsing MOG antibody-associated demyelination is strongly associated with ON across all age groups and ADEM in children. Patients are highly responsive to steroids, but vulnerable to relapse on steroid reduction and cessation.

Keywords: acute disseminated encephalomyelitis; myelin oligodendrocyte glycoprotein antibodies; optic neuritis; outcomes; therapy.

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Conflict of interest statement

Competing interests: Dr SR has received research funding from the National Health and Medical Research Council, the Petre Foundation and the Brain Foundation (Australia). Dr SM has received a scholarship from the National Health and Medical Research Council (Australia) and funding from the National Blood Authority IVIg grant. SB has received honoraria for attendance at advisory boards and travel sponsorship from Bayer-Schering, Biogen-Idec, Merck-Serono, Novartis and Sanofi-Genzyme, has received speakers honoraria from Biogen-Idec and Genzyme, is an investigator in clinical trials sponsored by Biogen-Idec, Novartis and Genzyme and was the recipient of an unencumbered research grant from Biogen-Idec. JL-S has accepted travel compensation from Novartis, Biogen and Merck-Serono. Her institution receives the honoraria for talks and advisory board commitment as well as research grants from Bayer Health Care, Biogen, Sanofi-Genzyme, Merck, Novartis and Teva. SR reports grants and personal fees from Sanofi-Genzyme, personal fees and departmental support from the Government of Australia, Baxter, Biogen, CSL and Merck; and departmental support from Novartis, outside the subject of the submitted work. Associate Professor FB has received research funding from the Star Scientific Foundation, The Trish Multiple Sclerosis Research Foundation, Multiple Sclerosis Research Australia and the National Health Medical Research Council (Australia). RD has received research funding from the Star Scientific Foundation, The Trish Multiple Sclerosis Research Foundation, Multiple Sclerosis Research Australia, the Petre Foundation and the National Health Medical Research Council (Australia). Dr RCD has received honoraria from Biogen-Idec as an invited speaker. Dr JLB has received compensation for education travel, honoraria for talks and advisory boards from Biogen, Teva, Merck-Serono, Sanofi-Genzyme, Novartis and Roche. Dr AC has received honoraria for attendance at advisory boards from Biogen and is an investigator in clinical trials sponsored by Biogen and Pfizer. Dr PC has accepted travel compensation from, Biogen and Merck Serono, and fellowship funding from Novartis/Biogen. Associate Professor CLF has received payment from Roche as a consultant. Dr MPM has received travel grants, speaking honoraria and unconditional research funding from Bayer, Biogen and Merck. Professor IES is supported by NHMRC Program Grant (1091593, 2016–2020) and Senior Practitioner Fellowship (1104831, 2016– 2020). IES serves on the editorial boards of Neurology and Epileptic Disorders; may accrue future revenue on a pending patent report: therapeutic compound; has received speakers honoraria from Athena Diagnostics, UCB, GSK, Eisai and Transgenomics; has received scientific advisory board honoraria from Nutricia and GSK, has received funding for travel from Athena Diagnostics, UCB and GSK and receives/has received research support from the NHMRC, ARC, NIH, Health Research Council of New Zealand, March of Dimes, the Weizmann Institute, CURE, US Department of Defense and the Perpetual Charitable Trustees. Dr EY is supported by an NHMRC Early Career Fellowship (APP1073323).

Figures

**Figure 1**
The clinical phenotype and steroid response in relapsing MOG antibody-associated demyelination. (A) Illustration of the clinical phenotype at first presentation of all patients in the cohort, with a breakdown reflecting the distribution of each clinical phenotype in the paediatric age group (0–16 years at disease onset), and adult group (>16 years at disease onset). (B) Illustration of the clinical phenotype at all presentations (n=218, initial presentation plus relapses) in the cohort, with a breakdown reflecting the distribution of each clinical phenotype in the paediatric and adult group. (C) An illustration of the number of relapses that occurred during tapering oral prednisone (and the dose of prednisone at which these relapses occurred), or following the cessation of an oral prednisone taper (and the time frame at which these relapses occurred). ADEM, acute disseminated encephalomyelitis; BON, bilateral optic neuritis; LETM, longitudinally extensive transverse myelitis; TM, transverse myelitis; UON, unilateral optic neuritis.

**Figure 2**
Disease activity of myelin oligodendrocyte glycoprotein antibody-positive patients on immunosuppressive therapy. (A) Depictions of the clinical course and disease activity in patients who underwent therapy with maintenance prednisone. In patients who had more than two courses of maintenance prednisone lasting ≥6 months each, the green lines depict the duration of each course of maintenance corticosteroid therapy. Depictions of the clinical course and disease activity in patients who underwent therapy with monthly intravenous immunoglobulin (IVIg) (B), mycophenolate (C) and rituximab (D). (E) Illustration of response to switched therapy in the event of side effects (patient 46 azathioprine to mycophenolate), treatment failure of the initial agent (patient 38 mycophenolate to rituximab, patient 58 methotrexate to rituximab, patient 39 methotrexate to mycophenolate, patient 8 mycophenolate to monthly IVIg and patient 57 azathioprine to mycophenolate), or after exceeding the maximum recommended cumulative dose of the first agent (patient 33 cyclophosphamide to azathioprine). All therapy (or switched therapy) commenced at time point 0. The magenta lines represent a demyelinating episode. The purple squares represent time of switched treatment cessation. The orange circles represent time of latest clinical follow-up. The blue arrows represent timing of rituximab dosing.

**Figure 3**
Recovery and outcomes in relapsing myelin oligodendrocyte glycoprotein antibody-associated demyelination. (A) Median EDSS and range of the cohort at the nadir and at recovery after each demyelinating episode. (B) Percentage of patients with residual disability in a particular domain. (C) Recovery status of all clinical episodes based on clinical phenotype. ADEM, acute disseminated encephalomyelitis; BON, bilateral optic neuritis; E, episode; EDSS, Expanded Disability Status Scale; cyclo, cyclophosphamide; IVIg, intravenous immunoglobulin; LETM, longitudinally extensive transverse myelitis; PLEX, plasma exchange; RTX, rituximab; TM, transverse myelitis; UON, unilateral optic neuritis.

See this image and copyright information in PMC

Comment in

Clinical course of MOG antibody-associated recurrent demyelinating diseases.
Reindl M. Reindl M. J Neurol Neurosurg Psychiatry. 2018 Feb;89(2):118. doi: 10.1136/jnnp-2017-317249. Epub 2017 Nov 24. J Neurol Neurosurg Psychiatry. 2018. PMID: 29175896 No abstract available.
Myelin oligodendrocyte glycoprotein antibody-associated disease: characterising clinical disease.
Willis MD, Robertson NP. Willis MD, et al. J Neurol. 2018 Aug;265(8):1950-1952. doi: 10.1007/s00415-018-8963-z. J Neurol. 2018. PMID: 29992350 Free PMC article. No abstract available.

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References

1. Schluesener HJ, Sobel RA, Linington C, et al. . A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyelination in central nervous system autoimmune disease. J Immunol 1987;139:4016–21. - PubMed
1. Brunner C, Lassmann H, Waehneldt TV, et al. . Differential ultrastructural localization of myelin basic protein, myelin/oligodendroglial glycoprotein, and 2',3'-cyclic nucleotide 3'-phosphodiesterase in the CNS of adult rats. J Neurochem 1989;52:296–304. 10.1111/j.1471-4159.1989.tb10930.x - DOI - PubMed
1. O’Connor KC, McLaughlin KA, De Jager PL, et al. . Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat Med 2007;13:211–7. 10.1038/nm1488 - DOI - PMC - PubMed
1. Brilot F, Dale RC, Selter RC, et al. . Antibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease. Ann Neurol 2009;66:833–42. 10.1002/ana.21916 - DOI - PubMed
1. Kitley J, Waters P, Woodhall M, et al. . Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol 2014;71:276–83. 10.1001/jamaneurol.2013.5857 - DOI - PubMed

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[1] Schluesener HJ, Sobel RA, Linington C, et al. . A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyelination in central nervous system autoimmune disease. J Immunol 1987;139:4016–21. - PubMed

[2] Schluesener HJ, Sobel RA, Linington C, et al. . A monoclonal antibody against a myelin oligodendrocyte glycoprotein induces relapses and demyelination in central nervous system autoimmune disease. J Immunol 1987;139:4016–21. - PubMed

[3] Brunner C, Lassmann H, Waehneldt TV, et al. . Differential ultrastructural localization of myelin basic protein, myelin/oligodendroglial glycoprotein, and 2',3'-cyclic nucleotide 3'-phosphodiesterase in the CNS of adult rats. J Neurochem 1989;52:296–304. 10.1111/j.1471-4159.1989.tb10930.x - DOI - PubMed

[4] Brunner C, Lassmann H, Waehneldt TV, et al. . Differential ultrastructural localization of myelin basic protein, myelin/oligodendroglial glycoprotein, and 2',3'-cyclic nucleotide 3'-phosphodiesterase in the CNS of adult rats. J Neurochem 1989;52:296–304. 10.1111/j.1471-4159.1989.tb10930.x - DOI - PubMed

[5] O’Connor KC, McLaughlin KA, De Jager PL, et al. . Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat Med 2007;13:211–7. 10.1038/nm1488 - DOI - PMC - PubMed

[6] O’Connor KC, McLaughlin KA, De Jager PL, et al. . Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat Med 2007;13:211–7. 10.1038/nm1488 - DOI - PMC - PubMed

[7] Brilot F, Dale RC, Selter RC, et al. . Antibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease. Ann Neurol 2009;66:833–42. 10.1002/ana.21916 - DOI - PubMed

[8] Brilot F, Dale RC, Selter RC, et al. . Antibodies to native myelin oligodendrocyte glycoprotein in children with inflammatory demyelinating central nervous system disease. Ann Neurol 2009;66:833–42. 10.1002/ana.21916 - DOI - PubMed

[9] Kitley J, Waters P, Woodhall M, et al. . Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol 2014;71:276–83. 10.1001/jamaneurol.2013.5857 - DOI - PubMed

[10] Kitley J, Waters P, Woodhall M, et al. . Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol 2014;71:276–83. 10.1001/jamaneurol.2013.5857 - DOI - PubMed

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Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination

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Clinical course, therapeutic responses and outcomes in relapsing MOG antibody-associated demyelination

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