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

      research-article
      1 , 2 , 3 , 1 , 2 , 4 , 1 , 2 , 5 , 1 , 2 , 1 , 2 , 3 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 3 , 6 , 3 , 6 , 13 , 14 , 14 , 1 , 2 , 14 , 4 , 14
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      Journal of Neurology, Neurosurgery, and Psychiatry
      BMJ Publishing Group
      myelin oligodendrocyte glycoprotein antibodies, optic neuritis, acute disseminated encephalomyelitis, therapy, outcomes

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          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.

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          Most cited references26

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          MOG antibody–positive, benign, unilateral, cerebral cortical encephalitis with epilepsy

          Objective: To describe the features of adult patients with benign, unilateral cerebral cortical encephalitis positive for the myelin oligodendrocyte glycoprotein (MOG) antibody. Methods: In this retrospective, cross-sectional study, after we encountered an index case of MOG antibody–positive unilateral cortical encephalitis with epileptic seizure, we tested for MOG antibody using our in-house, cell-based assay in a cohort of 24 consecutive adult patients with steroid-responsive encephalitis of unknown etiology seen at Tohoku University Hospital (2008–2014). We then analyzed the findings in MOG antibody–positive cases. Results: Three more patients, as well as the index case, were MOG antibody–positive, and all were adult men (median age 37 years, range 23–39 years). The main symptom was generalized epileptic seizure with or without abnormal behavior or consciousness disturbance. Two patients also developed unilateral benign optic neuritis (before or after seizure). In all patients, brain MRI demonstrated unilateral cerebral cortical fluid-attenuated inversion recovery hyperintense lesions, which were swollen and corresponded to hyperperfusion on SPECT. CSF studies showed moderate mononuclear pleocytosis with some polymorphonuclear cells and mildly elevated total protein levels, but myelin basic protein was not elevated. A screening of encephalitis-associated autoantibodies, including aquaporin-4, glutamate receptor, and voltage-gated potassium channel antibodies, was negative. All patients received antiepilepsy drugs and fully recovered after high-dose methylprednisolone, and the unilateral cortical MRI lesions subsequently disappeared. No patient experienced relapse. Conclusions: These MOG antibody–positive cases represent unique benign unilateral cortical encephalitis with epileptic seizure. The pathology may be autoimmune, although the findings differ from MOG antibody–associated demyelination and Rasmussen and other known immune-mediated encephalitides.
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            Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children.

            Forty-eight children with disseminated demyelination of the CNS, 28 with acute disseminated encephalomyelitis (ADEM), seven with multiphasic disseminated encephalomyelitis (MDEM) and 13 with multiple sclerosis were studied for a mean follow-up period of 5.64 years. The presentation findings of the ADEM/MDEM group were compared with those of the multiple sclerosis group. The following findings were more commonly seen in ADEM/MDEM presentation compared with the multiple sclerosis presentations: predemyelinating infectious disease (74 versus 38%, P: < 0.05); polysymptomatic presentation (91 versus 38%, P: < 0.002); pyramidal signs (71 versus 23%, P: < 0.01); encephalopathy (69 versus 15%, P: < 0.002); and bilateral optic neuritis (23 versus 8%, not significant). Seizures occurred only in the ADEM/MDEM group (17 versus 0%, not significant). Unilateral optic neuritis occurred only in the multiple sclerosis patients (23 versus 0%, P: < 0.01). There were no differences in the frequencies of transverse myelitis, brainstem involvement, cerebellar signs and sensory disturbance between the two groups. ADEM/MDEM patients were more likely to have blood leucocytosis (64 versus 22%, P: < 0.05), CSF lymphocytosis (64 versus 42%, not significant) and CSF protein elevation (60 versus 33%, not significant). Patients presenting with multiple sclerosis were more likely to have intrathecal synthesis of oligoclonal bands on presentation (64 versus 29%, not significant). MRI showed that subcortical white matter lesions were almost universal in both groups, though periventricular lesions were more common in multiple sclerosis (92 versus 44%, P: < 0.01). By contrast, in ADEM/MDEM there was absolute and relative periventricular sparing in 56 and 78% of patients, respectively. Follow-up MRI revealed complete or partial lesion resolution in 90% and no new lesions in the ADEM/MDEM group. All of the multiple sclerosis patients had new lesions on repeat MRI (five during relapse and six during asymptomatic convalescent phases). The outcome in the ADEM patients was mixed; 57% of patients made a complete recovery. The mean follow-up for the 35 ADEM/MDEM patients was 5.78 years (range 1.0-15.4 years). Eight of the 13 multiple sclerosis patients relapsed within the first year; 11 had a relapsing-remitting course, one a primary progressive course and one a secondary progressive course. These differences in the presentation of ADEM/MDEM compared with multiple sclerosis may help in the prognosis given to families regarding the possibility of later development of multiple sclerosis.
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              Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein.

              The role of autoantibodies in the pathogenesis of multiple sclerosis (MS) and other demyelinating diseases is controversial, in part because widely used western blotting and ELISA methods either do not permit the detection of conformation-sensitive antibodies or do not distinguish them from conformation-independent antibodies. We developed a sensitive assay based on self-assembling radiolabeled tetramers that allows discrimination of antibodies against folded or denatured myelin oligodendrocyte glycoprotein (MOG) by selective unfolding of the antigen domain. The tetramer radioimmunoassay (RIA) was more sensitive for MOG autoantibody detection than other methodologies, including monomer-based RIA, ELISA or fluorescent-activated cell sorting (FACS). Autoantibodies from individuals with acute disseminated encephalomyelitis (ADEM) selectively bound the folded MOG tetramer, whereas sera from mice with experimental autoimmune encephalomyelitis induced with MOG peptide immunoprecipitated only the unfolded tetramer. MOG-specific autoantibodies were identified in a subset of ADEM but only rarely in adult-onset MS cases, indicating that MOG is a more prominent target antigen in ADEM than MS.
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                Author and article information

                Journal
                J Neurol Neurosurg Psychiatry
                J. Neurol. Neurosurg. Psychiatry
                jnnp
                jnnp
                Journal of Neurology, Neurosurgery, and Psychiatry
                BMJ Publishing Group (BMA House, Tavistock Square, London, WC1H 9JR )
                0022-3050
                1468-330X
                February 2018
                15 November 2017
                : 89
                : 2
                : 127-137
                Affiliations
                [1 ] departmentBrain Autoimmunity Group , Institute for Neuroscience and Muscle Research, The Kids Research Institute at the Children’s Hospital , Westmead, New South Wales, Australia
                [2 ] departmentSydney Medical School , University of Sydney , Sydney, New South Wales, Australia
                [3 ] departmentDepartment of Neurology , Westmead Hospital , Westmead, New South Wales, Australia
                [4 ] departmentTY Nelson Department of Neurology and Neurosurgery , Children’s Hospital , Westmead, New South Wales, Australia
                [5 ] departmentDepartment of Clinical Medicine , Macquarie University , Sydney, New South Wales, Australia
                [6 ] University of Sydney , Sydney, New South Wales, Australia
                [7 ] departmentOcular Motor Research Laboratory , University of Melbourne , Melbourne, Victoria, Australia
                [8 ] departmentDepartment of Neurology , Royal Melbourne Hospital , Parkville, Victoria, Australia
                [9 ] departmentSchool of Medicine , Griffith University , Gold Coast, Queensland, Australia
                [10 ] departmentDepartment of Neurology , Gold Coast University Hospital , Gold Coast, Queensland, Australia
                [11 ] departmentDepartment of Neurology , John Hunter Hospital , Newcastle, New South Wales, Australia
                [12 ] departmentFaculty of Medicine and Public Health , Hunter Medical Research Institute, University of Newcastle , Newcastle, New South Wales, Australia
                [13 ] departmentDepartment of Ophthalmology , Westmead Hospital , Sydney, New South Wales, Australia
                [14 ] departmentBrain and Mind Centre , University of Sydney , Sydney, New South Wales, Australia
                Author notes
                [Correspondence to ] Russell C Dale, Clinical School, the Children’s Hospital at Westmead, Locked Bag 4001, NSW 2145, Australia; russell.dale@ 123456health.nsw.gov.au
                Author information
                http://orcid.org/0000-0002-2156-8864
                Article
                jnnp-2017-316880
                10.1136/jnnp-2017-316880
                5800335
                29142145
                f36ef98d-52de-4a6c-9488-b856ef2374ce
                © Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.

                This is an Open Access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

                History
                : 15 July 2017
                : 11 October 2017
                : 22 October 2017
                Funding
                Funded by: The Petre Foundation;
                Funded by: The National Blood Authorit IVIg Grant;
                Funded by: Sydney Research Excellence Initiative 2020 Neuroimmunology Group (University of Sydney, Australia);
                Funded by: The National Blood Authority IVIg Grant;
                Funded by: FundRef http://dx.doi.org/10.13039/501100000942, Brain Foundation;
                Funded by: FundRef http://dx.doi.org/10.13039/501100000924, Multiple Sclerosis Research Australia;
                Funded by: FundRef http://dx.doi.org/10.13039/501100000925, National Health and Medical Research Council;
                Categories
                Neuro-Inflammation
                1506
                Research paper
                Custom metadata
                unlocked

                Surgery
                myelin oligodendrocyte glycoprotein antibodies,optic neuritis,acute disseminated encephalomyelitis,therapy,outcomes

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