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      Microstructural visual system changes in AQP4-antibody–seropositive NMOSD

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          Abstract

          Objective:

          To trace microstructural changes in patients with aquaporin-4 antibody (AQP4-ab)-seropositive neuromyelitis optica spectrum disorders (NMOSDs) by investigating the afferent visual system in patients without clinically overt visual symptoms or visual pathway lesions.

          Methods:

          Of 51 screened patients with NMOSD from a longitudinal observational cohort study, we compared 6 AQP4-ab–seropositive NMOSD patients with longitudinally extensive transverse myelitis (LETM) but no history of optic neuritis (ON) or other bout (NMOSD-LETM) to 19 AQP4-ab–seropositive NMOSD patients with previous ON (NMOSD-ON) and 26 healthy controls (HCs). Foveal thickness (FT), peripapillary retinal nerve fiber layer (pRNFL) thickness, and ganglion cell and inner plexiform layer (GCIPL) thickness were measured with optical coherence tomography (OCT). Microstructural changes in the optic radiation (OR) were investigated using diffusion tensor imaging (DTI). Visual function was determined by high-contrast visual acuity (VA). OCT results were confirmed in a second independent cohort.

          Results:

          FT was reduced in both patients with NMOSD-LETM ( p = 3.52e −14) and NMOSD-ON ( p = 1.24e −16) in comparison with HC. Probabilistic tractography showed fractional anisotropy reduction in the OR in patients with NMOSD-LETM ( p = 0.046) and NMOSD-ON ( p = 1.50e −5) compared with HC. Only patients with NMOSD-ON but not NMOSD-LETM showed neuroaxonal damage in the form of pRNFL and GCIPL thinning. VA was normal in patients with NMOSD-LETM and was not associated with OCT or DTI parameters.

          Conclusions:

          Patients with AQP4-ab–seropositive NMOSD without a history of ON have microstructural changes in the afferent visual system. The localization of retinal changes around the Müller-cell rich fovea supports a retinal astrocytopathy.

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          Most cited references23

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          Robust determination of the fibre orientation distribution in diffusion MRI: non-negativity constrained super-resolved spherical deconvolution.

          Diffusion-weighted (DW) MR images contain information about the orientation of brain white matter fibres that potentially can be used to study human brain connectivity in vivo using tractography techniques. Currently, the diffusion tensor model is widely used to extract fibre directions from DW-MRI data, but fails in regions containing multiple fibre orientations. The spherical deconvolution technique has recently been proposed to address this limitation. It provides an estimate of the fibre orientation distribution (FOD) by assuming the DW signal measured from any fibre bundle is adequately described by a single response function. However, the deconvolution is ill-conditioned and susceptible to noise contamination. This tends to introduce artefactual negative regions in the FOD, which are clearly physically impossible. In this study, the introduction of a constraint on such negative regions is proposed to improve the conditioning of the spherical deconvolution. This approach is shown to provide FOD estimates that are robust to noise whilst preserving angular resolution. The approach also permits the use of super-resolution, whereby more FOD parameters are estimated than were actually measured, improving the angular resolution of the results. The method provides much better defined fibre orientation estimates, and allows orientations to be resolved that are separated by smaller angles than previously possible. This should allow tractography algorithms to be designed that are able to track reliably through crossing fibre regions.
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            Does MOG Ig-positive AQP4-seronegative opticospinal inflammatory disease justify a diagnosis of NMO spectrum disorder?

            While neuromyelitis optica (NMO) immunoglobulin (Ig) G is considered the hallmark serologic marker of NMO, its association is not absolute, as NMO IgG is not detected in approximately one-fourth of the patients diagnosed with NMO spectrum disorder (NMOSD). Thus, the recent discovery that antibodies to myelin oligodendrocyte glycoprotein (MOG) are detected in some NMO IgG-seronegative patients manifesting clinical and neuroimaging signs of NMO or NMOSD has created tremendous excitement. However, it may be premature to classify this subgroup as NMOSD. NMO is considered an autoimmune astrocytopathy, and aquaporin-4 (AQP4), expressed on astrocytes, is recognized as the target autoantigen of NMO IgG. As its name denotes, MOG is produced by oligodendrocytes, CNS myelin-producing cells, and MOG is well-recognized as one of the candidate autoantigens in multiple sclerosis (MS) and acute disseminated encephalomyelitis (ADEM). Thus, is it possible that the clinical NMOSD-like phenotype associated with MOG-specific antibodies represents a variant of opticospinal MS or ADEM but not AQP4 autoimmunity or NMOSD? Whether this MOG-Ig positive AQP4-seronegative phenotype should be classified as NMOSD, opticospinal MS, or a unique entity is not simply a theoretical question but rather has practical implications for patients, their physicians, insurance carriers, and clinical investigators conducting NMO treatment trials.
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              Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica

              Objective Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD). Methods Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1). Results Results of tests on 92 controls identified 12assays as highly specific (0–1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5–100%) of all 21 assays. The specificities (85.8–100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples. Conclusions The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.
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                Author and article information

                Contributors
                Journal
                Neurol Neuroimmunol Neuroinflamm
                Neurol Neuroimmunol Neuroinflamm
                nnn
                NEURIMMINFL
                Neurology® Neuroimmunology & Neuroinflammation
                Lippincott Williams & Wilkins (Hagerstown, MD )
                2332-7812
                22 February 2017
                May 2017
                22 February 2017
                : 4
                : 3
                : e334
                Affiliations
                From the NeuroCure Clinical Research Center (F.C.O., J.K., H.Z., C.C., F.S., J.B.-S., M.S., F.P., A.U.B.), and Department of Neurology (J.K., F.S., J.B.-S., K.R., F.P.), Charité—Universitätsmedizin Berlin; Department of Neurology (B.K., T.K.), Klinikum rechts der Isar, and Department of Experimental Neuroimmunology (T.K.), Technische Universität München; Munich Cluster for Systems Neurology (SyNergy) (T.K.), Germany; Clinical Ophthalmology and Eye Health (A.K.), Central Clinical School, Save Sight Institute, Sydney, Australia; and Experimental and Clinical Research Center (F.P.), Max Delbrueck Center for Molecular Medicine and Charité—Universitätsmedizin Berlin, Germany.
                Author notes
                Correspondence to Dr. Brandt: alexander.brandt@ 123456charite.de
                [*]

                These authors contributed equally to this work.

                Funding information and disclosures are provided at the end of the article. Go to Neurology.org/nn for full disclosure forms. The Article Processing Charge was paid by the authors.

                Article
                NEURIMMINFL2016011726
                10.1212/NXI.0000000000000334
                5322864
                28255575
                61cde411-2097-4493-bbc8-682f67067590
                Copyright © 2017 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.

                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.

                History
                : 01 December 2016
                : 10 January 2017
                Funding
                Funded by: German Research Foundation
                Award ID: DFG Exc. 257
                Funded by: German Federal Ministry of Economic Affairs and Energy
                Award ID: EXIST 03EFEBE079
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