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[This corrects the article DOI: 10.3389/fneur.2023.1216477.].
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INTRODUCTION: Body fluid markers could be helpful to predict the conversion into clinically definite multiple sclerosis (MS) in people with a first demyelinating event of the central nervous system (CNS). Consequently, biomarkers such as oligoclonal bands, which are integrated in the current MS diagnostic criteria, could assist early MS diagnosis. AREAS COVERED: This review examines existing knowledge on a broad spectrum of body fluid markers in people with a first CNS demyelinating event, explores their potential to predict conversion to MS, to assess MS disease activity, as well as their utility to differentiate MS from atypical demyelinating disorders such as neuromyelitis optica spectrum disorder and myelin oligodendrocyte glycoprotein associated disease. EXPERT OPINION: This field of research has shown a dramatic increase of evidence, especially in the last decade. Some biomarkers are already established in clinical routine (e.g. oligoclonal bands) while others are currently implemented (e.g. kappa free light chains) or considered as breakthroughs (e.g. neurofilament light). Determination of biomarkers poses challenges for continuous monitoring, especially if exclusively detectable in cerebrospinal fluid. A handful of biomarkers are measurable in blood which holds a significant potential.
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Transverse myelitis (TM) is the second most common presentation of myelin oligodendrocyte antibody-associated disease (MOGAD), occurring in approximately 26% of affected patients. The diagnosis may be complicated by the lack of diagnostic specificity of low titers of MOG antibody in serum, fluctuation in seropositivity overtime, including initially normal MRI in up to 10% of patients, and in many instances complete resolution of radiological abnormalities when MRI is done in a significantly delayed fashion. The use of preventive disease modifying treatments is limited by the uncertainty whether the disease process will remain monophasic or become relapsing, as well as by the lack FDA approved treatments. In this review, we discuss clinical, radiological and cerebrospinal fluid (CSF) characteristics, including the significance of MOG titers and changes in the seropositivity status for the diagnosis of MOGAD-associated TM, its radiological features and management options, highlighting the data on the risk of relapses associated with TM at presentation and the need for further randomized clinical trials to empower effective treatment algorithms.
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OBJECTIVE: The differences in magnetic resonance imaging (MRI) between children with classic acute disseminated encephalomyelitis (ADEM) and myelinal oligodendrocyte glycoprotein antibody associated disease (MOGAD) with ADEM-like presentation are controversial. The purpose of this study was to investigate whether the radiological characteristics of the MRI-FLAIR sequence can predict MOGAD in children with ADEM-like presentation and to further explore its imaging differences. METHODS: We extracted 1041 radiomics features from MRI-FLAIR lesions. Then we used the redundancy analysis (Spearman correlation coefficient), significance test (student test or Mann-Whitney U test), least absolute contraction and selection operator (LASSO) to select potential predictors from the feature groups. The selected potential predictors and MOG antibody test results were used to fit the machine learning model for classification. Combined with feature selection and machine learning classifiers, the optimal model for each subgroup was derived. The resulting models have been evaluated using the receiver operator characteristic curve (ROC) at the lesion level and the model performance was evaluated at the case level using decision curve analysis. RESULTS: We retrospectively reviewed and re-diagnosed 70 ADEM-like presentation cases in our center from April 2015 to January 2020. Including 49 cases with classic ADEM and 21 cases with MOGAD. 30(43%) were female, with a median age of 5.3 years. On the four subgroups by age and gender, the area under the curve (AUC) of the optimal models were 89%, 90%, 98%, and 99%, and the MOGAD detection rates (Specificity) were 83%, 83%, 92%, and 75%, respectively. CONCLUSIONS: The machine learning model trained on radiomics features of MR-FLAIR images can effectively predict patients' MOGAD. This study provides a fast, objective, and quantifiable method for MOGAD diagnosis.
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Encephalomyelitis, Acute Disseminated , Female , Male , Humans , Retrospective Studies , Magnetic Resonance Imaging/methods , AutoantibodiesABSTRACT
The first formal consensus diagnostic criteria for myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) were recently proposed. Yet, the distinction of MOGAD-defining characteristics from characteristics of its important differential diagnoses such as multiple sclerosis (MS) and aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder (NMOSD) is still obstructed. In preclinical research, MOG antibody-based animal models were used for decades to derive knowledge about MS. In clinical research, people with MOGAD have been combined into cohorts with other diagnoses. Thus, it remains unclear to which extent the generated knowledge is specifically applicable to MOGAD. Translational research can contribute to identifying MOGAD characteristic features by establishing imaging methods and outcome parameters on proven pathophysiological grounds. This article reviews suitable animal models for translational MOGAD research and the current state and prospect of translational imaging in MOGAD.
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BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an autoimmune demyelinating disorder of the central nervous system. METHODS: Extracted proteins from 34 cerebrospinal fluid (CSF) samples [patients with MOGAD (MOG group, n = 12); healthy controls (HC group, n = 12); patients with MOG seronegative and metagenomics next-generation sequencing-negative inflammatory neurological diseases (IND group, n = 10)] were processed and subjected to label-free quantitative proteomics. Supervised partial least squares-discriminant analysis (PLS-DA) and orthogonal PLS-DA (O-PLS-DA) models were also performed based on proteomics data. Functional analysis of differentially expressed proteins (DEPs) was performed using Gene Ontology, InterPro, and Kyoto Encyclopedia Genes and Genomes. An enzyme-linked immunosorbent assay was used to determine the complement levels in serum from patients with MOGAD. RESULTS: Four hundred and twenty-nine DEPs (149 upregulated and 280 downregulated proteins) were identified in the MOG group compared to the HC group according to the P value and fold change (FC). Using the O-PLS-DA model, 872 differentially abundant proteins were identified with variable importance projection (VIP) scores > 1. Five proteins (gamma-glutamyl hydrolase, cathepsin F, interalpha-trypsin inhibitor heavy chain 5, latent transforming growth factor beta-binding protein 4 and leukocyte-associated immunoglobulin-like receptor 1) overlapping between the top 30 DEPs with top-ranked P value and FC and top 30 proteins in PLS-DA VIP lists were acquired. Functional analysis revealed that the dysregulated proteins in the MOG group were primarily involved in complement and coagulation cascades, cell adhesion, axon guidance, and glycosphingolipid biosynthesis compared to the HC group. CONCLUSION: The proteomic alterations in CSF samples from children with MOGAD identified in the current study might provide opportunities for developing novel biomarker candidates.
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Transverse myelitis is a subacute immune mediated myelopathy secondary to a range of conditions. Post infectious transverse myelitis can be seen with several infectious etiologies. Myelin oligodendrocyte glycoprotein associated disease (MOGAD) is a relatively recently defined condition frequently manifesting with longitudinally extensive transverse myelitis. Cases of MOGAD have occurred after infection, typically respiratory tract infections. We report an unusual case of MOGAD transverse myelitis following a streptococcal brain abscess which has not been previously reported.
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Brain Abscess , Myelitis, Transverse , Myelitis , Autoantibodies , Brain Abscess/complications , Brain Abscess/etiology , Humans , Myelin-Oligodendrocyte Glycoprotein , Myelitis, Transverse/diagnostic imaging , Myelitis, Transverse/etiologyABSTRACT
PURPOSE: To identify the retina-structural and visual-functional alterations in the patients with aquaporin-4 (AQP4)-IgG-positive neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein-associated disease (MOGAD), and multiple sclerosis (MS) patients, all of whom had demyelinating transverse myelitis (TM) without optic neuritis (ON). METHODS: In this retrospective cross-sectional study, we reviewed the medical records of 97 patients, including 23 with AQP4-ON, 13 with AQP4-TM, 32 with MOG-ON, 3 with MOG-TM, 13 with MS-ON, and 13 with MS-TM. We measured the thickness of the retinal nerve fiber layer (RNFL) and the ganglion cell layer-inner plexiform layer (GCIPL) using optical coherence tomography to evaluate structural changes and compared these parameters with those of an age-matched healthy control. Functional outcomes were measured as visual acuity and mean deviation in visual field test. RESULTS: Mean RNFL and GCIPL thicknesses in all of the patients with TM were lower relative to the healthy control, while visual function was well preserved. Among the TM patients, RNFL thickness did not vary significantly among the groups, whereas GCIPL thickness in AQP4-TM and MS-TM was significantly lower than that in MOG-TM. All three TM groups showed significant mean RNFL reduction compared with the healthy control, whereas mean GCIPL thinning was evident only in AQP4-TM and MS-TM, not in MOG-TM. CONCLUSION: Patients with demyelinating TM incur retina-microstructural damage that varies by specific disease entity. Damage is distinct in AQP4-IgG-positive NMOSD and MS, but it is not so severe as to cause functional damage.
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Multiple Sclerosis , Myelitis, Transverse , Neuromyelitis Optica , Optic Neuritis , Humans , Myelitis, Transverse/diagnostic imaging , Retrospective Studies , Cross-Sectional Studies , Autoantibodies , Aquaporin 4 , Myelin-Oligodendrocyte Glycoprotein , Neuromyelitis Optica/diagnostic imaging , Optic Neuritis/diagnostic imaging , Retina/diagnostic imaging , Multiple Sclerosis/complications , Multiple Sclerosis/diagnostic imaging , Immunoglobulin GABSTRACT
Signs and symptoms of optic neuritis (ON), an autoimmune disorder of the central nervous system (CNS), differ between patients. Pain, which is commonly reported by ON patients, may be the major reason for some patients to visit the clinic. This article reviews the presence of pain related to ON with respect to underlying disorders, including multiple sclerosis (MS), neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein associated disease (MOGAD). The aim of this review is to provide an overview of pain symptoms in accordance with the context of various pathophysiological explanations, assist in differential diagnosis of ON patients, especially at the onset of disease, and make recommendations to aid physicians make decisions for follow up diagnostic examinations.
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BACKGROUND AND PURPOSE: Optic neuritis (ON) is often the initial symptom of neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein-associated disease (MOGAD). We aimed to compare the frequency and pattern of chiasmatic lesions in MOGAD-related ON (MOGAD-ON) and NMOSD-related ON (NMOSD-ON) using conventional brain imaging (magnetic resonance imaging [MRI]) in Latin America (LATAM). METHODS: We reviewed the medical records and brain MRI (≤30 days from ON onset) of patients with a first event of MOGAD-ON and NMOSD-ON. Patients from Argentina (n = 72), Chile (n = 21), Ecuador (n = 31), Brazil (n = 30), Venezuela (n = 10) and Mexico (n = 82) were included. Antibody status was tested using a cell-based assay. Demographic, clinical, imaging and prognostic (as measured by the Visual Functional System Score [VFSS] of the Expanded Disability Status Scale) data were compared. RESULTS: A total of 246 patients (208 NMOSD and 38 MOGAD) were included. No differences were found in gender and ethnicity between the groups. We observed chiasmatic lesions in 66/208 (31.7%) NMOSD-ON and in 5/38 (13.1%) MOGAD-ON patients (p = 0.01). Of these patients with chiasmatic lesions, 54/66 (81.8%) and 4/5 had associated longitudinally extensive optic nerve lesions, 45/66 (68%) and 4/5 had bilateral lesions, and 31/66 (47%) and 4/5 showed gadolinium-enhancing chiasmatic lesions, respectively. A positive correlation was observed between VFSS and presence of bilateral (r = 0,28, p < 0.0001), chiasmatic (r = 0.27, p = 0.0001) and longitudinally extensive lesions (r = 0,25, p = 0.0009) in the NMOSD-ON group, but no correlations were observed in the MOGAD-ON group. CONCLUSIONS: Chiasmatic lesions were significantly more common in NMOSD than in MOGAD during an ON attack in this LATAM cohort. Further studies are needed to assess the generalizability of these results.
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Neuromyelitis Optica , Optic Neuritis , Aquaporin 4 , Autoantibodies , Humans , Latin America , Magnetic Resonance Imaging , Myelin-Oligodendrocyte Glycoprotein , Optic Neuritis/diagnostic imagingABSTRACT
Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) causes major disability as a consequence of recurrent demyelinating events and neuronal loss. Biomarkers identifying different phenotypes of recurrence or tissue damage might be useful to guide individualized therapy. Herein, we evaluated serum neurofilament light chain (sNfL) as a potential biomarker in both adult and pediatric MOGAD patients. Forty-nine patients with MOGAD (37 adults, 12 children) and 71 healthy controls (HCs) (56 adults, 15 children) were enrolled prospectively from September 2019 to April 2021 at the Third Affiliated Hospital of Sun Yat-sen University and the Children's Hospital, Zhejiang University School of Medicine. sNfL levels were determined using ultrasensitive single-molecule array assay and correlated with clinical parameters. The sNfL levels in MOGAD adults in a relapsed state (median: 31.0 pg/ml) were higher than those in a remission state (8.1 pg/ml, p = 0.001) and in HC adults (10.3 pg/ml, p = 0.004). Similar results were observed in children (relapse: 46.8 pg/ml vs. remission: 13.1 pg/ml, p = 0.001; and vs. HCs: 8.2 pg/ml, p = 0.007) sNfL levels were correlated with recent relapses within 60 days (multivariate: ß = 2.02, p = 0.003), seizures (multivariate: ß = 2.50, p = 0.021) and brain lesions on magnetic resonance imaging (MRI) of a recent relapse (multivariate: ß = 1.72, p = 0.012). Our study showed that sNfL levels are beneficial for identifying recent relapses and seizures and suggest that adult and pediatric MOGAD patients had similar sNfL levels.
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Intermediate Filaments , Neurofilament Proteins , Biomarkers , Child , Humans , Myelin-Oligodendrocyte Glycoprotein , Recurrence , SeizuresABSTRACT
BACKGROUND: Optic neuritis (ON) is frequently encountered in multiple sclerosis, neuromyelitis optica spectrum disorder, anti-myelin oligodendrocyte glycoprotein associated disease, and other systemic autoimmune disorders. The hallmarks are an abnormal optic nerve and inflammatory demyelination; episodes of optic neuritis tend to be recurrent, and particularly for neuromyelitis optica spectrum disorder, may result in permanent vision loss. MAIN BODY: Mesenchymal stem cell (MSC) therapy is a promising approach that results in remyelination, neuroprotection of axons, and has demonstrated success in clinical studies in other neuro-degenerative diseases and in animal models of ON. However, cell transplantation has significant disadvantages and complications. Cell-free approaches utilizing extracellular vesicles (EVs) produced by MSCs exhibit anti-inflammatory and neuroprotective effects in multiple animal models of neuro-degenerative diseases and in rodent models of multiple sclerosis (MS). EVs have potential to be an effective cell-free therapy in optic neuritis because of their anti-inflammatory and remyelination stimulating properties, ability to cross the blood brain barrier, and ability to be safely administered without immunosuppression. CONCLUSION: We review the potential application of MSC EVs as an emerging treatment strategy for optic neuritis by reviewing studies in multiple sclerosis and related disorders, and in neurodegeneration, and discuss the challenges and potential rewards of clinical translation of EVs including cell targeting, carrying of therapeutic microRNAs, and prolonging delivery for treatment of optic neuritis.
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Extracellular Vesicles , Mesenchymal Stem Cells , Neuromyelitis Optica , Optic Neuritis , Animals , Myelin-Oligodendrocyte Glycoprotein , Neuromyelitis Optica/complications , Optic Neuritis/complications , Optic Neuritis/therapyABSTRACT
BACKGROUND: The impact of myelin oligodendrocyte glycoprotein antibody disease (MOGAD) on brain structure and function is unknown. OBJECTIVES: The aim of this study was to study the multimodal brain MRI alterations in MOGAD and to investigate their clinical significance. METHODS: A total of 17 MOGAD, 20 aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorders (AQP4 + NMOSD), and 28 healthy controls (HC) were prospectively recruited. Voxel-wise gray matter (GM) volume, fractional anisotropy (FA), mean diffusivity (MD), and degree centrality (DC) were compared between groups. Clinical associations and differential diagnosis were determined using partial correlation and stepwise logistic regression. RESULTS: In comparison with HC, MOGAD had GM atrophy in frontal and temporal lobe, insula, thalamus, and hippocampus, and WM fiber disruption in optic radiation and anterior/posterior corona radiata; DC decreased in cerebellum and increased in temporal lobe. Compared to AQP4 + NMOSD, MOGAD presented lower GM volume in postcentral gyrus and decreased DC in cerebellum. Hippocampus/parahippocampus atrophy associated with Expanded Disability Status Scale (R = -0.55, p = 0.04) and California Verbal Learning Test (R = 0.62, p = 0.031). The differentiation of MOGAD from AQP4 + NMOSD achieved an accuracy of 95% using FA in splenium of corpus callosum and DC in occipital gyrus. CONCLUSION: Distinct structural and functional alterations were identified in MOGAD. Hippocampus/parahippocampus atrophy associated with clinical disability and cognitive impairment.
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Aquaporin 4 , Neuromyelitis Optica , Brain/diagnostic imaging , Gray Matter/diagnostic imaging , Humans , Myelin-Oligodendrocyte Glycoprotein , Neuromyelitis Optica/diagnostic imagingABSTRACT
Myelin oligodendrocyte glycoprotein (MOG)-associated disease (MOGAD) is a rare, antibody-mediated inflammatory demyelinating disorder of the central nervous system (CNS) with various phenotypes starting from optic neuritis, via transverse myelitis to acute demyelinating encephalomyelitis (ADEM) and cortical encephalitis. Even though sometimes the clinical picture of this condition is similar to the presentation of neuromyelitis optica spectrum disorder (NMOSD), most experts consider MOGAD as a distinct entity with different immune system pathology. MOG is a molecule detected on the outer membrane of myelin sheaths and expressed primarily within the brain, spinal cord and also the optic nerves. Its function is not fully understood but this glycoprotein may act as a cell surface receptor or cell adhesion molecule. The specific outmost location of myelin makes it a potential target for autoimmune antibodies and cell-mediated responses in demyelinating processes. Optic neuritis seems to be the most frequent presenting phenotype in adults and ADEM in children. In adults, the disease course is multiphasic and subsequent relapses increase disability. In children ADEM usually presents as a one-time incident. Luckily, acute immunotherapy is very effective and severe disability (ambulatory and visual) is less frequent than in NMOSD. A critical element of reliable diagnosis is detection of pathogenic serum antibodies MOG with accurate, specific and sensitive methods, preferably with optimized cell-based assay (CBA). MRI imaging can also help in differentiating MOGAD from other neuro-inflammatory disorders. Reports on randomised control trials are limited, but observational open-label experience suggests a role for high-dose steroids and plasma exchange in the treatment of acute attacks, and for immunosuppressive therapies, such as steroids, oral immunosuppressants and rituximab as maintenance treatment. In this review, we present up-to-date clinical, immunological, radiographic, histopathological data concerning MOGAD and summarize the practical aspects of diagnosing and managing patients with this disease.
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Adrenal Cortex Hormones/therapeutic use , Autoantibodies/immunology , Demyelinating Autoimmune Diseases, CNS , Immunosuppressive Agents/therapeutic use , Myelin-Oligodendrocyte Glycoprotein/immunology , Plasma Exchange , Rituximab/therapeutic use , Animals , Demyelinating Autoimmune Diseases, CNS/diagnosis , Demyelinating Autoimmune Diseases, CNS/immunology , Demyelinating Autoimmune Diseases, CNS/physiopathology , Demyelinating Autoimmune Diseases, CNS/therapy , HumansABSTRACT
BACKGROUND: Patients with anti-aquaporin-4 (AQP4) water channel antibody-positive neuromyelitis optica spectrum disorders (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein (MOG) associated disease (MOGAD) often present with similar clinical symptoms, and some cases are hard to differentiate at the time of onset. In this study, we compared the clinical characteristics, cerebrospinal fluid (CSF) analysis parameters, and peripheral T/B lymphocyte subsets during the active and chronic phases in AQP4-NMOSD and MOGAD. METHODS: A total of 17 MOGAD cases and 24 AQP4-NMOSD cases were studied. The clinical characteristics in both groups were summarized, including disease duration, total number of attacks, lesions, prevention of relapse during remission, and CSF analysis results during the active phase. T/B lymphocyte subsets were further investigated in the active and chronic phases. RESULTS: In the comparative study on clinical symptoms, a large proportion of optic neuritis was unilateral in MOGAD. In the comparative study on CSF analysis, protein level was significantly lower in MOGAD compared with AQP4-NMOSD (p = 0.006); myelin basic protein was significantly lower in MOGAD compared with AQP4-NMOSD (p = 0.04); albumin quotient was significantly lower in MOGAD compared with AQP4-NMOSD (p = 0.02); and IgG Quotient was significantly lower in MOGAD compared with AQP4-NMOSD (p = 0.05). In the analysis of T/B lymphocyte subsets, plasmablasts of the B cell subset in the active phase were significantly lower in MOGAD (2.1 ± 2.4) compared to AQP4-NMOSD (7.8 ± 7.2) (p < 0.05). In the chronic phase, transitional B cells were significantly higher in MOGAD (2.1 ± 1.8) compared to AQP4-NMOSD (0.6 ± 0.4) (p < 0.01). CONCLUSION: Clinical characteristics of MOGAD were similar to those of AQP4-NMOSD, but increased blood brain barrier permeability was suggested to be less severe in MOGAD compared to AQP4-NMOSD from CSF analysis. Furthermore, the pathogenesis of the two diseases was clearly distinct as plasmablasts in the active phase were not elevated in MOGAD, but were increased in AQP4-NMOSD.