Myelin Oligodendrocyte Glycoprotein Research Articles

COVID-19 and optic neuritis: a series of three cases and a critical review

BackgroundThe novel coronavirus disease (COVID-19) has claimed innumerable lives globally since its onset and several extrapulmonary manifestations of the disease have been reported in association with COVID-19. Although optic neuropathy has been previously linked to a variety of infections, neuro-ophthalmological associations of SARS-CoV-2 have been sparsely reported till date. Our aim was to report the clinical profile and outcome of patients diagnosed with parainfectious/postinfectious optic neuritis (ON) associated with COVID-19.Case presentationIn this case series, we have discussed the clinical presentation, laboratory parameters and outcome in a series of three patients of ON associated with COVID-19 and also compared those findings against existing literature. Among the three patients, two patients (Case 1, 3) were incidentally diagnosed with COVID-19 during the course of hospital admission and contributed to a parainfectious association with ON, while one patient (Case 2) had an antecedent history of COVID-19 as evidenced by her antibody titers thus contributing to a postinfectious association. Notably, all these patients were asymptomatic or had mild manifestations of COVID-19 and all of them tested negative for myelin oligodendrocyte glycoprotein (MOG) antibodies. They were treated accordingly and their visual outcomes were noted in follow-up.ConclusionON with or without MOG seropositivity, probably attributed to molecular mimicry has surfaced up considerably in association with COVID-19. This article provides a comprehensive overview of clinical presentation and outcome of ON associated with parainfectious/postinfectious COVID-19 in three cases and a critical analysis of existing literature.

Myelin oligodendrocyte glycoprotein antibody‐associated disorders: An overview

AbstractIn recent years, there is growing evidence of associations between antibodies against myelin oligodendrocyte glycoprotein (MOG) and several phenotypes of acute inflammatory demyelinating diseases such as acute disseminated encephalomyelitis (ADEM), optic neuritis, brainstem, and cerebral cortical encephalitis, called MOG antibody associated disorders (MOGAD). Monophasic course is known in about half of cases especially in pediatric onset ADEM and optic neuritis, mainly in cases with transient positivity of MOG antibody. Pathological features of MOGAD are considered as acute demyelinating lesions with CD4 dominant cell infiltrations, the deposition of humoral immunity, perivascular inflammation and perivenous demyelination, which is distinct from multiple sclerosis. Now the diagnosis of MOGAD is based on the international panel criteria of MOGAD launched in 2023, which the diagnostic frameworks are three parts, including MOGAD‐specific clinical features, MOG antibody positivity, and the exclusion of other diseases. The prognosis of MOGAD patients is considered relatively mild, but the problem is refractory relapsing cases. For its prevention, there are no approved drugs, but oral tapering corticosteroids, immunosuppressants such as azathioprine and mycophenolic mofetil, rituximab, and the maintenance intravenous immunoglobulin are recommended, and now there are a few clinical trials of promising biological drugs already approved in other neurological disorders.

A 66-Year-Old Woman Presented with Sudden Onset Eye Pain and Loss of Vision: Do Not Miss MOGAD

A 66 -year- old woman presented to ED with sudden onset eye pain and unilateral loss of vision. She had considerable vascular risk factors including age, hypertension, diabetes mellitus and hypercholesterolemia. She was referred to neurology service with possible arteritic anterior ischemic optic neuropathy (AION). Given her age, painful visual loss and raised ESR, she was treated with steroids for possible giant cell arteritis (GCA). Because of her psychiatric history and poorly controlled diabetes mellitus, steroids were weaned quickly. 6 months later, she had a similar presentation affecting the other eye. MRI head showed disease progression with positive myelin oligodendrocyte glycoprotein (MOG) antibody in serum. MOG associated disorder (MOG-AD) is a steroid responsive inflammatory demyelinating disease but needs long term immunosuppression plan and monitoring of serum antibody.

Glymphatic System Dysfunction in Myelin Oligodendrocyte Glycoprotein Immunoglobulin G Antibody-Associated Disorders: Association with Clinical Disability.

Impaired glymphatic function has been suggested to be implicated in the pathophysiology of MS and aquaporin-4 immunoglobulin G-positive neuromyelitis optica spectrum disorder. This study aimed to investigate the interstitial fluid dynamics in the brain in patients with myelin oligodendrocyte glycoprotein antibody disorders (MOGAD), another demyelinating disorder, using a noninvasive imaging technique called the diffusivity along the perivascular space (ALPS) index. A prospective study was conducted on 16 patients with MOGAD in remission and 22 age- and sex-matched healthy control subjects. MR imaging was performed using a 3T scanner, and the ALPS index was calculated using diffusion MR imaging data with a b-value of 1000 s/mm2. The ALPS index and gray matter volumes were compared between the 2 groups, and these parameters were correlated with the Expanded Disability Status Scale. The mean ALPS index of patients with MOGAD was significantly lower than that of healthy controls (Cohen d = 0.93, false discovery rate-corrected P = .02). The lower mean ALPS index was significantly associated with a worse Expanded Disability Status Scale score (Spearman ρ = -0.51; 95% CI, -0.85 to -0.02; P = .03). However, cortical volume and deep gray matter volume were not significantly different between the 2 groups, and they were not correlated with the Expanded Disability Status Scale. This study suggests that patients with MOGAD may have impaired glymphatic function, as measured by the ALPS index, which is associated with patient disability. Further study is warranted with a larger sample size.

Tonabersat Significantly Reduces Disease Progression in an Experimental Mouse Model of Multiple Sclerosis.

Multiple sclerosis (MS) is a neurodegenerative disease marked by chronic neuroinflammation thought to be mediated by the inflammasome pathway. Connexin 43 (Cx43) hemichannels contribute to the activation of the inflammasome through the release of adenosine triphosphate (ATP) inflammasome activation signals. The objective of the study was to evaluate if the Cx43 hemichannel blocker, tonabersat, is effective in modulating the inflammatory response and reducing disability in the myelin oligodendrocyte glycoprotein 35-55-induced experimental autoimmune encephalomyelitis (MOG35-55 EAE) model of MS. Here, we show that the Cx43 hemichannel blocking drug, tonabersat, significantly reduced expression of neuroinflammatory markers for microglial activation (ionized calcium-binding adapter molecule 1 (Iba1)) and astrogliosis (glial fibrillary acidic protein (GFAP)) while preserving myelin basic protein (MBP) expression levels in the corpus callosum, motor cortex, and striatum regions of the brain in MOG35-55 EAE mice. Reduced NOD-like receptor protein 3 (NLRP3) inflammasome complex assembly and Caspase-1 activation confirmed the drug's mode of action. MOG35-55 EAE mice showed clinical signs of MS, but MOG35-55 EAE mice treated with tonabersat retained behavior closer to normal. These data suggest that clinical trial phase IIb-ready tonabersat may merit further investigation as a promising candidate for MS treatment.

Severe central nervous system demyelination in Sanfilippo disease.

Chronic progressive neuroinflammation is a hallmark of neurological lysosomal storage diseases, including mucopolysaccharidosis III (MPS III or Sanfilippo disease). Since neuroinflammation is linked to white matter tract pathology, we analyzed axonal myelination and white matter density in the mouse model of MPS IIIC HgsnatP304L and post-mortem brain samples of MPS III patients. Brain and spinal cord tissues of human MPS III patients, 6-month-old HgsnatP304L mice and age- and sex-matching wild type mice were analyzed by immunofluorescence to assess levels of myelin-associated proteins, primary and secondary storage materials, and levels of microgliosis. Corpus callosum (CC) region was studied by transmission electron microscopy to analyze axon myelination and morphology of oligodendrocytes and microglia. Mouse brains were analyzed ex vivo by high-filed MRI using Diffusion Basis Spectrum Imaging in Python-Diffusion tensor imaging algorithms. Analyses of CC and spinal cord tissues by immunohistochemistry revealed substantially reduced levels of myelin-associated proteins including Myelin Basic Protein, Myelin Associated Glycoprotein, and Myelin Oligodendrocyte Glycoprotein. Furthermore, ultrastructural analyses revealed disruption of myelin sheath organization and reduced myelin thickness in the brains of MPS IIIC mice and human MPS IIIC patients compared to healthy controls. Oligodendrocytes (OLs) in the CC of MPS IIIC mice were scarce, while examination of the remaining cells revealed numerous enlarged lysosomes containing heparan sulfate, GM3 ganglioside or "zebra bodies" consistent with accumulation of lipids and myelin fragments. In addition, OLs contained swollen mitochondria with largely dissolved cristae, resembling those previously identified in the dysfunctional neurons of MPS IIIC mice. Ex vivo Diffusion Basis Spectrum Imaging revealed compelling signs of demyelination (26% increase in radial diffusivity) and tissue loss (76% increase in hindered diffusivity) in CC of MPS IIIC mice. Our findings demonstrate an important role for white matter injury in the pathophysiology of MPS III. This study also defines specific parameters and brain regions for MRI analysis and suggests that it may become a crucial non-invasive method to evaluate disease progression and therapeutic response.

Delimiting MOGAD as a disease entity using translational imaging.

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.

An engineered Fc fusion protein that targets antigen-specific T cells and autoantibodies mitigates autoimmune disease

Current effective therapies for autoimmune diseases rely on systemic immunomodulation that broadly affects all T and/or B cell responses. An ideal therapeutic approach would combine autoantigen-specific targeting of both T and B cell effector functions, including efficient removal of pathogenic autoantibodies. Albeit multiple strategies to induce T cell tolerance in an autoantigen-specific manner have been proposed, therapeutic removal of autoantibodies remains a significant challenge. Here, we devised an approach to target both autoantigen-specific T cells and autoantibodies by producing a central nervous system (CNS) autoantigen myelin oligodendrocyte glycoprotein (MOG)-Fc fusion protein. We demonstrate that MOG-Fc fusion protein has significantly higher bioavailability than monomeric MOG and is efficient in clearing anti-MOG autoantibodies from circulation. We also show that MOG-Fc promotes T cell tolerance and protects mice from MOG-induced autoimmune encephalomyelitis. This multipronged targeting approach may be therapeutically advantageous in the treatment of autoimmunity.

Quantification of Autoreactive Antibodies in Mice upon Experimental Autoimmune Encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a disease model that recapitulates the autoimmune disorder multiple sclerosis (MS) at histopathological and molecular levels. EAE is induced by immunizing experimental animals via subcutaneous injection of short myelin peptides together with specific adjuvants to boost the immune response. Like the human counterpart, EAE mice develop demyelinating lesions, immune cell infiltration into the central nervous system (CNS), glia activation and neuronal injury. A consistent body of evidence also supports a mechanistic role for B cell dysfunction in the etiology of both MS and EAE. B cells can serve as antigen-presenting cells as well as a primary source of pro-inflammatory cytokines and autoantibodies. In EAE, antibodies are generated against the myelin peptides that were employed to induce the disease. Such autoantibodies have been shown to mediate either myelin loss or pathogenic T cell reactivation into the CNS. This article describes an efficient ELISA-based protocol to quantify autoantibodies in the serum of C57BL/6J mice immunized with the myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) peptide. The proposed method serves as a powerful tool to investigate the specificity and magnitude of the aberrant humoral response in the context of autoimmune demyelination.

Systematic review exploring the clinical features of optic neuritis after SARS-CoV infection and vaccination

BackgroundThis study aims to characterise the symptoms and clinical features of optic neuritis (ON) following SARS-CoV-2 infection and vaccination.MethodA literature search was conducted in four databases (PubMed, Medline, Embase and...

Upbeat Nystagmus and Ataxia in a Case of Myelin Oligodendrocyte Glycoprotein (MOG)-IgG-Associated Disease

Upbeat Nystagmus and Ataxia in a Case of Myelin Oligodendrocyte Glycoprotein (MOG)-IgG-Associated Disease

Characteristics of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease Patients at Cleveland Clinic Abu Dhabi: A Case Series

Characteristics of Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease Patients at Cleveland Clinic Abu Dhabi: A Case Series

Evolution of Brain MRI Lesions in Paediatric Myelin-Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD) and Its Relevance to Disease Course

Evolution of Brain MRI Lesions in Paediatric Myelin-Oligodendrocyte Glycoprotein Antibody-Associated Disease (MOGAD) and Its Relevance to Disease Course

Myelin-Oligodendrocyte Glycoprotein Antibody-Associated Disease and Intracranial Hypertension: A Case Report

Myelin-Oligodendrocyte Glycoprotein Antibody-Associated Disease and Intracranial Hypertension: A Case Report

Acute Optic Neuritis: An Update on Approach and Management.

This review discusses the physical examination and diagnostic tests necessary to diagnose optic neuritis (ON) and provides an update on the approach and management of acute ON. A comprehensive search of the PubMed database was conducted, limited to English-language journals and recent publications. A total of 160 articles were initially screened by title, of which 73 articles were included in the narrative synthesis. ON is an inflammation of the optic nerve that can be caused by different systemic and neurological disorders. It is commonly presented as a subacute unilateral painful vision loss, and based on its clinical manifestation, it can be classified as typical or atypical. Atypical ON is bilateral with visual acuity of worse than 20/200 or has an atypical demographic presentation for demyelination, such as a non-Caucasian male with optic disc swelling, for which neuromyelitis optica spectrum disorder (NMOSD), myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD), or other etiologies should be considered. Steroids and immunosuppressants are the main treatment options for ON, and timely treatment initiation is critical to preventing irreversible vision loss, especially in atypical cases.

A longitudinal analysis of brain volume changes in myelin oligodendrocyte glycoprotein antibody-associated disease.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a relapsing demyelinating condition. There are several cross-sectional studies showing evidence of brain atrophy in people with MOGAD (pwMOGAD), but longitudinal brain volumetric assessment is still an unmet need. Current recommendations do not include monitoring with MRI and assume distinct attacks. Evidence of ongoing axon loss will have diagnostic and therapeutic implications. In this study, we assessed brain volume changes in pwMOGAD over a mean follow-up period of 2years and compared this to changes in people with multiple sclerosis (pwMS). This is a retrospective single-center study over a 7-year period from 2014 to 2021. MRI brain scans at the time of diagnosis and follow-up in remission were collected from 14 Caucasian pwMOGAD, confirmed by serum myelin oligodendrocyte glycoprotein immunoglobulin G antibody presence, detected by live cell-based assays. Total brain volume (TBV), white matter (WM), gray matter (GM), and demyelinating lesion volumes were assessed automatically using the Statistical Parametric Mapping and FMRIB automated segmentation tools. MRI brain scans at diagnosis and follow-up on remission were collected from 32-matched pwMS for comparison. Statistical analysis was done using analysis of variance. There is evidence of TBV loss, affecting particularly GM, over an approximately 2-year follow-up period in pwMOGAD (p<.05), comparable to pwMS. WM and lesion volume change over the same period were not statistically significant (p>.1). We found evidence of loss of GM and TBV over time in pwMOGAD, similar to pwMS, although the WM and lesion volumes were unchanged.

Longitudinal evaluation of serum MOG-IgG titers in MOGAD after initiation of maintenance immunoglobulin: A case series.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a distinct demyelinating disease of the central nervous system. Immunoglobulin (Ig) has been used as a maintenance therapy to prevent relapses in MOGAD, but the impact of Ig on serum MOG-IgG titers is unclear. To characterize the variation in serum MOG-IgG titers after initiation of Ig treatment in people with MOGAD. We conducted a retrospective study of 10 patients with a diagnosis of MOGAD and available serum MOG-IgG titers before and after initiation of maintenance Ig treatment. We found that most of the patients remained MOG-IgG seropositive while on Ig treatment with a reduced or unchanged titer, despite a lack of disease activity. This case series suggests that the mechanism of action of Ig therapy in MOGAD is not exclusively dependent on MOG-IgG titer reduction.

Optic neuritis in Turkish children and adolescents: A multicenter retrospective study

BackgroundVarious etiologies may underlie optic neuritis, including autoantibody-mediated disorders described in the last decade. We re-examined demographic, clinical, laboratory features and prognostic factors in pediatric patients with autoimmune optic neuritis according to current knowledge. MethodsCases of pediatric ON from 27 centers in Türkiye diagnosed between 2009 and 2022 were included for retrospective evaluation. ResultsThe study included 279 patients, 174 females and 105 males, with a female-to-male ratio of 1.65. The average age at onset was 12.8 ± 3.4 years, and mean follow-up, 2.1 years (range: 1–12.1 years). Patients <10 years old were grouped as "prepubertal" and those ≥10 years old as "others”. The diagnoses made at the end of follow-up were multiple sclerosis associated optic neuritis (n = 90, 32.3 %), single isolated optic neuritis (n = 86, 31 %), clinically isolated syndrome (n = 41, 14.7 %), myelin oligodendrocyte glycoprotein antibody associated optic neuritis (n = 22, 7.9 %), and relapsing isolated optic neuritis (n = 18, 6.5 %). Predominant diagnoses were myelin oligodendrocyte glycoprotein antibody associated optic neuritis and acute disseminated encephalomyelitis associated optic neuritis in the prepubertal group and multiple sclerosis associated optic neuritis in the older group. Recurrences were observed in 67 (24 %) patients, including 28 with multiple sclerosis associated optic neuritis, 18 with relapsing isolated optic neuritis, 11 with myelin oligodendrocyte glycoprotein antibody associated optic neuritis, 8 with aquaporin-4 antibody related optic neuritis, and 2 with chronic relapsing inflammatory optic neuropathy. Recurrences were more common among female patients. Findings supporting the diagnosis of multiple sclerosis included age of onset ≥ 10 years (OR=1.24, p = 0.027), the presence of cranial MRI lesions (OR=26.92, p<0.001), and oligoclonal bands (OR=9.7, p = 0.001). Treatment in the acute phase consisted of intravenous pulse methylprednisolone (n = 46, 16.5 %), pulse methylprednisolone with an oral taper (n = 212, 76 %), and combinations of pulse methylprednisolone, plasmapheresis, or intravenous immunoglobulin (n = 21, 7.5 %). Outcome at 12 months was satisfactory, with 247 out of 279 patients (88.5 %) demonstrating complete recovery. Thirty-two patients exhibited incomplete recovery and further combination treatments were applied. Specifically, patients with relapsing isolated optic neuritis and aquaporin-4 antibody related optic neuritis displayed a less favorable prognosis. ConclusionOur results suggest optic neuritis is frequently bilateral in prepubertal and unilateral in peri‑ or postpubertal patients. Age of onset 10 or older, presence of oligoclonal bands, and brain MRI findings reliably predict the development of multiple sclerosis. The risk of developing multiple sclerosis increases mostly during the second and third years of follow-up. Relapsing isolated optic neuritis remains a separate group where the pathogenesis and outcome remain unclear. Investigation of predisposing and diagnostic biomarkers and long follow-up could help to define this group.

Classification of Myelin Oligodendrocyte Glycoprotein Antibody-Related Disease and Its Mimicking Acute Demyelinating Syndromes in Children Using MRI-Based Radiomics: From Lesion to Subject

To develop MRI-based radiomics models from the lesion level to the subject level and assess their value for differentiating myelin oligodendrocyte glycoprotein antibody-related disease (MOGAD) from non-MOGAD acute demyelinating syndromes in pediatrics. 66 MOGAD and 66 non-MOGAD children were assigned to the training set (36/35), internal test set (14/16), and external test set (16/15), respectively. At the lesion level, five single-sequence models were developed alongside a fusion model (combining these five sequences). The radiomics features of each lesion were quantified as the lesion-level radscore (LRS) using the best-performing model. Subsequently, a lesion-typing function was employed to classify lesions into two types (MOGAD-like or non-MOGAD-like), and the average LRS of the predominant type lesions in each subject was considered as the subject-level radscore (SRS). Based on SRS, a subject-level model was established and compared toboth clinical models and radiologists' assessments. At the lesion level, the fusion model outperformed the five single-sequence models in distinguishing MOGAD and non-MOGAD lesions (0.867 and 0.810 ofarea under the curve[AUC] in internal and external testing, respectively). At the subject level, the SRS model showed superior performance (0.844 and 0.846 of AUC in internal and external testing, respectively) compared to clinical models and radiologists' assessments for distinguishing MOGAD and non-MOGAD. MRI-based radiomics models have potential clinical value for identifying MOGAD from non-MOGAD. The fusion model and SRS model can distinguish between MOGAD and non-MOGAD at the lesion level and subject level, respectively, providing a differential diagnosis method for these two diseases.

Big Data Analysis of Inflammatory Conditions Associated With Optic Neuritis.

Previous studies in the United States established multiple sclerosis (MS) as the most common cause of optic neuritis (ON). ON can be associated with other systemic inflammatory conditions including sarcoidosis, neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), and lupus; however, prospective studies to establish risk of ON associated with these diseases are lacking. Furthermore, appropriate workup for ON is still debated. A deidentified electronic medical record of a tertiary care academic center was searched for ON and rheumatologic/neuro-inflammatory diseases in the medical history, diagnoses, and laboratory results; followed by the intersection of ON with each condition. We calculated frequency of systemic conditions among patients with ON and prevalence of ON in those conditions. We also calculated relative risk (RR) of underlying systemic conditions among patients with ON compared with the study patient population. In 6.7 million charts, 5,344 cases of ON were identified. Among those, MS occurred most commonly (20.6%), followed by NMOSD (10.5%). Conversely, ON occurred in 98.4% of NMOSD cases, 53.3% of MOGAD, and 10.0% of MS. NMOSD (RR = 1,233), MOGAD (RR = 688), and MS (RR = 126) had the highest RR among the conditions we evaluated. The subset analysis showed similar findings. The high RR for ON among patients with NMOSD and MOGAD suggests that clinical suspicion for ON should be high among patients with these conditions presenting with vision changes. Conversely, MS and NMOSD should initially be high on the differential diagnosis for any patient presenting with optic neuritis.