Anti-Myelin Oligodendrocyte Glycoprotein and Human Leukocyte Antigens as Markers in Pediatric and Adolescent Multiple Sclerosis: on Diagnosis, Clinical Phenotypes, and Therapeutic Responses

Early-onset (pediatric and adolescent) multiple sclerosis (MS) is a well-established demyelinating disease that accounts for approximately 3-5% of all MS cases. Thus, identifying potential biomarkers that can reflect the pathogenic mechanisms, disease course and prognosis, and therapeutic response in such patients is of paramount importance. Myelin oligodendrocyte glycoprotein (MOG) has been regarded as a putative autoantigen and autoantibody target in patients with demyelinating diseases for almost three decades. However, recent studies have suggested that antibodies against MOG represent a distinct clinical entity of dominantly humoral profile, with a range of clinical phenotypes closely related to the age of onset, specific patterns of disease course, and responses to treatment. Furthermore, the major histocompatibility complex (MHC)—which has been regarded as the “gold standard” for attributing genetic burden in adult MS since the early 1970s—has also emerged as the primary genetic locus in early-onset MS, particularly with regard to the human leukocyte antigen (HLA) alleles DRB1⁎1501 and DRB1⁎0401. Recent studies have investigated the potential interactions among HLA, MOG, and environmental factors, demonstrating that early-onset MS is characterized by genetic, immunogenetic, immunological, and familial trait correlations. In this paper, we review recent evidence regarding HLA-genotyping and MOG antibodies—the two most important candidate biomarkers for early-onset MS—as well as their potential application in the diagnosis and treatment of MS.

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111 Epileptic seizures in multiple sclerosis

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2018-anzan.110 ◽

2018 ◽

Vol 89 (6) ◽

pp. A44.1-A44

Author(s):

Stephen Walsh ◽

Joel Corbett ◽

K Meng Tan ◽

Simon Broadley

Keyword(s):

Multiple Sclerosis ◽

Demyelinating Disease ◽

Age Of Onset ◽

Case Reports ◽

Case Series ◽

Clinical Information ◽

Epileptic Seizures ◽

Disease Course ◽

Number Of Patients ◽

Significant Difference

IntroductionEpileptic seizures have been described in association with multiple sclerosis (MS) in both anecdotal case reports and case series. The recent identification of specific antibodies to myelin oligodendrocyte glycoprotein (MOG) protein in a small number of patients with demyelinating disease which may resemble neuromyelitis optica or acute disseminated encephalopathy, which may involve seizures, raises the possibility that anti-MOG antibody related demyelination may account for the association of epilepsy with MS.MethodsWe have undertaken a retrospective review of cases of MS diagnosed at the Gold Coast MS clinic over a 10 year period. All cases were systematically asked if they had ever had an epileptic seizure either via a patient completed questionnaire or at a clinic visit. Demographic and clinical information were also recorded. These data have been analysed using descriptive statistics and appropriate tests for significant differences between those with epilepsy and those without.Results428 cases with complete data were identified. Those with a history of epilepsy were slightly younger (median (range); 44.5 (27–64) years vs 4715–88 years), but this difference was not statistically significantly different. The gender ratio was the same for both groups (9/12 (75%) for those with epilepsy and 326/416 (78%)). There was no significant difference in age of onset, disease course, relapse frequency or level of disability. Although numbers are small, seizure appear to occur most frequently earlier in the disease course and are rarely an ongoing issue.ConclusionThese data support earlier work indicating that epilepsy occurs in people with MS who are younger. This fits with the notion that seizures arise in the context of the inflammatory stage of multiple sclerosis rather than the degenerative phase. Further work needs to be undertaken to assess any association with anti-MOG antibodies and epileptic seizures in demyelinating disease.

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Myelin oligodendrocyte glycoprotein antibody-associated disease: an immunopathological study

Brain ◽

10.1093/brain/awaa102 ◽

2020 ◽

Vol 143 (5) ◽

pp. 1431-1446 ◽

Cited By ~ 18

Author(s):

Yoshiki Takai ◽

Tatsuro Misu ◽

Kimihiko Kaneko ◽

Norio Chihara ◽

Koichi Narikawa ◽

...

Keyword(s):

Multiple Sclerosis ◽

Humoral Immunity ◽

Demyelinating Disease ◽

Myelin Oligodendrocyte Glycoprotein ◽

Demyelinating Diseases ◽

Perivascular Spaces ◽

Clinical Diagnoses ◽

Demyelinating Lesions ◽

Oligoclonal Igg ◽

Aqp4 Antibody

Abstract Conformation-sensitive antibodies against myelin oligodendrocyte glycoprotein (MOG) are detectable in patients with optic neuritis, myelitis, opticomyelitis, acute or multiphasic disseminated encephalomyelitis (ADEM/MDEM) and brainstem/cerebral cortical encephalitis, but are rarely detected in patients with prototypic multiple sclerosis. So far, there has been no systematic study on the pathological relationship between demyelinating lesions and cellular/humoral immunity in MOG antibody-associated disease. Furthermore, it is unclear whether the pathomechanisms of MOG antibody-mediated demyelination are similar to the demyelination patterns of multiple sclerosis, neuromyelitis optica spectrum disorders (NMOSD) with AQP4 antibody, or ADEM. In this study, we immunohistochemically analysed biopsied brain tissues from 11 patients with MOG antibody-associated disease and other inflammatory demyelinating diseases. Patient median onset age was 29 years (range 9–64), and the median interval from attack to biopsy was 1 month (range 0.5–96). The clinical diagnoses were ADEM (n = 2), MDEM (n = 1), multiple brain lesions without encephalopathy (n = 3), leukoencephalopathy (n = 3) and cortical encephalitis (n = 2). All these cases had multiple/extensive lesions on MRI and were oligoclonal IgG band-negative. Most demyelinating lesions in 10 of 11 cases showed a perivenous demyelinating pattern previously reported in ADEM (153/167 lesions) and a fusion pattern (11/167 lesions) mainly in the cortico-medullary junctions and white matter, and only three lesions in two cases showed confluent demyelinated plaques. In addition, 60 of 167 demyelinating lesions (mainly in the early phase) showed MOG-dominant myelin loss, but relatively preserved oligodendrocytes, which were distinct from those of AQP4 antibody-positive NMOSD exhibiting myelin-associated glycoprotein-dominant oligodendrogliopathy. In MOG antibody-associated diseases, MOG-laden macrophages were found in the perivascular spaces and demyelinating lesions, and infiltrated cells were abundant surrounding multiple blood vessels in and around the demyelinating lesions, mainly consisting of macrophages (CD68; 1814 ± 1188 cells/mm2), B cells (CD20; 468 ± 817 cells/mm2), and T cells (CD3; 2286 ± 1951 cells/mm2), with CD4-dominance (CD4+ versus CD8+; 1281 ± 1196 cells/mm2 versus 851 ± 762 cells/mm2, P < 0.01). Humoral immunity, evidenced by perivascular deposits of activated complements and immunoglobulins, was occasionally observed in some MOG antibody-associated demyelinating lesions, and the frequency was much lower than that in AQP4 antibody-positive NMOSD. Subpial lesions with perivenous demyelination were observed in both ADEM and cortical encephalitis. Our study suggests that ADEM-like perivenous inflammatory demyelination with MOG-dominant myelin loss is a characteristic finding of MOG antibody-associated disease regardless of whether the diagnostic criteria of ADEM are met. These pathological features are clearly different from those of multiple sclerosis and AQP4 antibody-positive NMOSD, suggesting an independent autoimmune demyelinating disease entity.

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Diagnosis of Multiple Sclerosis

10.1093/med/9780197512166.003.0065 ◽

2021 ◽

pp. 540-547

Author(s):

W. Oliver Tobin

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

Nervous System ◽

Demyelinating Disease ◽

Acute Disseminated Encephalomyelitis ◽

Myelin Oligodendrocyte Glycoprotein ◽

Spectrum Disorder ◽

Demyelinating Diseases ◽

Neuromyelitis Optica Spectrum Disorder ◽

The Central Nervous System

Multiple sclerosis is the most common idiopathic inflammatory demyelinating disease of the central nervous system (CNS), with a prevalence of 1 in 500 to 1 in 2,000 people, depending on geography and various other factors. Idiopathic inflammatory demyelinating diseases are a group of related disorders that include acute disseminated encephalomyelitis, neuromyelitis optica spectrum disorder, and myelin oligodendrocyte glycoprotein–immunoglobulin G–associated CNS demyelinating disease.

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Multiple Sclerosis in Malaysia: Demographics, Clinical Features, and Neuroimaging Characteristics

Multiple Sclerosis International ◽

10.1155/2013/614716 ◽

2013 ◽

Vol 2013 ◽

pp. 1-10 ◽

Cited By ~ 3

Author(s):

S. Viswanathan ◽

N. Rose ◽

A. Masita ◽

J. S. Dhaliwal ◽

S. D. Puvanarajah ◽

...

Keyword(s):

Multiple Sclerosis ◽

Neuromyelitis Optica ◽

Demyelinating Disease ◽

Age At Onset ◽

Positive Family History ◽

Disease Onset ◽

Demyelinating Diseases ◽

Lesion Length ◽

Relapsing Remitting ◽

Spectrum Disorders

Background. Multiple sclerosis (MS) is an uncommon disease in multiracial Malaysia. Diagnosing patients with idiopathic inflammatory demyelinating diseases has been greatly aided by the evolution in diagnostic criterion, the identification of new biomarkers, and improved accessibility to neuroimaging in the country.Objectives. To investigate the spectrum of multiple sclerosis in Malaysia.Methods. Retrospective analysis with longitudinal follow-up of patients referred to a single tertiary medical center with neurology services in Malaysia.Results. Out of 245 patients with idiopathic inflammatory demyelinating disease, 104 patients had multiple sclerosis. Female to male ratio was 5 : 1. Mean age at onset was 28.6 ± 9.9 years. The Malays were the predominant racial group affected followed by the Chinese, Indians, and other indigenous groups. Subgroup analysis revealed more Chinese having neuromyelitis optica and its spectrum disorders rather than multiple sclerosis. Positive family history was reported in 5%. Optic neuritis and myelitis were the commonest presentations at onset of disease, and relapsing remitting course was the commonest disease pattern observed. Oligoclonal band positivity was 57.6%. At disease onset, 61.5% and 66.4% fulfilled the 2005 and 2010 McDonald’s criteria for dissemination in space. Mean cord lesion length was 1.86 ± 1.65 vertebral segments in the relapsing remitting group as opposed to 6.25 ± 5.18 vertebral segments in patients with neuromyelitis optica and its spectrum disorders.Conclusion. The spectrum of multiple sclerosis in Malaysia has changed over the years. Further advancement in diagnostic criteria will no doubt continue to contribute to the evolution of this disease here.

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Multiple sclerosis risk genotypes correlate with an elevated cerebrospinal fluid level of the suggested prognostic marker CXCL13

Multiple Sclerosis Journal ◽

10.1177/1352458512463482 ◽

2012 ◽

Vol 19 (7) ◽

pp. 863-870 ◽

Cited By ~ 14

Author(s):

M Lindén ◽

M Khademi ◽

I Lima Bomfim ◽

F Piehl ◽

M Jagodic ◽

...

Keyword(s):

Multiple Sclerosis ◽

Cerebrospinal Fluid ◽

Neurological Diseases ◽

Severe Disease ◽

Human Leukocyte ◽

Disease Course ◽

Nucleotide Polymorphisms ◽

Treatment Protocols ◽

Tnfaip3 Gene ◽

Cerebrospinal Fluid Level

Background: The mechanisms of multiple sclerosis (MS) pathogenesis are still largely unknown. The heterogeneity of disease manifestations make the prediction of prognosis and choice of appropriate treatment protocols challenging. Recently, increased cerebrospinal fluid (CSF) levels of the B-cell chemokine CXCL13 was proposed as a possible marker for a more severe disease course and conversion from clinically isolated syndrome (CIS) to relapsing–remitting MS (RRMS). Objective: To investigate whether there are genetic susceptibility variants in MS that correlate with the levels of CXCL13 present in the CSF of MS patients. Methods: We genotyped the human leukocyte antigens HLA-DRB1 and HLA-A, plus a panel of single nucleotide polymorphisms (SNPs) that have been associated with susceptibility to MS and then correlated the genotypes with the levels of CXCL13, as measured with ELISA in the CSF of a total of 663 patients with MS, CIS, other neurological diseases (OND) or OND with an inflammatory component (iOND). Results: Presence of the HLA-DRB1*15 and the MS risk genotypes for SNPs in the RGS1, IRF5 and OLIG3/TNFAIP3 gene regions correlated significantly with increased levels of CXCL13. Conclusion: Our results pointed towards a genetic predisposition for increased CXCL13 levels, which in MS patients correlates with the severity of the disease course. These findings encourage further investigation and replication, in an independent patient cohort.

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Patients with neuromyelitis optica have a more severe disease than patients with relapsingremitting multiple sclerosis, including higher risk of dying of a demyelinating disease

Arquivos de Neuro-Psiquiatria ◽

10.1590/0004-282x20130020 ◽

2013 ◽

Vol 71 (5) ◽

pp. 275-279 ◽

Cited By ~ 15

Author(s):

Denis Bernardi Bichuetti ◽

Enedina Maria Lobato de Oliveira ◽

Nilton Amorin de Souza ◽

Mar Tintoré ◽

Alberto Alain Gabbai

Keyword(s):

Multiple Sclerosis ◽

Neuromyelitis Optica ◽

Disease Duration ◽

Demyelinating Disease ◽

Age Of Onset ◽

Severe Disease ◽

Expanded Disability Status Scale ◽

Disability Status ◽

Relapsing Remitting ◽

Relapsing Remitting Multiple Sclerosis

Although neuromyelitis optica (NMO) is known to be a more severe disease than relapsing-remitting multiple sclerosis (RRMS), few studies comparing both conditions in a single center have been done.Methods:Comparison of our previously published cohort of 41 NMO patients with 177 RRMS patients followed in the same center, from 1994 to 2007.Results:Mean age of onset was 32.6 for NMO and 30.2 for RRMS (p=0.2062) with mean disease duration of 7.4 years for NMO and 10.3 years for RRMS. Patients with NMO had a higher annualized relapse rate (1.0 versus 0.8, p=0.0013) and progression index (0.9 versus 0.6, p≪0.0001), with more patients reaching expanded disability status scale (EDSS) 6.0 (39 versus 17%, p=0.0036). The odds ratio for reaching EDSS 6.0 and being deceased due to NMO in comparison to RRMS were, respectively, 3.14 and 12.15.Conclusion:Patients with NMO have a more severe disease than patients with RRMS, including higher risk of dying of a demyelinating disease.

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Multiple Sclerosis

Neuropathic Pain ◽

10.1093/med/9780190298357.003.0024 ◽

2018 ◽

pp. 209-216

Author(s):

Samuel W. Samuel ◽

Jianguo Cheng

Keyword(s):

Multiple Sclerosis ◽

Central Nervous System ◽

Neuropathic Pain ◽

Demyelinating Disease ◽

Spontaneous Pain ◽

Disease Course ◽

The Central Nervous System ◽

Disease Modifying ◽

Multiple Treatments ◽

Surgical Treatments

Multiple sclerosis (MS) is a chronic autoimmune demyelinating disease of the central nervous system (CNS). The diagnosis is based on evidence of at lease two different lesions in the CNS, at least two different episodes in the disease course, and chronic inflammation of the CNS as determined by analysis of the cerebrospinal fluid. Central neuropathic pain is the most common form of pain in patients with MS, with an estimated prevalence of about 50%. Along with the classical neuropathic pain features, such as spontaneous pain (dysesthesia and burning) and evoked pain (allodynia and hyperalgesia), patients with MS may also suffer from intermittent neuropathic pain, such as trigeminal neuralgia, Lhermitte sign, and glossopharyngeal neuralgia. In addition to disease-modifying therapies of MS, multiple treatments are available to manage neuropathic pain secondary to MS, including medical, interventional, and surgical treatments with varying levels of evidence.

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Multiple sclerosis and other demyelinating diseases

10.1093/med/9780198569381.003.0871 ◽

2011 ◽

Author(s):

Alastair Compston

Keyword(s):

Multiple Sclerosis ◽

Demyelinating Disease ◽

Past History ◽

Central Pontine Myelinolysis ◽

Clinical Manifestations ◽

Nerve Impulse ◽

Demyelinating Diseases ◽

Clinical Neurology ◽

Disease Heterogeneity ◽

Axonal Dysfunction

The oligodendrocyte–myelin unit subserves saltatory conduction of the nerve impulse in the healthy central nervous system. At one time, many disease processes were thought exclusively to target the structure and function of myelin. Therefore, they were designated ‘demyelinating diseases’. But recent analyses, based mainly on pathological and imaging studies, (re)emphasize that axons are also directly involved in these disorders during both the acute and chronic phases. Another ambiguity is the extent to which these are inflammatory conditions. Here, distinctions should be made between inflammation, as a generic process, and autoimmunity in which rather a specific set of aetiological and mechanistic conditions pertain. And there are differences between disorders that are driven primarily by immune processes and those in which inflammation occurs in response to pre-existing tissue damage.With these provisos, the pathological processes of demyelination and associated axonal dysfunction often account for episodic neurological symptoms and signs referable to white matter tracts of the brain, optic nerves, or spinal cord when these occur in young people. This is the clinical context in which the possibility of ‘demyelinating disease’ is usually considered by physicians and, increasingly, the informed patient. Neurologists will, with appropriate cautions, also be prepared to diagnose demyelinating disease in older patients presenting with progressive symptoms implicating these same pathways even when there is no suggestive past history. Both in its typical and atypical forms multiple sclerosis remains by far the commonest demyelinating disease. But acute disseminated encephalomyelitis, the leucodystrophies, and central pontine myelinolysis also need to be considered in particular circumstances; and multiple sclerosis itself has a differential diagnosis in which the relapsing-remitting course is mimicked by conditions not associated with direct injury to the axon–glial unit. Since our understanding of the cause, pathogenesis and features of demyelinating disease remains incomplete, classification combines aspects of the aetiology, clinical features, pathology, and laboratory components. Whether the designation ‘multiple sclerosis’ encapsulates one or more conditions is now much debated. We anticipate that a major part of future studies in demyelinating disease will be further to resolve this question of disease heterogeneity leading to a new taxonomy based on mechanisms rather than clinical empiricism. But, for now, the variable ages of onset, unpredictable clinical course, protean clinical manifestations, and non-specific laboratory investigations continue to make demyelinating disease one of the more challenging diagnostic areas in clinical neurology.

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Myelin oligodendrocyte glycoprotein antibodies in pathologically proven multiple sclerosis: frequency, stability and clinicopathologic correlations

Multiple Sclerosis Journal ◽

10.1177/1352458506072189 ◽

2007 ◽

Vol 13 (1) ◽

pp. 7-16 ◽

Cited By ~ 29

Author(s):

S J Pittock ◽

M Reindl ◽

S Achenbach ◽

T Berger ◽

W Bruck ◽

...

Keyword(s):

Multiple Sclerosis ◽

Western Blot ◽

Demyelinating Disease ◽

Clinical Course ◽

Myelin Oligodendrocyte Glycoprotein ◽

Poor Agreement ◽

Predictive Role ◽

Mog Antibodies ◽

Serial Measurements

Controversy exists regarding the pathogenic or predictive role of anti-myelin oligodendrocyte glycoprotein (MOG) antibodies in patients with multiple sclerosis (MS). Four immunopathological patterns (IP) have been recognized in early active MS lesions, suggesting heterogeneous pathogenic mechanisms. Whether MOG antibodies contribute to this pathological heterogeneity and potentially serve as biomarkers to identify specific pathological patterns is unknown. Here we report the frequencies of antibodies to human recombinant MOG (identified by Western blot and enzymelinked immunoabsorbent assay (ELISA)) in patients with pathologically proven demyelinating disease, and investigate whether antibody status is associated with clinical course, HLA-DR2 genotype, IP or treatment response to plasmapheresis. The biopsy cohort consisted of 72 patients: 12 pattern I, 43 pattern II and 17 pattern III. No association was found between MOG antibody status and conversion to clinically definite MS, DR-2 status, IP or response to plasmapheresis. There was poor agreement between Western blot and ELISA (kappa=0.07 for MOG IgM). Fluctuations in antibody seropositivity were seen for 3/4 patients tested serially by Western blot. This study does not support a pathologic pattern-specific role for MOG-antibodies. Variable MOG-antibody status on serial measurements, coupled with the lack of Western blot and ELISA correlations, raises concern regarding the use of MOG-antibody as an MS biomarker and underscores the need for methodological consensus.

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