Blood parameters in pediatric myelin oligodendrocyte glycoprotein antibody-associated disorders.

BACKGROUND AND OBJECTIVES: Patients with myelin oligodendrocyte glycoprotein antibody-associated disorders (MOGAD) clinically present e.g. with acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), transverse myelitis (TM) or aquaporin-4-IgG (AQP4-IgG) negative neuromyelitis optica spectrum disorders (NMOSD)-like phenotypes. We aimed to analyze and compare blood parameters in children with MOGAD, AQP4-IgG-positive NMOSD (hence NMOSD), multiple sclerosis (MS) and healthy controls (HC). METHODS: We evaluated differences in complete blood counts (CBC), neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), monocyte-to-lymphocyte ratio (MLR) and C-reactive protein (CRP) between these four groups and within the groups between clinical attack, acute treatment and remission. RESULTS: Our cohort consisted of 174 children and adolescents with a total of 550 timepoints: 66 patients had MOGAD (202 timepoints), 11 NMOSD (76 timepoints), 58 MS (219 timepoints) and 39 were HC (53 timepoints). At clinical attack, leukocyte counts were elevated in MOGAD compared to remission (p < 0.001) and compared to all other groups (p < 0.001). NLR was high in MOGAD and NMOSD, and PLR was high in NMOSD, however, after correction for multiple testing these findings did not remain significant. While glucocorticoids caused an increase of leukocyte counts and NLR in NMOSD and MS, these values remained stable during acute treatment in MOGAD. In remission, NLR normalized in MOGAD, while it stayed high in NMOSD. PLR increased in NMOSD and was significantly higher compared to all other groups. DISCUSSION: Some blood parameters, mainly leukocyte and differential counts, might help clinicians to evaluate disease activity, differentiate relapses from pseudo-relapses and even distinguish between different disease entities.

Is there an immunological cross-reactivity of antibodies to the myelin oligodendrocyte glycoprotein and coronaviruses?

Recent reports indicated that myelin oligodendrocyte glycoprotein antibody-associated disease might be a rare complication after severe acute respiratory syndrome coronavirus 2 infection or vaccination. It is unclear whether this is an unspecific sequel of infection or vaccination or caused by possible immunological cross-reactivity of severe acute respiratory syndrome coronavirus 2 proteins and myelin oligodendrocyte glycoprotein. The aim of this study was therefore to elucidate whether there is an immunological cross-reactivity between severe acute respiratory syndrome coronavirus 2 spike or nucleocapsid proteins and myelin oligodendrocyte glycoprotein and to explore the relation of antibody responses against myelin oligodendrocyte glycoprotein and severe acute respiratory syndrome coronavirus 2 and other coronaviruses. We analysed serum samples from patients with severe acute respiratory syndrome coronavirus 2 infection and neurological symptoms with (myelin oligodendrocyte glycoprotein antibody-associated disease, n = 12) or without myelin oligodendrocyte glycoprotein-antibodies (n = 10); severe acute respiratory syndrome coronavirus 2 infection without neurological symptoms (n = 32); vaccinated patients with no history of severe acute respiratory syndrome coronavirus 2 infection and neurological symptoms with (myelin oligodendrocyte glycoprotein antibody-associated disease, n = 10) or without myelin oligodendrocyte glycoprotein-antibodies (n = 9); and severe acute respiratory syndrome coronavirus 2 negative/naïve unvaccinated patients with neurological symptoms with (myelin oligodendrocyte glycoprotein antibody-associated disease, n = 47) or without myelin oligodendrocyte glycoprotein-antibodies (n = 20). All samples were analysed for serum antibody responses to myelin oligodendrocyte glycoprotein, severe acute respiratory syndrome coronavirus 2, and other common coronaviruses (CoV-229E, CoV-HKU1, CoV-NL63 and CoV-OC43). Based on sample amount and antibody titres, 21 samples were selected for analysis of antibody cross-reactivity between myelin oligodendrocyte glycoprotein and severe acute respiratory syndrome coronavirus 2 spike and nucleocapsid proteins using affinity purification and pre-absorption. Whereas we found no association of immunoglobulin G and A myelin oligodendrocyte glycoprotein antibodies with coronavirus antibodies, infections with severe acute respiratory syndrome coronavirus 2 correlated with an increased immunoglobulin M myelin oligodendrocyte glycoprotein antibody response. Purified antibodies showed no cross-reactivity between severe acute respiratory syndrome coronavirus 2 spike protein and myelin oligodendrocyte glycoprotein. However, one sample of a patient with myelin oligodendrocyte glycoprotein antibody-associated disease following severe acute respiratory syndrome coronavirus 2 infection showed a clear immunoglobulin G antibody cross-reactivity to severe acute respiratory syndrome coronavirus 2 nucleocapsid protein and myelin oligodendrocyte glycoprotein. This patient was also seropositive for other coronaviruses and showed immunological cross-reactivity of severe acute respiratory syndrome coronavirus 2 and CoV-229E nucleocapsid proteins. Overall, our results indicate that an immunoglobulin G antibody cross-reactivity between myelin oligodendrocyte glycoprotein and severe acute respiratory syndrome coronavirus 2 proteins is rare. The presence of increased myelin oligodendrocyte glycoprotein-immunoglobulin M antibodies after severe acute respiratory syndrome coronavirus 2 infection may either be a consequence of a previous infection with other coronaviruses or arise as an unspecific sequel after viral infection. Furthermore, our data indicate that myelin oligodendrocyte glycoprotein-immunoglobulin A and particularly myelin oligodendrocyte glycoprotein-immunoglobulin M antibodies are a rather unspecific sequel of viral infections. Finally, our findings do not support a causative role of coronavirus infections for the presence of myelin oligodendrocyte glycoprotein-immunoglobulin G antibodies.

Body fluid markers for multiple sclerosis and differential diagnosis from atypical demyelinating disorders.

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.

Factors influencing the willingness to adopt telerehabilitation among rehabilitation professionals in Austria and Germany: a survey comparing data before and during COVID-19.

PURPOSE: To investigate determinants of willingness to adopt telerehabilitation, willingness of technology use, core affect regarding using telerehabilitation, and digital competencies in rehabilitation professionals in Austria and Germany before and during the COVID-19 pandemic. MATERIALS AND METHODS: A cross-sectional paper-based and online survey was conducted before and during COVID-19, respectively, with three cohorts of rehabilitation professionals. Outcomes were the willingness to adopt telerehabilitation evaluated using the extended Unified Theory of Acceptance and Use of Technology; willingness of technology use using the short scale for assessing the willingness of technology use; digital competencies and core affect using the Digital Competence Framework and semantic differential, respectively. Multivariate ordinal regression analysis was performed to determine predictors. RESULTS: Included were 603 rehabilitation professionals. Analysis revealed differences between Austria and Germany and before and during the pandemic for most outcomes. German residency, the pandemic, and a higher educational level were most important predictors of higher willingness to adopt telerehabilitation, willingness of technology use, digital competencies, and positive core affect.The pandemic increased most aspects of willingness to adopt telerehabilitation, willingness of technology use, digital competencies, and positive core affect. Results confirm that rehabilitation professionals with higher degrees are more prone to adopt innovations in healthcare.Registration: German Clinical Trials Register (DRKS00021464)IMPLICATIONS FOR REHABILITATIONThe willingness to adopt telerehabilitation is associated with external factors increasing the need for alternative rehabilitation delivery, such as COVID-19, and with financial facilitators, such as reimbursement.As the willingness to adopt telerehabilitation is higher among speech and language therapists and dietitians, efforts are necessary to enhance its use in physiotherapists and occupational therapists.As a higher willingness to adopt telerehabilitation was observed in younger rehabilitation professionals and those with higher education, increasing the importance of telerehabilitation in education curricula and further knowledge transfer into practice for those already working in the field seems necessary.

Combining specific task-oriented training with manual therapy to improve balance and mobility in patients after stroke: a mixed methods pilot randomised controlled trial.

PURPOSE: In absence of existing studies, to describe changes in balance and mobility, following specific task-oriented training (TOT), its combination with talocrural manual therapy (MT-TOT) or no intervention, in chronic stroke patients. To explore the feasibility of a full-scale randomised controlled trial (RCT) based on criteria of recruitment, retention and adherence rates, adverse events, falls and acceptability of the intervention. MATERIALS AND METHODS: Using an assessor-blinded pilot RCT, 36 stroke patients were allocated to either MT-TOT, TOT, or controls. Supervised interventions were performed 45 min, 2×/weekly, for 4 weeks, and home-based practice 20 min, 4x/weekly for 4 weeks. Qualitative interviews evaluated intervention acceptability. Outcomes of balance, mobility, ankle dorsiflexion range of motion (ROM), falls and health-related quality of life (HRQoL) were assessed at baseline, post-intervention and 4-week follow-up. RESULTS: Preliminary efficacy of MT-TOT and TOT was shown in improving balance (effect size 0.714), walking speed (0.683), mobility (0.265), dual-tasking mobility (0.595), falls (0.037), active and passive talocrural ROM (0.603; 0.751) and activities and social participation related HRQoL domains (0.332-0.784) in stroke patients. The feasibility of a larger RCT was confirmed. CONCLUSIONS: Specific MT-TOT and TOT appeared effective and are feasible in stroke patients. A larger RCT is needed to validate the results.Trial Registration: German Clinical Trials Register, DRKS00023068. Registered on 21.09.2020, https://www.drks.de/drks_web/navigate.do?navigationId=trial.HTML&TRIAL_ID=DRKS00023068.

A specific goal- and task-oriented training involving timed mobility and dynamic balance activities based on the demands of daily life, of high intensity and progressed in difficulty according to predefined criteria is feasible in patients after stroke.In this mixed methods pilot study patients indicated high acceptability of task-oriented training with and without ankle mobilisations, with their descriptions being in line with the Theoretical Framework of Acceptability.Specific task-oriented training and its combination with talocrural joint manual therapy improved balance, mobility, talocrural dorsiflexion range of motion and some domains of health-related quality of life in people after stroke.

Serum Biomarker Profiles Discriminate AQP4 Seropositive and Double Seronegative Neuromyelitis Optica Spectrum Disorder.

BACKGROUND AND OBJECTIVES: Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) serum levels are useful to define disease activity in different neurologic conditions. These biomarkers are increased in patients with aquaporin-4 antibody-positive NMOSD (AQP4+NMOSD) during clinical attacks suggesting a concomitant axonal and glial damage. However, there are contradictory results in double seronegative NMOSD (DS-NMOSD). The aim of this study was to characterize the neuronal, axonal, and glial damage of DS-NMOSD in comparison with AQP4+NMOSD. METHODS: Patients with DS-NMOSD (i.e., for AQP4 and myelin oligodendrocyte glycoprotein antibodies-MOG-Abs) and age-matched AQP4+NMOSD diagnosed according to the latest diagnostic criteria and with available serum samples obtained within 3 months from onset/relapse were retrospectively enrolled from 14 international centers. Clinical and radiologic data were collected. Serum NfL, GFAP, tau, and UCH-L1 levels were determined using an ultrasensitive paramagnetic bead-based ELISA (SIMOA). Statistical analysis was performed using nonparametric tests and receiver-operating characteristic (ROC) curve analysis. RESULTS: We included 25 patients with AQP4+NMOSD and 26 with DS-NMOSD. The median age at disease onset (p = 0.611) and female sex predominance (p = 0.072) were similar in the 2 groups. The most common syndromes at sampling in both AQP4+NMOSD and DS-NMOSD were myelitis (56% vs 38.5%) and optic neuritis (34.6% vs 32%), with no statistical differences (p = 0.716). Median EDSS at sampling was 3.2 (interquartile range [IQR] 2-7.7) in the AQP4+NMOSD group and 4 (IQR [3-6]) in the DS-NMOSD group (p = 0.974). Serum GFAP, tau, and UCH-L1 levels were higher in patients with AQP4+NMOSD compared with those with DS-NMOSD (median 308.3 vs 103.4 pg/mL p = 0.001; median 1.2 vs 0.5 pg/mL, p = 0.001; and median 61.4 vs 35 pg/mL, p = 0.006, respectively). The ROC curve analysis showed that GFAP, tau, and UCH-L1, but not NfL, values were able to discriminate between AQP4+ and DS-NMOSD (area under the curve (AUC) tau: 0.782, p = 0.001, AUC GFAP: 0.762, p = 0.001, AUC UCH-L1: 0.723, p = 0.006). NfL levels were associated with EDSS at nadir only in patients with AQP4+NMOSD. DISCUSSION: Serum GFAP, tau, and UCH-L1 levels discriminate between AQP4+NMOSD and DS-NMOSD. The different biomarker profile of AQP4+NMOSD vs DS-NMOSD suggests heterogeneity of diseases within the latter category and provides useful data to improve our understanding of this disease.

Basic CSF parameters and MRZ reaction help in differentiating MOG antibody-associated autoimmune disease versus multiple sclerosis.

Background: Myelin oligodendrocyte glycoprotein antibody-associated autoimmune disease (MOGAD) is a rare monophasic or relapsing inflammatory demyelinating disease of the central nervous system (CNS) and can mimic multiple sclerosis (MS). The variable availability of live cell-based MOG-antibody assays and difficulties in interpreting low-positive antibody titers can complicate diagnosis. Literature on cerebrospinal fluid (CSF) profiles in MOGAD versus MS, one of the most common differential diagnoses, is scarce. We here analyzed the value of basic CSF parameters to i) distinguish different clinical MOGAD manifestations and ii) differentiate MOGAD from MS. Methods: This is retrospective, single-center analysis of clinical and laboratory data of 30 adult MOGAD patients and 189 adult patients with relapsing-remitting multiple sclerosis. Basic CSF parameters included CSF white cell count (WCC) and differentiation, CSF/serum albumin ratio (QAlb), intrathecal production of immunoglobulins, CSF-restricted oligoclonal bands (OCB) and MRZ reaction, defined as intrathecal production of IgG reactive against at least 2 of the 3 viruses measles (M), rubella (R) and varicella zoster virus (Z). Results: MOGAD patients with myelitis were more likely to have a pleocytosis, a QAlb elevation and a higher WCC than those with optic neuritis, and, after review and combined analysis of our and published cases, they also showed a higher frequency of intrathecal IgM synthesis. Compared to MS, MOGAD patients had significantly more frequently neutrophils in CSF and WCC>30/µl, QAlb>10×10-3, as well as higher mean QAlb values, but significantly less frequently CSF plasma cells and CSF-restricted OCB. A positive MRZ reaction was present in 35.4% of MS patients but absent in all MOGAD patients. Despite these associations, the only CSF parameters with relevant positive likelihood ratios (PLR) indicating MOGAD were QAlb>10×10-3 (PLR 12.60) and absence of CSF-restricted OCB (PLR 14.32), whereas the only relevant negative likelihood ratio (NLR) was absence of positive MRZ reaction (NLR 0.00). Conclusion: Basic CSF parameters vary considerably in different clinical phenotypes of MOGAD, but QAlb>10×10-3 and absence of CSF-restricted OCB are highly useful to differentiate MOGAD from MS. A positive MRZ reaction is confirmed as the strongest CSF rule-out parameter in MOGAD and could be useful to complement the recently proposed diagnostic criteria.

Blood-Brain Barrier Breakdown in Neuroinflammation: Current In Vitro Models.

The blood-brain barrier, which is formed by tightly interconnected microvascular endothelial cells, separates the brain from the peripheral circulation. Together with other central nervous system-resident cell types, including pericytes and astrocytes, the blood-brain barrier forms the neurovascular unit. Upon neuroinflammation, this barrier becomes leaky, allowing molecules and cells to enter the brain and to potentially harm the tissue of the central nervous system. Despite the significance of animal models in research, they may not always adequately reflect human pathophysiology. Therefore, human models are needed. This review will provide an overview of the blood-brain barrier in terms of both health and disease. It will describe all key elements of the in vitro models and will explore how different compositions can be utilized to effectively model a variety of neuroinflammatory conditions. Furthermore, it will explore the existing types of models that are used in basic research to study the respective pathologies thus far.

Salivary antibodies induced by BA.4/BA.5-convalescence or bivalent booster Immunoglobulin vaccination protect against novel SARS-COV-2 variants of concern.

Currently, SARS-CoV-2 Omicron BA.5 subvariants BF.7 and BQ.1.1 are rapidly emerging worldwide. To evaluate the SARS-CoV-2-neutralizing capacity of sera and saliva from triple vaccinated individuals, either boosted with an adapted bivalent COVID-19 vaccine or recovered from BA.4/BA.5 infection, we analyzed the sensitivity of replication-competent SARS-CoV-2 Omicron subvariants BA.4/5, BQ.1.1 and BF.7 to neutralization. Analysis of SARS-CoV-2-specific IgGs and IgAs showed increased serum IgG titers in the vaccinated group, while the serum and salivary IgA levels were comparable. Similar and efficient serum neutralization against the ancestral strain of SARS-CoV-2 and Omicron BA.4/BA.5 was detected in both cohorts, but critically reduced for BQ.1.1 and BF.7. In contrast, salivary neutralization against BA.4/BA.5 was increased in the convalescent compared to the vaccinated group, while salivary neutralizing capacity against BQ.1.1 and BF.7 was comparable in these groups. Further, personalized protective effects studied in a human 3D respiratory model revealed the importance of salivary protection against different Omicron subvariants. IMPORTANCE In BA.4/BA.5-convalescent versus vaccinated groups, salivary neutralization capacity increased against SARS-CoV-2 Omicron BA.4/BA.5. In contrast, it neutralized novel Omicron subvariants BQ.1.1 and BF.7 similarly. Salivary protection against various Omicron subvariants was even more evident when tested in a personalized approach using highly differentiated respiratory human 3D models.

Immune profiling in multiple sclerosis: a single-center study of 65 cytokines, chemokines, and related molecules in cerebrospinal fluid and serum.

Introduction: The understanding of the pathophysiology of multiple sclerosis (MS) has evolved alongside the characterization of cytokines and chemokines in cerebrospinal fluid (CSF) and serum. However, the complex interplay of pro- and anti-inflammatory cytokines and chemokines in different body fluids in people with MS (pwMS) and their association with disease progression is still not well understood and needs further investigation. Therefore, the aim of this study was to profile a total of 65 cytokines, chemokines, and related molecules in paired serum and CSF samples of pwMS at disease onset. Methods: Multiplex bead-based assays were performed and baseline routine laboratory diagnostics, magnetic resonance imaging (MRI), and clinical characteristics were assessed. Of 44 participants included, 40 had a relapsing-remitting disease course and four a primary progressive MS. Results: There were 29 cytokines and chemokines that were significantly higher in CSF and 15 in serum. Statistically significant associations with moderate effect sizes were found for 34 of 65 analytes with sex, age, CSF, and MRI parameters and disease progression. Discussion: In conclusion, this study provides data on the distribution of 65 different cytokines, chemokines, and related molecules in CSF and serum in newly diagnosed pwMS.

Vaccination and Omicron BA.1/BA.2 Convalescence Enhance Systemic but Not Mucosal Immunity against BA.4/5.

Rising breakthrough infections with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron BA.4/5 led to the performance of various studies investigating systemic immunity and neutralizing antibodies in sera, but mucosal immunity remains understudied. In this cohort study, the humoral immune responses, including immunoglobulin levels and the presence of virus-neutralizing antibodies, of 92 vaccinated and/or BA.1/BA.2 convalescent individuals were investigated. Cohorts received two doses of ChAdOx1, BNT162b2, or mRNA-1273 and subsequent booster vaccination with either BNT162b2 or mRNA-1273, following BA.1/BA.2 infection. In addition, vaccinated and nonconvalescent or unvaccinated and BA.1 convalescent individuals were studied. Serum and saliva samples were used to determine SARS-CoV-2 spike-specific IgG and IgA titers and neutralizing activity against replication-competent SARS-CoV-2 wild-type virus and the Omicron BA.4/5 variant. Vaccinated/convalescent cohorts demonstrated strongest neutralization against BA.4/5, with 50% neutralization titer (NT50) values reaching 174.2; however, neutralization was reduced up to 11-fold, compared to wild-type virus. Both BA.1 convalescent and vaccinated nonconvalescent cohorts displayed the weakest neutralization against BA.4/5, with NT50 values being reduced to 4.6, accompanied by lower numbers of positive neutralizers. Additionally, salivary neutralization against wild-type virus was strongest in vaccinated and BA.2 convalescent subjects, but this elevated neutralization efficiency was lost when challenged with BA.4/5. Our data support the contention that current coronavirus disease 2019 (COVID-19) vaccines efficiently induce humoral immunity. However, antiviral effectiveness in serum and saliva is greatly reduced against novel variants of concern. These results suggest an adjustment of current vaccine strategies to an adapted or alternative vaccine delivery, such as mucosal booster vaccinations, which might establish enhanced or even sterilizing immunity against novel SARS-CoV-2 variants. IMPORTANCE Rising incidences of breakthrough infections caused by SARS-CoV-2 Omicron BA.4/5 have been observed. Although various studies were conducted investigating neutralizing antibodies in sera, mucosal immunity was barely evaluated. Here, we investigated mucosal immunity, since the presence of neutralizing antibodies at mucosal entry sites plays a fundamental role in disease limitation. We found strong induction of serum IgG/IgA, salivary IgA, and neutralization against SARS-CoV-2 wild-type virus in vaccinated/convalescent subjects but detected 10-fold reduced (albeit positive) serum neutralization against BA.4/5. Interestingly, vaccinated and BA.2 convalescent patients demonstrated the greatest serum neutralization against BA.4/5, but this advantageous neutralizing effect was not observed in the saliva. Our data support the contention that current COVID-19 vaccines are very efficient against severe/critical disease progression. Moreover, these results suggest an adjustment of the current vaccine strategy to adapted and alternative vaccine delivery, such as mucosal booster vaccinations, to establish robust sterilizing immunity against novel SARS-CoV-2 variants.

High serum neurofilament light chain levels correlate with brain atrophy and physical disability in multiple sclerosis.

BACKGROUND AND PURPOSE: Serum neurofilament light chain (sNfL) is a promising biomarker of neuroaxonal damage in persons with multiple sclerosis (pwMS). In cross-sectional studies, sNfL has been associated with disease activity and brain magnetic resonance imaging (MRI) changes; however, it is still unclear to what extent in particular high sNfL levels impact on subsequent disease evolution. METHODS: sNfL was quantified by an ultrasensitive single molecule array (Simoa) in 199 pwMS (median age = 34.2 years, 64.3% female) and 49 controls. All pwMS underwent 3-T MRI to assess global and compartmental normalized brain volumes, T2-lesion load, and cortical mean thickness. Follow-up data and serum samples were available in 144 pwMS (median follow-up time = 3.8 years). Linear and binary logistic models were used to estimate the independent contribution of sNfL for changes in MRI and Expanded Disability Status Scale (EDSS). Age-corrected sNfL z-scores from a normative database of healthy controls were used for sensitivity analyses. RESULTS: High sNfL levels at baseline were associated with atrophy measures of the whole brain (standardized beta coefficient ßj = -0.352, p < 0.001), white matter (ßj = -0.229, p = 0.007), thalamus (ßj = -0.372, p = 0.004), and putamen (ßj = -1.687, p = 0.012). pwMS with high levels of sNfL at baseline and follow-up had a greater risk of EDSS worsening (p = 0.007). CONCLUSIONS: Already single time point elevation of sNfL has a distinct effect on brain volume changes over a short-term period, and repeated high levels of sNfL indicate accumulating physical disability. Serial assessment of sNfL may provide added value in the clinical management of pwMS.

The Potential Pathogenicity of Myelin Oligodendrocyte Glycoprotein Antibodies in the Optic Pathway.

BACKGROUND: Myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) is an acquired inflammatory demyelinating disease with optic neuritis (ON) as the most frequent clinical symptom. The hallmark of the disease is the presence of autoantibodies against MOG (MOG-IgG) in the serum of patients. Whereas the role of MOG in the experimental autoimmune encephalomyelitis animal model is well-established, the pathogenesis of the human disease and the role of human MOG-IgG is still not fully clear. EVIDENCE ACQUISITION: PubMed was searched for the terms "MOGAD," "optic neuritis," "MOG antibodies," and "experimental autoimmune encephalomyelitis" alone or in combination, to find articles of interest for this review. Only articles written in English language were included and reference lists were searched for further relevant papers. RESULTS: B and T cells play a role in the pathogenesis of human MOGAD. The distribution of lesions and their development toward the optic pathway is influenced by the genetic background in animal models. Moreover, MOGAD-associated ON is frequently bilateral and often relapsing with generally favorable visual outcome. Activated T-cell subsets create an inflammatory environment and B cells are necessary to produce autoantibodies directed against the MOG protein. Here, pathologic mechanisms of MOG-IgG are discussed, and histopathologic findings are presented. CONCLUSIONS: MOGAD patients often present with ON and harbor antibodies against MOG. Furthermore, pathogenesis is most likely a synergy between encephalitogenic T and antibody producing B cells. However, to which extent MOG-IgG are pathogenic and the exact pathologic mechanism is still not well understood.

Impaired Brain Growth in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Acute Disseminated Encephalomyelitis.

BACKGROUND AND OBJECTIVES: Acute disseminated encephalomyelitis (ADEM) is the most common phenotype in pediatric myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease. A previous study demonstrated impaired brain growth in ADEM. However, the effect of MOG antibodies on brain growth remains unknown. Here, we performed brain volume analyses in MOG-positive and MOG-negative ADEM at onset and over time. METHODS: In this observational cohort study, we included a total of 62 MRI scans from 24 patients with ADEM (54.2% female; median age 5 years), of which 16 (66.7%) were MOG positive. Patients were compared with healthy controls from the NIH pediatric MRI data repository and a matched local cohort. Mixed-effect models were applied to assess group differences and other relevant factors, including relapses. RESULTS: At baseline and before any steroid treatment, patients with ADEM, irrespective of MOG antibody status, showed reduced brain volume compared with matched controls (median [interquartile range] 1,741.9 cm3 [1,645.1-1,805.2] vs 1,810.4 cm3 [1,786.5-1,836.2]). Longitudinal analysis revealed reduced brain growth for both MOG-positive and MOG-negative patients with ADEM. However, MOG-negative patients showed a stronger reduction (-138.3 cm3 [95% CI -193.6 to -82.9]) than MOG-positive patients (-50.0 cm3 [-126.5 to -5.2]), independent of age, sex, and treatment. Relapsing patients (all MOG positive) showed additional brain volume loss (-15.8 cm3 [-68.9 to 37.3]). DISCUSSION: Patients with ADEM exhibit brain volume loss and failure of age-expected brain growth. Importantly, MOG-negative status was associated with a more pronounced brain volume loss compared with MOG-positive patients.

Humoral signatures of MOG-antibody-associated disease track with age and disease activity.

Myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated disease (MOGAD) is an inflammatory demyelinating disease of the CNS. Although MOG is encephalitogenic in different mammalian species, the mechanisms by which human MOG-specific Abs contribute to MOGAD are poorly understood. Here, we use a systems-level approach combined with high-dimensional characterization of Ab-associated immune features to deeply profile humoral immune responses in 123 patients with MOGAD. We show that age is a major determinant for MOG-antibody-related immune signatures. Unsupervised clustering additionally identifies two dominant immunological endophenotypes of MOGAD. The pro-inflammatory endophenotype characterized by increased binding affinities for activating Fcγ receptors (FcγRs), capacity to activate innate immune cells, and decreased frequencies of galactosylated and sialylated immunoglobulin G (IgG) glycovariants is associated with clinically active disease. Our data support the concept that FcγR-mediated effector functions control the pathogenicity of MOG-specific IgG and suggest that FcγR-targeting therapies should be explored for their therapeutic potential in MOGAD.

Diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease: International MOGAD Panel proposed criteria.

Serum antibodies directed against myelin oligodendrocyte glycoprotein (MOG) are found in patients with acquired CNS demyelinating syndromes that are distinct from multiple sclerosis and aquaporin-4-seropositive neuromyelitis optica spectrum disorder. Based on an extensive literature review and a structured consensus process, we propose diagnostic criteria for MOG antibody-associated disease (MOGAD) in which the presence of MOG-IgG is a core criterion. According to our proposed criteria, MOGAD is typically associated with acute disseminated encephalomyelitis, optic neuritis, or transverse myelitis, and is less commonly associated with cerebral cortical encephalitis, brainstem presentations, or cerebellar presentations. MOGAD can present as either a monophasic or relapsing disease course, and MOG-IgG cell-based assays are important for diagnostic accuracy. Diagnoses such as multiple sclerosis need to be excluded, but not all patients with multiple sclerosis should undergo screening for MOG-IgG. These proposed diagnostic criteria require validation but have the potential to improve identification of individuals with MOGAD, which is essential to define long-term clinical outcomes, refine inclusion criteria for clinical trials, and identify predictors of a relapsing versus a monophasic disease course.

Significance of Myelin Oligodendrocyte Glycoprotein Antibodies in CSF: A Retrospective Multicenter Study.

BACKGROUND AND OBJECTIVES: Although the diagnosis of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is based on serum MOG antibodies (MOG-Abs) positivity, patients with coexisting or restricted MOG-Abs in the CSF have been reported. The aim of this study is to characterize the relevance of CSF MOG-Abs positivity in clinical practice. METHODS: Eleven medical centers retrospectively collected clinical and laboratory data of adult and pediatric patients with suspected inflammatory CNS disease and MOG-Abs positivity in serum and/or CSF using live cell-based assays. Comparisons were performed using parametric or nonparametric tests, as appropriate. Potential factors of unfavorable outcomes were explored by Cox proportional hazard models and logistic regression. RESULTS: The cohort included 255 patients: 139 (55%) women and 132 (52%) children (i.e., <18-year-old). Among them, 145 patients (56.8%) had MOG-Abs in both serum and CSF (MOG-Abs seropositive and CSF positive), 79 (31%) only in serum (MOG-Abs seropositive and CSF negative), and 31 (12%) only in CSF (MOG-Abs seronegative and CSF positive). MOG-Abs seronegative and CSF positive predominated in adults (22% vs 3% of children), presented more commonly with motor (n = 14, 45%) and sensory symptoms (n = 13, 42%), and all but 4 (2 multiple sclerosis, 1 polyradiculoneuritis, and 1 Susac syndrome) had a final diagnosis compatible with MOGAD. When comparing seropositive patients according to MOG-Abs CSF status, MOG-Abs seropositive and CSF positive patients had a higher Expanded Disability Status Scale (EDSS) at nadir during the index event (median 4.5, interquartile range [IQR] 3.0-7.5 vs 3.0, IQR 2.0-6.8, p = 0.007) and presented more commonly with sensory (45.5% vs 24%, p = 0.002), motor (33.6% vs 19%, p = 0.021), and sphincter symptoms (26.9% vs 7.8%, p = 0.001) than MOG-Abs seropositive and CSF negative. At the last follow-up, MOG-Abs seropositive and CSF positive cases had more often persistent sphincter dysfunction (17.3% vs 4.3%, p = 0.008). Compared with seropositive patients, those MOG-Abs seronegative and CSF positive had higher disability at the last follow-up (p ≤ 0.001), and MOG-Abs seronegative and CSF positive status were independently associated with an EDSS ≥3.0. DISCUSSION: Paired serum and CSF MOG-Abs positivity are common in MOGAD and are associated with a more severe clinical presentation. CSF-only MOG-Abs positivity can occur in patients with a phenotype suggestive of MOGAD and is associated with a worse outcome. Taken together, these data suggest a clinical interest in assessing CSF MOG-Abs in patients with a phenotype suggestive of MOGAD, regardless of the MOG-Abs serostatus.

[Psychometric Evaluation of the 'German Neurological Fatigue Index for Multiple Sclerosis (NFI-MS-G)' in a Sample of Rehabilitation Patients with Multiple Sclerosis]. / Psychometrische Prüfung des deutschsprachigen "Neurologischen Fragebogens zur Müdigkeit bei Multipler Sklerose (NFI-MS-G)" bei Rehabilitanden mit Multipler Sklerose.

PURPOSE: The purpose of this study was to provide a patient-reported outcome measure for people with multiple sclerosis (MS) comprehensively reflecting the construct of fatigue and developed upon the assumptions of the Rasch model. The Neurological Fatigue Index - Multiple Sclerosis (NFI-MS) is based on both a medical and patient-described symptom framework of fatigue and has been validated. Therefore, in this study the German version of the NFI-MS (NFI-MS-G) consisting of a physical and cognitive subscale and a summary scale was validated. METHOD: In this bi-centre-study, 309 people with MS undergoing outpatient rehabilitation or being≥2 months before or after their inpatient rehabilitation completed the German NFI-MS-G twice within 14-21 days together with other questionnaires. Correlation with established questionnaires and Rasch analysis were used for its validation. Additionally, psychometric properties of known-groups validity, internal consistency, test-retest reliability, measurement precision and readability were tested. Finally, the English NFI-MS and German NFI-MS-G were compared with each other to equate the language versions. RESULTS: The NFI-MS-G showed good internal construct validity, convergent and known-groups validity and internal consistency (Cronbach's alpha 0.84-0.93). The physical subscale showed minor local dependencies between items 1 and 7, 2 and 3 and 4 to 6, that could be treated by combining the respective items to testlets. Unidimensionality was found for the physical and cognitive subscales but not for the summary scale. Replacing the summary scale, a 2-domains subtest measuring the higher-order construct of fatigue was created. Good test-retest reliability (Lin's concordance correlation coefficient of 0.86-0.90) and low floor and ceiling effects were demonstrated. The NFI-MS-G was found easily readable and invariant across groups of gender, age, disease duration, timepoint and centre. CONCLUSION: The German version of the NFI-MS comprehensively represents the construct of fatigue and has adequate psychometric properties. The German version differs from the English original version with respect to a lack of unidimensionality of the summary scale and minor local dependencies of the physical subscale that could be canceled out using a testlet analysis.