Search

This article, published in the journal Neuropediatrics, discusses the treatment response in children with relapsing MOG-associated disease (MOGAD). The study evaluated the use of intravenous immunoglobulins (IVIG) compared to other therapies in children with relapsing disease course. The results showed that the annual relapse rate (ARR) was lower in all treatment groups compared to no treatment, with the lowest ARR observed in patients treated with IVIG alone. The study suggests that IVIG may have a favorable treatment effect in relapsing MOGAD, but further research is needed to determine the optimal treatment. [Extracted from the article]

Background: Continued phenotyping and ongoing molecular epidemiology are important in current and future monitoring of emerging SARS-CoV-2 lineages. Herein we developed pragmatic strategies to track the emergence, spread and phenotype of SARS-CoV-2 variants in Australia in an era of decreasing diagnostic PCR testing and focused cohort-based studies. This was aligned to longitudinal studies that span 4 years of the COVID-19 pandemic., Methods: Throughout 2023, we partnered with diagnostic pathology providers and pathogen genomics teams to identify relevant emerging or circulating variants in the New South Wales (NSW) community. We monitored emerging variants through viral culture, growth algorithms, neutralisation responses and changing entry requirements defined by ACE2 and TMPRSS2 receptor use. To frame this in the context of the pandemic stage, we continued to longitudinally track neutralisation responses at the population level using pooled Intravenous Immunoglobulins (IVIG) derived from in excess of 700,000 donations., Findings: In antibodies derived from recent individual donations and thousands of donations pooled in IVIGs, we observed continued neutralisation across prior and emerging variants with EG.5.1, HV.1, XCT and JN.1 ranked as the most evasive SARS-CoV-2 variants. Changes in the type I antibody site at Spike positions 452, 455 and 456 were associated with lowered neutralisation responses in XBB lineages. In longitudinal tracking of population immunity spanning three years, we observed continued maturation of neutralisation breadth to all SARS-CoV-2 variants over time. Whilst neutralisation responses initially displayed high levels of imprinting towards Ancestral and early pre-Omicron lineages, this was slowly countered by increased cross reactive breadth to all variants. We predicted JN.1 to have a marked transmission advantage in late 2023 and this eventuated globally at the start of 2024. We could not attribute this advantage to neutralisation resistance but rather propose that this growth advantage arises from the preferential utilisation of ACE2 pools that cannot engage TMPRSS2 at its Collectrin-Like Domain (CLD)., Interpretation: The emergence of many SARS-CoV-2 lineages documented at the end of 2023 was found to be initially associated with lowered neutralisation responses. This continued to be countered by the gradual maturation of cross-reactive neutralisation responses over time. The later appearance and dominance of the divergent JN.1 lineage cannot be attributed to a lack of neutralisation responses alone, and our data supports that its dominance is a culmination of both lowered neutralisation and changes in ACE2/TMPRSS2 entry preferences., Funding: This work was primarily supported by Australian Medical Foundation research grants MRF2005760 (ST, GM & WDR), MRF2001684 (ADK and ST) and Medical Research Future Fund Antiviral Development Call grant (WDR), Medical Research Future Fund COVID-19 grant (MRFF2001684, ADK & SGT) and the New South Wales Health COVID-19 Research Grants Round 2 (SGT)., Competing Interests: Declaration of interests Funding bodies did not contribute to study design, data collection, data analysis or writing of the manuscript. Study design, data collection, data analysis and data interpretation were performed by the listed authors. Writing and review was performed by the listed authors. JW has funding contracts from NSW Health for COVID-19 modelling (2021-23), was an investigator on Investigator on Australian government contracts for COVID-19 modelling (2021-22), Principal investigator on a NHMRC Partnership grant (2023-28) on respiratory virus modelling, forecasting and surveillance and a Voting member of Australian Technical Advisory Committee (on Immunisation (ATAGI) 2020-present. FB has funding from NSW Health for development of Covid serology and viral isolation platforms, is on the International Society for neuroimmunology: international advisory board (unpaid position). ADK has Australian National Health and Medical Research Council, Medical Future Fund and National Institutes of Health funding for research investigating SARS-CoV-2 immunological responses and SARS-CoV-2 therapeutics. Was the prior chair of the ASOT DSMB 2020–2022 and is the current Director of Scientia Clinical Research at UNSW. GM has active grants with ViiV and Janssen, has received travel support and honorariums through Gilead and is on Data Safety Monitoring Board at ViiV. N. Roth and T. Boss hold stock options in CSL Behring., (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: We sought to identify an optimal oral corticosteroid regimen at the onset of myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD), which would delay time to first relapse while minimising cumulative corticosteroid exposure., Methods: In a retrospective multicentre cohort study, Cox proportional hazards models examined the relationship between corticosteroid course as a time-varying covariate and time to first relapse. Simon-Makuch and Kaplan-Meier plots identified an optimal dosing strategy., Results: We evaluated 109 patients (62 female, 57%; 41 paediatric, 38%; median age at onset 26 years, (IQR 8-38); median follow-up 6.2 years (IQR 2.6-9.6)). 76/109 (70%) experienced a relapse (median time to first relapse 13.7 months; 95% CI 8.2 to 37.9). In a multivariable model, higher doses of oral prednisone delayed time to first relapse with an effect estimate of 3.7% (95% CI 0.8% to 6.6%; p = 0.014) reduced hazard of relapse for every 1 mg/day dose increment. There was evidence of reduced hazard of relapse for patients dosed ≥12.5 mg/day (HR 0.21, 95% CI 0.07 to 0.6; p = 0.0036), corresponding to a 79% reduction in relapse risk. There was evidence of reduced hazard of relapse for those dosed ≥12.5 mg/day for at least 3 months (HR 0.12, 95% CI 0.03 to 0.44; p = 0.0012), corresponding to an 88% reduction in relapse risk compared with those never treated in this range. No patient with this recommended dosing at onset experienced a Common Terminology Criteria for Adverse Events grade >3 adverse effect., Conclusions: The optimal dose of 12.5 mg of prednisone daily in adults (0.16 mg/kg/day for children) for a minimum of 3 months at the onset of MOGAD delays time to first relapse., Competing Interests: Competing interests: BPT receives a University of Sydney postgraduate scholarship and a stipend from CIA Ramanathan’s Royal Australasian College of Physicians Research Establishment Fellowship. RCD has received research funding from the Star Scientific Foundation, The Trish Multiple Sclerosis Research Foundation, Multiple Sclerosis Research Australia, the Petre Foundation and the NHMRC (Australia; Investigator Grant). He has also received honoraria from Biogen Idec as an invited speaker, and is on the IDMC for a Roche RCT in paediatric MS. He is on the medical advisory board (non-remunerated position). TAH has received research funding from MS Australia, the NHMRC Medical Research Future Fund (Australia), the Brain Foundation and has received honoraria for talks, advisory boards or support for scientific meetings from Bayer-Schering, Novartis, Biogen Idec, Merck, Teva, Alexion, Bristol Myers Squibb and Sanofi-Genzyme. AVDW receives funding from MS Australia, the NHMRC and the Trish Foundation. She has received research support from Roche pharmaceuticals, Biogen, Novartis and Merck. She has received honoraria for talks, advisory boards, and travel support from Novartis and Merck. She serves as the COO of the MSBase Foundation. JLS received travel compensation from Biogen, Merck, Novartis; has been involved in clinical trials with Biogen, Novartis, Roche; her institution has received honoraria for talks and advisory board service from Biogen, Merck, Novartis, Roche. She is on the board of directors for MSPlus. HB has received institutional compensation (To Monash University) for advisory board or trial steering committee membership or speaker bureaus from Biogen, Merck, Novartis, Roche, and UCB Pharma. Institutional Research Support to Monash University or MSBase Foundation from Merck, Biogen, Roche, Novartis, UCB Pharma, Alexion, Teva, NMHRC (Australia), MRFF (Australia), MS Australia, TRISH MS Research Foundation, Pennycook Foundation and Monash University. SAB has received honoraria for attendance at advisory boards and travel sponsorship from Bayer-Schering, Biogen-Idec, Merck-Serono, Novartis, and Sanofi-Genzyme, has received speaker’s honoraria from Biogen-Idec and Genzyme, is an investigator in clinical trials sponsored by Biogen Idec, Novartis and Genzyme, and was the recipient of an unencumbered research grant from Biogen-Idec. MB received research grants from Genzyme-Sanofi, Novartis, Biogen, Merck and BMS; and is a Research Consultant for RxMx and Research Director for the Sydney Neuroimaging Analysis Centre. He is on the board of the Research Management Council of MS Australia, or the Trish Foundation Board. SWR has received travel support, honoraria, trial payments, research and clinical support to the neurology department or academic projects from NHMRC, MRFF, NBA, Myasthenia Alliance Australia, Lambert Initiative, Beeren foundation, anonymous donors; and from pharmaceutical / biological companies: Alexion, Biogen, CSL, Genzyme, Grifols, Merck, Novartis, Roche, Sandoz, Sanofi, UCB. He is cofounder/shareholder of RxPx health, National IVIG Governance Advisory Council & Specialist Working Group Australia (Neurology) (paid), Australian Medical Services Advisory Committee ad hoc subcommittee on IVIG (paid), Australian Technical Advisory Group on Immunisation Varicella Zoster working party (unpaid), Medical advisor (unpaid) to various patient and advocacy groups. Funds over the last 5 years including but not limited to travel support, honoraria, trial payments, research and clinical support to the neurology department or academic projects from: NHMRC, MRFF, NBA, Myasthenia Alliance Australia, Lambert Initiative, Beeren foundation, anonymous donors; and from pharmaceutical/biological companies: Alexion, Biogen, CSL, Genzyme, Grifols, Merck, Novartis, Roche, Sandoz, Sanofi, UCB. FB has received research funding from NSW Health, MS Australia, the NHMRC (Australia), the Medical Research Future Fund (Australia), The MOG Project (Apollo Grant) and Novartis. She was on an advisory board for Novartis and Merck, and has been an invited speaker for Biogen, Novartis and Limbic Neurology. She is on the medical advisory board (non-remunerated positions) of The MOG Project and the Sumaira Foundation. TK served on scientific advisory boards for MS International Federation and World Health Organisation, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. SR has received research funding from the National Health and Medical Research Council (NHMRC, Australia), the Petre Foundation, the Brain Foundation, the Royal Australasian College of Physicians, and the University of Sydney. She is supported by an NHMRC Investigator Grant (GNT2008339). She serves as a consultant on an advisory board for UCB and Limbic Neurology and has been an invited speaker for educational/research sessions coordinated by Biogen, Alexion, Novartis, Excemed and Limbic Neurology. She is on the medical advisory board (non-remunerated positions) of The MOG Project and the Sumaira Foundation. All other authors have no relevant disclosures., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is diagnosed by serum MOG-immunoglobulin G (MOG-IgG) in association with typical demyelination. 111/1127 patients with paired CSF/serum samples were seropositive for MOG-IgG. Only 7/1016 (0.7%) seronegative patients had CSF-restricted MOG-IgG. While 3/7 patients had longitudinally extensive transverse myelitis, four had a confirmed alternate diagnosis (three multiple sclerosis, one CNS vasculitis). In a national referral setting, CSF-restricted MOG-IgG had a low sensitivity (2.63%, 95%CI 0.55-7.50%) and low positive predictive value (1.97%, 95%CI 0.45-8.13%). We strongly recommend serum as the preferred diagnostic biospecimen, and urge caution in the interpretation of CSF-restricted MOG-IgG in patients without clinico-radiological features consistent with MOGAD., (© 2024 The Author(s). Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

A minority of initial multiple sclerosis (MS) presentations clinically or radiologically resemble other central nervous system (CNS) pathologies, acute disseminated encephalomyelitis (ADEM) or tumefactive demyelination (atypical demyelination presentations). With the aim of better defining the long-term outcomes of this group we have performed a retrospective cohort comparison of atypical demyelination versus 'typical' MS presentations. Twenty-seven cases with atypical presentations (both first and subsequent demyelinating events) were identified and compared with typical MS cases. Disease features analysed included relapse rates, disability severity, whole brain and lesion volumes, lesion number and distribution. Atypical cases represented 3.9% of all MS cases. There was considerable overlap in the magnetic resonance imaging (MRI) features of ADEM-like and tumefactive demyelination cases. ADEM-like cases tended to be younger but not significantly so. Atypical cases showed a trend towards higher peak expanded disability severity score (EDSS) score at the time of their atypical presentation. Motor, cranial nerve, cerebellar, cerebral and multifocal presentations were all more common in atypical cases, and less likely to present with optic neuritis. Cerebrospinal fluid (CSF) white cell counts were higher in atypical cases (p = 0.002). One atypical case was associated with peripheral blood myelin oligodendrocyte glycoprotein (MOG) antibodies, but subsequent clinical and radiological course was in keeping with MS. There was no difference in long-term clinical outcomes including annualised relapse rates (ARR), brain volume, lesion numbers or lesion distributions. Atypical demyelination cases were more likely to receive high potency disease modifying therapy early in the course of their illness. Despite the severity of initial illness, our cohort analysis suggests that atypical demyelination presentations do not confer a higher risk of long-term adverse outcomes., (© 2024. Crown.)

Background: Myelin oligodendrocyte glycoprotein (MOG) IgG seropositivity is a prerequisite for MOG antibody-associated disease (MOGAD) diagnosis. While a significant proportion of patients experience a relapsing disease, there is currently no biomarker predictive of disease course. We aim to determine whether MOG-IgG epitopes can predict a relapsing course in MOGAD patients., Methods: MOG-IgG-seropositive confirmed adult MOGAD patients were included (n=202). Serum MOG-IgG and epitope binding were determined by validated flow cytometry live cell-based assays. Associations between epitopes, disease course, clinical phenotype, Expanded Disability Status Scale and Visual Functional System Score at onset and last review were evaluated., Results: Of 202 MOGAD patients, 150 (74%) patients had MOG-IgG that recognised the immunodominant proline42 (P42) epitope and 115 (57%) recognised histidine103/serine104 (H103/S104). Fifty-two (26%) patients had non-P42 MOG-IgG and showed an increased risk of a relapsing course (HR 1.7; 95% CI 1.15 to 2.60, p=0.009). Relapse-freedom was shorter in patients with non-P42 MOG-IgG (p=0.0079). Non-P42 MOG-IgG epitope status remained unchanged from onset throughout the disease course and was a strong predictor of a relapsing course in patients with unilateral optic neuritis (HR 2.7, 95% CI 1.06 to 6.98, p=0.038), with high specificity (95%, 95% CI 77% to 100%) and positive predictive value (85%, 95% CI 45% to 98%)., Conclusions: Non-P42 MOG-IgG predicts a relapsing course in a significant subgroup of MOGAD patients. Patients with unilateral optic neuritis, the most frequent MOGAD phenotype, can reliably be tested at onset, regardless of age and sex. Early detection and specialised management in these patients could minimise disability and improve long-term outcomes., Competing Interests: Competing interests: MF-P has received research grant from MS Australia and travel compensation from Merck. MB reports research grants from Genzyme-Sanofi, Novartis, Biogen, Merck and BMS; and is a Research Consultant for RxMx and Research Director for the Sydney Neuroimaging Analysis Centre. SWR has received funds over the last 5 years including but not limited to travel support, honoraria, trial payments, research and clinical support to the neurology department or academic projects of which he is a member has been received from bodies and charities: NHMRC, NBA, MAA, Lambert Initiative, Beeren foundation, anonymous donors; and from pharmaceutical/biological companies: Alexion, Biogen, CSL, Genzyme, Grifols, Merck, Novartis, Roche, Sanofi. MM has served on scientific and commercial advisory boards for Merck Serono. AvdW has received travel support from Merck Serono, Novartis, Biogen, Roche and Sanofi. She has served on scientific and commercial advisory boards for Merck, Novartis, Sanofi and Roche, and has received unencumbered research grants from Novartis, Biogen, Merck and Roche. JLS has accepted travel compensation from Novartis, Biogen and Merck Serono. Her institution receives the honoraria for talks and advisory board commitment as well as research grants from Bayer Health Care, Biogen, Genzyme Sanofi, Merck, Novartis and TEVA. AGK has in recent times received speaker honoraria and Scientific Advisory Board fees from Bayer, BioCSL, Biogen-Idec, Lgpharma, Merck, Novartis, Roche, Sanofi-Aventis, Sanofi-Genzyme, Teva, NeuroScientific Biopharmaceuticals, Innate Immunotherapeutics, and Mitsubishi Tanabe Pharma. His work has received grant funding from the Eyewall Foundation, Trish MS Foundation, MS Australia, MS Western Australia, the MS Base Foundation, the National Health and Medical Research Council of Australia, and the National Multiple Sclerosis Society, USA. He is an investigator in clinical trials sponsored by Biogen Idec and Novartis. TK served on scientific advisory boards for BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen, steering committee for Brain Atrophy Initiative by Sanofi Genzyme, received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Sanofi-Genzyme, Teva, BioCSL and Merck and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. SAB has received honoraria for attendance at advisory boards and travel sponsorship from Bayer-Schering, Biogen-Idec, Merck-Serono, Novartis and Sanofi-Genzyme, has received speakers honoraria from Biogen-Idec and Genzyme, is an investigator in clinical trials sponsored by Biogen Idec, Novartis and Genzyme, and was the recipient of an unencumbered research grant from Biogen-Idec. RCD received research funding from the Petre Foundation and National Health and Medical Research Council (Australia). He has received honoraria form Biogen Idec and Merck Serono as invited speaker. SR received research funding from the National Health and Medical Research Council (Australia), the Royal Australasian College of Physicians, and the University of Sydney. She serves as a consultant on an advisory board for UCB and Limbic Neurology, The MOG Project and the Sumaira Foundation, and has been an invited speaker for Biogen, Excemed, Alexxion, Limbic Neurology, and Novartis. FB has received research funding from NSW Health, MS Australia, the National Health Medical Research Council (Australia), the Medical Research Future Fund (Australia) and investigator-initiated research grant from Novartis. She was on an advisory boards for Novartis, Merck and The MOG Project and the Sumaira Foundation, and has been an invited speaker for Biogen, Novartis and Limbic Neurology., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

Background and Purpose: 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 2 years and compared this to changes in people with multiple sclerosis (pwMS)., Methods: 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., Results: 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)., Conclusion: We found evidence of loss of GM and TBV over time  in pwMOGAD, similar to pwMS, although the WM and lesion volumes were unchanged., (© 2023 The Authors. Journal of Neuroimaging published by Wiley Periodicals LLC on behalf of American Society of Neuroimaging.)

Although a more efficient adaptive humoral immune response has been proposed to underlie the usually favorable outcome of pediatric COVID-19, the breadth of viral and vaccine cross-reactivity toward the ever-mutating Spike protein among variants of concern (VOCs) has not yet been compared between children and adults. We assessed antibodies to conformational Spike in COVID-19-naïve children and adults vaccinated by BNT162b2 and ChAdOx1, and naturally infected with SARS-CoV-2 Early Clade, Delta, and Omicron. Sera were analyzed against Spike including naturally occurring VOCs Alpha, Beta, Gamma, Delta, and Omicron BA.1, BA.2, BA.5, BQ.1.1, BA2.75.2, and XBB.1, and variants of interest Epsilon, Kappa, Eta, D.2, and artificial mutant Spikes. There was no notable difference between breadth and longevity of antibody against VOCs in children and adults. Vaccinated individuals displayed similar immunoreactivity profiles across variants compared with naturally infected individuals. Delta-infected patients had an enhanced cross-reactivity toward Delta and earlier VOCs compared to patients infected by Early Clade SARS-CoV-2. Although Omicron BA.1, BA.2, BA.5, BQ.1.1, BA2.75.2, and XBB.1 antibody titers were generated after Omicron infection, cross-reactive binding against Omicron subvariants was reduced across all infection, immunization, and age groups. Some mutations, such as 498R and 501Y, epistatically combined to enhance cross-reactive binding, but could not fully compensate for antibody-evasive mutations within the Omicron subvariants tested. Our results reveal important molecular features central to the generation of high antibody titers and broad immunoreactivity that should be considered in future vaccine design and global serosurveillance in the context of limited vaccine boosters available to the pediatric population., (© 2023. The Author(s).)

Patients with Waldenström macroglobulinaemia (WM) are at increased risk of severe COVID-19 infection and have poor immune responses to COVID-19 vaccination. This study assessed whether a closely monitored pause in Bruton's Tyrosine Kinase inhibitor (BTKi) therapy might result in an improved humoral response to a 3rd COVID-19 vaccine dose. Improved response was observed in WM patients who paused their BTKi, compared to a group who did not pause their BTKi. However, the response was attenuated after BTKi recommencement. This data contributes to our understanding of vaccination strategies in this patient group and may help inform consensus approaches in the future., Competing Interests: The authors declare no conflict of interest., (© 2023 The Authors. eJHaem published by British Society for Haematology and John Wiley & Sons Ltd.)

Background: The Omicron era of the COVID-19 pandemic commenced at the beginning of 2022 and whilst it started with primarily BA.1, it was latter dominated by BA.2 and the related sub-lineage BA.5. Following resolution of the global BA.5 wave, a diverse grouping of Omicron sub-lineages emerged derived from BA.2, BA.5 and recombinants thereof. Whilst emerging from distinct lineages, all shared similar changes in the Spike glycoprotein affording them an outgrowth advantage through evasion of neutralising antibodies., Methods: Over the course of 2022, we monitored the potency and breadth of antibody neutralization responses to many emerging variants in the Australian community at three levels: (i) we tracked over 420,000 U.S. plasma donors over time through various vaccine booster roll outs and Omicron waves using sequentially collected IgG pools; (ii) we mapped the antibody response in individuals using blood from stringently curated vaccine and convalescent cohorts. (iii) finally we determine the in vitro efficacy of clinically approved therapies Evusheld and Sotrovimab., Findings: In pooled IgG samples, we observed the maturation of neutralization breadth to Omicron variants over time through continuing vaccine and infection waves. Importantly, in many cases, we observed increased antibody breadth to variants that were yet to be in circulation. Determination of viral neutralization at the cohort level supported equivalent coverage across prior and emerging variants with isolates BQ.1.1, XBB.1, BR.2.1 and XBF the most evasive. Further, these emerging variants were resistant to Evusheld, whilst increasing neutralization resistance to Sotrovimab was restricted to BQ.1.1 and XBF. We conclude at this current point in time that dominant variants can evade antibodies at levels equivalent to their most evasive lineage counterparts but sustain an entry phenotype that continues to promote an additional outgrowth advantage. In Australia, BR.2.1 and XBF share this phenotype and, in contrast to global variants, are uniquely dominant in this region in the later months of 2022., Interpretation: Whilst the appearance of a diverse range of omicron lineages has led to primary or partial resistance to clinically approved monoclonal antibodies, the maturation of the antibody response across both cohorts and a large donor pools importantly observes increasing breadth in the antibody neutralisation responses over time with a trajectory that covers both current and known emerging variants., Funding: This work was primarily supported by Australian Medical Foundation research grants MRF2005760 (SGT, GM & WDR), Medical Research Future Fund Antiviral Development Call grant (WDR), the New South Wales Health COVID-19 Research Grants Round 2 (SGT & FB) and the NSW Vaccine Infection and Immunology Collaborative (VIIM) (ALC). Variant modeling was supported by funding from SciLifeLab's Pandemic Laboratory Preparedness program to B.M. (VC-2022-0028) and by the European Union's Horizon 2020 research and innovation programme under grant agreement no. 101003653 (CoroNAb) to B.M., Competing Interests: Declaration of interests Funding bodies did not contribute to study design, data collection, data analysis or writing of the manuscript. Study design, data collection, data analysis and data interpretation was performed by the listed authors. Writing and review was performed by the listed authors. A.L.C. Participated on the AstraZeneca COVID-19 Advisory Board (2021), Seqirus COVID Advisory Board (2020) & CSL Seqirus APAC Advisory Council (2022). N.R., T.B., S.A.C., S.M., and T.H. are employees and shareholders of CSL LTD, a manufacturer of the polyclonal immunoglobulin preparations used as a reagent within the study., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

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., (© 2022 American Academy of Neurology.)

The field of autoimmune neurology is rapidly evolving, and recent discoveries have advanced our understanding of disease aetiologies. In this article, we review the key pathogenic mechanisms underlying the development of CNS autoimmunity. First, we review non-modifiable risk factors, such as age, sex and ethnicity, as well as genetic factors such as monogenic variants, common variants in vulnerability genes and emerging HLA associations. Second, we highlight how interactions between environmental factors and epigenetics can modify disease onset and severity. Third, we review possible disease mechanisms underlying triggers that are associated with the loss of immune tolerance with consequent recognition of self-antigens; these triggers include infections, tumours and immune-checkpoint inhibitor therapies. Fourth, we outline how advances in our understanding of the anatomy of lymphatic drainage and neuroimmune interfaces are challenging long-held notions of CNS immune privilege, with direct relevance to CNS autoimmunity, and how disruption of B cell and T cell tolerance and the passage of immune cells between the peripheral and intrathecal compartments have key roles in initiating disease activity. Last, we consider novel therapeutic approaches based on our knowledge of the immunopathogenesis of autoimmune CNS disorders., (© 2023. Springer Nature Limited.)

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., Competing Interests: Declaration of interests BB has or will potentially receive financial compensation for consultancy effort for Novartis, Roche, UCB, Horizon Therapeutics, Biogen, and Immunic Therapeutics for advice on clinical trial design. BB is funded by the National Multiple Sclerosis Society, National Institute of Health, and has been previously funded by the Canadian Multiple Sclerosis Society. JLB has received research grants from Novartis, Mallinckrodt Pharmaceuticals, Alexion, and the National Institutes of Health, license fees from a US patent (2014/0170140); consulting fees from Horizon Therapeutics, Alexion, BeiGene Chugai Pharmaceutical, Genentech, Genzyme, Mitsubishi-Tanabe Pharma, Reistone Biopharma, Roche, and AbbVie; and serves on Data Safety Monitoring Boards for Roche, Genentech, and Clene Nanomedicine. RM reports personal fees from Horizon Therapeutics, Alexion, Roche, and UCB and non-financial support from Horizon Therapeutics, Merck, Biogen, and Roche, outside the submitted work. HJK received a grant from the National Research Foundation of Korea and research support from Aprilbio and Eisai; received consultancy and speaker fees from Alexion, Aprilbio, Altos Biologics, Biogen, Celltrion, Daewoong, Eisai, GC Pharma, HanAll BioPharma, Handok, Horizon Therapeutics (formerly Viela Bio), Kolon Life Science, Mdimune, Merck Serono, Mitsubishi Tanabe Pharma, Novartis, Roche, Sanofi Genzyme, Teva-Handok, and UCB; and is a co-editor for the Multiple Sclerosis Journal and an associated editor for the Journal of Clinical Neurology. FB has received research funding from the National Health and Medical Research Council (Australia), Multiple Sclerosis Research Australia, New South Wales Health, Novartis, and the University of Sydney (Sydney, NSW, Australia). She has received speaker honoraria from Novartis, Biogen, Merck, and Limbic Neurology, and has been on advisory boards for Merck and Novartis. She works at the University of Sydney and at the Children's Hospital at Westmead, Westmead, New South Wales, Australia, which offers MOG-IgG testing. EPF has served on advisory boards for Alexion, Genentech, and Horizon Therapeutics. He has received speaker honoraria from Pharmacy Times and royalties from UpToDate for a topic on MOGAD. He was a site primary investigator in a randomised clinical trial on inebilizumab in neuromyelitis optica spectrum disorder run by Horizon Therapeutics. He is principal investigator on an RO1 on MOG-IgG disease. He works at Mayo Clinic, Rochester, MN, USA, which offers commercial MOG-IgG testing but he receives no royalties from such testing. SR has received research funding from the National Health and Medical Research Council (Australia), the Brain Foundation (Australia), the Royal Australasian College of Physicians, and the University of Sydney. She was supported by an National Health and Medicine Research Council Neil Hamilton Fairley Early Career Fellowship (APP1141169) and is currently supported by an NHMRC Emerging Leadership (EL2) Investigator Grant (APP2008339). She serves as a consultant on an advisory board for UCB and Limbic Neurology, and has been an invited speaker for Biogen, Limbic Neurology, and Excemed. PW has received research grants from Euroimmun AG, Commonwealth Serum Laboratories Behring and patent royalties for antibody testing (W02010046716A1). He is the co-director of the Oxford Autoimmune Neurology Diagnostic Laboratory (Oxford University, Oxford, UK) where MOG-IgG1 autoantibodies are tested and both he and the University of Oxford receive royalties (for antibody tests for LGI1 and CASPR2, W02010046716A1). He has received honoraria or consulting fees from Biogen Idec, F Hoffmann La-Roche, Mereo BioPharma, Retrogenix, UBC, Euroimmun AG, University of British Columbia, and Alexion; and travel grants from the Guthy-Jackson Charitable Foundation. Work in the Oxford Autoimmune Neurology Diagnostic Laboratory is supported by the UK National Health Service Commissioning service for NMOSD. ST has received speaker and consulting fees from Biogen-Idec Argentina, Merck SA, Genzyme-Sanofi, Roche, Novartis Argentina, and Novartis Pharma. She serves as a consultant on an advisory board for Genentech-Roche. and Alexion Pharmaceuticals. JSG has grant or contract research support from the National Multiple Sclerosis Society, Biogen, and Octave Biosciences for work unrelated to the present project. She serves on a steering committee for a trial supported by Novartis. She has received speaker fees from Alexion and Bristol Myers Sqiuibb, and served on an advisory board for Genentech. TC has received compensation for consulting from Biogen, Novartis Pharmaceuticals, Roche, Genentech, and Sanofi Genzyme. She has received research support from the National Institutes of Health, National Multiple Sclerosis Society, US Department of Defense, EMD Serono, Guthy-Jackson Charitable Foundation, I-Mab Biopharma, Mallinckrodt Pharmaceuticals, Novartis, Octave Bioscience, Roche Genentech, The Sumaira Foundation, and Tiziana Life Sciences. AUB has received grant support from Moore Foundation, Clinical and Trnaslational Awards Program, German Federal Ministry of Education and Research (BMBF). He has been named as inventor on several patents and patent applications describing multiple sclerosis serological biomarkers, drug targets for remyelination therapy, marker-less motor function analysis, and retinal image analysis methods. He serves on the Observational Study Monitoring Board for CAVS-MS. He is cofounder, board member, and currently serving as secretary treasurer of IMSVISUAL. He is cofounder and holds stocks of technology startups Motognosis GmbH and Nocturne GmbH. Motognosis GmbH develops and sells systems for assessing motor dysfunction in patients with neurological disorders. Nocturne GmbH offers analysis services for retinal optical coherence tomography. Both companies' products and services are relevant for neurology in general, but not specific to MOGAD. CH reports grant support from the Medical Research Council, Multiple Sclerosis Society, and Vasculitis UK. She serves as a consultant to Novartis, Biogen, Roche, UCB, Viela Bio, and Sanofi. She participated on an independent data safety monitoring board for the Wellcome Trust. RN reports grant support from Multiple Sclerosis Research Foundation (Netherlands). He has participated on a data safety monitoring board or advisory board for EXCEL study (neurofibromatosis). He is board member of the Dutch Pediatric Neurology Society. LP has received speaker honoraria and travel grants from Biogen, and has consulted for Biogen, Novartis, and Sanofi. Her university holds a patent for her invention: Live cell based assay for detection of autoantibodies for NMOSD and related disorders (Indian patent number 202141055841). MR is supported by research grants from the Austrian Science Fund (FWF project P32699), the Austrian Research Promotion Agency, Euroimmun, and Roche, and consulting fees and advisory board from Roche (to institution). MR works at the Clinical Department of the Medical University of Innsbruck (Innsbruck, Austria), which offers diagnostic testing for MOG-IgG and other autoantibodies. AS received personal compensation for consulting, serving on a scientific advisory board, speaking activities with Merck, Sanofi, Biogen, Roche, TEVA Pharmaceuticals, Novartis, Alexion, and Janssen. DKS has received research support from National council for Scientific and Technological Development CNPq Brazil (425331/2016-4 and 308636/2019-8), Fundacao de Amparo Pesquisa do Estado do Rio Grande do Sul (17/2551-0001391-3 and 21/2551-0000077-5), TEVA Pharmaceuticals, Merck, Biogen, and Euroimmun AG; speaker honoraria from Biogen, Novartis, Genzyme, TEVA Pharmaceuticals, Merck, Roche, and Bayer; and participates in advisory boards for Biogen, Roche, and Merck. KR has been an invited speaker for Merck and serves as a consultant for an advisory board for Roche. FP has received honoraria and research support from Alexion, Bayer, Biogen, Chugai, MerckSerono, Novartis, Genyzme, MedImmune, Shire, and Teva Pharmaceuticals, and serves on scientific advisory boards for Alexion, MedImmune, Novartis, and UCB. He has received funding from Deutsche Forschungsgemeinschaft (DFG Exc 257), Bundesministerium für Bildung und Forschung (Competence Network Multiple Sclerosis), Guthy-Jackson Charitable Foundation, EU Framework Program 7, and National Multiple Sclerosis Society of the USA. He serves on the steering committee of the N-Momentum study with inebilizumab (Horizon Therapeutics) and the OCTiMS Study (Novartis). He is an associatee editor with Neurology, Neuroimmunology, and Neuroinflammation and academic editor with PloS One. SJP reports grants, personal fees, and non-financial support from Alexion Pharmaceuticals; grants, personal fees, and non-financial support from MedImmune /Viela Bio; and personal fees for consulting from Genentech, Roche, UCB, and Astellas. He has two patents issued (8889102; application 12-678350; Neuromyelitis Optica Autoantibodies as a Marker for Neoplasia; and 9891219B2; application 12-573942; Methods for Treating Neuromyelitis Optica [NMO] by Administration of Eculizumab to an individual that is Aquaporin-4 [AQP4]-IgG Autoantibody positive). SJP also has patents pending for IgGs to the following proteins as biomarkers of autoimmune neurological disorders: septin-5, kelch-like protein 11, GFAP, PDE10A, and MAP1B. He works at Mayo Clinic, which offers commercial MOG-IgG testing. He receives no royalties from the sale of tests done at the neuroimmunology Laboratory at Mayo Clinic. KF serves as an advisor or on scientific advisory boards for Biogen, Mitsubishi Tanabe, Novartis, Chugai, Roche, Alexion, VielaBio/Horizon Therapeutics, UCB, Merck Biopharma, Japan Tobacco and Abbvie; has received funding for travel and speaker honoraria from Biogen, Eisai, Mitsubishi Tanabe, Novartis, Chugai, Roche, Alexion, VielaBio, Teijin, Asahi Kasei Medical, Merck, and Takeda; and has received the Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan and the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan. JP has received consulting fees from Merck, Novartis, Roche, Mitsubishi Tnabe Pharma, UCB, Alexion, Vitaccess, and Argenx, and MRI support from Medimmune, Merck, and Roche. She has received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing, or educational events from Merck, VielaBio, Roche and Alexion. She has participated on a data safety monitoring board or advisory board for Novartis, Roche, Argenx, UCB, Alexion, and Sanofi. She is member of the Charcot Foundation Board, Magnetic Resonance in Multiple Sclerosis steering committee, and National Health Service England Intravenous Immune Globulin Committee. She holds stock for AstraZeneca for a product that is not related to MOG-antibody associated disease. She has a patent for Diagnosing Multiple Sclerosis (application no PCT/GB2013/050285, final patent number 13704627.2–1408; client reference 4440; MS reference P37347WO; patent published Sept 13, 2021)., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

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., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Patients with indolent lymphoma undertaking recurrent or continuous B cell suppression are at risk of severe COVID-19. Patients and healthy controls (HC; N = 13) received two doses of BNT162b2: follicular lymphoma (FL; N = 35) who were treatment naïve (TN; N = 11) or received immunochemotherapy (ICT; N = 23) and Waldenström's macroglobulinemia (WM; N = 37) including TN (N = 9), ICT (N = 14), or treated with Bruton's tyrosine kinase inhibitors (BTKi; N = 12). Anti-spike immunoglobulin G (IgG) was determined by a high-sensitivity flow-cytometric assay, in addition to live-virus neutralization. Antigen-specific T cells were identified by coexpression of CD69/CD137 and CD25/CD134 on T cells. A subgroup (N = 29) were assessed for third mRNA vaccine response, including omicron neutralization. One month after second BNT162b2, median anti-spike IgG mean fluorescence intensity (MFI) in FL ICT patients (9977) was 25-fold lower than TN (245 898) and HC (228 255, p = .0002 for both). Anti-spike IgG correlated with lymphocyte count (r = .63; p = .002), and time from treatment (r = .56; p = .007), on univariate analysis, but only with lymphocyte count on multivariate analysis (p = .03). In the WM cohort, median anti-spike IgG MFI in BTKi patients (39 039) was reduced compared to TN (220 645, p = .0008) and HC (p < .0001). Anti-spike IgG correlated with neutralization of the delta variant (r = .62, p < .0001). Median neutralization titer for WM BTKi (0) was lower than HC (40, p < .0001) for early-clade and delta. All cohorts had functional T cell responses. Median anti-spike IgG decreased 4-fold from second to third dose (p = .004). Only 5 of 29 poor initial responders assessed after third vaccination demonstrated seroconversion and improvement in neutralization activity, including to the omicron variant., (© 2022 The Authors. American Journal of Hematology published by Wiley Periodicals LLC.)

Children infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) develop less severe coronavirus disease 2019 (COVID-19) than adults. The mechanisms for the age-specific differences and the implications for infection-induced immunity are beginning to be uncovered. We show by longitudinal multimodal analysis that SARS-CoV-2 leaves a small footprint in the circulating T cell compartment in children with mild/asymptomatic COVID-19 compared to adult household contacts with the same disease severity who had more evidence of systemic T cell interferon activation, cytotoxicity and exhaustion. Children harbored diverse polyclonal SARS-CoV-2-specific naïve T cells whereas adults harbored clonally expanded SARS-CoV-2-specific memory T cells. A novel population of naïve interferon-activated T cells is expanded in acute COVID-19 and is recruited into the memory compartment during convalescence in adults but not children. This was associated with the development of robust CD4 + memory T cell responses in adults but not children. These data suggest that rapid clearance of SARS-CoV-2 in children may compromise their cellular immunity and ability to resist reinfection., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

The depletion of B cells has proven to be beneficial in the treatment of autoimmune demyelinating disorders. The high efficacy of these therapies has highlighted the importance of B cells in autoimmunity and prompted investigations into specific B cell subsets that may be aberrant. Recently, a rise in the trialling of alternative B cell-targeting therapies that inhibit targets such as Bruton's tyrosine kinase, interleukin-6 receptor and fragment crystallisable neonatal receptor has also been observed. These agents interfere with specific dysregulated functions of B cells in contrast to the broad removal of many B cell subsets with depletion agents. The therapeutic benefit of these emerging agents will help delineate the contributions of B cells in demyelinating disorders and holds great potential for future treatment., Competing Interests: Declaration of competing interest GL reports funding from the Research Training Program Scholarship (Australia). FB has received research funding from NSW Health, Multiple Sclerosis Australia, Medical Research Future Fund (MRFF, Australia), the National Health and Medical Research Council (Australia), and Novartis. FB has also received honoraria from Biogen Idec, Novartis, and Merck as invited speaker., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Genetically distinct variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged since the start of the COVID-19 pandemic. Over this period, we developed a rapid platform (R-20) for viral isolation and characterization using primary remnant diagnostic swabs. This, combined with quarantine testing and genomics surveillance, enabled the rapid isolation and characterization of all major SARS-CoV-2 variants circulating in Australia in 2021. Our platform facilitated viral variant isolation, rapid resolution of variant fitness using nasopharyngeal swabs and ranking of evasion of neutralizing antibodies. In late 2021, variant of concern Omicron (B1.1.529) emerged. Using our platform, we detected and characterized SARS-CoV-2 VOC Omicron. We show that Omicron effectively evades neutralization antibodies and has a different entry route that is TMPRSS2-independent. Our low-cost platform is available to all and can detect all variants of SARS-CoV-2 studied so far, with the main limitation being that our platform still requires appropriate biocontainment., (© 2022. The Author(s).)

Background: Myelin oligodendrocyte glycoprotein antibodies (MOG Ab) are essential in the diagnosis of MOG Ab-associated disease (MOGAD). Live cell-based assays (CBAs) are the gold standard for MOG Ab detection with improved sensitivity and specificity over fixed CBAs. A number of testing centers have used flow cytometry for its high throughput and quantitative utility. Presently, there is increasing demand to translate these research-based methods into an accredited routine diagnostic setting., Methods: A flow cytometry live CBA was used to detect MOG Ab in patients with demyelination. Serostatuses were compared between a research-based assay and a streamlined diagnostic assay. Inter-laboratory validation of the streamlined assay was performed in an accredited diagnostic laboratory. Further streamlining was performed by introducing a borderline serostatus range and reducing the number of controls used to determine the positivity threshold., Results: High serostatus agreement (98%-100%) was observed between streamlined and research-based assays. Intra- and inter-assay imprecision was improved in the streamlined assay (mean intra- and inter-assay CV = 7.3% and 27.8%, respectively) compared to the research-based assay (mean intra- and inter-assay CV = 11.8% and 33.6%, respectively). Borderline positive and clear positive serostatuses were associated with confirmed phenotypes typical of MOGAD. Compared to using 24 controls, robust serostatus classification was observed when using 13 controls without compromising analytical performance (93%-98.5% agreement)., Conclusions: Flow cytometry live CBAs show robust utility in determining MOG Ab serostatus. Streamlining and standardizing use of this assay for diagnostics would improve the accuracy and reliability of routine testing to aid diagnosis and treatment of patients with demyelination., (© American Association for Clinical Chemistry 2021.)

Inflammation is increasingly recognised to play a major role in gene-environment interactions in neurodevelopmental disorders (NDDs). The effects of aberrant immune responses to environmental stimuli in the mother and in the child can affect neuroimmune signalling that is central to brain development. Toll-like receptors (TLR) are the best known innate immune pattern and danger recognition sensors to various environmental threats. In animal models, maternal immune activation (MIA), secondary to inflammatory factors including maternal gestational infection, obesity, diabetes, and stress activate the TLR pathway in maternal blood, placenta, and fetal brain, which correlate with offspring neurobehavioral abnormalities. Given the central role of TLR activation in animal MIA models, we systematically reviewed the human evidence for TLR activation and response to stimulation across the maternal-fetal interface. Firstly, we included 59 TLR studies performed in peripheral blood of adults in general population (outside of pregnancy) with six chronic inflammatory factors which have epidemiological evidence for increased risk of offspring NDDs, namely, obesity, diabetes mellitus, depression, low socio-economic status, autoimmune diseases, and asthma. Secondly, eight TLR studies done in human pregnancies with chronic inflammatory factors, involving maternal blood, placenta, and cord blood, were reviewed. Lastly, ten TLR studies performed in peripheral blood of individuals with NDDs were included. Despite these studies, there were no studies which examined TLR function in both the pregnant mother and their offspring. Increased TLR2 and TLR4 mRNA and/or protein levels in peripheral blood were common in obesity, diabetes mellitus, depression, autoimmune thyroid disease, and rheumatoid arthritis. To a lesser degree, TLR 3, 7, 8, and 9 activation were found in peripheral blood of humans with autoimmune diseases and depression. In pregnancy, increased TLR4 mRNA levels were found in the peripheral blood of women with diabetes mellitus and systemic lupus erythematosus. Placental TLR activation was found in mothers with obesity or diabetes. Postnatally, dysregulated TLR response to stimulation was found in peripheral blood of individuals with NDDs. This systematic review found emerging evidence that TLR activation may represent a mechanistic link between maternal inflammation and offspring NDD, however the literature is incomplete and longitudinal outcome studies are lacking. Identification of pathogenic mechanisms in MIA could create preventive and therapeutic opportunities to mitigate NDD prevalence and severity., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: Optic neuritis (ON) occurs in immune-mediated disorders including multiple sclerosis (MS), aquaporin-4 antibody-positive (AQP4) neuromyelitis optica spectrum disorder (AQP4-NMOSD) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination (MOGAD). Accurate determination of aetiology is critical for appropriate treatment and prognostication., Objective: To evaluate demyelination and axonal loss in MOG-ON to facilitate differentiation from MS-ON and AQP4-ON., Methods: 15 MOGAD patients with previous ON (25 eyes) underwent multifocal visual evoked potential (mfVEP) recordings and optical coherence tomography scans. Comparison was made to previously reported MS patients ( n  = 67, 69 eyes) and AQP4-NMOSD patients ( n  = 15, 23 eyes) with prior ON and healthy controls ( n  = 37, 74 eyes)., Results: MOG-ON patients had less retinal nerve fibre layer (RNFL) loss than AQP4-ON patients ( p  < 0.05) and less mfVEP latency prolongation than MS-ON patients ( p  < 0.01). Number of ON episodes in MOGAD was associated with reduced RNFL thickness (global, p  = 0.07; temporal, p  < 0.001) and mfVEP amplitude ( p  < 0.001). There was no abnormality in non-ON eyes., Conclusions: Our study demonstrated a distinct pattern of damage in MOG-ON compared to AQP4-ON and MS-ON. ON in MOGAD produces less axonal loss than AQP4-NMOSD. Damage accumulates with relapses, supporting the role of maintenance immunosuppression to induce remission. Compared to MS, MOGAD causes less demyelination., Competing Interests: Declaration of conflicting interests: Dr Stephanie Barnes has accepted travel compensation from Merck and Sanofi Genzyme, and fellowship funding from Allergan. A/Prof Todd Hardy has served on advisory boards for Merck, Biogen, Roche and Bristol Myers Squibb, received personal compensation for speaking engagements from Biogen, Merck, Novartis, Sanofi Genzyme and Teva. He has received research/grant support from Multiple Sclerosis Research Australia and Novartis. He serves as co-editor of Advances in Clinical Neuroscience and Rehabilitation. A/Prof Stephen Reddel reports grants and personal fees from Sanofi Genzyme, personal fees and departmental support from Biogen, CSL, and Baxter; and departmental support from Novartis, outside the subject of the submitted work. A/Prof Fabienne Brilot has received funding from the National Health and Medical Research Council (Australia), Multiple Sclerosis Research Australia, the University of Sydney Research Excellence Initiative grant (Australia). She has received honoraria from Biogen Idec and Merck Serono as an invited speaker. Dr Sudarshini Ramanathan has received research funding from the National Health and Medical Research Council (Australia), the Petre Foundation (Australia), the Brain Foundation (Australia), the Royal Australasian College of Physicians, and the University of Sydney. She serves as a consultant on an advisory board for UCB, and has been an invited speaker for Biogen and Excemed. Prof Con Yiannikas serves on advisory boards for Lundbeck and Abbvie., (© The Author(s), 2021.)

Myelin oligodendrocyte glycoprotein (MOG)-antibody (Ab)-associated diseases (MOGADs) account for a substantial proportion of pediatric and adult patients who present with acquired demyelinating disorders. Its pathogenesis and optimal therapy are incompletely understood. We profiled systemic complement activation in adult and pediatric patients with MOGAD compared with patients with relapse-onset multiple sclerosis, patients with neuromyelitis optica spectrum disorder, and pediatric control and adult healthy donors. Proteins indicative of systemic classical and alternative complement activation were substantially increased in patients with MOGAD compared to control groups. Elevated levels were detected in both adult and pediatric cases and across all clinical syndromes. Complement inhibition should be explored for its therapeutic merit in patients with MOGAD. ANN NEUROL 2021;90:976-982., (© 2021 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)