BACKGROUND:Detection of immunoglobulin G targeting myelin oligodendrocyte glycoprotein (MOG-IgG) is the mainstay of laboratory diagnosis of MOG antibody-associated disease. Laboratory biomarkers have the potential to predict disease course and activity, thus informing prompt therapeutic decisions to minimise relapse-associated disability accrual. METHODS:This systematic review with meta-analysis was registered in PROSPERO (CRD42024554429). MEDLINE, Embase and Scopus databases were searched. Random-effects or mixed-effects modelling was performed and OR or HR with 95% CIs reported. RESULTS:106 studies with ≥1710 individuals were included. A relapsing course was associated with persistent seropositivity on serial samples collected ≥3 months apart (OR 2.7 (95% CI 1.8 to 4.0), p<0.0001), lower likelihood of seroreversion to negative status (HR 0.19 (95% CI 0.14 to 0.26), p<0.0001) and delayed seroreversion compared with monophasic participants (median 19 years vs 2.5 years, p<0.0001). Acute disseminated encephalomyelitis was associated with a non-relapsing course (OR 0.049 (95% CI 0.0029 to 0.84), p=0.037). Serum MOG-IgG titre-negative, low positive or clear positive-discriminated disease state: attack was associated with clear positive titre (OR 3.6 (95% CI 2.6 to 5.0), p<0.0001), but not negative titre (OR 0.073 (95% CI 0.028 to 0.19), p<0.0001). Cerebrospinal fluid (CSF) leucocytosis (≥5 cells/µL) was associated with attack (OR 3.1 (95% CI 1.7 to 5.9), p=0.0004). Neither serum glial fibrillary acidic protein nor neurofilament light chain correlated with disease activity. Novel biomarkers of disease course and activity have also been assessed qualitatively. CONCLUSIONS:MOG-IgG serostatus and titre and CSF leucocytosis are biomarkers of disease course and activity. The findings provide rationale for serial serum MOG-IgG testing at an interval of 3-6 months in the first 12 months of disease to assist in relapse risk stratification. PROSPERO REGISTRATION NUMBER:CRD42024554429.

Paediatric Acute-Onset Neuropsychiatric Syndrome (PANS) is characterised by abrupt onset obsessive compulsive disorder and regression in neurodevelopmental skills, triggered by infection or stress. Whether PANS is a distinct entity or part of a neurodevelopmental spectrum is uncertain, and its pathophysiology remains unclear. We show that children with PANS (n = 32) and other non-PANS (n = 68) neurodevelopmental disorders (total n = 100) have higher reported early childhood infections and a loss of previously acquired developmental skills compared to neurotypical controls (n = 58). Children with PANS have normal routine immune testing, however bulk RNA-sequencing (PANS n = 20 vs controls n = 15) revealed upregulated pathways in ribosomal biogenesis and RNA methyltransferases, and downregulated pathways in diverse cellular functions such as mitochondrial activity, cell signalling, endocytosis, and immune responses. Single-cell RNA-sequencing (PANS n = 2 vs controls n = 2) confirmed these findings but showed heterogeneity across immune cell types. Toll-like receptor stimulation assay using peripheral blood mononuclear cells revealed reduced TNF and interleukin-6 responses in PANS patients (n = 7) compared to controls (n = 7). RNA sequencing before and after intravenous immunoglobulin treatment in PANS patients (n = 9 vs controls n = 10) revealed reversal of the dysregulated ribosomal, epigenetic, and cell signaling pathways. Given the central role of the immune system in synaptic pruning and neurodevelopment, these insights provide rationale for novel epigenetic and immune modulating therapies to optimize neurodevelopmental trajectories and minimize neuropsychiatric impairment in PANS.

MOG antibody-associated disease (MOGAD) diagnosis rests on seropositivity for MOG antibody (MOG-IgG). Live cell-based assays (CBA) are gold standards. Although flow cytometry live CBAs have high real-world sensitivity, their global implementation and diagnostic deployment have been challenged by perceptions of "in-house" design and custom optimization. Herein, we compared the analytical robustness of flow live MOG-IgG CBA across various cytometers in both research and diagnostic laboratories. Flow live CBAs were performed on three conventional (Fortessa, BDLSRII, Gallios), and two spectral cytometers (Aurora, ID7000). MOG-IgG titers were calculated by median fluorescence intensity (MFI), and intra- and inter assay precisions (CV%) and serostatuses were determined. The MFI detection range on Fortessa, currently used for testing, was significantly lower than spectral ID7000 (4.75-fold, p = 0.04) and Aurora (12-fold, p = 0.0001), albeit all MFIs correlated (p < 0.0001; R2 = 0.99). Interestingly, the high detection range was attributed to technology, not laboratory environments (p > 0.05). Intra- and inter-assay precisions were similar across cytometers. ID7000 and Fortessa had the lowest variation, with 4.6 % and 6.8 % intra-CV, respectively, and 15.7 % inter-CV. FACS ratio, currently reported as MOG-IgG titre, and MFIs were comparable and correlated for all cytometers (p < 0.001; R2 ≤ 0.99), regardless of the analysis software (p < 0.0001, R2 = 0.98). All serostatuses were highly concordant (κ = 1). Our results demonstrate that flow live CBAs can be validated in diagnostic laboratories across a range of flow cytometers with high reproducibility and repeatability. In particular, excellent assay performance on spectral flow cytometry strongly supports the proof-of-concept use of this technology for diagnostic purposes.

INTRODUCTION:Myelin-oligodendrocyte glycoprotein antibody-associated disease (MOGAD) commonly manifests as optic neuritis (ON) in association with serum MOG immunoglobulin G (MOG-IgG). This review will evaluate the literature on visual dysfunction in MOG-IgG ON, with a focus on ophthalmic structural biomarkers and ancillary outcome measures. METHODS:PubMed was systematically searched using the terms "optic neuritis", "visual outcomes" and "myelin-oligodendrocyte glycoprotein" between 2007 to January 2025. High-contrast visual acuity (HCVA), low-contrast visual acuity (LCVA), contrast sensitivity, visual fields (VF), electrophysiology, optical coherence tomography (OCT)/angiography, magnetic resonance imaging (MRI) and quality of life (QoL) were evaluated. RESULTS:35 studies and 2335 patients were included. 89 % of studies reported HCVA. OCT and MRI were reported in 63 % and 43 % of studies, respectively. MOG-IgG ON had moderate-severe HCVA loss at nadir but good HCVA recovery. MRI features characteristic to MOG-IgG ON include longitudinally extensive lesions +/- perineural enhancement. OCT in acute MOG-IgG ON revealed moderate-severe peripapillary retinal nerve fibre layer (p-RNFL) swelling. However severe axonal loss was noted in chronic outcomes, despite preservation of HCVA, highlighting a recognised structure-function discordance. Only 31 % reported on VFs, 17 % on LCVA, and 14 % on VEPs, all of which demonstrated abnormalities even in patients with normal HCVA. Only one study reported on contrast sensitivity or QoL. CONCLUSION:Current clinical assessments may underestimate visual dysfunction in MOG-IgG ON. Prospective, longitudinal multimodal evaluation should be a key focus for future research, to identify the most sensitive biomarkers to be incorporated into routine clinical practice. This will better identify patients at risk of adverse visual outcomes in MOG-IgG ON, guide clinical management and improve QoL.

Vaccines generate long-lived plasma cells and memory B cells (Bmems) that may re-enter secondary germinal centers (GCs) to further mutate their B cell receptor upon boosting and re-exposure to antigen. We show in mouse models that lymph nodes draining the site of primary vaccination harbor a subset of Bmems that reside in the subcapsular niche, generate larger recall responses, and are more likely to re-enter GCs compared with circulating Bmems in non-draining lymph nodes. This location-dependent recall of Bmems into the GC in the draining lymph node was dependent on CD169+ subcapsular sinus macrophages (SSMs) in the subcapsular niche. In human participants, boosting of the BNT162b2 vaccine in the same arm generated more rapid secretion of broadly neutralizing antibodies, GC participation, and clonal expansion of SARS-CoV-2-specific B cells than boosting of the opposite arm. These data reveal an unappreciated role for primed draining lymph node SSMs in Bmem cell fate determination.

BACKGROUND:Data regarding treatment in pediatric relapsing MOGAD are limited. OBJECTIVE:To evaluate response of intravenous immunoglobulin (IVIG) compared to other therapies in relapsing pediatric MOGAD. METHODS:In this retrospective multicenter study, children with MOGAD were recruited from different medical centers. Inclusion criteria encompassed: age <18 years, MOGAD diagnosis, relapsing disease course, >6 months of maintenance treatment and >12 months follow-up. RESULTS:Seventy children with relapsing MOGAD were stratified into two groups. The first group received IVIG alone (n = 23), IVIG preceded by (n = 16) or in combination with other immunomodulating therapies (IMT) (n = 7). The second group received mycophenolate mofetil, azathioprine, rituximab, or other IMTs (n = 24). 13 % (6/46) of patients with IVIG relapsed in the first year, compared to 33 % (8/24) in the IMT group (relative risk 0.70, 95 % CI 0.53 to 0.99, p = 0.061). Annual relapse rate (ARR) was decreased under therapy compared to pre-treatment in both groups (IVIG: p < 0.001; other IMTs: p = 0.006). ARR was lower in the IVIG group (p = 0.040) in addition to a reduced risk of an early relapse compared to the other IMT group (hazard ratio 0.36, 95 % CI 0.15 to 0.87, p = 0.023). CONCLUSION:Our study supports monthly IVIG as maintenance therapy in children after the second MOGAD episode.

MOG antibody-associated disease (MOGAD), an inflammatory demyelinating pathology, is typically associated with the clinical phenotypes acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), or transverse myelitis (TM). The mainstay of diagnosis is detection of antibodies targeting oligodendrocyte-expressed MOG (MOG-IgG). MOG-IgG-mediated demyelination occurs via complement-dependent cytotoxicity (CDC), antibody-dependent cellular cytotoxicity (ADCC), enhanced cognate T-cell CNS infiltration and activation, and oligodendrocyte cytoskeleton disruption, but the exact role of the immune system in MOGAD is still poorly understood. The disease course is either monophasic or relapsing, with relapsing course affecting approximately two-thirds of individuals. Neurological disability accumulates with relapse and may manifest as visual, motor, sensory, and cognitive deficits. Thus, accurate disease course prediction is of paramount importance. Prognostic biomarkers, implemented at a global scale, have the potential to guide timely therapeutic decisions to limit relapse-associated disability accrual while simultaneously avoiding unnecessary immunosuppression in monophasic individuals. This review explores recent insights in the understanding of MOGAD pathogenesis as well as advances in prognostic biomarkers of relapsing course and disease activity.

BACKGROUND AND OBJECTIVES:Although disease-modifying therapies (DMTs) may suppress coronavirus disease 2019 (COVID-19) vaccine responses in people with multiple sclerosis (pwMS), limited data are available on the cumulative effect of additional boosters. Maturation of Spike immunoglobulin G (IgG) to target a greater diversity of SARS-CoV-2 variants, especially past the BA.1 variant, has not been reported. In addition, the prediction of variant-specific protection, given that Spike antibody testing is not performed routinely, remains a challenge. We, therefore, evaluated whether additional vaccine doses improved the breadth of cross-variant recognition to target emerging SARS-CoV-2 variants. Machine learning-based models were designed to predict variant-specific protection status. METHODS:In a prospective observational cohort (n = 442), Spike IgG titers and live virus neutralization against D614, BA.1, BA.2, BA.5, XBB.1.1, XBB.1.5, and EG.5.1 variants were determined in 1,011 serum samples (0-12 months after 2-4 doses). Predictive protection models were developed by K-fold cross-validation on training and test data sets (random split 70:30). RESULTS:After primary vaccination, pwMS on immunosuppressive disease-modifying therapy (IMM-DMT) had 10-fold and 7.2-fold lower D614 Spike IgG titers than pwMS on low-efficacy (LE)-DMT and cladribine (p < 0.01). After 4 doses, pwMS on IMM-DMT had significantly lower Spike IgG titers, compared with pwMS on low-efficacy disease-modifying therapy, for D614 (p < 0.05), as well as BA.1, BA.2, BA.5, XBB.1, XBB.1.5, and EG.5.1(p < 0.01). The breadth of Spike IgG to recognize variants other than the cognate antigen increased after 4 doses of all DMTs. Although pwMS on IMM-DMT displayed reduced cross-variant recognition, a fourth dose resulted in a 2-4-fold increase in protection against newer variants and a reduction in two-thirds of pwMS without protective Spike IgG (p < 0.0001). Tixagevimab and cilgavimab did not induce additional cross-variant protection. Variant-specific predictive models of vaccine protection were influenced by treatment, time since primary vaccination, and age, with high sensitivity (99.4%, 95% CI 96.8-99.99) and specificity (72.0%, 95% CI 50.6-87.9) for XBB.1.5/EG.5.1 variants. DISCUSSION:Despite not eliciting adequate antibody response in pwMS on IMM-DMT, COVID-19 boosters improve the breadth of the humoral response against SARS-CoV-2 emerging variants. Vaccine protection can be predicted by statistical modeling.

The Omicron variant of SARS-CoV-2 emerged in late 2021 and since then Omicron subvariants have continued to evolve and dominate globally. The viral S protein evolved towards highly efficient antibody evasion and replicative capacity in the upper respiratory tract resulting in high transmissibility. At the same time, the mutations acquired in the S protein diminish infection of the lung epithelium and pathogenic potential. The changing entry requirements for Omicron sub-lineages that lead to this shift in tropism remain poorly understood. We resolve the changing replication requirements of SARS-CoV-2 to be related to two distinct pools of ACE2. The first pool relates to ACE2’s role in the renin angiotensin system (RAS) and this pool can complex with TMPRSS2 (RAS-ACE2). The second pool relates to ACE2’s role as a protein solute carrier chaperone than cannot complex with TMPRSS2 (Chaperone ACE2). Here, we demonstrate that pre-Omicron lineages replicate in a TMPRSS2 dependent manner across both ACE2 pools, whilst Omicron lineages can only spread and replicate using chaperone ACE2. This provides a mechanistic basis for the evolving infectivity requirements of SARS-CoV-2 and furthermore provides approaches to track and monitor ACE2 utilizing coronaviruses. Graphical Abstract Mechanistic basis for shift in SARS-CoV-2 tropism with the arrival of Omicron. A. Chaperone ACE2 is defined structurally as a heterodimer of dimers with a solute carrier protein-SLC6A19 or SLC6A20. Here this ACE2 structure can exist uncomplexed from TMPRSS2 and enables TMPRSS2 use by both pre-Omicron and Omicron lineages. B. Renin Angiotensin ACE2 is defined by ACE2 with an exposed collectrin-like domain (CLD), which enables binding of TMPRSS2 or ADAM-17. Here ACE2 can form a complex with TMPRSS2 in a manner that allows pre-Omicron but not Omicron lineages to utilize TMPRSS2 to facilitate infection. Here Omicron lineages are heavily attenuated as they cannot use TMPRSS2 to spread. C. to E. Based on single cell profiles, ACE2 can exist as a chaperone with SLC6A20 in C. the Nasal Cavity or D. primarily as RAS-ACE2 in the lung to respond to acute lung injury. E. The largest pool of ACE2 in our body resides within the small intestine on enterocytes and this further facilitates replication in this tissue by pre-Omicron and Omicron lineages. ![Figure][1] ### Competing Interest Statement The authors have declared no competing interest. New South Wales Department of Health, https://ror.org/03tb4gf50 National Health and Medical Research Council, https://ror.org/011kf5r70 Medical Research Future Fund, AU [1]: pending:yes

Biomarkers for predicting myelin oligodendrocyte glycoprotein antibody (Ab)-associated disease (MOGAD) clinical course are still missing. Binding capacity to a mutant MOG protein variant (MOG-P42S; non-P42) was shown to correlate with an increased relapse risk in adult patients.The objective of our study was to assess the frequency of binding to the non-P42 MOG variant in a cohort of paediatric MOGAD and to investigate its association with specific clinical profiles and disease course. We included children with MOG-Ab seropositive samples collected after their first demyelinating episode from five different centres. We performed live cell-based assays with native full-length MOG (MOG-FL) and mutant MOG-P42S and correlated the results with clinical data. Of the 81 MOG-FL identified patients serum, 40 bound the non-P42 MOG. Non-P42 patients exhibited an earlier median age of onset (p=0.002). Phenotype distribution was different between groups (p=0.001), with non-P42 patients predominantly exhibiting acute disseminated encephalomyelitis phenotype. Notably, the non-P42 group was associated with a higher relapse rate (relative rate: 2.6 (95% CI 1.1 to 6.2), p=0.03), adjusted for clinical phenotype. Non-P42 is a promising biomarker for predicting relapse in paediatric MOGAD patients.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is one of the most common antibody-mediated CNS disorders. Optimal diagnostic and prognostic biomarkers remain unclear. Our aim was to clarify these biomarkers and therapeutic outcomes internationally. We reviewed articles from 2007 to 2022 and identified 194 unique cohorts encompassing 4699 paediatric and adult patients from 31 countries. Where phenotypes were specified, the most common initial presentation overall was optic neuritis (ON; paediatric 34 %; adults 60 %), during which 71 % had papilloedema on fundoscopy. The most common phenotype at latest follow-up was relapsing ON (20 %). Only 47 % of patients with 6-24 months of follow-up exhibited a relapsing course, while this proportion was much higher (72 %) when follow-up was extended beyond 5 years. Despite a similar relapse rate, the time to first relapse was much shorter in paediatric than adult patients (6 vs 17 months). Adult MRI-Brain scans performed at onset were more frequently normal than in paediatric patients (50 % vs 27 %). Abnormal MRI scans showing involvement of deep grey matter, cortico-subcortical, periventricular lesions, leptomeningeal enhancement, H-shaped spinal cord lesions, and bilateral optic nerve abnormalities were more common in paediatric patients compared to adults. Conversely, adults demonstrated higher frequencies of eccentric spinal cord lesions and intraorbital involvement. CSF analysis demonstrated intrathecally restricted oligoclonal bands in 12 %, elevated protein in 35 %, and pleocytosis in 54 %. Peripapillary retinal nerve fibre layer (pRNFL) thickness, measured acutely, frequently demonstrated swelling (weighted-median 145 mu m; normal 85-110). Most cohorts demonstrated notable pRNFL atrophy at latest follow-up (weighted-median 67 mu m). pRNFL thickness was significantly lower when measured at or after six months following ON onset, compared to measurements taken within the first six months following ON onset (p < 0.001). Therapeutic and outcome data was available for 3031 patients with a weighted-median disease duration of 32 months. Acute immunotherapy was initiated in 97 %, and maintenance immunotherapy in 64 %, with considerable regional variation. Expanded Disability Status Scale (EDSS) scores and visual acuities improved from nadir to latest follow-up in most patients. A negative correlation was noted between follow-up pRNFL thickness and latest follow-up visual acuity (r = -0.56). Based on this unprecedented global aggregation of MOGAD patients, we reveal a higher proportion of relapsing patients than previously recognised. While commonly used measures like EDSS show significant recovery, they underestimate visual disability following optic neuritis, the most frequent clinical presentation. Our findings suggest that RNFL thickness, especially when measured at least 6 months post-ON, may serve as a more sensitive biomarker for long-term visual impairment.

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).

BACKGROUND:Current literature informs us that bivalent vaccines will generate a broader serum neutralizing antibody response to multiple SARS-CoV-2 variants, but studies on how this breadth relates to the memory B cell (MBC) and T cell responses are sparse. This study compared breadth of neutralising antibody, and memory B and T cell responses to monovalent or a bivalent ancestral/Omicron BA.1 COVID-19 booster vaccine. METHODS:At baseline and 1-month post-booster, neutralisation activity and frequencies of receptor binding domain (RBD)-specific MBCs and Spike-specific memory T cells were measured against a panel of variants. FINDINGS:Both vaccines boosted neutralising antibodies to 5 variants - Wuhan-Hu-1, Delta, BA.1, BA.5 and JN.1, the latter of which had not yet emerged at the time of sample collection. The bivalent vaccine induced a significantly larger increase in nAb against BA.1 and JN.1. Both vaccines boosted RBD-specific MBC responses to Wuhan-Hu-1, Delta, BA.1 and BA.5 variants with a significantly greater increase for BA.1 in the bivalent group. The breadth of MBCs was significantly higher in those who received the bivalent boost and correlated with nAb breadth. Both vaccines significantly boosted Spike-specific T cell responses to the Wuhan-Hu-1 and BA.5 variants, but only the bivalent vaccine boosted BA.1 responses. INTERPRETATION:These results suggest that the bivalent vaccine confers an advantage against future novel variants due to increased frequency of broadly reactive RBD-specific B cells. FUNDING:Work supported by NSW Health for the NSW Vaccine, Infection and Immunology Collaborative (VIIM).

Since the discoveries of autoantibodies in neurological diseases, women have had a fascinating journey in neuroimmunology. At a time when groundbreaking advances are being made, let’s continue the conversation about women in science.

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.

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.

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.