MOG Antibody-associated Disease Research Articles

Radiologic Lag and Brain MRI Lesion Dynamics During Attacks in MOG Antibody-Associated Disease.

Knowledge of the evolution of CNS demyelinating lesions within attacks could assist diagnosis. We evaluated intra-attack lesion dynamics in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) vs multiple sclerosis (MS) and aquaporin-4 antibody seropositive neuromyelitis optica spectrum disorder (AQP4+NMOSD). This retrospective observational multicenter study included consecutive patients from Mayo Clinic (USA) and Great Ormond Street Hospital for Children (UK). Inclusion criteria were as follows: (1) MOGAD, MS, or AQP4+NMOSD diagnosis; (2) availability of ≥2 brain MRIs (within 30 days of attack onset); and (3) brain involvement (i.e., ≥1 T2 lesion) on ≥1 brain MRI. The initial and subsequent brain MRIs within a single attack were evaluated for the following: new T2 lesions(s); resolved T2 lesion(s); both; or no change. This was compared between MOGAD, MS, and AQP4+NMOSD attacks. We used the Mann-Whitney U test and χ2/Fisher exact test for statistical analysis. Our cohort included 55 patients with MOGAD (median age, 14 years; interquartile range [IQR] 5-34; female sex, 29 [53%]) for a total of 58 attacks. The comparison groups included 38 patients with MS, and 19 with AQP4+NMOSD. In MOGAD, the initial brain MRI (median of 5 days from onset [IQR 3-9]) was normal in 6/58 (10%) attacks despite cerebral symptoms (i.e., radiologic lag). The commonest reason for repeat MRI was clinical worsening or no improvement (33/56 [59%] attacks with details available). When compared with the first MRI, the second intra-attack MRI (median of 8 days from initial scan [IQR 5-13]) showed the following: new T2 lesion(s) 27/58 (47%); stability 24/58 (41%); resolution of T2 lesion(s) 4/58 (7%); or both new and resolved T2 lesions 3/58 (5%). Findings were similar between children and adults. Steroid treatment was associated with resolution of ≥1 T2 lesion (6/28 [21%] vs 1/30 [3%], p = 0.048) and reduced the likelihood of new T2 lesions (9/28 vs 18/30, p = 0.03). Intra-attack MRI changes favored MOGAD (34/58 [59%]) over MS (10/38 [26%], p = 0.002) and AQP4+NMOSD (4/19 [21%], p = 0.007). Resolution of ≥1 T2 lesions was exclusive to MOGAD (7/58 [12%]). Radiologic lag is common within MOGAD attacks. Dynamic imaging with frequent appearance and occasional disappearance of lesions within a single attack suggest MOGAD diagnosis over MS and AQP4+NMOSD. These findings have implications for clinical practice, clinical trial attack adjudication, and understanding of MOGAD pathogenesis.

A.5 Investigating myelitis and rheumatologic disease overlap in the era of neuromyelitis optica spectrum disorder and MOG Antibody-associated disease

Background: Historical studies of myelitis associated with rheumatologic disease may have featured patients with unrecognized aquaporin-4 (AQP4)-IgG seropositive neuromyelitis optica spectrum disorder (NMOSD) or MOG-IgG associated disease (MOGAD). Methods: Cases with rheumatologic disease and myelitis unrelated to multiple sclerosis (MS) seen at Johns Hopkins between 2018-2023 were identified by medical record query and chart review. Descriptive statistics were used to compare AQP4-IgG seropositive to seronegative subjects. Results: Of 234 patients screened, 190 were excluded (144 did not have inflammatory myelopathy, 46 had MS), resulting in a cohort of 44 patient (43 female, mean age 45 years [SD±14]). Twenty patients (45%) had AQP4-IgG seropositive NMOSD, 1 (2%) MOGAD, 20 (45%) other myelitis, and 3 (7%) AQP4-IgG seronegative NMOSD. AQP4-IgG seropositive subjects were more likely to have longitudinally extensive central cord lesions than seronegative patients. Most (n=43; 98%) were tested for serum AQP4-IgG, and 20 (46%) were positive by cell-based assay (CBA) or enzyme-linked immunosorbent assay. Of 24 AQP4-IgG seronegative patients, 8 were tested only by ELISA/unknown assay. Serum MOG-IgG was positive in 2/18 subjects. Conclusions: AQP4-IgG seropositive NMOSD was common in this cohort of patients with rheumatologic disease and myelitis, with the caveat that several seronegative cases were never tested with gold-standard CBA.

Diagnostic Utility of MOG Antibody Testing in Cerebrospinal Fluid.

The aim of this study was to assess the diagnostic utility of cerebrospinal fluid (CSF) myelin oligodendrocyte glycoprotein antibodies (MOG-IgG) testing. We retrospectively identified patients for CSF MOG-IgG testing from January 1, 1996, to May 1, 2023, at Mayo Clinic and other medical centers that sent CSF MOG-IgG for testing including: controls, 282; serum MOG-IgG positive MOG antibody-associated disease (MOGAD), 74; serum MOG-IgG negative high-risk phenotypes, 73; serum false positive MOG-IgG with alternative diagnoses, 18. A live cell-based assay assessed CSF MOG-IgG positivity (IgG-binding-index [IBI], ≥2.5) using multiple anti-human secondary antibodies and end-titers were calculated if sufficient sample volume. Correlation of CSF MOG-IgG IBI and titer was assessed. The pan-IgG Fc-specific secondary was optimal, yielding CSF MOG-IgG sensitivity of 90% and specificity of 98% (Youden's index 0.88). CSF MOG-IgG was positive in: 4/282 (1.4%) controls; 66/74 (89%) serum MOG-IgG positive MOGAD patients; and 9/73 (12%) serum MOG-IgG negative patients with high-risk phenotypes. Serum negative but CSF positive MOG-IgG accounted for 9/83 (11%) MOGAD patients, and all fulfilled 2023 MOGAD diagnostic criteria. Subgroup analysis of serum MOG-IgG low-positives revealed CSF MOG-IgG positivity more in MOGAD (13/16[81%]) than other diseases with false positive serum MOG-IgG (3/15[20%]) (p = 0.01). CSF MOG-IgG IBI and CSF MOG-IgG titer (both available in 29 samples) were correlated (Spearman's r = 0.64, p < 0.001). CSF MOG-IgG testing has diagnostic utility in patients with a suspicious phenotype but negative serum MOG-IgG, and those with low positive serum MOG-IgG results and diagnostic uncertainty. These findings support a role for CSF MOG-IgG testing in the appropriate clinical setting. ANN NEUROL 2024.

Visual Evoked Potentials in MOG Antibody-associated Disease (P9-14.007)

Visual Evoked Potentials in MOG Antibody-associated Disease (P9-14.007)

Myelin oligodendrocyte glycoprotein antibody titers by fixed cell-based assay: positive predictive value and impact of sample collection timing.

In January 2023, our laboratory began performing serum myelin oligodendrocyte glycoprotein antibody (anti-MOG) titers by fixed cell-based assay (CBA). As a quality assurance (QA) assessment, we evaluated titer positive predictive value (PPV) as well as impact of sample collection timing on titers. Among patients who underwent antibody titers to distinguish between low-positive (<1:100) and clear-positive (≥1:100) anti-MOG, records were reviewed to classify results as true-positive (TP) or false-positive (FP) and facilitate PPV calculation. Timing of sample collection relative to administration of immunotherapy and symptom onset was determined for TP results. Overall PPV of anti-MOG was 70/85 (82%). The PPV of low-positive anti-MOG was significantly lower than clear-positive anti-MOG (72% vs. 95%, p = 0.009). The difference in PPV between low-positive and clear-positive anti-MOG was significant among adults tested, but not children. Among patients with TP anti-MOG, the proportion who received immunotherapy prior to sample collection was significantly higher and median time from symptom onset to sample collection was significantly longer for low-positive compared to clear-positive results. Overall PPV of anti-MOG testing by fixed CBA was reasonably high. The PPV of low-positive anti-MOG was significantly lower than clear-positive anti-MOG. This was driven by the significantly lower PPV of low-positive anti-MOG in adults, possibly reflecting the lower prevalence of MOG antibody-associated disease among adults tested. Timing of sample collection relative to administration of immunotherapy and symptom onset may substantially impact titers, indicating that testing should ideally be performed prior to immunotherapy and close to time of attack.

Isolated myelin oligodendrocyte glycoprotein antibody-associated optic neuritis in adults: The importance of age of onset and prognosis-related radiological features

BackgroundMyelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD) exhibits phenotypic diversity and it varies by age. However, less is known about whether the manifestations of isolated MOG antibody-associated optic neuritis (iMOG-ON) vary across different age groups. We aimed to investigate the clinical and prognostic features of iMOG-ON in young and middle-aged adult patients. MethodsPatients with iMOG-ON were enrolled in the Department of Neurology, Beijing Tongren Hospital, Capital Medical University between January 2018 and October 2021. Medical records were reviewed to obtain clinical data and orbital MRI images of adult patients with iMOG-ON. Multivariate linear regression analysis was performed to investigate the associations between final best-corrected visual acuity (BCVA) in logMAR and clinical characteristics. ResultsBased on the age of onset, 70 patients were divided into 2 groups: 38 young (< 46 years; female/male = 0.76:1) and 32 middle-aged (≥ 46 years; female/male = 5.56:1) adults. There were statistical differences in both the female-to-male ratio and frequencies of contrast enhancement of the optic nerve sheaths and surrounding orbital tissues between both groups (p = 0.001, p = 0.004, respectively). The average follow-up periods were 28.04 ± 11.22 months. The median final BCVA was 0 (0 - 0.50) logMAR and 0.5 (0.3 - 1.0) logMAR in the young and middle-aged patients, respectively (p = 0.000). The multivariate linear regression analysis indicated significant positive relationships between final BCVA and age of onset (p = 0.038, 95 % CI: 0.020 - 0.728), sex (p = 0.030, 95 % CI: -0.793 - -0.042), BCVA at nadir (p = 0.000, 95 % CI: 0.164 - 0.386), and numbers of segments of optic nerve lesions (p = 0.009, 95 % CI: 0.068 - 0.450) with a coefficient of determination (R2) of 0.359 after adjusting for prior attacks of ON, time intervals between sudden-onset vision loss and administration of intravenous methylprednisolone, and corticosteroid dosages. The worst final BCVA was observed in afflicted eyes with lesions extending across three segments of the optic nerve. ConclusionCompared to young adults with iMOG-ON, the middle-aged patients tended to have a female predominance, higher frequencies of perineural enhancement, and worse visual outcomes. In addition to age of onset, visual recovery may also be influenced by patient's sex, BCVA at nadir, and lengths of longitudinally expansive lesions of the optic nerve to a certain extent.

Global trends in research on MOG antibody-associated disease: bibliometrics and visualization analysis.

The purpose of this study was to investigate the current research status, focus areas, and developmental trends in the field of Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) through an analysis of scientific literature. The relevant research articles on MOGAD published from 1947 to 2022 were retrieved from the Web of Science database. The quantitative output of MOGAD related research articles, their distribution by country/region, data on collaborative publishing, influential authors, high-yield institutions, keywords, hotspots, and development trends were analyzed. Additionally, visual knowledge maps were generated using VOSviewer and Citespace. There has been a steady increase in the number of MOGAD related publications indicating that the subject has garnered increasing interest among researchers globally. The United States has been the leading contributor with 496 papers (19.25%), followed by China (244, 9.63%), Japan (183, 7.10%), the United Kingdom (154, 5.98%), and Germany (149, 5.78%). Among these countries, the United Kingdom boasts the highest citation frequency at the rate of 46.49 times per paper. Furthermore, active collaboration in MOGAD related research is observed primarily between the United States and countries such as Canada, Germany, Australia, Italy, the United Kingdom and Japan. Mayo Clinic ranks first in total articles published (109) and frequency of citations per article (77.79). Takahashi Toshiyuki from Tohoku University is the most prolific author, while Multiple Sclerosis and Related Disorders is the most widely read journal in this field. "Disease Phenotype", "Treatment", "Novel Coronavirus Infection and Vaccination", "Immunopathological Mechanisms", "Clinical characteristics of children" and "Prognosis" are the primary keywords clusters in this field. "Novel Coronavirus Infection and Vaccination" and "Immunopathological Mechanisms" are research hotspots and have great development potential. The past three decades have witnessed a significant expansion of research on MOGAD. The pathogenetic mechanism of MOGAD is poised to be the prominent research focus in this field in the foreseeable future.

The MOG antibody non-P42 epitope is predictive of a relapsing course in MOG antibody-associated disease

BackgroundMyelin 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...

Characteristics of cerebrospinal fluid oligoclonal band in anti-myelin oligodendrocyte glycoprotein (MOG) antibody associated disease

ObjectiveTo analyze the immune parameters of cerebrospinal fluid (CSF) and oligoclonal band (OCB) type in patients with anti-myelin oligodendrocyte glycoprotein (MOG) antibody-associated diseases (MOGAD). MethodsPatients who were seropositive for MOG-IgG and diagnosed with MOGAD according to the diagnosis criteria in the Department of Neurology, Huashan Hospital, Fudan University from December 2020 to June 2022 were retrospectively included in this study. Complete clinical data, blood and cerebrospinal fluid samples were collected from all the participants. Paired serum and CSF MOG-IgG and autoimmune encephalitis antibody were assayed by Cell Based Assay (CBA) based on transfected target antigens. Paired serum and CSF albumin and IgG were detected by turbidimetric scattering method, and OCB was detected by standard operation procedure as described. ResultsA total of 86 patients (44 males and 42 females) with MOGAD were included in this study, with a median age of 30 years (range: 5–82 years). Among all the patients, 73 patients showed OCB type I, 12 patients showed OCB type II, and one patient showed OCB type III. The overall positive rate of CSF-OCB in MOGAD patients was 15.1 %. The 24-h intrathecal synthesis rate of CSF in the OCB-positive group (n = 13) was higher than that in the OCB-negative group [n = 73, 0.62 (0.26) vs 5.11 (13.67), P = 0.003]. Subgroup analysis revealed that the positive rates of CSF-OCB in the single MOG group (n = 61) and the group combined with other antibodies (n = 25) were 14.8 % and 16.0 %, respectively. The incidence of meningoencephalitis (13/61 vs 13/25, P = 0.011) was significantly different between the two groups. The proportion of patients with high (≥1:32) or low (≤1:10) CSF MOG-IgG also showed significant difference in the group combined with other antibodies (P = 0.032). Optic neuritis was more common in the relapse course group (n = 49) than the monophasic course group (n = 37, P < 0.001) No significant diferences of CSF immune parameters were found in the MOG-IgGserum+/CSF− group and the MOG-IgGserum+/CSF + group, and the titer of MOG-IgG in the serum or CSF did not influence CSF immune parameters in different subgroups. ConclusionThe overall positive rate of CSF-OCB in MOGAD patients was 15.1 %. The 24-h intrathecal synthesis rate of cerebrospinal fluid in the OCB-positive group was higher than that in the OCB-negative group. This study illustrated OCB characterization in MOGAD patients, and will shed light on the standardization of OCB test in the study of immune diseases.

Peripheral nervous system manifestations of MOG antibody associated disease.

Recent studies have reported the involvement of peripheral nervous system (PNS) in association with MOG-IgG, including isolated neuropathies. In this retrospective study we characterized the PNS involvement in MOG antibody associated disease (MOGAD). Six out of 215 MOGAD patients had PNS involvement (all polyradiculopathy) that occurred concurrently with a CNS demyelinating episode. We also demonstrated MOG expression in healthy human controls' proximal nerve root. Nine patients with true-positive MOG-IgG1 had PNS involvement temporally unrelated to a CNS demyelinating event. All these patients had an alternate etiology of PNS involvement. Isolated peripheral neuropathy is not a feature of MOGAD, but inflammatory nerve root involvement can occur concurrently with CNS demyelinating events.

Reply to Kim et al. Acute Hemorrhagic Encephalomyelitis in the Context of MOG Antibody-Associated Disease. Comment on “Chen et al. Rapid Progressive Fatal Acute Hemorrhagic Encephalomyelitis. Diagnostics 2023, 13, 2481”

We want to express our appreciation for the insightful comments [...]

Acute Hemorrhagic Encephalomyelitis in the Context of MOG Antibody-Associated Disease. Comment on Chen et al. Rapid Progressive Fatal Acute Hemorrhagic Encephalomyelitis. Diagnostics 2023, 13, 2481.

The study by Chen et al. of a 56-year-old man diagnosed with acute hemorrhagic encephalomyelitis (AHEM) had a significant impact on us. The authors provided a comprehensive account of their diagnostic journey and emphasized the need to differentiate myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) from AHEM. However, recent research suggests that AHEM may not be an isolated entity, but rather a phenotype within MOGAD. The patient's clinical presentation included MRI brain lesions characteristic of MOGAD in addition to hemorrhagic abnormalities. These findings raise the possibility that AHEM in this case represents a MOGAD phenotype. In conclusion, it is important to recognize the potential association between AHEM and MOGAD, especially when distinct MOGAD brain MRI patterns are present, as in this case.

NF-κB and STAT3 activation in CD4 T cells in pediatric MOG antibody-associated disease

In this study, we examined CD4 T cell activation using various stimuli in pediatric MOGAD patients (n = 4, untreated remission samples) and healthy controls (n = 5), to understand how both antigen-specific and bystander mechanisms contribute to CD4 T cell activation in MOGAD. TNFα, IL6, and MOG peptide pool were found to activate NF-κB or STAT3 pathways by measuring the expression of regulators (A20, IκBα) and phosphorylated subunits (phospho-p65 and phospho-STAT3) using immunolabeling. Prednisolone reversed activation of both NF-κB and STAT3 and increased the expression of A20 and IκBα. TNFR blocking partially reversed NF-κB activation in certain CD4 T cell subsets, but did not effect STAT3 activation. We observed that activation of NF-κB and STAT3 in response to various stimuli behaves mostly same in MOGAD (remission) and HC. IL6 stimulation resulted in higher STAT3 phosphorylation in MOGAD patients at 75 min, specifically in central and effector memory CD4 T cells (with unadjusted p-values). These findings suggest the potential therapeutic targeting of NF-κB and STAT3 pathways in MOGAD. Further investigation is needed to validate the significance of extended STAT3 phosphorylation and its correlation with IL6 receptor blocker treatment response.

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

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

Novel index, neutrophil percentage (%) is a useful marker for disease activity in MOG antibody-associated disease.

Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is a CNS autoimmune disease affecting the brain, spinal cord, and optic nerve. The neutrophil-to-lymphocyte ratio (NLR) is related to autoimmune disease activity. However, the clinical implication of index ratios such as the NLR is unclear in patients with MOGAD. We investigated the relationship between index ratios such as the NLR and disease activity and disability to discover the index that best correlates with an attack in MOGAD. Using a CNS demyelinating disease cohort, we reviewed 39 patients with MOGAD (age 37.4±12.0 years; F:M=20:19) who had 390 blood samples available for cell count analysis. We calculated the NLR, eosinophil-to-lymphocyte-ratio (ELR), platelet-to-lymphocyte-ratio (PLR), monocyte-to-lymphocyte ratio (MLR), basophil-to-lymphocyte ratio (BLR), and neutrophil percentage (N%) [neutrophil count (/mm3) / WBC (/mm3) x 100 (%)]. We investigated the associations between each index ratio and disease activity and disability using the receiver operating characteristic (ROC) curve, machine learning program (kNN algorithm), and generalized estimating equations (GEE) analysis. In patients with MOGAD, the NLR, PLR, and N% were higher and ELR was lower during an attack than in remission (all p<0.001). The areas under the ROC curve for the NLR, ELR, PLR, and N% were 0.68, 0.69, 0.61, and 0.68, respectively, with the highest sensitivity of 76.0% in the ELR and the highest specificity of 76.3% in the N%. The classification accuracy scores of the kNN machine learning algorithm were 71% for the NLR, 62% for the ELR, 63% for the PLR, and 72% for the N%. In the GEE analysis of attack samples, both the NLR and treatment-naive had positive associations with the Expanded Disability Status Scale (EDSS) score (β=0.137, p=0.008 and β=1.142, p=0.003, respectively), and the PLR was negatively associated with the EDSS score (β=-0.004, p=0.022). Our study suggests that the novel index, neutrophil% is the simplest and the most useful marker to differentiate between attack and remission and shows comparable reliability with NLR in MOGAD. Moreover, the NLR and PLR could be used as supportive biomarkers for disease disability during an attack in patients with MOGAD.

Two cases of unilateral cortical fluid‐attenuated inversion recovery‐hyperintense lesions in anti‐myelin oligodendrocyte glycoprotein‐associated encephalitis with seizures (FLAMES)

AbstractBackgroundMyelin oligodendrocyte glycoprotein (MOG) antibody‐associated disease (MOGAD) is a rare inflammatory disease of the central nervous system. Unilateral cortical fluid‐attenuated inversion recovery‐hyperintense lesions in anti‐MOG‐associated encephalitis with seizures (FLAMES) has recently been proposed as a subcategory of MOGAD. FLAMES is characterized by fluid‐attenuated inversion recovery (FLAIR) imaging showing hyperintense cortical lesions in MOG‐associated encephalitis with seizures.Case PresentationWe herein report two cases of unilateral cortical FLAMES. The first case was a 29‐year‐old woman who developed headaches, fever, convulsions and right hemiparesis. Brain FLAIR magnetic resonance imaging (MRI) showed hyperintense cortical lesions on the left side. The second case was a 37‐year‐old women who developed headaches and fever. Brain FLAIR MRI showed hyperintense cortical lesions on the left side. Both cases were positive for anti‐MOG antibodies in cerebrospinal fluid and serum, and were diagnosed with unilateral cortical FLAMES in MOGAD. Both patients were treated with intravenous methylprednisolone followed by oral corticosteroids, which improved MRI findings and clinical symptoms.ConclusionsBoth patients were diagnosed with MOGAD due to characteristic unilateral cortical encephalitis on brain FLAIR MRI. Unilateral cortical FLAMES is an important clue for the clinical diagnosis of MOGAD.

High serum neurofilament levels are observed close to disease activity events in pediatric-onset MS and MOG antibody-associated diseases.

Serum neurofilament light chain (sNfL) is an emerging multiple sclerosis (MS) biomarker which measures neuro-axonal damage. However, understanding its temporal association with disease activity in pediatric-onset MS (POMS) and Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) remains limited. To investigate the association of sNfL levels and time from disease activity in children with MS and MOGAD. POMS and MOGAD cases with onset before 18 years of age were enrolled at the University of California San Francisco (UCSF) Regional Pediatric MS Center. Frequency-matched healthy subjects were recruited from general pediatric clinics. Serum samples were tested for MOG-IgG at Mayo Clinic using a live cell-based fluorescent activated cell sorting assay. sNfL levels were measured using single-molecule array (Simoa) technology measured in pg/mL. Data on demographics, clinical features, MRI, CSF, and treatment data were collected by chart review. We included 201 healthy controls healthy controls, 142 POMS, and 20 confirmed MOGAD cases with available sNfL levels. The median (IQR) age at the time of sampling was 15.6 (3.9), 15.5 (3.1), and 8.8 (4.1) years for controls, POMS, and MOGAD, respectively. Median sNfL levels (pg/ml) were higher in POMS (19.6) and MOGAD (32.7) cases compared to healthy controls (3.9) (p<0.001). sNfL levels ≥100 pg/ml were only detected within four months of a clinical event or MRI activity in both POMS and MOGAD cases. In addition, sNfL levels were higher in POMS patients with new/enlarged T2 and gadolinium-enhanced lesions than those without MRI activity within four months of sampling in POMS cases. High sNfL levels were observed close to clinical or MRI events in POMS and MOGAD. Our findings support sNfL as a biomarker of disease activity in pediatric demyelinating disorders.

Deviation From Normative Whole Brain and Deep Gray Matter Growth in Children With MOGAD, MS, and Monophasic Seronegative Demyelination.

Pediatric-acquired demyelination of the CNS associated with antibodies directed against myelin oligodendrocyte glycoprotein (MOG; MOG antibody-associated disease [MOGAD]) occurs as a monophasic or relapsing disease and with variable but often extensive T2 lesions in the brain. The impact of MOGAD on brain growth during maturation is unknown. We quantified the effect of pediatric MOGAD on brain growth trajectories and compared this with the growth trajectories of age-matched and sex-matched healthy children and children with multiple sclerosis (MS, a chronic relapsing disease known to lead to failure of normal brain growth and to loss of brain volume) and monophasic seronegative demyelination. We included children enrolled at incident attack in the prospective longitudinal Canadian Pediatric Demyelinating Disease Study who were recruited at the 3 largest enrollment sites, underwent research brain MRI scans, and were tested for serum MOG-IgG. Children seropositive for MOG-IgG were diagnosed with MOGAD. MS was diagnosed per the 2017 McDonald criteria. Monophasic seronegative demyelination was confirmed in children with no clinical or MRI evidence of recurrent demyelination and negative results for MOG-IgG and aquaporin-4-IgG. Whole and regional brain volumes were computed through symmetric nonlinear registration to templates. We computed age-normalized and sex-normalized z scores for brain volume using a normative dataset of 813 brain MRI scans obtained from typically developing children and used mixed-effect models to assess potential deviation from brain growth trajectories. We assessed brain volumes of 46 children with MOGAD, 26 with MS, and 51 with monophasic seronegative demyelinating syndrome. Children with MOGAD exhibited delayed (p < 0.001) age-expected and sex-expected growth of thalamus, caudate, and globus pallidus, normalized for the whole brain volume. Divergence from expected growth was particularly pronounced in the first year postonset and was detected even in children with monophasic MOGAD. Thalamic volume abnormalities were less pronounced in children with MOGAD compared with those in children with MS. The onset of MOGAD during childhood adversely affects the expected trajectory of growth of deep gray matter structures, with accelerated changes in the months after an acute attack. Further studies are required to better determine the relative impact of monophasic vs relapsing MOGAD and whether relapsing MOGAD with attacks isolated to the optic nerves or spinal cord affects brain volume over time.

High-throughput Multidimensional Characterization of CD8 T cells in MOG Antibody-Associated Disease

Abstract Inflammatory demyelinating diseases of the central nervous system (CNS) include clinically and pathologically distinct disorders. Myelin oligodendrocyte glycoprotein-associated disease (MOGAD) is a recently characterized antibody-mediated inflammatory demyelinating disorder of the CNS with clinical presentations which include optic neuritis, transverse myelitis, and acute disseminated encephalomyelitis. The heterogenous clinical course of MOGAD along with unclear prognostic biomarkers makes treatment challenging, as some individuals have monophasic disease while others relapse. Recent work has attempted to identify biomarkers by performing scRNA-seq on the peripheral blood mononuclear cells (PBMC) of MOGAD patients and has highlighted an enrichment for a cytotoxic effector CD8 +T cell subset in MOGAD compared to healthy controls. However, this subset of cells remains under characterized, with questions regarding their antigen specificity, clonality, and overall involvement in MOGAD. To further characterize this cell subset, we utilize a single cell technology, TetTCR-SeqHD, to evaluate the antigen-specificity, clonality, gene expression, and surface protein expression of CD8 +T cells isolated from the PBMC of MOGAD patients. In this approach, a large library of fluorescently labeled, DNA barcoded peptide-MHC tetramers are generated utilizing peptides derived from MOG or associated proteins such as myelin basic protein and proteolipid protein which are then used to isolate antigen specific CD8+ T cells for single cell analysis. Preliminary results show an enrichment of a distinct CD161 ++TRAV1–2 +MAIT cell population in MOGAD, which has been previously implicated in other chronic inflammatory diseases. This work is supported by the Chan Zuckerberg Initiative Neurodegeneration Challenge Network Ben Barres Early Career Acceleration Award.

Comparing Lesion Distribution on Presentation of Pediatric and Adult Patients with MOG Antibody-Associated Disease (MOGAD) (P13-5.023)

<h3>Objective:</h3> To determine MRI lesion frequency in distinct neuro-anatomic compartments in MOGAD patients at different ages of presentation. <h3>Background:</h3> MOGAD is a novel neuro-inflammatory disorder that appears to present differently clinically in children (usually acute disseminated encephalomyelitis) and adults (usually more restricted forms, e.g. optic neuritis or myelitis). Relatively little is known about differences in radiologic involvement in adults and children at the time of presentation. <h3>Design/Methods:</h3> We included all patients with neurologist-diagnosed MOGAD in NYU MS Center database who had both brain and spinal cord MRIs available for review from the time of presentation. MRI and reports were reviewed and the presence of lesions in the optic nerve, supra- and infra-tentorial brain, spinal cord, and spinal roots were ascertained (present v absent). Patients were divided into pediatric (0–17 years) and adult (18+ years) groups and lesion frequency in each compartment were compared with chi-square test, χ². p&lt;0.05 was considered significant. <h3>Results:</h3> 54 patients met inclusion criteria (all seropositive for MOG antibody by cell-based assay). Mean age in years, was 9.52 ± 4.1 in children and 40.31 ± 14 in adults; male-to-female ratio was 2:3 in children and 1:1.2 in adults; 60.0% of children were non-White, as were 39.7% of adults. Course was monophasic in 24.0% of children and 34.5% in adults. A significant difference in lesion frequency between groups was found in the supratentorial compartment (72.0% pediatric vs 31.0% adult, p=0.003) but not in the optic nerve (60.0% vs 55.2%, p=0.72), infratentorial brain (36.0% vs 31.0%, p=0.70), spinal cord (56.0% vs 41.4%, p=0.29), and spinal nerve roots (12.0% vs 24.1%, p=0.25) <h3>Conclusions:</h3> In children with MOGAD, supratentorial brain was more frequently involved than in adults, while other neuroanatomic compartments were similarly affected. <b>Disclosure:</b> Mr. Ahmad has nothing to disclose. Dr. Kister has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Genentech-Roche. The institution of Dr. Kister has received research support from Genentech. Dr. Kister has received publishing royalties from a publication relating to health care.