Yael Hacohen

Antibody-mediated inflammatory diseases of the CNS, including aquaporin-4 antibody neuromyelitis optica spectrum disorder (AQP4-Ab NMOSD) and myelin oligodendrocyte glycoprotein antibody–associated...

ObjectivesAcute treatment for myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) includes high-dose IV methylprednisolone (IVMP), with escalation to IV immunoglobulin (IVIG) an...

The 2024 McDonald criteria provide new recommendations for multiple sclerosis (MS) diagnosis, but validation of the criteria is lacking. We wanted to investigate the application and performance of the 2024 McDonald criteria in patients with suspected MS seen in routine clinical practice. We retrospectively identified patients referred with clinical and/or radiologic suspicion for MS between January and December 2024. All patients had a minimum diagnostic evaluation with brain and spinal cord MRI. The 2017 McDonald criteria were applied prospectively, and the 2024 McDonald criteria were applied retrospectively after the initial diagnostic workup and at last follow-up. We investigated (1) the number of patients diagnosed with MS using the 2017 McDonald criteria or the 2024 McDonald criteria, and (2) the diagnostic performance of the 2024 McDonald criteria when applied during the initial diagnostic workup, with an MS diagnosis using the 2017 McDonald criteria as the reference-standard. In 347 patients (mean age 39.4 years, 66% female) with suspected MS followed up for mean 15.3 (range 8-20) months, 73 (21%) had alternative disorders and were excluded. After applying the 2024 McDonald criteria in the remaining 274 patients, more patients were diagnosed with MS after the initial diagnostic workup (220 vs 172, p < 0.01), and at follow-up (237 vs 204, p < 0.01), compared with the 2017 McDonald criteria, and fewer patients were diagnosed with clinically or radiologically isolated syndrome. The median time to diagnosis was 40 vs 84 days (p < 0.01), respectively. After initial diagnostic workup, the 2024 McDonald criteria demonstrated high sensitivity (92.6%, 95% CI 88.1%-95.8%) and accuracy (83.6%, 95% CI 78.7%-87.8%), for an MS diagnosis using 2017 McDonald criteria at last follow-up, but moderate specificity (57.8%, 95% CI 45.4%-69.4%). The increased rate of MS diagnosis and the diagnostic performance of the revised criteria was similar in children (50 years). Use of the 2024 McDonald allows for earlier MS diagnosis, but also more frequent diagnosis including in patients with radiologically isolated syndrome. The revised criteria have similar performance across the lifespan. Limitations include the lack of data on central vein sign and kappa free light chains, and missing optic nerve assessment in some patients.

Central vein sign (CVS) is a common feature in multiple sclerosis (MS) lesions, but its frequency in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) varies significantly across studies. Paramagnetic rim lesions (PRLs) are described in MS, but not in MOGAD. Our goals were to evaluate the prevalence of PRLs and CVS in a large multicenter cohort of pediatric MOGAD. We compared CVS frequencies between acute vs remission phases, as well as with longitudinal dynamics of lesion evolution. In this longitudinal retrospective multicenter study, clinical MRIs were assessed from pediatric patients with MOGAD, who had (1) ≥1 brain lesion, (2) susceptibility-based imaging (SBI), and (3) follow-up MRI at least 3 months apart. T2-weighted and fluid-attenuated inversion recovery sequences were analyzed for lesion detection and resolution. SBI was used to assess CVS and PRLs following North American Imaging in MS Cooperative criteria. A total of 65 patients and 130 scans were included. A total of 520 lesions were evaluated. The most common reason for lesion exclusion was size (n = 143, large confluent lesions, n = 122, p = 0.002) and lesions suitable for CVS analysis (p < 0.001). Of the 31 patients with ≥3 brain lesions, 11 of 31 (35.5%) had >40% CVS+ lesions and 7 (22.5%) had >50% CVS+ lesions. Only 4 patients had ≥6 CVS+ lesions. The proportion of CVS+ lesions was lower in patients who had SBI acquired during an acute attack vs patients scanned during remission (16% vs 33%, p = 0.015). The rate of lesion resolution was higher in CVS- lesions (177/230, 76%) compared with CVS+ (42/97, 42%, p < 0.001). No PRLs were identified. Lesion pathobiology in MOGAD is heterogeneous. CVS identified persistent rather than transient lesions, with resolution more common among CVS- lesions. The high frequency of confluent or multivein lesions limited the proportion suitable for CVS analysis. MRI timing influenced CVS detection, which was higher in remission, suggesting that time of acquisition contributes to variability across MOGAD studies. No PRLs were found, supporting their potential as biomarkers distinguishing MOGAD from MS.

It is not known what the relapse risk is after immunomodulatory treatment discontinuation in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). Evidence suggests “at least” 3 months of oral corticosteroids reduces the relapse risk after a single attack and that it may be possible to stop maintenance treatment in relapsing stable disease but the optimal duration of treatment is unknown. We therefore aimed to investigate relapse outcomes following maintenance treatment discontinuation. We conducted a cohort study of MOGAD patients seen in the Oxford Neuromyelitis Optica Highly Specialised Service between January 2010 and May 2025. Patients with MOGAD, at least 12 months follow-up, and who commenced and then discontinued maintenance treatment were included. Associations of factors including treatment duration prior to discontinuation, disease course at discontinuation (after a single attack/monophasic or relapsing course) and MOG IgG1 status on live cell-based assay were investigated. Primary outcome was time-to-relapse following treatment discontinuation. Cox regression was used. We included 190 MOGAD patients with 236 discontinued treatment intervals. 150 (63.6%) discontinuations were after a single attack and before a first relapse when disease course was monophasic, and 86 (36.4%) discontinuations occurred in patients who had a relapsing disease course. Most patients used corticosteroids alone (84.7% IT intervals), and non-steroid IT were used in 15.2% of IT intervals either alone or in combination with steroids. Post-discontinuation relapse occurred after 92 (39.0%) discontinuations at a median time of 5.4 (interquartile range 1.4-20.1) months after treatment cessation. Those who relapsed were more likely to have a relapsing course at time of discontinuation (50% vs 27.8%, P=0.001) and a positive/low positive pre-discontinuation MOG IgG1 result (89.8% vs 71.5%, P=0.005). In multivariable analysis, a relapsing course at time of discontinuation was associated with an elevated relapse risk (hazard ratio 1.95, 95% confidence interval 1.25-3.06, P=0.003). Overall, prolonged treatment durations prior to discontinuation beyond 3 months significantly reduced relapse risk. Optimal treatment durations were estimated as at least 10-18 months for patients treated after their onset attack and 20-30 months for relapsing patients, following which treatment discontinuation could be considered in patients who were relapse-free on treatment. Identifying the relapse risk when discontinuing maintenance immunomodulatory treatment in MOGAD should aid management decisions in patients presenting with their first attack and also in those on longer-term treatment for relapsing disease. Our findings, from a cohort predominantly treated with steroids, provide evidence to inform joint decision-making for stable patients who are considering treatment cessation.

Paramagnetic rim lesions (PRLs), visible on susceptibility-based imaging (SbI), reflect chronic active inflammation in multiple sclerosis (MS). In adult-onset MS, PRLs are associated with a more aggressive disease course.The objectives of this study were to assess the prevalence of PRLs in children with MS and to examine how baseline PRL count relates to clinical disability and brain tissue volume loss, both cross-sectionally and over short-term follow-up. We retrospectively analyzed pediatric patients from 4 UK tertiary neuroimmunology centers who met the 2017 McDonald diagnostic criteria and had 3D T1-weighted, T2-weighted, fluid-attenuated inversion recovery, and SbI MRI available. PRLs were identified per North American Imaging in MS criteria and anatomically classified. Brain volumes were segmented using Mindglide, with z-scores derived from NIH normative data. Associations between baseline PRL burden, clinical variables, and brain volumes were assessed using univariable and multivariable stepwise regression. Linear mixed-effects models evaluated the predictive value of baseline PRL burden on longitudinal brain volume changes. Fifty-four patients (mean age 14.0 ± 2.2 years; 75.9% female) were included. At least 1 PRL was seen in 74.1% of patients, with a median number of 2 PRLs (interquartile range [IQR] = 0-6), predominantly in periventricular regions, and accounting for 25% of total T2-weighted hyperintense lesions. In multivariable Poisson regression, at baseline, shorter disease duration (incidence rate ratio [IRR] = 0.987, 95% CI 0.975-0.999, p = 0.035), and greater number (IRR 1.045, 95% CI 1.035-1.054, p < 0.001) and volume (IRR 1.018, 95% CI 1.004-1.032, p = 0.012) of T2-hyperintense lesions were associated with higher PRL count. Cross-sectionally, a higher PRL count was associated with lower cortical (β = -0.139, 95% CI -0.231 to -0.047, p = 0.016) and deep (β = -0.096, 95% CI -0.166 to -0.026, p = 0.032) gray matter volume z-scores. No significant association was observed between clinical disability and PRL count. In 45 patients followed up for a median 17 months (IQR 12-24), a higher baseline PRL count predicted greater deep gray matter volume loss over time (β = -0.020, 95% CI -0.034 to -0.006, p = 0.036). PRLs are common in pediatric MS and are linked to greater lesion burden and gray matter atrophy. These findings suggest that PRLs are promising imaging biomarkers of more severe brain tissue damage although their ability to predict future disability requires confirmation in longer term studies.

Data on the plasma exchange (PLEX) in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are limited. Herein, we evaluate outcomes after PLEX in MOGAD. This international multicenter retrospective cohort study included patients from 18 tertiary care centers in 6 countries. Inclusion criteria included fulfillment of the 2023 International MOGAD panel criteria, receipt of at least 3 sessions of PLEX, and follow-up of ≥3 months after PLEX. Patients with coexisting neuroinflammatory disorders were excluded. We assessed the frequency of complete recovery (CR), clinically significant improvement (CSI), visual acuity (VA), and Expanded Disability Status Scale (EDSS). Logistic regression analyses were performed to identify predictors of CR and CSI. Of 234 patients, 135 (58%) were female. The median (interquartile range [IQR]) age at attack was 34 (IQR 22-49) years, and 42 (17%) were children. In 165 of 243 (68%), the attack treated with PLEX was the first attack. Attack phenotypes included 161 optic neuritis (235 eyes), 77 myelitis, 24 acute disseminated encephalomyelitis, 15 brainstem/cerebellar, 3 cerebral-cortical encephalitis attack, and 1 cerebral polyfocal deficit-36 with >1 core phenotypes. A total of 239 (99%) attacks were also treated with corticosteroids and 32 (13%) with IV immunoglobulins. VA in optic neuritis improved from 20/400 (20/70-hand motion) to 20/20 (20/20-20/30), p < 0.001, and EDSS decreased from a median of 4.0 (3.0-6.5) to 1.0 (0.0-2.5), p < 0.001. Of 229 attacks without subsequent attacks within 3 months, 100 (44%) achieved CR and 213 (93%) CSI. The probability of CR was decreased with advanced age (adjusted odd ratio [95% CI] 0.97 [0.96-0.99] per year), higher EDSS worsening from baseline (0.66 [0.54-0.81] per 0.5 increment) and delayed PLEX (0.98 [0.96-0.99] per day). Advanced age (0.97 [0.96-0.99] per year) and delayed PLEX (0.95 [0.94-0.96] per day) decreased the probability of CSI. We observed favorable outcomes after PLEX in MOGAD attacks. However, advanced age and delayed initiation of PLEX were associated with a reduced probability of improvement. The absence of a control group limits our ability to differentiate PLEX effects from spontaneous recovery, prior corticosteroid response, or long-term immunotherapy. Future prospective studies are needed to assess the impact of PLEX on improvement. This study provides Class IV evidence that PLEX is associated with favorable clinical outcomes in patients with MOGAD.

The benefit of disease-modifying therapies (DMTs) in relapsing-remitting multiple sclerosis (RRMS) is believed to decrease with age. We aimed to compare disease outcomes with DMTs between patients with late-onset RRMS (LO-RRMS) and adult-onset RRMS (AO-RRMS). This was a single-center, longitudinal, prospective analysis of patients who fulfilled the following criteria: (1) a diagnosis of RRMS and (2) initiation of a new DMT (dimethyl fumarate, fingolimod, glatiramer acetate, natalizumab, and ocrelizumab) within 3 months. Patients were followed up at years 1 and 2. We compared treatment outcomes (relapses, radiologic activity, disability progression, and no evidence of disease activity [NEDA]) between LO-RRMS (defined as age at onset of first symptom >45 years) and AO-RRMS (≥18 years and 45 years) using Poisson, logistic, and Cox regression models while adjusting for baseline variables. The analyses were repeated with an age cutoff of 50 years. We studied 1,494 patients with AO-RRMS (mean age at onset: 29.6 years, 71% female) and 150 patients with LO-RRMS (50.2 years, 73% female) at treatment initiation. At DMT commencement, patients with LO-RRMS had shorter disease duration, higher Expanded Disability Status Scale (EDSS), more comorbidities, and were more likely to be treatment naive than patients with AO-RRMS. However, when adjusted, there were no differences in the probability of relapses (Coeff = -0.07; 95% CI -0.19 to 0.04, p = 0.24), EDSS progression (odds ratio [OR] 1.43, 95% CI 0.69-2.93, p = 0.33), MRI activity (OR 0.77; 95% CI 0.21-2.83, p = 0.70), and losing NEDA status (hazard ratio [HR] 0.93; 95% CI 0.73-1.18, p = 0.58) at year 1. Similar results were observed at year 2 in relapses (Coeff = -0.04; 95% CI -0.19 to 0.11, p = 0.60), EDSS progression (OR 1.33; 95% CI 0.69-2.93, p = 0.33), MRI activity (OR 1.30; 95% CI 0.38-4.38, p = 0.67), and loss of NEDA status (HR 0.99; 95% CI 0.77-1.26, p = 0.96). Similar results were observed using an age cutoff of 50 years. The percentages of patients who stopped DMTs because of side effects were similar between AO-RRMS and LO-RRMS. Treatment outcomes over 2 years were similar between LO-RRMS and AO-RRMS. This indicates that care should be taken not to bias treatment decisions due to older age at onset of MS when patients demonstrate evidence of inflammatory activity. Limitations are the observational design, the single-center setting, and a relatively small LO-RRMS group. This study provides Class III evidence that patients with LO-RRMS have comparable outcomes with DMTs as patients with AO-RRMS over a 2-year period; this rating is because of baseline imbalances between treatment groups and a nonmasked outcome assessment.