Prior studies have suggested that subclinical retinal abnormalities may be present in aquaporin-4 immunoglobulin G (AQP4-IgG) seropositive neuromyelitis optica spectrum disorder (NMOSD), in the absence of a clinical history of optic neuritis (ON).Our aim was to compare retinal layer thicknesses at the fovea and surrounding macula between AQP4-IgG+ NMOSD eyes without a history of ON (AQP4-nonON) and healthy controls (HC).In this single-center cross-sectional study, 83 AQP4-nonON and 154 HC eyes were studied with spectral-domain optical coherence tomography (OCT).Total foveal thickness did not differ between AQP4-nonON and HC eyes. AQP4-nonON eyes exhibited lower outer nuclear layer (ONL) and inner photoreceptor segment (IS) thickness at the fovea (ONL: -4.01 ± 2.03 μm, p = 0.049; IS: -0.32 ± 0.14 μm, p = 0.029) and surrounding macula (ONL: -1.98 ± 0.95 μm, p = 0.037; IS: -0.16 ± 0.07 μm, p = 0.023), compared to HC. Macular retinal nerve fiber layer (RNFL: -1.34 ± 0.51 μm, p = 0.009) and ganglion cell + inner plexiform layer (GCIPL: -2.44 ± 0.93 μm, p = 0.009) thicknesses were also lower in AQP4-nonON compared to HC eyes. Results were similar in sensitivity analyses restricted to AQP4-IgG+ patients who had never experienced ON in either eye.AQP4-nonON eyes exhibit evidence of subclinical retinal ganglion cell neuronal and axonal loss, as well as structural evidence of photoreceptor layer involvement. These findings support that subclinical anterior visual pathway involvement may occur in AQP4-IgG+ NMOSD.
Rituximab is used widely for relapse prevention in neuromyelitis optica spectrum disorder (NMOSD) and myelin oligodendrocyte glycoprotein (MOG)-IgG-associated disease (MOGAD); however, data regarding the effectiveness and safety of long-term rituximab use in these conditions are limited. In this study, we sought to evaluate long-term clinical outcomes in patients with aquaporin-4 IgG-seropositive (AQP4-IgG+) NMOSD and MOGAD treated with rituximab.We performed a retrospective chart review of patients with AQP4-IgG+ NMOSD or MOGAD followed at the Johns Hopkins Neuromyelitis Optica Clinic and included patients who had received at least 1 dose of rituximab.We identified 111 patients with NMOSD and 23 patients with MOGAD who fulfilled the inclusion criteria. The median duration of rituximab treatment for the patients with NMOSD was 3.7 years (range: 0.5-13.2 years) and for the patients with MOGAD was 2.1 years (range: 0.5-7.0 years). The annualized relapse rate (ARR) decreased after rituximab initiation in both NMOSD (median ARR: pretreatment 1.1, posttreatment 0; p < 0.001) and MOGAD (median ARR: pretreatment 1.9, posttreatment 0.3; p = 0.002). Relapses on rituximab occurred in 31 patients with NMOSD (28%) and 14 patients with MOGAD (61%). The majority of NMOSD treatment failures (37/48 relapses; 77%) occurred either within the initial 6 months after starting rituximab (n = 13 relapses) or in the setting of delayed/missed rituximab doses and/or peripheral B-cell reconstitution (n = 24 relapses), whereas in MOGAD, these circumstances were present in a smaller proportion of treatment failures (19/35 relapses; 54%). The risk of relapse on rituximab was greater for patients with MOGAD compared with patients with NMOSD (hazard ratio: 2.8, 95% CI: 1.5-5.2, p = 0.001). Infections requiring hospitalization occurred in 13% and immunoglobulin G (IgG) hypogammaglobulinemia in 17% of patients. The median rituximab treatment duration before IgG hypogammaglobulinemia onset was 5.4 years (interquartile range: 3.8-7.7 years).Rituximab treatment is associated with the reduced annualized relapse rate in AQP4-IgG-seropositive NMOSD, especially in the absence of gaps in treatment and/or B-cell reconstitution. In MOGAD, although a reduction in relapses was observed after initiation of rituximab, this association appeared to be less robust than in AQP4-IgG-seropositive NMOSD. Severe infections and hypogammaglobulinemia occurred in a significant proportion of patients, highlighting the need for close monitoring of infectious complications.This study provides Class IV evidence that rituximab decreases the annualized relapse rate in AQP4-IgG-seropositive NMOSD and MOGAD.
Background: The relative contribution and interaction of risk factors for multiple sclerosis (MS) have not been evaluated. Objectives: To determine whether vitamin D status is associated with antibody levels to common viruses in pediatric-onset MS or clinically isolated syndrome (CIS) patients and controls. Methods: We assessed whether vitamin D status was associated with viral antibody levels to Epstein–Barr virus, cytomegalovirus (CMV), and herpes simplex virus (HSV)-1 or -2 in subjects who demonstrated evidence of remote infection with these viruses and whether these associations differed depending on disease status. Results: In 140 subjects, vitamin D status was weakly associated with antibody levels to CMV but not to the other viruses. However, there were some interactions between vitamin D status and disease state. Among those with vitamin D sufficiency (≥30 ng/ml), MS/CIS patients had higher antibody levels to Epstein–Barr nuclear antigen-1 than controls. Vitamin D sufficiency was associated with higher CMV antibody levels in MS/CIS subjects but lower CMV antibody levels in controls. Higher vitamin D levels appeared to be associated with higher titers to HSV-2 in MS/CIS patients but not controls. Conclusions: Vitamin D status may be differentially associated with antibody levels to common childhood viruses among seropositive subjects.
Demyelinating events in relapsing-remitting multiple sclerosis (RRMS) can involve several locations in the central nervous system. We sought to determine if initial clinical demyelinating event (IDE) location predicts subsequent clinical relapse locations in early RRMS.We identified all RRMS patients from two large MS clinics who were seen within 1 year of disease onset. Logistic regression was performed with the outcome defined as the second or third exacerbation location and the predictor defined as IDE+/-second event location.195 patients with at least two clinical exacerbations were identified. There was an increased odds of a patient's second relapse occurring in the spinal cord if the IDE was in the spinal cord (odds ratio (OR) = 3.79, 95% CI 2.06 to 7.00, p<0.001). There was more than a sixfold increase in the odds of a patient's second relapse occurring in the optic nerve if the IDE was in the optic nerve (OR = 6.18, 95% CI 2.90 to 13.18, p<0.001). These associations remained similar after adjusting for treatment and patient characteristics. If the IDE and second event were both in the same location (spinal cord, optic nerve or brainstem/cerebellum), the third event was likely to remain in that location.Patients with RRMS have relatively localised clinical relapses. It remains to be determined if genetic or biological processes are responsible for this pattern.
Abstract Background Multiple sclerosis (MS) is one of the most common non-traumatic neurologic disorders affecting young adults in the United States. Brain MRI is an important tool for monitoring disease activity and treatment efficacy in people with MS. Spinal cord (SC) imaging has been less consistently used for monitoring inflammatory disease activity, and the frequency of clinically silent breakthrough disease in the SC is still unknown. Given the particular vulnerability of the cervical spinal cord (c-SC) to inflammatory demyelination, it is important to evaluate the necessity of routine c-SC scanning or to ascertain appropriate strategies for its monitoring, considering the burden of each scan on a person with MS, including scanner discomfort and cost. Objective To determine how frequently follow-up magnetic resonance imaging (MRI) of the cervical spinal cord (c-SC) in patients with relapsing remitting multiple sclerosis (RRMS) reveals asymptomatic T2 hyperintense lesions, either in combination or in the absence of new MRI brain lesions, and to identify potential associated risk factors for developing such lesions. Methods Patients aged 18-65 years who were diagnosed with RRMS and were seen in longitudinal follow-up at the Johns Hopkins MS Center from January 1, 2014, to December 1, 2019, with an MRI brain and C spine performed during that period, were included. The results of up to four c-SC scans were considered during this study period. Asymptomatic new lesions were identified as new hyperintense T2 lesions, with or without enhancement, observed on MRI during routine follow-up surveillance. Univariate and multivariable-adjusted logistic regression (sex at birth, age, race, and current disease modifying therapy [DMT] category) were employed to identify factors associated with the development of an asymptomatic c-SC lesion for the first scan. Additionally, a mixed-effects logistic regression analysis was performed to assess factors associated with developing asymptomatic lesions across successive scans. Results A total of 869 individuals were included in the cohort, contributing a median of 3 (interquartile range: 2,4) scans per person. The proportion of incidental asymptomatic lesions identified ranged from 4.8 to 12.1% across the four scans analyzed in the study. Among those with new lesions in the c-SC, roughly half also showed concomitant new activity on brain MRI. The multivariate model was notable for Black/African Americans having higher odds of an asymptomatic new lesion (OR= 3.26, 95% CI 0.79, 5.93, p<0.0001), a result that persisted in mixed effects logistic regression models (OR = 1.73, 95% CI = 1.27, 2.35, p = 0.001). Higher-efficacy therapies were associated with higher odds of detection of a new lesion in the mixed-effects model, an association that was not present when considering just the first scan results as the outcome. Conclusion While the association of higher-efficacy therapy is presumed to be related to confounding by indication, Black/African American individuals with MS appear to be at higher risk of developing an asymptomatic c-SC lesion on MRI surveillance, which could suggest higher value of ordering asymptomatic screening imaging of the cord in this subpopulation. Ultimately, however, a very small percentage of the overall population of those with MS has a new cord lesion in the absence of symptoms, and half of those have a new lesion on screening brain MRI. These findings should motivate the creation and validation of predictive models to inform the utility cord imaging at a given timepoint for a given individual with MS, which could enhance healthcare quality and reduce costs.
Antibodies to the aquaporin-4 (AQP4) water channel in neuromyelitis optica spectrum disorder (NMOSD) are reported to trigger the complement cascade, which is implicated in astrocyte damage and subsequent neuronal injury. The PREVENT study demonstrated that the terminal complement inhibitor eculizumab reduces adjudicated relapse risk in patients with anti-AQP4 immunoglobulin G-positive (AQP4+) NMOSD. The objective of this analysis was to evaluate the efficacy of eculizumab in reducing relapse risk and its safety in AQP4+ NMOSD across clinically relevant subgroups in PREVENT.In the randomized, double-blind, time-to-event, phase 3 PREVENT trial, 143 adults received eculizumab (maintenance dose, 1200 mg/2 weeks) or placebo (2:1), with stable-dose concomitant immunosuppressive therapy (IST) permitted (except rituximab and mitoxantrone). Post hoc analyses of relapses and adverse events were performed for prespecified and post hoc subgroups based on concomitant IST and prior rituximab use, demographic and disease characteristics, and autoimmune comorbidity.The significant reduction in relapse risk observed for eculizumab versus placebo in the overall PREVENT population was consistently maintained across subgroups based on concomitant IST and previous rituximab use, age, sex, region, race, time since clinical onset of NMOSD, historical annualized relapse rate, baseline Expanded Disability Status Scale score, and history of another autoimmune disorder. The serious infection rate was lower with eculizumab than placebo regardless of rituximab use in the previous year, concomitant IST use, or history of another autoimmune disorder.Across a wide range of clinically relevant AQP4+ NMOSD patient subgroups in PREVENT, eculizumab therapy was consistently effective versus placebo in reducing relapse risk, with no apparent increase in serious infection rate.NCT01892345 (ClinicalTrials.gov).
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)