Background:
Optic neuritis (ON) is a cardinal manifestation of multiple sclerosis (MS), aquaporin-4 (AQP4)-IgG-, and myelin oligodendrocyte glycoprotein (MOG)-IgG-associated disease. However, the ...prevalence of AQP4-IgG seropositivity and MOG-IgG seropositivity in isolated ON is unclear, and studies comparing visual outcomes and optical coherence tomography (OCT)-derived structural retinal measures between MS-ON, AQP4-ON, and MOG-ON eyes are limited by small sample sizes.
Objectives:
(1) To assess the prevalence of AQP4-IgG and MOG-IgG seropositivity among patients presenting with isolated ON; (2) to compare visual outcomes and OCT measures between AQP4-ON, MOG-ON, and MS-ON eyes.
Methods:
In this systematic review and meta-analysis, a total of 65 eligible studies were identified by PubMed search. Statistical analyses were performed with random effects models.
Results:
In adults with isolated ON, AQP4-IgG seroprevalence was 4% in non-Asian and 27% in Asian populations, whereas MOG-IgG seroprevalence was 8 and 20%, respectively. In children, AQP4-IgG seroprevalence was 0.4% in non-Asian and 15% in Asian populations, whereas MOG-IgG seroprevalence was 47 and 31%, respectively. AQP4-ON eyes had lower peri-papillary retinal nerve fiber layer (pRNFL; −11.7 μm, 95% CI: −15.2 to −8.3 μm) and macular ganglion cell + inner plexiform layer (GCIPL; −9.0 μm, 95% CI: −12.5 to −5.4 μm) thicknesses compared with MS-ON eyes. Similarly, pRNFL (−11.2 μm, 95% CI: −21.5 to −0.9 μm) and GCIPL (−6.1 μm, 95% CI: −10.8 to −1.3 μm) thicknesses were lower in MOG-ON compared to MS-ON eyes, but did not differ between AQP4-ON and MOG-ON eyes (pRNFL: −1.9 μm, 95% CI: −9.1 to 5.4 μm; GCIPL: −2.6 μm, 95% CI: −8.9 to 3.8 μm). Visual outcomes were worse in AQP4-ON compared to both MOG-ON (mean logMAR difference: 0.60, 95% CI: 0.39 to 0.81) and MS-ON eyes (mean logMAR difference: 0.68, 95% CI: 0.40 to 0.96) but were similar in MOG-ON and MS-ON eyes (mean logMAR difference: 0.04, 95% CI: −0.05 to 0.14).
Conclusions:
AQP4-IgG- and MOG-IgG-associated disease are important diagnostic considerations in adults presenting with isolated ON, especially in Asian populations. Furthermore, MOG-IgG seroprevalence is especially high in pediatric isolated ON, in both non-Asian and Asian populations. Despite a similar severity of GCIPL and pRNFL thinning in AQP4-ON and MOG-ON, AQP4-ON is associated with markedly worse visual outcomes.
Myelin oligodendrocyte glycoprotein antibody disease (MOGAD) and aquaporin-4 IgG seropositive neuromyelitis optica spectrum disorder (AQP4-IgG+ NMOSD) are generally considered to be relapsing ...disorders, without clinical progression or subclinical disease activity outside of clinical relapses, in contrast to multiple sclerosis (MS). With advances in the diagnosis and treatment of these conditions, prolonged periods of remission without relapses can be achieved, and the question of whether progressive disease courses can occur has re-emerged. In this review, we focus on studies exploring evidence for and against relapse-independent clinical progression and/or subclinical disease activity in patients with MOGAD and AQP4-IgG+ NMOSD.
•We review evidence of relapse-independent disease activity in MOGAD and NMOSD.•Existing studies are limited by small sample sizes and heterogeneous populations/outcomes.•The most compelling evidence is for subclinical visual pathway involvement in NMOSD.•The clinical relevance of these findings remains to be determined.•Larger, prospective, well-designed longitudinal studies in MOGAD and NMOSD are needed.
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;
< 0.001) and MOGAD (median ARR: pretreatment 1.9, posttreatment 0.3;
= 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,
= 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.
To evaluate whether a retinal spectral-domain optical coherence tomography (SD-OCT) assessment at baseline is associated with long-term disability worsening in people with multiple sclerosis (PwMS), ...we performed SD-OCT and Expanded Disability Status Scale (EDSS) assessments among 132 PwMS at baseline and at a median of 10 years later.
In this prospective, longitudinal study, participants underwent SD-OCT, EDSS, and visual acuity (VA) assessments at baseline and at follow-up. Statistical analyses were performed using generalized linear regression models, adjusted for age, sex, race, multiple sclerosis (MS) subtype, and baseline disability. We defined clinically meaningful EDSS worsening as an increase of ≥2.0 if baseline EDSS score was <6.0 or an increase of ≥1.0 if baseline EDSS score was ≥6.0.
A total of 132 PwMS (mean age 43 years; 106 patients with relapsing-remitting MS) were included in analyses. Median duration of follow-up was 10.4 years. In multivariable models excluding eyes with prior optic neuritis, relative to patients with an average baseline ganglion cell + inner plexiform layer (GCIPL) thickness ≥70 µm (the mean GCIPL thickness of all eyes at baseline), an average baseline GCIPL thickness <70 µm was associated with a 4-fold increased odds of meaningful EDSS worsening (adjusted odds ratio OR 3.97, 95% confidence interval CI 1.24-12.70;
= 0.02) and an almost 3-fold increased odds of low-contrast VA worsening (adjusted OR 2.93, 95% CI 1.40-6.13;
= 0.04).
Lower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS. Accordingly, SD-OCT at a single time point may help guide therapeutic decision-making among individual PwMS.
This study provides Class I evidence that lower baseline GCIPL thickness on SD-OCT is independently associated with long-term disability worsening in MS.
Disease course in multiple sclerosis is notably heterogeneous, and few prognostic indicators have been consistently associated with multiple sclerosis severity. In the general population, ...socioeconomic disparity is associated with multimorbidity and may contribute to worse disease outcomes in multiple sclerosis. Herein, we assessed whether indicators of socioeconomic status are associated with disease progression in patients with multiple sclerosis using highly sensitive imaging tools such as optical coherence tomography, and determined whether differential multiple sclerosis management or comorbidity mediate any observed socioeconomic status-associated effects. We included 789 participants with longitudinal optical coherence tomography and low contrast letter acuity (at 1.25 and 2.5%) in whom neighbourhood- (derived via nine-digit postal codes) and participant-level socioeconomic status indicators were available ≤10 years of multiple sclerosis symptom onset. Sensitivity analyses included participants with socioeconomic status indicators available ≤3years of symptom onset (n = 552). Neighbourhood-level indicators included state and national area deprivation indices, median household income and the Agency for Healthcare Research and Quality (AHRQ) Socioeconomic Status Index. Participant-level indicators included education level. Biannual optical coherence tomography scans were segmented to quantify thickness of the composite macular ganglion cell+inner plexiform (GCIPL) layer. We assessed the association between socioeconomic status indicators and GCIPL atrophy or low contrast letter acuity loss using mixed models adjusting for demographic (including race and ethnicity) and disease-related characteristics. We also assessed socioeconomic status indicators in relation to multiple sclerosis therapy changes and comorbidity risk using survival analysis. More disadvantaged neighbourhood-level and patient-level socioeconomic status indicators were associated with faster retinal atrophy. Differences in rate of GCIPL atrophy for individuals in the top quartile (most disadvantaged) relative to the bottom quartile (least) for state area deprivation indices were -0.12 µm/year faster 95% confidence interval (CI): -0.19, -0.04; P = 0.003, for national area deprivation indices were -0.08 µm/year faster (95% CI: -0.15, -0.005; P = 0.02), for household income were -0.11 µm/year faster (95% CI: -0.19, -0.03; P = 0.008), for AHRQ Socioeconomic Status Index were -0.12 µm/year faster (95% CI: -0.19, -0.04) and for education level were -0.17 µm/year faster (95% CI: -0.26, -0.08; P = 0.0002). Similar associations were observed for socioeconomic status indicators and low contrast letter acuity loss. Lower socioeconomic status was associated with higher risk of incident comorbidity during follow-up. Low socioeconomic status individuals had faster rates of therapy escalation, suggesting the association between socioeconomic status and GCIPL atrophy may not be explained by differential contemporaneous multiple sclerosis therapy management. In conclusion, socioeconomic disparity is associated with faster retinal neurodegeneration in multiple sclerosis. As low socioeconomic status was associated with a higher risk of incident comorbidities that may adversely affect multiple sclerosis outcomes, comorbidity prevention may mitigate some of the unfavourable socioeconomic status-associated consequences.
Background:
Sphingolipids are myelin components and inflammatory signaling intermediates. Sphingolipid metabolism may be altered in people with multiple sclerosis (PwMS), but existing studies are ...limited by small sample sizes.
Objectives:
To compare the levels of serum ceramides between PwMS and healthy controls (HCs) and to determine whether ceramide levels correlate with disability status, as well as optical coherence tomography (OCT)-derived rates of retinal layer atrophy.
Methods:
We performed targeted lipidomics analyses for 45 ceramides in PwMS (n = 251) and HCs (n = 68). For a subset of PwMS, baseline and 5-year Expanded Disability Status Scale (EDSS) assessments (n = 185), or baseline and serial spectral-domain OCT (n = 180) were assessed.
Results:
Several ceramides, including hexosylceramides, lactosylceramides, and dihydroceramides, were altered in PwMS compared with HCs. Higher levels of Cer16:0 were associated with higher odds of EDSS worsening at 5 years in univariable (odds ratio (OR) = 3.84, 95% confidence interval (CI) = 1.41–10.43) and multivariable analyses accounting for age, sex, and race (OR = 2.97, 95% CI = 1.03–8.59). Each 1 ng/mL higher concentration of Hex-Cer22:0 and DH-HexCer22:0 was associated with accelerated rates (μm/year) of ganglion cell + inner plexiform layer (–0.138 ± 0.053, p = 0.01; –0.158 ± 0.053, p = 0.003, respectively) and peripapillary retinal nerve fiber layer thinning (–0.305 ± 0.107, p = 0.004; –0.358 ± 0.106, p = 0.001, respectively).
Conclusion:
Ceramide levels are altered in PwMS and may be associated with retinal neurodegeneration and physical disability.
Serum neurofilament light chain (sNfL) and optical coherence tomography (OCT)-derived retinal measures (including peripapillary retinal nerve fiber layer pRNFL and macular ganglion cell layer/inner ...plexiform layer GCIPL thickness) have been proposed as biomarkers of neurodegeneration in multiple sclerosis (MS). However, studies evaluating the associations between sNfL and OCT-derived retinal measures in MS are limited.
In this retrospective analysis of a longitudinal, observational, single-center cohort study, sNfL levels were measured in people with MS and healthy controls (HCs) using single molecule array. Participants with MS were followed with serial OCT for a median follow-up of 4.5 years. Eyes with optic neuritis (ON) within 6 months of baseline OCT or ON during follow-up were excluded. Age-normative cutoffs of sNfL were derived using the HC data, and MS participants with sNfL greater than the 97.5th percentile for age were classified as having elevated sNfL (sNfL-E). Analyses were performed with mixed-effects linear regression models and adjusted for age, sex, race, and history of ON.
A total of 130 HCs (age: 42.4 ± 14.2 years; 62% female) and 403 people with MS (age: 43.1 ± 12.0 years; 78% female) were included. Elevated sNfL levels were present at baseline in 80 participants with MS (19.9%). At baseline, sNfL-E participants had modestly lower pRNFL (-3.03 ± 1.50 μm;
= 0.044) and GCIPL thickness (-2.74 ± 1.02 μm;
= 0.007). As compared with those with sNfL within the reference range, eyes from NfL-E participants exhibited faster longitudinal thinning of the pRNFL (45% faster; -0.74 vs -0.51 μm/y;
= 0.015) and GCIPL (25% faster; -0.35 vs -0.28 μm/y;
= 0.021). Significant differences in rates of pRNFL and GCIPL thinning between sNfL groups were found only in those with relapsing-remitting MS but not progressive MS.
Elevated baseline sNfL is associated with accelerated rates of retinal neuroaxonal loss in relapsing-remitting MS, independent of overt ON, but may be less reflective of retinal neurodegeneration in progressive MS.
Ganglion cell + inner plexiform layer (GCIPL) thinning, measured by optical coherence tomography (OCT), reflects global neurodegeneration in multiple sclerosis (MS). Atrophy of the inner (INL) and ...outer nuclear layer (ONL) may also be prominent in progressive MS (PMS). The phase 2, SPRINT-MS trial found reduced brain atrophy with ibudilast therapy, in PMS. In this post-hoc analysis of the SPRINT-MS trial, we investigate (1) retinal atrophy (2) differences in response by subtype, and (3) associations between OCT and MRI measures of neurodegeneration.
In the multi-center, double blinded SPRINT-MS trial, participants with SPMS or PPMS were randomized to ibudilast or placebo. OCT and MRI data were collected every 24 weeks for 96 weeks. Extensive OCT quality control and algorithmic segmentation produced consistent results across Cirrus HD-OCT and Spectralis devices. Primary endpoints were GCIPL, INL, and ONL atrophy, assessed by linear mixed-effects regression. Secondary endpoints were associations of OCT measures, brain parenchymal fraction, and cortical thickness, assessed by partial Pearson correlations.
134 PPMS and 121 SPMS participants were included. GCIPL atrophy was 79% slower in the ibudilast (-0.07±0.23 µm/year) vs. placebo group (-0.32±0.20 µm/year, p=0.003). This effect predominated in the PPMS cohort (Ibudilast: -0.08±0.29 µm/year vs placebo: -0.60±0.29 µm/year, a decrease of 87%, p<0.001), and was not detected in the SPMS cohort (Ibudilast: -0.21±0.28 µm/year vs placebo: -0.14±0.27 µm/year, p=0.55). GCIPL, INL, and ONL atrophy rates correlated with whole brain atrophy rates across the cohort (r=0.27, r=0.26, and r=0.20 respectively; p<0.001). Power calculations from these data show future trials of similar size and design have ≥80% power to detect GCIPL atrophy effect sizes of approximately 40%.
Ibudilast treatment decreased GCIPL atrophy in PMS, driven by the PPMS cohort, with no effect seen in SPMS. Modulated atrophy of retinal layers may be detectable in sample sizes smaller than the SPRINT-MS trial and correlate with whole brain atrophy in PMS, further highlighting their utility as outcomes in PMS.
This study provides Class II evidence that ibudilast reduces composite ganglion cell and inner plexiform layer atrophy, without reduction of inner or outer nuclear layer atrophy, in patients with progressive MS but not those with secondary progressive MS.
Background:
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).
Objective:
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).
Methods:
In this single-center cross-sectional study, 83 AQP4-nonON and 154 HC eyes were studied with spectral-domain optical coherence tomography (OCT).
Results:
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.
Conclusions:
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.
To investigate the effects of rituximab on retinal atrophy in patients with relapsing-remitting multiple sclerosis (RRMS), we performed serial optical coherence tomography (OCT) scans among a cohort ...of patients with RRMS on rituximab and compared rates of ganglion cell + inner plexiform layer (GCIPL) atrophy to those observed among age- and sex-matched glatiramer acetate (GA)-and natalizumab-treated patients with RRMS and healthy controls (HCs).
In this observational study, patients with RRMS treated with a single disease-modifying therapy and HCs were followed with serial OCT for a median duration of 2.8 years. Participants with uncontrolled hypertension, diabetes mellitus, or glaucoma, and eyes with optic neuritis ≤6 months prior to baseline OCT, or during follow-up, were excluded. Statistical analyses were performed using linear mixed-effects regression.
During the overall follow-up period, rates of GCIPL atrophy were -0.28 ± 0.11 µm/y among rituximab-treated patients with RRMS (n = 35). This was similar to GA-treated (n = 49; -0.33 ± 0.05 µm/y;
= 0.69) and natalizumab-treated patients (n = 88; -0.17 ± 0.10 µm/y;
= 0.13) and faster than HCs (n = 78; -0.15 ± 0.03 µm/y;
= 0.006). Rituximab-treated patients exhibited 0.55 ± 0.23 µm/y faster rates of GCIPL atrophy during the first 12 months of treatment, relative to afterwards (n = 25;
= 0.02), during which period GCIPL atrophy rates were -0.14 ± 0.13 µm/y.
Retinal atrophy in RRMS is modulated by rituximab. Greater attenuation of retinal atrophy may occur after 12 months of rituximab treatment, following which time GCIPL atrophy rates are similar to those observed among natalizumab-treated patients with RRMS and HCs. Our findings raise the possibility that the neuroprotective therapeutic response with rituximab in RRMS may take up to 12 months, which should be confirmed by larger studies.
This study provides Class IV evidence on the difference in rate of change of the GCIPL thickness in patients with RRMS comparing rituximab to other disease-modifying therapies.
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