Association between demographics, socioeconomics, and disease-related factors and the perception of stigma in people with MS.

BACKGROUND: Stigma is prevalent among individuals with chronic diseases, such as multiple sclerosis (MS) and those with comorbid mental health disorders, but its associated factors are poorly understood. OBJECTIVE: To investigate the prevalence and correlates of stigma in people living with MS. METHODS: We analyzed data from the MS Partners Advancing Technology and Health Solutions (MS PATHS) network, which collected patient information and outcomes during routine clinic visits. We used a multinomial logistic regression model to examine the cross-sectional association between stigma and demographic, socioeconomics, and MS-related factors. RESULTS: We included 11,634 participants. The mean Neuro-QoL stigma T-score was 47.2 ± 8.6, and 17.7% of participants were classified as having moderate to severe stigma using established cutoffs. Multinomial logistic regression models suggest that higher disability levels, progressive form of the disease, shorter duration of the disease, and unemployment were associated with higher stigma while being male, married, undergoing treatment with high-efficacy disease-modifying therapies (DMTs), and being from European MS centers were associated with lower stigma perception. Disability levels, measured by Patient-Determined Disease Steps (PDDS), had the strongest independent association with stigma. CONCLUSION: Stigma remains a relevant issue for people living with MS. Factors, such as physical and cognitive disability, DMT, and employment status may influence the severity of perceived stigma.

Structural MRI measures are associated with fatigue severity and persistence in a large, real-world cohort of people with multiple sclerosis.

BACKGROUND: Results of research on radiological hallmarks of multiple sclerosis (MS) fatigue have been conflicting. OBJECTIVE: To investigate the associations of lesion and brain compartment volumes with fatigue severity and persistence in people with multiple sclerosis (PwMS). METHODS: The Multiple Sclerosis Partners Advancing Technology and Health Solutions (MS PATHS) network collects standardized data during routine care of PwMS from 10 healthcare institutions. Magnetic resonance imaging (MRI) predictors included baseline brain parenchymal (BPF) and gray matter fractions (GMF) and T2 lesion volume (T2LV). The Quality of Life in Neurological Disorders (Neuro-QOL) fatigue subscore was analyzed linearly and categorically using T-score cutpoints, with a period of elevated symptoms defined as T-score ⩾ mean + 0.5 SD over follow-up. RESULTS: At baseline, of 4012 participants (average age: 45.6 ± 11.8 years; 73% female; 31% progressive MS), 2058 (51%) had no fatigue, 629 (16%) had mild fatigue, and 1325 (33%) had moderate-to-severe fatigue. One SD greater baseline BPF and GMF were associated with 0.83 (p < 0.001) and 0.38 (p = 0.02) lower values in the baseline Neuro-QOL fatigue T-score. A 1 SD lower log of total T2LV was associated with a 0.49 (p < 0.001) lower baseline fatigue T-score. Higher BPF and lower T2LV at baseline were associated with lower odds of subsequent periods of elevated fatigue. CONCLUSION: Baseline lesion burden and lower generalized whole-brain volumes were associated with MS fatigue in cross-sectional and longitudinal analyses in a large, real-world cohort of PwMS.

Several serum lipid metabolites are associated with relapse risk in pediatric-onset multiple sclerosis.

BACKGROUND: The circulating metabolome is altered in multiple sclerosis (MS), but its prognostic capabilities have not been extensively explored. Lipid metabolites might be of particular interest due to their multiple roles in the brain, as they can serve as structural components, energy sources, and bioactive molecules. Gaining a deeper understanding of the disease may be possible by examining the lipid metabolism in the periphery, which serves as the primary source of lipids for the brain. OBJECTIVE: To determine if altered serum lipid metabolites are associated with the risk of relapse and disability in children with MS. METHODS: We collected serum samples from 61 participants with pediatric-onset MS within 4 years of disease onset. Prospective longitudinal relapse data and cross-sectional disability measures (Expanded Disability Status Scale [EDSS]) were collected. Serum metabolomics was performed using untargeted liquid chromatography and mass spectrometry. Individual lipid metabolites were clustered into pre-defined pathways. The associations between clusters of metabolites and relapse rate and EDSS score were estimated utilizing negative binomial and linear regression models, respectively. RESULTS: We found that serum acylcarnitines (relapse rate: normalized enrichment score [NES] = 2.1, q = 1.03E-04; EDSS: NES = 1.7, q = 0.02) and poly-unsaturated fatty acids (relapse rate: NES = 1.6, q = 0.047; EDSS: NES = 1.9, q = 0.005) were associated with higher relapse rates and EDSS, while serum phosphatidylethanolamines (relapse rate: NES = -2.3, q = 0.002; EDSS: NES = -2.1, q = 0.004), plasmalogens (relapse rate: NES = -2.5, q = 5.81E-04; EDSS: NES = -2.1, q = 0.004), and primary bile acid metabolites (relapse rate: NES = -2.0, q = 0.02; EDSS: NES = -1.9, q = 0.02) were associated with lower relapse rates and lower EDSS. CONCLUSION: This study supports the role of some lipid metabolites in pediatric MS relapses and disability.

Multiple Sclerosis Is Rare in Epstein-Barr Virus-Seronegative Children with Central Nervous System Inflammatory Demyelination.

Although Epstein-Barr virus (EBV) is hypothesized to be a prerequisite for multiple sclerosis (MS), up to 15% of children with a diagnosis of MS were reported to be EBV-seronegative. When re-evaluating 25 EBV-seronegative children out of 189 pediatric patients with a diagnosis of clinically isolated syndrome/MS, we found anti-myelin oligodendrocyte glycoprotein (MOG) antibody in 11 of 25 (44%) EBV-seronegative but only 9 of 164 (5.5%, p < 0.001) EBV-seropositive patients. After critical review, MS remained a plausible diagnosis in only 4 of 14 EBV-seronegative/MOG antibody-negative patients. In children with an MS-like presentation, EBV seronegativity should alert clinicians to consider diagnoses other than MS, especially MOG-antibody disease. ANN NEUROL 2021;89:1234-1239.

Pilot randomized active-placebo-controlled trial of low-dose ketamine for the treatment of multiple sclerosis-related fatigue.

BACKGROUND: Fatigue is the most common symptom of MS and has no effective pharmacotherapy. OBJECTIVE: To determine the tolerability, safety, and efficacy of low-dose ketamine infusion for MS-related fatigue. METHODS: In this double-blind, randomized, active-placebo-controlled trial, 18 subjects with multiple sclerosis (MS) and reported fatigue received a single intravenous infusion of ketamine (0.5 mg/kg) or midazolam (0.05 mg/kg). The primary outcome was change in Daily Fatigue Severity (DFS) for 7 days following the infusion. Secondary outcomes included Fatigue Severity Scale (FSS) and Modified Fatigue Impact Scale (MFIS) measured up to day 28 post-infusion. We analyzed changes in all outcomes using mixed-effect models. RESULTS: In total, 18 participants were enrolled; 67% participants received ketamine. Side effects of ketamine were transient. No change in the DFS was observed after 7 days (-0.10 point; 95% confidence interval (CI): -0.32, 0.12; p = 0.40). We observed a trend in reduced FSS scores at 1 week (-5.2 points; 95% CI: -10.4, 0.14; p = 0.06) and a clinically and statistically significant reduction in MFIS score at day 28 (-13.5 point; 95% CI: -25.0, -1.98; p = 0.04). CONCLUSIONS: Ketamine infusions were safe and well-tolerated. While no change in DFS after 7 days was observed, secondary analyses suggest a benefit of ketamine infusion for reduction of longer term fatigue severity in people with MS.

Dietary salt intake and time to relapse in paediatric multiple sclerosis.

BACKGROUND: Salt intake was reported to be associated with increased clinical and MRI activity in adult patients with relapsing-remitting multiple sclerosis (MS). OBJECTIVE: To determine if salt intake is associated with time to relapse in patients with paediatric-onset MS. METHODS: Paediatric-onset MS and patients with clinically isolated syndrome (CIS) within 4 years of disease onset were recruited from 15 paediatric MS centres in the USA as part of a case-control study. Patients with available prospective relapse data subsequent to enrolment were included in this project. Dietary sodium intake was assessed by self-report questionnaire using the validated Block Kids Food Screener. Cox proportional-hazards regression models were employed to determine the association of sodium density, excess sodium intake and sodium density tertiles with time to relapse following study enrolment, adjusting for several confounders. RESULTS: 174 relapsing-remitting MS/CIS patients were included in this analysis (mean age of 15.0 years, and 64.9% females). Median duration of follow-up was 1.8 years. In an unadjusted analysis, density of daily sodium intake was not associated with time to relapse, and patients with excess sodium intake had no decrease in time to relapse as compared with patients with non-excess sodium intake. The multivariable analysis demonstrated that patients in the medium and high tertile of sodium density had a HR of 0.69 (95% CI 0.37 to 1.30, p=0.25) and 1.37 (95% CI 0.74 to 2.51, p=0.32) compared with patients in the lowest tertile, respectively. CONCLUSIONS: Higher salt intake was not associated with decreased time to relapse in patients with paediatric-onset MS.

Ocrelizumab alters the circulating metabolome in people with relapsing-remitting multiple sclerosis.

BACKGROUND: Circulating metabolite levels are altered in multiple sclerosis (MS) and are associated with MS severity. However, how metabolic profiles shift following highly efficacious therapies, like ocrelizumab remains unclear. OBJECTIVE: Circulating metabolite levels are altered in multiple sclerosis (MS) and are associated with MS severity. However, how metabolic profiles shift following highly efficacious therapies, like ocrelizumab remains unclear. To assess changes in the circulating metabolome produced by ocrelizumab treatment in people with relapsing-remitting MS (RRMS). METHODS: Thirty-one individuals with RRMS eligible for beginning treatment with ocrelizumab were recruited and followed with demographic, clinical, quality-of-life, and global metabolomics data collected at each visit. Modules of highly correlated metabolites were identified using the weighted correlation network analysis approach. Changes in each module's eigenmetabolite values and individual metabolites during the study were evaluated using linear mixed-effects models. RESULTS: Patients with a mean age of 40.8 (SD = 10.30) years, and median disease duration of 4.0 (IQR = 8.5) years, were monitored for a median of 3.36 (IQR = 1.43) years. Two out of twelve identified sets of metabolites were altered significantly. The first module mainly contained androgenic and pregnenolone steroids (p-value <0.001, coefficient: -0.10). The second module primarily consisted of several lysophospholipids, arachidonic acid, some endocannabinoids, and monohydroxy fatty acid metabolites (p-value = 0.016, coefficient: -0.12), which its reduction was significantly associated with improvement based on overall disability response score (OR 3.09e-01, 95% CI: 6.83e-02, 9.09e-01, p-value = 3.15E-02). INTERPRETATION: In this longitudinal observational study, using a global untargeted metabolomics approach, we showed significant alteration in circulating metabolome in RRMS patients undergoing ocrelizumab treatment. In particular, we observed a significant reduction in metabolites involved in the lysophospholipid pathway, which was associated with patients' improvement.

Synaptic injury in the inner plexiform layer of the retina is associated with progression in multiple sclerosis.

While neurodegeneration underlies the pathological basis for permanent disability in multiple sclerosis (MS), predictive biomarkers for progression are lacking. Using an animal model of chronic MS, we find that synaptic injury precedes neuronal loss and identify thinning of the inner plexiform layer (IPL) as an early feature of inflammatory demyelination-prior to symptom onset. As neuronal domains are anatomically segregated in the retina and can be monitored longitudinally, we hypothesize that thinning of the IPL could represent a biomarker for progression in MS. Leveraging our dataset with over 800 participants enrolled for more than 12 years, we find that IPL atrophy directly precedes progression and propose that synaptic loss is predictive of functional decline. Using a blood proteome-wide analysis, we demonstrate a strong correlation between demyelination, glial activation, and synapse loss independent of neuroaxonal injury. In summary, monitoring synaptic injury is a biologically relevant approach that reflects a potential driver of progression.

Kit (W-sh) mice develop earlier and more severe experimental autoimmune encephalomyelitis due to absence of immune suppression.

Mast cells (MCs) have been thought to play a pathogenic role in the development of autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. However, an immunoregulatory function of these cells has recently been suggested. We investigated the role of MCs in EAE using the W(-sh) mouse strain, which is MC deficient. W(-sh) mice developed earlier and more severe clinical and pathological disease with extensive demyelination and inflammation in the CNS. The inflammatory cells were mainly composed of CD4(+) T cells, monocyte/macrophages, neutrophils, and dendritic cells. Compared with wild-type mice, MC-deficient mice exhibited an increased level of MCP-1/CCR2 and CD44 expression on CD4(+) T cells in addition to decreased production of regulatory T cells, IL-4, IL-5, IL-27, and IL-10. We also found that levels of IL-17, IFN-γ, and GM-CSF were significantly increased in peripheral lymphocytes from immunized W(-sh) mice compared with those in peripheral lymphocytes from wild-type mice. Reconstitution of W(-sh) mice downregulated susceptibility to EAE, which correlated with MC recruitment and regulatory T cell activation in the CNS. These findings indicate that responsiveness is not required in the pathogenesis of inflammatory demyelination in the CNS and that, in the absence of MCs, increased MCP-1, CCR2, IL-17, IFN-γ, CD44, and other inflammatory molecules may be responsible for increased severity of EAE.

Low-dose ketamine infusion for the treatment of multiple sclerosis fatigue (INKLING-MS): Study protocol for a randomized, double-blind, active placebo-controlled phase II trial.

BACKGROUND: Fatigue is one of the most common symptoms of people with Multiple Sclerosis (MS). However, currently-used medications for the treatment of fatigue probably do not work better than a placebo. In a pilot trial, we showed that one infusion of low-dose ketamine significantly improved fatigue severity measured four weeks after the infusion. METHODS: The proposed study is a single-center, phase II, randomized, double-blind, parallel-group, active-placebo-controlled trial of intravenous low-dose ketamine in patients with MS fatigue. Participants will be randomized 1:1:1 into three groups: receiving either one or two infusions of ketamine (0.5 mg/kg over 40 min) or zero to one infusion of the active placebo (midazolam, 0.05 mg/kg over 40 min). Eligibility criteria include adult patients diagnosed with MS based on the latest criteria, complaining of fatigue as one of the main symptoms, and having a screening MFIS score higher than a pre-specified threshold. RESULTS: One hundred and ten participants will be randomized over 30 months at Johns Hopkins MS Center. Complete enrollment is expected by mid-2025. The study's primary outcome will be the MFIS score at the end of week 4, comparing two-thirds of the participants who received ketamine with one-third who received midazolam. The secondary and exploratory outcomes (measured four weeks after the second infusion) will show how long the effects of a single infusion last and if two infusions of ketamine are better than one in improving MS fatigue. CONCLUSION: This study can show whether intervening in the glutamatergic pathways would improves MS fatigue.

Serum Sickness/Serum Sickness-like Reactions Following Ocrelizumab Infusion in 2 Patients With Multiple Sclerosis.

Serum sickness (SS) is a rare hypersensitivity reaction that can occur with monoclonal antibodies, and only 1 case of SS has been reported with ocrelizumab. We describe 2 patients with multiple sclerosis (MS) who developed SS/SS-like reactions (SSLRs) following ocrelizumab infusions. A man, aged 45 years, and a woman, aged 59 years, both with primary progressive MS, developed generalized weakness and arthralgias following their ocrelizumab infusions. Brain and spinal cord MRIs revealed no new or enhancing demyelinating lesions in both cases. They both had elevated inflammatory markers and negative infectious workups. They were subsequently treated for presumed SS with a steroid taper (and with potent anti-inflammatories in the second case), and symptoms improved dramatically after a few days. These cases suggest that SS/SSLRs should be suspected in a patient with new-onset arthralgia following ocrelizumab infusion who has an otherwise negative workup and rapid response to steroids.

IL-9 is important for T-cell activation and differentiation in autoimmune inflammation of the central nervous system.

Experimental autoimmune encephalomyelitis (EAE) is generally believed to be an autoimmune disease of the central nervous system (CNS) caused by myelin-specific Th1 and/or Th17 effector cells. The underlying cellular and molecular mechanisms, however, are not fully understood. Using mice deficient in IL-9 (IL-9(-/-) ), we showed that IL-9 plays a critical role in EAE. Specifically, IL-9(-/-) mice developed significantly less severe EAE than their WT counterparts following both immunization with myelin proteolipid protein (PLP)(180-199) peptide in the presence of Complete Freund's Adjuvant (CFA), and adoptive transfer of PLP(180-199) peptide-specific effector T cells from WT littermates. EAE-resistant IL-9(-/-) mice exhibited considerably fewer infiltrating immune cells in the CNS, with lower levels of IL-17 and IFN-γ expression, than their WT littermates. Further studies revealed that null mutation of the IL-9 gene resulted in significantly lower levels of PLP(180-199) peptide-specific IL-17 and IFN-γ production. Moreover, IL-9(-/-) memory/activated T cells exhibited decreased C-C chemokine receptors (CCR)2, CCR5, and CCR6 expression. Interestingly, IL-10 was significantly increased in IL-9(-/-) mice compared with WT littermates. Importantly, we found that IL-9-mediated Th17-cell differentiation triggers complex STAT signaling pathways.

Neutralization of IL-9 ameliorates experimental autoimmune encephalomyelitis by decreasing the effector T cell population.

Multiple sclerosis is a CD4(+) T cell-mediated autoimmune disease affecting the CNS. Multiple sclerosis and its animal model, experimental autoimmune encephalomyelitis (EAE), have been thought to be Th1-mediated diseases. However, recent studies provide strong evidence that the major pathogenic T cell subsets in EAE are Th17 cells. IL-9, a hematopoietic growth factor, is considered to be a mediator of Th17 cells, but the precise mechanisms of its action are largely unknown. The present study was designed to investigate the role of IL-9 in autoimmune demyelination. IL-9 blockade with anti-IL-9 mAb inhibited the development of EAE, reduced the serum levels of IL-17, the CNS mRNA expression of IL-17, IL-6, IFN-γ, and TNF-α, and the myelin oligodendrocyte glycoprotein (MOG)-induced IL-17, IFN-γ secretion of lymphocytes. Furthermore, anti-IL-9 mAb in culture suppressed IL-17 production of MOG-reactive T cells and their potency in adoptive transfer EAE. These findings indicate that the protective effect of IL-9 blockade in EAE was likely mediated via inhibition of the development of MOG peptide-specific T cells, which in turn led to reduced infiltration of T cells into the CNS. Thus, anti-IL-9 mAb treatment may provide an effective therapeutic strategy against autoimmune diseases.

The Role of Remote Monitoring in Evaluating Fatigue in Multiple Sclerosis: A Review.

Fatigue is one of the most common multiple sclerosis (MS) symptoms. Despite this, monitoring and measuring fatigue (subjective lack of energy)- and fatigability (objectively measurable and quantifiable performance decline)- in people with MS have remained challenging. Traditionally, administration of self-report questionnaires during in-person visits has been used to measure fatigue. However, remote measurement and monitoring of fatigue and fatigability have become feasible in the past decade. Traditional questionnaires can be administered through the web in any setting. The ubiquitous availability of smartphones allows for momentary and frequent measurement of MS fatigue in the ecological home-setting. This approach reduces the recall bias inherent in many traditional questionnaires and demonstrates the fluctuation of fatigue that cannot be captured by standard measures. Wearable devices can assess patients' fatigability and activity levels, often influenced by the severity of subjective fatigue. Remote monitoring of fatigue, fatigability, and activity in real-world situations can facilitate quantifying symptom-severity in clinical and research settings. Combining remote measures of fatigue as well as objective fatigability in a single construct, composite score, may provide a more comprehensive outcome. The more granular data obtained through remote monitoring techniques may also help with the development of interventions aimed at improving fatigue and lowering the burden of this disabling symptom.

N-Acetyl Cysteine as a Neuroprotective Agent in Progressive Multiple Sclerosis (NACPMS) trial: Study protocol for a randomized, double-blind, placebo-controlled add-on phase 2 trial.

INTRODUCTION: Patients with progressive multiple sclerosis (PMS) experience relentless disability worsening. Current approved therapies have very modest effects on disability progression and purely focus on immunomodulation. While some inflammatory processes exist in non-active PMS, other biological processes such as neuronal injury from oxidative stress are likely more critical. N-acetyl cysteine (NAC) directly scavenges free radicals and restores neuronal glutathione, a major endogenous antioxidant. Our group has recently evaluated the safety of high dose NAC in a pilot trial in PMS with no tolerability concerns. We aim now to assess the safety, tolerability, and effect of NAC on progression of several MRI, clinical and biological markers in PMS patients. METHODS: The NACPMS trial is a multi-site, randomized, double-blind, parallel-group, placebo-controlled add-on phase 2 trial. Ninety-eight PMS patients with EDSS 3.0-7.0 and aged 40-70 years will be randomized to NAC 1200 mg TID or matching placebo (1:1) as an add-on to the standard of care stratified by site and disease type during a 15-month intervention period. It is hypothesized that a reduction in oxidative stress injury will lessen brain atrophy estimated by MRI. The primary outcome analysis will compare the percent change over 12 months (Month 15 vs Month 3) between treatment and control arms using multivariable linear regression adjusted by age, sex, and disease duration. ETHICS: This study was approved by the Institutional Review Board at the University of California, San Francisco (IRB21-34143), and an Investigational New Drug approval was obtained from the FDA (IND127184). TRIAL REGISTRATION: NCT05122559.

Fatigue is a common symptom in myelin oligodendrocyte glycoprotein antibody disease.

Background: Unlike multiple sclerosis and neuromyelitis optica, the burden of fatigue in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is unclear. Objective: To compare fatigue levels between people with MOGAD and household controls (HC) and explore factors associated with fatigue severity. Methods: In a cross-sectional survey, data were collected from people with MOGAD and HC by utilizing an online questionnaire. Data elements included demographics, sleep quality measures, comorbidities, MOGAD characteristics, and fatigue severity measured by the Modified Fatigue Impact Scale (MFIS). We compared fatigue severity between MOGAD participants and HC and assessed the associations between demographic and disease characteristics and fatigue severity. Results: There were 180/283 MOGAD and 61/126 HC respondents. Compared to HC, people with MOGAD reported more severe fatigue, as measured by the MFIS total score (49.3 vs. 36.5; p < 0.001), and a larger proportion of MOGAD participants (75.6% vs. 44.3%; p < 0.001) were classified as fatigued. Among MOGAD participants, higher age (p = 0.04), history of bilateral optic neuritis (p = 0.02), and current use of acute treatment (p = 0.04) were independently associated with higher fatigue. Conclusions: Fatigue is common in people with MOGAD, and a history of bilateral optic neuritis, comorbid conditions, and ongoing disease activity appear to contribute to fatigue severity.