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Background and ObjectivesThe timing of neurodegeneration in multiple sclerosis (MS) remains unclear. It is critical to understand the dynamics of neuroaxonal loss if we hope to prevent or forestall permanent disability in MS. We therefore used a deeply phenotyped longitudinal cohort to assess and compare rates of neurodegeneration in retina and brain throughout the MS disease course.MethodsWe analyzed 597 patients with MS who underwent longitudinal optical coherence tomography imaging annually for 4.5 ± 2.4 years and 432 patients who underwent longitudinal MRI scans for 10 ± 3.4 years, quantifying macular ganglion cell-inner plexiform layer (GCIPL) volume and cortical gray matter (CGM) volume. The association between the slope of decline in the anatomical structure and the age of entry in the cohort (categorized by the MRI cohort's age quartiles) was assessed by hierarchical linear models.ResultsThe rate of CGM volume loss declined with increasing age of study entry (1.3% per year atrophy for the age of entry in the cohort younger than 35 years; 1.1% for older than 35 years and younger than 41; 0.97% for older than 41 years and younger than 49; 0.9% for older than 49 years) while the rate of GCIPL thinning was highest in patients in the youngest quartile, fell by more than 50% in the following age quartile, and then stabilized (0.7% per year thinning for the age of entry in the cohort younger than 35 years; 0.29% for age older than 35 and younger than 41 years; 0.34% for older than 41 and younger than 49 years; 0.33% for age older than 49 years).DiscussionAn age-dependent reduction in retinal and cortical volume loss rates during relapsing-remitting MS suggests deceleration in neurodegeneration in the earlier period of disease and further indicates that the period of greatest adaptive immune–mediated inflammatory activity is also the period with the greatest neuroaxonal loss.

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.

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.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.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).NCT05122559.

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 11/25 (44%) EBV-seronegative, but only 9/164 (5.5%, p < 0.001) EBV-seropositive patients. After critical review, MS remained a plausible diagnosis in only four 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. This article is protected by copyright. All rights reserved.

Objective To assess feasibility, tolerability, and safety of N‐acetyl cysteine (NAC) for fatigue in progressive MS. Secondary objectives evaluated changes in fatigue and oxidative pathway biomarkers on NAC versus placebo. Methods Individuals with progressive MS with Modified Fatigue Impact Scale (MFIS) > t38 were randomized 2:1 to NAC 1250mg TID or placebo for 4 weeks. The primary outcome was tolerability and safety. The secondary outcome to evaluate efficacy was MFIS change from baseline to week 4 between groups. Exploratory biomarker outcomes included change in blood GSH/GSSG ratio (reduced‐to‐oxidized glutathione (GSH)) and in vivo relative GSH using 7T MR spectroscopy (MRS) between groups. Fisher exact test was used for categorical and rank sum for continuous outcomes. Results Fifiteen were randomized (10 NAC, 5 placebo; mean age 56.1 years, 80% female, median EDSS 6.0). At least one adverse event (AE) occurred in 60% on NAC versus 80% on placebo (p = 0.75). There were two AEs attributed to NAC in one patient (abdominal pain and constipation), with 94% adherence to NAC. MFIS decreased in both groups at week 4, with the mean improvement of 11‐points on NAC versus 18‐points on placebo (p = 0.33). GSH/GSSG ratio decreased on placebo (−0.6) and NAC (−0.1) (p = 0.18). Change in GSH levels to total creatine in anterior and posterior cingulate cortex, insula, caudate, putamen, and thalamus did not differ between groups. Interpretation NAC was well‐tolerated in progressive MS, although reduction in fatigue on NAC was similar to placebo. Antioxidant blood and MRS biomarkers were not significantly altered by NAC, which could be due to dose, route of administration, time of sample collection, short half‐life, or lack of effect. Registered clinicaltrials.gov NCT02804594.

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.

ObjectiveTo determine whether a small, wearable multisensor device can discriminate between progressive versus relapsing multiple sclerosis (MS) and capture limb progression over a short interval, using finger and foot tap data.MethodsPatients with MS were followed prospectively during routine clinic visits approximately every 6months. At each visit, participants performed finger and foot taps wearing the MYO-band, which includes accelerometer, gyroscope, and surface electromyogram sensors. Metrics of within-patient limb progression were created by combining the change in signal waveform features over time. The resulting upper (UE) and lower (LE) extremity metrics' discrimination of progressive versus relapsing MS were evaluated with calculation of AUROC. Comparisons with Expanded Disability Status Scale (EDSS) scores were made with Pearson correlation.ResultsParticipants included 53 relapsing and 15 progressive MS (72% female, baseline mean age 48years, median disease duration 11years, median EDSS 2.5, median 10months follow-up). The final summary metrics differentiated relapsing from secondary progressive MS with AUROC UE 0.93 and LE 0.96. The metrics were associated with baseline EDSS (UE P=0.0003, LE P=0.0007). While most had no change in EDSS during the short follow-up, several had evidence of progression by the multisensor metrics.InterpretationWithin a short follow-up interval, this novel multisensor algorithm distinguished progressive from relapsing MS and captured changes in limb function. Inexpensive, noninvasive and easy to use, this novel outcome is readily adaptable to clinical practice and trials as a MS vital sign. This approach also holds promise to monitor limb dysfunction in other neurological diseases.

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.

Importance Cerebrospinal fluid (CSF) cytologic testing and flow cytometry are insensitive for diagnosing neoplasms of the central nervous system (CNS). Such clinical phenotypes can mimic infectious and autoimmune causes of meningoencephalitis. Objective To ascertain whether CSF metagenomic next-generation sequencing (mNGS) can identify aneuploidy, a hallmark of malignant neoplasms, in difficult-to-diagnose cases of CNS malignant neoplasm. Design, setting, and participants Two case-control studies were performed at the University of California, San Francisco (UCSF). The first study used CSF specimens collected at the UCSF Clinical Laboratories between July 1, 2017, and December 31, 2019, and evaluated test performance in specimens from patients with a CNS malignant neoplasm (positive controls) or without (negative controls). The results were compared with those from CSF cytologic testing and/or flow cytometry. The second study evaluated patients who were enrolled in an ongoing prospective study between April 1, 2014, and July 31, 2019, with presentations that were suggestive of neuroinflammatory disease but who were ultimately diagnosed with a CNS malignant neoplasm. Cases of individuals whose tumors could have been detected earlier without additional invasive testing are discussed. Main outcomes and measures The primary outcome measures were the sensitivity and specificity of aneuploidy detection by CSF mNGS. Secondary subset analyses included a comparison of CSF and tumor tissue chromosomal abnormalities and the identification of neuroimaging characteristics that were associated with test performance. Results Across both studies, 130 participants were included (median [interquartile range] age, 57.5 [43.3-68.0] years; 72 men [55.4%]). The test performance study used 125 residual laboratory CSF specimens from 47 patients with a CNS malignant neoplasm and 56 patients with other neurological diseases. The neuroinflammatory disease study enrolled 12 patients and 17 matched control participants. The sensitivity of the CSF mNGS assay was 75% (95% CI, 63%-85%), and the specificity was 100% (95% CI, 96%-100%). Aneuploidy was detected in 64% (95% CI, 41%-83%) of the patients in the test performance study with nondiagnostic cytologic testing and/or flow cytometry, and in 55% (95% CI, 23%-83%) of patients in the neuroinflammatory disease study who were ultimately diagnosed with a CNS malignant neoplasm. Of the patients in whom aneuploidy was detected, 38 (90.5%) had multiple copy number variations with tumor fractions ranging from 31% to 49%. Conclusions and relevance This case-control study showed that CSF mNGS, which has low specimen volume requirements, does not require the preservation of cell integrity, and was orginally developed to diagnose neurologic infections, can also detect genetic evidence of a CNS malignant neoplasm in patients in whom CSF cytologic testing and/or flow cytometry yielded negative results with a low risk of false-positive results.

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 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.

Fatigue is the most common symptom and a leading cause of disability multiple sclerosis (MS). Despite the lack of evidence, several medications are frequently prescribed by physicians to ameliorate fatigue in patients with MS. However, a recent study demonstrated that improvement in fatigue severity with these medications appears to be due to placebo effect and is also is associated with more frequent adverse events than the placebo. These findings raise ethical concerns surrounding the initiation and discontinuation of these treatments for fatigue in MS. Starting these medications for the treatment of MS fatigue for their placebo effect may not be justified. However, stopping the medications in patients who report symptomatic benefits and have no side effects may also not be ethical. In MS care non-pharmacological approaches for fatigue treatment, such as exercise and cognitive behavioral therapy, should now be prioritized. Novel study designs may be necessary to address placebo response in future clinical trials evaluating interventions for fatigue in MS.

This article summarizes recent advances in the identification of genetic and environmental factors that affect the risk of developing multiple sclerosis (MS) and the pathogenic processes involved in acute relapses and relapse-independent disability progression.The number of single-nucleotide polymorphisms associated with increased risk of MS has increased to more than 200 variants. The evidence for the association of Epstein-Barr virus infection, vitamin D deficiency, obesity, and smoking with increased risk of MS has further accumulated, and, in cases of obesity and vitamin D deficiency, the evidence for causal association has strengthened. Interactions between genetic and environmental factors have been studied more extensively. Dietary factors and changes in the gut microbiota are emerging as possible modulators of the disease risk. Several processes important to MS pathogenesis have been newly investigated or investigated more comprehensively, including the role of B cells, innate immune cells, meningeal inflammation, cortical and gray matter demyelination, and early axonal and neuronal loss.MS is a complex disease in which the interaction between genetic and environmental factors causes a cascade of events, including activation of the adaptive and innate immune system, blood-brain barrier breakdown, central nervous system demyelination, and axonal and neuronal damage with variable degrees of repair. These events manifest as potentially reversible focal neurologic symptoms or progressive nonremitting physical and cognitive disability, or both. Advances in the understanding of the risk factors and pathogenic mechanisms of MS have resulted in improved therapeutic strategies. The results of ongoing or future studies are needed to successfully and fully translate these advances into clinical practice.

Summary Background Methylphenidate, modafinil, and amantadine are commonly prescribed medications for alleviating fatigue in multiple sclerosis; however, the evidence supporting their efficacy is sparse and conflicting. Our goal was to compare the efficacy of these three medications with each other and placebo in patients with multiple sclerosis fatigue. Methods In this randomised, placebo-controlled, four-sequence, four-period, crossover, double-blind trial, patients with multiple sclerosis who reported fatigue and had a Modified Fatigue Impact Scale (MFIS) score of more than 33 were recruited at two academic multiple sclerosis centres in the USA. Participants received oral amantadine (up to 100 mg twice daily), modafinil (up to 100 mg twice daily), methylphenidate (up to 10 mg twice daily), or placebo, each given for up to 6 weeks. All patients were intended to receive all four study medications, in turn, in one of four different sequences with 2-week washout periods between medications. A biostatistician prepared a concealed allocation schedule, stratified by site, randomly assigning a sequence of medications in approximately a 1:1:1:1 ratio, in blocks of eight, to a consecutive series of numbers. The statistician and pharmacists had no role in assessing the participants or collecting data, and the participants, caregivers, and assessors were masked to allocation. The primary outcome measure was the MFIS measured while taking the highest tolerated dose at week 5 of each medication period, analysed by use of a linear mixed-effect regression model. This trial is registered with ClinicalTrials.gov, NCT03185065 and is closed. Findings Between Oct 4, 2017, and Feb 27, 2019, of 169 patients screened, 141 patients were enrolled and randomly assigned to one of four medication administration sequences: 35 (25%) patients to the amantadine, placebo, modafinil, and methylphenidate sequence; 34 (24%) patients to the placebo, methylphenidate, amantadine, and modafinil sequence; 35 (25%) patients to the modafinil, amantadine, methylphenidate, and placebo sequence; and 37 (26%) patients to the methylphenidate, modafinil, placebo, and amantadine sequence. Data from 136 participants were available for the intention-to-treat analysis of the primary outcome. The estimated mean values of MFIS total scores at baseline and the maximal tolerated dose were as follows: 51·3 (95% CI 49·0–53·6) at baseline, 40·6 (38·2–43·1) with placebo, 41·3 (38·8–43·7) with amantadine, 39·0 (36·6–41·4) with modafinil, and 38·6 (36·2–41·0) with methylphenidate (p=0·20 for the overall medication effect in the linear mixed-effect regression model). As compared with placebo (38 [31%] of 124 patients), higher proportions of participants reported adverse events while taking amantadine (49 [39%] of 127 patients), modafinil (50 [40%] of 125 patients), and methylphenidate (51 [40%] of 129 patients). Three serious adverse events occurred during the study (pulmonary embolism and myocarditis while taking amantadine, and a multiple sclerosis exacerbation requiring hospital admission while taking modafinil). Interpretation Amantadine, modafinil, and methylphenidate were not superior to placebo in improving multiple sclerosis fatigue and caused more frequent adverse events. The results of this study do not support an indiscriminate use of amantadine, modafinil, or methylphenidate for the treatment of fatigue in multiple sclerosis. Funding Patient-Centered Outcomes Research Institute.

Objective While prior Epstein–Barr virus (EBV) infection has been consistently associated with subsequent risk of developing multiple sclerosis (MS), the association with other common herpesviruses has been more controversial. Our objectives were to determine whether remote infection with EBV and other common herpesviruses affect the susceptibility to pediatric MS and if there are interactions between genetic and demographic factors and viral infections. Methods Cases with pediatric‐onset MS or clinically isolated syndrome within 4 years of disease onset, and controls were recruited from 16 American pediatric MS centers. Logistic regression models adjusted for potential confounders assessed the association between case status and serological evidence for past infection with EBV, cytomegalovirus (CMV), Herpes Simplex viruses‐1 (HSV‐1) and ‐2. We determined the heterogeneity of the effect of viral infection on the risk of having MS according to race, ethnicity and HLA‐DRB1:1501 status. Results A total of 356 pediatric cases and 493 controls were recruited. In multivariable models, EBV‐viral capsid antigen (VCA) seropositivity was associated with increased odds of having MS by 7.4 times (95% CI: 4.5–12.0, P < 0.001). Seropositivity for HSV‐1 was also associated with increased odds of having MS (OR 1.54, 95% CI: 1.06–2.25, P = 0.025) but this increase was seen only in Whites (OR = 2.18, 95% CI 1.35–3.52, P < 0.001) and those negative for HLA‐DRB1*1501 (OR = 1.89, 95% CI 1.17–3.03, P = 0.009). The effect of remote EBV infection on the risk of pediatric MS depended on race and HLA‐DRB1*15:01 status. Interpretation EBV seropositivity is strongly associated with pediatric MS, as is HSV‐1 seropositivity in subjects negative for HLA‐DRB1*15:01. Our report of interactions between select viral exposures, and age, race and DRB1 status suggests a complex effect of environmental and genetic risk factors on MS development.

Objective To determine if altered tryptophan (Trp) metabolism is associated with MS risk or disease severity in children. Methods Participants with pediatric‐onset MS and clinically isolated syndrome (CIS) within 4 years of disease onset and healthy controls underwent collection of serum. Longitudinal disability and processing speed measures and relapse data were collected in cases. Global metabolomics were conducted in 69/67 cases/controls. Targeted Trp measurement was performed in a discovery group (82 cases, 50 controls) and a validation group (92 cases, 50 controls), while functional gut microbiome analysis was done in 17 cases. Adjusted logistic, linear and negative binomial regression and Cox‐proportional hazard models were used. Results Using global metabolomics data, higher relative abundances of Trp and indole lactate, a known gut microbiota‐derived Trp metabolite, were associated with lower risk of MS. In cases, higher relative abundances of gut microbiota‐derived Trp metabolites were associated with lower disability and higher processing speed scores and higher relative abundance of kynurenine was associated with higher relapse rate. Using targeted tryptophan measures, in the discovery and validation groups, each 1 mcg/mL increase in serum Trp level was associated with 20% (95% CI: 4–34%) and 32% (95% CI: 16–44%) decrease in adjusted odds of having MS, respectively. A lower relative abundance of gut microbial genes involved in Trp catabolism was associated with higher relapse risk. Interpretation Trp metabolism by the gut microbiota and the kynurenine pathway may be relevant to the risk of MS in children as well as MS activity and severity.

BACKGROUND Fatigue is the most common symptom of multiple sclerosis (MS). Amantadine, modafinil and amphetamine-like stimulants are commonly used in clinical practice for treatment of fatigue; however, the evidence supporting their effectiveness is sparse and conflicting. OBJECTIVE To describe the design of a trial study funded by Patient-Centered Outcome Research Institute (PCORI) that will compare the efficacy of commonly used fatigue medications in patients with MS. DESIGN/METHODS The study is a randomized, placebo-controlled, crossover, four-sequence, four-period, double-blind, multicenter trial of three commonly used medications for the treatment of MS-related fatigue (amantadine, modafinil, methylphenidate) versus placebo in fatigued subjects with MS. Adult patients with MS, with an Expanded Disability Status Scale of

Summary The circulating metabolome provides unique insights into multiple sclerosis (MS) pathophysiology, but existing studies are relatively small or characterized limited metabolites. We test for differences in the metabolome between people with MS (PwMS; n = 637 samples) and healthy controls (HC; n = 317 samples) and assess the association between metabolomic profiles and disability in PwMS. We then assess whether metabolic differences correlate with changes in cellular gene expression using publicly available scRNA-seq data and whether identified metabolites affect human immune cell function. In PwMS, we identify striking abnormalities in aromatic amino acid (AAA) metabolites (p = 2.77E−18) that are also strongly associated with disability (p = 1.01E−4). Analysis of scRNA-seq data demonstrates altered AAA metabolism in CSF and blood-derived monocyte cell populations in PwMS. Treatment with AAA-derived metabolites in vitro alters monocytic endocytosis and pro-inflammatory cytokine production. We identify shifts in AAA metabolism resulting in the reduced production of immunomodulatory metabolites and increased production of metabotoxins in PwMS., Graphical abstract, Highlights • Significant alterations in the circulating metabolome are noted in multiple sclerosis • Aromatic amino acid (AAA) metabolite levels are linked to disease severity • Expression of AAA metabolism genes is altered in MS blood and CSF immune cells • AAA metabolites alter human monocyte cytokine production and endocytosis, Fitzgerald et al. identify alterations in circulating aromatic amino acid (AAA) metabolites in multiple sclerosis that are related to disease severity. They also demonstrate changes in AAA metabolism-related gene expression in blood and cerebrospinal fluid immune cells, and that treatment with AAA metabolites alters monocyte pro-inflammatory cytokine production and endocytosis.

In adults, multiple sclerosis (MS) is associated with executive dysfunction, anxiety, depression, fatigue, and lowered quality of life. Similar problems may occur in pediatric MS, but the relationships between these variables have not yet been investigated. This study examined the associations among some of the most salient cognitive (executive functioning), psychological (anxiety, depression), and psychosocial (fatigue, quality of life, externalizing symptoms) factors affecting children with MS. Sixty-five patients with MS ages 6 to 18 were evaluated through the UCSF Regional Pediatric Multiple Sclerosis Center. Participants completed a neuropsychological assessment battery including the Verbal Fluency Test and Trail Making Test. Parents and children also completed rating forms assessing emotional functioning, fatigue, quality of life, and executive functioning. After controlling for significant demographic variables, higher levels of anxiety and depressive symptoms were associated with executive dysfunction on testing and self-report. In addition, higher reported executive dysfunction was associated with psychosocial difficulties, including higher levels of fatigue, worse quality of life, and more severe externalizing symptoms. The present study furthers our knowledge of the psychological and psychosocial factors associated with neurocognitive outcomes in pediatric MS. Recognition of these variables can inform medical and psychological treatment, as well as interventions in the home and community, to maximize a positive developmental trajectory.

Objective:To investigate a potential effect of riluzole on serum neurofilaments (Nf) compared to placebo and the relationship between longitudinal clinical and MRI outcomes and serum Nf levels.Methods:Serum samples were obtained from participants enrolled in a randomized double-blind trial of neuroprotection with riluzole vs placebo as an add-on to weekly interferon-β (IFN-β)–1a IM initiated 3 months after randomization. Nf measurements were performed by ELISA and electrochemiluminescence immunoassay.Results:Longitudinal serum samples were available from 22 riluzole and 20 placebo participants over 24 months. There was no observed treatment effect with riluzole. Nf light chain (NfL) levels decreased over time (p = 0.007 at 24 months), whereas the Nf heavy chain was unchanged (p = 0.997). Changes in NfL were correlated with EDSS change (p = 0.009) and neuropsychological outcomes. Brain volume decreased more rapidly in patients with high baseline NfL (p = 0.05 at 12 months and p = 0.008 at 24 months) and this relationship became stronger at 24 months (p = 0.024 for interaction). Higher and increasing NfL predicted higher number of gadolinium-enhancing lesions (p < 0.001 for both).Conclusions:Our findings support the potential value of serum NfL as a marker of neuroaxonal injury in early multiple sclerosis. Its reduction over time could represent regression to the mean, or a possible treatment effect of IFN-β-1a. The association with whole brain atrophy and the formation of acute white matter lesions has relevant implications to use serum NfL as a noninvasive biomarker of the overall consequences of brain damage and ongoing disease activity.ClinicalTrials.gov identifier:NCT00501943.

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including in the CNS and the immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric patients with MS compared with controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid, tauroursodeoxycholic acid (TUDCA), on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and proinflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced the severity of disease through its effects on G protein-coupled bile acid receptor 1 (GPBAR1). We demonstrate that bile acid metabolism was altered in MS and that bile acid supplementation prevented polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorated neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.

Multiple sclerosis (MS) is an inflammatory demyelinating disorder of the CNS. Bile acids are cholesterol metabolites that can signal through receptors on cells throughout the body, including the CNS and immune system. Whether bile acid metabolism is abnormal in MS is unknown. Using global and targeted metabolomic profiling, we identified lower levels of circulating bile acid metabolites in multiple cohorts of adult and pediatric MS patients compared to controls. In white matter lesions from MS brain tissue, we noted the presence of bile acid receptors on immune and glial cells. To mechanistically examine the implications of lower levels of bile acids in MS, we studied the in vitro effects of an endogenous bile acid – tauroursodeoxycholic acid (TUDCA) on astrocyte and microglial polarization. TUDCA prevented neurotoxic (A1) polarization of astrocytes and pro-inflammatory polarization of microglia in a dose-dependent manner. TUDCA supplementation in experimental autoimmune encephalomyelitis reduced severity of disease, based on behavioral and pathological measures. We demonstrate that bile acid metabolism is altered in MS; bile acid supplementation prevents polarization of astrocytes and microglia to neurotoxic phenotypes and ameliorates neuropathology in an animal model of MS. These findings identify dysregulated bile acid metabolism as a potential therapeutic target in MS.

Disability measures in multiple sclerosis (MS) rely heavily on ambulatory function, and current metrics fail to capture potentially important variability in walking behavior. We sought to determine whether remote step count monitoring using a consumer-friendly accelerometer (Fitbit Flex) can enhance MS disability assessment. 99 adults with relapsing or progressive MS able to walk ≥2-min were prospectively recruited. At 4weeks, study retention was 97% and median Fitbit use was 97% of days. Substudy validation resulted in high interclass correlations between Fitbit, ActiGraph and manual step count tally during a 2-minute walk test, and between Fitbit and ActiGraph (ICC=0.76) during 7-day home monitoring. Over 4 weeks of continuous monitoring, daily steps were lower in progressive versus relapsing MS (mean difference 2546 steps, p&nbsp

Background and purpose The clinical predictors of health-related quality of life (HRQoL) in multiple sclerosis (MS) have mainly been studied in patients with long-standing disease. The objective of this study was to investigate the longitudinal association among HRQoL and clinical characteristics in early MS. Methods Relapsing MS patients within 12 months of clinical onset were enrolled in a neuroprotection trial of riluzole versus placebo as an add-on to weekly interferon with up to 36 months of follow-up. Serial clinical measures included Short Form-36 (SF-36) as the measure of HRQoL, MS Functional Composite (as a measure of disability), Modified Fatigue Impact Scale, Patient Health Questionnaire-9 (as a measure of depression) and a cognitive battery. Multivariable linear regression analyses assessed cross-sectional associations. Mixed model regressions with mutual adjustments were used to assess the longitudinal association of HRQoL components and clinical, cognitive and demographic variables. Results Forty-three patients were enrolled within 7.5 ± 4.9 months of clinical onset (72% female, mean age 36 years). The baseline severity of fatigue and depression predicted subsequent changes in SF-36 Physical Component Summary (PCS) (P values of 0.001 and 0.021, respectively). In longitudinal analyses, changes in disability and depression were associated with changes in SF-36 PCS (P values of 0.002 and 0.009, respectively), whereas changes in cognitive function and fatigue were associated with changes in SF-36 Mental Component Summary (P values of 0.037 and 0.001, respectively). A 1-unit increase in MS Functional Composite was associated with a 7.1-point increase in SF-36 PCS (95% CI, 2.6–11.6). Conclusions Fatigue, depression, cognition and disability are independently associated with HRQoL in early MS.

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.

Objectives Cognitive dysfunction in multiple sclerosis (MS) has been primarily examined in patients with advanced disease. Our objective was to study the longitudinal associations between brain magnetic resonance imaging (MRI) metrics and neuropsychological outcomes in patients with early MS. Methods Relapsing MS patients within 12 months of onset were enrolled in a neuroprotection trial of riluzole versus placebo with up to 36 months of follow-up. MRI metrics included percent brain volume changes measured by SIENAX normalized measurements [normalized brain parenchymal volume (nBPV), normalized normal-appearing white and gray matter volume (nNAWMV and nGMV)] and T2 lesion volume (T2LV). A neuropsychological battery was performed annually. Mixed model regression measured time trends and associations between imaging and neuropsychological outcomes, adjusting for sex, age and education level. Results Forty-three patients (mean age 36 years; 31 females) were enrolled within 7.5±4.9 months of disease onset. 11.6% of patients with baseline cognitive assessment met conservative criteria for cognitive impairment. Compared to placebo, riluzole had no significant effect on neuropsychological performance; thus, both groups were combined for the association analyses. Baseline T2LV predicted subsequent changes in PASAT (p=0.006) and SDMT (p=0.002) scores. Longitudinal changes of T2LV were associated with changes in CVLT-II (p Conclusion These findings suggest that cognitive impairment is relatively common in patients with very early MS. Baseline and longitudinal changes in the lesion load may be associated with some of the most frequently identified changes in cognitive function in MS.

Highlights • 4.8% of MS patients fulfilled defined criteria for COVID-19-suspect group. • Two patients required hospitalization; no intubation or ICU admission was reported. • Patients on B-cell depleting agents had higher risk of being in the COVID-19-suspect group., Objective To determine whether the course of COVID-19 is more severe in patients with MS and if MS disease-modifying treatments (DMTs) affect the risk of contracting the disease. Methods In a cross-sectional survey, data were collected by sending a questionnaire to 2000 patients with a demyelinating disease through an online portal system. Collected data included the current MS DMT and patient-reported disability level, history of recent sick contact, recent fever, respiratory symptoms, diagnosis with COVID-19, and the disposition after the diagnosis. We defined a COVID-19-suspect group as patients having fever and cough or fever and shortness of breath, or a presumptive diagnosis based on suggestive chest computed tomography. We calculated the proportion of COVID-19-suspect patients and compared their demographics, clinical characteristics, and DMT categories with the rest of survey-responders, using univariable and multivariable models. Results Out of 712 patients, 34 (4.8%) fulfilled our criteria for being in the COVID-19-suspect group. Only two patients required hospitalization. No patient required intensive care. In a multivariable model, disease duration (p-value=0.017), DMT category (p-value=0.030), and history of sick contact (p-values

Context Research on the effect of osteopathic manipulative therapy (OMTh; manipulative care provided by foreign-trained osteopaths) on chronic symptoms of multiple sclerosis (MS) is lacking. Objective To evaluate the effect of OMTh on chronic symptoms of MS. Methods Patients with MS who were evaluated at the neurology clinic at Genoa University in Italy were recruited for this study. Participants received 5 forty-minute MS health education sessions (control group) or 5 OMTh sessions (OMTh group). All participants completed a questionnaire that assessed their level of clinical disability, fatigue, depression, anxiety, and quality of life before the first session, 1 week after the final session, and 6 months after the final session. The Extended Disability Status Scale, a modified Fatigue Impact Scale, the Beck Depression Inventory-II, the Beck Anxiety Inventory, and the 12-item Short Form Health Survey were used to assess clinical disability, fatigue, depression, anxiety, and quality of life, respectively. Results Twenty-two participants were included in the study (10 in the control group and 12 in the OMTh group). In the OMTh group, statistically significant improvements in fatigue and depression were found 1 week after the final session (P=.002 and PP=.36). Conclusion Results demonstrate that OMTh should be considered in the treatment of patients with chronic symptoms of MS.

The aim of the present study was to assess sensitivity and specificity of McDonald criteria 2010 revision for primary progressive multiple sclerosis (PPMS),1 since this was not done in previous studies. In addition, the performance of MRI guidelines for dissemination in space (DIS) demonstration proposed in 2016 by the MRI in multiple sclerosis (MAGNIMS) group was evaluated.2 The study was approved by the ethics committee of participating institutions as required. Patients who were seen at University of California San Francisco and University of Verona multiple sclerosis (MS) centres for suspected PPMS after 1997 were retrospectively identified from existing databases. Data were obtained from review of charts with adequate documentation of clinical, MRI and cerebrospinal fluid (CSF) status to determine the fulfilment of 2010 McDonald criteria. Cases with less than 1-year interval between clinical onset and last follow-up visit were excluded. One-year disease progression demonstration as required by diagnostic criteria was based on documented worsening of neurological disability unrelated to relapse. First available brain and spinal cord MRI of adequate quality performed after symptom onset was used to determine criteria fulfilment at time of initial visit. MRI scans were reviewed by a single experienced reader (AG) who was not blinded to clinical data. CSF data were taken from the lumbar puncture performed by the time of first visit if available. Exclusion of a …

A previously healthy 16-year-old girl developed numbness and tingling in the lower extremities that progressed over a 10-week period to the upper limbs. Two weeks prior to admission, she also developed weakness in her arms and legs, to the point of needing help getting dressed and support for walking. She denied sphincter or systemic symptoms. During the previous year, she had complained of intermittent shooting pains and tingling down her arms. Her psychiatric history was relevant for obsessive-compulsive traits and depression, and family history included autoimmune diseases in 2 sisters, an uncle, and 2 grandparents.

OBJECTIVE: To determine if prenatal, pregnancy, or postpartum-related environmental factors are associated with multiple sclerosis (MS) risk in children. METHODS: This is a case-control study of children with MS or clinically isolated syndrome and healthy controls enrolled at 16 clinics participating in the US Network of Pediatric MS Centers. Parents completed a comprehensive environmental questionnaire, including the capture of pregnancy and perinatal factors. Case status was confirmed by a panel of 3 pediatric MS specialists. Multivariable logistic regression analyses were used to determine association of these environmental factors with case status, adjusting for age, sex, race, ethnicity, US birth region, and socioeconomic status. RESULTS: Questionnaire responses were available for 265 eligible cases (median age 15.7 years, 62% girls) and 412 healthy controls (median age 14.6, 54% girls). In the primary multivariable analysis, maternal illness during pregnancy was associated with 2.3-fold increase in odds to have MS (95% confidence interval [CI] 1.20–4.21, P = .01) and cesarean delivery with 60% reduction (95% CI 0.20–0.82, P = .01). In a model adjusted for these variables, maternal age and BMI, tobacco smoke exposure, and breastfeeding were not associated with odds to have MS. In the secondary analyses, after adjustment for age, sex, race, ethnicity, and socioeconomic status, having a father who worked in a gardening-related occupation (odds ratio [OR] 2.18, 95% CI 1.14–4.16, P = .02) or any use in household of pesticide-related products (OR 1.73, 95% CI 1.06–2.81, P = .03) were both associated with increased odds to have pediatric MS. CONCLUSION Cesarean delivery and maternal health during pregnancy may influence risk for pediatric-onset MS. We report a new possible association of pesticide-related environmental exposures with pediatric MS that warrants further investigation and replication.

Traumatic myelopathy is thought to be an obvious diagnosis. However, trauma may not be obvious, and the resultant lesion can resemble transverse myelitis. Here we describe the case of a 16-year-old female that presented with subacute distal sensory changes progressing to quadriparesis with prominent upper motor neuron signs. MRI revealed an enhancing lesion in the cervical cord with moderate degenerative changes in discs and vertebrae. Workup did not show evidence of infection or inflammation on both serum and cerebrospinal fluid (CSF). Despite empirical treatment with high-dose steroids and plasma exchange (PE), the patient continued to worsen. Subsequently, a long history of a motor tics involving her neck causing repetitive low-grade trauma to her spinal cord was identified. Dynamic MRI showed cervical spine compression on neck extension. After surgical decompression, the patient neurologically stabilized, and her neuropathic pain improved.

MS is an inflammatory and neurodegenerative disease of the CNS (including the retina) that leads to progressive neurologic disability. Disability correlates with the degree of axonal pathology in the disease.1,2 The clinical course of MS is unpredictable, making the search for biomarkers associated with enhanced risk of disease progression a major unmet need. Spectral domain optical coherence tomography (SD-OCT) is a potential predictor of disability worsening up to 5 years of follow-up after a single evaluation of the peripapillary retinal nerve fiber layer (pRNFL).3 Time domain OCT (TD-OCT) is an older technology, characterized by lower axial resolution and slower acquisition speed (400 axial scans per second) resulting in lower resolution images and more frequent motion artifacts compared with SD-OCT.4 TD-OCT was used over 10 years ago to assess retinal neurodegeneration in patients with MS but only now has enough time passed to assess its actual predictive potential for clinical progression.

Thrombotic thrombocytopenic purpura (TTP) is an episodic microangiopathic coagulopathy characterized by profound thrombocytopenia and hemolytic anemia. Neurovascular complications, including stroke and TIA, occur commonly upon initial TTP presentation, and the underlying etiology of such neurologic manifestations is usually hinted by the concomitant hematologic abnormalities.