A randomized cross-over trial of prebiotics and probiotics in multiple sclerosis: Trial feasibility, supplement tolerability and symptom abatement.

BACKGROUND: Dietary supplements can modulate the gut microbial ecosystem and affect the immune system. This has potential implications for autoimmune diseases, including multiple sclerosis (MS). Prior studies explored tolerability, symptomatic improvement, and immunologic effects of probiotics in people with MS (pwMS), but no study has examined prebiotics in this population or compared prebiotics with probiotics. METHODS: This is a randomized, open-label trial of participants with relapsing-remitting MS on B-cell depletion therapy from two MS centers. 22 participants enrolled in the original cross-over study in which probiotic (Visbiome, containing Lactobacillus, Bifidobacterium and Streptococcus species) or prebiotic (Prebiotin, containing oligofructose enriched inulin) supplementation for 6 weeks was randomized, each followed by a washout period. Due to pandemic-related interruptions and expiration of the study supply of probiotics, another 15 participants enrolled in a single-arm study to receive prebiotic supplementation for 6 weeks followed by a washout period. We assessed supplement tolerability and patient-reported outcomes (PRO) relevant to MS (disability, fatigue, mood, and bowel symptoms) before and after each supplement administration period and each washout period. We bio-archived plasma, serum, peripheral blood mononuclear cells and stool samples at each timepoint for future multi-omic assessment. RESULTS: Prebiotics and probiotics had comparable adherence rates and both supplements were well tolerated in pwMS. Participants on either supplement reported minor adverse events, most of which were mild and self-limited. There was a subjective preference for prebiotics over probiotics. Comparing supplement-associated changes in PRO scores from baseline to 6 weeks post-supplementation, there were significant difference between prebiotics and probiotics for the change in patient-reported global symptom burden (MSRS-R Total) and bowel control (BWCS), but only probiotics statistically improved bowel control from baseline to post-supplementation. CONCLUSION: Supplementation with either prebiotics or probiotics is reasonably well-tolerated and safe. Probiotics improved bowel control, but did not improve other PROs in a 6-week time frame. These data regarding feasibility, tolerability, adherence, and adverse events of supplements will inform future clinical trial designs to definitively compare the efficacy and safety of prebiotics and probiotics. The biological data that will be generated from this study in the future will provide mechanistic insights into the effects of these dietary supplements on MS pathophysiology.

A randomized controlled trial of oral antipyretic treatment to reduce overheating during exercise in adults with multiple sclerosis.

BACKGROUND: Some people with multiple sclerosis (pwMS) avoid exercise due to overheating. Evidence from a variety of cooling treatments shows benefits for pwMS. OBJECTIVE: Conduct a randomized controlled trial of antipyretic treatment before exercise in pwMS. METHODS: Adults over age 18 diagnosed with relapsing-remitting MS reporting heat sensitivity during exercise were randomly assigned to one of six sequences counterbalancing aspirin, acetaminophen, placebo. At each of three study visits separated by ≥ one week, participants received 650-millograms of aspirin, acetaminophen, or placebo before completing a maximal exercise test. Primary outcomes were body temperature change and total time-to-exhaustion (TTE), secondary outcomes were physiological and patient-reported outcomes (PROs). RESULTS: Sixty participants were enrolled and assigned to treatment sequence; 37 completed ≥ one study visit. After controlling for order effects, we found that body temperature increase was reduced after aspirin (+ 0.006 ± 0.32 degrees Fahrenheit, p < 0.001) and after acetaminophen (+ 0.31 ± 0.35; p = 0.004) compared to placebo (+ 0.68 ± 0.35). TTE after aspirin (331.6 ± 76.6 s) and acetaminophen (578.2 ± 82.1) did not differ significantly from placebo (551.0 ± 78.4; p's > 0.05). Aspirin benefited all secondary outcomes compared to placebo (all p's < 0.001); acetaminophen showed broadly consistent benefits. CONCLUSION: These results support antipyretic treatment as effective for reducing overheating during exercise in pwMS and failed to support antipyretics for increasing TTE in the context of a maximal exercise test. Benefits were shown for physiological markers of exercise productivity and PROs of fatigue, pain, and perceived exertion.

A structured evaluation of cryopreservation in generating single-cell transcriptomes from cerebrospinal fluid.

Single-cell transcriptomics allows characterization of cerebrospinal fluid (CSF) cells at an unprecedented level. Here, we report a robust cryopreservation protocol adapted for the characterization of fragile CSF cells by single-cell RNA sequencing (RNA-seq) in moderate- to large-scale studies. Fresh CSF was collected from twenty-one participants at two independent sites. Each CSF sample was split into two fractions: one was processed fresh, while the second was cryopreserved for months and profiled after thawing. B and T cell receptor sequencing was also performed. Our comparison of fresh and cryopreserved data from the same individuals demonstrates highly efficient recovery of all known CSF cell types. We find no significant difference in cell type proportions and cellular transcriptomes between fresh and cryopreserved cells. Results were comparable at both sites and with different single-cell sequencing chemistries. Cryopreservation did not affect recovery of T and B cell clonotype diversity. Our CSF cell cryopreservation protocol provides an important alternative to fresh processing of fragile CSF cells.

Hypogonadism in men with multiple sclerosis: Prevalence and clinical associations.

It has been hypothesized that multiple sclerosis (MS) has hormonal influences, and testosterone may have anti-inflammatory functions in this context. Given prior reports of lower testosterone levels in men with MS in archival serum samples, we evaluated the prevalence of hypogonadism in the clinical setting and its association with disability in men with MS. Subjects were screened for symptoms of hypogonadism using a clinical instrument, and those with positive screens had total and free morning testosterone levels checked. Of the 64 subjects who were screened, 50 (78%) had positive results, and 46 (92%) had morning testosterone levels checked. Among the latter, 5 were found to have testosterone levels below lower limit of normal. Other than the expected inverse relation with BMI, testosterone did not correlate with demographic or disease related factors. Baseline testosterone did not predict risk of EDSS or T25-FW progression or future MRI activity.

Worsening physical functioning in patients with neuroinflammatory disease during the COVID-19 pandemic.

OBJECTIVE: To quantify changes in psychological wellbeing and physical function as reported by people with neurological inflammatory disease (PwNID) during the COVID-19 pandemic. METHODS: 1134 PwNID and 868 control participants were recruited through five major academic medical centers in the Northeast/Mid-Atlantic U.S. beginning in April 2020. Participants completed serial surveys throughout the COVID-19 pandemic that aimed to quantify mood symptoms and physical function, analyzed cross-sectionally with a smaller cohort analyzed longitudinally. RESULTS: Throughout the pandemic, depression scores were not significantly different between PwNID and controls, although a higher proportion of PwNID reported clinically significant depression at study entry. Depression scores did not worsen over time for either group. Loneliness was the strongest predictor of worse depression, along with older age, male gender in both PwNID and controls, as well as lack of disease modifying therapy use, and disease duration in PwNID only. In contrast, physical disability worsened significantly over time for both PwNID and controls. Age, DMT status and comorbid health conditions emerged as significant predictors of physical function. CONCLUSIONS: Depressive symptoms remained consistent for both PwNID and controls throughout the COVID-19 pandemic, but physical function worsened significantly over time for both groups. This is particularly impactful for PwNID, who have higher baseline levels of physical disability, and underscores the importance of reinstituting services and interventions that facilitate exercise and reconditioning for this population.

Myelin oligodendrocyte glycoprotein (MOG) antibody-mediated disease: The difficulty of predicting relapses.

BACKGROUND: While many patients with myelin oligodendrocyte glycoprotein antibody-mediated disease (MOG-AD) will have a monophasic course, 30-80% of patients will relapse after the initial attack. It is not known which factors predict relapse. Here we describe our clinical experience with MOG-AD and evaluate for factors that correlate with relapsing disease. METHODS: This was a retrospective, multi-institutional study of 54 patients with MOG-AD, including 17 children and 37 adults. Mann-Whitney U and Fischer's Exact tests were used for comparisons and logistic regression for correlations. RESULTS: Incident attack phenotype included acute disseminated encephalomyelitis (15%), unilateral optic neuritis (ON; 39%), bilateral ON (24%), transverse myelitis (TM; 11%) and ON with TM (11%). Pediatric patients were more likely than adults to present with ADEM (p = .009) and less likely to present with unilateral ON (p = .04). 31 patients (57%) had a relapsing disease course, with time to first relapse of 8.2 months and median annualized relapse rate of 0.97 months. In 40% of patients (n = 22) the first relapse occurred following the withdrawal of treatment for the incident attack. 5 patients converted to seronegative at follow up, 2 of whom later relapsed. Logistic regression revealed no significant relationship between age, gender, race, presentation phenotype, antibody titer, or cerebrospinal fluid results with risk of relapse. For patients who started disease modifying therapy (DMT) prior to the first relapse (n = 11), 64% remained monophasic. 50% (n = 15) of patients on DMT continued to have disease activity, requiring treatment adjustment. CONCLUSIONS: It is difficult to predict which patients with MOG-AD will relapse. Research is needed to determine the optimal timing and choice of treatment.

Manifestations and impact of the COVID-19 pandemic in neuroinflammatory diseases.

OBJECTIVE: To report initial results of a planned multicenter year-long prospective study examining the risk and impact of COVID-19 among persons with neuroinflammatory disorders (NID), particularly multiple sclerosis (MS). METHODS: In April 2020, we deployed online questionnaires to individuals in their home environment to assess the prevalence and potential risk factors of suspected COVID-19 in persons with NID (PwNID) and change in their neurological care. RESULTS: Our cohort included 1115 participants (630 NID, 98% MS; 485 reference) as of 30 April 2020. 202 (18%) participants, residing in areas with high COVID-19 case prevalence, met the April 2020 CDC symptom criteria for suspected COVID-19, but only 4% of all participants received testing given testing shortages. Among all participants, those with suspected COVID-19 were younger, more racially diverse, and reported more depression and liver disease. PwNID had the same rate of suspected COVID-19 as the reference group. Early changes in disease management included telemedicine visits in 21% and treatment changes in 9% of PwNID. After adjusting for potential confounders, increasing neurological disability was associated with a greater likelihood of suspected COVID-19 (ORadj  = 1.45, 1.17-1.84). INTERPRETATIONS: Our study of real-time, patient-reported experience during the COVID-19 pandemic complements physician-reported MS case registries which capture an excess of severe cases. Overall, PwNID seem to have a risk of suspected COVID-19 similar to the reference population.

Association of social network structure and physical function in patients with multiple sclerosis.

OBJECTIVE: To test the association between physical function and the social environment in multiple sclerosis (MS), we quantified personal social networks. METHODS: In this cross-sectional study, we analyzed data from 2 academic MS centers, with center 1 serving as a discovery group and center 2 as the extension group. We performed a meta-analysis of the centers to extend the analysis. We used responses from a questionnaire to map the structure and health habits of participants' social networks as well as the NIH Patient-Reported Outcomes Measurement Information System (PROMIS) physical function scale (0-100, mean 50 for US general population) as the primary outcome. We applied multivariable models to test the association between network metrics and physical function. RESULTS: The discovery cohort included 263 patients with MS: 81% were women, 96% non-Hispanic European, 78% had relapsing MS, average age was 50 (12.4) years, and mean disease duration was 17 (12.3) years. The extension group included 163 patients, who were younger, more racially diverse, and less physically disabled, and had shorter disease duration. In the meta-analysis, higher network constraint, a measure of tightly bound networks, was associated with worse physical function (ß = -0.163 ± 0.047, p < 0.001), while larger network effective size, a measure of clustered groups in the network, correlated with better physical function (ß = 0.134 ± 0.046, p = 0.003). CONCLUSIONS: Our study highlights personal networks as an important environmental factor associated with physical function in MS. Patients with close-knit networks had worse function than those with more open networks. Longitudinal studies are warranted to evaluate a causal relationship between network structure and physical impairment.

Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD.

Objective: To develop a resource of systematically collected, longitudinal clinical data and biospecimens for assisting in the investigation into neuromyelitis optica spectrum disorder (NMOSD) epidemiology, pathogenesis, and treatment. Methods: To illustrate its research-enabling purpose, epidemiologic patterns and disease phenotypes were assessed among enrolled subjects, including age at disease onset, annualized relapse rate (ARR), and time between the first and second attacks. Results: As of December 2017, the Collaborative International Research in Clinical and Longitudinal Experience Study (CIRCLES) had enrolled more than 1,000 participants, of whom 77.5% of the NMOSD cases and 71.7% of the controls continue in active follow-up. Consanguineous relatives of patients with NMOSD represented 43.6% of the control cohort. Of the 599 active cases with complete data, 84% were female, and 76% were anti-AQP4 seropositive. The majority were white/Caucasian (52.6%), whereas blacks/African Americans accounted for 23.5%, Hispanics/Latinos 12.4%, and Asians accounted for 9.0%. The median age at disease onset was 38.4 years, with a median ARR of 0.5. Seropositive cases were older at disease onset, more likely to be black/African American or Hispanic/Latino, and more likely to be female. Conclusions: Collectively, the CIRCLES experience to date demonstrates this study to be a useful and readily accessible resource to facilitate accelerating solutions for patients with NMOSD.

Efficacy of transsphenoidal surgery in achieving biochemical cure of growth hormone-secreting pituitary adenomas among patients with cavernous sinus invasion: a systematic review and meta-analysis.

OBJECTIVES: Growth hormone-secreting pituitary adenomas in adults can result in severe craniofacial disfigurement and potentially fatal medical complications. Surgical resection leading to remission of the disease is dependent on complete surgical resection of the tumor. Lesions that invade the cavernous sinus may not be safely accessible via an endonasal transsphenoidal surgery (TSS), and the rates of biochemical remission of patients with residual disease vary widely in the literature. We conducted a meta-analysis to examine the prevalence of biochemical remission after TSS among patients with growth hormone-secreting pituitary adenomas with and without cavernous sinus invasion. METHODS: Embase, PubMed, and Cochrane Library databases were searched for relevant publications. Fourteen studies with 972 patients with biochemically confirmed growth hormone-secreting pituitary adenomas were included in the meta-analysis. RESULTS: The overall remission prevalence under a fixed-effect model was 47.6% (95% CI = 40.8-54.4%) for patients with invasive macroadenomas (I2 = 74.6%, p < 0.01); 76.4% (95% CI = 72.2-80.1%) for patients with non-invasive macroadenomas (I2 = 59.6%, p = 0.03); and 74.2% (95% CI = 66.3-80.7%) for patients with non-invasive microadenomas (I2 = 36.4, p = 0.10). The significant difference among the three groups resulted from the difference between patients with or without cavernous sinus invasion (p = 0.01) and not from the size of adenomas among those without cavernous sinus invasion (p = 0.66). DISCUSSION: The prevalence of biochemical remission in patients with cavernous sinus invasion was lower than in patients without cavernous sinus invasion after TSS for acromegaly.