Multiple Sclerosis and Related Disorders

Treatment with fingolimod for multiple sclerosis (MS) reduces the efficacy of COVID-19 vaccination. We evaluated by a multivariate linear regression model whether main lymphocyte subsets and demographic feature correlated to the subsequent increase in anti-SARS-CoV2 antibodies following the third dose of COVID-19 vaccination in fingolimod-treated MS patients. We found that number and proportion of peripheral blood CD19+ B lymphocytes before the third dose of vaccination in MS patients treated with fingolimod, predict the subsequent increase of anti-SARS-CoV2 antibodies (respectively p = 0.013; p = 0.015). This work suggests that evaluating the numbers of CD19+ B cells may be important to identify patients at risk of not producing SARS-CoV-2 antibodies, with possible reduced protection from COVID-19.

Background: Rituximab is used off-label for multiple sclerosis (MS), and biosimilar substitution raises a distinct extrapolation challenge, as MS is not an approved indication for the reference product. Real-world nonmedical switching data inform biosimilar appropriateness decisions by clinicians, societies, and payers. Objective: To report the effectiveness and tolerability of nonmedical switching from originator (MabThera) to biosimilar rituximab (Truxima) in people with MS (pwMS). Methods: A retrospective, single-center observational cohort study of 50 pwMS switched after at least two originator infusions, followed for two years. Results: Annualized relapse rate declined from 0.45 (95% CI 0.28 - 0.68) prerituximab to 0.02 (95% CI 0.00 - 0.13) on originator and 0.00 (95% CI 0.00 - 0.05) on biosimilar (p = 0.367 between products). In paired imaging analysis (n = 29), the proportion with active scans declined progressively (50.0%, 34.5%, 17.2%; Cochrans Q, p = 0.040), with no difference between the originator and biosimilar periods (McNemar, p = 0.227). B-cell depletion deepened progressively. All patients remained on biosimilar through the end of follow-up. Conclusion: Nonmedical switching from originator to biosimilar rituximab was associated with comparable clinical and radiological outcomes, supporting its use in pwMS without concern for inferior efficacy or diminished tolerability.

IntroductionPsychological distress is a major issue in multiple sclerosis (MS), having a significant impact on quality of life. Antidepressants are generally unhelpful for subsyndromal symptomatology, and psychological treatment approaches often not accessible or too cognitively demanding for some patients. There is an urgent need for low-cost interventions to improve wellbeing in MS. MethodsThis was a pilot randomised controlled trial (RCT) of Positive Mental Training (PosMT), a low intensity intervention providing training in positivity, optimism and resilience previously shown to improve anxious and depressive symptomotology. 28 patients with MS were randomised to the intervention and 30 to the control group. ResultsFollow-up data was obtained from 39 patents. The majority of participants receiving PosMT reported that they had used the intervention, with few reporting side effects. The intervention group reported a significant improvement in self-rated health as measured by the EuroQual visual analogue scale, F(4,34) = 3.204, p = 0.025, R2 = 0.274. DiscussionThis preliminary RCT found that PosMT in its current form could be used by patients with MS with little difficulty. Despite the small size of the study, allocation to the intervention was found to be associated with a significant improvement in self-rated health. Given the low cost of PosMT and its easy availability (it can simply be downloaded from a website), this pilot RCT suggests it could be a useful tool for MS patients. We believe this intervention warrants further study, ideally in a large multi-centre RCT.

BackgroundThere is increasing evidence that Epstein-Barr virus (EBV) plays a causal role in MS. No treatments have been shown to reduce EBV turnover. We studied the effect of famciclovir on salivary EBV shedding in people with MS (NCT05283551). MethodsPeople with MS receiving natalizumab provided weekly saliva samples for 12 weeks before starting Famciclovir 500mg bd. 12 saliva samples were provided on treatment and 12 following treatment. A real-time quantitative PCR Taqman assay targeted to a non-repeated sequence of the EBV polymerase gene was used to detect EBV DNA in saliva. The proportion of saliva samples containing EBV DNA was compared using the Friedman test. Results30 patients were recruited (19F; mean age 41 years; median EDSS 3.5). 29 patients received famciclovir, 24 completed the 12-week course. 21 participants provided at least one usable saliva sample in all 3 epochs. 10/21 participants had shedding in at least one sample pre-drug; 7/21 when taking famciclovir (not significant). No difference in EBV DNA copy number was seen. There were no drug-related serious adverse events. ConclusionsNo significant effect of famciclovir on EBV shedding was seen. Salivary EBV shedding in this natalizumab-treated cohort was lower than in previous studies; this requires replication.

In January 2024, all persons with multiple sclerosis (pwMS) treated with natalizumab (NTZ) at Oslo University Hospital switched from originator to biosimilar NTZ. We prospectively monitored 39 pwMS during the first year of treatment with biosimilar NTZ and evaluated change in disease activity, side effects, serum NTZ levels, anti-drug antibodies (ADAb), and anti-John Cunningham virus (JCV) antibody levels. Serum NTZ levels and ADAb were measured using in-house assays, while JCV antibody levels were evaluated using Stratify (Biogen) and Immunowell (Sandoz) platforms. One new relapse occurred during the first year and 11 pwMS (28%) reported new side effects after switching to the biosimilar; whereof fatigue, headache, and muscle pain were most frequent. Serum NTZ levels were similar between pwMS on originator (15.1 mg/L, SD 8.9) and biosimilar NTZ (14.9 mg/L, SD 9.0; p = 0.63). We identified ADAb in one pwMS, present both before and after switching. The proportion of pwMS with positive JCV antibody levels increased from 13% in 2023 (Stratify) to 52% in 2024 (Immunowell). Four pwMS discontinued NTZ due to high anti-JCV antibody levels (in the Immunowell assay) in the first 10 months.

We investigated performance validity tests (PVTs) in patients presenting with new onset cognitive complaints associated with post-acute sequelae of COVID-19 infection (PASC). Retrospective data were obtained from IRB-approved registries. All patients completed the Victoria Symptom Validity Test (VSVT) in conjunction with a neuropsychological evaluation. A sub-analysis included 7 other PVT measures. The PASC sample was compared to an analogous multiple sclerosis (MS) sample with known PVT failure rates. The PASC sample consisted of 177 patients (49.4 {+/-} 11.2 years), educated (14.7 {+/-} 2.3 years), predominantly female (81.4%), and white, non-Hispanic (85.3%) patients. Seven percent of the PASC sample scored below the established VSVT hard item cut-off, and of those with invalid VSVT over 50% failed 3 or more additional PVTs. In comparison to a MS sample, the PASC sample reported comparable psychological symptoms, but were significantly less likely to produce invalid VSVT scores and seek disability benefits. This study provides a profile of PVTs in patients presenting with PASC. The general infrequence of invalid responding in this PASC sample (7%) is noteworthy compared to an MS sample and highlights the role of additional factors in non-credible response such as elevated psychological symptoms or pursuit of disability.

BackgroundMultiple Sclerosis (MS) often results in gait impairment and disability. ObjectiveTo investigate differences in spatiotemporal gait characteristics of people with MS who have low versus high levels of disability. Between trial and inter-limb consistency and the association of gait variables with level of disability were also investigated. MethodsParticipants with MS who had either low-disability [n=7; 3 females; EDSS mean: 2.7{+/-}0.5, range 2.0-4.5; BMI=26.9{+/-}6.6] or high-disability [n=11; 6 females; EDSS mean: 2.7{+/-}0.5, range 6.0-6.5; BMI=27.8{+/-}1.5) performed 2 trials of self-selected walking on an instrumented walkway. Differences in group, limb, and group by limb interactions were assessed using analysis of variance, independent-measures t-tests, and Cohens d effect sizes (ES). Between-trial consistency of gait were assessed with intra-class correlation coefficients (2, k). ResultsParticipants in the high disability group had increased step time (ES=0.8), cycle time (ES=0.8), and ambulation time (ES=1.2) while taking shorter strides (ES=0.9) and more steps at a slower rate (ES=1.1). The high disability group demonstrated less between-trial consistency for 69% of gait variables when compared to the low disability group. ConclusionPeople with MS who have high levels of disability walk differently and with less consistency than those with lower levels of disability.

BackgroundPeople with multiple sclerosis (pwMS) often experience impaired quality of life (QoL) despite receiving standard care. Digital therapeutics (DTx) may offer support, but prior trials yielded mixed results, possibly due to active controls and high baseline QoL. We therefore evaluated a DTx (levidex) as an adjunct to treatment as usual (TAU) in pwMS with impaired QoL. MethodsIn this pragmatic, online randomised controlled trial (LAMONT; NCT06090305), n = 470 pwMS with a score [≥]2 on the Hamburg Quality of Life Questionnaire in Multiple Sclerosis (HAQUAMS) were randomised to levidex + TAU or TAU alone. The primary endpoint was HAQUAMS total score at 6 months, analysed by intention-to-treat ANCOVA. ResultsCompared with TAU, levidex + TAU improved MS-specific QoL at 6 months (baseline-adjusted mean difference -0.10; 95% CI -0.18 to -0.03; p = 0.008; Cohens d = 0.26). Clinically relevant HAQUAMS improvement ([≥]0.22) occurred more often with levidex (39.5% vs 27.8%; number needed to treat = 9). Benefits also emerged for depressive symptoms and social/work functioning but not for anxiety. No serious adverse events occurred and user satisfaction was high. ConclusionsIn pwMS with impaired QoL, adding the scalable DTx levidex to TAU yields meaningful improvements in QoL and functioning.

Background: Real-world evidence evaluating the long-term effectiveness and safety of dimethyl fumarate (DMF) in relapsing-remitting multiple sclerosis (RRMS) remains limited, particularly in Middle Eastern populations. Furthermore, whether previous exposure to disease-modifying therapies influences longitudinal treatment response has not been adequately characterized. We evaluated the real-world effectiveness, safety, and temporal treatment dynamics of DMF in RRMS and compared outcomes between treatment-naive and previously treated patients. Methods: This longitudinal observational cohort study enrolled 120 adults with RRMS initiating DMF (TECRA (R)) at two multiple sclerosis centers in Iran. Clinical outcomes, magnetic resonance imaging (MRI) activity, disability progression, and adverse events were assessed over 18 months at 6-month intervals. Repeated Expanded Disability Status Scale (EDSS) measurements were analyzed using linear mixed-effects models, while relapse counts and MRI lesion activity were evaluated using generalized estimating equations. Prespecified subgroup analyses examined differences according to prior treatment status. Results: Ninety-five patients completed the study. DMF produced a marked suppression of disease activity, reducing the annualized relapse rate by 95% (1.56 {+/-} 0.93 to 0.08 {+/-} 0.24; P < 0.001). EDSS improved during the first year and remained near baseline after 18 months despite a modest increase during the final follow-up interval. MRI inflammatory activity declined significantly throughout follow-up, although a mild increase in gadolinium-enhancing lesions after 12 months suggested possible attenuation of treatment effect over time. Overall, 88.4% of patients remained relapse-free, 70.5% demonstrated no MRI disease activity, and 64.2% achieved no evidence of disease activity (NEDA-3). While overall clinical outcomes were comparable between treatment-naive and previously treated patients, longitudinal analyses revealed distinct temporal patterns of MRI activity between groups. DMF was well tolerated, with predominantly mild cutaneous and gastrointestinal adverse events and infrequent treatment discontinuation. Conclusions: In conclusion, DMF was well tolerated and effective in reducing clinical and radiological disease activity. These findings support the long-term effectiveness of DMF in routine clinical practice while highlighting the importance of continued clinical and radiological monitoring to optimize individualized treatment strategies.

OBJECTIVESTo analyze the symptoms and severity of coronavirus disease 2019 (COVID-19) in people with multiple sclerosis (pwMS) on immunotherapy using data from the COVID-19 in multiple sclerosis (MS) Global Data Sharing Initiative dataset provided by PhysioNet. METHODSThe open-access COVID-19 in MS Global Data Sharing Initiative dataset was obtained through credentialed access using PhysioNet. The variables analyzed included body mass index (BMI), symptoms of COVID-19, age, current use of disease-modifying therapy (DMT), efficacy of DMT, comorbidities, hospitalization status, and type of MS. A linear regression analysis was completed. Data analysis and visualization were completed using STATA v1.5, R-Studio v1.1.447, Python v3.8, and its associated libraries, including NumPy, Pandas, and Matplotlib. RESULTSA total of 1141 participants were included in the analysis. 904 women and 237 men were diagnosed with MS. Among the pwMS included in the study; 208 (19.54%) had a suspected infection with COVID-19 and only 49 (5.25%) were confirmed. Any COVID-19 symptom was present in 360 individuals. The commonly reported DMT agents included dimethyl fumarate (12.71%) and fingolimod (10.17%). 101 in total (8.85%) reported not using any DMT. Factors associated with hospitalization and/or admission to the ICU included having any comorbidity (p = 0.01), neuromuscular disorder (p = 0.046), hypertension (p = 0.005), chronic kidney disease (p < 0.001), and immunodeficiency (p = 0.003). The type of MS, the duration of the disease, and high-efficacy DMT therapy did not have a statistically significant influence on hospitalization. CONCLUSIONThis study underscores the importance of comorbidities, especially neuromuscular disorders, hypertension, chronic kidney disease (CKD), and immunodeficiencies, as possible prognostic indicators for worse outcomes of COVID-19 in pwMS. On the contrary, the type of MS, the duration of the disease, and the efficacy of disease-modifying therapy did not significantly affect the severity of the symptoms of COVID-19 in this cohort.

Background Social and geographic barriers contribute to worse outcomes in patients with multiple sclerosis (MS) and related disorders, but these factors remain poorly characterized among Latino patients. We evaluated associations between distance to specialty care, neighborhood deprivation, insurance status, and clinical outcomes among Latinos with MS and related disorders. Methods We conducted a retrospective study of Latino adults with MS, neuromyelitis optica spectrum disorder, and myelin oligodendrocyte glycoprotein antibody-associated disease. Demographic, clinical, and socioeconomic variables were abstracted from the medical record. Distance to care was defined as residence [&ge;]50 vs. <50 miles from clinic and neighborhood deprivation as Area Deprivation Index (ADI) state rank. We used unadjusted and multivariable regression to evaluate associations with Expanded Disability Status Scale (EDSS) score, annualized relapse rate (ARR), and disease-modifying therapy (DMT) non-adherence. Results Among 99 Latino patients, 84 had MS, 11 MOGAD, and 4 NMOSD; 46.5% lived [&ge;]50 miles from clinic. Living [&ge;]50 miles from clinic was associated with higher EDSS scores in unadjusted analyses, but not after covariate adjustment. In multivariable analyses, Medicaid insurance was associated with higher EDSS compared with commercial insurance ({beta}=1.071, p=0.031) and higher ARR ({beta}=0.230, p=0.022). Higher ADI showed a non-significant trend toward higher EDSS ({beta}=0.147 per 1-decile increase, p=0.068). DMT non-adherence was not significantly associated with covariates. Conclusions In this cohort of Latinos with CNS demyelinating diseases, Medicaid insurance was associated with greater disability level and higher relapse activity. These findings suggest that insurance status should be considered when designing strategies to improve access to neuroimmunology care.

ObjectivesTo examine whether the dynamic range of 1.25% low-contrast visual acuity (LCVA) measurement in MS patients with optic neuritis (ON) can be improved by using the Early Treatment Diabetic Retinopathy Study (ETDRS) letter scoring method. MethodsLCVA was tested using 2.5% and 1.25% low contrast ETDRS-style 4m Sloan letter charts. When [&ge;]20 letters were read correctly, the letter score was equal to letter count plus 30. If <20 letters were read correctly, the letter score was equal to letter count at 4m plus the total number of letters read correctly at 1m. Results51 relapsing-remitting MS patients with unilateral ON were enrolled and 60.8% ON eyes had a 1.25% LCVA letter count worse than 1 line (5 letters). In ON eyes with <20 letter count, ETDRS letter score showed a significantly improved correlation with both macular GCIPL thickness (r=0.71, p<0.0001; vs r=0.31, p=0.08 for letter count) and VEP latency (r=-0.47, p=0.003; vs r=-0.15, p=0.4 for letter count). DiscussionGiven ON with VEP monitoring has been frequently used as a model in MS remyelination clinical trials, our proposed ETDRS-style LCVA letter scoring method may be considered to enhance the functional outcome measure, which is necessary for regulatory approval.

BackgroundNatalizumab is a high-efficacy therapy for RRMS. While EID may reduce PML risk, critical gaps persist in understanding post-cessation outcomes, posing urgent clinical challenges for neurologists discontinuing treatment. ObjectivesTo compare efficacy/safety of natalizumab SID vs. EID and quantify relapse/disability risk after cessation in adults with RRMS. MethodsWe conducted a systematic review/meta-analysis (PROSPERO: CRD420251103014) following PRISMA guidelines. We searched MEDLINE, Cochrane Library, ClinicalTrials.gov, and other sources (2015-2025) for RCTs and observational studies. Primary outcomes: ARR and disability progression; secondary: PML incidence and post-cessation relapse. Risk of bias was assessed using Cochrane RoB 2.0 and ROBINS-I. Data were synthesized narratively or via meta-analysis, with evidence certainty graded (GRADE). ResultsTwenty-eight studies (n=45,803) were included. The key finding was a substantial 41.7% (95% CI 30.8-53.6%) pooled relapse risk within 12 months of cessation (4 studies, n=857) using a random-effects model. Sensitivity analysis excluding the outlier study (Weinstock-Guttman 2016) showed a relapse risk of 36.9% (95% CI 33.7-40.3%). Narrative synthesis of ARR (9 studies) showed no consistent SID vs. EID difference (median difference 0.00). Meta-analysis of PML risk (3 studies) found no significant difference (RR 0.70, 95% CI 0.20-2.54). Disability outcomes were too heterogeneous for meta-analysis. Evidence certainty was low for most outcomes. ConclusionThis review demonstrates a substantial 41.7% relapse risk within 12 months of natalizumab cessation, representing the most critical clinical implication. While EID may maintain efficacy comparable to SID, the high withdrawal relapse rate necessitates prompt therapy transition and patient counseling. Treatment decisions must encompass the entire continuum from initiation to discontinuation.

ObjectivesMultiple sclerosis (MS) is a complex autoimmune neurological disorder that frequently impacts vision. One of the most frequent initial presentations of MS is acute vision loss due to optic neuritis, an acute disorder caused by MS involvement with the optic nerve. While vision impairment is often the first sign of MS, it can occur or recur at any time during the patients course. In this study, we aim to develop and evaluate machine learning models to predict vision impairment in patients with MS, both at the time of first MS diagnosis and throughout their course of care. Early awareness and intervention in patients likely to have vision loss can help preserve patient quality of life. Materials and MethodsUsing the Epic Cosmos de-identified electronic health record (EHR) dataset, we queried 213+ million patients to extract our MS cohort. Cases were defined as MS patients with vision impairment or optic neuritis (VI) following their first MS diagnosis, while controls were MS patients without VI. We trained logistic regression (LR), light gradient boosting machine (LGBM), and recurrent neural network (RNN) models to predict future VI in MS patients. The models were evaluated for two distinct clinical tasks: prediction of VI at the time of the first MS diagnosis and prediction of VI at the most recent visit. Similarly, we trained the models on different segments of the patient trajectory including up until the first MS diagnosis (MS-First Diagnosis), or until the most recent visit before developing the outcome (MS-Progress) as well as the combination of both (MS-General). Finally, we trained a survival model with the goal of predicting patient likelihood of vision loss over time. We compared the models performance using AUROC, AUPRC, and Brier scores. ResultsWe extracted a cohort of 377,097 patients with MS, including 42,281 VI cases. Our trained models achieved [~]80% AUROC, with RNN-based models outperforming LGBM and LR (79.6% vs 72.8% and 68.6%, respectively) when considering the full patient trajectory. The MS-General RNN model had the highest AUROC (64.4%) for predicting VI at the first MS diagnosis. The MS-Progress survival model achieved a 75% concordance index on the full trajectory, while the more clinically relevant MS-First Diagnosis model achieved 63.1% at initial diagnosis. Discussion and ConclusionThe MS-Progress and MS-General RNN models performed best in both prediction scenarios. While MS-General achieved the best performance at the time of first MS diagnosis with around 1% AUROC increase compared to the MS-First Diagnosis model, it showed around 1% AUROC decrease on the MS progress scenario. All RNN survival models performed the best when they were trained on data corresponding to the evaluation use-case scenarios. RNN based models showed promising performance that demonstrates that they can be useful clinical tools to predict risk of future VI events in patients with MS. Further development of these models will focus on expanding to predict other comorbidities associated with MS relapse or progression.

IntroductionMultiple sclerosis (MS) is a chronic progressive neurological disease. There is ample evidence that exercise can be beneficial. The advancement of modern technology led to improvements in the way therapy can be offered and can make it more motivating, thereby increasing adherence. The primary objective of this two site single blinded randomized control trial (RCT) is to explore the feasibility of conducting a multicentre definite RCT trial with a neuroanimation intervention of high-dose practice in people with mild-to-moderate MS. The secondary objective is to collect data on the variability of outcome measures to inform sample size calculations for a RCT. The tertiary outcome is to assess if this intervention changes exercise behaviour. Methods and analysisThis study is in preparation for a future definitive randomised control trial (RCT) where the efficacy compared to a dose matched control therapy will be assessed. The setting for this study is a research laboratory at Edith Cowan University (ECU) and a neurological service provider, Multiple Sclerosis Society of Western Australia (MSWA). This feasibility study will recruit people with MS who have mild to moderate disability. Subjects will participate in 24 session, 2 times a week, of 60 minutes time-on-task intense arm training, using an exergaming system. Participants will undergo a follow up within 3 days and at 6 months after the final study visit. Ethics and disseminationThis study was approved by the local Ethics Committee of Edith Cowan University. Subjects will be included after signing informed consent. Study outcomes will be disseminated through presentations at scientific conferences and through peer-reviewed journals. Trial registrationACTRN12622000281796 Strengths and limitations of this studyO_LIThe study intervention is a newly developed exercise intervention protocol designed to be engaging and motivating C_LIO_LINext to investigating primary efficacy in order to determine sample size for a larger trial, the study also uses implementation science to assess future obstacles in a follow up randomized control trial C_LIO_LIThe feasibility of conducting a larger trial will be based on standardised criteria regarding process, resource, and management metrics C_LIO_LIThis study without a control group demonstrates feasibility rather than efficacy C_LI

ObjectiveCardiopulmonary Exercise Testing (CPET) is challenging among persons with mobility disability. We sought the optimal adapted device to achieve a maximal CPET. DesignRandomized crossover trial, within-subjects, repeated measures design SettingPrimary Care and Referral Center ParticipantsClinic-referred persons with multiple sclerosis (PwMS) (n=10) with three-month stability, no exercise obstruction, MoCa>24, ability to walk with or without assistance, and sex- and age-matched ({+/-}3 years) Controls (n=7) recruited by convenience sampling InterventionsCPET on body weight-supported treadmill (BWST) and total body recumbent stepper (TBRS) Main Outcome MeasuresStandard aerobic metrics ([V]O2max, % normative values for [V]O2max [%[V]O2max], heart rate maximum [HRmax], age-predicted HRmax, and Respiratory Exchange Ratio) ResultsPwMS achieved similar [V]O2max (mL{middle dot}min-1{middle dot}kg-1) on the TBRS and BWST (26.53{+/-}8.7 vs. 24.24{+/-}7.8) while Controls obtained higher values on BWST than TBRS (40.27{+/-}7.6 vs. 34.32{+/-}7.1, p<0.001). PwMS more consistently achieved criteria for maximum CPET using TBRS. During the preliminary investigation of the MS subgroup with a higher mobility disability, CPET using BWST exaggerated already low CPET metrics. ConclusionsAlthough Controls achieved higher CPET values on BWST, [V]O2max between devices were similar among PwMS. Only when using BWST, PwMS [V]O2max and %[V]O2max were lower than Controls, likely because of leg fatigue and weakness. Using TBRS permits persons with mobility disability to achieve more criteria for a maximum CPET. Our results suggest that CPET using BWST, being reliant on the lower body, likely disadvantages PwMS, especially those with mobility disability.

IntroductionMultiple Sclerosis (MS) is a debilitating neurodegenerative disease in which demyelination due to auto-inflammation is considered to be the underlying pathogenesis, though the exact etiology is not known. Most of the management strategies involve medications that are anti-inflammatory or immune-suppressive, which do have associated side effects. In this study we have evaluated in MS patients, the clinical effects of a novel beta-glucan which has a track record of anti-inflammatory, immune-modulating potentials in earlier clinical and pre-clinical studies. MethodThe study involved 12 MS patients who consumed two sachets of N-163 strain of Aureobasidium pullulans produced B-Glucan, daily for 60 days along with routine medication. ResultsThe Expanded Disability Status Scale (EDSS) improved by 0.5 in two patients and by 1 in one patient post-intervention, worsened in 1 patient, remaining stable in the rest. Decrease in IL-6, improvement in CD4+ve, CD19+ve, CD3+ve, and CD8+ ve cell count, increase in Lymphocyte to C-reactive protein ratio (LCR), Leukocyte to CRP ratio (LeCR) and a decrease in Neutrophil to Lymphocyte ratio (NLR) were observed. ConclusionThis study having proven the safety of N-163 strain of A.pullulans produced B-Glucan food supplement and the efficacy by improvement in the EDSS score, besides beneficial modulation of inflammation and immune parameters of relevance in MS patients in a short duration of 60 days, has significant potential as a disease modifying adjuvant in MS. Immunological parameters like NLR, LCR, LeCR correlating with clinical improvement, in line with earlier reports using the same beta-glucans, gain further significance for their potentials as biomarkers in MS.

BackgroundAccelerated long-term forgetting (ALF), defined as an increased rate of memory loss over extended intervals, has so far been detected in a pilot study of patients with mild multiple sclerosis (MS). This study aimed to (I) confirm the presence of ALF in a larger, heterogeneous MS sample, (II) explore associations with patient-reported outcomes, and (III) assess the diagnostic performance of ALF tests for subjective memory impairment. MethodsThis study compared 62 MS patients and 65 age-, sex-, and education-matched healthy controls using standardized memory tests (RAVLT, WMS-IV Logical Memory subtest). Recall was assessed immediately, after 30 minutes, and after 7 days. Seven-day/30-minute recall ratios (QRAVLT, QWMS) served as primary outcomes. Self-report measures included memory complaints, fatigue, depression, and sleep disturbances. Linear regression and Receiver operating characteristic (ROC) analyses assessed predictors and diagnostic accuracy. ResultsALF was observed in multiple sclerosis since QRAVLT was lower in patients than in controls (0.64 [95% CI 0.59-0.69] vs. 0.78 [0.73-0.82], p < 0.001), as was QWMS (0.79 [95% CI 0.74-0.84] vs. 0.95 [0.90-1.00], p < 0.001), despite comparable initial learning. Greater fatigue, higher memory complaints, longer disease duration, older age, and greater disability were associated with lower ALF scores. The combined ALF score moderately discriminated subjective memory impairment (AUC 0.74; sensitivity 0.73; specificity 0.73). ConclusionMS patients showed ALF despite normal initial learning, indicating a specific memory deficit undetected by standard tests. Long-delay recall using RAVLT and WMS-IV Logical Memory subtest may improve cognitive impairment detection in MS.

ObjectiveThe field of multiple sclerosis (MS) has seen a tremendous expansion of treatments in the past decade. However, treatment response in individual patients can currently be determined only by waiting for breakthrough disease activity to occur. This highlights a critical need for biomarkers that can predict treatment response and stratify the risk of impeding disease activity before damage is inflicted to the CNS. Here we show that CCR6+CD3+ T-cell surveillance in peripheral blood can be used to discriminate responders and non-responders to dimethyl-fumarate. MethodsA cohort of 101 treatment-naive, dimethyl-fumarate (DMF) treated MS patients and healthy controls was immunophenotyped and then responders and non-responders were determined retrospectively after clinical and radiographic follow up. Receiver operating characteristic (ROC) curve, linear and logistic regression, mixed effects models, and cox proportional hazards were used for the analysis. ResultsAmong various clinical and immunophenotypic metrics, the percentage of CCR6+CD3+ T-cells was the most significant predictor of impending disease activity. This immunophenotypic metric was able to discriminate responders and non-responders to DMF with an area under the ROC of 0.85 (95% CI: 0.71-0.99), which was higher than that achieved using surrogate metrics for T-helper-1-like T-helper-17 or T-cytotoxic-17 cells. DMF-treated patients with the highest percentage of CCR6+CD3+ T-cells had a significantly higher risk of impending disease activity compared to patients with a low percentage. InterpretationChanges in CCR6+CD3+ T-cells in the periphery could precede disease activity by many months and potentially serve as an early biomarker of treatment response, at least for DMF. These results have implications for novel personalized treatment strategies in MS.

BackgroundDiabetes (DM), a common comorbidity, results in poorer cognition in people with multiple sclerosis (PwMS). Metformin may be a treatment option given cognitive benefits. Metformin represses monoacylglycerol lipase (Mgll), accompanied by improvements in cognition in animals. AimsTo determine 1) whether metformin represses Mgll in humans, 2) if Mgll correlates with cognition/emotion recognition, and 3) if cognition differs between groups. MethodsA convenience sample of seventeen PwMS and DM on metformin, 4 with MS and DM not on metformin, 10 with MS, and 21 healthy controls completed BICAMS and measures of premorbid ability, emotion recognition, mood and fatigue. Blood draw established Mgll levels. T-tests determined group differences in Mgll. Correlational analyses examined if Mgll correlated with cognition. ANCOVA evaluated differences in cognition/emotion recognition. ResultsGiven small samples, we combined groups to determine if metformin impacted Mgll regardless of diabetes status. Significant differences in Mgll (t = -2.07, p = .05), suggested that metformin suppresses Mgll. No relationship was found between Mgll and cognition/emotion recognition. Differences were found between PwMS and DM compared to controls in verbal learning (F = 5.85, p = .02) and memory (F = 5.62, p = .02). ConclusionsMetformin suppresses Mgll in humans suggesting metformin be evaluated as a potential MS treatment. Mgll did not correlate with cognition possibly due to sample size or methodology. Combined impact of MS and DM negatively impacts cognition, supporting literature demonstrating that vascular comorbidity increases risk of cognitive dysfunction. Findings support pursuing clinical trials evaluating metformin efficacy.