Clinical effectiveness of coronavirus disease 2019 vaccination in patients with multiple sclerosis stratified by disease-modifying treatment.

BACKGROUND AND PURPOSE: Coronavirus disease 2019 (COVID-19) vaccination has been associated with a dampened humoral and/or cellular immune response in patients with multiple sclerosis (MS) who were concurrently on disease-modifying treatment (DMT) with B-cell depleting agents or sphingosine-1-phosphate receptor modulators (S1PRMs). Our main goal was to investigate the impact of these DMT classes on the clinical effectiveness of COVID-19 vaccination. METHODS: Since March 2020, demographics and clinical data of patients with MS who developed COVID-19 have been collected at the Belgian National MS Centre in Melsbroek. Patients were considered to be 'protected by vaccination' if they were (i) fully vaccinated and (ii) tested positive for COVID-19 in the period ranging from 14 days to 6 months after the last administered vaccine. RESULTS: On 19 December 2022, 418 COVID-19 cases were retrospectively identified in 389 individual patients. Hospitalization and mortality rates resulting from the infection were 10.8% and 2.4%, respectively. Being 'unprotected by vaccination' was significantly associated with a worse COVID-19 outcome (i.e., hospitalization and/or death) in the total cohort (N = 418, odds ratio [OR] 3.96), in patients on ongoing DMT other than anti-CD20 agents or S1PRMs (N = 123, OR 31.75) and in patients without DMT (N = 182, OR 5.60), but not in those receiving anti-CD20 agents (N = 91, OR 0.39); the S1PRMs subgroup was considered too small (22 infections) for any meaningful analysis. CONCLUSIONS: Coronavirus disease 2019 vaccination protects against severe infection in patients with MS but it was not possible to confirm this effect in those on DMT with B-cell depleting agents.

The Finger Dexterity Test: Validation study of a smartphone-based manual dexterity assessment.

BACKGROUND: The Nine-Hole Peg Test (9HPT) is the golden standard to measure manual dexterity in people with multiple sclerosis (MS). However, administration requires trained personnel and dedicated time during a clinical visit. OBJECTIVES: The objective of this study is to validate a smartphone-based test for remote manual dexterity assessment, the icompanion Finger Dexterity Test (FDT), to be included into the icompanion application. METHODS: A total of 65 MS and 81 healthy subjects were tested, and 20 healthy subjects were retested 2 weeks later. RESULTS: The FDT significantly correlated with the 9HPT (dominant: ρ = 0.62, p < 0.001; non-dominant: ρ = 0.52, p < 0.001). MS subjects had significantly higher FDT scores than healthy subjects (dominant: p = 0.015; non-dominant: p = 0.013), which was not the case for the 9HPT. A significant correlation with age (dominant: ρ = 0.46, p < 0.001; non-dominant: ρ = 0.40, p = 0.002), Expanded Disability Status Scale (EDSS, dominant: ρ = 0.36, p = 0.005; non-dominant: ρ = 0.31, p = 0.024), and disease duration for the non-dominant hand (ρ = 0.31, p = 0.016) was observed. There was a good test-retest reliability in healthy subjects (dominant: r = 0.69, p = 0.001; non-dominant: r = 0.87, p < 0.001). CONCLUSIONS: The icompanion FDT shows a moderate-to-good concurrent validity and test-retest reliability, differentiates between the MS subjects and healthy controls, and correlates with clinical parameters. This test can be implemented into routine MS care for remote follow-up of manual dexterity.

Occurrence and Severity of Coronavirus Disease 2019 Are Associated With Clinical Disability Worsening in Patients With Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Large-scale observational studies have shown that, in patients with multiple sclerosis (MS), the risk of becoming more severely ill from coronavirus disease 2019 (COVID-19) is determined by older age, male sex, cardiovascular comorbidities, African American ethnicity, progressive disease, recent use of corticosteroids, and B cell-depleting disease-modifying treatment. In contrast, the effect of COVID-19 on the disease course of MS has been studied much less extensively. Our main goal was to explore whether COVID-19 is associated with accelerated clinical disability worsening in patients with MS. METHODS: Since March 2020, demographics and infectious outcome (categorized as ambulatory, hospitalized, and/or death) of patients with MS who developed COVID-19 have been collected at the Belgian National MS Center in Melsbroek. On February 28, 2022, this database was locked and complemented with clinical disability measures-Expanded Disability Status Scale (EDSS), Timed 25-Foot Walk Test (T25FWT), 9-Hole Peg Test (9HPT), and Symbol Digit Modalities Test (SDMT)-that were available from a larger local database, obtained during routine medical follow-up. For each parameter, the first 2 assessments before COVID-19 diagnosis (T0 and T1; T1 is the closest to COVID-19 diagnosis), and the first thereafter (T2), were retrieved. RESULTS: We identified 234 unique cases of COVID-19. Thirty-one patients were hospitalized (13.2%), and 5 died (2.1%) as a result of their infection. Among survivors with complete EDSS results (N = 138), mean annualized T1-to-T2 EDSS worsening was more pronounced, compared with the respective change between T0 and T1 (0.3 ± 0.9 vs 0.1 ± 0.9, p = 0.012). No such differences were found for the T25FWT, 9HPT, and SDMT scores. Severe COVID-19 (hospitalization) was associated with clinically relevant T1-to-T2 EDSS worsening (OR 2.65, p = 0.042). Vaccination coverage in the total cohort was 53.8%. Being unprotected by vaccination at the time of infection was associated with a worse COVID-19 outcome (hospitalization and/or death; OR 3.52, p = 0.002) but not with clinically relevant T1-to-T2 EDSS worsening. DISCUSSION: The occurrence and severity of COVID-19 are both associated with clinical disability worsening in patients with MS. Vaccination protects against a more severe course of COVID-19 in this specific population. TRIAL REGISTRATION INFORMATION: The study has been registered at ClinicalTrials.gov (study registration number: NCT05403463).

Gut microbiome composition is associated with long-term disability worsening in multiple sclerosis.

Predicting the long-term outcome of multiple sclerosis (MS) remains an important challenge to this day. As the gut microbiota is emerging as a potential player in MS, we investigated in this study whether gut microbial composition at baseline is related to long-term disability worsening in a longitudinal cohort of 111 MS patients. Fecal samples and extensive host metadata were collected at baseline and 3 months post-baseline, with additional repeated neurological measurements performed over (median) 4.4 y. Worsening (with EDSS-Plus) occurred in 39/95 patients (outcome undetermined for 16 individuals). The inflammation-associated, dysbiotic Bacteroides 2 enterotype (Bact2) was detected at baseline in 43.6% of worsened patients, while only 16.1% of non-worsened patients harbored Bact2. This association was independent of identified confounders, and Bact2 was more strongly associated with EDSS-Plus than neurofilament light chain (NfL) plasma levels. Furthermore, using fecal sampling performed 3 months post-baseline, we observed Bact2 to be relatively stable, suggesting its potential use as a prognostic biomarker in MS clinical practice.

Plasma glial fibrillary acidic protein and neurofilament light chain in relation to disability worsening in multiple sclerosis.

BACKGROUND: Predicting disability worsening in multiple sclerosis (MS) remains an important challenge. Glial fibrillary acidic protein (GFAP) and neurofilament light chain (NfL) seem promising biomarkers. Studies investigating blood GFAP in relation to longitudinal outcome measures in MS are scarce. OBJECTIVE: To compare plasma-GFAP (p-GFAP) and plasma-NfL (p-NfL) levels in relation to sustained disability worsening. METHODS: We measured baseline p-GFAP and p-NfL in a prospective cohort of 115 individuals with MS and 30 matched controls, using Single Molecule Array (Simoa). Disability worsening was defined as an increase in at least one of three measures (Expanded Disability Status Scale, Timed 25-foot walk, 9-Hole Peg test), confirmed after 6 months and persistent upon data closure. RESULTS: In a multivariable Cox proportional-hazards model, p-GFAP was not significantly associated with sustained disability worsening after 4.40 ± 0.82 years, while p-NfL (HR = 1.046, p = 0.001), EDSS (HR = 1.24, p = 0.039), and disease duration (HR = 1.048, p = 0.017) were. Area under the curve of ROC curves in relation to worsening was 0.61 for p-GFAP (p = 0.031) and 0.63 for p-NfL (p = 0.015). Kaplan-Meier curves showed similar patterns for both proteins. CONCLUSION: p-NfL emerged as a significant explanatory variable for worsening in Cox regression analysis, and p-GFAP did not. Both p-GFAP and p-NfL were related to worsening based on ROC curves.

Gut microbiome variation is associated to Multiple Sclerosis phenotypic subtypes.

OBJECTIVE: Multiple sclerosis (MS) is a heterogenous, inflammatory disease of the central nervous system. Microbiota alterations in MS versus healthy controls (HC) are observed, but results are inconsistent. We studied diversity, enterotypes, and specific gut microbial taxa variation between MS and HC, and between MS subgroups. METHODS: Amplicon sequencing of the 16S ribosomal RNA V4 region (Illumina MiSeq) was used to evaluate alpha and beta diversity, enterotypes, and relative taxa abundances on stool samples. MS subgroups were based on phenotype, disease course modifiers, and treatment status. Results were controlled for recently identified confounders of microbiota composition. RESULTS: Ninety-eight MS patients and 120 HC were included. Microbial richness was lower in interferon-treated (RRMS_I, N = 24) and untreated relapsing-remitting MS during relapse (RRMS_R, N = 4) when compared to benign (BMS, N = 20; Z = -3.07, Pcorr = 0.032 and Z = -2.68, Pcorr = 0.055) and primary progressive MS (PPMS, N = 26; Z = -2.39, Pcorr = 0.062 and Z = -2.26, Pcorr = 0.071). HC (N = 120) and active untreated MS (RRMS_U, N = 24) showed intermediate microbial richness. Enterotypes were associated with clinical subgroups (N = 218, χ2  = 36.10, P = 0.002), with Bacteroides 2 enterotype being more prevalent in RRMS_I. Butyricicoccus abundance was lower in PPMS than in RRMS_U (Z = -3.00, Pcorr = 0.014) and BMS (Z = -2.56, Pcorr = 0.031), lower in RRMS_I than in BMS (Z = -2.50, Pcorr = 0.034) and RRMS_U (Z = -2.91, Pcorr = 0.013), and inversely correlated with self-reported physical symptoms (rho = -0.400, Pcorr = 0.001) and disease severity (rho = -0.223, P = 0.027). INTERPRETATION: These results emphasize the importance of phenotypic subcategorization in MS-microbiome research, possibly explaining previous result heterogeneity, while showing the potential for specific microbiome-based biomarkers for disease activity and severity.

Correlations of health status indicators with perceived neuropsychological impairment and cognitive processing speed in multiple sclerosis.

BACKGROUND: Comorbidity and health behaviours may explain heterogeneity regarding cognitive performance in multiple sclerosis. Patient-reported cognitive difficulties have impact but do not consistently correlate with objective cognitive performance. Our study aims to investigate whether health status indicators including comorbidities, body mass index, physical activity, smoking, sleeping behaviour and consumption patterns for fish, alcohol and caffeinated drinks are associated with measures of subjective and objective cognitive performance. METHODS: Survey data on self-reported cognitive performance, assessed with the MS Neuropsychological Screening Questionnaire (MSNQ), were related to the presence of arterial hypertension, diabetes mellitus, cardiovascular and chronic renal diseases, hypercholesterolemia, depression based on 2-question screening tool, health and consumption behaviors. We included the Symbol Digit Modalities Test when available within 6 months as an objective, performance-based metric of cognitive processing speed. We investigated the interrelation between all variables with a Spearman correlation matrix and corrected for multiple testing. Regression models were built and controlled for age, sex and phenotype. RESULTS: We used available data from 751 patients with definite MS, including 290 SDMT scores within a time window of 6 months, to study relations between variables. MSNQ and SDMT scores were not significantly correlated. Correlation patterns for subjective and objective performance differed. Age, disease duration and physical disability correlated with SDMT scores only. Regression analyses could be performed for MSNQ scores in 595/751 (79.2%) and for SDMT scores in 234/751 (31.2%) participants. After restricting variables to avoid collinearity and adjusting for the number of variables, regression models explained 15% of the variance for subjective and 14% of the variance for objective cognitive performance. A higher number of physical comorbidities, reporting depressive symptoms, sleeping 9 h or more and daily use of sleeping medication were associated with lower subjective cognitive performance, whereas increasing age was associated with reduced processing speed. These associations persisted after correction for multiple testing. CONCLUSION: Increasing age is associated with reduced cognitive processing speed whereas comorbidities and sleep behaviors contribute to subjective cognitive performance.

Relation between Heart Rate Variability and Disease Course in Multiple Sclerosis.

Little is known about the interplay between the autonomic nervous system and disease activity in multiple sclerosis (MS). We examined the relationship between heart rate variability (HRV), a reliable measure of vagal nerve function, and disease characteristics in a prospective MS cohort. Standard deviation of each normal-to-normal inter-beat interval (SDNN) and root mean square of successive differences (RMSSD), global indices of HRV, were measured in 114 MS patients, which included four predefined subgroups, and 30 age and sex-matched healthy controls (HC). We assessed group differences at baseline, HRV reproducibility at month 3, and used logistic regression modeling to relate baseline HRV with relapse occurrence. No significant HRV differences were found between MS and HC and between MS subgroups. In MS patients, both HRV indices correlated with age (r = -0.278, p = 0.018 and r = -0.319, p < 0.001, respectively) and with month 3 assessments (r = 0.695 and r = 0.760, p < 0.001). Higher SDNN and RMSSD at baseline were associated with self-reported relapses at month 3 (OR = 1.053, 95% CI (1.013-1.095), p = 0.009 and OR = 1.065, 95% CI (1.016-1.117), p = 0.009), and SDNN at baseline with relapses at month 12 (OR = 1.034, 95% CI (1.009-1.059), p = 0.008; ROC, AUC = 0.733, p = 0.002). There were no baseline HRV differences between MS and HC or between subgroups. Post-hoc analysis showed an association with an increased relapse risk.

The Impact of Cognitive Dysfunction on Locomotor Rehabilitation Potential in Multiple Sclerosis.

BACKGROUND: Cognitive dysfunction is a frequent manifestation of multiple sclerosis (MS) but its effect on locomotor rehabilitation is unknown. OBJECTIVE: To study the impact of cognitive impairment on locomotor rehabilitation outcome in people with MS. METHODS: We performed a retrospective analysis involving ambulatory patients with MS who were admitted for intensive, inpatient, multidisciplinary rehabilitation at the National Multiple Sclerosis Center of Melsbroek between the years 2012 and 2017. The Brief Repeatable Battery of Neuropsychological Tests (BRB-N) was used to determine the cognitive status of subjects as either impaired (COG-) or preserved (COG+). Locomotor outcome was compared between groups with the difference in 6-minute walk test (6MWT) measured at admission and discharge (Δ6MWT). In addition, individual test scores of the BRB-N for attention (Paced Auditory Serial Addition Test 2" and 3"), visuospatial learning/memory (7/24 Spatial Recall Test), verbal learning/memory (Selective Reminding Test) and verbal fluency (Controlled Oral Word Association Test) were correlated to the Δ6MWT. RESULTS: A total of 318 complete and unique records were identified. Both groups showed a significant within-group Δ6MWT during hospitalization (COG+: 47.51 m; COG-: 40.97 m; P < .01). In contrast, Δ6MWT values were comparable between groups. The odds of achieving a minimal clinical important difference on the 6MWT did not differ significantly between both groups. Only attention/concentration was significantly correlated with Δ6MWT (r = 0.16, P = .013). CONCLUSION: Cognitive impairment based on BRB-N results appears not to impede locomotor rehabilitation in ambulatory patients with MS. Attentional deficits are correlated to the extent of locomotor rehabilitation, suggesting the presence of a subtle effect of cognition.

Single MRI-Based Volumetric Assessment in Clinical Practice Is Associated With MS-Related Disability.

BACKGROUND: The added value of brain volume measurements in the clinical practice of multiple sclerosis (MS) has been questioned. PURPOSE: To investigate the contribution of volume measures obtained with magnetic resonance scans performed as part of regular care to predict measures of cognitive and physical MS disability in a real-world setting. STUDY TYPE: Retrospective. SUBJECTS: In all, 470 adults with diagnosed MS. FIELD STRENGTH/SEQUENCE: 3D fluid attenuation inversion recovery (FLAIR) and 3D T1 -weighted MR images at 3.0T MR. ASSESSMENT: Lesion and brain volume were measured by an automated method, MSmetrix, developed by icometrix. STATISTICAL TESTS: We used stepwise linear regression models to assess the added value of a single volumetric assessment in predicting Expanded Disability Status Scale (EDSS) and Symbol Digit Modalities Test (SDMT). Brain volumes categorized into quartiles were used as predictive variables in a time-to-event analysis and Cox proportional hazard regression with time to worsening from baseline as outcome measures. RESULTS: Brain and lesion volume in relapsing onset MS strongly contributed to the best models, with a substantial role for age in the EDSS model and a modest role for education in the SDMT model. Adding MR volumetric information increased the explained variance from 17% to 28% in the best model for EDSS and from 9% to 25% in the best model for SDMT. A significantly reduced hazard (P < 0.05) of SDMT worsening was found in the highest normalized brain volume quartiles (1375-1608 ml), compared with the lowest quartile (1201-1374 ml) in the total study population. DATA CONCLUSION: Our findings indicate that a single brain volumetric assessment contributes to the prediction of MS-related disability, with distinct patterns for EDSS as a measure of physical disability, and SDMT as a measure of cognitive disability. A threshold effect for the lowest brain volumes with regard to SDMT worsening over time was found. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:1312-1321.