The potential impact of disease-modifying therapies (DMTs) for multiple sclerosis (MS) on COVID-19 vaccination is poorly understood. According to recent observations, the humoral immune response ...could be impaired in patients treated with ocrelizumab or fingolimod. Our study evaluated the immunogenicity and safety of mRNA COVID-19 vaccines in a convenience sample of 140 MS patients treated with different DMTs, undergoing vaccination between April and June 2021. Humoral immune response was tested 1 month after the second dose, using a chemiluminescent microparticle immunoassay to detect IgG against SARS-CoV-2 nucleoprotein. We explored the potential correlation between the IgG titer and DMTs. All patients in treatment with first-line DMTs, natalizumab, cladribine, and alemtuzumab, developed a measurable humoral response. In patients treated with ocrelizumab and fingolimod, the IgG level was significantly lower, but only some patients (22.2% for fingolimod and 66% for ocrelizumab) failed to develop a measurable humoral response. In the ocrelizumab group, the IgG level was positively correlated with the time from last infusion. No SARS-CoV-2 infections were reported after vaccination. The most reported side effects were pain at the injection site (57.1%) and fatigue (37.9%). No patient experienced severe side effects requiring hospitalization. Our study confirms that COVID-19 vaccination is safe and well-tolerated in MS patients and should be recommended to all patients regardless of their current DMTs. Since fingolimod and ocrelizumab could reduce the humoral immune response, in patients treated with these drugs, detecting SARS-CoV-2 antibodies could be helpful to monitor the immune response after vaccination.
Objectives
To evaluate the accuracy of a data-driven approach, such as machine learning classification, in predicting disability progression in MS.
Methods
We analyzed structural brain images of 163 ...subjects diagnosed with MS acquired at two different sites. Participants were followed up for 2–6 years, with disability progression defined according to the expanded disability status scale (EDSS) increment at follow-up. T2-weighted lesion load (T2LL), thalamic and cerebellar gray matter (GM) volumes, fractional anisotropy of the normal appearing white matter were calculated at baseline and included in supervised machine learning classifiers. Age, sex, phenotype, EDSS at baseline, therapy and time to follow-up period were also included. Classes were labeled as stable or progressed disability. Participants were randomly chosen from both sites to build a sample including 50% patients showing disability progression and 50% patients being stable. One-thousand machine learning classifiers were applied to the resulting sample, and after testing for overfitting, classifier confusion matrix, relative metrics and feature importance were evaluated.
Results
At follow-up, 36% of participants showed disability progression. The classifier with the highest resulting metrics had accuracy of 0.79, area under the true positive versus false positive rates curve of 0.81, sensitivity of 0.90 and specificity of 0.71. T2LL, thalamic volume, disability at baseline and administered therapy were identified as important features in predicting disability progression. Classifiers built on radiological features had higher accuracy than those built on clinical features.
Conclusions
Disability progression in MS may be predicted via machine learning classifiers, mostly evaluating neuroradiological features.
In this independent, multicenter, post-marketing study, we directly compare induction immunosuppression versus escalation strategies on the risk of reaching the disability milestone of Expanded ...Disability Status Scale (EDSS) ≥ 6.0 over 10 years in previously untreated patients with relapsing-remitting multiple sclerosis. We collected data of patients who started interferon beta (escalation) versus mitoxantrone or cyclophosphamide (induction) as initial treatment. Main eligibility criteria included an EDSS score ≤ 4.0 at treatment start and either ≥ 2 relapses or 1 disabling relapse with evidence of ≥ 1 gadolinium-enhancing lesion at magnetic resonance imaging scan in the pre-treatment year. Since patients were not randomized to treatment group, we performed a propensity score (PS)–based matching procedure to select individuals with homogeneous baseline characteristics. Comparisons were then conducted using Cox models stratified by matched pairs. Overall, 75 and 738 patients started with induction and escalation, respectively. Patients in the induction group were older and more disabled than those in the escalation group (
p
< 0.05). The PS-matching procedure retained 75 patients per group. In the re-sampled population, a lower proportion of patients reached the outcome after induction (21/75, 28.0%) than escalation (29/75, 38.7%) (hazard ratio = 0.48;
p
= 0.024). Considering the whole sample, serious adverse events occurred more frequently after induction (8/75, 10.7%) than escalation (18/738, 2.4%) (odds ratio = 3.36,
p
= 0.015). These findings suggest that, in patients with poor prognostic factors, induction was more effective than escalation in reducing the risk of reaching the disability milestone, albeit with a worse safety profile. Future studies are warranted to explore if newer induction agents may provide a more advantageous long-lasting risk:benefit profile.
OBJECTIVETo directly compare fingolimod (FNG) and dimethyl fumarate (DMF) on no evident disease activity (NEDA) status in patients with relapsing-remitting multiple sclerosis (RRMS) from 7 multiple ...sclerosis outpatient clinics in Central Italy.
METHODSWe analyzed data of patients with RRMS who started an oral agent, namely DMF or FNG, either as first treatment (naives) or after switching from self-injectable drugs (switchers). We performed a propensity score (PS)–based nearest-neighbor matching within a caliper of 0.05 to select patients with homogeneous baseline characteristics. Pairwise censoring was adopted to adjust for difference in length of follow-up between the 2 treatment groups. Comparisons were then conducted in matched samples with Cox models (stratified by center) with NEDA-3 as the main outcome. NEDA-3 was defined as no relapses, no disability worsening, and no MRI activity.
RESULTSOverall, 483 and 456 patients eligible for analysis started on FNG and DMF, respectively. The PS-matching procedure retained a total of 550 patients (275 per group). After a median on-study follow-up of 18 months, the proportions of patients with NEDA-3 were similar (FNG 73%, DMF 70%; hazard ratio HR 0.74, p = 0.078). Subgroup analyses showed a comparable effectiveness of the 2 drugs in naives (n = 170, HR 1.15, p = 0.689), whereas FNG was superior to DMF in the achievement of NEDA-3 status among switchers (n = 380, HR 0.57, p = 0.007).
CONCLUSIONWe found no significant difference between FNG and DMF on NEDA-3 status, while subgroup analyses suggest the superiority of FNG over DMF in patients switching from self-injectable drugs.
CLASSIFICATION OF EVIDENCEThis study provides Class IV evidence that for patients with RRMS, DMF and FNG have comparable efficacy in treatment-naive patients and that FNG is superior to DMF in patients switching from self-injectable drugs.
As atrophy represents the most relevant driver of progression in multiple sclerosis (MS), we investigated the impact of different patterns of brain and spinal cord atrophy on disability worsening in ...MS. We acquired clinical and MRI data from 90 patients with relapsing–remitting MS and 24 healthy controls (HC). Clinical progression at follow-up (mean 3.7 years) was defined according to the Expanded Disability Status Scale-Plus. Brain and spinal cord volumes were computed on MRI brain scans. After normalizing each participants’ brain and spine volume to the mean of the HC, z-score cut-offs were applied to separate pathologically atrophic from normal brain and spine volumes (accepting a 2.5% error probability). Accordingly, MS patients were classified into four groups (Group I: no brain or spinal cord atrophy
N
= 40, Group II: brain atrophy/no spinal cord atrophy
N
= 11, Group III: no brain atrophy/ spinal cord atrophy
N
= 32, Group IV: both brain and spinal cord atrophy
N
= 7). All patients’ groups showed significantly lower brain volume than HC (
p
< 0.0001). Group III and IV showed lower spine volume than HC (
p
< 0.0001 for both). Higher brain lesion load was identified in Group II (
p
= 0.049) and Group IV (
p
= 0.023) vs Group I, and in Group IV (
p
= 0.048) vs Group III. Spinal cord atrophy (OR = 3.75,
p
= 0.018) and brain + spinal cord atrophy (OR = 5.71,
p
= 0.046) were significant predictors of disability progression. The presence of concomitant brain and spinal cord atrophy is the strongest correlate of progression over time. Isolated spinal cord atrophy exerts a similar effect, confirming the leading role of spinal cord atrophy in the determination of motor disability.
We assessed 168 patients with multiple sclerosis (MS) by force platform to obtain the dual-task cost (DTC) of balance, that is, the change in postural sway from quiet standing to dual-task condition ...(Stroop test). After a median follow-up time of 3.5 years from this assessment, disability progression occurred in 45 (27%) patients. Disability progression was predicted by the adoption of a ‘posture second’ strategy, that is, values of DTC of balance exceeding those obtained from 62 healthy controls, even after controlling by demographic and clinical characteristics. The DTC of balance may potentially represent a novel and easy tool to predict MS progression.
Objective:
To investigate the disease-altered structure–function relationship underlying the cognitive–postural interference (CPI) phenomenon in multiple sclerosis (MS).
Methods:
We measured postural ...sway of 96 patients and 48 sex-/age-matched healthy controls by force platform in quiet standing (single-task (ST)) while performing the Stroop test (dual-task (DT)) to estimate the dual-task cost (DTC) of balance. In patient group, binary T2 and T1 lesion masks and their corresponding lesion volumes were obtained from magnetic resonance imaging (MRI) of brain. Normalized brain volume (NBV) was also estimated by SIENAX. Correlations between DTC and lesion location were determined by voxel-based lesion symptom mapping (VLSM) analyses.
Results:
Patients had greater DTC than controls (p < 0.001). Among whole brain MRI metrics, only T1 lesion volume correlated with DTC (r = −0.27; p < 0.01). However, VLSM analysis did not reveal any association with DTC using T1 lesion masks. By contrast, we found clusters of T2 lesions in distinct anatomical regions (anterior and superior corona radiata, bilaterally) to be correlated with DTC (p < 0.01 false discovery rate (FDR)-corrected). A multivariable stepwise regression model confirmed findings from VLSM analysis. NBV did not contribute to fit the model.
Conclusion:
Our findings suggest that the CPI phenomenon in MS can be explained by disconnection along specific areas implicated in task-switching abilities and divided attention.
Background:
Frailty is an age-related status of increased vulnerability to stressors caused by the accumulation of multiple health deficits. This construct may allow to capture the clinical ...complexity of patients with multiple sclerosis (MS).
Objective:
To investigate the relationship between frailty and the clinical manifestations of MS.
Methods:
Patients with MS were consecutively enrolled at five tertiary dedicated services. Disability and fatigue were assessed. The phenotypes of MS were also identified. Frailty was measured using a frailty index (FI), computed by cumulatively considering 42 age-related multidimensional health deficits.
Results:
Overall, 745 MS patients (mean age = 48.2 years, standard deviation = 11.7 years; women 68%) were considered. The median FI value was 0.12 (interquartile range = 0.05–0.19) and the 99th percentile was 0.40. FI scores were associated with MS disease duration, disability, fatigue, as well as with the number of previous disease-modifying treatments and current symptomatic therapies. A logistic regression analysis model showed that FI score was independently associated with the secondary progressive phenotype.
Conclusion:
Frailty is significantly associated with major characteristics of MS. The findings of the present cross-sectional investigation should be explored in future longitudinal studies.
Background
Premorbid physically and intellectually enriching lifestyles have increasingly been recognized as able to mitigate the risk of disease-related disability in patients with multiple ...sclerosis (MS).
Objective
To explore if premorbid physical activity, cognitive reserve and trait personality act as proxies for functional reserve that contributes to rehabilitation outcome.
Methods
We recruited all patients previously enrolled in two pilot trials investigating the effect of home-based video game training in improving balance (Study 1) and attention (Study 2) for additional assessments with the Historical Leisure Activity Questionnaire (HLAQ; a proxy for premorbid physical activity), Cognitive Reserve Index Questionnaire (CRIQ), and Temperament and Character Inventory (TCI). Hierarchical logistic regression (HLR) analyses tested the association of HLAQ, CRIQ, and TCI with training effect on balance (static posturography) and on attention (Symbol Digit Modalities Test).
Results
We identified 94% (34/36) and 74% (26/35) of patients participating at the original Study 1 and Study 2, respectively. HLR analyses showed an exclusive “intra-modal” modulation of rehabilitation outcome by functional reserve, given that (1) larger training effect on balance was associated with higher HLAQ (OR = 2.03,
p
= 0.031); (2) larger training effect on attention was associated with higher CRIQ (OR = 1.27,
p
= 0.033). Furthermore, we found specific personality traits associated with (1) greater training effect on balance (self-directedness; OR = 1.40,
p
= 0.051) and lower training effect on attention (harm avoidance; OR = 0.66,
p
= 0.075).
Conclusion
We hypothesize that premorbid physical and intellectual activities not only act as a buffer for limiting the MS-related damage but also as functional reserve that can be retrieved by task-oriented training to promote recovery through rehabilitation.
Purpose
In multiple sclerosis (MS), how brain functional changes relate to clinical conditions is still a matter of debate. The aim of this study was to investigate how functional connectivity (FC) ...reorganization at three different scales, ranging from local to whole brain, is related to tissue damage and disability.
Methods
One-hundred-nineteen patients with MS were clinically evaluated with the Expanded Disability Status Scale and the Multiple Sclerosis Functional Composite. Patients and 42 healthy controls underwent a multimodal 3 T MRI, including resting-state functional MRI.
Results
We identified 16 resting-state networks via independent component analysis and measured within-network, between-network, and whole-brain (global efficiency and degree centrality) FC. Within-network FC was higher in patients than in controls in default mode, frontoparietal, and executive-control networks, and corresponded to low clinical impairment (default mode network versus Expanded Disability Status Scale
r
= − 0.31,
p
< 0.01; right frontoparietal network versus Paced Auditory Serial Addition Test
r
= 0.33,
p
< 0.01). All measures of between-network and whole-brain FC, except default mode network global efficiency, were lower in patients than in controls, and corresponded to high disability (i.e., basal ganglia global efficiency versus Timed 25-Foot Walk
r
= − 0.25,
p
< 0.03; default mode global efficiency versus Expanded Disability Status Scale
r
= − 0.44,
p
< 0.001). Altered measures of within-network, between-network, and whole-brain FC were combined in functional indices that were linearly related to disease duration, Paced Auditory Serial Addition Test and lesion load and non-linearly related to Expanded Disability Status Scale.
Conclusion
We suggest that the combined evaluation of functional alterations occurring at different levels, from local to whole brain, could exhaustively describe neuroplastic changes in MS, while increased within-network FC likely represents adaptive compensatory processes, decreased between-network and whole-brain FC likely represent loss of functional network integration consequent to structural disruption.
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