Evoked potentials (EPs) are a measure of the conductivity of the central nervous system. They are used to monitor disease progression of multiple sclerosis patients. Previous studies only extracted a ...few variables from the EPs, which are often further condensed into a single variable: the EP score. We perform a machine learning analysis of motor EP that uses the whole time series, instead of a few variables, to predict disability progression after two years. Obtaining realistic performance estimates of this task has been difficult because of small data set sizes. We recently extracted a dataset of EPs from the Rehabiliation & MS Center in Overpelt, Belgium. Our data set is large enough to obtain, for the first time, a performance estimate on an independent test set containing different patients.
We extracted a large number of time series features from the motor EPs with the highly comparative time series analysis software package. Mutual information with the target and the Boruta method are used to find features which contain information not included in the features studied in the literature. We use random forests (RF) and logistic regression (LR) classifiers to predict disability progression after two years. Statistical significance of the performance increase when adding extra features is checked.
Including extra time series features in motor EPs leads to a statistically significant improvement compared to using only the known features, although the effect is limited in magnitude (ΔAUC = 0.02 for RF and ΔAUC = 0.05 for LR). RF with extra time series features obtains the best performance (AUC = 0.75±0.07 (mean and standard deviation)), which is good considering the limited number of biomarkers in the model. RF (a nonlinear classifier) outperforms LR (a linear classifier).
Using machine learning methods on EPs shows promising predictive performance. Using additional EP time series features beyond those already in use leads to a modest increase in performance. Larger datasets, preferably multi-center, are needed for further research. Given a large enough dataset, these models may be used to support clinicians in their decision making process regarding future treatment.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Multiple sclerosis (MS) is the leading cause of chronic neurological disability in young adults. The clinical disease course of MS varies greatly between individuals, with some patients progressing ...much more rapidly than others, making prognosis almost impossible. We previously discovered that cytotoxic CD4+ T cells (CD4+ CTL), identified by the loss of CD28, are able to migrate to sites of inflammation and that they contribute to tissue damage. Furthermore, in an animal model for MS, we showed that these cells are correlated with inflammation, demyelination, and disability. Therefore, we hypothesize that CD4+ CTL drive progression of MS and have prognostic value. To support this hypothesis, we investigated whether CD4+ CTL are correlated with worse clinical outcome and evaluated the prognostic value of these cells in MS. To this end, the percentage of CD4+CD28null T cells was measured in the blood of 176 patients with relapsing-remitting MS (=baseline). Multimodal evoked potentials (EP) combining information on motoric, visual, and somatosensoric EP, as well as Kurtzke expanded disability status scale (EDSS) were used as outcome measurements at baseline and after 3 and 5 years. The baseline CD4+CD28null T cell percentage is associated with EP (
= 0.003,
= 0.28), indicating a link between these cells and disease severity. In addition, the baseline CD4+CD28null T cell percentage has a prognostic value since it is associated with EP after 3 years (
= 0.005,
= 0.29) and with EP and EDSS after 5 years (
= 0.008,
= 0.42 and
= 0.003,
= 0.27). To the best of our knowledge, this study provides the first direct link between the presence of CD4+ CTL and MS disease severity, as well as its prognostic value. Therefore, we further elaborate on two important research perspectives: 1° investigating strategies to block or reverse pathways in the formation of these cells resulting in new treatments that slow down MS disease progression, 2° including immunophenotyping in prediction modeling studies to aim for personalized medicine.
Background:
Exercise therapy studies in persons with multiple sclerosis (pwMS) primarily focused on motor outcomes in mid disease stage, while cognitive function and neural correlates were only ...limitedly addressed.
Objectives:
This pragmatic randomized controlled study investigated the effects of a remotely supervised community-located “start-to-run” program on physical and cognitive function, fatigue, quality of life, brain volume, and connectivity.
Method:
In all, 42 pwMS were randomized to either experimental (EXP) or waiting list control (WLC) group. The EXP group received individualized training instructions during 12 weeks (3×/week), to be performed in their community aiming to participate in a running event. Measures were physical (VO2max, sit-to-stand test, Six-Minute Walk Test (6MWT), Multiple Sclerosis Walking Scale-12 (MSWS-12)) and cognitive function (Rao’s Brief Repeatable Battery (BRB), Paced Auditory Serial Attention Test (PASAT)), fatigue (Fatigue Scale for Motor and Cognitive Function (FSMC)), quality of life (Multiple Sclerosis Impact Scale-29 (MSIS-29)), and imaging. Brain volumes and diffusion tensor imaging (DTI) were quantified using FSL-SIENA/FIRST and FSL-TBSS.
Results:
In all, 35 pwMS completed the trial. Interaction effects in favor of the EXP group were found for VO2max, sit-to-stand test, MSWS-12, Spatial Recall Test, FSMC, MSIS-29, and pallidum volume. VO2max improved by 1.5 mL/kg/min, MSWS-12 by 4, FSMC by 11, and MSIS-29 by 14 points. The Spatial Recall Test improved by more than 10%.
Conclusion:
Community-located run training improved aerobic capacity, functional mobility, visuospatial memory, fatigue, and quality of life and pallidum volume in pwMS.
Cytomegalovirus (CMV) is a latent virus which causes chronic activation of the immune system. Here, we demonstrate that cytotoxic and pro-inflammatory CD4
CD28
T cells are only present in CMV ...seropositive donors and that CMV-specific Immunoglobulin (Ig) G titers correlate with the percentage of these cells. In vitro stimulation of peripheral blood mononuclear cells with CMVpp65 peptide resulted in the expansion of pre-existing CD4
CD28
T cells. In vivo, we observed de novo formation, as well as expansion of CD4
CD28
T cells in two different chronic inflammation models, namely the murine CMV (MCMV) model and the experimental autoimmune encephalomyelitis (EAE) model for multiple sclerosis (MS). In EAE, the percentage of peripheral CD4
CD28
T cells correlated with disease severity. Pre-exposure to MCMV further aggravated EAE symptoms, which was paralleled by peripheral expansion of CD4
CD28
T cells, increased splenocyte MOG reactivity and higher levels of spinal cord demyelination. Cytotoxic CD4
T cells were identified in demyelinated spinal cord regions, suggesting that peripherally expanded CD4
CD28
T cells migrate towards the central nervous system to inflict damage. Taken together, we demonstrate that CMV drives the expansion of CD4
CD28
T cells, thereby boosting the activation of disease-specific CD4
T cells and aggravating autoimmune mediated inflammation and demyelination.
Background/objective:
Endurance exercise can improve memory function in persons with multiple sclerosis (pwMS), but the effects on hippocampal functioning are currently unknown. We investigated the ...effects of a running intervention on memory and hippocampal functional connectivity in pwMS.
Methods/results:
Memory and resting-state functional magnetic resonance imaging (fMRI) data were collected in a running intervention (n = 15) and waitlist group (n = 14). Visuospatial memory improvement was correlated to increased connectivity between the hippocampus and the default-mode network (DMN) in the intervention group only.
Conclusion:
As a result of endurance exercise, improvements in visuospatial memory may be mediated by a stronger functional embedding of the hippocampus in the DMN.
Multiple sclerosis (MS) is a chronic disease affecting millions of people worldwide. Through the demyelinating and axonal pathology of MS, the signal conduction in the central nervous system is ...affected. Evoked potential measurements allow clinicians to monitor this process and can be used for decision support. We share a dataset that contains motor evoked potential (MEP) measurements, in which the brain is stimulated and the resulting signal is measured in the hands and feet. This results in time series of 100 milliseconds long. Typically, both hands and feet are measured in one hospital visit. The dataset contains 5586 visits of 963 patients, performed in day-to-day clinical care over a period of 6 years. The dataset consists of approximately 100,000 MEP. Clinical metadata such as the expanded disability status scale, sex, and age is also available. This dataset can be used to explore the role of evoked potentials in MS research and patient care. It may also be used as a benchmark for time series analysis and predictive modelling.
Background:
Alemtuzumab is a highly effective therapy for relapsing-remitting multiple sclerosis (RRMS), and immune thrombocytopenia (ITP) has been identified as a risk.
Objective:
To examine ITP ...incidence, treatment, and outcomes during the clinical development of alemtuzumab for RRMS and discuss postmarketing experience outside clinical trials.
Methods:
CAMMS223 and Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) I and II investigated two annual courses of alemtuzumab 12 mg (or 24 mg in CAMMS223/CARE-MS II) versus subcutaneous interferon beta-1a three times per week. Patients completing core studies could enroll in an extension. Monthly monitoring for ITP continued until 48 months after the last alemtuzumab infusion.
Results:
Of 1485 alemtuzumab-treated MS patients in the clinical development program, 33 (2.2%) developed ITP (alemtuzumab 12 mg, 24 2.0%; alemtuzumab 24 mg, 9 3.3%) over median 6.1 years of follow-up after the first infusion; most had a sustained response to first-line ITP therapy with corticosteroids, platelets, and/or intravenous immunoglobulin. All cases occurred within 48 months of the last alemtuzumab infusion. Postmarketing surveillance data suggest that the ITP incidence is not higher in clinical practice than in clinical trials.
Conclusion:
Alemtuzumab-associated ITP occurs in approximately 2% of patients and is responsive to therapy. Careful monitoring is key for detection and favorable outcomes.
Background:
Cognitive–motor interference (CMI) has been well recognized in persons with multiple sclerosis (pwMS); however, there are limited data on effects of task difficulty.
Objective:
Examine ...(1) the effects of motor and cognitive tasks varying in difficulty on the magnitude of CMI and (2) the discriminative validity of CMI between pwMS and healthy controls (HC).
Methods:
Nine cognitive–motor dual-task (DT) conditions (combinations of three cognitive and three walking tasks) were examined. Outcome measures were DT-performance and dual-task cost (DTC) of gait parameters and correct answers. Task differences and overall group-effects were analysed by mixed model analysis, plus the Wilcoxon signed-rank tests or multivariate analysis of variances (MANOVAs), respectively.
Results:
Task effects were examined in 82 pwMS (Expanded Disability Status Scale (EDSS): 3.3 ± 1.0) and discriminative validity in a subsample (35 pwMS and 33 HC). Motor-DTC and DT-performance were affected by difficulty of both the cognitive task (p < 0.001) and the walking condition (p ⩽ 0.002), while cognitive-DTC only varied between cognitive tasks with a large difference in difficulty (p ⩽ 0.005) and not between walking conditions (p ⩾ 0.125). None of the DTCs differed between groups.
Conclusion:
CMI, and especially motor performance, is affected by difficulty of the DT. Although pwMS performed worse on the tasks than HC, none of the DT-conditions showed a discriminative DTC.
Background:
Alemtuzumab is administered as two annual courses for relapsing–remitting multiple sclerosis (MS). Patients may relapse before completing the two-course regimen.
Objective:
The objective ...was to evaluate 6-year outcomes in patients who relapsed between alemtuzumab Courses 1 and 2 (early relapsers).
Methods:
Post hoc analysis of patients from the Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) studies who enrolled in the extension.
Results:
Early relapsers (CARE-MS I: 15%; CARE-MS II: 24%) had more relapses in 1–2 years pre-alemtuzumab and higher mean baseline Expanded Disability Status Scale score than patients without relapse. Their annualized relapse rate declined from Year 1 (CARE-MS I: 1.3; CARE-MS II: 1.2) to Year 2 following Course 2 (0.3; 0.5) and remained low thereafter. Over 6 years, 60% remained free of 6-month confirmed disability worsening; 24% (CARE-MS I) and 34% (CARE-MS II) achieved 6-month confirmed disability improvement. During Year 6, 69% (CARE-MS I) and 68% (CARE-MS II) were free of magnetic resonance imaging (MRI) disease activity. Median percent yearly brain volume loss (Year 1: −0.67% (CARE-MS I); −0.47% (CARE-MS II)) declined after Course 2 (Year 6: −0.24%; −0.13%).
Conclusion:
Early relapsers’ outcomes improved after completing the second alemtuzumab course. These findings support administering the approved two-course regimen to maximize clinical benefit.
ClinicalTrials.gov registration numbers:
CARE-MS I, II, extension: NCT00530348, NCT00548405, NCT00930553.
Abstract
Objective: Persons with multiple sclerosis (PwMS) experience several physical and cognitive problems which can influence their travel behaviour. This study aimed to document the number of ...activities, the activity type and the transport mode of the related trips that are daily made by PwMS. Their outdoor activity and travel behaviour was studied in relation to disease-related disability. Methods: Thirty six PwMS (Expanded Disability Status Scale, EDSS, 1.5-8.0, age 27-63) and 24 healthy controls (age 25-62) were studied, using activity-related travel diaries and GPS tracking devices. Information about overall disability characteristics was gained by standard clinical tests and questionnaires. PwMS were further divided in three subgroups based on EDSS cut-off scores 4.5 and 6.5. Results: Persons with mild ambulatory dysfunction (EDSS 1.5-4.0, n = 17) showed similar travel characteristics to healthy controls, with few restrictions during travelling. Statistically significant changes in activity and travel behaviour were detected in the moderate (EDSS 4.5-6.5, n = 8) and severe MS subgroups (EDSS > 6.5-8.0, n = 11) compared with healthy controls: driving independently became less frequent, significant more trips were made with company and the duration of performed activities had increased. Conclusion: The combination of self-reported travel diaries and objective GPS loggers offered detailed information about the actual outdoor travel behaviour of PwMS, which was significantly changed in PwMS with EDSS greater than 4.Implications for RehabilitationActivity and travel behaviour changes significantly in persons with multiple sclerosis (MS) with moderate to severe disability (EDSS greater than 4).Behavioural therapy could help to develop better coping and problem-solving skills to overcome anxiety in the making of trips by persons with MS with a mild severity.Enhancing community environments could serve as a promising approach to increase the outdoor participation of persons with (more severe) impairments.
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