Diagnosing multiple sclerosis with a gait measuring system, an analysis of the motor fatigue, and machine learning

GAIM

Variation individuelle des paramètres de marche au long d'une distance de 500m chez des personnes atteintes de sclérose en plaques et chez des volontaires sains

Background: we previously demonstrated the usefulness of the Deceleration Index (DI, the ratio between the last 100m of the Timed 500-Meter Walk test –T500MW – and the walking speed - WS – of the Timed 25-Foot Walk Test with a propelled start – T25FW+) to evaluate motor fatigue over a long walking distance in people with multiple sclerosis (pwMS). We also recently designed and internally validated a new gait analysis tool for pwMS (GAIMS) that can measure other relevant gait characteristics than the sole WS, such as ataxia, asymmetry and perhaps spasticity. Aims: (i) To compare various gait characteristics between the last and the first 100m of the T500MW in a population of pwMS and healthy volunteers (HV), (ii) to compare the ratio between the last and the first 100m of the T500MW with the DI, and (iii) their relationship with the EDSS. Methods : Subjects were asked to perform the T25FW+ and the T500MW as part of a multimodal evaluation at the MS Clinic of the CHU of Liège. Their gait characteristics were measured using GAIMS. (i) Paired Student’s t-tests were performed on various gait characteristics extracted during the last and first 100m of the T500MW with .05 as a level of significance, (ii) Spearman correlation coefficient (ρ) was calculated (ii) between these ratio and (iii) subject’s EDSS. Results: Seventy-one pwMS and 129 were enrolled in our study. (i) Significant differences were observed for speed related gait characteristics between the last and first 100m of the T500MW, but also for gait characteristics related to ataxia and precision of foot placement. (ii) A moderate positive correlation was observed between the WS ratio of the last and first 100m of the T500MW and the DI. (iii) The correlation between the DI and the EDSS was weakly negative, while the one between the last and first 100m of the T500MW ratio and the EDSS was moderatly negative. Conclusion: (i) As previously demonstrated, we here confirm that alongside to WS, there are other gait features affected by locomotor fatigue over a long walking distance, (ii) the moderate positive correlation between the DI and the last/first 100m of the T500MW indicates that these measures are not the same and that next to a long distance walking test such as the T500MW, a short one such as the T25FW+ remains useful. (iii) The last/first 100m of the T500MW is better correlated to the EDSS and might be a better predictive tool of pwMS’ neurologic state than the DI

Motor Fatigue Measurement by Distance-Induced Slow Down of Walking Speed in Multiple Sclerosis

Background: Motor fatigue and ambulation impairment are prominent clinical features of people with multiple sclerosis (pMS). We hypothesized that a multimodal and comparative assessment of walking speed on short and long distance would allow a better delineation and quantification of gait fatigability in pMS. Objectives: To compare 4 walking paradigms: the timed 25-foot walk (T25FW), a corrected version of the T25FW with dynamic start (T25FW+), the timed 100-meter walk (T100MW) and the timed 500-meter walk (T500MW). Methods: Thirty controls and 81 pMS performed the 4 walking tests in a single study visit. Results: The 4 walking tests were performed with a slower WS in pMS compared to controls even in subgroups with minimal disability. The finishing speed of the last 100-meter of the T500MW was the slowest measurable WS whereas the T25FW+ provided the fastest measurable WS. The ratio between such slowest and fastest WS (Deceleration Index, DI) was significantly lower only in pMS with EDSS 4.0-6.0, a pyramidal or cerebellar functional system score reaching 3 or a maximum reported walking distance !4000m. Conclusion: The motor fatigue which triggers gait deceleration over a sustained effort in pMS can be measured by the WS ratio between performances on a very short distance and the finishing pace on a longer more demanding task. The absolute walking speed is abnormal early in MS whatever the distance of effort when patients are unaware of ambulation impairment. In contrast, the DI-measured ambulation fatigability appears to take place later in the disease course

Natalizumab induces a rapid improvement of disability status and ambulation after failure of previous therapy in relapsing-remitting multiple sclerosis.

peer reviewedBackground: Natalizumab (Tysabri) is a monoclonal antibody that was recently approved for the treatment of relapsing-remitting multiple sclerosis (RRMS). Our primary objective was to analyse the efficacy of natalizumab on disability status and ambulation after switching patients with RRMS from other disease-modifying treatments (DMTs). Methods: A retrospective, observational study was carried out. All patients (n = 45) initiated natalizumab after experiencing at least 1 relapse in the previous year under interferon-beta (IFNB) or glatiramer acetate (GA) treatments. The patients also had at least 1 gadolinium-enhancing (Gd+) lesion on their baseline brain MRI. Expanded Disability Status Scale (EDSS) scores, and performance on the Timed 25-Foot Walk Test and on the Timed 100-Metre Walk Test were prospectively collected every 4 weeks during 44 weeks of natalizumab treatment. Brain MRI scans were performed after 20 and 44 weeks of treatment. Results: Sixty-two per cent of patients showed no clinical and no radiological signs of disease activity, and 29% showed a rapid and confirmed EDSS improvement over 44 weeks of natalizumab therapy. Patients with improvement on the EDSS showed similar levels of baseline EDSS and active T1 lesions, but had a significantly higher number of relapses, and 92% of them had experienced relapse-mediated sustained EDSS worsening in the previous year. A clinically meaningful improvement in ambulation speed was observed in approximately 30% of patients. Conclusions: These results indicate that natalizumab silences disease activity and rapidly improves disability status and walking performance, possibly through delayed relapse recovery in patients with RRMS who had shown a high level of disease activity under other DMTs

Natalizumab treatment shows low cumulative probabilities of confirmed disability worsening to EDSS milestones in the long-term setting.

Abstract Background Though the Expanded Disability Status Scale (EDSS) is commonly used to assess disability level in relapsing-remitting multiple sclerosis (RRMS), the criteria defining disability progression are used for patients with a wide range of baseline levels of disability in relatively short-term trials. As a result, not all EDSS changes carry the same weight in terms of future disability, and treatment benefits such as decreased risk of reaching particular disability milestones may not be reliably captured. The objectives of this analysis are to assess the probability of confirmed disability worsening to specific EDSS milestones (i.e., EDSS scores ≥3.0, ≥4.0, or ≥6.0) at 288 weeks in the Tysabri Observational Program (TOP) and to examine the impact of relapses occurring during natalizumab therapy in TOP patients who had received natalizumab for ≥24 months. Methods TOP is an ongoing, open-label, observational, prospective study of patients with RRMS in clinical practice. Enrolled patients were naive to natalizumab at treatment initiation or had received ≤3 doses at the time of enrollment. Intravenous natalizumab (300 mg) infusions were given every 4 weeks, and the EDSS was assessed at baseline and every 24 weeks during treatment. Results Of the 4161 patients enrolled in TOP with follow-up of at least 24 months, 3253 patients with available baseline EDSS scores had continued natalizumab treatment and 908 had discontinued (5.4% due to a reported lack of efficacy and 16.4% for other reasons) at the 24-month time point. Those who discontinued due to lack of efficacy had higher baseline EDSS scores (median 4.5 vs. 3.5), higher on-treatment relapse rates (0.82 vs. 0.23), and higher cumulative probabilities of EDSS worsening (16% vs. 9%) at 24 months than those completing therapy. Among 24-month completers, after approximately 5.5 years of natalizumab treatment, the cumulative probabilities of confirmed EDSS worsening by 1.0 and 2.0 points were 18.5% and 7.9%, respectively (24-week confirmation), and 13.5% and 5.3%, respectively (48-week confirmation). The risks of 24- and 48-week confirmed EDSS worsening were significantly higher in patients with on-treatment relapses than in those without relapses. An analysis of time to specific EDSS milestones showed that the probabilities of 48-week confirmed transition from EDSS scores of 0.0–2.0 to ≥3.0, 2.0–3.0 to ≥4.0, and 4.0–5.0 to ≥6.0 at week 288 in TOP were 11.1%, 11.8%, and 9.5%, respectively, with lower probabilities observed among patients without on-treatment relapses (8.1%, 8.4%, and 5.7%, respectively). Conclusions In TOP patients with a median (range) baseline EDSS score of 3.5 (0.0–9.5) who completed 24 months of natalizumab treatment, the rate of 48-week confirmed disability worsening events was below 15%; after approximately 5.5 years of natalizumab treatment, 86.5% and 94.7% of patients did not have EDSS score increases of ≥1.0 or ≥2.0 points, respectively. The presence of relapses was associated with higher rates of overall disability worsening. These results were confirmed by assessing transition to EDSS milestones. Lower rates of overall 48-week confirmed EDSS worsening and of transitioning from EDSS score 4.0–5.0 to ≥6.0 in the absence of relapses suggest that relapses remain a significant driver of disability worsening and that on-treatment relapses in natalizumab-treated patients are of prognostic importance

Multimodal evaluation of gait alterations in persons with multiple sclerosis

Gait impairment is a frequent manifestation of multiple sclerosis and is of the utmost functional importance for those who live with this chronic inflammatory neurological condition. It is also a useful clinical outcome measure, usually evaluated on the basis of walking speed measured on a short distance.In this work, our first hypothesis is that walking speed is a construct significantly influenced by several confounders. Through the use of conventional methods to test gait, we successively address the importance of the distance (and hence locomotor fatigability, first on 100 and next on 500 metres), acceleration capacity and type of walk instructed to the subject. We show that the Timed 25 foot walk test suffer from several shortcomings related to each of these factors. We demonstrate that these are differentially affected in persons with multiple sclerosis as compared to healthy subjects, representing potential individual outcome measures themselves. Next, our second hypothesis is that walking speed is not the only feature characterizing the gait of persons with multiple sclerosis. We review the different available gait analysis technologies, their application in multiple sclerosis and create a new gait analysis system adapted to our needs. After technical validation, we design 26 gait features in order to capture other dimensions of walk than its speed, such as ataxia. We define those using factorial analysis. Finally, we use this system to explore the variance of gait in a population of healthy subjects and persons with multiple sclerosis. Using a mixed model analysis, we show that while walking speed is the main contributing factor to gait variance in such populations, other dimensions significantly come into play and should be considered in order to fully characterize ambulation in multiple sclerosis

Machine learning techniques to assess the performance of a gait analysis system

peer reviewedThis paper presents a methodology based on machine learning techniques to assess the performance of a system measuring the trajectories of the lower limbs extremities for the follow-up of patients with multiple sclerosis. We show how we have established, with the help of machine learning, four important properties about this system: (1) an automated analysis of gait characteristics provides an improved analysis with respect to that of a human expert, (2) after learning, the gait characteristics provided by this system are valuable compared to measures taken by stopwatches, as used in the standardized tests, (3) the motion of the lower limbs extremities contains a lot of useful information about the gait, even if it is only a small part of the body motion, (4) a measurement system combined with a machine learning tool is sensitive to intra-subject modifications of the walking pattern.GAIM

Understanding how people with MS get tired while walking

BACKGROUND. Walking impairment is frequent, appears early in the disease course of MS patients (MSP), and is perceived as the most disabling symptom. When walking, patients get tired more and differently than healthy people (HP) [Phan-Ba et al PLOS 2012]. This limits their walking perimeter. Understanding this phenomenon is thus important to suggest adequate therapies at the right time. OBJECTIVE. Our aim is to understand how MSP get tired while walking compared to HP. Two groups of MSP are considered: those with a low disability level (MSPL) and those with a high one (MSPH). We consider two criteria to measure the disability: the EDSS and the deceleration index (DI) [Phan-Ba et al PLOS 2012]. The limit between the groups is set at DI=0.8 and EDSS=3 (inclusive for MSPL). METHODS. Many gait characteristics (GC) have been measured with the system GAIMS along a 500m path walked as fast as possible. The dataset gathers 464 visits of HP and 70 of MSP. Some people have been assessed several times. There are 33 visits in the group MSPL with the EDSS criterion, and 25 with the DI criterion. Statistical tests (Welch) were performed on the differences and relative differences of the GC measured during the first and last 100m of the test to detect differences between HP and MSPL, and between MSPL and MSPH, as in [ECTRIMS 2012 P755]. RESULTS. Both criteria for defining the groups lead to similar conclusions. For many GC, the distributions of the variations are significantly different between MSPL and MSPH. The largest difference is for the relative difference of speed (p=0.000119 for EDSS and p=0.000021 for DI). In contrast, only the variation of the average lateral distance between the feet, which is related to the size of the base of support (and thus to the balance) shows a very significant difference between HP and MSPL (p=0.000116 for EDSS and p=0.000120 for DI). The balance does not seem to change much from MSPL to MSPH. Besides, we note that the variance decreases slightly from HP to MSPL and increases a lot from MSPL to MSPH. CONCLUSIONS. Statistically, from the motor fatigue point of view, it seems that the course of the MS disease is divided in two different stages. In the first one, MSP get more tired than HP because of a deterioration of the balance. Then, in the second one, their fatigue becomes related to a faster decrease of the walking speed. This suggests that physical therapy exercises focused on the balance could be given to MSP in the early stage of the disease.GAIM