Limb apraxia in individuals with multiple sclerosis: Is there a role of semi-immersive virtual reality in treating the Cinderella of neuropsychology?

BACKGROUND: Limb apraxia is an acquired cognitive-motor disorder characterized by spatial and temporal disorganization of limb movements, negatively affecting the quality of life of patients, including those with multiple sclerosis (MS). Although recent studies have shown the potential role of VR in increasing cognitive and motor functions, only a few studies have been carried out on the rehabilitation of upper limb apraxia. Hence, our study aims to evaluate the potential efficacy of VR training to improve upper limb ideomotor apraxia in patients with MS. METHODS: One hundred and six patients, affected by secondary progressive MS, who attended our Robotic and Behavioral Neurorehabilitation Service from March 2019 to February 2020, were enrolled in this study and randomly divided into two groups: the control group (CG: 53 patients) performed traditional therapy whereas the experimental group (EG:53 patients) received training using semi-immersive VR. All patients underwent the same amount of cognitive training, 3 times a week for 8 weeks. They were submitted to a specific neuropsychological assessment before (T0) and after the rehabilitation treatment (T1). RESULTS: The VR training led to a significant improvement in global cognitive functions, with regard to constructive and ideomotor apraxia. On the contrary, the CG achieved significant improvements only in ideomotor apraxia. Moreover, only in the EG, we observed an improvement in the mood at the end of training. CONCLUSION: The present study demonstrates that VR rehabilitation can be an effective tool for the treatment of apraxia, which is a neuropsychological problem often underestimated in MS patients. Further studies with long-term follow-up periods are needed to confirm the effect of this promising approach.

Baseline and overtime variations of soluble adhesion molecule plasma concentrations are associated with mobility recovery after rehabilitation in multiple sclerosis patients.

Rehabilitative exercise outcomes and plasma concentrations of soluble adhesion molecules (sEndoglin, sE-Selectin, sL-Selectin, sICAM-1, sNCAM, sNCAM-1, sVCAM-1, sPECAM-1, sVAP-1) were evaluated in 60 severely disabled progressive multiple sclerosis (MS) patients at 4-time points. Changes of sE-Selectin, sL-Selectin, and sPECAM-1 concentrations were observed over time, and their variations were significantly correlated with rehabilitative outcome variations. Baseline sVAP-1 concentrations were able to predict functional mobility recovery. Our data suggest that the evaluation of adhesion molecules in plasma provides useful information to interpret rehabilitative exercise processes and to identify potential predictors of the rehabilitation-induced changes in mobility outcomes in MS patients.

Blood-Flow Restriction Training for a Person With Primary Progressive Multiple Sclerosis: A Case Report.

OBJECTIVE: Blood flow restriction (BFR) training, in which an inflatable cuff partially occludes blood flow around the proximal portion of a limb, coupled with low-intensity resistance training (LIRT) has resulted in gains comparable with traditional progressive resistive exercise in healthy populations. The use of BFR with LIRT may enable people with multiple sclerosis (MS) to improve strength without an increase in fatigue. The purpose of this case report is to describe the use of a BFR/LIRT program for a person with MS. METHODS: The patient was a 54-year-old woman with a 13-year history of primary progressive MS with an Extended Disability Severity Score of 3.0 out of 10. She received a BFR/LIRT program for both lower extremities biweekly for 12 weeks. Outcomes measured at baseline and at 6 and 12 weeks included the 12-item Multiple Sclerosis Walking Scale (MSWS-12), Fatigue Severity Scale, Patient-Specific Functional Scale (PSFS) (goals: running for exercise and pleasure for 45 minutes, 100% confidence in negotiating a flight of stairs, confidently and safely drive without restriction), and 14 lower extremity strength tests. RESULTS: The intervention was well tolerated without adverse events. After 6 weeks, the MSWS-12 score improved; however, it did not exceed minimum detectable change (MDC). Fatigue Severity Scale was unchanged. All PSFS goals improved beyond MDC, and improvements in strength exceeded MDC in 2 out of 14 tests. After 12 weeks, MSWS-12 improvements persisted and the Fatigue Severity Scale score improved, but neither exceeded MDC. The PSFS improvements persisted. There were improvements exceeding MDC for 8 out of 14 strength tests. The remaining 6 strength tests improved but did not exceed MDC. CONCLUSION: The patient had measurable improvements following the use of a BFR/LIRT program. BFR/LIRT may be an option for strength training in people with MS; however, research is needed to determine its safety and effectiveness across the population of people with MS. IMPACT: Traditional physical therapist interventions for people with MS have been shown to be beneficial; however, their usefulness has been limited by fatigue. A growing body of literature has demonstrated the effects of a BFR/LIRT program on strength and other measures of physical function in healthy populations and those with chronic disease. This case report adds missing information to the existing literature and suggests directions for research on the effectiveness of BFR/LIRT in people with primary progressive MS. LAY SUMMARY: Blood flow restriction, which has been used to help improve strength in healthy adults and in some people with chronic disease, applies pressure around the arm or leg to limit the flow of blood to that body part during exercise, helping to reduce fatigue. Blood flow restriction coupled with low-intensity strengthening exercises can be used for a person with MS.

Effectiveness of blood flow-restricted slow walking on mobility in severe multiple sclerosis: A pilot randomized trial.

OBJECTIVE: We tested the safety, feasibility, and effectiveness of blood flow restriction-empowered low-intensity interval walking exercise (BFR-W) compared with conventional intensive overground walking (CON-W) at improving gait speed and functional capacity in patients with multiple sclerosis (MS) and severe gait disabilities. METHODS: 24 patients (58 ± 5 years; 7 males) with progressive MS (Expanded Disability Status Scale 5.5 - 6.5) were randomized to receive 12 rehabilitation sessions over 6 weeks. The BFR-W group (n = 12) performed interval walking (speed paced by a metronome that increased weekly) with BFR bands at the thighs. The CON-W group (n = 12) received physiotherapist-assisted overground walking therapy. The primary outcome was gait speed, measured by the timed 25-foot walk test. Secondary outcomes included walking endurance, balance, strength, fatigue, and quality of life. The measurements were collected at baseline, at the end of training, and a 6-week follow-up. RESULTS: The two groups did not present any baseline difference. BFR-W group safely walked without limitations due to sleeve compression, with lower increase in perceived exertion (RPE) (P < .001) and heart rate (P = .031) compared with the CON-W. Gait speed improved significantly in both groups (BFR-W + 13%; CON-W + 5%) with greater increases in the BFR-W group at end of the training (P = .001) and at the follow-up (P = .041). Most of the secondary outcomes significantly improved in the two groups, without between-group differences. CONCLUSIONS: Slow interval walking with moderate BFR to the lower limbs was superior to overground walking in improving gait speed in patients with MS with a lower training load and a more durable clinical benefit.

Study protocol: improving cognition in people with progressive multiple sclerosis: a multi-arm, randomized, blinded, sham-controlled trial of cognitive rehabilitation and aerobic exercise (COGEx).

BACKGROUND: Cognitive dysfunction affects up to 70% of people with progressive MS (PMS). It can exert a deleterious effect on activities of daily living, employment and relationships. Preliminary evidence suggests that performance can improve with cognitive rehabilitation (CR) and aerobic exercise (EX), but existing data are predominantly from people with relapsing-remitting MS without cognitive impairment. There is therefore a need to investigate whether this is also the case in people with progressive forms of the disease who have objectively identified cognitive impairment. It is hypothesized that CR and EX are effective treatments for people with PMS who have cognitive impairment, in particular processing speed (PS) deficits, and that a combination of these two treatments is more effective than each individual treatment given alone. We further hypothesize that improvements in PS will be associated with modifications of functional and/or structural plasticity within specific brain networks/regions involved in PS measured with advanced MRI techniques. METHODS: This study is a multisite, randomized, double-blinded, sham controlled clinical trial of CR and aerobic exercise. Three hundred and sixty subjects from 11 sites will be randomly assigned into one of four groups: CR plus aerobic exercise; CR plus sham exercise; CR sham plus aerobic exercise and CR sham plus sham exercise. Subjects will participate in the assigned treatments for 12 weeks, twice a week. All subjects will have a cognitive and physical assessment at baseline, 12 weeks and 24 weeks. In an embedded sub-study, approximately 30% of subjects will undergo structural and functional MRI to investigate the neural mechanisms underlying the behavioral response. The primary outcome is the Symbol Digit Modalities Test (SDMT) measuring PS. Secondary outcome measures include: indices of verbal and non-verbal memory, depression, walking speed and a dual cognitive-motor task and MRI. DISCUSSION: The study is being undertaken in 6 countries (11 centres) in multiple languages (English, Italian, Danish, Dutch); with testing material validated and standardized in these languages. The rationale for this approach is to obtain a robustly powered sample size and to demonstrate that these two interventions can be given effectively in multiple countries and in different languages. TRIAL REGISTRATION: The trial was registered on September 20th 2018 at www.clinicaltrials.gov having identifier NCT03679468. Registration was performed before recruitment was initiated.

Neuroplasticity and brain reorganization associated with positive outcomes of multidisciplinary rehabilitation in progressive multiple sclerosis: A fMRI study.

BACKGROUND: Multiple sclerosis (MS) is characterized by a range of symptoms, including motor, sensorimotor and cognitive impairments, that limit the quality of life. A multidisciplinary rehabilitation approach in people affected by multiple sclerosis was recently reported to improve the functional abilities of MS patients in daily activities. The purpose of the study was to assess the effect of multidisciplinary rehabilitation on the whole brain of MS patients by means of functional magnetic resonance imaging (fMRI). METHODS: Thirty individuals affected by MS (49.9 ± 12.1 years; disease duration: 16.0 ± 8.5 years) with a medium-high severity of disease were enrolled. The fMRI examination assessed a range of action-related tasks involving passive movement, mental simulation of action and miming of action triggered by external stimuli, such as object photography. The three tasks were performed using each arm separately. The fMRI acquisitions were performed at T1 (inclusion in the study), T2 (3 months later, at the start of rehabilitation) and T3 (after 3 months of multidisciplinary rehabilitation). RESULTS: The fMRI results revealed a significant reduction in the activity of brain areas related to task-specific networks as well as the activation of cerebral regions not usually involved in task-specific related network, such as the medial prefrontal area. CONCLUSIONS: The effectiveness of multidisciplinary rehabilitation on activity and participation has been established in previous studies. Our study sheds new light on the effect of such treatment on brain reorganization.

Robot-assisted gait training is not superior to intensive overground walking in multiple sclerosis with severe disability (the RAGTIME study): A randomized controlled trial.

BACKGROUND: Rehabilitation may attenuate the impact on mobility of patients with progressive multiple sclerosis (MS) and severe gait disabilities. OBJECTIVE: In this randomized controlled trial, we compared robot-assisted gait training (RAGT) with conventional therapy (CT) in terms of gait speed, mobility, balance, fatigue and quality of life (QoL). METHODS: Seventy-two patients with MS (expanded disability status scale score 6.0-7.0) were randomized to receive 12 training sessions over a 4-week period of RAGT (n = 36) or overground walking therapy (n = 36). The primary outcome was gait speed, assessed by the timed 25-foot walk test. Secondary outcome measures were walking endurance, balance, depression, fatigue and QoL. Tests were performed at baseline, intermediate, at the end of treatment and at a 3-month follow-up. RESULTS: Sixty-six patients completed the treatments. At the end of treatment with respect to baseline, both groups significantly improved gait speed (p < 0.001) and most secondary outcomes without between-group differences. Outcome values returned to baseline at follow-up. CONCLUSIONS: RAGT was not superior to CT in improving gait speed in patients with progressive MS and severe gait disabilities where a positive, even transitory, effect of rehabilitation was observed.

The efficacy of the modified Story Memory Technique in progressive MS.

BACKGROUND: Impairments in new learning and memory are common in individuals with multiple sclerosis (MS), negatively impacting everyday life, including occupational and social functioning. OBJECTIVE: This study examined the efficacy of the modified Story Memory Technique (mSMT) in a progressive multiple sclerosis (PMS) sample through a double-blind, placebo-controlled, randomized clinical trial (RCT). METHODS: Thirty (30) individuals with PMS, naïve to the mSMT, were randomized to the treatment or placebo control group. The Treatment Group completed mSMT training twice per week for 5 weeks while the Placebo Group met with the therapist at the same frequency, engaging in non-training-oriented tasks to control for professional contact and disease alterations. RESULTS: The treatment group showed significant improvements in learning compared with the placebo control group, evident on both objective evaluation of new learning and self-report of functioning in daily life. Increased awareness of cognitive deficits was also noted post-treatment. CONCLUSION: These data provide Class I evidence supporting the efficacy of the mSMT in PMS. A behavioral intervention, targeted to specifically strengthen new learning, can significantly improve memory performance in PMS, and this improvement in memory performance is maintained 3 months later.

Assessment of a home-based standing frame programme in people with progressive multiple sclerosis (SUMS): a pragmatic, multi-centre, randomised, controlled trial and cost-effectiveness analysis.

BACKGROUND: People severely impaired with progressive multiple sclerosis spend much of their day sitting, with very few options to improve motor function. As a result, secondary physical and psychosocial complications can occur. Effective and feasible self-management strategies are needed to reduce sedentary behaviour and enhance motor function. In this study, we aimed to assess the clinical and cost effectiveness of a home-based, self-managed, standing frame programme. METHODS: SUMS was a pragmatic, multicentre, randomised controlled superiority trial of people with progressive multiple sclerosis and severe mobility impairment, undertaken in eight centres from two regions in the UK. The study had assessor-blinded outcome assessments with use of clinician-rated and patient-rated measures at baseline, 20 weeks, and 36 weeks. After baseline assessment, participants were randomised (1:1) by computer-generated assignment to either a standing frame programme plus usual care or usual care alone. The intervention consisted of two home-based physiotherapy sessions (60 min each) to set up the standing frame programme, supported by six follow-up telephone calls (15 min per call). Participants were asked to stand for 30 min, three times per week over 20 weeks, and encouraged to continue in the longer term, although no further physiotherapy support was provided. The primary clinical outcome was motor function measured by the Amended Motor Club Assessment (AMCA) score at week 36, analysed in the modified intention-to-treat population (excluding only patients who were deemed ineligible after randomisation, those who withdrew from the trial and were unwilling for their previously collected data to be used, or those who did not provide baseline and week 36 measurements). A 9-point AMCA score change was considered clinically meaningful a priori. Adverse events were collected through a daily preformatted patient diary throughout the 36 weeks and analysed in the modified intention-to-treat population. An economic assessment established the resources required to provide the standing frame programme, estimated intervention costs, and estimate cost effectiveness. This trial is registered with the International Standard Randomised Controlled Trials, number ISRCTN69614598. FINDINGS: Between Sept 16, 2015, and April 28, 2017, 285 people with progressive multiple sclerosis were screened for eligibility, and 140 were randomly assigned to either the standing frame group (n=71) or the usual care group (n=69). Of these, 122 completed the primary outcome assessment (61 participants in both groups) for the modified intention-to-treat analysis. The use of the standing frame resulted in a significant increase in AMCA score compared with that for usual care alone, with a fully adjusted between-group difference in AMCA score at 36 weeks of 4·7 points (95% CI 1·9-7·5; p=0·0014). For adverse events collected through patient diaries, we observed a disparity between the two groups in the frequency of short-term musculoskeletal pain (486 [41%] of 1188 adverse events in the standing frame group vs 160 [22%] of 736 adverse events in the usual care group), which was potentially related to the intervention. The musculoskeletal pain lasted longer than 7 days in five participants (two in the standing frame group and three in the usual care group). No serious adverse events related to the study occurred. The standing frame group had a mean 0·018 (95% CI -0·014 to 0·051) additional quality-adjusted life-years (QALYs) compared with those of the usual care group, and the estimated incremental cost-per-QALY was approximately £14 700. INTERPRETATION: The standing frame programme significantly increased motor function in people with severe progressive multiple sclerosis, although not to the degree that was considered a priori as clinically meaningful. The standing frame is one of the first physiotherapy interventions to be effective in this population. We suggest that the programme is feasible as a home-based, self-managed intervention that could be routinely implemented in clinical practice in the UK. FUNDING: UK National Institute of Health Research.

Influence of different rehabilitative aerobic exercise programs on (anti-) inflammatory immune signalling, cognitive and functional capacity in persons with MS - study protocol of a randomized controlled trial.

BACKGROUND: Studies have shown positive effects of therapeutic exercise on motor- and cognitive function as well as on psychosocial outcomes in persons with multiple sclerosis (MS). A reduction of inflammatory stress through physical exercise has been suspected as one key mechanism, mediating the positive effects of exercise in the context of MS. The primary objective of this trial is to investigate the acute and chronic effects of different exercise modalities on (anti-)inflammatory immune signalling as well as on cognitive and functional capacity in persons with MS. METHODS: A two armed single-blind randomized controlled design will investigate 72 persons with relapsing remitting or secondary progressive MS (EDSS 3.0-6.0), during 3 weeks of inpatient rehabilitation. Participants will be randomized into either a high-intensity interval training (HIIT) or a moderate continuous training group; the latter represents the local standard therapy (ST). Both groups will exercise 3x per week. The HIIT group will perform 5 × 1.5-min high-intensive exercise bouts at 95-100% of their maximum heart rate (HRmax) followed by active breaks of unloaded pedalling (60% HRmax) for 2 min. In contrast, the ST group will exercise for 24 min continuously at 65% of HRmax. The proportion of circulating regulatory T-cells will be measured as primary outcome. Secondary outcomes comprise numbers and proportions of further immune cells including Th17-cells, soluble factors ((anti-) inflammatory cytokines, tryptophan metabolites), endurance capacity, cognitive performance, processing skills for activities of daily living, fatigue, depression and healthcare-related quality of life. Outcomes will be assessed before (T0) and after (T3) the 3-week exercise intervention program. Blood samples of T0 will be taken immediately before the first exercise session. Additionally, blood samples for the soluble factors will be collected immediately after (T1) and three hours (T2) after the first exercise session of each group. DISCUSSION: This study will be the first to investigate both acute and chronic effects of aerobic exercise on immune function and disease associated biomarkers in persons with MS. Combining biological analyses with cognitive and functional capacity assessments may contribute to a better understanding of responses to rehabilitative training, needed to improve exercise recommendations for persons with MS. TRIAL REGISTRATION: This trial was prospectively registered at ClinicalTrials.gov ( NCT03652519 ; 29 August 2018).

Can we trust self-reported walking distance when determining EDSS scores in patients with multiple sclerosis? The Danish MS hospitals rehabilitation study.

BACKGROUND: In multiple sclerosis (MS), the Expanded Disability Status Scale (EDSS) reflects disease severity. Although parts of the EDSS are dependent on actual walking distance, self-reported statements are often applied. OBJECTIVES: The purpose of the present study was, therefore, to compare self-reported walking distance to actual walking distance to outline how this influences EDSS scoring. METHODS: MS patients with EDSS 4.0-7.5 (n = 273) were included from the Danish MS hospitals rehabilitation study (n = 427). All patients subjectively classified their maximal walking distance according to one of seven categories (>500; 300-499; 200-299; 100-199; 20-99; 5-19; 0-4 m). Subsequently, actual maximal walking distance was assessed and EDSS was determined from both self-reported walking distance (EDSSself-report) and actual walking distance (EDSSactual). RESULTS: In 145 patients (53%), self-reported walking distance was misclassified when compared to the actual walking distance. Misclassification was more frequent in patients using walking aids (64% vs. 44%, p < 0.05) and in patients with primary progressive MS (69%, p < 0.05). Misclassification of walking distance corresponded to incorrect EDSS scores (EDSSself-report vs EDSSactual) of ⩾0.5 point in 24%. CONCLUSION: In MS patients with EDSS 4.0-7.5, 53% misclassified their walking distance yielding incorrect EDSS scores in 24%. Therefore, correct EDSS determination must be based on measurement of actual walking distance.

Recommended outcome measures for inpatient rehabilitation of multiple sclerosis are not appropriate for the patients with substantially impaired mobility.

BACKGROUND: In multiple sclerosis (MS) rehabilitation, most currently used outcome measures were validated in patients with a relapsing remitting MS and mild to moderate impairments. We aimed to assess whether these measures were also adequate in more impaired patients, frequently encountered in those with progressive MS (PMS). METHODS: Outcome measurements were extracted from medical records of 229 patients with PMS undergoing 3 weeks of routine inpatient rehabilitation between 2011 and 2015. We assessed the acceptability of Nine-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW), 2-Minute Walk Test (2MWT), Rivermead Mobility Index (RMI) and the Functional Independence Measure (FIM) by analysing their statistical distributions, concurrent validity by comparing Spearman correlations with pre-specified hypotheses, and responsiveness across impairment status by calculating standardized response means. RESULTS: Our concurrent validity hypotheses were mainly satisfied. However, all outcome measures had skewed distributions, showed low variability, and thus were inadequately discriminative. Moreover, 9HPT was never responsive across the impairment states, whereas the T25FW was responsive for mildly impaired patients, and the 2MWT for mild to moderate MS, respectively. Generic multi-items measures such as RMI and FIM-motor were adequately responsive for all severity levels. CONCLUSIONS: Currently used outcome measures are inadequate for patients with impaired mobility, and there is a dire need of specifically designed outcome measures for routine care that are less burdensome and short-term responsive.

Persons with secondary progressive and relapsing remitting multiple sclerosis reveal different responses of tryptophan metabolism to acute endurance exercise and training.

Disturbances in Tryptophan metabolism play a crucial role in multiple sclerosis (MS). Exercise is suspected to counteract the progress of MS and its side effects. Current research suggests alterations of Tryptophan metabolism in healthy individuals in response to exercise. We investigated the influence of acute aerobic exercise and training on Tryptophan metabolism in 57 inpatients with relapsing remitting ((RRMS) n=33) and secondary progressive ((SPMS) n=24) MS. Serotonin increased after training, whereas the kynurenine pathway was only activated in persons with RRMS. Further research is warranted to investigate whether these changes are associated with clinical measures (e.g. depressions and immune function).

Short-Term Motor Learning and Retention During Visually Guided Walking in Persons With Multiple Sclerosis.

BACKGROUND: The ability to adapt, a form of short-term motor learning, and retain this adaptation, is essential for rehabilitation and for day-to-day living. Yet little research is available on this topic in persons with multiple sclerosis (PwMS), particularly in relation to complex walking tasks. OBJECTIVE: To determine the ability of PwMS to learn and retain a novel relationship between visual input and motor output-or visuomotor map-during visually guided walking. METHODS: Nineteen PwMS and 17 healthy controls performed a precision walking task while adapting to prism lenses that altered the normal visuomotor map on 1 day, and again after a 1-week delay. The task required individuals to walk and step onto 2 targets without stopping. To quantify motor performance, we determined foot placement error relative to the targets. RESULTS: PwMS with mild disability and healthy controls attenuated foot placement error over repeated trials when exposed to the novel mapping and demonstrated a similar rate and magnitude of adaptation in the first learning session. Both groups equally retained the adaptation 1 week later, reflected by reduced foot placement error and a faster rate of error reduction in that session. CONCLUSION: PwMS can learn and retain a novel visuomotor mapping during a precision-based walking task. This suggests that PwMS with mild disability have the capacity for short-term motor learning and retention, indicating that neural plasticity is preserved.

A qualitative investigation of lay perspectives of diagnosis and self-management strategies employed by people with progressive multiple sclerosis.

This article explores how people with progressive multiple sclerosis give meaning to their experiences. It builds upon the self-management literature, which has captured the tension between the desire for retaining normalcy and the increasing burden of self-management associated with chronic disease progression. This repeat interview study is empirically grounded in 28 interviews with 14 people with progressive multiple sclerosis. We identified gender differences in diagnosis-seeking which impacted subsequent sense-making. Male respondents found a diagnosis of multiple sclerosis difficult to come to terms with, and an enduring sense of loss or anger could inhibit further sense-making. A diagnosis of multiple sclerosis was more difficult to obtain for women respondents, and any sense of certainty that diagnosis provided framed their subsequent sense-making strategies. The complex sequelae of multiple sclerosis require that self-management strategies are both contextual and timely, although even the most accomplished self-managers can lose their sense of self with neurodegeneration. Disease progression can be associated with suicidal ideation, suggesting the need for greater dialogue to ensure that people with multiple sclerosis are adequately supported to fulfil their quality of life at all stages of neurodegeneration. These lay perspectives emphasise the articulation of affect rather than the rendering of a medical diagnosis, although diagnosis may provide a degree of certainty in the short term. The ethos of self-management ensures people attempt to retain their sense of 'normality' and existent social roles for as long as possible, but this ethos can negate both one's ability to self-manage and the management of self.

Challenge of progressive multiple sclerosis therapy.

PURPOSE OF REVIEW: Understanding the mechanisms underlying progression in multiple sclerosis (MS) and identifying appropriate therapeutic targets is a key challenge facing the MS community. This challenge has been championed internationally by organizations such as the Progressive MS Alliance, which has raised the profile of progressive MS and identified the key obstacles to treatment. This review will outline the considerable progress against these challenges. RECENT FINDINGS: New insights into mechanisms underlying progression have opened up potential therapeutic opportunities. This has been complemented by ongoing validation of clinical and imaging outcomes for Phase II trials of progression, coupled with the development of innovative trial designs. The field has been greatly encouraged by recent positive Phase III trials in both primary and secondary progressive MS, albeit with modest benefit. Early trials of neuroprotection and repair have provided important new data with which to drive the field. Improving symptom management and advancing rehabilitation approaches, critical for this patient population which, taken together with identifying and managing comorbidities and risk factors, has an appreciable impact on health-related quality of life. SUMMARY: Raising the profile of progressive MS has resulted in the first effective treatments with the promise of more to come.

Physiotherapy Rehabilitation for People With Progressive Multiple Sclerosis: A Systematic Review.

OBJECTIVE: To assess the efficacy of physiotherapy interventions, including exercise therapy, for the rehabilitation of people with progressive multiple sclerosis. DATA SOURCES: Five databases (Cochrane Library, Physiotherapy Evidence Database [PEDro], Web of Science Core Collections, MEDLINE, Embase) and reference lists of relevant articles were searched. STUDY SELECTION: Randomized experimental trials, including participants with progressive multiple sclerosis and investigating a physiotherapy intervention or an intervention containing a physiotherapy element, were included. DATA EXTRACTION: Data were independently extracted using a standardized form, and methodologic quality was assessed using the PEDro scale. DATA SYNTHESIS: Thirteen studies (described by 15 articles) were identified and scored between 5 and 9 out of 10 on the PEDro scale. Eight interventions were assessed: exercise therapy, multidisciplinary rehabilitation, functional electrical stimulation, botulinum toxin type A injections and manual stretches, inspiratory muscle training, therapeutic standing, acupuncture, and body weight-supported treadmill training. All studies, apart from 1, produced positive results in at least 1 outcome measure; however, only 1 article used a power calculation to determine the sample size and because of dropouts the results were subsequently underpowered. CONCLUSIONS: This review suggests that physiotherapy may be effective for the rehabilitation of people with progressive multiple sclerosis. However, further appropriately powered studies are required.

The effects of robot-assisted gait training in progressive multiple sclerosis: A randomized controlled trial.

BACKGROUND: Gait and mobility impairments are common in progressive multiple sclerosis (MS), leading to reduced quality of life (QoL). OBJECTIVE: In this randomized controlled study, we tested the effects of robot-assisted gait training (RAGT) and compared it to conventional physiotherapy, measuring walking ability, depression, fatigue, and QoL in patients with progressive MS and severe gait disability. METHODS: Fifty-two participants (Expanded Disability Status Scale score 6-7) completed the study protocol. They received two sessions/week over 6 weeks of RAGT or conventional walking therapy. Outcome measures were Six-Minute Walk Test, Ten-Meter Walk Test, Timed Up and Go Test, Berg Balance Scale, Fatigue Severity Scale, Patient Health Questionnaire, and Short Form 36. They were performed pre-treatment, post-treatment, and at 3 months. RESULTS: Walking endurance (p < 0.01) and balance (p < 0.01) were improved among those in the RAGT group. Positive effects on depression in both treatment groups were highlighted. However, only among those in the RAGT group was perceived physical functioning QoL increased. No significant effects on fatigue were found. CONCLUSION: RAGT is a treatment option in progressive MS patients with severe gait impairments to induce short-lasting effects on mobility and QoL.

Functional electrical stimulation through direct 4-channel nerve stimulation to improve gait in multiple sclerosis: a feasibility study.

BACKGROUND: Gait dysfunction due to lower limb central paralysis, frequently involving drop foot, is a common cause of disability in multiple sclerosis and has been treated with transcutaneous functional electrical stimulation (FES). We provide here the first report of 4-channel semi-implantable FES of the peroneal nerve which has been successfully used for rehabilitation in patients following stroke. METHODS: FES was implemented via a 4-channel semi-implantable closed-loop system (ActiGait(®), ©Ottobock), generating dorsiflexion in drop foot. Walking distance, gait symmetry (temporospatial gait analyses, Vicon Motion Systems(®)), gait velocity (10 m walking test) and quality of life (SF-36 questionnaire) were measured to evaluate the therapeutic benefit of this system in two patients with progressive MS. RESULTS: Walking distance increased from 517 to 1884 m in Patient 1 and from 52 to 506 m in Patient 2. Gait velocity did not change significantly in Patient 1 and increased from 0.6 to 0.8 m/s in Patient 2. Maximum deviations of center of mass from the midline to each side changed significantly after 3 months of stimulation compared to baseline, decreasing from 15 to 12 mm in Patient 1 and from 47 to 37 mm in Patient 2. Both patients experienced reduced pain and fatigue and benefits to quality of life. Adverse events did not occur during the observation period. CONCLUSION: We conclude that implantable 4-channel FES systems are not only feasible but present a promising new alternative for treating central drop foot in MS patients.