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Rehabilitation in multiple sclerosis in 2020

Cécile Donzé Caroline Massot

PII: S0755-4982(21)00005-1
DOI: https://doi.org/doi:10.1016/j.lpm.2021.104066
Reference: LPM 104066

To appear in: La Presse Médicale

Accepted Date: 24 March 2021

Please cite this article as: Donzé C, Massot C, Rehabilitation in multiple sclerosis in 2020, La
Presse Médicale (2021), doi: https://doi.org/10.1016/j.lpm.2021.104066

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© 2020 Published by Elsevier.

Rehabilitation in multiple sclerosis in 2020

Cécile Donzé1; Caroline Massot1

1: Faculté de médecine et de maïeutique de Lille, service de médecine physique et

réadaptation ; hôpital Saint-Philibert, groupement des hôpitaux de l’institut catholique de

Lille, Lomme, France.

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Corresponding author: C. Donzé ; Service de médecine physique et réadaptation, hôpital
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Saint-Philibert, rue du Grand But, BP 249, 59462 Lomme cedex, France.

E-mail : donze.cecile@ghicl.net
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Disclosure of interest : none

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Abstract

Patients with multiple sclerosis, despite advances in therapy, often suffer from
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locomotor impairment that limits their mobility and affect quality of life. Rehabilitation is part

of the treatment of MS and has shown its beneficial effects in numerous studies. While

traditional rehabilitation techniques remain in the limelight, new technologies are emerging

and make it possible to improve the management of disabling symptoms. The aim of this

update is to synthesize the new therapy techniques proposed in rehabilitation for patients with

multiple sclerosis according to the symptoms as balance, gait, upper limb disorders, fatigue,

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spasticity and disease progression published over the past 5 years. With regard to balance and

walking disorders, neuromotor rehabilitation, physical exercise, rhythmic auditory

stimulation, gait robot training and exergaming are effective. Only physical exercise has

shown a positive effect on fatigue management. Spasticity is improved by classic

rehabilitation techniques however non-invasive brain stimulation are promising.

The rehabilitation of upper limb dysfunctions uses various effective techniques such as

the repetition of functional tasks in real or virtual situations. In case of a more severe

disability, arm robots can be used to relearn the impaired movement. Action observation

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training in real or virtual situations is also effective. Finally, under certain conditions the

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constraint induced movement therapy is proposed. The effects of rehabilitation are not only

positive on the pyramidal symptoms and fatigue but also increase neuroplasticity and perhaps
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a neuroprotective effect as shown in some studies.
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I- Introduction

The management of multiple sclerosis (MS) disease has been improved thanks to
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several rehabilitation techniques which demonstrated their efficiency.

Various techniques have been proposed for many years with a certain effectiveness

demonstrated on locomotor disorders. The aim of this update is to synthesize the new therapy

techniques commonly proposed in MS rehabilitation according to the symptoms as balance,

gait, upper limb (UL) disorders, fatigue, spasticity and disease progression. We propose to

analyze the research on the topic that has been published over the past 5 years.

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 II- Advances in balance and gait rehabilitation in MS

Balance and gait disturbance are the major health problem that compromise activity of

daily living (ADL) and quality of life in patients with multiple sclerosis (PwMS)1.

Rehabilitation of balance and gait deficit usually rely on principle of neuroplasticity and

motor learning strategies2. These interventions aim to promote personalized training in order

to improve sensory-motor skills through intensive, task-oriented circuit training (TOCT)3.

TOCT involves practicing real-life tasks (such as pour a glass of water), with the intention of

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acquiring or reacquiring a competency. TOCT can involve the use of a technological aid as

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long as the technology allows the patient to be actively involved. One of the main targets of

the TOCT is UL rehabilitation, but it can also be used to work on balance and walking in
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concrete situations.
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II-1- Balance
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6 studies (5 RCTs and one observational) were conducted including patients with

progressive and / or relapsing forms with an EDSS between 2.5 and 5.5. Various approaches
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have been assessed: TOCT, vestibular rehabilitation training (VRT), resistance and aerobic
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training and interactive videogames, with a wide variety of program durations ranging from 4

to 8 weeks4.
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II-1-1- Task oriented circuit training (TOCT)

Several authors have recently evaluated the value of TOCT to improve balance in

PwMS. Different exercise modalities are commonly used to control ataxic symptoms in MS

patients. Balance-specific exercises involving somatosensory and motor strategy facilitation

are accepted as standard training modalities. Recently, lumbar stabilization exercises have

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been incorporated into MS rehabilitation programs after the effects of core trunk muscles on

postural control, ambulation and skilled motor function were noted5–7.

In the past 5 years, some authors confirmed this efficacy. Salci et al., proposed to

investigate the effects of different exercise protocols on ataxia in PwMS. 42 PwMS (EDSS:

3–5), were enrolled in this randomized controlled study (RCT). The patients were divided into

three groups: a balance training (BT) group, a lumbar stabilization (LS) group and a TOCT

group. Balance and gait evaluation were performed before and at the end of the 18 training

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sessions. Clinical outcomes measures included: Berg balance scale (BBS), International

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Cooperative Ataxia Rating Scale (ICARS), functional reach test (FRT) and 2min-walk-test

(2MWT). The BBS, FRT, 2MWT, were improved in all groups. The ICARS kinetic function
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sub-score was increased significantly in both the TOCT and the LS groups. According to
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multiple comparison analyses of the ICARS total score and the composite balance score, the

LS, and the TOCT group were different from the BT group (p<0.005), while the LS and the
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TOCT groups improved similarly. The 2MWT results were better for the LS group than the

BT group, while the BT and the TOCT groups improved similarly. Authors concluded that
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BT alone is not sufficient for rehabilitation of ataxic MS patients and proposed to perform a

combination of LS exercises or TOCT to increases the success of balance rehabilitation8.

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Amiri et al., analyzed the effect of 10-week core stability training (CST) program on
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balance in women with relapsing-remitting MS according to EDSS. 69 MS women were

randomly assigned into 2 groups (intervention group and control group). These groups were

categorized into three subgroups according to the EDSS as follows: subgroup A (EDSS 2.5 to

3.5), subgroup B (EDSS 3.5 to 4.5), and subgroup C (EDSS 4.5 to 5.5). The intervention

group performed a CST program for 10 weeks. The Biodex Stability System (BSS) have been

used to evaluate static and dynamic balance performance in pre-and post-tests. In addition, the

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participants’ core muscle function was evaluated using the endurance and isometric muscle

strength tests. The results show a significant difference between post-test variables of the core

muscles function, static and dynamic balances in interventional subgroups in comparison with

the control subgroups. The improved balance order has been given as subgroup C > B > A.

The CST program could be suggested as an efficient clinical intervention for improving

dynamic and static balance in the MS women due to the improvement of core muscle

function, especially for the EDSS score more than 3.59.

Arntzen et al., performed an RCT assessor-blinded study included 80 PwMS

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randomized in experimental group (n=40): 3 patients per group follow program “GroupCore

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DIST” who provide Individualized exercises undivided in 6 categories. The program includes

3 sessions of 30 min/week during 6 weeks; control group (n=40) continues routine care;
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balance and gait were analyzed at 7, 18 and 30 weeks with balance evaluation system test
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(BesTest); 2MWT, 10 min-walk-test (10MWT), multiple sclerosis walking scale-12

(MSWS12), patient global impression of walking change (PGIC), Rivermead Visual Gait
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Assessment (RVGA) and Actigraph; Outcomes were significant at all follow-up time point in

favor to GroupCore DIST for 2MWT and PGIC-walking. 10MWT and MSWS12 improved
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significatively at 7 and 18 weeks and the RVGA at 7 weeks. No difference for Actigraph.
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Compared with standard care, 6 weeks of GroupCoreDIST produce immediate and long-term

significant effect on balance and walking10.

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Pavlikova et al., compared in a RCT rated-blinded; 3 physiotherapy programs:

Group1: balance specific physiotherapy; Group2: non-balance specific physiotherapy;

Group3: control .149 PwMS; Outcomes including BBS and dynamic balance with time up

and go (TUG) were performed at baseline and immediately after the program. Balance

specific physiotherapy significantly improved static balance, and had a higher effect than non-

balance specific approach11.

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 Ozkul et al., reported the result of a RCT with 20 PwMS (EDSS 2-5.5) divided in 2

groups: 10 PwMS performing TOCT 2 sessions per week during 6 weeks and 10 PwMS

following relaxation session at home as control group. Outcomes: BBS, Activities-specific

Balance Confidence Scale (ABC), TUG, functional gait ambulation, (FGA), MSWS12, nine

hole peg test (NHPT). Balance and walking performance were improved after TOCT. TOCT

is quite effective to improve balance and gait in PwMS12.

One author in an observational study with 50 PwMS proposed to discriminate

responders and non-responders of a TOCT program. Univariate analysis revealed a clinical

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meaningful improvement in balance associated with PwMS, inpatient therapy, using a

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walking aid and low baseline BBS score; Multivariate analysis probability of improvement

was similar for participants with progressive MS and relapsing remittent MS but was
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associated with low baseline BBS score and specific treatment. A clinically meaningful
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improvement in balance was more likely when MS individuals with moderate to high

disability had specific exercises targeting balance, but MS type did no influence the
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outcome13.
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II-1-2- Exercises and balance

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Exercise is widely used to improve balance disorders in MS patients. Exercise is most

often offered on conventional fitness equipment or in an aquatic environment. More recently,

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new technologies have emerged and are being developed to offer patients the opportunity to

rehabilitate themselves at home14.

A RCT blind study of home-based balance training was conducted in 39 PwMS

(Median EDSS 4) divided in 2 groups: experimental on HomeBalance (15 min/day for 4

weeks) (n=23) vs control (n=16). Balance (BBS; mini BEST test, and ABC; Falls Efficacy

Scale (FES) was evaluated at baseline and after program and 4 weeks later. Statistically

Page 6 of 38
significant improvements within the home exercise group were present for the BBS and the

Mini-BESTest. This improvement was more significant in the subgroup with moderate and

higher disability (EDSS 4.5 - 7). Follow-up assessment showed that the reached improvement

persisted for a short time period after finishing the regular training regimen15.

Yazgan et al., showed the positive results of a Nintendo wii-fit-based rehabilitation

program in 42 PwMS conducted for 8 weeks, twice a week. Experimental group (G1) was

compared with balance trainer group (G2) and control group (G3) before and after the

program. BBS, TUG, 6 min-walk-test (6MWT), fatigue severity scale (FSS), Multiple

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Sclerosis International Quality of Life (MusiQOL) in G1 et G2 showed statistically significant

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improvement after treatment and outcomes were found to be superior in G1 vs G2; Change in

BBS and QOL were found superior in G1vsG216.

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Another observational study found the same result with 20 sessions of Balance
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exercise using Nintendo Wii Fit in 20 PwMS with mild to moderate disability17.

Finally, VRT can be proposed in some specific cases in order to improve balance
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disorders and dizziness. A Meta-analysis review with 7 studies (321 PwMS) concluded that

compared with no intervention VRT was more effective for balance and dizziness symptoms
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improvement. Compared with other exercises interventions improvements in favour of VRT

were observed but not reached statistical significativity18.

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TOCT is effective in improving balance in the short and long term in PwMS

regardless of clinical form with the need to adapt exercises to the level of disability. In

addition, it seems that home-based balance training tailored by a physiotherapist may be a

future approach to consider for telerehabilitation of PwMS.

II-2- Gait

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 Different training techniques are proposed to improve gait disorders in MS including

exercises and TOCT. More recently, studies exploring others techniques like non-invasive

brain stimulation (NIBS), rhythmic auditory stimulation (RAC), robot assisted gait training

(RAGT) and exoskeleton gait training (EGT) have been conducted.

II-2-1- TOCT

Prokopiusova et al., investigated the effectiveness of 2 months functional electrical

stimulation associated to corrective postural program (G1) compared to TOCT (G2) in 44

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PwMS in a blinded RCT. Gait and balance evaluation (2MWT; time-25-foot-walk (T25FW),

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MSWS12, BBS, ABC, TUG) were evaluated at baseline, immediately after and 2 months

after the end. G1 showed immediate improvement in BBS and ABC who persist and TUG has
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a delayed effect. G2 showed an immediate effect in BBS was significantly higher than the G1.
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FES in the posturally corrected position has an immediate effect on balance and patients’

perception comparable to TOCT program and even persistent18.

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Tavazzi et al., have studied efficacy of a 4 weeks neurorehabilitation program (TOCT)

followed by 29 PwMS (EDSS 4.5–6.5). Several clinical measures were obtained, including:
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2MWT, dynamic gait index (DGI) and BBS and were performed at baseline, after the end of
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the rehabilitation period and 3 months later. After the end of rehabilitation, there was a

significant improvement of 2MWT, DGI, and BBS scores but none after. These findings have
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showed a short-term beneficial effect of motor rehabilitation on gait performances in MS19.

II-2-2- Exercises

Exercise has been recommended for several years now to improve the walking

abilities of patients with MS 14. Exercise training remains the cornerstone therapeutic

intervention for the management of gait impairment in MS. Many studies report positive

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effects from variable exercise interventions as summarized in recent reviews and Meta-

analyses that confirm combined aerobic and resistance exercises can improve both walking

speed and endurance20. Over the last 5 years 4 studies (2 RCTs, 1 observational and 1 review)

on the subject have been published all but one evaluated patients with EDSS<6 all clinical

forms with programs duration ranging from 4 to 6 weeks.

Hayes et al., have investigated the feasibility of MS exercise guidelines for inactive

PwMS, efficacy for walking performance and the effect of augmenting that intervention with

education based on social cognitive theory (SCT). Pilot multicenter, double-blind, parallel

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RCT. 65 physically inactive PwMS walked independently enrolled in a 10 weeks exercise

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plus SCT education (SCT) compared with exercise plus attention control education (CON).

The intervention was feasible and delivered as intended. 68% of SCT group and 50% of
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control group met the exercise guidelines after intervention. There was significant treatment
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effect favouring the intervention group with mean effect for 6MWT at 12 weeks and 36

weeks. Both groups improved in 6MWT TUG and MSWS-12 after 10-week intervention. A
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10-weeks exercise program based on the MS exercise guidelines for improving gait in

previously inactive PwMS was feasible20.

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Jondsdottir et al., reported the effect of a 4 weeks intensive multimodal treadmill

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training on functional mobility, balance, executive functions and participation in 38 PwMS

with moderate to severe disability. Patients have participated in a 2 arm RCT (2:1).
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Experimental group received supervised intensive treadmill training including cognitive and

motor dual tasks (DT-group, n = 26), 5 sessions per week and a control group received the

same amount of supervised strength training (S-group, n = 12). Evaluation were performed

before and after the rehabilitation period with the 2MWT, speed and static and dynamic

balance measures, the Frontal Assessment Battery (FAB) and the short Form-12 questionnaire

(SF-12) questionnaire. The DT-group improved more in gait resistance, speed and mobility.

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Balance and executive functions instead improved moderately in both groups following

training while perception of health remained similar in both groups. A 4 weeks multimodal

training on treadmill was highly effective in increasing gait resistance and mobility in

moderately to severely affected persons with MS21.

Campbell et al., have conducted a review to evaluate effectiveness and safety of

aerobic high intensity interval training (HIIT) in PwMS. 7 studies were identified: 4 RCT, 1

cross-over RCT and 2 cohort’s studies. 249 PwMS predominantly mildly disabled were

included. 6 studies used cycle ergometer and 1 arm ergometer to deliver HIIT. 6 studies

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reported improvements in at least one outcome measure. The most commonly measured

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domain was fitness, which improved in 5/6 studies measuring this aspect. The only trial not to

report positive results included people with progressive and a more severe level of disability
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(EDSS 6.0–8.0). HIIT appears to be safe and effective in increasing fitness in people with MS
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with low levels of disability. Further research is required to explore the effectiveness of HIIT

in people with progressive MS with higher levels of disability 21.

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A pilot study, explored the feasibility of a vigorous harness-supported treadmill

training in a room cooled to 16°C in 10 PwMS (EDSS: 6-7); Functional outcomes (T25FW,
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modified fatigue impact scale (MFIS), short-form-36 (SF-36)) and VO2 Max assessed before
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and after and 3 months later. No AE was noted. Fast walking speed, gait quality improved

after training and improvements were sustained after 3 months; Vigorous cool room training
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is feasible and can potentially improve walking, among people with moderate to severe MS22.

These different studies confirm the fact that physical exercise is effective in MS

patients with positive effects demonstrated especially in patients with EDSS < 6.

II-2-3- Rhythmic auditory cueing (RAC)

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 Several types of rehabilitation approaches have been reported in the literature for

delivering external auditory stimulations, such as RAC. However, RAC is widely studied in

patients affected by Parkinson disease, stroke, and cerebral palsy. RAC can improve motor

execution and finally reduce cognitive overload. RAC is an effective strategy, cheap, and can

also be applied as a home-based intervention23–25.

Seebaeker et al., have proposed to investigate the effect of motor imagery combined

with RAC on gait in 101 PwMS (EDSS:1.5-4.5) randomized into 1 of 3 groups: 17 min of

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motor imagery, 6 times per week, for 4 weeks, with music (A) or metronome cues (B), both

with verbal cueing, and controls(C). Gait was evaluated using T25FW and 6MWT. Compared

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to controls, both interventions significantly improved walking speed and distance23. A
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systematic review and meta-analysis was carried out to analyze the effects of RAC in gait

performance in PwMS. These studies involving 188 participants. The meta-analysis revealed
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enhancements in spatiotemporal parameters of gait: velocity, stride length, cadence, and
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reduction in T25FW. This present review bridges the gaps in literature by suggesting

application of RAC in conventional rehabilitation approaches to enhance gait performance in

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PwMS 24. More recently, Moumdejian et al., compared the effect on walking of two types of

RAC: music, metronome and silence in PwMS. RAC using music was more effective25.
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RAC appears to be an interesting technique to improve gait in PwMS and should be

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evaluated in larger studies.

II-2-4- Robot assisted gait training (RAGT)

Training PwMS with a high degree of disability is still very difficult and often requires

the use of body-weight supported treadmill training (BWSTT) to counteract gravity and

facilitate safe exercise. To facilitate the delivery of this technique, robot-assisted gait training

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(RAGT) was developed. But literature reviews on the use of RAGT have not shown greater

effectiveness than other conventional rehabilitation techniques26,27.

A recent review and meta-analysis analyzed 10 studies on RAGT vs conventional

rehabilitation concluded that Its efficacy on MS is comparable to conventional

rehabilitation28. Straudi et al., found the same conclusion in a RCT that compared RAGT to

conventional therapy (12 training sessions during 4 weeks) in 72 PwMS; (EDSS 6-7). Both

groups significantly improved gait speed without between-group differences. Outcome return

to baseline at follow-up. RAGT was not superior to CT in improving gait speed in patients

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with progressive MS and severe gait disabilities29. Munari et al., in a RCT blinded rater

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investigated effectiveness of RAGT in 2 group of PwMS (n=17): RAGT combined with

virtual reality (VR) and RAGT alone during 1 month. Gait and balance analysis (2MWT,
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10MWT, BBS, stabilometric assessment) were performed at baseline and after 1 month.
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Authors showed significant change in G1 on 2MWT, both gains maintained at the 1-month

follow-up evaluation in G1. Larger positive effect was observed after RAGT with VR on gait
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ability in PwMS. These techniques could be a therapeutic alternative of conventional

physiotherapy30.
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II-2-5- Exoskeleton

Wearable exoskeletons assist individuals with lower limb paralysis for ambulation and
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can be used as a gait training device. Computer-controlled motors placed at knee and hip level

lead to provide assistance in performing different tasks. Recently, Kozlowski et al., have

shown the feasibility and safety of EGT in PwMS (EDSS range 5.5-7)31. Keeogo®

exoskeleton, an assistive robotic device that only provides assistance at the knee joints, was

used in persons with MS having EDSS≤6.5, and observed improvement in gait endurance and

stair climbing capacity 32. Another observational pilot study have explored the feasibility and

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effect of EGT on gait, metabolic expenditure and physical function. 15 sessions of EGT in 10

PwMS (EDSS 6-7.5) have been achieved. T25FW at self-selected speed and fast speed,

6MWT, TUG, and metabolic expenditure with and without Exoskeleton were carried out.

After training gait speed was improved and metabolic expenditure was reduced significantly

during the T25FW at self-selected speed. Authors concluded that EGT is a feasible treatment,

safe and efficacious33. Promising results have been obtained with this technique, further

studies with larger sample size and a more reliable methodology are needed.

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II-2-6- Non-invasive brain stimulation (NIBS)

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NIBS, repetitive transcranial magnetic stimulation (rTMS) and transcranial direct
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current stimulation (tDCS), is widely applied in neurorehabilitation and neuroplasticity

research, for their capability of inducing changes in neural excitability and, with repeated
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sessions, in promoting synaptic changes in humans34. Preliminary data also suggest that 3
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weeks of treatment of HF-rTMS delivered with the H-coil targeting the leg motor areas

bilaterally could improve gait abilities together with reducing spasticity in patients with
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PMS34.
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2 studies have investigated recently effectiveness of NIBS in PwMS. Craig et al.

searched for the best time to apply tDCS in a double-blind, sham-controlled, randomized
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crossover design. 6 PwMS received tDCS before 6MWT and 6 tDCS during 6MWT. The

results found significant decrease in distance walked in the “during group” and significant

increase in gait velocity in the “before group”. tDCS seem to be more effective before than

during a 6MWT and a single session of tDCS may not be sufficient to influence gait32.

Williams et al., have evaluated the efficacy of intermittent theta‐burst stimulation (iTBS) in a

double blind RCT in PwMS who compared one group (iTBS) versus another group with

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Sham-iTBS, before being treating by VRT, and exercise-based program. A significant

improvement Combined c-i-TBS with VRT improved gait and balance abilities more than

standard VRT treatment in PwMS with a high level of disability35.

NIBS appears to be a technique of the future in the management of gait disorders in

MS patients, but studies are still needed before it can be offered in current clinical practice in

this indication.

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III- Rehabilitation effect in spasticity and fatigue

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III-1- Spasticity -p
Spasticity management involves various approaches including physiotherapy (PT). PT

interventions include a wide range of therapeutic approaches such as: exercise training, shock
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waves, electrical stimulation, and vibration. The PT interventions are intended to maintain the
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muscle length, prevent contracture, and change mechanical properties of the musculoskeletal

system and plasticity within the central nervous system14.

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III-1-2- Exercises
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Barclay et al., have assessed in a RCT, 24 progressives PwMS (median EDSS: 7)

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divided in: exercise group (cycling 30 min, 5/week for 4 weeks) and a control group with a

multidisciplinary program. No significant difference between the intervention group and

control in all evaluations were found36.

III-1-3- NIBS

San et al., performed one RCT included 16 PwMS with spasticity of the hip adductors.

One group received 10 sessions of rTMS and 6 receiving Sham as control group. The program

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is combined with PT in the 2 groups. Assessments were performed at baseline, 1 week and 1

month after stimulation. Results showed a significant spasticity reduction in modified

Ashworth spasticity score (MAS) for the hip adductors bilaterally. Active rTMS combined

with PT program reduced spasticity in PwMS compared to control group (PT alone)37.

Leocani et al., in a review summarized the effectiveness of 8 studies especially on

spasticity and NIBS and concluded that spasticity could be controlled by rTMS and iTBS.

Clinical improvement was long-lasting, up to 1 week after the end of treatment. The effects of

iTBS were significantly greater when combined with exercise therapy, suggesting that the

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association of these two strategies is a promising tool for motor rehabilitation34. The

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application of these techniques in clinical practice requires conclusive evidence on clinical

indications, technical procedures, and treatment schedule, as well as criteria for identifying
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the ideal candidates for NIBS treatment.
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III-2- Fatigue
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MS-related fatigue is one of the most often reported symptoms that leads to

restrictions in societal participation and performance in daily life at home, at work and in
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leisure activities38.
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III-2-1- Exercise
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Exercise therapy may positively affect MS-related fatigue, and some mechanisms like

neuroprotective effect, normalization of hypothalamic–pituitary–adrenal axis imbalances or

an anti-inflammatory effect could explain possible beneficial effects. In addition, aerobic

training may reduce the effects of restricted physical activity and the vicious cycle of

deconditioning38.

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 Heine et al., have proposed to estimate the effectiveness of aerobic training on MS-

related fatigue and social participation in ambulant patients with severe MS-related fatigue. 89

PwMS (median EDSS 3.0) were allocated to 16-week aerobic training (n=43) or control

(n=46). Outcomes were assessed by a blinded observer at baseline, 2, 4, 6 and 12 months. A

significant post-intervention between-group mean difference on the fatigue subscale was

found in favour of aerobic training after the program, however, was not sustained during

follow-up. Aerobic training in PwMS with severe fatigue does not lead to a clinically

meaningful reduction in fatigue or social participation when compared to a low-intensity

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control intervention38.

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Kargarfar et al., have assessed the effects of 8-weeks aquatic exercise training program

on functional capacity, balance, and perception of fatigue in 32 women with RRMS (age: 36.4
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±8.2) in a RCT. After undergoing baseline testing by a neurologist, participants were
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allocated to either an intervention (aquatic training program; n=17) or a control group (n=15).

The intervention consisted of an 8-week aquatic training program (3 supervised 10 training

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sessions (45-60 min) per week). Evaluation were performed at baseline and after an 8 weeks

intervention. All outcomes measures improved in the experimental group. Authors concluded
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that aquatic exercise training improved functional capacity, balance, and perception of fatigue

in women with MS39. Gervasoni and al., found the same result in a cross over comparative
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study compared a combined arm cycling group and a TOCT group with 20 sessions
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supervised by a physiotherapist during 8 weeks for 20 PwMS. After treatment the combined

group showed improvement in fatigue40.

Mayo et al., have explored in a RCT, 2 groups of PwMS. Group1 (n=34): Personally,

tailored exercise programs (MSTEP) vs Group2 (n=37): general exercises guideline.137

patients at baseline and 71 PwMS at 12 months. The effect on fatigue was larger in the

MSTEP group, effect on Physical Fatigue was modest. The disappointed exercise retention

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suggest that PwMS may not consider exercise important to their brain health and need more

information to increase program adherence41.

A metanalysis (1996-2019) included 31 study and 704 PwMS intervention group vs

720 PwMS control was done by Razazian et al. in 2020 and after treatment, the combined

group showed significant improvement in fatigue42.

The literature have shown us that physical exercise remains the best treatment for

fatigue at the present time, except perhaps in cases of severe fatigue.

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IV- UL dysfunction rehabilitation

About 60% to 75% of PwMS were affected by UL dysfunction more over in the
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progressive forms of the disease43. A combination of motor, sensory and cerebellar symptoms
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can lead to UL dysfunction and interferes with ADL and quality of life. Despite the clinical

relevance of ULD, limited research has been specifically dedicated to UL rehabilitation in

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PwMS43. The techniques used in the UL dysfunction rehabilitation of PwMS has benefited

from the advances obtained in the stroke rehabilitation. TOCT, CIMT but also mirror therapy
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with action observation training (AOT) associated or not with virtual reality (VR), serious
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games or robots arm training (RAT) are increasingly being proposed and are being evaluated

more and more in this indication.

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The studies reported evaluated different techniques with very disparate populations in

terms of clinical forms and levels of disability (EDSS 1.5 to 6). The duration of the programs

are also varied and range from 2 weeks to 4 months depending on the techniques used. On the

other hand, the assessments are fairly homogeneous, most of them using the NHPT and

functional MRI.

Page 17 of 38
IV-1- TOCT

Ozkul C et al., did not find any significant change in dexterity performance in RCT

included 20 PwMS (EDSS 2-5.5) divided in 2 group: 10 PwMS with TOCT (2/week for 6

weeks) to 10 PwMS (control followed relaxation at home)12.

Gervasoni et al., in a crossover RCT have compared the effectiveness of TOCT

combined with arm cycling. After treatment the combined group showed no effect in NHPT40.

One RCT have investigated TOCT applied by RAT in 41 PwMS with UL impairment.

17 PwMS followed RAT and 11 sensorimotor rehabilitation including 8 training sessions

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(40min) twice a week. The absolute change was only significant in the TOCT-RAT-group on

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NHPT but not in Action Research Arm Test (ARAT) scores. Authors concluded that TOCT-

RAT may improve UL function in PwMS especially in prevalent pyramidal impaired subjects
-p
without maintain the effects after 3 months44.
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IV-2- Virtual reality (VR) and action observation training (AOT)

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The discovery that Mirror Neurons (MN) are involved in motor learning has allowed

the development of a new rehabilitation approach, called AOT. During AOT session, the
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patient is asked to observe different actions presented through a video, in order to try and
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imitate them after the observation. This action provide a tool to recover damaged cerebral

networks and need to consider as an alternative or complement to physiotherapy45.

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Rocca et al., investigated AOT effects on dominant-hand motor performance in PwMS

with UL motor impairment and performed an explorative analysis of their anatomical and

functional MRI substrates. 46 healthy controls (HC) and 41 PwMS with dominant-hand motor

impairment were randomized to AOT (HC-AOT = 23; MS-AOT = 20; watching daily-life

action videos and execution) or control-training (HC-Control = 23; MS-Control = 21;

watching landscapes videos and execution). Behavioral, structural, and functional (at rest and

Page 18 of 38
during object manipulation) MRI scans were acquired before and after a 2-week training.

After training, MS groups improved in right UL functions, mainly in AOT group. The 10-day

AOT promotes clinical improvements in PwMS through structural and functional

modifications of the action observation matching system46.

45 women with MS performed a RCT who have compared 3 groups: VR vs

conventional physical training (CPT) vs VR combined with CPT during 8 weeks. Bimanual

coordination improved over time from baseline to study completion and to follow-up.

Compared to the VR and CPT condition the combination condition led to higher coordination

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accuracy and consistency47.

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Boffa et al., have conducted RCT pilot study comparing AOT (n=13) vs passive

treatment control group (n=13). PwMS (EDSS 5-6), right-handed have performed 36 sessions
-p
(1h twice a week) in 26 progressives MS. UL motor performance (ARAT, NHPT,
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ABILHAND, MFIS and motor finger performance measured by engineered glove) were

assessed at baseline and after treatment. After rehabilitation, AOT group improved in several
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finger motor tasks48.

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IV-3- NIBS
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Improvement in ULD in PwMS after rTMS has been reported after a single session

and up to 1month after two consecutive sessions. Also, 10 daily sessions of iTBS over the
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hand were associated with significantly better improvement of manual dexterity compared

with sham stimulation. tDCS applied to contralateral area to the more severely impaired hand

increased the corticospinal output and projection strength evaluated with the input/output

curve, but no clinical effects were measured34.

IV-4- Serious game

Page 19 of 38
 Jonsdottir et al., in an observational study have showed that 12 sessions (45min) of

supervised serious game used for rehabilitation of the most affected upper limb in 18 PwMS

improved dexterity and arm function bilaterally with a statistically significant improvement

only in the treated arm. An in-clinic intervention with serious game virtual reality approach

positively influenced arm recovery in Patient moderately to severely affect by MS49.

60 PwMS were included in a RCT divide in 3 groups: video-based exergaming (n=21),

conventional rehabilitation (n=19) 1/week for 8 weeks and control (n=20). Significant

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improvements were observed in NHPT in the video-based exergaming and conventional

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rehabilitation groups. Exergaming is almost effective as conventional rehabilitation regarding

improving UL functions in PwMS50.

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Cuesta-Gomez et al., in a RCT blinded have evaluated the effectiveness of serious
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game combined with conventional rehabilitation compared with control who received

conventional rehabilitation (2/week for 10 weeks) in ULF. Significant improvements were

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found in the combined group for coordination, speed of movements, fine and gross UL

dexterity. Significant results were found in follow-up in coordination, speed of movements,

na

fine and gross UL dexterity for the most affected side. An experimental protocol using a
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serious game designed for UL rehabilitation showed improvements for unilateral gross and

fine manual dexterity and coordination in MS patient with high satisfaction and excellent
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compliance51.

40 PwMS (EDSS: 1.5-6), RR and PMS with altered dexterity were included in RCT

divided in two groups: Computer-assisted training program with rehacom cognitive function

platform (n=20) vs: control (n=20). Program was performed 3 times (20 min) a week during 3

months. More evident effects of dominant limb therapy are demonstrated in PwMs with

Page 20 of 38
EDSS score <3 and < 60 years. Application of cognitive software training for manual therapy

in PwMS has positive effects on both dominant and non -dominant hands52.

IV-5-1- Constraint induced movement therapy (CIMT)

CIMT is a new treatment technique that claims to improve the arm motor ability and

the functional use of a paretic arm - hand. CIMT forces the use of the affected side by

restraining the unaffected side. The less-affected arm remains blocked 90% of their waking

hours and patients perform repetitive exercises with the more affected arm 6 to 7 h per day

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during 2 to 3 weeks45. CIMT has controlled evidence of efficacy for improving real-world

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paretic limb use in non-progressive physically disabling disorders (stroke, cerebral palsy) 53.

In contrast, the benefits of CIMT for progressive neurological disorders such as MS have been
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little studied. A pilot study of CIMT for hemiparetic PwMS demonstrated safety, tolerance,
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and functional efficacy53.

Mark et al., conducted a preliminary phase II RCT of CIMT versus a program of

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complementary and alternative medicine (CAM) treatments for PwMS. 20 hemiparetic PwMS

underwent 35 hours of either CIMT or CAM over 10 consecutive weekdays. The primary
na

clinical outcome was change from pretreatment on the Motor Activity Log (MAL). The
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CIMT group improved more on the MAL than did the CAM group. These results did not

change at 1-year follow-up, indicating long-term retention of functional benefit for CIMT.
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The treatments were well tolerated and without AE. These results suggest that CIMT can

increase real-world use of the more-affected arm in patients with MS for at least 1 year53.

Barghi et al., tested whether CIMT can also induce increases in white matter integrity

in patients with MS and concluded that CIMT produced a very large improvement in real-

world limb use and induced white matter changes in hemiparetic PwMS when compared with

CAM54.

Page 21 of 38
 If classical TOCT does not seem to be effective in improving the function of the UL,

new technologies can support the rehabilitation technique and could be a suitable solution to

offer to PwMS with ULD. More large studies are necessary to prove its effectiveness.

V- New measurement of rehabilitation effects

The objective of rehabilitation programs is not only to improve some deficient

functions but also to try to slow down the progression of the disease. For these reasons some

authors proposed to evaluate the effect of rehabilitation using measurements of biological and

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morphological biomarkers (MRI).

V-1- Inflammatory biomarkers

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-p
Scares studies have used biological biomarkers to evaluate the effect of rehabilitation
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programs in PwMS. Abbaspoor et al., conducted a RCT to compare combined functional

training (CFT) (8 weeks, 3/week of rhythmic aerobic exercises, TRX® suspension, elastic
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band training and bodyweight training) and control with conventional therapy. 20 women

with RRMS were included. Walking speed, strength of the right-and left-hand and biological
na

markers as BDNF and IGF-1 level were performed at baseline and immediate post treatment.
ur

Results showed no significant difference in the BDNF level between groups. IGF-1 level,

walking speed and strength hands was significantly increased in the CFT group vs control
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group. Correlation was found between IGF-1 and some fitness components. CFT might be a

useful training mode in the rehabilitation of MS women and improved IGF-1 level that is a

neuroprotective agent in MS55. Zilioto et al., in a RCT performed in 61 PwMS severely

disabled progressive MS following 12 walking sessions of RAGT vs conventional therapy.

Gait and balance analysis (T25FW; 6MWT; BBS) and plasma level of coagulation inhibitors

protein S (PS), soluble thrombomodulin (sTM) and tissue factor pathway inhibitor (TFPI)

Page 22 of 38
were evaluated at Baseline, intermediate and immediate posttreatment and 3-months follow-

up. Plasma level of coagulation inhibitors were related to variations of outcome measurements

after high-intensity walking rehabilitation programs. PwMS with decreased TFPI levels from

T0 to T2 displayed the most significant functional recovery following rehabilitation and

particularly after RAGT. Authors concluded that higher baseline total PS levels were

associated with favorable outcomes of rehabilitation. Plasma level of hemostasis inhibitors

might have implication for rehabilitative therapy option in MS56.

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V-2- Neuroplasticity

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MS is characterized by accelerated brain atrophy, which induce disease progression.
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Rehabilitation seems to promote brain plasticity, but objective measures of efficacy are

lacking and there is a limited understanding of the mechanisms underlying functional

re
recovery. More and more studies are trying to demonstrate this fact57.
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Kjølhede et al., proposed to investigate the effects of progressive resistance training

(PRT) by MRI and clinical measures of disease progression in 35 PwMS. This study was a
na

24-week cross-over RCT, including a Training (n = 18, 24 weeks of PRT followed by self-
ur

guided physical activity) and Waitlist group (n = 17, 24 weeks of habitual lifestyle followed

by PRT). Assessments included disability measures (EDSS; MFSC) and MRI (lesion load,
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global brain volume, percentage brain volume change (PBVC) and cortical thickness). While

the MSFC score improved, EDSS, lesion load and global brain volumes did not differ

between groups. PBVC tended to differ between groups and higher absolute cortical thickness

values were observed in 19 of 74 investigated cortical regions after PRT. Observed changes

were confirmed and reproduced when comparing relative cortical thickness changes between

groups for 4 areas: anterior cingulate gyrus, temporal pole, orbital sulcus and inferior

Page 23 of 38
temporal sulcus. PRT seem to induce an increase in cortical thickness, indicating that PRT

have a neuroprotective or even neuro-regenerative effect in RR PwMS. These results suggest

a possible restorative effect of PRT on brain structures, but the interpretation should be

cautious due to the study duration and sample size57.

Barghi et al., tested whether CIMT can also induce increases in white matter integrity

in PwMS and concluded that CIMT produced a very large improvement in real-world limb

use and induced white matter changes in patients with hemiparetic MS when compared with

of
CAM. The findings suggest in preliminary fashion that the adverse changes in white matter

integrity induced by MS might be reversed by CIMT 54.

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Tavazzi et al., have hypothesized that gait rehabilitation could change functional and
-p
structural brain. They enrolled 29 PwMS (EDSS 4.5–6.5) undergoing a 4-week
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neurorehabilitation program. Several clinical measures were obtained, including: 2MWT,

DGI, BBS and motor-task functional MRI (fMRI) of plantar dorsiflexion, resting state fMRI,
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and regional diffusion tensor imaging (DTI) metrics. After program, there was a significant

improvement of 2MWT, DGI, and BBS scores, along with a reduced extent of the widespread
na

activation related to the motor task at the fMRI and an increased functional connectivity in the
ur

precentral and post-central gyrus, bilaterally only immediately after the program. Authors

concluded a short-term beneficial effect of motor rehabilitation on gait performances in

Jo

PwMS, accompanied by brain functional reorganization in the sensory-motor network19.

Rocca et al., investigated AOT effects on dominant-hand motor performance in PwMS with

UL motor impairment and performed an explorative analysis of their anatomical and

functional magnetic resonance imaging (MRI) substrates. After training, all groups showed

regional increased and decreased gray matter volume, with specific AOT effects in fronto-

temporal areas, without white matter integrity modifications. Increased and reduced

Page 24 of 38
recruitments of the action observation matching system and its connections in AOT group

were found. Motor improvements were correlated with volumetric and functional MRI

modifications40.

Boffa et al., have conducted RCT pilot study comparing AOT (n=13) vs passive

treatment control group (n=13) in 26 PwMS (EDSS 5-6), right-handed. MRI measures were

done: lesions and brain volumes; diffusion tensor imaging and resting state fMRI. The AOT

group showed increased functional connectivity within the cerebellar and thalamic resting

of
state networks compared with the cingulate gyrus. Correlations were found between several

measures of motor improvement and thalamic and sensorimotor networks. No change in

ro
cerebral volume score was noted48. -p
24 PwMS enrolled in RCT included in multidisciplinary based-center rehabilitation vs

24 healthy control (HC) during 4 weeks. A motor sequence learning (MSL) task was
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presented during fMRI. Baseline, immediate post-treatment and 4 week’s follow-up. Patients
lP

had less perceived fatigue, improved walking speed and following rehabilitation which could

be maintained at follow-up. After rehabilitation difference in accuracy of the MSL task

na

between groups diminished and went along with changes of brain activity in the left

cerebellum and right frontal lobe post rehabilitation while there is no change in HC group.
ur

MD rehabilitation may improve highly impacting symptoms through more efficient

recruitment of brain regions58.

Jo

Péran P et al., in an observational study have investigated effectiveness of MD

rehabilitation in patient’s fMRI evaluation assessed a range of tasks: passive movement,

mental stimulation of action and miming of action triggered by external stimuli. 30 PwMS

medium-high severity of disease performed fMRI at inclusion, 3months later and after 3

months of the program. Significant reduction was observed in the activity of brain areas

Page 25 of 38
related to task-specific networks as well as the activation of cerebral regions not usually

involved in task specific related network, such as medial prefrontal area59.

Sandroff et al. in a review contained 10 studies exploring exercises training,

neuroimaging outcomes and functional outcomes in MS. There is mixed evidence for exercise

training as a neuroplasticity-inducing behavior in PwMS. Such a paucity of evidence

supporting exercise-induced neuroplasticity in MS is likely a product of a very small number

of papers that do not sufficiently examine hypothesized mechanisms of action60.

of
Consequently, longer (years) and larger exercise studies are warranted, to confirm the

observed trends, as these findings implicate that exercise might provide an adjunct therapy to

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the medical treatments. -p
VI- Conclusion
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During MS, patients will present locomotor disorders (balance and gait disorders,

spasticity), fatigue and ULD leading to limited social participation and impaired quality of
lP

life. Some rehabilitation techniques are likely to improve these symptoms with specific

techniques. TOCT and exercises have positive effects on balance disorders. More recent
na

techniques using serious games or RAGT have shown encouraging results that need to be
ur

confirmed in larger studies. For gait disorders exercise is recommended with numerous

studies confirming a positive effect of exercise and muscle strengthening. RAGT,

Jo

exoskeletons, RAC, serious games and NIBS have positive effects at least equal to other

techniques but need to be validated. The effects of TOCT, physical exercise and NIBS are

also possible to reduce spasticity with the need for additional studies to confirm their effects.

Only exercise has been proved to be effective in the management of fatigue. The techniques

that have shown a possible effect on upper limb function are represented by exercise, AOT in

virtual reality or with upper limb robot-assisted movement, serious games and CIMT.

Page 26 of 38
Conflicting effects have been shown in studies using TOCT and NIBS for ULD (Table 1).

The effects of rehabilitation are not only positive on the motor symptoms and fatigue

encountered during MS but also increase neuroplasticity and perhaps a neuroprotective effect.

of
ro
-p
re
lP
na
ur
Jo

Page 27 of 38
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Table 1: Target MS symptoms for rehabilitation stratified by current evidence for each

technique

Rehabilitation Balance Gait Spasticity Fatigue UL dysfunction

techniques

TOCT ++ + + - +/-

VRT + - - - -

Exercise ++ ++ + ++ +

of
RAC - + - - -

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RAGT /RAT + + - - +

EGT - + - - -
-p
rTms - + + - +/-
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tDCS - + - - +/-
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iTBS - + + - -

VR (AOT) +/- - - - +
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Serious game + + - - +

CIMT - - - - +
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(++): Positive effect; (+): Possible effect; (+/-): Contradictory results; (-): Negative or

Unknown effect
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