Modern Technologies in the Rehabilitation of Patients with Multiple Sclerosis and Their Potential Application in Times of COVID-19

Background and Objectives: The COVID-19 pandemic required the adoption of new technologies to improve access to healthcare at an unprecedented speed, as social distancing became mandatory. The aim of this systematic review was to analyze the effectiveness of using new technologies in the rehabilitation of multiple sclerosis (MS) patients and discuss their potential role during the COVID-19 pandemic. Material and Methods: The studies were identified by searching two online databases—PUBMED and Web of Science. Combinations of the key words “Multiple sclerosis” and “e-health”; “Multiple sclerosis” and “virtual reality”; “Multiple sclerosis” and “telerehabilitation”; “Multiple sclerosis” and “new technologies”; “Multiple sclerosis” and “tele-exercise” were used to find suitable publications. Results: A total of 17 studies were included. Although the overall number of participants in all the studies was 904, two of the studies were conducted on the same group. Thus, a total of 854 participants were involved in the studies included. All participants were diagnosed with MS. In 10 studies, participants had to be diagnosed according to the McDonald criteria. Of the included studies: five involved intervention at participants’ home, six were conducted using Xbox Kinect, and seven studies reported no adverse outcomes. Conclusion: The review proves telerehabilitation to be an effective motivational tool to restore and maintain both physical and cognitive function in patients with MS. Remote communication technologies seem to be measures of high effectiveness in rehabilitating and supporting MS patients especially during the COVID-19 pandemic, as the traditional rehabilitation option is less accessible or in some cases inaccessible for these patients.


Introduction
Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system of unknown etiology and multifactorial origin [1]. MS is the most common chronic neurological disease among young adults in Europe and North America. Typical symptoms include fatigue, visual disturbances, balance and coordination problems, sensitivity disorders, spasticity, cognitive function and emotional disturbances, speech disorders, bladder and bowel problems, and sexual dysfunction [2,3]. Balance disorders and postural control impairment are among the most common motor disorders associated with MS, occurring in 20% of patients at the onset of disease and in 80% of patients with chronic MS symptoms [4]. Specifically, decreased speed and efficiency for timed walking is associated with occupational changes, loss of independence in activities of daily living (ADLs) and self-reported disability [5,6].
Neurorehabilitation programs are the most common therapies used to reduce disability and social disadvantage resulting from MS. Physical rehabilitation is one of the This systematic review aims to analyze the effectiveness of using new technologies in the rehabilitation of MS patients and to discuss their potential role in the era of the COVID-19 pandemic.

Material and Methods
A review of the literature was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines [17]. The procedures (search strategy, inclusion/exclusion criteria, and data extraction) were established and included in the protocol. An approval of an Ethics Committee is not required in such studies. The study was registered in the Research Registry and received Review Registry UIN: reviewregistry1138.

Search Strategy
The studies were identified by searching two online databases-PUBMED and Web of Science. The following combinations of the key words with Boolean operator "AND": Multiple sclerosis AND e-health; Multiple sclerosis AND virtual reality; Multiple sclerosis AND telerehabilitation; Multiple sclerosis AND new technologies; Multiple sclerosis AND tele-exercise were used to find suitable publications. Two of the authors (TT and EZ) conducted their independent searches of the literature published in recent 10 years (between 1 January 2011 and 18 January 2021). Studies conducted on human subjects were identified, and the language was limited to English. Abstracts or unpublished reports were not considered.

Inclusion and Exclusion Criteria
The inclusion criteria for the reports were as follows: (a) published in English in a journal with a review process, after 2010; (b) original research study with a control group or presentation of comparative pre-and post-therapy results of therapy involving new technology in MS patients; (c) clearly defined inclusion and exclusion criteria for the study groups and controls.
The following articles were excluded: (a) studies on populations including other patients than those with MS; (b) animal studies; (c) studies examining the effect of robotic intervention in MS patients; (d) studies lacking approval of local ethics committee; (e) studies with incomplete outcome data; (f) studies using additional therapies only in the study group, but not in the control group; (g) studies of undetermined type; (h) pilot studies and conference proceedings.

Quality Assessment
To determine methodological quality of the studies included, the Quality Assessment Tool for Quantitative Studies (QATQS) [18] was used. QATQS assesses eight domains of methodological quality: selection bias, study design, confounders, blinding, data collection methods, withdrawals and dropouts, intervention integrity, and analysis. The first six domains may be classified as 'weak', 'moderate' or 'strong', according to a reviewer's dictionary. If one domain is rated as 'weak', the entire study is deemed 'moderate', if more than one section is 'weak', the study is considered automatically 'weak', and if neither section is 'weak', the study is rated as 'strong'. The intervention integrity section helps to answer the question of the risk of overestimating or underestimating the intervention. This may be a consequence of e.g., delivering interventions to different participants in a heterogeneous manner, or accidental receipt of an intervention by a person from the control group.
The assessments were performed independently by two authors (TT and EZ). If agreement on the quality assessment could not be reached by the two authors, the third author was consulted (KH).

Data Extraction
The following data were extracted from each study: first author, year of publication, study population characteristics, study design, inclusion/exclusion criteria, intervention characteristics, assessment of the outcome, and results. For this review's purpose, we had not extracted information regarding satisfaction and adherence to intervention (as the outcomes).

Evaluation of the Study
From a total of 1364 only 17 studies were included. The search results and the flow diagram of the study selection are summarized in Figure 1. Although the overall number of participants from all the studies was 904, two of the studies were conducted on the same group of participants [19,20]. Thus, a total of 854 participants were involved in the studies included. All participants were diagnosed with MS. In 10 studies [19][20][21][22][23][24][25][26][27][28], participants had to be diagnosed according to the McDonald criteria (2010 [29] or 2017 [30] revision-depending on the date of the study conduction).
Using QATQS, 11 studies were deemed to be 'strong', 5-'moderate' and 1-weak'. Detailed results are presented in Table 1. Study design, confounder control, and data collection methods sections were rated highest, while selection and blinding sections overall scored as weakest. The results for individual sections are presented in Figure 2.

Characteristics of Research Participants and Study Criteria
Participants' characteristics are presented in Tables 2-4. The studies were selected according to a selected function in MS patients and divided into subgroups: studies of new technologies and balance and gait parameters; studies of new technologies and hand function; studies of new technologies and other health-related outcomes.   Diagnosis of MS according to the McDonald criteria with over 2 years evolution; a score of between 3.5 and 7.5 on the EDSS; with stable medical treatment during at least the 6 months prior to the intervention; muscle tone in the upper limbs ≤2 on the modified Ashworth Scale; ≤4 in the "Pyramidal Function" section of the EDSS functional scale; absence of cognitive decline (≥24 in the MMSE; and ≤2 in the "Mental Functions" section of the EDSS) Diagnosis of another neurological illness or musculoskeletal disorder different to MS; the diagnosis of a cardiovascular, respiratory, or metabolic illness or other conditions which may interfere with the study; suffering a flare-up or hospitalization in the last 3 months. prior to commencement of the assessment protocol or during the process of the therapeutic intervention; receiving a cycle of steroids 6 months. prior to the commencement of the assessment protocol and within the study period of intervention; receiving treatment with botulinum toxin in the 6 months. prior to the beginning of the study; visual disorders non-corrected by optical devices Relapsing-remitting or secondary progressive type of MS, being able to walk at least 100 m without resting, being able to stably stand for half an hour, relapse-free period of 3 months, willing to participate in the study Another neurological disorder, relapse during the study period, orthopedic surgery history covering the ankle-foot, knee, hip, or spine, affecting balance, and diagnosis of severe cognitive and/or psychiatric impairment  A diagnosis of MS according to the McDonald criteria with over two years evolution; a score of between 3.5 and 6 on the EDSS (as well as a score ≤ 4 in the "Pyramidal Function" section of the EDSS functional scale, or score ≤ 2 in the "Mental Functions" section of the EDSS); stable medical treatment during at least the six months prior to the intervention; muscle tone in the upper limbs not greater than two points on the modified Ashworth Scale; absence of cognitive decline; ability to understand instructions and a score ≥ 24 in MMSE Diagnosis of another neurological illness or musculoskeletal disorder different to MS; the diagnosis of a cardiovascular, respiratory, or metabolic illness or other conditions which may interfere with the study; suffering a flare-up or hospitalization in the last 3 months. prior to commencement of the assessment protocol or during the process of the therapeutic intervention; receiving a cycle of steroids 6 months. prior to the commencement of the assessment protocol and within the study period of intervention; receiving treatment with botulinum toxin in 6 month.
Characteristics of the studies are presented in Table 5.
Conroy et al. [22] compared two physiotherapy training programs. In the intervention group (IG), there were exercises with asynchronous text messaging for exercise updates from the therapist via communication application, while there were only exercises prescribed at baseline in the control group (CG). The authors failed to observe any improvements in regard to the parameters measured (balance and gait) both in IG ( [Mean difference (p-value)] respectively: six-minute walk test . However, the authors pointed out that the high attrition rate in their study (only 24 from 54 participants originally enrolled at the baseline completed the study), which resulted in a small sample size, may be the factor that reduced the possibility to detect changes in the population studied.
Maggio et al. [24] reported significant improvements in regard to balance and neuropsychological parameters in both experimental (receiving VR-based, semi-immersive motor and cognitive rehabilitation) and control (receiving only conservative rehabilitation) groups. However, an increase in all the parameters measured was observed only in the group receiving VR-based intervention. The authors concluded that VR can be an effective tool for functional recovery in MS patients.
Molhemi et al. [25] found that VR-based balance training can be as efficient in balance improvement and reduction of fall risk as conventional physical exercises. Those authors [25] reported that certain effects of VR-based training lasted longer than the effects of exercises. The authors observed an improvement in regard to the Timed Up and Go test, and the reaction time remained significant at three-month follow-up only in the group receiving VR-based training.
Another study included in this review [26] proved that home-based balance rehabilitation, in the form of exercises on a balance platform with visual and auditory feedback, can be beneficial to MS patients. Novotna et al. [26] showed that the above-mentioned training conducted for four weeks improved balance among participants at the end of the study period (in terms of the BBS and Mini-BESTest p = 0.001) and after four weeks of follow-up (in terms of the BBS and Mini-BESTest p = 0.001). However, no changes regarding the gait parameters measured were observed. Those authors pointed that despite the total improvement in the BBS (mean 1.9 points) being lower than the minimal clinically important difference (3 points), home-based, individually adjusted balance training could improve balance in a clinically observable manner. In their opinion, the improvement was clinically insufficient (although statistically significant) due to the too-short time of intervention, which they pointed out as a study limitation [26].
Two research papers, authored by Ortiz-Gutierez et al. [19,20], studied the effectiveness of telerehabilitation on improving balance parameters. Both papers reported results of a study conducted on the same group of participants (which was confirmed via contact with the corresponding author of both papers). The results of the above-mentioned papers [19,20] showed greater, significant improvement in terms of the BBS (F = 29.896, p < 0.001), Tinetti Test (F = 46.898, p < 0.001) and Composite Equilibrium Score (part of The Sensory Organization Test) (F = 37.873, p < 0.001) in the group receiving telerehabilitation compared to the controls (conventional rehabilitation treatment).    Peruzzi et al. [33] studied the effect of VR on treadmill training effectiveness regarding balance and gait among MS patients. The results showed significant improvements in both groups (treadmill training as control and treadmill training with VR as intervention group) in terms of gait speed, cadence, and stride length. Significantly more considerable improvements in the knee (p < 0.013) and hip (p < 0.001) range of motion were observed in the VR with treadmill group. The authors [33] also explained that the increase in lower limb joint kinematics, increased hip power generated at the terminal stance, and increased peak ankle power generated at push-off (which were more pronounced in the VR with treadmill group) were facilitated by the need to negotiate the virtual obstacles.
Robinson et al. [34] investigated the effects of exergaming on postural sway and gait in people with MS in comparison to traditional balance training and no intervention (control group). Improvements were present in the exergaming group compared to the control, although there were no statistically significant differences between the exergaming group and the group receiving traditional balance training.
Lozano-Quilis et al. [31] studied the effectiveness of a Kinect-based system named RemoviEM, which is designed to motivate patients and give them visual feedback during motor rehabilitation. Comparing standard rehabilitation with rehabilitation using RemoviEM, these authors found differences in BBS improvement over time in favor of the group that used RemoviEM. In regard to other balance parameters measured, they found similar improvements in both groups. The authors emphasized that because most of the participants admitted that they had fun during the exercises, this type of using new technologies in rehabilitation may have a beneficial motivational effect.
Yazgan et al. [37] compared two exergaming treatments (with commercial exergames on Nintendo Wii Fit-group 1 and Balance Trainer device with games especially designed to train balance-group 2) with the control group (comprised of waitlist participants). The authors [37] found improvements in both intervention groups regarding the BBS; the mean difference in group 1 was 5.80 (SD = 5.29) and in group 2 2.66 (SD = 1.92). Improvements were significant in the comparison between both intervention groups and CG (p < 0.001), as well as in the comparison between group 1 and group 2 in favor of group 1 (p < 0.001). Statistically significant differences in favor of the intervention groups compared to the control were also observed regarding other outcomes measured (Timed up and go test, 6-min walking distance, Fatigue Severity Scale, and Multiple Sclerosis International Quality Of Life Questionnaire). The authors stated that exergaming, both with Nintendo Wii Fit and Balance Trainer, is fun, enjoyable, and competitive, which can improve exercise effectiveness [37].
The effect of treatment using new technologies on manual dexterity was studied in other four studies [23,27,28,36]. Cuesta-Gómez et al. [23] studied the effect of 10-week VR training of the hand (added to traditional rehabilitation of the hand) on manual dexterity. As an intervention, the authors [23] used a set of games prepared especially for this purpose and proved it to be successful at improving manual dexterity. The results of the Purdue Pegboard Test (more affected side (p = 0.032), both hands (p = 0.019), assembly (p = 0.008)) and the Box and Blocks Test (on the more affected side (p = 0.036)) improved significantly in the group which received VR training in comparison to CG (which was constituted by participants receiving only conventional rehabilitation treatment). The change in the above-mentioned parameters proved to be persistent after one-month follow-up in regard to the Box and Blocks Test on the more affected side (p = 0.010). The change between the groups in the Nine Hole Peg test score on the more affected side also proved to be significant (p = 0.011) in follow-up evaluation. Although this intervention was conducted at the study site, the authors pointed out that future studies of their training system should be conducted as an at-home rehabilitation system [23].
Upper limb function was also the topic of another study included in the present systematic review. Ozdogar et al. [27] found that the video-based exergaming performed for 8 weeks resulted in improvements in the Nine Hole Peg test score compared to baseline. The observed effect was significant both in the group treated with exergaming and in the group treated with a conventional rehabilitation program. No significant differences between the two treated groups were found. The authors [27] also demonstrated that differences between CG and both treated groups were statistically significant. An improvement in most cognitive function, leg function and balance-related outcome measures in the treated groups was also observed.
Pawlukowska et al. [28] conducted a study of the effect of computer-assisted hand therapy versus traditional hand therapy. The authors proved that adding computer-assisted exercises, oriented at improving attention, concentration, learning, and executive functions in standard hand therapy, is beneficial for MS patients. In the population studied, an improvement in time-to-complete The Nine Hole Peg Test in the computer-assisted therapy group was significant for dominant (p = 0.007) and for non-dominant (p = 0.037) hand, which was not observed in the control group [28].
Another study concerning manual dexterity was conducted by Walino-Peniagua et al. [36]. The authors failed to prove the effectiveness of game-based VR training in addition to occupational therapy in improving the function of the hand. In both intervention (VR+ OT) and control group (OT only), improvements were observed regarding the precision and effectiveness of specific functional tasks (such as picking small objects). However, the results did not differ significantly between both groups. The authors [36] hypothesized that the observed lack of differences may have been caused by the small sample size and high attrition rate in their study, which could possibly have compromised the results.
Another study, by Norouzi et al. [32], investigated the effect of VR bimanual coordination training on bimanual coordination among persons diagnosed with MS. In the three-arm, randomized, controlled trial, the authors demonstrated improvement in all three groups (VR, VR+ conventional rehabilitation, and conventional rehabilitation only). However, the greatest impact on the bimanual coordination accuracy and consistency was observed in the group receiving combined intervention (VR+ conventional rehabilitation). The authors [32] emphasized that treatment comprised of both VR and conventional rehabilitation can be more beneficial to MS patients, and its effects can last longer. Table 6 presents characteristics of the studies.
Tallner et al. [35] investigated the effectiveness of an internet-based exercise intervention on improving health-related quality of life, muscle strength, respiratory function, physical activity, and fatigue among MS patients. The CG was comprised of waitlist participants. After three months from study baseline, CG participants received the same intervention as IG had received from the beginning. Thus, a between-group comparison was conducted based on the data obtained at assessment performed three months after the study beginning. The authors found that internet-based training intervention did not influence the health-related quality of life and fatigue, but muscle strength of the lower extremities, lung function and physical activity improved significantly. The results obtained after three months of training showed that the maximum muscle strength of the knee increased (by 9% and 13% in extensors and flexors of the knee, respectively). The authors indicated that the lack of direct supervision during training could be the factor potentially limiting the outcome and influencing the correctness of the performed exercise [35].
Charvet et al. [21] evaluated the effect of a home-performed, computer-based adaptive training program on MS participants' cognitive functioning. This cognitive training was comprised of adaptive exercises aiming at improving speed, attention, working memory, and executive function through the visual and auditory domains. In the intervention group (IG), during the exercises, participants also received visual/ audio stimulation (initially, the auditory signals were slowed down to make them easier to remember; similarly, the visual signals were more contrasting than in the later stage of the exercises). The intervention group had a significantly higher change in the neuropsychological composite at the end of the study (estimated difference = 0.16 with 95% CI: 0.02 ± 0.30, p = 0.0286). The authors emphasized that their intervention can be successfully provided to MS patients at home. Characteristics of those studies are shown in Table 7.   In March 2020, the WHO declared the COVID-19 pandemic [38]. Since then, the virus has spread widely and rapidly. In the face of a lack of effective therapy against SARS-CoV 2, it is crucial to prevent infection. The preventive measures include increased hygiene and disinfection, social distancing, and avoiding unnecessary contact with other people [39,40]. For this reason, in order to provide care to vulnerable patients with an increased risk of developing COVID-19 and its severe course, healthcare requires reorganization and the use of new solutions.
In the situation of the COVID-19 pandemic, patients with neurological disorders may be deprived of their usual care [41]. During the pandemic, there was a tendency to implement home exercise programs due to the limited duration of therapy and access to physical therapy [42]. Home self-rehabilitation is an increasingly common element of rehabilitation programs, especially in the case of various long-term conditions such as MS. Patient adherence to physiotherapy programs recommended to be performed at home is crucial for the success and effectiveness of therapy and some studies show that patients who follow the prescribed program have better treatment outcomes [43,44]. Although adherence to prescribed home physiotherapy regimens is considered particularly important for a successful rehabilitation outcome, there are studies that show compliance problems between clinic and home self-exercise and non-adherence is often very high [45,46]. Participants are considered not to adhere to home rehabilitation regimens if they do not achieve the specified recommended repetition values [47], the recommended exercise duration [48], and the recommended frequency of exercise [49]. The reasons for non-compliance include the lack of support and supervision, no need to change lifestyle, lack of immediate relief of symptoms, and doubts and uncertainty about the therapy [50]. Previous research shows that adherence to recommendations for home rehabilitation is determined by the following factors: intention to engage in independent exercise, self-motivation, self-efficacy, prior exercise adherence [51], and social support [52]. Social support is believed to facilitate adherence by encouraging optimism and self-esteem, lowering stress related to illness, reducing depression, and providing practical help [52]. Understanding the factors influencing independent exercise at home gives researchers and practitioners greater opportunities to improve adherence by designing and implementing interventions aimed at reinforcing positive factors and minimizing barriers to compliance [52]. This also applies to the design of telerehabilitation using VR systems. The current health system contingency due to the COVID-19 pandemic requires an acceleration in the use of telemedicine to enable neurorehabilitation outside the traditional settings such as hospitals, rehabilitation centers, private practices, and in the community. Teletherapy may replace and complement in-person treatment to mitigate constraints on service delivery that currently limit access to rehabilitation care.
The review shows that TR is applicable in the cognitive rehabilitation of patients with MS, which may also be particularly important in the COVID-19 pandemic situation. The review has demonstrated that in most studies rehabilitation interventions using new technologies have produced similar results to those obtained by direct exercise and sometimes even better results than those observed in traditional schemes. TR has proven to have a positive effect not only on general fitness but particularly on gait, balance, and upper limb function in MS individuals [19,20,23]. Tallner and co-authors [35] analyzed TR exercise programs in MS patients and observed that features promoting self-directed care and internet access to individualized tele-management resources were beneficial to physical activity and function.
Telemedicine, virtual reality, and gamification seem to be effective rehabilitation tools especially in the MS patient group. The systematic review presented confirms good tolerance and therapeutic effects in this group of patients. Additionally, most of the studies analyzed had not reported any harmful effects of the interventions.
Moti with co-authors [53,54] showed that the content of web-based programs caused essential and remarkable increase in physical activity in research highlighting self-efficacy and use of a social cognitive-behavior-based framework. To be effective, both physical and cognitive rehabilitation programs should be intensive and sustained. Current limited access to cognitive rehabilitation can impair the relationship between the patient and medical staff. Remote communication technologies are increasingly seen as potential, effective options for supporting healthcare interventions including neurorehabilitation and cognitive rehabilitation [21]. The presented research shows a wide range of communication formats using the Internet, teleconferences, VR and a variety of interventions aimed at improving physical activity, cognitive function, education, and reducing fatigue. The promising effect of gamification in MS patients also manifests as its positive emotional impact. Gamification rewards users with numerical values. The scoring system associated with gaining rewards for achieving a certain number of points allows the patient to feel positively motivated and also influences their emotional skills such as self-satisfaction and self-esteem. Immediate feedback during gamification informs the patient about their current progress and the level of rehabilitation. This is ensured by auditory, visual and textual feedback that appears immediately after the patient's action and informs them about their progress and the results of the exercises performed.
Numerous studies have proven in-home interventions to be effective, which is of great importance presently. Remote communication technologies seem to be measures of high effectiveness in rehabilitating and supporting MS patients, especially during the COVID-19 pandemic, as the traditional rehabilitation option is less accessible or in some cases inaccessible for patients. Therefore, it would be useful to confirm the effectiveness of this promising rehabilitation treatment option and conduct long-term research involving large samples including MS patients with severe and progressive disability.
The present paper has some limitations. First, we have included only English-language articles from two databases in the analysis. The second limitation may be that despite the promising results of treatment involving new technologies in MS patients, only five of the studies assessed the effectiveness of home-based therapy. Therefore, in relation to the effectiveness of outpatient therapies involved in this review, possible discrepancies regarding therapy adherence may occur in the case of home treatment. This could possibly compromise the therapy effectiveness as compared to the studies analyzed.

Conclusions
The COVID-19 pandemic required a rapid adoption of new technologies to improve access to healthcare, as social distancing became mandatory. The present review proves telerehabilitation to be an effective motivational tool to restore and maintain both physical and cognitive function in patients with MS. In addition to improving motivation, another advantage of gamification is the possibility of choosing a convenient time of day for exercise, as well as reducing the costs associated with traveling to the clinic.
Further studies are needed to confirm the effectiveness of this promising rehabilitation treatment option. In particular, it would be useful to conduct long-term research involving large samples including MS patients with severe and progressive disability.