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Safety and Tolerability of Delayed-Release Dimethyl Fumarate Administered with Interferon Beta or Glatiramer Acetate in Relapsing-Remitting Multiple Sclerosis

Backward walking (BW) interventions have improved gait and balance in persons with stroke, cerebral palsy, and Parkinson disease but have not been studied in persons with multiple sclerosis (MS). We examined the feasibility of a BW intervention and how it affected strength, balance, and gait vs forward walking (FW) in persons with MS.

Sixteen persons with MS with a Patient-Determined Disease Steps (PDDS) scale score of 3 to 5 (gait impairment-late cane) were randomized to the FW (n = 8) or BW (n = 8) group. Participants did 30 minutes of FW or BW on a treadmill 3 times per week for 8 weeks (24 visits). Enrollment, adherence rate, and safety were tracked. The Timed Up and Go test, Six-Spot Step Test, single-leg stance, and abbreviated Activities-specific Balance Confidence scale were used to measure balance. Hip and knee flexion and extension strength (isometric peak torque), gait speed, and spatiotemporal gait parameters were measured. A 2×2 factorial multivariate analysis of covariance was used to examine changes in strength, balance, and gait, with the PDDS scale score as the covariate.

Treatment adherence rate was 99.7%, with no safety concerns. After controlling for baseline differences in disability (PDDS scale score; 

 = .041), the BW group improved dominant hip flexion strength preintervention to postintervention compared with the FW group (

 = .010). No other significant differences were seen between groups.

This was the first study to look at BW as an intervention in persons with MS. Based on its feasibility, safety, and significant finding, BW should be studied in a larger, definitive trial in the future.

From the Joyce D. and Andrew J. Mandell Center for Comprehensive Multiple Sclerosis Care and Neuroscience Research, Mount Sinai Rehabilitation Hospital, Trinity Health Of New England, Hartford, CT, USA (HMDM, JAR, ESG, LON, ACL); Department of Rehabilitative Medicine (HMDM, JAR, ESG, LON) and Department of Medical Sciences (JAR, ESG, EW), Frank H. Netter MD School of Medicine at Quinnipiac University, North Haven, CT, USA; Department of Physical Therapy (LBS), School of Health Sciences at Quinnipiac University, North Haven, CT, USA; Department of Neurology, University of Connecticut School of Medicine, Farmington, CT, USA (ESG); School of Health Professions, Rutgers, The State University of New Jersey, Blackwood, NJ, USA (ETC); and Mary Free Bed Rehabilitation Hospital, Grand Rapids, MI, USA (RJK). 

: Heather M. DelMastro, MS, 490 Blue Hills Ave, Hartford, CT 06112, USA; 

: Heather.Delmastro@TrinityHealthOfNE.org.

The authors thank Elizabeth Triche for her guidance; Kayla Olson for helping with training and data collection; the clinical team, specifically Peter Wade, MD; Mary Bailey, MD; and Amy Neal, PA-C, for their clinical research support; Joan Karpuk for helping with training; and Mount Sinai Rehabilitation Hospital, Trinity Health Of New England, and the Mandell Center for Multiple Sclerosis for providing facilities, equipment, and staff support for the study.

 The authors declare no conflicts of interest.

 This work was supported by the National Multiple Sclerosis Society (G-1510-07287). Elizabeth Gromisch, PhD, is a Harry Weaver Scholar of the National Multiple Sclerosis Society.

 The funding source was not involved in the study design, collection, analysis, or interpretation of data, or in the writing and submission of the manuscript.

 Portions of this research were presented as posters at the Consortium of Multiple Sclerosis Centers’ Annual Meeting; May 2019; Seattle, Washington.

Gait impairment occurs in approximately 85% of persons with multiple sclerosis (MS) and greatly affects participation and independence.

 Impairment in gait stems from multiple factors, including muscle weakness

 Compared with controls, persons with MS exhibit decreased gait velocity, shorter step and stride lengths, and lower percentage of time in the swing phase.

 In addition, persons with MS spend increased time in double limb support,

 which is thought to be a compensation for postural instability.

 The medication dalfampridine sustained-release has been shown to increase gait velocity, but only in individuals who are responders to the drug.

 Other typical interventions to address gait impairments include combined exercise training, such as aerobic and resistance training; physical therapy activities, such as balance training and neurofacilitation; and gait training via a treadmill, robot-assisted training, or conventional overground training.

 Regardless of the mode of gait training, the most common direction is forward walking (FW), which has been shown to improve balance in persons with MS

 and improve walking velocity by treadmill training,

 Although FW is often used to improve gait and balance in persons with MS, to our knowledge, its effect on lower limb strength

Alternatively, backward walking (BW) has been incorporated into rehabilitation approaches,

 resulting in improvements in objectively measured balance,

 and gait characteristics such as velocity,

 When specifically compared with FW, BW has resulted in greater improvements in step length,

 in these populations. Although motor learning theory requires repetition of the task that is being learned, FW and BW share the same central pattern generator,

 allowing adaptations made from BW to translate to FW. Training in BW may address balance and gait impairments by improving postural stability,

 increasing neural and muscular activity,

 due to the novelty, increased complexity, and longer duration of muscle activity

 during backward movement; however, limited studies have reviewed BW in persons with MS.

Given the promising early evidence to support BW as an intervention in other populations and the importance of understanding the effect of walking interventions on strength in persons with MS, understanding the role of BW as an intervention for persons with MS is imperative. The purpose of this study was to establish the feasibility of BW as a therapeutic intervention and to explore the effects of a BW intervention vs a FW intervention on strength, balance, and gait in persons with MS. Because previous studies found that BW resulted in greater improvements in balance and gait parameters over FW,

 in addition to the effects from the novelty of the movement, we hypothesized that a BW intervention would result in greater improvements in balance, walking velocity, step length, and stride length in persons with MS.

This was a randomized, single-blind pilot study that examined the effects of BW vs FW training on lower limb strength, balance, and gait in persons with MS. The study was approved by the Trinity Health Of New England institutional review board and was performed in accordance with the Declaration of Helsinki. Recruitment occurred between April 2016 and September 2017. Participants completed a preintervention visit to determine eligibility and collect baseline assessments. Demographic and disease characteristics collected included self-reported disability (Patient-Determined Disease Steps [PDDS] scale score), age, sex, disease duration, pain (visual analog scale [VAS]–pain), fatigue (VAS-fatigue and Daily Fatigue Impact Scale), and percentage use of assistive devices (no assistance, wall or furniture, unilateral, bilateral, or wheelchair/scooter). After confirmation of eligibility and baseline assessment, participants were randomly assigned to the FW group (n = 8) or the BW group (n = 8) in a 1:1 ratio. Depending on randomization, participants completed 30 minutes of FW or BW on a treadmill during a 1-hour session 3 times per week for 8 weeks (24 visits).

Eligible participants were English-speaking adults aged 18 to 65 years with a clinical diagnosis of MS; a score of 22 or greater on the Mini-Mental State Examination; gait impairment, defined as a PDDS scale score of 3 to 5 (in the past 12 months); and were able to complete the 6-Minute Walk Test. Individuals were excluded if they were unwilling or unable to complete the assessments and intervention; were currently participating in physical therapy; had major changes in exercise habits in the past 3 months (ie, starting or stopping a new program, or a change in frequency, intensity, or duration); had an MS relapse within the past 2 months; required constant bilateral support for ambulation and/or could not walk at least 100 m without resting; had a self-reported history of any absolute contraindications for exercise

; and/or could not safely adhere to the protocol. A convenience sample of participants was recruited from a comprehensive MS clinic, the Mandell Center for Multiple Sclerosis, at Mount Sinai Rehabilitation Hospital, Trinity Health Of New England.

Given that BW has not been studied as an intervention for persons with MS or determined to be a feasible and tolerable intervention for this population, the following study was designed as a pilot study to inform the sample size required for a larger definitive trial. A sufficient sample size to calculate the same size of a 90% powered main trial with a large, standardized difference on the primary treatment outcome

 was deemed to be 10 participants per trial arm.

Each 1-hour treatment session consisted of a 5- to 10-minute, low-intensity warm-up (including the participant’s unsupervised walk from the parking lot [2–5 minutes] and marching in place), stretching of the lower limb, and then 3 to 5 minutes of slow walking on the treadmill. The warm-up was followed by 30 minutes of walking at 0% incline (FW or BW) for the intervention. Finally, the session ended with a 5- to 10-minute cooldown, walking at a slow speed on the treadmill for 5 minutes, followed by stretching and taking deep, slow breaths.

For the intervention, each participant was placed in a harness mounted over a treadmill to prevent falls (no weight support was provided). All participants started at a comfortable walking speed, determined by slowly increasing the speed throughout the first session to where the participant was able to maintain the exercise and reported that they were working at a Borg rating of perceived exertion (RPE) between very light (9) and somewhat hard (13). Due to the heterogeneity of the population, each participant was progressed according to their abilities and response to the training with the goal of completing 30 minutes of walking. To accommodate this heterogeneity, the treatment was progressed by first decreasing rest breaks and then by increasing speed and was customized for each participant at the most challenging speed they could tolerate to complete the full 30 minutes.

Heart rate, oxygen saturation, and RPE were collected every 3 minutes to monitor intensity. The research therapist controlled the speed and provided verbal cues to promote a normal gait pattern. Measures were collected before the session (blood pressure [BP], VAS-fatigue, and Daily Fatigue Impact Scale), during rest breaks (BP), and after the session (BP and VAS-fatigue) for safety monitoring. Rest breaks were incorporated as needed to ensure completion of the intervention and did not count toward the 30 minutes of walking. Reasons for rest included shortness of breath; lightheadedness; feelings of fainting, fatigue, or cramping; inability to safely perform the walking protocol; unsafe drop in oxygen saturation; and at the therapist’s discretion to maximize the potential for the completion of 30 minutes of walking.

Enrollment was tracked throughout the recruitment and study procedures, including how many people were approached or expressed interest; reasons why people declined or did not meet the inclusion criteria; and reasons why participants discontinued the trial. Adherence to the treatment program was noted, including the number of sessions completed by each participant and the overall adherence rate by treatment group. Safety and adverse effects were logged. Baseline and posttreatment strength, balance, and gait functioning were assessed by a blinded evaluator unaware of group assignment using the measures detailed in 

; all supplemental material is available in a PDF at the bottom of this article). All participants were educated on the importance of not informing the evaluator of any details of the intervention they received, especially walking direction, at the posttreatment assessment, which was completed within 1 week of the final treatment session.

Statistical analyses were performed using IBM SPSS Statistics for Windows, version 26.0 (IBM Corp). Descriptive statistics were used to report enrollment, adherence, and safety data. Baseline demographics were analyzed using the Kolmogorov-Smirnov test to determine normality. Age, fatigue in the past month, and percentage of time not using an aid were normally distributed (

 > .05); however, all other measures significantly deviated from normal (

 test (nonnormal) were used to compare the groups’ baseline demographics to check for significant differences. A Fisher exact test compared sex, and a median test compared disability level (PDDS scale score). Two-tailed 

 < .05 was considered significant for the bivariate analysis. Two-tailed 

 < .01 was considered significant for the multivariate analyses due to the multiple comparisons. Due to some of the outcome measures deviating from normal, all the measures were individually ranked to meet assumptions. After ranking, baseline outcome measures were compared using a multivariate analysis of covariance (MANCOVA) between the groups, with PDDS scale score as the covariate. A 2 (BW group and FW group) × 2 (pretreatment and posttreatment) factorial MANCOVA examined changes in the strength, balance, and gait outcome measures, with PDDS scale score as the covariate.

Enrollment and Participants’ Demographics 

A total of 48 persons with MS were contacted or inquired about the study (

). Seven had time conflicts (eg, work schedules), 8 were not eligible (ie, currently in physical therapy, use of bilateral support, or not within the age parameters), 3 were not interested, and 6 did not respond to follow-up contact. The remaining 24 persons with MS provided written consent; however, 6 of these individuals were excluded during the baseline assessment for not meeting the inclusion criteria (for having an absolute contraindication to exercise or a PDDS scale score outside of the 3–5 range). Two participants assigned to the FW group withdrew after randomization: 1 due to a schedule conflict and the other after reporting fatigue after treatments. The remaining 16 individuals completed the study.

Participant demographics are displayed in 

. A baseline difference in disability level (PDDS scale score) was observed between groups (χ

 = .041), but no differences were observed in any of the other demographic and baseline characteristics. There was no baseline difference (

 > .01) between the outcome measures (strength, gait, balance) as measured by the MANCOVA after controlling for PDDS scale score.

There was an overall treatment adherence rate of 99.7% (n = 16). The BW group had a 100% adherence rate, and the FW group had a 99.5% adherence rate due to 1 participant completing 23 of 24 sessions (scheduling conflict). In the BW group, 62.5% of participants (n = 5) completed the 24 sessions within 8 weeks ± 5 days; 12.5% (n = 1) completed the 24 sessions over 9 to 10 weeks; and 25% (n = 2) completed the sessions over 10 to 11 weeks. In the FW group, 75% (n = 6) completed the 24 sessions within 8 weeks ± 5 days and 25% (n = 2) completed the 24 sessions over 9 to 10 weeks. Median (interquartile range) of the metrics (heart rate, RPE, fatigue, oxygen saturation, rest, BP, distance) collected during the first and last sessions for each group are presented in 

. No adverse effects or safety concerns were reported.

Greater improvement in dominant hip flexion strength was observed in the BW group compared with the FW group from preintervention to postintervention (

 = .010). No other significant differences were observed in any of the other strength, balance, or gait measures between groups (

This pilot study evaluated the feasibility of BW as a therapeutic intervention and compared the effect of BW and FW as an intervention on strength, balance, and gait in persons with MS. Overall, BW was a well-tolerated intervention with no safety issues. Although 2 participants randomized to the FW group withdrew from the study, those who completed the study had 99.7% adherence to the treatment program. No difference was found between the 2 groups for any of the balance measures, spatiotemporal gait characteristics, or Timed 25-Foot Walk test. Therefore, the data did not support the hypothesis that BW would result in greater improvements in balance, walking velocity, step length, and stride length.

The results of this study indicate an increased use of and resultant strengthening of hip flexors during BW that may not occur with FW training. The increased dominant hip flexion strength is likely due to the increased eccentric control required by this muscle group during BW. Comparing the intermuscular synergies between FW and BW, the main propulsive thrust for FW is from the plantar flexors through the ankle joint. Two studies reported that the main propulsive thrust for BW is not provided by the ankle

 Given that this study did not find increases in hip or knee extension strength, although these muscle groups are suspected to provide the main source of propulsion, monitoring these outcomes in a larger sample size is recommended.

The increased dominant hip flexion strength may have occurred in the BW group from the increase in hip flexion required to lift the leg high enough while stepping BW or during the stance phase while eccentrically contracting to improve control during the contralateral swing phase. Due to the repetitive nature of continuously flexing the swing phase hip with each step for 30 minutes, the participants completed many repetitions of this movement, allowing for the possibility for neural adaptations to occur. The BW group may have had greater room for improvement in hip flexor strength due to the difference in the baseline assessment compared with the FW group (median: 18.4 ft-lb at baseline; BW group median: 7.4 ft-lb at baseline). Currently, the literature supports the use of resistance training, among other physical therapy strategies, to address hip muscle weakness for persons with MS.

 Now, BW may be considered as an option for persons with MS to improve hip flexor strength.

No differences were found between the groups for the balance measures (Timed Up and Go test, Six-Spot Step Test, single-leg stance, and abbreviated Activities-specific Balance Confidence scale) or any of the gait measures (Timed 25-Foot Walk test, velocity, bilateral step length, bilateral stride length, and bilateral double limb support), which was inconsistent with previous findings. However, only 2 of the previous studies compared BW and FW,

 and others compared BW with a balance program

 or conventional physical therapy (consisting of approximately strengthening, function, and mobility activities and 30% gait training).

Two factors may explain the limited differences between the 2 groups. One may be the statistical power of the present sample size. Given the lack of evidence of BW as an intervention in persons with MS, this study was designed as a small pilot study to inform a larger, definitive clinical trial. Another factor is that an objective measure of spasticity was not included. Spasticity could have been a confounding variable, affecting motor recruitment and gait, and ultimately affecting progression throughout the intervention. Omission of a spasticity measurement may have masked some of the adaptations and made it more difficult to demonstrate statistical significance in the findings.

The current literature in other special populations (ie, Parkinson disease, stroke, cerebral palsy) suggests that BW is a useful intervention to improve spatiotemporal gait parameters and balance. Backward walking is a novel task that can challenge the body differently than FW while still training the same central pattern generator,

 Weakness affects 70% of persons with MS,

 which can lead to gait changes and balance deficits, so studying this intervention in persons with MS is vital, as these deficits can lead to an increased risk of falls, which can lead to many negative consequences (ie, injury, fear of falling, decreased physical activity, decreased activities of daily living). Although this study did not demonstrate greater improvement from BW compared with FW, positive changes were observed and the intervention was well tolerated with a high adherence rate, supporting investigation of the use of BW as another treatment for persons with MS.

The study design was a simple 1:1 randomization with a small sample size; therefore, it would have been difficult to control for differences at baseline. Given the small sample size, a crossover design may have been helpful in interpreting the effect of baseline differences. The intervention was performed over a treadmill in a harness; however, this setup may not be readily available in all rehabilitation settings, making clinical application a challenge.

Future research could explore targeted interventions based on individual goals and existing deficits to assess the potential benefit from combined interventions, including BW and cross-training.

Effect of Backward and Forward Walking on Lower Limb Strength, Balance, and Gait in Multiple Sclerosis: A Randomized Feasibility Trial

Fatigue is one of the most common and annoying symptoms in patients with multiple sclerosis (MS). The purpose of this study was to investigate the effect of sensory interventions on fatigue in people with MS based on a systematic review of sensory evidence.

The Google Scholar, PubMed, Scopus, and Cochrane Library databases were searched from January 1990 to July 2020. Studies with nonpharmacologic sensory interventions as a main or secondary intervention according to the assessment of fatigue as the primary or secondary therapy outcome in patients with MS were included.

Nine articles were reviewed by examining the inclusion and exclusion criteria. Four types of interventions were related to exercises, including sensory integration exercises, vestibular rehabilitation, Frenkel exercises, and exercises with or without vibration; and 2 types were performed using robots and 1 type using vibration only. Vestibular rehabilitation therapies, exercise-based sensory integration interventions, and the use of vibration have shown significant effects in relieving fatigue in patients with MS.

The evidence in this study is insufficient to show a dramatic effect of sensory integration therapy in various forms. However, despite the studies, sensory integration therapy can be considered a potential treatment for fatigue in patients with MS. Further studies with stronger methods are needed to make this treatment a reality.

From the Department of Occupational Therapy, School of Rehabilitation Sciences, Iran University of MedicalSciences, Tehran, Iran (MM, MS, GJ); and Neuromuscular Rehabilitation Research Center, Semnan University of Medical Sciences, Semnan, Iran (FM). 

: Ghodsiyeh Joveini, MSc, Department of Occupational Therapy, School of Rehabilitation Sciences, Iran University of Medical Sciences, Maddadkaran St, Shahid Nazari St, Mother Square, Mirdamad Blvd, Tehran, Iran; 

Multiple sclerosis (MS) is a lesser-known degenerative disease that occurs in early adulthood.

 A wide range of symptoms, including visual impairment, muscle weakness, sensory impairment, and pain, are reported in these individuals.

 Fatigue is 1 of the most common and annoying symptoms of this disease, which has been reported in 50% to 92% of people with MS.

 Fatigue is defined as the lack of mental or physical energy that is perceived by sufferers or caregivers to affect a person’s normal and desirable activities. Patients with MS can distinguish between physical fatigue and other physical symptoms of the disease, such as weakness in certain muscle groups, neurologic defects in the production of insufficient muscle strength, and physical tiredness, as well as between mental fatigue and emotional and mental symptoms of depression such as decreased motivation, decreased mood, inability to complete tasks, and lack of concentration.

 The possibility of fatigue in people with MS increases with recurrence of the disease, increased disability, lack of mobility, and the experience of heat and decreases with cold.

 All kinds of activities in a person’s daily life, including finding and keeping a job, home management, child care, and leisure, can be affected by fatigue.

 Damage to sensory and motor patterns and to functional communication of nerve cells has been known as the central cause of MS-related fatigue.

 In topography by electroencephalopathy, it has been shown that there is a decrease in the amount of excitability in the primary sensory area and an increase in the amount of excitability in the primary motor area.

Therefore, it seems that by affecting these areas, sensory interventions such as transcranial direct current stimulation can be effective in reducing fatigue in patients with MS.

 The vestibular rehabilitation protocol, which aims to increase balance in people with MS, has also had a significant effect on reducing fatigue.

 Therefore, to investigate the effect of sensory interventions on fatigue in people with MS, this study aimed to identify and review studies that use sensory approaches to reduce fatigue in people with MS.

The study was conducted based on PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines.

To identify studies related to the effect of sensory interventions on fatigue in people with MS, the Google Scholar, PubMed, Scopus, and Cochrane Library databases were searched for English-language articles published between January 1990 and July 2020 using the keywords 

multiple sclerosis, MS, fatigue, touch, proprioceptive

. Articles both with and without open access were searched.

Two experts (M.M. and M.S.) independently examined the studies in terms of compliance of the title or summary with the inclusion criteria. The inclusion criteria for this review are studies with sensory interventions as a main or secondary intervention in people with MS, considering the effect on fatigue as a main or secondary outcome. Only English-language studies are included in this review.

Data extraction from studies was performed using a standardized form of data extraction based on CONSORT (Consolidated Standards of Reporting Trials).

The quality of evidence of the studies included in this review was evaluated by the Downs and Black checklist.

 The checklist is a 32-point scale that was developed by Downs and Black

 to assess the methodological quality of randomized controlled trials and nonrandomized studies. It consists of 27 items distributed across 5 subscales: (1) reporting (10 items); (2) external validity (3 items); (3) bias (7 items); (4) confounding (6 items); and (5) power (1 item). This checklist provides a profile of the methodological strengths and weaknesses of studies. Each item scores 0 or 1, except for item 5 (in the reporting subscale), which scores 0 to 2, and item 27 (in the power subscale), which scores 0 to 5. Item 27 of the checklist was modified based on the presence (score 1) or absence (score 0) of sample size calculation, resulting in a total possible score of 28. The quality of the studies was classified into 4 levels based on the following score ranges: excellent (26–28), good (20–25), fair (15–19), and poor (≤14). This modification was done in 3 systematic review studies related to MS.

 Studies were evaluated independently by 2 of us (M.M. and G.J.).

Of the 94 studies obtained from the search, 21 were omitted due to duplication in the first stage. In the next step, 57 studies were omitted based on the title and another 7 based on the study abstract. Nine studies were entered for full-text screening, and all nine

 were submitted to a review of the entire text and had inclusion criteria and did not have exclusion criteria (

The quality of the studies based on the Downs and Black checklist is summarized in 

 (all supplemental material is available in a PDF at the end of this article).

Of the studies included in this systematic review, 8 are randomized controlled trials

 and 1 is a pretest/posttest quasi-experimental study.

 The treatment period in the studies ranged from 5 days to 12 weeks and consisted of 5 to 60 sessions. The duration of the sessions varied from 10 to 75 minutes. Only 3 articles were accompanied by follow-up: 4 weeks in 2 studies

The articles included in this study had variable sample sizes of 17 to 80 people. In total, these studies included 357 people: 223 who received a research-related intervention and 134 in the control group or on the waiting list. The dropout percentage also varied from 2.66% to 47.05%.

In the 9 studied articles, 3 fatigue-related assessments were used to measure the severity and extent of the effect of fatigue. The Fatigue Severity Scale (FSS) was used in 5 studies

 and the Modified Fatigue Impact Scale (MFIS) in 4 studies,

 1 of which was also associated with the FSS.

 The Fatigue Impact Scale (FIS) was also used in an independent study.

The types of interventions performed in the articles were divided into 3 categories: those related to exercises (n = 4),

 those performed with the help of robots (n = 2),

 and those performed only by vibration (n = 1).

 Among the 4 types of interventions related to exercises, 6 studies examined sensory integration exercises,

 Also, 1 study investigated performing exercises with and without whole-body vibration.

 Exercises related to these studies were in the intervention or control groups. Exercises in these studies were designed to integrate multiple sensory inputs while evoking a postural equilibrium response. Another study performed therapeutic exercises in 1 group on a vibrating platform and in another group without vibration. The exercises were the same in the intervention groups, and the difference was in being on or off the platform. In the study by Brichetto et al,

 balance exercises were performed in various positions using a biofeedback plate, on the floor, and in front of a mirror. Gandolfi et al

 used sensory integration exercises in 3 levels of open eyes, closed eyes, and with visual conflict (to create wrong inputs) and also on 2 levels of floor and foam mat. Both static and dynamic exercises were used in their study to further simulate daily life activities. Protocols of 3 vestibular rehabilitation studies

 were reviewed. They all had 2 training sections: position and eye movements. Of the exercises performed, only 1 study in 1 of the intervention groups used Frenkel exercises.

 These exercises were performed in 3 positions: lying down, sitting, and standing. In both robotics articles

 the robot was used as a gait aid and taught how to gait correctly. In both studies, assisted devices such as a harness supported the body weight so that it could use these robots more safely. Alguacil Diego et al

 used vibration only in semi-squat mode in which the patient was balanced by the handles of the Zeptoring vibrating platform (Scisen GmbH), and external support was used if necessary. No exercise was used in this intervention, and the total vibration and rest for each treatment session were recorded for 10 minutes.

Comparing 2 types of interventions based on walking robots with sensorimotor exercises, Saggini et al

 found that the group based on FSS exercise therapy showed a decrease in fatigue, but this decrease was not significant (

 = .2058). However, not only was there a decrease in fatigue on the MFIS in this treatment group, but this decrease was significant (

 = .0353). In another study, Gandolfi et al

 examined the effect of integration interventions using the FSS and showed that participants had a significant reduction in fatigue on the FSS (

 = .052). In a study with 2 intervention groups, Uszynski et al

 tested a series of movement exercises with the same dose and duration with the difference of standing or not standing on the vibrating platform to obtain the most effective method. In this study, it was shown that a significant reduction in fatigue is observed only in the group of exercises without standing on the platform (

 compared the effect of sensory integration exercises in the 3 senses (visual sense, somatosensory and vestibular systems) and conventional rehabilitation exercises; no significant change in fatigue was achieved using the MFIS (

 comparing conventional rehabilitation exercises and balance exercises of sensory integration using the FSS, showed a significant improvement in the intervention group (

 < .002). In a study considering 2 types of exercises, Karami et al

 found that both Frenkel exercises and vestibular rehabilitation can lead to a significant reduction in fatigue and FIS score, and there was a significant difference between the two intervention groups. Vestibular rehabilitation intervention with a significant difference compared with the Frenkel exercise intervention group led to a decrease in fatigue scores (

 = .007). Examining these 2 interventions, they found that the difference between the 2 intervention groups was not in the cognitive subtest (

 test, showed that in the vestibular rehabilitation group there was a significant increase in FSS function, but this increase was not observed in the control group. Hebert et al

 showed that there was a significant difference in recovery based on MFIS score in the intervention group with vestibular rehabilitation compared with the control group (

 = .005). However, no difference was observed between the control group and the wait-list group (

Among the 2 studies using gait robot interventions, Gandolfi et al

 did not observe a significant change in the target group in the FSS assessment before and after the intervention. Also, in the study by Saggini et al,

 a decrease in mean FSS scores was observed in the whole sample and in the intervention groups, but this change was not statistically significant. In this study, the change in MFIS scores in the whole sample was statistically significant, but there was no significant difference between the intervention groups with robots and the training group.

Of the studies included in this article, only 1 used vibration as the sole intervention without performing any other exercises or interventions. The study by Alguacil Diego et al

 did not show a significant change in the reduction of fatigue on the FSS for the intervention group.

The aim of this study was to systematically review past studies that have examined the effectiveness of sensory integration–based interventions on fatigue in patients with MS. The results of these studies showed that sensory integration interventions based on exercise therapy techniques had significant positive effects on survival in patients with MS, which ultimately led to improved balance and quality of life in these patients.

 Studies have also shown that approaches based on assisted therapies and robotics, as well as the use of vibration, which are used to improve sensory integration, reduce fatigue.

 In the present study, 9 articles were reviewed on the effectiveness of sensory integration-based approaches on fatigue in patients with MS.

 The evidence for the effect of fatigue is discussed in the following subsection.

Confirmatory Evidence of Effect on Fatigue

Exercise-Based Sensory Integration Interventions

Exercise therapy is a nonpharmacologic approach that affects the symptoms of MS.

 Changes and improvements in fatigue based on exercise therapy have been shown in several studies.

 There are different forms of exercise therapy, including exercises based on sensory integration and a range of vestibular exercises. These exercises improve the functions of the visual and cerebellar systems and balance by compensating for the defects of the vestibular system, and also reduce fatigue by improving balance.

 In the present study, 7 studies examined the effect of exercise-based sensory integration interventions on fatigue recovery.

 The results of these studies showed that vestibular exercises, exercise therapy interventions, and sensory integration have beneficial effects on reducing the severity and effects of fatigue in people with MS. Also, it can help to improve other symptoms of the disease. However, in a study by Brichetto et al,

 no significant positive effect was found in patients’ MFIS scores. Reduction of fatigue was demonstrated after various types of exercise therapy, including aerobics and treadmills. In all the studies, the mechanism of the effect of exercise on fatigue is still unknown, and different mechanisms have been proposed for this effect. Exercise is thought to have a protective role and helps regenerate nerves by modulating the growth of central nervous system neurons functionally and structurally.

 On the other hand, it seems that this change may occur by affecting and correcting the symptoms of secondary fatigue in patients. Past studies have shown that exercise therapy can reduce fatigue by improving symptoms such as depression, anxiety, and sleep disorders.

 However, the effect of factors such as duration of illness, Expanded Disability Status Scale (EDSS) score, or cognitive impairment on people with MS cannot be ignored, and the severity and weakness of these factors can change the outcome of the intervention. However, exercise therapy programs, even with a small number of participants in these groups, have shown improvement in mild fatigue.

Robot-Assisted Sensory Integration Interventions

Therapies using robotic devices have advanced a lot in the past 2 decades; they can use frequent, specific, and intense exercises with a wide range of active and active assistive exercises in patients.

 There are different types of robotic aids that can be used in a variety of ways. In 2 studies by Gandolfi et al

 the effect of training and application of robotic devices on balance disorders and fatigue in patients with MS were examined. The results of these studies in the groups that used exercises based on robotic devices compared with exercise therapy did not show a statistically significant difference in the change and improvement of fatigue and helped only in items such as walking speed. Sagini et al

 chose a double proprioceptive rehabilitation training that could have a clear positive spillover on a patient’s impairment and sense of fatigue and gait and balance impairment; however, Sagini et al point to the role and logical relationship between EDSS and fatigue scores, but that is an aspect that has not yet been adequately investigated in the literature. On the other hand, Gandolfi et al,

 with a larger sample, could stratify patients by EDSS score, which would allow us to better understand the robot-assisted approach. In most previous studies, robotic devices have been used to improve balance and gait.

 In recent years, the use of this approach has shown positive effects on gait status and balance in chronic diseases such as stroke and Parkinson disease.

 In all these studies, patients’ balance was reported to be improved by motivating patients through the use of a new robotic approach and the application of deep sense stimuli. Because only 2 studies of robot-assisted sensory integration interventions were included in this review, it is not possible to reach any conclusions regarding their effectiveness in reducing the severity or impact of fatigue. In any case, it seems that more studies are needed in this area to evaluate the impact of the use of new technologies on the symptoms of MS, especially fatigue.

Vibration-Based Sensory Integration Interventions

The use of vibration and whole-body vibration technology is now proposed as a complementary technique in the treatment and rehabilitation of neurologic patients. In the present study, 2 of the 9 studies used these techniques to evaluate the effect of recovery and control of MS symptoms such as fatigue.

 The results of these studies showed that the application of these techniques with or without exercise therapy has beneficial effects in the treatment of fatigue in patients with MS. Although in the study by Alguacil Diego et al

 there was no significant difference between the 2 groups in the fatigue score, the authors reported a positive change and suggested factors such as the use of more reliable tools such as the MFIS to more accurately assess fatigue. Uszynski et al

 were the first to examine the effect of whole-body vibration on fatigue, and they reported a greater reduction in fatigue than the group that used exercise therapy alone. The true mechanism of recovery through vibration was not known in neurologic patients and is still under investigation, but some have suggested that vibration improves muscle contraction by stimulating muscle spindles and increases muscle strength.

 Numerous studies have shown the beneficial effects of vibration on muscle strength, pain, balance, and quality of life in patients with neurologic disease.

 suggested using the vibration effects at a tolerable frequency dose in patients with MS. However, factors such as a patient’s type of MS, EDSS score, and cognitive status that may affect the vibration therapy dose should be considered.

In this review study, we tried to show the significant effects of sensory integration approaches on reducing fatigue in people with MS, but the important point to note is that there is not sufficient evidence to determine which approach or technique is more effective. And items such as the primary outcome of fatigue in the studies, tools used to assess fatigue and their validity and reliability, and the number of participants in the intervention groups were the limitations of these studies.

Despite the existing limitations in the reviewed studies and the insufficient evidence, reviewing past studies and reviewing effective techniques in this area can provide a clear perspective on the rehabilitation and treatment of patients with MS. Future studies can complement this review and area of research.

Sarah I. Sheikh, MD, MRCP

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