TITLE: Immersive Virtual Reality and Exercise Programs in Multiple Sclerosis: ExeRVIEM III. INTRODUCTION: Multiple sclerosis (MS) is a chronic neuroimmunological and degenerative disease characterized by demyelination within the central nervous system. Its clinical course involves motor impairment, sensory disturbances, cognitive dysfunction, and a progressive decline in functional independence. MS is one of the leading causes of non-traumatic disability in young adults. This highlights the considerable impact of the disease, both in terms of healthcare burden and healthcare expenditure. Within this context, therapeutic exercise has evolved from being considered potentially harmful to being recognized as a safe and effective intervention capable of improving gait, balance, cardiorespiratory fitness, fatigue, and quality of life in people with MS. A model has been proposed for prescribing and progressing exercise at different stages of MS: passive range-of-motion exercises designed for patients with the most severe symptoms, a second stage incorporating active muscle-strengthening exercises, and finally, integrated exercise programs that incorporate strength, endurance, balance, and coordination training. Evidence from systematic reviews and meta-analyses shows that structured exercise (including high-intensity protocols when performed under supervision) is safe and can improve functional outcomes. Our ExeRVIEM III project (Physiotherapy program with High-Intensity Exercise Program and Immersive Virtual Reality in Multiple Sclerosis) represents a novel strategy to facilitate rehabilitation exercise programs using head-mounted virtual reality displays. HYPOTHESIS: The ExeRVIEM III project, based on training physical function in people with MS, is feasible and safe, and could have a potential clinical impact in the motor and cognitive domains, as well as applicability in community settings, such as patient associations. GENERAL OBJECTIVES: 1.1 To design and implement an ExeRVIEM III exercise program/protocol for people with MS. 1.2 To evaluate the safety of the high-intensity virtual reality exercise program. SPECIFIC OBJECTIVES: 2.1 To analyze the possible changes in disability, functional variables, cognitive domains and biomarkers in the short and medium term in people who attend a patient association and carry out the ExeRVIEM III exercise program for people with MS. METHODOLOGY: A randomized controlled trial, double-arm (experimental and control group) study will be conducted at a patient association (Santiago de Compostela, Spain). The intervention will consist of an 6-month supervised virtual rehabilitation program, with two weekly sessions on alternate days, in addition to the standard rehabilitation prescribed by the patient association clinical team (physiotherapy, occupational therapy, and cognitive training sessions). An inmersive virtual reality (IVR) body combat exercise videogame will be used, administered via a virtual reality headset. In accordance with clinical guidelines for IVR, sessions will be intentionally brief (10 minutes) to minimize cybersickness and excessive fatigue. Assessments will be conducted at baseline (week 0) and immediately after the intervention (week 24). Demographic and clinical data will also be collected, including sex, age, comorbidities, disease duration, MS subtype, and pharmacological treatment. Assessments will be conducted at the patient association and in the Neurology Department of the referral hospital. Feasibility, safety, strength parameters, dual-task performance and fatigue levels assessments will be performed at the patient association by physiotherapists, while the remaining assessments will be completed at the hospital by a neurologist specializing in MS. The content of the assessments will be: Patient characteristics that will include data on age, sex, years since diagnosis, MS subtype, and pharmacological treatment. Feasibility: Number of virtual sessions attended by each participant (adherence rate via registration sheet). Rate Perceived Effort using the modified Borg scale, which measures the level of perceived exertion on a scale of 0 to 10 from no effort to maximum effort. Safety: adverse events using the Simulator Sickness Questionnaire (SSQ).Strength parameters using Five times sit to stand test (FTSST) and handgrip test. Functional mobility will be assessed using Timed and Go test (TUG) and with dual task performance using TUG-cog. Level of fatigue using the Fatigue Severity Scale (FSS). Level of disability: using the Expanded Disability Status Scale (EDSS).Gait will be evaluated using the 25Foot Walk Test (25FWT). Manual dexterity will be assessed using 9-Hole Peg Test (9HPT). Cognitive domains evaluated by the Symbol Digit Modalities Test (SDMT)Axonal injury biomarker evaluated by Neurofilament light chain (sNfL) concentrations.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
SUPPORTIVE_CARE
Masking
SINGLE
Enrollment
30
The intervention will consist of a supervised virtual rehabilitation program delivered over 6 months, with two sessions per week on alternating days. An Immersive Virtual Reality body combat-based exergame executed through a VR headset will be used.
Standard rehabilitation provided by the clinical team of the patient association (physiotherapy, occupational therapy and cognitive training sessions).
University of Vigo
Pontevedra, Spain
RECRUITINGLevel of disability using the Expanded Disability Status Scale (EDSS)
EDSS quantifies Multiple sclerosis (MS) related disability on a scale from 0 (normal neurological exa-mination) to 10 (MS related death). Lower scores indicate less disability and generally, and a change of between 0.5 and 1.0 points on the EDSS scale is considered clinically significant, indicating actual progression or improvement in disability.
Time frame: Baseline
Level of disability using the Expanded Disability Status Scale (EDSS)
EDSS quantifies Multiple sclerosis (MS) related disability on a scale from 0 (normal neurological exa-mination) to 10 (MS related death). Lower scores indicate less disability and generally, and a change of between 0.5 and 1.0 points on the EDSS scale is considered clinically significant, indicating actual progression or improvement in disability
Time frame: week 24
Gait evaluated by 25Foot Walk Test (25FWT)
25FWT assesses walking speed over 25 feet; shorter times reflect better gait capacity. The 25FWT is a validated, reliable measure accepted by regulatory consortia, predictive of disability progression, where a change greater than 20% in the time taken to walk 25 feet (7.6 meters) is considered relevant to the patient's daily life, indicating a real improvement or deterioration of their functional capacity, beyond the natural variability of the test.
Time frame: Baseline
Gait evaluated by 25Foot Walk Test (25FWT)
25FWT assesses walking speed over 25 feet; shorter times reflect better gait capacity. The 25FWT is a validated, reliable measure accepted by regulatory consortia, predictive of disability progression, where a change greater than 20% in the time taken to walk 25 feet (7.6 meters) is considered relevant to the patient's daily life, indicating a real improvement or deterioration of their functional capacity, beyond the natural variability of the test.
Time frame: Week 24
Manual dexterity assessed by 9-Hole Peg Test (9HPT)
9HPT (right and left) evaluates fine manual dexterity. Lower times indicate better performance. Reductions of approximately 20% are often considered clinically meaningful, particularly in progressive Multiple sclerosis (MS) phenotypes. Often in clinical studies, a change of 2 seconds or more in the average test execution time is considered clinically relevant, indicating an impairment in manual dexterity and fine motor function
Time frame: Baseline
Manual dexterity assessed by 9-Hole Peg Test (9HPT)
9HPT (right and left) evaluates fine manual dexterity. Lower times indicate better performance. Reductions of approximately 20% are often considered clinically meaningful, particularly in progressive Multiple sclerosis (MS) phenotypes. Often in clinical studies, a change of 2 seconds or more in the average test execution time is considered clinically relevant, indicating an impairment in manual dexterity and fine motor function
Time frame: Week 24
Cognitive domains evaluated by the Symbol Digit Modalities Test (SDMT)
SDMT assesses cognitive processing speed; higher scores indicate better performance. The SDMT is highly sensitive to cognitive impairment in Multiple sclerosis (MS) and a variation of 4 to 5 points (or a change of at least 10% from baseline) is generally considered to indicate a real and clinically relevant change in the patient's cognitive performance
Time frame: Baseline
Cognitive domains evaluated by the Symbol Digit Modalities Test (SDMT)
SDMT assesses cognitive processing speed; higher scores indicate better performance. The SDMT is highly sensitive to cognitive impairment in Multiple sclerosis (MS) and a variation of 4 to 5 points (or a change of at least 10% from baseline) is generally considered to indicate a real and clinically relevant change in the patient's cognitive performance
Time frame: Week 24
Axonal injury biomarker evaluated by Neurofilament light chain (sNfL) concentrations
sNfL expressed in serum (pg/mL) evaluates disease progression. Lower levels suggest reduced neuroaxonal damage and may reflect decreased disease activity. In this study, it was performed using an automated assay for measuring sNfL.
Time frame: Baseline
Axonal injury biomarker evaluated by Neurofilament light chain (sNfL) concentrations
sNfL expressed in serum (pg/mL) evaluates disease progression. Lower levels suggest reduced neuroaxonal damage and may reflect decreased disease activity. In this study, it was performed using an automated assay for measuring sNfL.
Time frame: Week 24
Lower limbs strength evaluated by five times sit to stand test (FTSST)
FTSST is used to objectively determine measures to provide a method to quantify functional lower extremity strength and/or identify movement strategies a patient uses to complete transitional movement (5 repetitions standing up and sitting in a chair). Lower times indicate better performance.
Time frame: Baseline
Lower limbs strength evaluated by five times sit to stand test (FTSST)
FTSST is used to objectively determine measures to provide a method to quantify functional lower extremity strength and/or identify movement strategies a patient uses to complete transitional movements (5 repetitions standing up and sitting in a chair). Lower times indicate better performance
Time frame: Week 24
Functional mobility evaluated by five timed and go test (TUG)
TUG is a standardized test to assess the basic functional mobility of elderly persons and requires both static and dynamic balance. The patient is observed and timed while he rises from an arm chair, walks 3 meters, turns, walks back, and sits down again. Lower times indicate better performance.
Time frame: Baseline
Functional mobility evaluated by five timed and go test (TUG)
TUG is a standardized test to assess the basic functional mobility of elderly persons and requires both static and dynamic balance. The patient is observed and timed while he rises from an arm chair, walks 3 meters, turns, walks back, and sits down again. Lower times indicate better performance.
Time frame: Week 24
Dual task performance evaluated by five timed and go test- cognitive (TUG-cog)
It involves performing the TUG physical test while simultaneously carrying out a mental task (such as counting backwards in increments of three). It is an ideal tool for assessing the ability to multitask in older adults or individuals with neurological impairment. Lower times indicate better performance.
Time frame: Baseline
Dual task performance evaluated by five timed and go test- cognitive (TUG-cog)
It involves performing the TUG physical test while simultaneously carrying out a mental task (such as counting backwards in increments of three). It is an ideal tool for assessing the ability to multitask in older adults or individuals with neurological impairment. Lower times better performance.
Time frame: Week 24
Upper limbs strength evaluated by handgrip test
A handgrip strength test measures the maximum force your hand and forearm muscles can make. It acts as a key indicator for overall body strength and healthy aging. Higher scores indicates better performance.
Time frame: Baseline
Upper limbs strength evaluated by handgrip test
A handgrip strength test measures the maximum force your hand and forearm muscles can make. It acts as a key indicator for overall body strength and healthy aging. Higher scores indicates better performance.
Time frame: Week 24
Levels of fatigue evaluated with The Fatigue Severity Scale (FSS)
The FSS is a questionnaire with 9 questions that measures the extreme fatigue that affects many people with multiple sclerosis. Lower scores in the scale indicate less fatigue.
Time frame: Baseline
Levels of fatigue evaluated with The Fatigue Severity Scale (FSS)
The FSS is a questionnaire with 9 questions that measures the extreme fatigue that affects many people with multiple sclerosis. Lower scores in the scale indicate less fatigue.
Time frame: Week 24
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