Effectiveness of virtual reality training for balance and gait rehabilitation in people with multiple sclerosis: a systematic review and meta-analysis

Depósito de investigación de la Universidad de Sevilla https://idus.us.es/ “This is an Accepted Manuscript of an article published by Sage in [Clinical rehabilitation] on [2018], available at https://https://journals.sagepub.com/ doi/10.1177/0269215518768084, DOI: https://doi.org/10.1177/02692155187680.” For Peer Review EFFECTIVENESS OF VIRT UAL REALITY TRAINING FOR BALANCE AND GAIT REHABILITATION IN PEOPLE WITH MULTIPLE SCLEROSIS: A SYSTEMATIC REVIEW AND METAANALYSIS Journal: Clinical Rehabilitation Manuscript ID CRE-2017-6596.R1 Manuscript Type: Original Article Date Submitted by the Author: 10-Mar-2018 Complete List of Authors: CASUSO-HOLGADO, MARIA JESUS; UNIVERSITY OF SEVILLE, PHYSIOTHERAPY Martin-Valero, Rocio; Universidad de Cadiz, Physiotherapy Carazo, Ana F.; University of Pablo Olavide, Economía MEDRANO-SÁNCHEZ, ESTHER; UNIVERSITY OF SEVILLA, PHYSIOTHERAPY CORTES-VEGA, MARIA DOLORES; UNIVERSITY OF SEVILLA, PHYSIOTHERAPY MONTERO-BANCALERO, FRANCISCO JOSE; UNIVERSITY OF OSUNA, PHYCHOLOGY Keywords: virtual reality, postural control, Gait, Physical Therapy, Multiple Sclerosis Abstract: Objective. To evaluate the evidence for the use of virtual reality to treat balance and gait impairments in multiple sclerosis rehabilitation. Design. Systematic review and meta-analysis of randomised controlled trials and quasi-randomised clinical trials. Methods. An electronic search was conducted using the following databases: MEDLINE (PubMed), Physiotherapy Evidence Database (PEDro), Cochrane Database of Systematic Reviews (CDSR) and CINHAL. A quality assessment was performed using the PEDro scale. The data were pooled and a metaanalysis was completed. This systematic review was conducted in accordance with the PRISMA guideline statement. It was registered in PROSPERO database (CRD42016049360). Results. Eleven studies were included. The data were pooled, allowing meta-analysis of seven outcomes of interest. A total of 466 participants clinically diagnosed with multiple sclerosis were analysed. Results showed that virtual reality balance training is more effective than no intervention for postural control improvement (SMD= -0.64; 95% CI= -1.05,-0.24; P=0.002). However, significant overall effect was not showed when compared with conventional training (SMD= -0.04; 95% CI=-0.70,0.62; P=0.90). Inconclusive results were also observed for gait rehabilitation. Conclusions. Virtual reality training could be considered at least as effective as conventional training and more effective than no intervention to treat balance and gait impairments in multiple sclerosis rehabilitation. http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation For Peer Review Page 1 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review EFFECTIVENESS OF VIRTUAL REALITY TRAINING FOR BALANCE AND GAIT REHABILITATION IN PEOPLE WITH MULTIPLE SCLEROSIS: A SYSTEMATIC REVIEW AND META-ANALYSIS ABSTRACT Objective. To evaluate the evidence for the use of virtual reality to treat balance and gait impairments in multiple sclerosis rehabilitation. Design. Systematic review and meta-analysis of randomised controlled trials and quasi-randomised clinical trials. Methods. An electronic search was conducted using the following databases: MEDLINE (PubMed), Physiotherapy Evidence Database (PEDro), Cochrane Database of Systematic Reviews (CDSR) and CINHAL. A quality assessment was performed using the PEDro scale. The data were pooled and a metaanalysis was completed. This systematic review was conducted in accordance with the PRISMA guideline statement. It was registered in PROSPERO database (CRD42016049360). Results. Eleven studies were included. The data were pooled, allowing meta-analysis of seven outcomes of interest. A total of 466 participants clinically diagnosed with multiple sclerosis were analysed. Results showed that virtual reality balance training is more effective than no intervention for postural control improvement (SMD= -0.64; 95% CI= -1.05,-0.24; P=0.002). However, significant overall effect was not showed when compared with conventional training (SMD= -0.04; 95% CI=-0.70,0.62; P=0.90). Inconclusive results were also observed for gait rehabilitation. Conclusions. Virtual reality training could be considered at least as effective as conventional training and more effective than no intervention to treat balance and gait impairments in multiple sclerosis rehabilitation. Key words: multiple sclerosis; virtual reality; postural control; gait; physical therapy. Page 2 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review EFFECTIVENESS OF VIRTUAL REALITY TRAINING FOR BALANCE AND GAIT REHABILITATION IN PEOPLE WITH MULTIPLE SCLEROSIS: A SYSTEMATIC REVIEW AND META-ANALYSIS Authors: Casuso-Holgado, MJ.* University of Sevilla, Spain [email protected] Martín-Valero, R. University of Cádiz, Spain [email protected] Carazo, A.F. University Pablo Olavide, Spain [email protected] Medrano-Sánchez, E. University of Sevilla, Spain [email protected] Cortés-Vega, MD. University of Sevilla, Spain [email protected] Montero-Bancalero, FJ. University of Osuna, Spain [email protected] * Corresponding author. Page 3 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review EFFECTIVENESS OF VIRTUAL REALITY TRAINING FOR BALANCE AND GAIT REHABILITATION IN PEOPLE WITH MULTIPLE SCLEROSIS: A SYSTEMATIC REVIEW AND META-ANALYSIS ABSTRACT Objective. To evaluate the evidence for the use of virtual reality to treat balance and gait impairments in multiple sclerosis rehabilitation. Design. Systematic review and meta-analysis of randomised controlled trials and quasi-randomised clinical trials. Methods. An electronic search was conducted using the following databases: MEDLINE (PubMed), Physiotherapy Evidence Database (PEDro), Cochrane Database of Systematic Reviews (CDSR) and CINHAL. A quality assessment was performed using the PEDro scale. The data were pooled and a metaanalysis was completed. This systematic review was conducted in accordance with the PRISMA guideline statement. It was registered in PROSPERO database (CRD42016049360). Results. Eleven studies were included. The data were pooled, allowing meta-analysis of seven outcomes of interest. A total of 466 participants clinically diagnosed with multiple sclerosis were analysed. Results showed that virtual reality balance training is more effective than no intervention for postural control improvement (SMD= -0.64; 95% CI= -1.05,-0.24; P=0.002). However, significant overall effect was not showed when compared with conventional training (SMD= -0.04; 95% CI=-0.70,0.62; P=0.90). Inconclusive results were also observed for gait rehabilitation. Conclusions. Virtual reality training could be considered at least as effective as conventional training and more effective than no intervention to treat balance and gait impairments in multiple sclerosis rehabilitation. Key words: multiple sclerosis; virtual reality; postural control; gait; physical therapy. Page 4 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review EFECTIVENESS OF VIRTUAL REALITY TRAINING FOR BALANCE AND GAIT REHABILITATION IN PEOPLE WITH MULTIPLE SCLEROSIS: A SYSTEMATIC REVIEW AND META-ANALYSIS INTRODUCTION Balance impairment is frequently observed in people with multiple sclerosis and is considered to be one of the most disabling symptoms because it reduces mobility and independence and affects overall quality of life(1). Impaired balance and gait has been also associated with increased risk of falling in multiple sclerosis patients(2). Specific rehabilitation programmes for balance and gait improvement have showed small but significant effects in this population(3). In recent years, the effectiveness of virtual reality as a therapeutic tool has become an interesting topic of research in neurorehabilitation(4). From a motor learning approach, virtual reality offers the possibility of high intensity, task-oriented, multisensorial feedback training. Several systematic reviews and meta-analysis have been conducted concerning its use for balance and gait training in stroke patients (5–9),sufferers of Parkinson’s disease(10), or in older populations(10–13). Exergaming or interactive gaming-systems are terms usually used to describe non-immersive commercially available virtual reality systems(13). The clinical effectiveness of virtual reality for balance and gait training in multiple sclerosis remains unclear. Concerning this topic, only two bibliographic reviews focusing on general motor rehabilitation benefits have been published(14,15). These previous reviews reported only a narrative description of the results; different types of designs were included, quality assessment of the publications was not provided and pooled effects were not calculated. Therefore, it is necessary to systematically evaluate the evidence for the use of virtual reality to treat balance and gait impairments in multiple sclerosis rehabilitation. For these reasons, the objectives of this research were: (1) to systematically review and summarise the evidence about virtual reality interventions for balance and gait training in multiple sclerosis patients; (2) to determine the magnitude of the effects of these interventions in a meta-analysis. Page 5 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review METHODS Data Sources and Search Strategy This systematic review was performed following the PRISMA guidelines (Preferred Reporting Items for Systematic Reviews and Meta-Analyses)(16) and was registered in the PROSPERO database (CRD42016049360). An electronic search was conducted using the following databases: MEDLINE (PubMed), Physiotherapy Evidence Database (PEDro), Cochrane Database of Systematic Reviews and CINHAL. All databases were searched from their inception until February, 2018. Search terms included key words related to virtual reality interventions (e.g, "game", "gaming", "exergaming"), balance (e.g, "postural control", "posture"), gait (e.g, "walking", "ambulation") and "multiple sclerosis". These terms were used as key words in the title and abstract in all databases. Simple or advanced search when possible was conducted (refer to the Appendix for an example of the search strategy). Research Question and Study Selection Our research question was established following recommendations from the PICO model (Population, Intervention, Comparison and Outcome measures). Patients included were male and female subjects, clinically diagnosed with multiple sclerosis in accordance with the revised McDonald criteria(17), with an Expanded Disability Status Scale(18) ≤6 (equivalent to being at least able to walk 100 meters with or without resting with the use of one stick or crutch). The intervention was balance and gait training using any virtual reality system, compared with no intervention or conventional balance and gait rehabilitation. The primary outcome measures were postural control, functional balance and walking speed. Secondary outcomes were mobility, negotiation of standing obstacles and self-reported measures. Clinical trials and randomised controlled trials that used virtual reality (immersive and nonimmersive), including interactive gaming or commercially available systems, for balance and gait rehabilitation were included. Only the systems that provided an interaction and/or engagement of the participants with the computer hardware or software were included. Full texts in English were included. Other methodological designs were excluded. Page 6 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Data Extraction and Quality Assessment First, articles were selected by screening of the title, and abstract if available, by two independent reviewers (MJCH and MDCV) and duplicates were removed. After that, the full texts of selected studies and those for which abstracts were not accessible were analysed. The reviewers then checked whether the studies met the inclusion and exclusion criteria. When articles suitable for inclusion in this research were identified, data extraction and quality assessment (risk of bias) was carried out independently by the reviewers named above. Data extraction consisted of summarising the information for qualitative and quantitative synthesis. The study characteristics (type of intervention, comparison group, outcome measures) were determined and the results (mean and SD) for primary and secondary outcome measures were also recorded using Excel files. Quality assessment was assessed using the PEDro scale, which is a valid and reliable tool for rating the quality of clinical trials and randomized clinical trials(19–21). Any disagreements on data extraction or quality assessment were resolved by consensus. Data Synthesis and Meta-analysis The results for the primary and secondary outcome measures were described narratively and where possible study results were pooled and meta-analysis was conducted. Mean differences (MD) or standard mean differences (SMD) were calculated with 95% confidence intervals (95% CI). A random-effects model was applied to present the pooled effect. We decided to pool studies based on the control group (no intervention or standard balance training) and the same underlying outcome. Analysis of the effect size values was based on the work of Cohen (22), who determined 0.2, 0.5 and 0.8 as small, moderate and large effect sizes, respectively. Heterogeneity was assessed using the I 2 statistic. Review Manager (RevMan) version 5.0 software was used to summarise the effects and construct forest plots. Page 7 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Author contributions MJCH and RMV established the research question and conducted the data extraction and quality assessment of the studies. AFC performed the statistical analysis and the forest plots. All the authors draft the manuscript. All authors read and approved the final manuscript. Competing interests The authors declare that there is no conflict of interest. Funding support The authors declare that there is any funding support. References 1. Prosperini, L., Fanelli, F., Petsas, N., Sbardella, E., Tona, F., Raz, E., & Pantano P. Multiple Sclerosis: Changes in Microarchitecture of White Matter Tracts after Training with a Video Game Balance Board. Radiology. 2014;273(2):529–38. 2. Gunn HJ, Newell P, Haas B, Marsden JF, Freeman J a. Identification of risk factors for falls in multiple sclerosis: a systematic review and meta-analysis. Phys Ther [Internet]. 2013;93(4):504–13. Available from: http://ptjournal.apta.org/cgi/doi/10.2522/ptj.20120231\ninternalpdf://0995276497/Gunn et al. 2013. Identification of Risk Facto.pdf\nhttp://www.ncbi.nlm.nih.gov/pubmed/23237970 3. Paltamaa J, Sjögren T, Peurala SH, Heinonen A. Effects of physiotherapy interventions on balance in multiple sclerosis : A systematic review and meta-analysis of randomized controlled trials. J Rehabil Med. 2012;44:811–23. 4. Peñasco-Martin B, de los Reyes-Guzman A, Gil-Agudo A, Bernal-Sahun A, Perez-Aguilar B, de la Peña-Gonzalez A. Application of virtual reality in the motor aspects of neurorehabilitation. Rev Neurol. 2010;51(8):481–8. 5. Iruthayarajah J, McIntyre A, Cotoi A, Macaluso S, Teasell R. The use of virtual reality for balance among individuals with chronic stroke: a systematic review and meta-analysis. Top Stroke Rehabil. 2016;16:1–12. 6. De Rooij I, Van de Port I, Meijer J. Effect of virtual reality training on balance and gait ability in patients with stroke: systematic review and meta-analysis. Phys Ther. 2016;96(12):1905-18. 7. Gibbons E, Thomson A, de Noronha M, Joseph S. Are virtual reality technologies effective in improving lower limb outcomes for patients following stroke- a systematic review with meta-analysis. Top Stroke Rehabil. 2016;23(6):440–57. Page 14 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review 8. Finestone H, Kumbhare D. Second-order peer reviews of clinically relevant articles for the physiatrist: rehabilitation that incorporates virtual reality is more effective than standard rehabilitation for improving walking speed, balance and mobility after stroke: a systematic rev. Am J Phys Med Rehabil. 2016;95(12):e202-e203. 9. Li Z, Han X, Sheng J, Ma S. Virtual reality for improving balance in patients after stroke: a systematic review and meta-analysis. Clin Rehabil. 2016;30(5):432–40. 10. Harris DM, Rantalainen T, Muthalib M, Johnson L, Teo WP. Exergaming as a viable therapeutic tool to improve static and dynamic balance among older adults and people with idiopathic Parkinson’s disease: A systematic review and meta-analysis. Front Aging Neurosci. 2015;7:167. 11. Donath L, Rössler R, Faude O. Effects of virtual reality training (exergaming) compared to alternative exercise training and passive control on standing balance and functional mobility in healthy community-dwelling seniors: a meta-analytical review. Sport Med. 2016;46(9):1293–309. 12. Molina K, Ricci N, De Moraes S, Perracini M. Virtual reality using games for improving physical functioning in older adults: a systematic review. J Neuroeng Rehabil. 2014;15(11):156. 13. Booth V, Masud T, Connell L, Bath-Hextall F. The effectiveness of virtual reality interventions in improving balance in adults with impaired balance compared to standard or no treatment: A systematic review. Clin Rehabil. 2014;28(5):419–31. 14. Massetti T, Trevizan IL, Arab C, Favero FM, Ribeiro-Papa DC, De Mello Monteiro CB. Virtual reality in multiple sclerosis - A systematic review. Mult Scler Relat Disord [Internet]. Elsevier; 2016;8:107–12. Available from: http://dx.doi.org/10.1016/j.msard.2016.05.014 15. Taylor M, Griffin M. The use of gaming technology for rehabilitation in people with multiple sclerosis. Mult Scler J [Internet]. 2014;21:355–71. Available from: http://www.ncbi.nlm.nih.gov/pubmed/25533296 16. Moher D, Liberati a, Tetzlaff J, Altman DG. Preferred reporting itemps for systematic reviews and meta-analyses: The PRISMA Statement. Ann Intern Med. 2009;151:264–9. 17. Polman CH, Reingold SC, Banwell B, Clanet M, Cohen J a., Filippi M, et al. Diagnostic criteria for multiple sclerosis: 2010 Revisions to the McDonald criteria. Ann Neurol. 2011;69:292–302. 18. Kurtzke JF. Rating neurologic impairment in multiple sclerosis and expanded disability status scale (EDSS). Neurology. 1983;33(11):1444–52. 19. Maher C, Sherrington C, Herbert R, Moseley A, Elkins M. Reliability of the PEDro scale for rating quality of randomized controlled trials. Phys Ther. 2003;83(8):713–21. 20. Foley N, Bhogal S, Teasell R, Bureau Y, Speechley M. Estimates of quality and reliability with the physiotherapy evidencebased database scale to assess the methodology of Page 15 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review randomized controlled trials of pharmacological and nonpharmacological interventions. Phys Ther. 2006;86(6):817–24. 21. De Morton N. he PEDro scale is a valid measure of the methodological quality of clinical trials: a demographic study. Aust J Physiother. 2009;55(2):129–33. 22. Cohen J. The concepts of power analysis. In: Inc AP, editor. Statistical power analysis for the behavioral sciences. 2nd ed. hillsdale, NJ; 1988. p. 1–17. 23. Robinson J, Dixon J, Macsween A, van Schaik P, Martin D. The effects of exergaming on balance, gait, technology acceptance and flow experience in people with multiple sclerosis: a randomized controlled trial. BMC Sports Sci Med Rehabil [Internet]. 2015;7:8. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=4427959&tool=pmcentrez &rendertype=abstract 24. Prosperini L, Fortuna D, Gianni C, Leonardi L, Marchetti MR, Pozzilli C. Home-Based Balance Training Using the Wii Balance Board: A Randomized, Crossover Pilot Study in Multiple Sclerosis. Neurorehabil Neural Repair [Internet]. 2013;27:516–25. Available from: http://nnr.sagepub.com/cgi/doi/10.1177/1545968313478484 25. Brichetto G, Spallarossa P, de Carvalho MLL, Battaglia M a. The effect of Nintendo® Wii® on balance in people with multiple sclerosis: a pilot randomized control study. Mult Scler [Internet]. 2013;19:1219–21. Available from: http://www.scopus.com/inward/record.url?eid=2-s2.0- 84878864717&partnerID=tZOtx3y1 26. Nilsagård YE, Forsberg AS, von Koch L. Balance exercise for persons with multiple sclerosis using Wii games: a randomised, controlled multi-centre study. Mult Scler [Internet]. 2013;19:209–16. Available from: http://www.ncbi.nlm.nih.gov/pubmed/22674972 27. Kalron A, Fonkatz I, Frid L, Baransi H, Achiron A. The effect of balance training on postural control in people with multiple sclerosis using the CAREN virtual reality system: a pilot randomized controlled trial. J Neuroeng Rehabil [Internet]. Journal of NeuroEngineering and Rehabilitation; 2016;13:13. Available from: http://jneuroengrehab.biomedcentral.com/articles/10.1186/s12984-016-0124-y 28. Eftekharsadat B, Babaei-Ghazani A, Mohammadzadeh M, Talebi M, Eslamian F, Azari E. Effect of virtual reality-based balance training in multiple sclerosis. Neurol Res. 2015;37(6):539–44. 29. Lozano-Quilis J, Gil-Gómez H, Gil-Gómez J, Arbiol-Pérez S, Palacios-Navarro G, Fardoun H, et al. Virtual rehabilitation for Multiple Sclerosis using a Kinect-Based System: randomized controlled trial. JMIR Serious Games. 2014;2(2):e12. 30. Peruzzi A, Zarbo IR, Cereatti A, Della Croce U, Mirelman A. An innovative training program based on virtual reality and treadmill: effects on gait of persons with multiple sclerosis. Disabil Rehabil [Internet]. 2016;1–7. Available from: https://www.tandfonline.com/doi/full/10.1080/09638288.2016.1224935 Page 16 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review 31. Thomas S, Fazakarley L, Thomas PW, Collyer S, Brenton S, Perring S, et al. Mii-vitaliSe: A pilot randomised controlled trial of a home gaming system (Nintendo Wii) to increase activity levels, vitality and well-being in people with multiple sclerosis. BMJ Open. 2017;7:1–16. 32. Gutiérrez RO, Galán Del Río F, De La Cuerda RC, Alguacil Diego IM, González RA, Page JCM. A telerehabilitation program by virtual reality-video games improves balance and postural control in multiple sclerosis patients. NeuroRehabilitation. 2013;33:545–54. 33. Kramer A, Dettmers C, Gruber M. Exergaming with additional postural demands improves balance and gait in patients with multiple sclerosis as much as conventional balance training and leads to high adherence to home-based balance training. Arch Phys Med Rehabil [Internet]. Elsevier Ltd; 2014;95(10):1803–9. Available from: http://dx.doi.org/10.1016/j.apmr.2014.04.020 34. Dockx K, Bekkers E, Van den Bergh V, Ginis P, Rochester L, Hausdorff J, et al. Virtual reality for rehabilitation in Parkinson’s disease. Cochrane database Syst Rev. 2016;21(12):CD010760. 35. Weiss PL, Rand D, Katz N, Kizony R. Video capture virtual reality as a flexible and effective rehabilitation tool. J Neuroeng Rehabil. 2004;1:12. Search strategy for PubMed: ((((((((((("virtual reality"[Title/Abstract]) OR game[Title/Abstract]) OR gaming[Title/Abstract]) OR exergaming[Title/Abstract]) OR interactive[Title/Abstract]) AND balance[Title/Abstract]) OR "postural control"[Title/Abstract]) OR posture[Title/Abstract]) OR gait[Title/Abstract]) OR walking[Title/Abstract]) OR ambulation[Title/Abstract]) AND "multiple sclerosis"[Title/Abstract] Filters: Clinical Trial; Randomized Controlled Trial. Page 17 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Table 1. PEDro Scale items assessment. Note: Eligibility criteria item does not contribute to total score. √= yes/ X= No Section/Theme Robinson et al. (23) Prosperini et al. (24) Brichetto et al. (25) Nilsagard et al. (26) Kalron et al. (27) Eftekharsadat et al. (28) Lozano - Quilis et al. (29) Ortiz - Gutierrez et al. (32) Kramer et al. (33) Peruzzi et al. (30) Thomas et al. (31) Eligibility criteria √ √ √ √ √ √ √ √ √ √ √ Random alloca tion √ √ √ √ √ √ √ X X √ √ Concealled allocation X √ X √ √ X X X X √ √ Baseline comparability √ √ √ √ √ √ √ √ √ √ √ Blind subjects X X X X X X X X X √ X Blind therapists X X X X X X X X X X X Blind assessors X √ √ √ √ √ X √ √ √ X Adequate follow - up X √ X √ √ √ √ √ √ √ √ Intention to treat analysis √ X X X X X X X X X √ Between - group comparisons √ √ √ √ √ √ √ √ √ √ √ Point estimates and variability √ √ √ √ √ √ √ √ √ √ √ Total score 5/10 7/10 5/10 7/10 7/10 6/10 5/10 5/10 5/10 8/10 7/10 Page 18 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Table 2. Main characteristics of included studies. Study Design, PEDro Score Participants Characteristics, Sample size Intervention (VR group) Control Group (or intervention 2) Outcome measures Main Results Robinson et al. (23 ) RCT 5/10 Mean age= 52 , SD=5.8 38 women Mean EDSS score: no reported N=56 2 drop out Individual s upervised exercise sessions with Nintendo Wii Fit ™ games in standing position 2 sessions/week, 40-60 min Duration: 4 weeks, 8 sessions Group 2: balance training exercises replicating the actions and demands of the Wii Fit games Same frequency and duration CG: no intervention Postural control (force plate): CoP displacements bipedal (BP) and monopedal (MP) eyes opened Gait parameters (GAITRite ™ ) Technology acceptance (UTAUT) Flow experience (FSS) Self-reported walking ability (MSWS-12) Perceived activity and participation restrictions (WHODAS 2.0) VR - CG (favors VR group) : AP CoP range (p=0.04) ML CoP range (p=0.04) COP velocity (p=0.01) WHODAS (P<0.001) MSWS-12 (P=NS) Group 2-CG (favors group 2): AP CoP range (p=0.04) ML CoP range (p=0.01) COP velocity (p=NS) WHODAS (P<0.001) MSWS-12 (P=0.03) Only for flow experience, significant differences were found between the two intervention groups (p≤0.05) in favor VR Page 19 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Prosperini et al. (24) RCT Crossover 6/10 Mean age=36 .2, SD=8.6 25 women Mean EDSS score=3.5 ( range 1.5-5.0) Mean disease duration=10.7,SD=5.8 N=36 2 drop out Home - Based Balance training with Nintendo Wii™ Balance Board in sitting and standing position 4 sessions/week, 30 min First session and one session every 4 weeks supervised by PT Duration: 12 weeks, 48 sessions CG: no intervention 12 weeks Postural control (force plate): CoP displacements bipedal, eyes opened Walking speed (T25- WT) Obstacles negotiation (FSST) Physical and psychological perceived impact of MS (MSIS-29) Significant between - group differences over time favors intervention: CoP displacements (p=0.016) FSST (p=0.034) 25-FWT (p=0.048) MSIS-29 (p=0.023) Virtual training was effective in all endpoints, regardless of the order of treatment. A residual effect was observed Brichetto et al. ( 2 5 ) RCT 7/10 Mean age=41.9, SD=11 22 women Mean EDSS score=4, SD= 1.6 Mean disease duration=11.7,SD=6.8 N=36 Supervised exercise sessions with Nintendo Wii Fit TM games in sitting and standing position 3 sessions/week, 60 min Duration: 4 weeks, 12 sessions CG: standard balance training Static and dynamic exercises in single and double leg stance, with or without equilibrium board and half-kneeling, tailored to each participant Same frequency and duration Postural control (force plate): CoP displacements bipedal, eyes opened and closed Functional balance (BBS) Fatigue (MFIS) Significant between - group differences favors experimental group: CoP displacements eyes opened and closed (p<0.05) BBS (p<0.05) MFIS (p<0.05) Page 20 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Nilsagard et al. (26) RCT 7/10 Mean age=49.7, SD=11.3 64 women Mean EDSS score: no reported Mean disease duration=12.3,SD=8.6 N=84 4 drop out Individual PT - supervised sessions with Nintendo Wii Fit TM games in standing position 2 sessions/week, 30 min Duration: 6 weeks, 12 sessions CG: no intervention Functional balance (TCS, DGI) Walking speed (T25- WT) Mobility (TUG) Obstacles negotiation (FSST) Self-reported walking ability (MSWS-12) Self-confident related falling (ABC) There were no statistically significant differences between groups after the intervention period in any outcome Kalron et al. (27 ) RCT 7/10 Mean age=45.2 , SD=11.6 19 women Mean EDSS score=4.1, SD= 1.3 Mean disease duration=11, SD=8.9 N=32 2 drop out Individual PT - supervised sessions with CAREN™ VR system in standing position 2 sessions/week, 30 min Duration: 6 weeks, 12 sessions CG : convenctional balance training 10 min stretching 20 min training (static postural control, weight shifting and perturbation exercises) Postural control (force plate): CoP displacements, bipedal eyes opened and closed Functional balance (FRT, BBS) Obstacles negotiation (FSST) Fear of falling (FES-I) Significant differences in favor of VR group were observed for FRT (p=0.009) and FES-I (p=0.021) Both groups improved significantly postural control (p=0.024), FRT (p=0.001), FSST (p=0.031) and FES-I (p=0.023) Page 21 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Eftekharsadat et al. (28) RCT 6/10 Mean age=35.2, SD=8.2 22 women Mean EDSS score: no reported Mean disease duration=7.1, SD=4.2 N=30 Individual PT - supervised sessions with BIODEX™ Balacne System in standing position 2 sessions/week, 20 min Duration: 12weeks, 24 sessions CG: no intervention Postural control (force plate): OSI Functional balance (BBS) Mobility (TUG) Fall Risk (FRi) Significant differences in favor VR group were observed for TUG (p=0.01), FRi (p=0.002) and OSi (p<0.04) Lozano - Quilis et al. (29) RCT 5/10 Mean age=44.4, SD=10 4 women Mean EDSS score: no reported Mean disease duration=9.3, SD=7.9 N=11 Individual PT - supervised sessions with RemoviEM™ VR system in standing position 1 session/week, 60 min (45 min standard rehabilitation + 15 min VR training) Duration: 10 weeks, 10 sessions CG: standard balance and gait rehabilitation exercises Same frequency and duration Functional balance (SLB, BBS, TBT) Walking speed (10 Mwt) Mobility (TUG) Significant differences in favor control group for TUG test (p=0.027) Ortiz - Gutierrez et al. (32) CT 5/10 Mean age=41.23, SD=7.7 27 women Mean EDSS score=3.95, SD= 0.6 Mean disease duration=10.27, SD=6.1 Individual m onitored telerehabilitation via videoconference usin X- Box 360™ 4 sessions/week, 20 min Duration: 10 weeks, 40 sessions CG: : convenctional balance training 2 sessions/week, 40 min 10 weeks 10 min low loads strength exercises Postural control (force plate): CES, MTC Functional balance (BBS, TBT) Significant differences in favor VR group were observed for CES (p<0.001), MTC (p=0.003) Page 22 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review N=50 3 drop out 20 min propioception on unstable surfaces and gait facilitation exercises 10 min muscle-tendon stretching Kramer et al. (33 ) CT 5/10 Mean age=47, SD=9 44 women Mean EDSS score=3, SD= 1 N=70 9 drop out Individual PT - supervised sessions with Nintendo Wii Fit TM games in standing position 3 sessions/week, 30 min Duration: 3 weeks, 9 sessions Group 2: 5 single task exercises over the posturomed CG: standard balance training Romberg stance, tandem stance, one leg stance on an aerobic mall, standing on the toe or the heel, walking forward and backward on a line Postural control (force plate): CoP displacements bipedal and monopedal, single and dual task Walking speed (10Mwt) There were no statistically significant differences between groups after the intervention period in any outcome Only VR group showed significant improvements in postural control, single and dual task Peruzzi et al. (3 0 ) RCT 8/10 Mean age=42.8, SD=11.1 15 women Mean EDSS score=3.8, SD=0.9 Mean disease duration=12.1, SD=5.4 N=31 Supervised treadmill walking while watching a VR tree-lined trail with obstacles 3 sessions/week, 45 min First week treadmill speed 80% of the subject overground walking spedd; every CG: supervised treadmill walking Same frequency, duration and speed parameters Gait data (six camera stereophotogram metric system) Functional balance: BBS Walking speed (10Mwt) Significant improvements over time in the 6Mwt in both groups with no differences between groups Significant improvement on 10Mwt (p<0.001), TUG (p=0.042), BBS (p=0.003) and FSST (p=0.028) only observed in the VR group, Page 23 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review 999x646mm (120 x 120 DPI) Page 30 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review 999x646mm (120 x 120 DPI) Page 31 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review 999x646mm (120 x 120 DPI) Page 32 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review Appendix 1. Detailed search strategy. N° Terms used #1 “Virtual reality” #2 “Game” #3 “Gaming” #4 “Exergaming” #5 “Interactive” #6 "Balance" #7 "Postural control" #8 "Posture" #9 “Gait” #10 “Walking” #11 "Ambulation" #12 "Multiple Sclerosis" PUBMED (257 potencial articles): ((((((((((("virtual reality"[Title/Abstract]) OR game[Title/Abstract]) OR gaming[Title/Abstract]) OR exergaming[Title/Abstract]) OR interactive[Title/Abstract]) AND balance[Title/Abstract]) OR "postural control"[Title/Abstract]) OR posture[Title/Abstract]) OR gait[Title/Abstract]) OR walking[Title/Abstract]) OR ambulation[Title/Abstract]) AND "multiple sclerosis"[Title/Abstract] Filters: Clinical Trial; Randomized Controlled Trial Page 33 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review PEDro (14 potencial articles): • #1 AND #6 AND #12 (6 potencial articles) • #4 AND #6 AND #12 (1 potencial article) • #5 AND #6 AND #12 (2 potencial articles) • #1 AND #9 AND #12 (2 potencial articles) • #4 AND #9 AND #12 (1 potencial article) • #5 AND #9 AND #12 (1 potencial article) • #3 AND #6 AND #12 (1 potencial article) Cochrane Database of Systematic Reviews (56 potencial articles): • #1 AND #6 AND #12 (13 potencial articles) • #2 OR #3 AND #6 AND #12 (10 potencial articles) • #4 AND #6 AND #12 (2 potencial articles) • #5 AND #6 AND #12 (5 potencial articles) • #1 AND #7 AND #12 (7 potencial articles) • #1 AND #9 AND #12 (3 potencial articles) • #2 AND #7 AND #12 (1 potencial article) • #2 OR #3 OR #4 AND #8 AND #12 (1 potencial article) • #1 AND #9 OR 10 AND #12 (3 potencial articles) • #2 OR #3 AND #9 AND #12 (3 potencial articles) • #4 AND #9 AND #12 (2 potencial article) • #5 AND #9 AND #12 (1 potencial article) • #2 OR #3 AND #10 AND #12 (2 potencial articles) • #4 AND #10 AND #12 (1 potencial article) • #5 AND #10 AND #12 (3 potencial articles) CINAHL (72 potencial articles): • t:("virtual reality") t:(balance) t:("multiple sclerosis") c:1 (10 potencial articles) • t:("virtual reality") t:("postural control") t:("multiple sclerosis") c:1 (6 potencial articles) • t:("virtual reality") t:(gait) t:("multiple sclerosis") c:1 (14 potencial articles) Page 34 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review • t:(game) t:(balance) t:("multiple sclerosis") c:1 (16 potencial articles) • t:(game) t:("postural control") t:("multiple sclerosis") c:1 (5 potencial articles) • t:(gaming) t:(balance) t:("multiple sclerosis") c:1 (1 potencial article) • t:(exergaming) t:(balance) t:("multiple sclerosis") c:1 (8 potencial articles) • t:(exergaming) t:(gait) t:("multiple sclerosis") c:1 (8 potencial articles) • t:(interactive) t:(walking) t:("multiple sclerosis") c:1 (4 potencial articles) Note: only search strategies with results are showed.  Page 35 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review PRISMA 2009 Checklist Section/topic # Checklist item Reported on page # TITLE Title 1 Identify the report as a systematic review, meta-analysis, or both. 1 ABSTRACT Structured summary 2 Provide a structured summary including, as applicable: background; objectives; data sources; study eligibility criteria, participants, and interventions; study appraisal and synthesis methods; results; limitations; conclusions and implications of key findings; systematic review registration number. Abstract page INTRODUCTION Rationale 3 Describe the rationale for the review in the context of what is already known. 1 Objectives 4 Provide an explicit statement of questions being addressed with reference to participants, interventions, comparisons, outcomes, and study design (PICOS). 2 METHODS Protocol and registration 5 Indicate if a review protocol exists, if and where it can be accessed (e.g., Web address), and, if available, provide registration information including registration number. 2 Eligibility criteria 6 Specify study characteristics (e.g., PICOS, length of follow-up) and report characteristics (e.g., years considered, language, publication status) used as criteria for eligibility, giving rationale. 2-3 Information sources 7 Describe all information sources (e.g., databases with dates of coverage, contact with study authors to identify additional studies) in the search and date last searched. 2 Search 8 Present full electronic search strategy for at least one database, including any limits used, such that it could be repeated. 2 Study selection 9 State the process for selecting studies (i.e., screening, eligibility, included in systematic review, and, if applicable, included in the meta-analysis). 2-3 Data collection process 10 Describe method of data extraction from reports (e.g., piloted forms, independently, in duplicate) and any processes for obtaining and confirming data from investigators. 3 Data items 11 List and define all variables for which data were sought (e.g., PICOS, funding sources) and any assumptions and simplifications made. 2-3 Risk of bias in individual studies 12 Describe methods used for assessing risk of bias of individual studies (including specification of whether this was done at the study or outcome level), and how this information is to be used in any data synthesis. 3 Summary measures 13 State the principal summary measures (e.g., risk ratio, difference in means). 3 Synthesis of results 14 Describe the methods of handling data and combining results of studies, if done, including measures of consistency (e.g., I 2) for each meta-analysis. 3 Page 1 of 2 Page 36 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review PRISMA 2009 Checklist Section/topic # Checklist item Reported on page # Risk of bias across studies 15 Specify any assessment of risk of bias that may affect the cumulative evidence (e.g., publication bias, selective reporting within studies). 3 Additional analyses 16 Describe methods of additional analyses (e.g., sensitivity or subgroup analyses, meta-regression), if done, indicating which were pre-specified. 3 RESULTS Study selection 17 Give numbers of studies screened, assessed for eligibility, and included in the review, with reasons for exclusions at each stage, ideally with a flow diagram. Page 4 and Figure 1 Study characteristics 18 For each study, present characteristics for which data were extracted (e.g., study size, PICOS, follow-up period) and provide the citations. 4 Risk of bias within studies 19 Present data on risk of bias of each study and, if available, any outcome level assessment (see item 12). Page 4 and Table 1 Results of individual studies 20 For all outcomes considered (benefits or harms), present, for each study: (a) simple summary data for each intervention group (b) effect estimates and confidence intervals, ideally with a forest plot. Page 5 and table 2 Synthesis of results 21 Present results of each meta-analysis done, including confidence intervals and measures of consistency. 6-9 Risk of bias across studies 22 Present results of any assessment of risk of bias across studies (see Item 15). Additional analysis 23 Give results of additional analyses, if done (e.g., sensitivity or subgroup analyses, meta-regression [see Item 16]). 6-9 DISCUSSION Summary of evidence 24 Summarize the main findings including the strength of evidence for each main outcome; consider their relevance to key groups (e.g., healthcare providers, users, and policy makers). 9-11 Limitations 25 Discuss limitations at study and outcome level (e.g., risk of bias), and at review-level (e.g., incomplete retrieval of identified research, reporting bias). 11-12 Conclusions 26 Provide a general interpretation of the results in the context of other evidence, and implications for future research. 12 FUNDING Funding 27 Describe sources of funding for the systematic review and other support (e.g., supply of data); role of funders for the systematic review. 13 From: Moher D, Liberati A, Tetzlaff J, Altman DG, The PRISMA Group (2009). Preferred Reporting Items for Systematic Reviews and Meta-Analyses: The PRISMA Statement. PLoS Med 6(7): e1000097. Page 37 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 For Peer Review PRISMA 2009 Checklist doi:10.1371/journal.pmed1000097 For more information, visit: www.prisma-statement.org. Page 2 of 2 Page 38 of 37 http://mc.manuscriptcentral.com/clinrehab Clinical Rehabilitation 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60