Multiple sclerosis (MS) is one of the most common causes of progressive neurological disability among young adults (1). Upper limb impairments, muscle weakness, spasticity, reduced functional performance, and fatigue are common clinical manifestations in patients with MS (2–6). A crucial impairment that might be often showed by patients with MS is balance disturbance, which could result in a higher risk of falling and reduced independence in the activities of daily living (ADLs) (7–10). To overcome these highly disabling issues, different rehabilitative approaches have been proposed so far in the literature (11, 12). In addition to conventional physiotherapy and rehabilitation interventions, technological devices are a promising therapeutic intervention in the complex framework of MS treatment. In this scenario, virtual reality (VR) approaches are suggested as potentially useful tools in several rehabilitative pathological conditions (13). Indeed, VR might enhance the interaction with surrounding artificial environment created to appear similar to the original one, allowing a multisensorial feedback training that might further increase the rehabilitation efficacy. Indeed, human balance control is the results of multiple sensory system inputs, integrated into a complex mechanism of constant reweight and adjustments, as visual, vestibular, and proprioception signals are continuously converted to corrective motor actions (14). Hence, a multisensorial augmented reality might be a particularly effective rehabilitation approach in MS balance impairments.

Moreover, it is provided though a display that can be also head-mounted, with complementary motion tracking devices, sound effects, and eventually end-effectors such as joysticks or sensors able to capture even muscle and brain signals (15). VR has been integrated in several neurological diseases rehabilitative protocols, including patients affected by MS, with promising results (13, 16–18). As a complementary tool of VR in rehabilitation programs (19), patients could also perform exergames, defined as the activity of playing video games that involve physical exertion (20). In the recent years, exergaming has been widely used in several rehabilitative programs and clinical study (21–23). Active video game therapy could reduce the boredom of the rehabilitation process, increasing patient motivation, providing direct feedback, and enabling dual-task training. In this study, commercially available exergames (e.g., Nintendo Wii and Microsoft Kinect) have successfully transformed living rooms into playful training environments for about 10 years (24). Clinical and home trials have been conducted to investigate the effectiveness of Nintendo Wii Fit in patients with MS, focusing on balance and gait improvement, but the results are controversial (25). In the recent years, researchers started to evaluate exergames as a rehabilitation tool for patients with MS (26). Exergaming has proved to be an acceptable, feasible, safe, fun, stimulating, and self-motivating tool (27). However, there is limited evidence of its efficacy among neurological pathologies, in particular, in patients with Parkinson's disease, stroke, and hereditary sensory motor neuropathy (28–30). To the best of our knowledge, few randomized controlled trials (RCTs) investigated the efficacy of exergaming in MS. Therefore, in systematic review and meta-analysis, we sought to evaluate the efficacy of exergames and VR compared with conventional rehabilitation treatment in terms of balance improvement in patients affected by MS.

Virtual reality has recently emerged as a promising intervention in the rehabilitation of several neurological diseases (28–30, 43). This intriguing and complex technique can evoke brain behavioral responses that mimic real-world interaction, acting in real-time but in a safe environment. Exergaming consists of whole-body physical exercises comparable to a moderate intensity training, performed through active video games (44). It has been used in the rehabilitation of several neurological diseases to enhance both the cognitive and physical function and improve balance (45–47), as it offers task-oriented exercises enhancing motor learning and neural plasticity (48). Our findings are in line with previous evidence in the neurorehabilitation field, reporting that VR and exergaming are cumulatively effective on gait and balance in Parkinson's disease (49, 50), patients with poststroke (51), traumatic brain injury (52), and cerebral palsy (53). Despite the overall significance demonstrated for these two rehabilitation approaches (p = 0.00001), it should be noted that in the subgroup analysis, only exergames reported a significant effect size (p = 0.00001) compared to VR (p = 0.39).

Although robotic rehabilitation effects on balance and gait have been recently investigated with positive results in patients with MS (54), few studies in literature addressed the effectiveness of VR and exergames compared with conventional treatment in patients with MS and in most cases only considering VR as a complementary tool in MS rehabilitation concerning balance. This could be related to the relative novelty of these devices and the difficult implementation in the clinical setting.

Firstly, Casuso-Holgado et al. (55), analyzed in a systematic review the effectiveness of VR on gait and balance in patients affected by MS, showing significant differences in comparison with no interventions and inconclusive evidence compared with standard treatment. However, the authors included several different outcome measures (i.e., walking speed and postural balance). Moreover, Cano Porras et al. (56) in a systematic review found only three studies focusing on the BBS as primary outcome in patients with MS and VR rehabilitation, with inconclusive results.

Evidence on the role of VR in rehabilitative management of patients with MS is scarce, even though, in 2016, Massetti et al. (57) performed a systematic review on the effects of VR in patients affected by MS, including also observational studies and considering mixed outcomes. Although this approach widened the number of studies included, the low quality of the studies precluded to perform a meta-analysis. Furthermore, a recent meta-analysis performed by Nascimento et al. (58) suggested that VR could induce benefits that can be similar or greater than conventional exercises in patients with MS. However, taken together, all these studies were unable to draw strong conclusion about the real impact of VR on balance improvement in patients with MS, even though the effects of this approach are promising, considering the evidence obtained in other chronic neurological disorders (59, 60).

Concerning exergames, Mura et al. (45), found that in mixed neurological pathologies, including MS, they might significantly improve executive functions and visuospatial perception compared with no intervention or standard rehabilitative treatment. Concerning balance, successive studies in mixed neurological diseases confirmed that exergames might be at least equivalent to conventional therapy (59) and are able to improve balance dysfunction (60).

In the present systematic review and meta-analysis, we found that VR and exergaming might significantly improve balance in terms of the BBS compared with standard treatment alone in patients affected by MS. Among balance assessment, we assessed the BBS as primary outcome, since it is widely used and recommended in different neurological settings for patients with MS with EDSS ranging from 0 to 7.5 (61). Given that the esteemed minimal clinically important difference for the BBS is 3 points (62), most of the selected studies showed a clinically significant difference between standard treatment and exergaming/VR interventions. Furthermore, VR and exergames might improve balance proposing simultaneous motor and cognitive tasks (63) that might also be addictive, improving both the motivation and treatment adherence (64). In this study, repetitive practice and observation are crucial for motor learning and VR might induce plastic changes in central nervous system that has been associated with mirror imagery in other neurological disorders such as stroke survivors through a facilitation effect on sensorimotor networks (65). The high adherence observed in patients performing exergaming might be due to the low practical barriers, high accessibility, low cost of the consoles, and the social impact because of the potential involvement of family members in multiplayer games (21). Moreover, exergames provide visual and auditory feedback, currently altered in patients affected by MS (66), thus improving the self-awareness of the patients during the training. Furthermore, Yazgan et al. (67) demonstrated a significant improvement in terms of fatigue and gait after exergaming treatment. The authors suggested that these improvements were obtained thanks to the less anxiety and greater confidence in the balance raised by the videogame approach and not a low energy expenditure compared to standard treatments.

This systematic review and meta-analysis have also some clinical implications for the rehabilitation clinical practice, considering that VR resulted to be an intriguing alternative for balance training in patients with MS, with psychological advantages that could enhance their motivation and treatment adherence (68). Clinicians should strike the right balance between too difficult and too easy tasks and as such keeping the motivation of the patients high. Objective progression and extrinsic feedback encourage robot-assisted rehabilitation that might play a critical role on neuroplasticity (69, 70). Lastly, it should be considered that VR might be home based, with a telerehabilitation approach, which is highly encouraged during coronavirus disease 2019 (COVID-19) pandemic, due to psychological and hospitalization issues (71–73).

We are aware that our systematic review considered only a small number of RCTs due to the limited evidence available in the literature. Hence, further high-quality studies investigating exergames and VR effects in improving balance in patients with MS compared with conventional rehabilitation treatment are still warranted and the use of relatively recent exergaming devices is not created specifically for neurorehabilitation. Moreover, to improve the strength of evidence on VR, future RCTs addressing this specific issue in patients with MS are warranted.

This study suggested that rehabilitative interventions using exergames and VR appear to be more effective than conventional rehabilitation to improve balance in patients with MS. More in detail, exergames showed to have a significant efficacy in improving balance outcomes and considering its safety and its effects on neuroplasticity, sensorimotor training, and motivation of the patients, it could be implemented as an effective technique in the complex rehabilitative treatment framework of neurological diseases including MS. Starting from these promising data, further evidence is warranted in the next future to focus on VR and its role in the rehabilitative approach to neurological disorders.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

DC and AS contribute to the study design and conceptualization. AS contributes to the databases searching. DC, CC, and AC-S contribute to the data screening. AA, FFo, and AS contribute to the data extraction. DC, MI, and AS contribute to the data synthesis and interpretation. NM contributes to the statistical analysis. DC contributes to the manuscript drafting. MI and AS contribute to the critical revision, study supervision, and study submission. AA, NM, FFo, TP, FFe, CC, and AC-S contribute to the visualization. All the authors read and approved the final version of the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.