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. 2025 Oct 9;41:100591. doi: 10.1016/j.ensci.2025.100591

Rehabilitation for functional enhancement of myasthenia gravis: A systematic review and meta-analysis

Wen Xiangxiang a, Shen Mengjiao c, Jia Shoumei e, Yu Kaitao a, Xu Yafang b, Jia Jie b,d,f,⁎
PMCID: PMC12547834  PMID: 41142446

Abstract

Myasthenia gravis (MG) is a rare neuromuscular disorder that causes muscle weakness and fatigue. This review evaluated the current evidence on the efficacy, tolerance and adherence of rehabilitative interventions. Based on the PRISMA guidelines, 445 articles were identified from major scientific databases. After applying the inclusion and exclusion criteria, 6 studies were included in the final analysis. Two primary rehabilitative strategies - physical and respiratory training - were identified. The results of the systematic review and meta-analysis showed that both interventions improved functional capacity and enhanced the quality of life, with good tolerance and high adherence. This review summarizes the effects of rehabilitative interventions on improving 6-min walk distance (6MWD), quality of life (MG-QOL15), and respiratory function (FEV1 and FVC) in MG patients. One study was rated as high quality (OCEBM level 1b), and five as moderate quality (OCEBM level 2b). Five findings were established and rated as Grade B, according to the OCEBM recommendations. This review demonstrated the potential of structured rehabilitation programs to improve functioning and quality of life in patients with MG, while highlighting the need for further research to optimize and standardize these interventions.

Keywords: Myasthenia gravis, Muscle weakness, Rehabilitative interventions, Neuromuscular junction, Physical training, Respiratory training

1. Introduction

Myasthenia gravis (MG) is a chronic autoimmune disorder that affects the neuromuscular junction, resulting in fluctuating muscle weakness and fatigability. This condition is characterized by the presence of autoantibodies that target components of the neuromuscular junction, predominantly acetylcholine receptors (AChRs), muscle-specific kinase (MuSK), and other related proteins [1]. The incidence of MG varies from 4.1 to 30 cases per million person-years, with a prevalence of 150 to 200 cases per million and a bimodal age distribution [2,3].

Clinically, MG manifests as a variety of symptoms, predominantly muscle weakness, that worsens with activity and improves with rest. This weakness can affect ocular muscles, leading to ptosis and diplopia, as well as bulbar, respiratory, and limb muscles [4]. The severity and specific symptoms can vary depending on the type of autoantibody present and whether thymoma, a tumor of the thymus gland, is involved [2,5]. The diagnosis of MG typically involves clinical evaluation, antibody testing, and neurophysiological examinations. Treatment strategies for MG are diverse and aim to achieve clinical remission or minimal symptoms [6,7]. Active physical training is also recommended to help manage symptoms and improve the quality of life [8].

The impact of MG on quality of life is significant. They often experience extreme physical and mental fatigue, a symptom reported by many MG patients [9]. The disease can lead to considerable disability, frequent hospitalizations, and life-threatening myasthenic crises that require intensive care. Despite advances in treatment, the burden of illness remains high, particularly for those with refractory MG who do not respond to conventional therapies [4].

Rehabilitation is a comprehensive and multidisciplinary approach that includes exercise among other treatments that aims at improving the quality of life and physical function of individuals with various health conditions. As a critical component of rehabilitation, exercise specifically targets at physical improvements [[10], [11], [12]]. It plays a vital role in the management of neuromuscular disorders, offering benefits such as improved muscle strength, positive psychosocial impact, and enhanced quality of life. Many rehabilitation treatment modalities have demonstrated positive effects on neuromuscular function and functional outcomes [[13], [14], [15], [16], [17], [18], [19], [20]]. Rehabilitation interventions have been explored for their effects on MG patients [[21], [22], [23], [24], [25]].

The potential benefits and safety of physical exercise for patients with MG have been extensively studied, given the impact of the disease on muscle function. Exercise is safe and well tolerated in patients with mild to moderate MG, improving muscle strength and daily function through aerobic and resistance training, particularly high-resistance strength exercises [[26], [27], [28]]. Exercise interventions also enhance quality of life, daily functioning, and physical performance in patients with MG [29,30], while reducing overall fatigue, anxiety, depression, and improving psychological well-being [31,32]. Respiratory muscle training (RMT) improves maximal inspiratory pressure (PImax) and maximal expiratory pressure (PEmax), which enhances muscle strength and endurance in patients with MG and provides long-term benefits [33]. While some studies have shown improvements in lung function parameters, such as forced vital capacity (FVC) and forced expiratory volume in one second (FEV1) [34], others have not demonstrated similar findings [35]. RMT can reduce fatigue and enhance physical fitness in patients who report symptom relief [36]. Additionally, respiratory training programs enhance functional outcomes and quality of life in MG patients, as measured by various scales, with continuous training being essential for maintaining these benefits [37,38].

A systematic review [23] indicates that rehabilitative modalities, including physical, respiratory, and balance training, have positive effects on patients with MG. However, the lack of high-quality evidence, particularly the cross-comparative studies, limits the development of clear guidelines and protocols. Recently, several randomized controlled trials (RCTs) [31,37] have been conducted to further investigate the effects of exercise and respiratory training on patients with MG.

Given the lack of high-quality evidence on the effectiveness of rehabilitation therapies for patients with MG, this systematic review aims to clarify the role of physical and respiratory training in the management of patients with MG. Additionally, the secondary objective is to explore patients' tolerance and compliance with different rehabilitation methods and intervention intensities.

2. Materials and methods

The PICO method [39] was applied to define the clinical question based on the following parameters.

  • -

    Population: MG patient

  • -

    Intervention: rehabilitation/ physiotherapy /exercise

  • -

    Comparator: control/ conventional means

  • -

    Outcome: improvement of functional outcome and quality of life

This systematic review was conducted in accordance with PRISMA guidelines for systematic reviews and meta-analyses of intervention trials.

2.1. Study eligibility criteria

The eligibility criteria for this systematic review were as follows: (a) MG patients of any age and severity classification; (b) rehabilitation interventions applied to at least a subset of the patients; (c) sufficient data provided for the review's objectives; and (d) no restrictions on the minimum follow-up duration. The criteria for the report were as follows: (a) it was written in English, (b) it contained previously published data, and (c) it included studies published until September 2024. Letters, comments, editorials, and practice guidelines were excluded.

2.2. Information sources

This systematic literature review was conducted using the PubMed, EMBASE, CINHAL, Cochrane Library, and MEDLINE databases to identify relevant studies. Only randomized controlled trials (RCTs) and randomized crossover trials (RCT-Cs) were included. Two investigators independently performed the literature search.

2.3. Study selection and evaluation

The eligibility assessment of the selected studies was performed independently by two reviewers in an unblinded and standardized manner. All titles and abstracts were screened, and ineligible articles were excluded. The full text of the studies meeting the inclusion criteria was then reviewed in detail by the investigators. Disagreements between reviewers were resolved through discussion. If no agreement was reached after the discussion, a third reviewer was involved.

2.4. Data collection process

Data from the original articles were recorded using a data-extraction form. One investigator extracted the following data, which were then cross-checked by the other investigator: general study information (lead author and publication year), study design, rehabilitation approaches in the experimental group, intervention duration, number of participants, and main results/findings. Any disagreements between the two reviewers were resolved through discussion. If consensus could not be reached, a third reviewer was consulted to make the final decision.

2.5. Methodological quality and level of evidence assessment process

Two investigators independently evaluated the methodological quality and level of evidence. Methodological quality was assessed using the revised Cochrane Risk of Bias (RoB2) tool for RCTs and RCT-Cs [40], while the level of evidence was determined based on the Oxford Centre for Evidence-Based Medicine (OCEBM) Levels of Evidence [41]. Any discrepancies in the quality assessment were resolved through discussion to reach a consensus, and a third reviewer was consulted if agreement could not be achieved. The Meta-analysis was conducted using the Review Manager software (version 5.3).

3. Results

3.1. Results of the search

A total of 445 studies were initially identified from PubMed, EMBASE, CINHAL, Cochrane Library, and MEDLINE databases. After removing duplicates (n = 378), 67 articles remained. Screening titles and abstracts led to the exclusion of 38 additional records. The full texts of 20 articles were assessed, of which 14 were excluded for not meeting the inclusion criteria. In the end, 6 studies were included. These studies comprised five RCTs [31] [[42], [43], [44], [45]] and one RCT-Cs [37]. Two main rehabilitation approaches for MG have been identified: physical training and respiratory training. The PRISMA flow diagram outlining the study selection process is presented in Fig. 1, and the details of the included studies are shown in Table 1.

Fig. 1.

Fig. 1

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PRISMA flow diagram of the selection of articles for review.

Table 1.

Summary of the articles included in the review.

Author and Year Type of Study Intervention Duration Total Number of Participants Outcome
Aslan 2014 [45] RCT Inspiratory and expiratory muscle training, using the Threshold Inspiratory Muscle Trainer and Threshold Positive Expiratory Pressure devices. 8 weeks 26 The experimental group showed significant improvements in maximal inspiratory pressure (p = 0.002), maximal expiratory pressure (p = 0.003), and sniff nasal inspiratory pressure (p = 0.04) compared to the sham group.
Birnbaum 2021 [31] RCT 3-weekly 40-min sessions of an unsupervised, moderate-intensity home rowing program 3 months 45 The exercise group showed significant improvements, with a mean difference of −1.9 points in MG-ADL scores (95 % CI -3.0 to −0.9) and 27.7 m in 6-min walking distance (95 % CI 7.2 to 48.1) compared to the control group.
Ceren 2022 [37] RCT-C Group A completed SSE three times weekly, followed by a rest and a tailored home exercise program, while Group B started with the home exercise program, followed by rest and then SSE.- 6 months 10 SSE led to significant improvements in fatigue, muscle strength, and quality of life compared to home exercise (p < 0.0125), with an effect size of 1.76 and a power of 83.88 %.
Fregonezi 2005 [44] RCT 3-weekly 40-min sessions of Interval-based inspiratory muscle training (IMT) and breathing retraining (diaphragmatic breathing and pursed-lips breathing) 8 weeks 27 The training group showed significant improvements in maximal inspiratory pressure (p = 0.001), maximal expiratory pressure (p = 0.01), respiratory rate/tidal volume ratio (p = 0.05), and upper chest wall expansion (p = 0.02).
Misra 2021 [43] RCT 30-min walk as exercise intervention 3 months 40 The exercise arm had >50 % improvement in the MG-QOL15 (p = 0.020) and distance travelled in 6MWT (p = 0.007) to the rest arm. The exercise arm also had reduction in the number of steps (p = 0.001) and dose of pyridostigmine (p = 0.024) and prednisone (p = 0.023).
Mohamed 2022 [42] RCT Control group only underwent a designed physical therapy program three times a week while Intervention group underwent a partial body weight supported treadmill training in addition 12 weeks 30 A significant increase in PFTs, CMAP amplitude and isometric muscle force, 6MWD, PedsQL TM MFS, and (p < 0.001) and a significant decrease in APSI, MLSI, and OASI (p < 0.001) of both groups.
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RCT = randomized controlled trial; RCT-C = randomized crossover trial; MGADL = myasthenia gravis activities of daily living scale; SSE = spinal stabilization exercises; MGQOL15 = myasthenia gravis quality of life 15; PFTs = pulmonary functional tests; CMAP = compound motor action potential; 6MWD = six-minute walk distance; PedsQL TM MFS = multidimensional fatigue scale (MFS) of the pediatric quality of life inventory; APSI = anterior–posterior stability index; MLSI = medial-lateral stability index; OASI = overall stability index.

3.2. Description of studies

3.2.1. Physical training

Four studies were included in this group. Birnbaum 2021 [31] evaluated a 3-month home rowing exercise program for adults with MG. The participants received either usual care or exercise sessions three times per week. The intervention commenced in the 3rd month, and by the 6th month, the exercise group showed improvements in daily life impact (MG-ADL score decreased by 1.9) and 6-minute walking distance (increased by 27.7 m), although these benefits were not sustained at the 9-months follow up.

Ceren 2022 [37] conducted a single-blinded, randomized crossover trial to assess the effects of spinal stabilization exercises (SSE) on adults with MG. 10 participants aged 18 to 65 underwent six weeks of SSE alongside a home exercise program. The results demonstrated significant improvements in fatigue, as measured by the fatigue severity scale (FSS), visual analog fatigue scale (VAFS), muscle strength, 6-minute walk distance (6MWD), and quality of life (MGQOL-15) in the SSE group compared to the home program group.

Misra 2021 [43] aimed to evaluate the efficacy and safety of exercise versus rest in MG patients. 40 patients with mild-to-moderate MG were randomized to either a 30-minute walking exercise group or a rest group, alongside standard treatment, for 12 weeks. The primary outcome was defined as a >50% improvement in the myasthenia gravis quality of life scale (MG-QOL15). Results showed that the exercise group had significantly better quality of life (p=0.02) and walking distance (p=0.007) compared to the rest group, with no adverse events reported.

Mohamed 2022 [42] evaluated the effectiveness of specialized physical therapy with or without partial body weight-supported treadmill training (PBWSTT) in children with MG. 30 children aged 13-16 were randomized into two groups; both received physical therapy, while Group A also participated in PBWSTT. After 12 weeks, both groups showed significant improvements in pulmonary function, neuromuscular function, and quality of life, with more pronounced enhancements in Group A, highlighting the added benefit of PBWSTT.

  • •

    Functional capacity determined with the 6MWD

The six-minute walk distance (6MWD) is a measure derived from the six-minute walk test (6MWT), which assesses the distance an individual can walk in six minutes. It is widely used to evaluate functional exercise capacity in various patient populations and correlates strongly with peak work capacity and physical activity [46].

All four studies utilized the six-minute walk distance (6MWD) as one of the outcome measures to evaluate the effects of the intervention. Study Misra 2021 [43] used a binary variable for statistical analysis, defining a significant improvement as an increase of over 50% in the 6MWD from the baseline. The number of participants exhibiting significant differences between the intervention and control groups was reported. The remaining three studies applied continuous variables for statistical analysis and reported the mean and standard deviation of the 6MWD for both groups.

The forest plot indicated that studies Birnbaum 2021 [31], Mohamed 2022 [42], and Misra 2021 [43] demonstrated a significant improvement in patients' 6MWD following the intervention, while Study Ceren 2022 [37] reported no significant benefit of physical exercise on 6 MWD. Nevertheless, the overall trend suggests that physical exercise effectively enhances the 6MWD (n=82, 95% CI 17.47 to 21.06; P = 0.57; I2 = 0%; evidence level 1b; Fig. 2(b)). This trend remained consistent after excluding the study with the highest weight (n=52, 95% CI -32.09 to 63.69; P = 0.29; I2 = 10%; evidence level 2b; Fig. 2(b)). Both forest plots, before and after the exclusion, demonstrated low heterogeneity among the included studies (P > 0.1; I2 ≤ 25%). However, individual studies, such as Study Birnbaum 2021 [31] and Study Ceren 2022 [37], have demonstrated significant variability in their findings, likely due to their small sample sizes.

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    Improvement in quality of life determined with the MG-QOL15

Fig. 2.

Fig. 2

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The effects of physical exercise as reflected in the 6MWD (six-minute walk distance). (a) Forest plot for binary variables; (b) Forest plot for continuous variables; (c) Forest plot for continuous variables (after omitting the maximum weight).

The MG-QOL15 is a 15-item questionnaire specifically designed to assess the health-related quality of life (HRQOL) in patients with myasthenia gravis (MG). It is widely used in both clinical and research settings to evaluate the impact of MG on patients' daily lives and overall well-being [[47], [48], [49]].

Except for study Mohamed 2022 [42], the other three studies employed the MG-QOL15 scale as an outcome measure to evaluate the effects of the intervention. Study Misra 2021 [43] utilized a binary variable for statistical analysis, considering a reduction of more than 50% in the MG-QOL15 score compared to baseline as a significant improvement, and reported that the number of participants demonstrated significant differences between the intervention and control groups. The other two studies used continuous variables for statistical analysis, reporting the mean and standard deviation of the MG-QOL15 scores in both the intervention and control groups post-intervention (Fig. 3).

Fig. 3.

Fig. 3

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The effects of physical exercise as reflected in the MGQOL. (a) Forest plot for binary variables; (b) Forest plot for continuous variables.

The forest plot results indicated that physical exercise significantly improved the MG-QOL15 score in Misra 2021 [43] (n=38, RR=1.44, 95% CI 1.06 to 1.97; P = 0.02; Fig. 3(a)). In contrast, Birnbaum 2021 [31] and Ceren 2022 [37] report non-significant and significant improvements, respectively (n=53, 95% CI -7.30 to -1.15; P = 0.89; I2=0%; Fig. 3(b)). The low heterogeneity observed between these two studies (I2=0; P=0.89>0.10) indicates a strong result consistency for Birnbaum 2021 [31] and Ceren 2022 [37].

Although it is not possible to include all three studies in a meta-analysis due to the differing statistical analysis methods employed in Misra 2021 [43], the overall results showed that physical exercise has a significant benefit in reducing the MG-QOL15 scores of MG patients, suggesting that physical exercise can improve the daily quality of life and overall well-being of MG patients.

3.2.2. Respiratory training

The effects of respiratory training were examined in two additional studies. Fregonezi 2005 [44] evaluated the influence of interval-based inspiratory muscle training (IMT) combined with breathing retraining (BR) in patients with generalized MG. A total of 27 participants were randomized into a training group, which performed IMT and BR three times weekly for 8 weeks, and a control group. The training group demonstrated significant improvements in respiratory strength (with Pimax increased by 27%), thoracic mobility, and health-related quality of life, particularly in the physical role domain, compared to the control group.

Aslan 2014 [45] assessed the effects of inspiratory and expiratory muscle training on pulmonary functions in 26 patients with slowly progressive neuromuscular disease, who were randomized into experimental (n=14) and sham groups (n=12). The experimental group engaged in 15 minutes of inspiratory and expiratory muscle training twice daily for eight weeks, resulting in significant increases in maximum inspiratory pressure (MIP, cm H2O and % predicted), maximum expiratory pressure (MEP, cm H2O and % predicted), and sniff nasal inspiratory pressure (SNIP) compared to the sham group.

  • •

    Improvement in the Pulmonary Function determined with the FEV1(L) and FVC(L)

Forced Expiratory Volume in 1 second (FEV1) and Forced Vital Capacity (FVC) are key spirometry measures used to assess pulmonary function. FEV1 evaluates airway flow limitation, whereas FVC reflects lung volume. Both parameters are crucial in clinical practice and research for predicting disease progression, assessing respiratory health, and determining survival outcomes [[50], [51], [52]].

The results of the meta-analysis forest plot (Fig. 4) showed no significant difference in FEV1 (n=51, 95% CI -0.64 to 0.16; P = 0.81; I2=0%; Fig. 4 (a)) and FVC (n=51, 95% CI -0.67 to 0.17; P = 0.82; I2=0%; Fig. 4 (b)) in MG patients between the two studies investigating respiratory exercise intervention (Fregonezi 2005 [44]; Aslan 2014 [45]). Despite the low heterogeneity (I2=0%), the limited number of included studies and the low stability of individual study outcomes prevented us from making definitive conclusions regarding the assertion that respiratory exercise is ineffective in improving FEV1 and FVC in MG patients.

Fig. 4.

Fig. 4

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Effects of physical exercise as reflected in FEV1(L) and FVC(L). (a) Forest plot of FEV1(L); (b) Forest plot of FVC(L).

3.2.3. Adherence and tolerance of exercises

Birnbaum 2021 [31] assessed monthly tolerance through cardiorespiratory evaluations including cardiorespiratory parameters, muscular pain, or joint pain. There were no significant intergroup differences in exercise tolerance (dyspnea on exertion, p=0.32, RR=0.59, 95% CI: 0.23 to 1.51; articular pain, p=0.32, RR=0.70, 95% CI: 0.37 to 1.27; muscular pain, p=0.74, RR=0.85, 95% CI: 0.49 to 1.48). Additionally, no differences were observed in the incidence of non-serious adverse events such as infections, allergic reactions, or headaches (p=0.58). Two participants in the control group required hospitalization due to MG exacerbations, whereas no such exacerbations were observed in the experimental group (M6, p=0.084, RR=0, 95% CI 0 to 0.98; M9, p=0.011, RR=0, 95% CI 0 to 0.55). Approximately 70% of participants adhered to the exercise regimen, with the primary reason for non-adherence being work-related commitments.

In the study by Mohamed 2022 [42], all participants demonstrated good tolerance, with no MG exacerbations reported during the 12-week treatment period. Adherence was also high, with a compliance rate of approximately 98% and no patient dropouts. In the study by Misra 2021 [43], patients underwent regular cardiac monitoring to assess their cardiac status. Despite the withdrawal of one patient from each group (exercise and rest arms) due to complications unrelated to the intervention, overall tolerance was deemed satisfactory. The adherence rates were similarly high in both groups, at 97.10% in the exercise arm and 97.5% in the rest arm.

Ceren 2022 [37] reported no adverse events or complaints during or after the rehabilitation sessions but did not report adherence. In the study by Fregonezi 2005 [44], the severity of myasthenia gravis remained stable during the eight-week rehabilitation intervention. All 27 participants met the study requirements, indicating satisfactory adherence to the partial home program. Similarly, Aslan 2014 [45] reported no adverse effects, and participants demonstrated high adherence to both hospital sessions and home exercises, as confirmed by their diary entries and weekly evaluations.

3.3. Summary of clinical findings

This review includes six studies, comprising five RCTs and one RCT-C. These findings indicate that both physical and respiratory training provide significant benefits to patients. Physical training resulted in substantial improvements in functional capacity, fatigue levels, and overall quality of life, with no reported adverse events. Various forms of physical exercise, including home-based programs and tailored exercise regimens, significantly enhance muscle strength and endurance, as evidenced by increased walking distances and decreased fatigue. Furthermore, respiratory training, which focuses on strengthening the inspiratory and expiratory muscles, effectively improves pulmonary function and overall respiratory health.

The results suggest that these rehabilitative interventions are generally well-tolerated, with high adherence rates among participants, reflecting the positive acceptance of the exercise regimens. Notably, these studies reported no significant adverse events associated with the interventions, further confirming the safety of these rehabilitation strategies. Overall, these findings underscore the potential of structured rehabilitation programs to enhance the daily functioning and quality of life for individuals with MG, emphasizing the need for further research to optimize and standardize these interventions.

3.4. Clinical heterogeneity

Clinical heterogeneity among the selected studies was substantial, affecting the overall interpretation of the findings. The studies displayed significant variations in rehabilitation approaches, primarily focusing on physical and respiratory training. There was a lack of consistency in the diagnostic criteria for MG and in the classification of disease severity among participants, which varied significantly across the established scales. Additionally, differences in intervention protocols, such as the type, intensity, and duration of training, further contributed to this heterogeneity.

Although the 6MWD and MG-QOL15 were common outcome measures, the statistical analyses varied, with some studies employing binary variables and others utilizing continuous variables, leading to additional discrepancies in results. This inconsistency in methodologies and participant characteristics limits the ability to draw robust conclusions regarding the efficacy of interventions. Overall, these variations underscore the need for standardized protocols in future research to enhance comparability and improve understanding of rehabilitation strategies for patients with MG.

3.5. Methodological quality

The results of the risk of assessment for the five randomized controlled trials and one randomized crossover trial included in this systematic review are shown in Figs. 6 and 7.

Fig. 6.

Fig. 6

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Risk of bias graph: Review authors' judgements about each risk of bias item presented as percentages across all included studies.

Fig. 7.

Fig. 7

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Risk of bias summary: Review authors' judgements about each risk of bias item for each included study.

Study Aslan 2014 [45] was assessed to have a high risk of attrition bias due to an excessive dropout rate in the control group (2 out of 12 participants), which could potentially impact the results of the study. Study Fregonezi 2005 [44] exhibited a high risk of both selection bias and performance bias, as the allocation process for participants in the intervention and control groups was not clearly explained, blinding was not implemented, and there was no explanation provided for the lack of blinding. Study Misra 2021 [43] was also found to carry a high risk of performance bias and reporting bias due to the absence of blinding without explanation, as well as the omission of partial results (e.g., outcomes such as Myasthenic Muscle Score (MMS) and MG Activities of Daily Living (MGADL) score were not reported).

In contrast, study Mohamed 2022 [42] provided a detailed report on the blinding process, citing practical reasons for not implementing full blinding due to the transparency of the intervention to participants. However, blinding was still applied to the interventionists and outcome assessors. Additionally, primary outcome measures were obtained from Pulmonary Functional Tests (PFTs), which are relatively objective indicators. Therefore, this study was judged to have a low risk of performance bias. A similar judgment was made for study Aslan 2014 [45].

3.6. Quality of evidence

In this review, one RCT by Mohamed 2022 [42] was classified as level 1b according to the OCEBM standards. This study demonstrated a low risk of bias and a narrow confidence interval, indicating that it is a high-quality RCT. The remaining five studies, comprising four RCT (Birnbaum 2021 [31], Misra 2021 [43], Fregonezi 2005 [44], and Aslan 2014 [45]) and one RCT-C (Ceren 2022 [37]), were classified as level 2b. The RCT-C study Ceren 2022 [37] also exhibited a low risk of bias and provided a detailed account of each step of the research, thus earning a level 2b classification as well.

A systematic review and meta-analysis revealed five key findings.

  • (a)

    Physical exercise increased endurance, as shown by improved 6MWD. Patients with mild to moderate MG should exercise three times a week for 40 min per session, as tolerated (based on Birnbaum 2021 [31], Ceren 2022 [37], Mohamed 2022 [42] and Misra 2021 [43]; OCEBM Grade B recommendation).

  • (b)

    Regular exercise lowers MG-QOL15 scores and enhances quality of life; at least three weekly sessions, each lasting over 40 min, are recommended (based on Mohamed 2022 [42] and Misra 2021 [43]; OCEBM Grade B recommendation).

  • (c)

    Partial body weight-supported treadmill training significantly improves pulmonary function in adolescents, enhancing FEV1 and FVC (based on Mohamed 2022 [42]; OCEBM Grade B recommendation).

  • (d)

    Respiratory muscle training, conducted three times a week, strengthens respiratory muscles (based on Fregonezi 2005 [44] and Aslan 2014 [45]; OCEBM Grade B recommendation).

  • (e)

    Rehabilitation interventions are generally well tolerated, although work commitments may hinder adherence; home-based programs improve compliance (based on Birnbaum 2021 [31], Mohamed 2022 [42], Fregonezi 2005 [44] and Aslan 2014 [45]; OCEBM Grade B recommendation).

While these interventions were generally well tolerated, common barriers included work commitments.

4. Discussion

MG is a chronic autoimmune disorder that affects the neuromuscular junction and leads to muscle weakness and fatigue. It has a substantial impact on quality of life, resulting in fatigue, disability, and potentially life-threatening crises, although there has been some progress in treatment. Rehabilitation played a vital role in MG management and provided benefits such as enhanced muscle strength, functional outcomes, and overall quality of life. Aerobic and resistance training are both safe and effective for patients with mild to moderate MG [[26], [27], [28], [29], [30], [31], [32]], while RMT improves respiratory function and alleviates fatigue [33,[36], [37], [38]]. In the past two decades, there have been an increasing amount of evidences regarding to the rehabilitation on patients with MG [53,54]. However, there is limited evidence on effective rehabilitation measures for patients with MG and rehabilitation tolerance and adherence [55]. Additionally, although there are various rehabilitation methods available for MG patients, nearly all programs lack high homogeneity and supporting evidence that are needed in high-quality studies, and they also lack detailed explanations regarding to the rationale and necessity of the rehabilitation programs [23,[56], [57], [58]]. This systematic review seeks to elucidate the role of physical and respiratory training in the management of MG, and assesses patient tolerance and compliance with these interventions.

There are five RCTs and one RCT-Cs met the inclusion criteria for this review. A total of 171 participants were analyzed. Specifically, 90 in the rehabilitation group and 81 in the control group. The overall risk of bias was assessed as moderate. It was reported that physical exercise significantly increased the 6MWD in patients with MG, and reduced their MG-QOL15 scores [31,37,42,43]. Respiratory exercises were reported to significantly increase respiratory strength in patients with MG [44], but there was no significant enhancement in respiratory function (Aslan 2014 [45], Mohamed 2022 [42]). Overall, the level of evidence that included in this review was rated as moderately high, particularly with the presence of one high-quality RCT (Mohamed 2022 [42]) that enhanced the stability and certainty of the evidence to some extent. However, it should be noted that the number of studies included in this review and participants in each study were both insufficient, so we encourage future researchers to provide more high-quality studies with larger sample sizes.

The heterogeneity analysis results for the included studies in this review indicate that, although the statistical heterogeneity of these studies was relatively low except for Misra 2021 [43], there was a significant clinical heterogeneity between these studies. These differences were primarily reflected in the rehabilitation methods, particularly in physical and respiratory training. Furthermore, there was a lack of consistency among the studies regarding to the diagnostic criteria for MG and the classification of participants based on disease severity. Additionally, there were differences in tools that were used to evaluate the intervention effects, either. The variability in intervention protocols—such as the type, intensity, and duration of training—further exacerbated this heterogeneity. Although heterogeneity among different studies is unavoidable, the differences, such as the inclusion of adolescent patients with MG in Mohamed 2022 [42] compared to adult patients in the other studies, may have directly contributed to significant discrepancies in intervention outcomes. Therefore, a random-effects model was employed for this review, to control the impact of these heterogeneity on the results in conducting the meta-analysis to some extent.

Based on the systematic review and meta-analysis of the included studies, five findings were formed. Specifically, three findings relates to physical exercise, one concerns respiratory exercise, and the last one indicated that patients with MG demonstrated good tolerance and adherence to the rehabilitation intervention programs. The safety of each intervention program was also good, with no serious adverse events reported. Study Birnbaum 2021 [31] provided a detailed report on the barriers to adherence faced by patients in the intervention group, which mainly included work obligations and commuting time.

In summary, by analyzing the RCTs and RCT-Cs researches, this review studiesthe effectiveness as well as the tolerance and adherence of rehabilitation programs for patients with MG, focusing on physical and respiratory training. While, the heterogeneity between studies included in this review cannot be ignored, and the absence of high-homogeneity RCTs has resulted that any single reviewed method cannot be recommended as superior to others (even though there is one high-quality study assessed as having low risk of bias with a narrow confidence interval, Mohamed 2022 [42]). Nevertheless, each intervention has some degree of effect based on the specific outcomes reported in each study. According to the findings of this review, the best approach may be a multidisciplinary strategy that combines physical and respiratory training [38,56,58]. Notably, several articles all recommended that patients with MG engage in moderate or low intensity exercise (Birnbaum 2021 [31], Ceren 2022 [37], and Misra 2021 [43]), suggesting that low to moderate intensity combined rehabilitation intervention programs have greater benefits in improving the symptoms, functional outcomes, and quality of life of patients with MG.

Although the included studies reported good safety of rehabilitation programs, it is still advisable to limit the interventions to MG patients that were classified as mild to moderate severity to prevent serious adverse events [37,43]. Furthermore, by analyzing the adherence of exercise among the included studies, we find that patients with MG are more likely to choose home-based exercise programs that under the supervision of clinical practitioners, which can minimize the time and energy spent on exercising. Additionally, family members of MG patients should provide more practically and psychologically support to help patients adhere to their rehabilitation programs better [23,[59], [60], [61]].

More high-quality and large-sample RCTs as well as more reasonable and reliable programs are still needed to demonstrate the effectiveness of rehabilitation interventions for patients with MG. The tolerance and adherence of rehabilitation methods for patients with MG should not be overlooked. Additionally, the economic viability and convenience of rehabilitation programs could be focal points for future research to ensure that patients can maintain their physical function by adhering to rehabilitation programs even after the interventions conclude.

CRediT authorship contribution statement

Wen Xiangxiang: Writing – original draft, Conceptualization, Formal analysis, Methodology, Project administration, Software, Visualization. Shen Mengjiao: Conceptualization, Data curation, Formal analysis, Software, Visualization, Writing – original draft. Jia Shoumei: Data curation, Formal analysis, Funding acquisition, Methodology, Resources, Supervision, Writing – review & editing. Yu Kaitao: Investigation, Resources, Validation, Writing – original draft. Xu Yafang: Investigation, Methodology, Software, Writing – review & editing. Jia Jie: Funding acquisition, Project administration, Resources, Supervision, Validation, Writing – review & editing.

Declaration of competing interest

None.

Acknowledgement

I sincerely thank the editor and reviewers for the invaluable feedback suggestions. My gratitude goes to my advisor for guidance, to my labmates for collaboration, and to my roommates for their support. I also appreciate my family and Shami's unwavering encouragement and comforting presence throughout this research.

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