Practice Points
- Respiratory dysfunction in multiple sclerosis (MS) is associated with disease progression, respiratory muscle weakness, fatigue, impaired trunk control, and thoracic kyphosis.
- Nonpharmacological interventions such as inspiratory and expiratory muscle training, breathing exercises, lung volume recruitment, Pilates, and proprioceptive neuromuscular facilitation may improve respiratory function in people with MS.
- Clinicians can identify early signs of respiratory decline by acquiring a full understanding of the factors associated with respiratory dysfunction in MS.
Multiple sclerosis (MS) is a chronic autoimmune disorder characterized by demyelination of the central nervous system, leading to a range of neurological symptoms.1 It is one of the most widespread, disabling neurological conditions in young adults worldwide. The prevalence of this condition continues to rise, with nearly 1 million people in the United States living with MS and over 2.8 million cases of MS reported globally in 2020, a 30% increase from 2013.2 MS can cause serious impairments, such as vertigo, ataxia, cognitive impairment, sensory impairment, muscle weakness, and vision problems.3 Respiratory diseases and infections are a major contributor to morbidity and mortality in people with MS, with a mortality rate nearly 2.7 times higher than that of the general population.4
Respiratory dysfunction refers to the impairment of the normal functioning of the respiratory system and impaired gas exchange, leading to inadequate oxygenation or carbon dioxide removal from the blood.5 Respiratory dysfunction in MS is caused by demyelinating lesions in the central nervous system, which disrupt neural signals to the muscles of respiration. This can lead to muscle weakness, impaired coughing, breathing control issues, and respiratory failure. Pulmonary function tests (PFTs) provide a quantitative assessment of the physiological properties of the respiratory system, including the lungs and chest wall, to diagnose and evaluate respiratory dysfunction.6
Pulmonary function decreases as severity progresses, particularly in people with MS and mobility impairments.7 Ambulatory people with MS who can walk without assistance (Expanded Disability Status Scale [EDSS] score < 7) typically have normal forced vital capacity (FVC), whereas wheelchair users show moderate FVC reduction and nonambulatory individuals experience a more substantial decline of approximately 50% of predicted FVC.8-11 Similar declines have been observed in forced expiratory volume in 1 second (FEV1) and maximum voluntary ventilation (MVV).
Despite the known respiratory complications of MS, there is limited research on the factors that could influence declining respiratory function, particularly in the early stages of the disease. This knowledge gap hinders the development of early intervention strategies that could improve patient outcomes. This review aims to (1) examine how respiratory function differs across MS disease stages; (2) examine how various factors are associated with differences in respiratory function, as measured by PFTs and respiratory muscle strength (maximal inspiratory pressure [MIP] and maximal expiratory pressure [MEP]) in people with MS; and (3) assess the effectiveness of nonpharmacological interventions for improving respiratory function in people with MS.
By mapping the literature, we hope to provide a comprehensive understanding of the factors influencing respiratory function and identify nonpharmacological interventions that have been explored. We will also highlight key areas where further research is needed and provide direction for future investigations aimed at improving respiratory outcomes in individuals with MS.
Methods
This review was conducted according to the guidelines for Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews. It was registered with the Open Science Framework (https://osf.io/dashboard) and followed the JBI Manual for Evidence Synthesis.12
Search Strategy and Eligibility Criteria
The review used the population, concept, and context framework to conceptualize the research focus. The population of interest was people with MS. The concept involved factors affecting pulmonary function. The context includes studies conducted in various settings, including clinical and community environments, focusing on different stages of MS.
A comprehensive search strategy was developed in collaboration with a professional librarian who specializes in systematic health science literature reviews. The search was conducted using 3 major databases: PubMed, Embase, and Scopus. The search terms included a combination of keywords and Medical Subject Headings (MeSH) related to respiration and multiple sclerosis to create the search strategy (Lung* OR respiratory-disease* OR breath*[MeSH] OR “lung function”[MeSH] OR “Respiratory Muscles”[MeSH] OR “Respiratory Function Tests”[Mesh] OR “Airway Resistance”[MeSH] OR “Pulmonary Ventilation”[MeSH] OR “Respiration”[Mesh] OR “Total Lung Capacity”[MeSH] OR “Work of Breathing”[MeSH]) AND (“Multiple Sclerosis”[MeSH]).
Our inclusion criteria were original research studies measuring respiratory muscle function tests and PFTs involving adults with MS, written in English, and published as full-text, peer-reviewed papers between January 2014 and December 2024. Foundational studies published prior to 2014 were considered when necessary to help provide clinical context and support interpretation of the findings. Exclusion criteria were studies unrelated to respiratory function, non–peer-reviewed articles, protocols, reviews, conference papers, case reports, case series, studies where the primary objectives were not related to respiratory function and/or rehabilitation, and studies using only qualitative methods.
Study Selection and Data Extraction
The study selection process had 2 stages: the initial screening of titles and abstracts and the following full-text reviews. Two independent reviewers (A.M.A. and A.A.A.) screened the titles and abstracts of all identified articles. Records obtained from the searches were compiled and organized using Covidence Review Software (Veritas Health Innovation) for abstract and full-text screening. Full-text articles were retrieved for the studies that met the inclusion criteria. Any disagreements between the 2 reviewers were discussed, and if no agreement was reached, a third reviewer (A.P.) was consulted to make the final decision.
A.M.A. and A.A.A also carried out data extraction independently via a standardized data extraction form and recorded these data in Excel (Microsoft). The extracted data included study characteristics, participant characteristics, PFTs measured, factors affecting pulmonary function, and key findings and conclusions. A descriptive synthesis of the included studies was conducted to summarize results by study design, population features, types of pulmonary assessments used, and key reported factors.
Results
Study Selection
The initial database search yielded 7059 potentially relevant articles (Figure). After removing duplicates, 4095 papers were screened based on title and abstract. Sixty-five articles were selected for full-text review. Of these, 20 met the eligibility criteria and were included in the review. The primary reasons for exclusion included a lack of focus on respiratory function (15), interventions irrelevant to the scope of this review (11), incorrect study design (14), full text not available (2), and studies involving non-MS populations (3).
Study Characteristics
Studies included in this review were conducted in Turkey (n = 6; 30%), Spain (n = 5; 25%), the US (n = 4; 20%), Italy (n = 2; 10%), Cyprus (n = 2; 10%), and Iran (n = 1; 5%). The most frequently used study design was a randomized controlled trial (RCT; n = 9; 45%), followed by cross-sectional studies (n = 6; 30%), case-control studies (n = 2; 10%), a quasi-randomized trial (n = 1; 5%), and observational repeated-measures designs (n = 2; 10%). Sample sizes ranged from 24 participants13 to 146 participants.14 The mean participant age across studies was 46.73 ± 7.59 years,15 with the youngest mean age at 29.3 ± 5.43 years14 and the oldest at 60.5 ± 8.6 years.16 Most participants were female, with the proportion ranging from 51.1% to 85.5% across studies. The average disease duration ranged from 6.33 ± 2.14 years14 to 24 ± 11 years.17 EDSS scores ranged from 8.5 ± 0.4 to 2.0 ± 1.0,16,18 reflecting a wide range of disability severity. Across the included studies, a variety of respiratory function measures were used to evaluate respiratory status. The most reported outcomes included MIP (15 studies), MEP (15 studies), FEV1 (7 studies), FVC (7 studies), peak expiratory flow (PEF; 3 studies), and MVV (3 studies). Four studies also assessed maximal insufflation capacity (MIC) and peak cough flow (PCF).
The respiratory assessments demonstrated strong clinical properties. Findings from several studies reported excellent test-retest reliability, with intraclass correlation coefficients of 0.92 or higher, supporting the consistency and reproducibility of respiratory muscle strength and spirometry measurements.19 To obtain these measures, common tools included threshold resistance devices, spirometry, and cough assist devices, emphasizing the careful methods used to accurately measure lung function in this population.
Relationship Between Respiratory Function and Disease State
Respiratory function tends to decline as MS severity increases, with evidence emerging from mild to moderate and advanced stages (Table 1). In individuals with mild to moderate MS, Westerdahl et al assessed 48 participants with a median EDSS score of 4.5 and found no significant associations between EDSS score and PFT values such as VC, FVC, or FEV1, which remained within normative ranges.20 However, MEP showed a significant but weak inverse correlation with EDSS score (r = –0.312; P = .031), suggesting that expiratory muscle strength may decline with increasing disability, even when general lung volumes are preserved. Similarly, Aguilar-Zafra et al reported that higher expiratory muscle strength in 41 people with MS was associated with lower disability (r ≤ –0.66; P < .01) and reduced dyspnea (r ≤ –0.61; P < .01), underscoring the functional relevance of respiratory muscle capacity in MS.19 Further supporting this trend, Muhtaroglu et al found that people with MS with EDSS scores between 2.5 and 5 had significantly lower MEP (P = .048; statistic test value was not provided) compared with those with lower EDSS scores (0-2), although MIP, FVC, and FEV1 did not differ significantly between groups.21 When the entire MS participant sample was compared with controls, both MIP and MEP were found to be significantly reduced in people with MS (P = .042 and P = .003; statistic test value was not provided), with large effect sizes (Cohen d = 0.87 for MIP; d = 0.92 for MEP). As disability progressed to more advanced stages, pulmonary impairments became more noticeable. Supporting this, Levy et al examined 73 individuals with advanced MS (EDSS score ≥ 7) and found severe respiratory dysfunction in 72.6%. VC was reduced to a mean of 57.9%, with nearly half of the participants having values below 50%, and PCF was impaired in 61.6%. Importantly, EDSS score was significantly associated with both VC and PCF (Q= 0.56; P = .0006), confirming a progressive decline in pulmonary function with disease severity.22 Interestingly, respiratory muscle strength did not correlate with EDSS score, indicating that factors such as decreased lung compliance or mechanical restriction may also contribute to respiratory decline in advanced MS.
Factors Associated With Respiratory Function in MS
A range of physiological, functional, psychological, psychosocial, and cognitive factors appears to influence respiratory function, highlighting the complex and multifaceted nature of respiratory impairment in people with MS (Table 2). Physiological and functional factors include urinary incontinence, which has been associated with impaired trunk muscle strength, an essential component of respiratory mechanics. Aguilar-Zafra et al found that MEP correlated more strongly with urinary incontinence (r = 0.559; P < .01) and physical function, as measured by the Timed Up and Go (TUG) test (r = 0.508; P < .01), than MIP (r = 0.312; P < .05), suggesting that expiratory muscle weakness may underlie both continence control and mobility deficits.19 This association may reflect shared neurological involvement affecting trunk stabilizing musculature, particularly given the coordinated role of abdominal, diaphragmatic, and pelvic floor muscles in respiratory and urinary function. However, lesion location was not directly examined in the included studies.
Trunk control and core stability further emerged as significant functional determinants of respiratory performance. Ozen et al reported that MEP was moderately correlated with trunk stability (r = 0.735; P < .001), and people with MS demonstrated reduced spirometric values and respiratory muscle strength compared with controls, emphasizing the mechanical interplay between postural control and breathing function.23 Similarly, thoracic posture appears to affect pulmonary outcomes; Muhtaroglu et al observed that individuals with MS with more noticeable thoracic kyphosis had significantly lower pulmonary function values, including FVC, FEV1, and PEF, compared with healthy participants, indicating that spinal curvature may restrict chest wall expansion and respiratory efficiency.13 Motor performance, particularly during dynamic tasks, also contributes to respiratory limitations. Charro et al demonstrated that worse performance on the TUG test and Berg Balance Scale was associated with reduced PEF (r = –0.281; P < .05), FVC (r = –0.350; P < .05), and FEV1 (r = –0.338; P < .05), underscoring the relevance of mobility impairments to breathing function.24
Psychological factors such as fatigue, anxiety, and depression also play important roles. Fatigue, a prevalent MS symptom, has been associated with respiratory muscle weakness. Ray et al reported that MEP was negatively correlated with both total fatigue (r = –0.362; P < .03) and physical fatigue (r = –0.360; P < .03), as measured by the Modified Fatigue Impact Scale.25 These findings suggest a possible bidirectional relationship between fatigue and respiratory function, though causality remains unclear. In addition, anxiety and depression have also been implicated in diminished respiratory outcomes.26 Eren et al found that depression and anxiety were correlated with lowering FVC and FEV1, and even after adjusting for disease severity, anxiety maintained a moderate negative correlation with FEV1 and FVC (r = –0.367 and –0.360; P = .001), and there was a low negative correlation between depression and FEV1 (r = –0.214; P = .045), underscoring the potential respiratory consequences of psychological comorbidities.18 Fatigue contributes to respiratory impairment by reducing overall physical activity, which weakens the respiratory muscles, diaphragm, and intercostal muscles.25 Chronic fatigue also limits participation in pulmonary rehabilitation or physical activity routines that are necessary to maintain and improve lung function. Similarly, depression is associated with systemic inflammation, which can contribute to both neurodegenerative and pulmonary pathology.27
Psychosocial and cognitive factors also play a role. Sleep quality and cognition deficits were both linked to respiratory function in the results from a study by Hashim et al, which found that increased daytime sleepiness and cognitive deficits were associated with lower FEV1/FVC (r = –0.186; P = .03), lower FEV1 (r = –0.488; P < .001), and lower FVC (r = –0.633; P < .001), suggesting a bidirectional relationship between respiratory capacity and neurological symptoms.14 Cognitive decline can disrupt the basic neuronal mechanisms regulating both voluntary and automatic respiratory regulation, particularly through impairments in the cortical and brainstem pathways that regulate respiratory rhythm. This condition is prevalent in neurodegenerative disorders such as Parkinson disease and amyotrophic lateral sclerosis, which affect both motor and nonmotor systems, including respiratory control centers.28,29 In addition, cognitive impairment can affect an individual’s ability to detect and react to dyspnea, leading to delays in seeking medical care or insufficient adherence to therapy protocols, exacerbating respiratory diseases. Declined cognitive function is also associated with decreased physical activity, which, over time, causes respiratory muscle deconditioning and reduced respiratory function. These results focus on the need to routinely assess respiratory function in neurological diseases and suggest that early recognition and management of respiratory symptoms may help mitigate cognitive deterioration.
Interventions for Improving Respiratory Function in MS
Nine studies tested the effects of nonpharmacological respiratory interventions in people with MS (Table 3). Seven of these studies evaluated types of breathing exercises, 1 assessed proprioceptive neuromuscular facilitation (PNF), and 1 tested a Pilates intervention.
Westerdahl et al reported that a 2-month home-based deep breathing program using a positive expiratory pressure device significantly improved VC and FVC (P < .043 and P < .025; statistic test value was not provided), despite no significant changes in MIP or MEP. Nearly half (48%) of participants reported perceived respiratory improvements.17 Enrichi et al investigated lung volume recruitment (LVR) therapy in individuals with secondary progressive MS. Using a cough-assist machine twice daily for 5 days weekly for 4 weeks, participants practiced air stacking to total lung capacity, followed by short rest periods, and found a significant increase in MIC percentage (r = 0.15; P = .02), indicating enhanced passive lung inflation through air stacking.15
Respiratory muscle training (RMT), including both inspiratory muscle training (IMT) and expiratory muscle strength training (EMST), has been widely studied. Ghannadi et al demonstrated that an 8-week RMT protocol significantly improved respiratory muscle strength, fatigue, quality of life, and pulmonary function in people with MS (r = 0.29; P < .001).30 Similarly, Huang et al observed significant gains in MIP (η2p = 0.18; P < .013) after 10 weeks of IMT in nonambulatory participants with MS, with improvements sustained up to 8 weeks after the intervention.16 Martin-Sanchez et al assessed a low-resistance IMT protocol of 15 minutes daily for 5 days weekly for 12 weeks and found improvement in MIP (r = 0.53; P = .002) and reduced dyspnea (r = 0.35; P = .046), emphasizing the superior efficacy of low-resistance IMT.31
The benefits of EMST have also been demonstrated. Silverman et al found significant improvements in MEP (P < .001; statistic test value was not provided) following a 5-week protocol in people with moderate to advanced MS, regardless of intervention intensity.32 Further, Srp et al reported significant increases in both MEP (P < .0001; effect size d = 0.94) and voluntary PCF (P = .0036; d = 0.57) after a 12-week EMST program, with gains maintained above baseline even after a detraining period, supporting the long-term effectiveness of expiratory training.33
Beyond breathing-focused techniques, Kesebir et al examined an 8-week PNF program targeting the head and neck, trunk, upper limb, and breathing and found significant within-group improvements in MIP (P = .005); MEP (P = .001); PEF percentage (P = .010); FEV1/FVC percentage (P = .003); forced expiratory flow, midexpiratory phase (P = .023); and PCF (P < .001); statistic test values were not provided. The PNF group had significantly higher FEV1 percentage (P = .011) than the control group, though the control group achieved greater MIP gains (P = .013), suggesting selective advantages across different respiratory outcomes.34 Complementarily, Abasıyanık et al tested the impact of clinical Pilates over 8 weeks and found significantly greater improvements in both MIP (F = 4.77; P = .037) and MEP (F = 7.94; P = .008) compared with a home-based control group, highlighting Pilates as a feasible and effective approach for people with MS to strengthen respiratory muscles.35
Discussion
This study reviewed the existing literature related to pulmonary function across various MS disease stages, factors known to be associated with respiratory dysfunction in MS, and nonpharmacological treatment for respiratory dysfunction in people with MS. Consistent with prior research, findings from many studies demonstrated that PFTs tend to remain stable in the early stages of MS but decline as the disease progresses. However, reductions in respiratory muscle strength, particularly in MIP and MEP, have been reported even in individuals with mild to moderate disability, suggesting that respiratory muscle impairment may occur earlier than changes detected by PFTs.36,37 Westerdahl et al found that respiratory muscle strength decreases as EDSS scores increase, whereas Levy et al and Muhtaroglu et al reported that cough effectiveness and expiratory muscle strength are reduced in individuals with more advanced MS.20-22
In addition to disease progression, fatigue, thoracic kyphosis, weak trunk control, and cognitive or motor impairments have all been linked to reduced lung capacity and respiratory efficiency. Given these associations, early and regular respiratory monitoring in people with MS may be an important clinical practice to promote early intervention. In addition to overall disease progression, lesion location may play an important role in respiratory compromise. Cervical spinal cord involvement can impair phrenic nerve function and diaphragmatic activation, given that the phrenic nerve originates from the C3 to C5 spinal segments, whereas brainstem lesions, although less common, may directly affect central respiratory control mechanisms. Lesion burden at these levels may therefore contribute to reduced respiratory muscle strength, ineffective cough, and increased risk of respiratory complications.38,39
Emerging evidence suggests that nonpharmacological interventions may improve respiratory outcomes in people with MS; however, most studies to date are limited by small sample sizes and short intervention durations, making it difficult to generalize findings. IMT, EMST, LVR, Pilates, PNF, and deep breathing exercises were all associated with increased cough strength, improved respiratory muscle function, and decreased dyspnea. EMST showed notable improvements in voluntary cough flow and swallowing function, particularly among those with more severe disease, whereas IMT was effective at all stages of MS. Additional studies are needed to further validate these initial findings and determine whether different interventions work better for different patient groups or symptoms. For instance, physical activity and exercise have also been identified as beneficial nonpharmacological interventions for respiratory symptoms in neurological conditions and have demonstrated other positive benefits in MS.40-43 Physical activity not only helps in weight management but also enhances neuroplasticity, contributing to improved motor and respiratory function. Such interventions are particularly crucial in mitigating the effects of respiratory muscle weakness and improving the overall quality of life for patients.40
Additional studies are also needed to explore the impact of common MS comorbidities that may compound respiratory dysfunction. For example, none of the included studies directly explored the impact of obesity, which affects between 40% and 60% of people with MS. Obesity may exacerbate respiratory disorders through both mechanical and inflammatory mechanisms.44,45 Obesity leads to decreased chest wall and lung compliance, increased work of breathing, and reduced lung capacities, which may, in turn, raise the possibility of respiratory disorders such as obstructive sleep apnea, obesity hypoventilation syndrome, and respiratory failure, especially if combined with MS-related symptoms such as muscle weakness and fatigue.46,47 Future research should investigate how obesity, body fat distribution, and nutritional status affect respiratory outcomes as well as whether weight loss programs can be successful and effective rehabilitation strategies. In addition to obesity, other respiratory-related comorbidities such as obstructive sleep apnea, asthma, chronic obstructive pulmonary disease, smoking history, and occupational exposures were not systematically examined in the included studies. These factors may independently affect pulmonary function and could confound respiratory outcomes in people with MS. Future research should account for these comorbid conditions to better isolate MS-specific respiratory impairment.
Another important but underexplored factor is the potential influence of disease-modifying therapies and immunosuppressive treatments on respiratory outcomes in people with MS. Many MS treatments alter immune function and may increase susceptibility to infections, including respiratory infections. Most studies included in this review did not account for treatment type or duration when examining respiratory function. Future research should consider treatment status as a potential confounding factor when evaluating respiratory health in this population.
The findings of this review also highlight the complex interaction between respiratory dysfunction and psychological and cognitive factors. Sleep disturbances, common in MS, may impair ventilatory control and contribute to daytime fatigue, further weakening respiratory muscle performance. Mood disorders such as anxiety and depression may alter breathing patterns and reduce engagement in rehabilitation efforts. Cognitive impairment may additionally affect adherence to respiratory exercises and self-management strategies. These interconnected factors suggest that respiratory dysfunction in MS is not solely mechanical but multifactorial, underscoring the importance of multidisciplinary and integrated care approaches.
Limitations
The search strategy was limited to studies published in English, 3 databases, and a specific time, which may have excluded important studies published in other languages or other databases. The results were difficult to assess because of significant variations in study design, particularly differences in defining MS stages, severity levels, and intervention characteristics (including type, duration, and intensity). The generalizability and reliability of the findings may have been affected by methodological limitations, including a lack of a control group in some studies, small sample sizes, and variability in study design, which may introduce risk of bias. In addition, many of the included studies were cross-sectional or had relatively short follow-up periods. This limits the ability to conclude long-term respiratory decline and the sustained effects of interventions in people with MS. Future research should incorporate longer longitudinal designs to better understand the progression of respiratory dysfunction over time.
Conclusions
Current literature suggests promising effects for interventions such as breathing exercises, inspiratory and expiratory muscle training, Pilates, and PNF; however, there are some notable gaps in the literature.
In particular, studies are generally small and highly variable in measures and methods. Given the variability in study design and outcome measures, future research should prioritize more consistent respiratory end points in people with MS. Standard measures should include spirometry (FVC, FEV1, PEF) and respiratory muscle strength (MIP and MEP), along with disability status (eg, EDSS) and clinically meaningful outcomes such as respiratory infections and functional performance. Patient-reported outcomes, including fatigue, sleep, mood, and quality of life, should also be considered. Greater consistency in these measures would improve comparability across studies and strengthen the evidence base. There is also limited research examining the role of complex comorbidities such as obesity and related metabolic conditions in contributing to respiratory health in people with MS. To address these gaps, future studies need to (1) include well-defined control/comparison groups, (2) develop common data elements or standard reporting procedures, and (3) examine the relationship between obesity and compromised respiratory function in MS and establish the effects of weight loss interventions on respiratory health. Interventional and longitudinal studies are needed for a better understanding of correlates and long-term effects. Future studies should focus on well-designed RCTs that examine aerobic, resistance, and respiratory muscle training across different levels of MS disability. Understanding whether exercise benefits vary by disease stage or phenotype may help clinicians better tailor rehabilitation strategies to individual patient needs. This type of evidence can form the basis for the development of specific rehabilitation intervention strategies and the further investigation of respiratory complications in MS. Finally, evaluation of these elements can aid in the optimization of respiratory dysfunction and improve general health outcomes for individuals with MS.
