Efficacy of Rehabilitation Interventions in Children with Spinal Muscular Atrophy to Improve Their Motor Function: Systematic Review

INTRODUCTION:

Spinal muscular atrophy (SMA) is a rare autosomal recessive neuromuscular disease 1,2. It is a progressive disease characterized by motor neuron degeneration, muscle atrophy and reduced muscle control 1,3. SMA is caused by deficiency of the survival of motor neuron (SMN) protein due to homozygous deletions and/or mutations of the SMN1 gene 1,2. SMN2 is a similar gene, which produce functional SMN protein at insufficient levels to fully compensate for the deficiency of SMN1 gene 1,4.

The number of protein copies produced by SMN2 gene is inversely correlated with the disease severity, it can produce a milder phenotype as the number of copies increases 3. Nonetheless, due to other genetic disease modifiers, this correlation is not absolute. SMA are classified into five phenotypes that is vary in onset age, life span, motor milestones, which are: SMA0, SMA I, SMA II, SMA III, and SMA IV 4.

SMA0 is characterized by early prenatal onset, severe hypotonia, and weakness. Affected fetuses often exhibit reduced movements, and infants born with SMA0 may experience respiratory distress, areflexia, facial diplegia, atrial septal defects, and joint contractures. Without supportive care, life expectancy is typically less than six months 5,6.

SMA I, also known as Werdnig-Hoffmann disease, typically presents before six months of age with severe hypotonia and poor head control. Despite normal cognitive development, affected individuals exhibit severe muscle weakness, difficulty swallowing and speaking, and respiratory issues. Respiratory failure usually occurs before age two 7,8.

SMA II typically begins between 6 and 12 months, with gradual motor milestone development until age five. Affected individuals have hypotonia, muscle weakness (more pronounced in the lower body), and may develop joint contractures, scoliosis, and respiratory issues 9. While they can typically sit independently, walking is not possible. Cognitive function remains normal, but motor skills decline over time, with loss of independent sitting by the mid-teens 10,11.

SMA III (Kugelberg-Welander disease) begins after 18 months, primarily affecting lower limb muscles. While individuals can initially walk independently, weakness gradually worsens, leading to difficulty walking and eventual wheelchair use 12. Unlike other SMA types, scoliosis and respiratory problems are less common. Furthermore, cognitive function remains normal 13,14. However, The age at which SMA III begins affects when walking is lost. People with an onset before age three typically lose the ability to walk within their twenties 13. If symptoms start between three and twelve years old, they usually lose the ability to walk in their forties 13.

SMA IV is the rarest form of SMA, affecting less than 5% of patients. It is characterized by mild symptoms with an adult onset, typically between the ages of 30 and 40. Individuals with SMA Type IV can walk independently. Unique features include weakness in the deltoid, triceps, and quadriceps muscles, absent knee-jerk reflexes (patellar areflexia), reduced reflexes in the arms and ankles, and potential hand tremors 7,13,14.

Globally, SMA is estimated to have an incidence of approximately 1 in 10,000 newborns. While many people carry the SMA gene, the condition is relatively uncommon, with 1 to 2 cases per 100,000 individuals. The occurrence of SMA varies globally due to factors like population size and genetics 15–17. Notably, in Saudi Arabia, the prevalence of SMA is calculated to be 1 in 6,000 live births, while the estimated incidence is approximately 32 cases per 100,000 live births. This is largely due to the high rate of consanguineous marriages in the region, which increases the chances of children inheriting the SMA gene 18.

SMA treatment options have significantly advanced. Gene-based therapies, such as Zolgensma, Spinraza, and Evrysdi, target the underlying genetic cause of the disease. While there's no cure yet, these treatments, combined with supportive care including physical, occupational, and speech therapy, respiratory support, and assistive devices, can significantly improve quality of life for individuals with SMA 19.

Rehabilitation for SMA focuses on improving physical abilities, managing symptoms, and enhancing quality of life. Tailored treatment plans are developed based on thorough patient assessments. These assessments often include the Children’s Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) 20 and Hammersmith Functional Motor Scale-Expanded (HFMSE) 21 to evaluate gross motor skills, the Six-Minute Walk Test (6MWT) for endurance 22, and the Revised Upper Limb Module (RULM) for fine motor function 23.

Rehabilitation intervention emphasizes stretching, strengthening, balance, and aerobic exercises to maintain function and prevent deformities 24,25. Assistive devices and proper positioning are essential, especially for those unable to sit independently 26. While head-pods and cervical braces might be considered, their use should be individualized 25. The effectiveness of these interventions varies based on SMA severity 24.

Current rehabilitation approaches for SMA involve a multidisciplinary team and typically include physical therapy, occupational therapy, respiratory therapy, and the use of assistive devices 25. Physical therapy focuses on maintaining muscle strength and preventing contractures through targeted exercises and stretching 26. Occupational therapy aims to enhance independence in daily activities by providing adaptive equipment and strategies 27. Respiratory therapy is crucial for managing respiratory complications, a leading causes of morbidity in SMA 28. However, current rehabilitation practices are often characterized by a lack of standardized protocols, leading to significant variability in interventions delivery 29. Furthermore, the evidence base supporting the effectiveness of specific rehabilitation strategies for motor function improvement remains limited 29.

Despite advances in pharmacological treatments, rehabilitation remains a key component in SMA management. However, there is no standardized approach to optimize motor function rehabilitation, and existing studies show high variability in intervention protocols and outcome measures^{25, 26}. Previous reviews have primarily focused on disease-modifying therapies, while the role of rehabilitation in motor function preservation and enhancement remains underexplored^{35, 37}. However, existing research on SMA rehabilitation is often fragmented, with studies employing diverse interventions, outcome measures, and methodologies. Previous reviews have largely focused on disease-modifying therapies, leaving a gap in our understanding of the most effective rehabilitation approaches for motor function improvement.

This systematic review aims to examine the effectiveness of specific rehabilitation interventions in improving motor function including muscle strength, lung function, and range of motion for individuals with SMA. By identifying evidence-based practices and tailoring rehabilitation programs to individual needs, this research seeks to contribute to improved care and quality of life for individuals living with SMA.

METHOD:

This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines 27.

1. Search Strategy:

A comprehensive electronic search was conducted across four major databases: CINAHL, PubMed, ScienceDirect, and PEDro, convering studies published from2014 to 2024. This search focused on rehabilitation interventions for SMA. To ensure a thorough capture of relevant literature, particularly those addressing motor function improvement, the search strategy utilized a combination of Medical Subject Headings (MeSH) terms and a broad range of keywords. These keywords include “Spinal Muscular Atrophy”, “SMA”, “Physical Therapy”, Rehabilitation”, “Physiotherapy”, “Intervention”, “Motor Function”, “Motor Skills”, Functional Mobility”, Neuromuscular Function”, and “Motor Development”. Boolean operators (AND, OR) were employed to refine the search and combine terms effectively. The specific searc strings used for each database are detailed in (Table 1), which has been revised to reflect the inclusion of motor function-related terms.

1. Inclusion Criteria:

The included studies were selected according to the following inclusion criteria: (1) children diagnosed with SMA with different phenotypes; (2) studies that were published from 2014 to 2024; to focus in recent technologies; and (3) studies measured the functional outcomes whether upper limbs functions or lower limbs functions.

1. Exclusion Criteria:

Only records that written in English were included, any other languages were excluded. Further, animal studies, assessment or diagnostic studies, studies that focused in other outcomes such as cost-effectiveness of the intervention, and studies that published prior to 2014 were also excluded.

1. Data Extraction:

The extracted data from the selected studies include the citation details, study design, participants characteristics (Number of participants, Age, Gender, and Condition), the concluded outcomes, and the parameters and the duration of the intervention, and the outcome measures used in the selected studies.

1. Quality Assessment:

Two independent assessors evaluated the selected studies using different scales based on the study design. Randomized Controlled Trials (RCTs) were assessed using the PEDro scale, while other study designs were evaluated with the National Heart, Lung, and Blood Institute's quality assessment tool.

The PEDro scale is a tool used to assess the quality of clinical trials, especially in physiotherapy research. It evaluates factors like randomization, blinding, and statistical reporting. A higher score indicates a higher-quality study, making it easier to identify reliable evidence. The scale has been shown to be reliable and valid for assessing research quality 28,29.

The National Heart, Lungs, and Blood Institute (NHLBI) provided a variety of quality assessment tools for different study designs. The tools were developed to screen for potential problems in the implementation or use of certain study designs. NHLBI offers the tools through the website (https://www.nhlbi.nih.gov/health-topics/study-quality-assessment-tools).

RESULTS:

1. Study Selection:

The initial literature search identified 295 articles. After removing duplicates, 265 articles underwent title and abstract screening. Following a full-text assessment of 11 shortlisted articles, we excluded 6 studies due to irrelevant outcomes, unsuitable study designs, or not being original research. Ultimately, 5 studies 30–34 were included for qualitative analysis (Figure 1).

1. Study characteristics:

A total of 109 participants (91 males and 18 females) were included across 5 studies. Gross motor function was assessed using the HFMSE in studies 32, 33, and 34, while fine motor function was assessed using the RULM in studies 32 and 34. Lung function was assessed using Forced Vital Capacity (FVC) and range of motion were assessed in studies 32 and 34. Functional status and endurance were assessed using the Adult Myopathy Assessment (AMAT) in study 33. Study 30 compared conventional physical therapy and medication on gross motor function using CHOP-INTEND and Hammersmith Infant Neurological Examination (HINE-2). Muscle power was measured using Quantitative Muscle Assessment (QMA) in study 31 (Table 2).

1. Quality assessment:

To assess the methodological quality of the included studies, the PEDro scale was used for RCTs, and the NHLBI quality assessment tool was used for case studies. Overall, the included studies had a moderate risk of bias. Most studies had a low risk of selection bias but a high risk of performance bias due to the lack of blinding. Additionally, several studies had a high risk of detection bias, as outcome assessment was not blinded.

While there limitations may have influenced the results of the review, the consistent findings across multiple studies suggest that the interventions may have a positive effect. The PEDro scale indicated that studies 33 and 30 were of fair quality. Common reasons for this rating included issues with concealed allocation, blinding of subjects, therapists, and assessors, and the use of intention-to-treat analysis (Table 3).

In contrast, the NHLBI assessment yielded different results. Studies 32 and 34 were rated as good quality, while study 31 was rated as fair quality. The common reasons for the identified risks of bias were inadequate follow-up duration and lack of comparability between study subjects (Table 4).

A discrepancy was observed between the two tools. While the PEDro scale rated studies 30 and 33 as “fair quality”, the NHLBI tool rated studies 32 and 34 as “good quality” and study 31 as “fair quality” (Table 3 & 4). These differences primarily arose due to the following factors; Blinding Differences The PEDro scale places strong emphasis on blinding of participants, therapists, and assessors, which was lacking in most included studies. In contrast, the NHLBI tool does not penalize studies as heavily for blinding issues, particularly in observational and case studies. Follow-up Duration, The NHLBI tool penalized studies with short follow-up periods, contributing to the lower rating of study 31. Study Design Sensitivity, The PEDro scale is specifically designed for RCTs, while the NHLBI tool accommodates different study designs, leading to different ratings for the same studies. Despite these discrepancies, the overall risk of bias across studies remained moderate, with consistent findings across multiple studies supporting the effectiveness of rehabilitation interventions. The methodological limitations, particularly related to blinding and follow-up duration, should be considered when interpreting the results. Future research should address these issues by incorporating better blinding strategies and longer follow-up periods to enhance study quality.

1. Data analysis:

A meta-analysis was considered but deemed not feasible due to substantial heterogeneity across studies in terms of study design, interventions, outcome measures, and population characteristics. The included studies utilized different rehabilitation approaches, including physical therapy, transcutaneous spinal cord stimulation, and multidisciplinary interventions, making direct comparisons challenging. To further quantify this heterogeneity, we attempted to calculate the I² statistic, which assesses statistical heterogeneity across studies. However, due to the small number of included studies (n = 5) and variability in study designs (RCTs vs. case studies), pooling the data was not methodologically appropriate. Differences in outcome measures, such as HFMSE, RULM, FVC, CHOP INTEND, and AMAT, also contributed to the inability to generate a meaningful combined effect estimate. Given these limitations, we adopted a narrative synthesis approach, summarizing the findings qualitatively to provide a comprehensive interpretation of the available evidence. Future research with standardized intervention protocols and outcome measures will be necessary to facilitate meta-analysis and strengthen the evidence base.

DISCUSSION:

This systematic review aimed to evaluate the effectiveness of rehabilitation interventions in individuals with SMA. Five studies were included, investigating a variety of interventions across different SMA phenotypes and age groups. The findings suggest that rehabilitation interventions may have positive effects on various functional outcomes in SMA patients, including gross motor function, fine motor function, muscle strength, lung function, and range of motion. However, the overall quality of evidence was moderate due to limitations in the included studies.

Several studies reported improvements in gross motor function, as measured by HFMSE, indicating that rehabilitation can enhance mobility and daily activities in individuals with SMA. Notably, studies 32 and 34 demonstrated tSCS combined physical therapy resulted in significant improvement in HFMSE scores. This suggests that tSCS may potentiate the effects of physical therapy, leading to enhanced motor function. Clinically, these improvements could translate to patients being able to perform activities of daily living with greater ease, such as transferring, dressing, or ambulating 37. Additionally, these improvements were observed across different interventions, including physical therapy, occupational therapy, and assistive technology, suggesting that multidisciplinary approach may be beneficial 35.

Furthermore, studies employing Quantitative Muscle Assessment (QMA) and Non-Invasive Electrical Spinal Cord Stimulation (NES) observed increased muscle strength. Specifically, study 31 reported improvements in muscle power following a combined approach of Nusinersen and physical therapy, as measured by QMA. From a clinical standpoint, increased muscle strength can lead to improved endurance, reduced fatigue, and enhanced ability to perform functional tasks, suggesting potential benefits for muscle function and endurance 38. This is particularly important for individuals with SMA, as muscle weakness is a hallmark of the disease 1.

32 and 34 reported increased FVC after a combined intervention of NES and physical therapy, indicating potential improvements in respiratory function. This finding is significant, as respiratory complications are a major cause of morbidity and mortality in individuals with SMA 36. Clinically, improvements in FVC suggest enhanced respiratory muscle function, potentially reducing the risk of respiratory failure and improving overall quality of life 40.

A decrease in muscle contractures was observed following NES intervention in both studies, highlighting the potential of rehabilitation to improve joint flexibility and range of motion. Clinically, reducing muscle contractures can prevent or delay the onset of secondary complications such as scoliosis, improve posture, and enhance comfort and mobility 37.

It is important to note that the impact of rehabilitation may vary depending on the specific SMA type and disease severity. Individuals with milder forms of SMA may experience greater benefits from certain interventions compared to those with more severe forms 38. For example, individuals with SMA type III may benefit more from strengthening exercises, while those with SMA type 1 may require a greater focus on respiratory support and positioning strategies. Furthermore, the role of caregiver involvement and support cannot be underestimated. Family members and caregivers play a crucial role in implementing and supporting rehabilitation program at home 39. Providing education and training to caregivers on appropriate exercise techniques, positioning strategies, and the use of assistive devices can significantly enhance the effectiveness of rehabilitation 25.

This systematic review has several limitations that should be considered when interpreting the findings. While the small sample sizes and lack of blinding in many studies were acknowledged, additional potential confounders may have influenced the results, variability in intervention protocols, the included studies employed different rehabilitation approaches, frequencies, and durations, making direct comparisons challenging. For example, studies 32, 33, and 34 used tSCS combined with physiotherapy, while studies30,33implemented functional and strengthening exercises. These variations may have contributed to differences in reported outcomes. Heterogeneity in patient characteristics, participants varied in SMA type, disease severity, and age range, which could affect their response to rehabilitation. Studies with older participants. 33 reported less pronounced improvements, possibly due to disease progression. Differences in outcome measures while some studies used HFMSE and RULM to assess motor function, others relied on 6MWT, AMAT, or CHOP-INTEND, limiting cross-study comparability.

These findings have important clinical implications for the management of children with SMA. The results suggest that incorporating a comprehensive rehabilitation program, which may include physiotherapy, occupational therapy, and assistive technology, into the overall treatment plan for children with SMA can be beneficial in improving their physical function and quality of life 35. However, further research is needed to address the limitations of existing studies and to optimize rehabilitation strategies for individuals with SMA.

It is crucial to emphasize the importance of individualized rehabilitation plans. Given the variability in disease severity and individual needs, a personalized approach is essential for optimizing outcomes. This may involve incorporating patient preferences, caregiver involvement, and regular reassessment of treatment goals 26.

Furthermore, this review highlights the need for ongoing research to address the limitations of existing studies and to optimize rehabilitation strategies for individuals with SMA. Further research should consider employing larger sample sizes and robust methodologies, including randomization and blinding, in well-designed RCTs. Utilizing standardized protocols for rehabilitation interventions and outcome measures would facilitate comparisons across studies. Studies with longer follow-up periods are needed to assess the sustainability of rehabilitation benefits. Tailoring rehabilitation programs to specific SMA phenotypes and age groups may optimize outcomes. Finally, evaluating the cost-effectiveness of different rehabilitation approaches can inform healthcare decision-making.

CONCLUSION:

In conclusion, this systematic review suggests that rehabilitation interventions have the potential to improve various functional outcomes in individuals with SMA. However, the quality of evidence is moderate due to limitations in the included studies. Further research is necessary to strengthen the evidence base and optimize rehabilitation strategies for this population. By incorporating the recommendations for future research, healthcare professionals can develop more effective individualized rehabilitation programs to improve the quality of life for individuals with SMA.

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