Differences in the Impact of Intensive Rehabilitation on Hereditary Ataxias and the Cerebellar Subtype of Multiple System Atrophy

doi:10.21203/rs.3.rs-4823055/v1

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Differences in the Impact of Intensive Rehabilitation on Hereditary Ataxias and the Cerebellar Subtype of Multiple System Atrophy

https://doi.org/10.21203/rs.3.rs-4823055/v1

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Background

Multiple system atrophy-cerebellar type (MSA-C) exhibits faster disease progression than hereditary spinocerebellar degeneration (hSCD). This study aimed to investigate the differences in the treatment effects and sustainability of intensive rehabilitation between patients with hSCD and those with MSA-C.

Methods

Forty-nine patients (hSCD = 30, MSA-C = 19) underwent a 2- or 4-week intensive rehabilitation program. Balance function was assessed using the scale for the assessment and rating of ataxia (SARA) and the balance evaluation systems test (BESTest) at pre-intervention, post-intervention, and 6-month follow-ups.

Results

Both groups showed improvements in SARA and BESTest scores after the intervention. In the hSCD group, the SARA scores remained similar to baseline at follow-up, indicating sustained benefits. The MSA-C group showed some deterioration in SARA scores compared with baseline but maintained improvements on the BESTest, demonstrating partial sustainability. Differences, mainly in sustainability, were observed between the hSCD and MSA-C groups. This may be due to varying rates of symptom progression.

Conclusions

The findings of this study are significant when considering the frequency of follow-ups based on disease type.

Spinocerebellar Degenerations

Postural Balance

Rehabilitation

Multiple System Atrophy

Spinocerebellar degeneration (SCD) is a disorder primarily characterized by progressive cerebellar degeneration, resulting in impairments in coordination and balance [1]. SCD can be classified into hereditary (hSCD) and sporadic forms [2]. Among the sporadic forms, multiple system atrophy-cerebellar type (MSA-C) is noteworthy for its rapid progression compared with the hereditary forms of SCD (hSCD) [3]. Recent studies have indicated that patients with MSA-C experience faster disease progression and shorter survival. For example, the 10-year survival rate for patients with spinocerebellar ataxia type 6 (SCA6), a type of hSCD with relatively slow progression, exceeds 80%. By contrast, the average lifespan of patients with MSA-C post-diagnosis is approximately 10 years [4, 5].

Given the distinct differences in disease progression between MSA-C and hSCD, these variations may influence the effectiveness and sustainability of rehabilitation interventions. Rehabilitation programs, including vibration stimulation, aerobic exercises, and Tai Chi, have been widely studied and implemented as therapeutic approaches for patients with SCD [6, 7]. Intensive rehabilitation programs spanning two to four weeks have demonstrated significant benefits in several studies [8–10]. However, further research is needed to compare the immediate and long-term effects of these interventions in patients with hSCD and MSA-C.

Considering the progressive nature of SCD, the long-term sustainability of rehabilitation programs is clinically important. Previous studies have reported mixed outcomes regarding the durability of rehabilitation effects across various SCD types. For example, Miyai et al. found that patients with SCA6 and idiopathic cerebellar ataxia who underwent intensive rehabilitation returned to baseline levels of function within six months [9]. Conversely, other studies have shown that continued rehabilitation can sustain benefits over an extended period, especially in certain types of hSCD, such as SCA7 and SCA2 [8, 11].

Despite the documented benefits of rehabilitation, comprehensive studies that directly compare rehabilitation outcomes between patients with hSCD and those with MSA-C remain lacking. This comparison is crucial for developing tailored intervention strategies and determining the appropriate follow-up frequency for each disease subtype.

Therefore, this study aimed to investigate the effects of intensive rehabilitation programs and their sustainability on balance function in patients with hSCD and MSA-C. Specifically, we aimed to assess immediate and six-month post-intervention outcomes using the scale for the assessment and rating of ataxia (SARA) and the balance evaluation systems test (BESTest). Understanding these differences will provide valuable insights for optimizing rehabilitation protocols and follow-up schedules tailored to the specific needs of patients with hSCD and MSA-C.

Participants

This retrospective cohort study analyzed electronic medical records of patients with SCD who participated in an intensive rehabilitation program at the National Center of Neurology and Psychiatry (Tokyo, Japan) from June 2015 to April 2021. The program at the center was limited to those who could walk independently, although the use of assistive devices was permitted. Therefore, participants could live independently or with minimal assistance at home. The study adhered to the principles of the Declaration of Helsinki and received approval from the Ethics Committee of the National Center of Neurology and Psychiatry (Approval No. A2018-104). Volunteers were given verbal explanations about the purpose, methods, safety considerations, and risks of the experiment and provided informed consent in advance.

Rehabilitation Training Procedure

The subjects underwent either a 4-week or a 2-week intensive rehabilitation program, conducted five times a week. Each daily schedule comprised one hour of individual training with a physical therapist, one hour with an occupational therapist or speech therapist, and one hour of self-balance training. The personal training with the physical therapist focused on movement balance and muscle strengthening exercises performed on a mat, as well as standing and walking without special equipment. This component adhered to the rehabilitation program of the Research Committee for Ataxia Disease (research team under the Ministry of Health, Labour and Welfare in Japan; http://ataxia.umin.ne.jp/rehabilitation/). Occupational therapy sessions included manual dexterity training, while speech therapy sessions focused on improving articulation for patients with speech disorders. The self-balance training was mainly conducted on a mat and featured exercises that could be safely performed within the context of the individual physical therapy sessions, including kneeling and crawling.

Outcomes

Outcomes were assessed at three time points: baseline (pre-intervention), end of the intervention (post-intervention), and six-month follow-up. The primary outcome measure was the SARA, which quantifies the severity of cerebellar ataxia symptoms on a scale ranging from 0 to 40, with higher scores indicating more severe symptoms [12]. Based on previous research [13], the minimal detectable change (MDC) for SARA was established at 1.0 points.

Balance impairment in SCD is multifactorial [14, 15]. Therefore, the BESTest was used as a secondary outcome measure to comprehensively assess balance function. The BESTest evaluates balance function across six systems, with a total score ranging from 0 to 108, where higher scores represent better balance capabilities. The six subcategories assessed are biomechanical constraints, stability limits/verticality, anticipatory postural adjustments, postural responses, sensory orientation, and stability in gait. Each subcategory independently evaluates critical aspects of balance function [16]. The reliability and validity of the BESTest in individuals with SCD have been established [17], and the MDC for the BESTest was calculated to be 8.7 points.

To minimize evaluator bias, the individuals administering the training were different from those conducting the assessments.

Statistics

All statistical analyses were performed using R (version 4.0.2)[18]. We initially examined the differences in demographic data between the hSCD and MSA-C groups using Pearson's chi-squared test for categorical variables and Welch's t-test for continuous variables. Next, a three-way (2 × 2 × 3) repeated-measures analysis of variance (ANOVA) was performed to observe the main and interaction effects of two between-subject factors (diagnosis: hSCD vs. MSA-C, and intervention term: 2 weeks vs. 4 weeks) and one within-subject factor (time: pre vs. post vs. follow-up). Greenhouse–Geisser epsilon corrections were used as needed to meet the sphericity assumption. Post-hoc comparisons were conducted using Bonferroni significant difference tests, with family-wise alpha levels set at 0.05. The effect size was determined by generalized eta squared (η2G), and percentage changes with 95% confidence intervals were calculated. The Anovakun function in R was used for the analysis. All statistical analyses were performed using complete case analysis without missing data imputation. Statistical significance was set at p < 0.05.

Total Patient Population

During the designated study period, 160 patients were enrolled. For individuals who participated in the program multiple times, only data from their initial participation were considered. At this stage, data from 74 participants remained viable for further evaluation. Of these, 24 patients with complete pre- and post-intervention outcome data and 6-month follow-up information were included in the study. One patient was excluded due to sustaining a fracture during participation in the program.

Consequently, the final cohort for analysis comprised 49 patients, as shown in Figure 1. This group included 30 patients with hSCD, specifically: 15 with SCA6, 10 with SCA31, and 5 with SCA3. Additionally, 19 patients were diagnosed with MSA-C. The baseline characteristics of both groups are detailed in Table 1, which shows no significant differences in sex, age, baseline SARA scores, or baseline BESTest scores.

Differences in SARA Changes between hSCD and MSA-C

The analysis indicated that while SARA scores improved due to the intervention, the extent of improvement varied between disease types (hSCD or MSA-C). A three-way repeated ANOVA revealed a significant main effect of time (F(1, 89) = 15.012, p = 0.001, η²G = 0.039) (Table 2). This effect was moderated by a significant interaction between diagnosis and time (F(1, 89) = 7.266, p = 0.001, η²G = 0.019). Subsequent simple main effect tests showed a significant effect of disease type at the six-month follow-up (F(1, 45) = 12.193, p = 0.001, η²G = 0.213), indicating differences in the temporal changes in SARA scores between the hSCD and MSA-C groups.

For the hSCD group, post-hoc tests revealed a mean score improvement of 1.02 points after the intervention compared with pre-intervention (Bonferroni-corrected p-value = 0.024). However, at the six-month follow-up, the mean score declined by 0.97 points from the post-intervention score (Bonferroni-corrected p-value = 0.028), resulting in a score that was essentially back to baseline levels, with a mean difference of only 0.04 points compared with pre-intervention (Bonferroni-corrected p-value = 0.921).

By contrast, the MSA-C group demonstrated a minor mean improvement of 0.53 points post-intervention compared with pre-intervention (Bonferroni-corrected p-value = 0.498). However, at the six-month follow-up, their scores had declined by an average of 2.77 points from the post-intervention scores (Bonferroni-corrected p-value = 0.001) and by 3.3 points compared with the pre-intervention scores (Bonferroni-corrected p-value = 0.001).

Differences in BESTest Changes between hSCD and MSA-C

The analysis revealed that the intervention had different effects on the BESTest scores between the hSCD and MSA-C groups. A three-way repeated measures ANOVA showed a significant main effect of time (F(1, 71) = 33.982, p = 0.001, η²G = 0.0746) (Table 2). This effect was moderated by a significant interaction between diagnosis and time (F(1, 71) = 5.484, p = 0.01, η²G = 0.012). Additionally, a significant simple main effect of disease type was found at the six-month follow-up (F(1, 45) = 4.549, p = 0.038, η²G = 0.091), indicating differences in the temporal changes of BESTest scores between the hSCD and MSA-C groups.

Post-hoc tests for the hSCD group demonstrated a mean improvement of 9.17 points in BESTest scores after the intervention compared with pre-intervention (Bonferroni-corrected p-value = 0.001). However, at the six-month follow-up, the scores declined by an average of 6.74 points from the post-intervention scores (Bonferroni-corrected p-value = 0.001). Despite this decline, the scores at the six-month follow-up remained an average of 2.43 points higher than the pre-intervention scores (Bonferroni-corrected p-value = 0.05).

By contrast, the MSA-C group exhibited a mean improvement of 7.56 points in BESTest scores after the intervention compared with pre-intervention (Bonferroni-corrected p-value = 0.001). However, at the six-month follow-up, the scores deteriorated by an average of 13.26 points from the post-intervention scores (Bonferroni-corrected p-value = 0.001) and by 5.71 points compared with pre-intervention scores, although this latter difference was not statistically significant (Bonferroni-corrected p-value = 0.114).

Subcategory-specific Intervention Outcomes in the BESTest

The effect was observed in the “biomechanical constraints” diagnosis (F(1 45) = 11.592, p = 0.001, η² = 0.134). The hSCD group exhibited higher mean scores at follow-up than the MSA-C group. In the “stability limits/verticality” category, a significant time effect was detected (F(1 71) = 6.298, p = 0.005, η² = 0.06), showing a decline in scores over six months, although they remained comparable to baseline levels. For “anticipatory postural adjustments,” significant effects were found for both diagnosis (F(1 45) = 6.524, p = 0.014, η² = 0.106) and time (F(1 90) = 10.796, p = 0.001, η² = 0.04), indicating improvements post-intervention but a decline at follow-up, with scores returning to baseline levels. Significant time effects were also observed in “postural responses,” “sensory orientation,” and “stability in gait,” with improvements noted post-intervention that partially regressed over six months but generally remained similar to baseline.

This study is the first to investigate the effects of intensive rehabilitation on hSCD and MSA-C using the SARA and BESTest tests, which are commonly employed outcome measures in previous research. The results reveal that the effects of rehabilitation became distinctly apparent during the follow-up period. A detailed discussion of these findings is presented below.

Differential Intervention Outcomes in hSCD and MSA-C Groups

The hSCD group demonstrated an improvement of 1.02 points in SARA scores after the intervention (Fig. 2), while the MSA-C group showed a smaller improvement of 0.53 points. Only the hSCD group showed a statistically significant improvement. Additionally, the change in the hSCD group exceeded the MDC. Regarding the BESTest results, the hSCD group improved by 9.17 points, compared with a 7.56-point improvement in the MSA-C group. Both groups showed statistically significant improvements; however, only the hSCD group's change exceeded the MDC. These results indicate that intensive rehabilitation significantly improved ataxia symptoms and balance function in the hSCD group.

The MSA-C group did not show significant improvement in SARA scores or changes beyond the MDC in the BESTest. These results suggest potential differences in the learning effects of rehabilitation interventions for cerebellar ataxia symptoms between patients with hSCD and those with MSA-C. A study investigating the relationship between motor learning effects using upper limb reaching tasks and changes in brain gray matter volume in hSCD found an increase in premotor cortex volume after training [19]. This change is considered to be compensatory remodeling associated with dysfunction in the cerebello-cerebral motor system. By contrast, a study using transcranial magnetic stimulation suggested impaired plasticity in the primary motor cortex in MSA [20]. This indicates that patients with MSA may have reduced compensatory brain function compared with patients with hSCD.

The MSA-C group showed significant improvement in BESTest scores, although not reaching MDC, highlighting the test's comprehensive evaluation of balance function beyond the cerebellar ataxia symptoms assessed by SARA [21]. This study investigated intervention effects across BESTest subdomains and observed improvements in all areas except “biomechanical constraints” (Fig. 3). These findings suggest that intensive rehabilitation in patients with MSA-C and hSCD may enhance balance function through factors beyond cerebellar ataxia, including postural stability and vestibular function [14, 22, 23]. The sensitivity of the BESTest to these changes underscores its potential value in assessing rehabilitation outcomes for these disorders, particularly in capturing improvements in extracerebellar symptoms that contribute to overall balance function.

Divergent Long-term Effects in SCD and MSA-C Groups at 6-month Follow-up

The results of this study clearly demonstrate differences in outcome changes at the 6-month follow-up between the hSCD and MSA-C groups. For individuals with hSCD, the SARA score at the 6-month follow-up remained similar to or better than the baseline. By contrast, those with MSA-C exhibited apparent deterioration compared with baseline (Fig. 2). This difference can be attributed to the varying speeds of disease progression; MSA-C progresses much more rapidly than other SCDs.

The annual increase in SARA scores was reported to be 1.5 points for SCA3, 0.8 points for SCA6, and 0.8 points for SCA31, a pure cerebellar SCD unique to Japan [1, 24, 25]. In comparison, the annual increase in SARA scores for MSA is approximately 4 points [26]. Differences were also observed in the rate of decline in mobility. Previous studies have shown that individuals with MSA typically require a walking aid about three years after onset [27]. Conversely, those with SCA6 generally need a walking aid 11.2 years after onset and a wheelchair after a median of 24 years [28, 29].

Furthermore, individuals with SCA31 typically require a wheelchair 20 years after onset [25]. By contrast, SCA3, a form of hSCD known for its relatively rapid progression, necessitates the use of a walking aid 6 years after onset and a wheelchair 7.1 years after onset [29]. This study showed a clear difference in score changes at the 6-month follow-up between the hSCD and MSA-C groups. The MSA-C group exhibited worse scores at the 6-month follow-up compared with baseline.

However, the BESTest scores for both groups did not show a significant decline at the six-month follow-up compared with baseline despite improvements after the intervention (Fig. 2). The hSCD group scored 2.43 points higher than baseline, whereas the MSA-C group maintained scores comparable with baseline.

SCD is a progressive disease [29], meaning that its natural course may result in declining outcome scores over time [30]. Maintaining baseline scores over a long-term follow-up period can indicate an intervention's efficacy [31]. MSA-C shows a faster rate of cerebellar ataxia symptom deterioration than hSCD [32]. The 6-month follow-up SARA scores in this study reflect these differences in the natural progression of the disease. From these results, it can be inferred that SARA is sensitive to changes in cerebellar ataxia, which is central to SCD pathology. By contrast, BESTest scores were maintained at or above baseline in both groups. Studies using voxel-based morphometry to investigate brain volume changes before and after balance training in patients with SCD have found that the SCD group showed an increase in the volume of compensatory brain regions, such as the supplementary motor area, rather than the cerebellum [33]. The retention of compensatory improvements in balance function beyond cerebellar ataxia symptoms may explain the stable BESTest results.

Limitations

The MSA group experienced a decline in function at the 6-month follow-up compared with baseline. By contrast, the hSCD group maintained their baseline function levels. Maintaining these functions in progressive diseases is essential for effective interventions. Nevertheless, the duration for which these functions can be maintained at baseline levels remains undetermined. This survey is significant for patients with SCD, who require continuous rehabilitation.

In addition, the hSCD group was analyzed as a single entity. However, within hSCD, diseases such as SCA6, which is a pure cerebellar form, may have different prognoses compared with multisystem atrophy types such as SCA3. Further investigations with larger sample sizes are necessary.

The results of this study revealed differences in the effects of intensive rehabilitation programs between the hSCD and MSA-C groups. The hSCD group showed improvements in both ataxia symptoms and balance, whereas the MSA-C group exhibited improvements only in balance function. Notably, these differences were still evident at the 6-month follow-up. The SARA scores in the hSCD group returned to approximately baseline levels, while the MSA-C group showed scores lower than baseline. However, the BESTest scores were maintained at or above baseline in both groups. These differences are likely due to variations in the rate of disease progression and the presence of symptoms other than cerebellar ataxia. This study provides important insights for planning rehabilitation programs to specific disease types.

Acknowledgments

We thank the patients and their families who participated in this study, as well as Taro Kato, Yosuke Ariakea, Kyoko Todoroki, Wakana Oba, and Yu Ogasawara for their contributions to its organization and data collection.

Ethical Approval.This study was approved by the local ethics committee (National Center of Neurology and Psychiatry), Approval No. A2018-104. All participants were briefed on the experiment and signed a consent form before participation.

Competing interests.The authors declare no competing interests.

Authors' contributions.K.B., Y.K., Y.M., T.H., and Y.T. contributed to the conception and design of the study, statistical analysis, drafting the text and preparing the figures. K.B., and Y.K. contributed to acquisition and analysis of data.

Funding. This work was supported by JSPS KAKENHI Grand Number JP21K17485, Intramural Research Grants (Grant Numbers 30-4 and 3-4) for Neurological and Psychiatric Disorders of NCNP.

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Tables 1 to 3 are available in the Supplementary Files section.

No competing interests reported.

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Differences in the Impact of Intensive Rehabilitation on Hereditary Ataxias and the Cerebellar Subtype of Multiple System Atrophy

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Abstract

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Introduction

Patients and Methods

Participants

Rehabilitation Training Procedure

Outcomes

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Results

Discussion

Differential Intervention Outcomes in hSCD and MSA-C Groups

Divergent Long-term Effects in SCD and MSA-C Groups at 6-month Follow-up

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Conclusion

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Supplementary Files

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