Long-term Effects of Annual Intensive Rehabilitation in Patients with Hereditary Pure Cerebellar Ataxia: A 7-year Follow-up Study

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Oba, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6630053/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 04 Sep, 2025 Read the published version in The Cerebellum → Version 1 posted 7 You are reading this latest preprint version Abstract Background : Although intensive rehabilitation has achieved short-term benefits in patients with spinocerebellar degeneration, long-term outcomes of periodic intervention remain unclear, particularly in patients with pure spinocerebellar ataxia types 6 (SCA6) and 31 (SCA31). Objective : To investigate the longitudinal effects of annual intensive rehabilitation on ataxic symptoms and balance function in patients with pure cerebellar type SCA6 and SCA31. Methods : Seven patients with genetically confirmed SCA6 or SCA31 participated in annual 4-week intensive rehabilitation programs. Each program consisted of daily physical therapy, occupational/speech therapy, and self-directed balance training. The participants were assessed annually at pre-intervention, post-intervention, and the 6-month follow-up using the Scale for the Assessment and Rating of Ataxia (SARA) and Balance Evaluation Systems Test (BESTest). Changes were analyzed using linear mixed-effect models. Results : SARA scores were stable, indicating slower progression than the expected natural history, through year 6, with significant improvement observed post-intervention in year 2 (p=0.04). Significant deterioration occurred at year 7 based on pre-intervention scores (p=0.01), suggesting prolonged sustained benefits for coordination. The BESTest scores revealed an earlier decline, with significant deterioration from year 3 (p=0.04), which progressed until year 7 (p<0.01). Conclusions : Annual intensive rehabilitation demonstrated potential long-term benefits on motor functions in patients with pure cerebellar-type ataxia. Coordination function improved, suggesting prolonged slowing of progression. However, maintaining balance function may be more challenging under an annual intervention schedule. More frequent or comprehensive approaches, specifically targeting balance, may be necessary to complement the observed benefits in coordination and address the progressive decline in balance function. Spinocerebellar Ataxia Rehabilitation Postural Balance Ataxia Longitudinal Studies Figures Figure 1 Introduction Spinocerebellar degeneration (SCD) encompasses a group of progressive neurodegenerative disorders that primarily affect the cerebellum [ 1 ]. Although hereditary SCDs comprise multiple subtypes with diverse clinical presentations based on their pathophysiology and causative genes, they share common cerebellar ataxia symptoms, including impaired coordination, intention tremor, dysarthria, and oculomotor abnormalities [ 2 ]. Spinocerebellar ataxia types 6 (SCA6) and 31 (SCA31) are classified as pure cerebellar types, characterized by the predominant degeneration of Purkinje cells in the cerebellar cortex [ 3 – 5 ]. These subtypes typically present with coordination deficits and intention tremor, followed by progressive deterioration of balance function. Pure cerebellar types generally exhibit slower disease progression than other genetic variants, necessitating treatment interventions with that consider long-term efficacy [ 6 ]. Recent studies have suggested that intensive rehabilitation may lead to short-term improvements in coordination deficits and gait ability [ 7 – 9 ]. Intensive and repetitive motor learning programs are considered practical approaches, potentially promoting neuroplasticity at cerebellar and cerebral cortical levels [ 10 – 12 ]. However, studies investigating the long-term effects of continuous intervention over multiple years remain scarce, with no long-term intervention studies specifically targeting patients with SCA6 and SCA31 types [ 13 , 14 ]. Furthermore, understanding which symptoms show sustained improvements following intensive rehabilitation is crucial. Aerobic exercise using ergometers may improve coordination deficits, whereas balance training may be more effective for improving balance function than for coordination deficits [ 15 ]. The cerebellar cortex exhibits functional segregation, with the vermis primarily controlling standing balance and the intermediate portion regulating limb coordination [ 16 , 17 ]. Thus, the effects of long-term interventions should be evaluated from perspectives of coordination and balance function. In this study, we conducted annual intensive rehabilitation sessions for up to 7 years in patients with SCA6 and SCA31. We assessed yearly progression using the Scale for the Assessment and Rating of Ataxia (SARA) for ataxic symptoms and Balance Evaluation Systems Test (BESTest) for balance function [ 18 , 19 ]. Our objective was to elucidate the differential progression patterns of ataxic symptoms versus balance function and to determine the potential role of annual interventions. The findings of this study may contribute to establishing comprehensive long-term rehabilitation strategies for pure cerebellar-type ataxia. Patients and Methods Study design and participants This retrospective cohort study was conducted at the National Center of Neurology and Psychiatry between June 2015 and April 2021. The study included patients with SCD who participated in an intensive rehabilitation program. Eligible participants could walk independently (with or without assistive devices) and preserve community living with minimal or no assistance. We analyzed seven patients with SCA6 and SCA31 who participated in the annual program at least three times. The demographic and clinical characteristics of the participants are presented in Table 1 . The cohort included two patients with SCA6 and five patients with SCA31. The mean age of onset was 53.9 years and at study entry was 66.4 years. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the National Center of Neurology and Psychiatry (approval number A2018-104). All participants provided informed consent after receiving verbal explanation of the purpose, methods, anticipated benefits, and potential risks of the study. Rehabilitation Intervention Program Participants underwent rehabilitation 5 days per week over a 4-week period while hospitalized. The daily program consisted of three 1-hour sessions, consisting of individualized physical therapy, occupational or speech therapy, and self-directed balance training. The physical therapy sessions incorporated balance training and ergometer exercises for lower limb ataxia, following the rehabilitation guidelines established by the Research Committee on Ataxia of the Ministry of Health, Labour and Welfare of Japan ( http://ataxia.umin.ne.jp/rehabilitation/ ). Occupational therapy focused on fine motor skills, whereas speech therapy provided articulation training for patients with dysarthria. Self-directed training sessions included safety-monitored mat exercises, kneeling, and quadruped positions, as prescribed by physical therapists for individual practice. Outcome Measures Assessments were conducted annually at three-time points: pre-intervention (pre), post-intervention (post), and at 6 months post-intervention (follow-up). The primary outcome measure was the SARA scale, with scores ranging from 0 to 40 points and higher scores indicating greater severity of ataxia [ 20 ]. The balance function was evaluated using the BESTest, which was scored from 0 to 108 points, with higher scores indicating better balance function [ 21 ]. To minimize measurement bias, evaluations were conducted by physical therapists who were not involved in the intervention and had received comprehensive training in assessment procedures. Statistical Analysis To analyze the yearly changes in SARA and BESTest scores, we employed a linear mixed-effect model (LMM) using R (v.4.0.2; R Foundation for Statistical Computing, Vienna, Austria) with the lme4 and lmerTest packages [ 22 ]. The dependent variables were changes in SARA and BESTest scores from baseline (year 1), fixed effects for evaluation year and disease type (SCA31 and SCA6), and random effects for individual ID. Analyses were conducted separately for pre-intervention (to investigate yearly changes), for post-intervention (to assess intervention effects), and at the follow-up (to evaluate effect retention) time points. Results Changes in SARA Scores The linear mixed model analysis of SARA scores revealed several significant temporal changes (Fig. 1 and Table 2 ). Analysis of yearly changes from baseline pre-intervention scores showed estimated changes of -1.34 (95% confidence intervals [CI] [-4.24, 1.56], p = 0.37) at year 2 and 0.16 (95% CI [-2.74, 3.06], p = 0.92) at year 3. The 95% CI continued to cross zero through year 6. A significant increase of 5.78 (95% CI [1.54, 10.03], p = 0.01) was observed at year 7. Post-intervention evaluation revealed significant improvement at year 2 (-2.68, 95% CI [-5.01, -0.35], p = 0.04). The estimated change in year 3 was − 0.11; at year 4, it was − 0.02. Although estimates showed an increasing trend from year 5 onward, all 95% CI values crossed zero. At the 6-month follow-up, despite no significant differences at year 2 (0.47, 95% CI [-0.95, 1.89], p = 0.52), significant increases were observed in year 3 (1.90, 95% CI [0.39, 3.41], p = 0.02) and year 4 (2.07, 95% CI [0.55, 3.58], p = 0.02), with evidence of more pronounced deterioration in years 6 to 7. Changes in BESTest Scores The analysis of BESTest scores demonstrated a more pronounced pattern of decline (Fig. 1 and Table 3 ). Pre-intervention BESTest scores showed no significant differences at year 2 (-3.71, 95% CI [-10.24, 2.81], p = 0.28), but a significant decline was observed from year 3 (-7.14, 95% CI [-13.66, -0.62], p = 0.04) onward, reaching − 32.04 (95% CI [-42.30, -21.79], p < 0.01) by year 7. Post-intervention assessments demonstrated a consistent significant decline from year 3 onward, with follow-up evaluations showing significant balance deterioration from year 4 (-8.50, 95% CI [-16.01, -1.00], p = 0.04) onward. Notably, years 5 to 7 showed decreases exceeding 19 points in BESTest scores, suggesting a relatively faster progression of balance dysfunction compared to that observed with the SARA scores. Discussion To the best of our knowledge this study represents the first longitudinal investigation of annual intensive rehabilitation programs in patients with hereditary pure cerebellar ataxia (SCA6 and SCA31) over an extended follow-up period of up to 7 years. The study examined ataxic symptoms (SARA) and balance function (BESTest). The findings indicate that annual intensive rehabilitation can slow the progression of coordination deficits, as indicated by SARA, over several years, providing valuable long-term benefits. However, balance function, assessed by the BESTest, showed a different trajectory, highlighting potential areas for refinement of long-term management strategies. Examining the effects on coordination, assessed using the SARA scale, the primary goal of rehabilitation intervention in patients with SCD is to minimize disease progression [ 23 ]. The natural history of SARA scores in patients with SCA6 and SCA31 typically presents an average annual deterioration of 0.8 points [ 24 , 25 ]. Our results demonstrated that the pre-intervention SARA estimates remained relatively stable compared with the reported natural history through year 6, suggesting that the annual intervention may have contributed to slowing disease progression in terms of coordination. Although year 7 showed a significant increase in the pre-intervention score compared to baseline, this finding may be influenced by the smaller sample size in the final year. Intervention effects, assessed post-intervention, showed significant improvement in year 2 (-2.68, p = 0.04) and remained relatively stable through years 3 and 4 (-0.11 and − 0.02, respectively), with a trend towards deterioration from year 5 onward. However, the 95% CIs for post-intervention change continued to cross zero through year 7, which indicated that the annual rehabilitation program had a lasting, albeit diminishing, effect on coordination deficits even after 7 years. One contributing factor may have been our program's emphasis on aerobic exercise using ergometers, which targets limb coordination and is effective in improving SARA scores [ 15 , 26 ]. These findings underscore the long-term value of periodic intensive rehabilitation for maintaining coordination. The retention effect at the 6-month follow-up showed a decreasing trend over the years, becoming significantly worse than baseline from year 3 onwards. The cerebellum plays a crucial role in motor learning [ 27 , 28 ], and intensive motor programs in patients with SCD induce plastic changes in the cerebellum and in functionally connected cerebral cortical areas [ 11 , 12 ]. However, SCD causes progressive reduction in cerebellar cortical volume over time [ 29 , 30 ], and motor learning capacity reportedly declines with increasing disease duration [ 31 ]. These factors likely contributed to the observed decline in the retention of intervention effects, suggesting that although short-term motor learning remains possible, long-term retention capacity may be compromised by disease progression. This highlights the importance of the annual repetition of the intensive program to reinforce benefits. A key finding of this long-term study is the positive impact of annual intensive rehabilitation on coordination function, as assessed by the SARA scale. Our results suggest that this periodic intervention helped to stabilize SARA scores compared with the expected natural history for up to six years, demonstrating valuable long-term benefits in managing core ataxic symptoms in patients with SCA6 and SCA31. This underscores the potential of structured, repeated rehabilitation efforts to mitigate disease progression in specific functional domains. In contrast, balance function, measured by the BESTest, showed a significant decline starting from years 3 to 4, a trend observed across all assessment time points. This earlier deterioration highlights a divergence in the long-term response between coordination and balance under this specific annual intervention protocol. Several factors may contribute to this difference. Balance control relies on a more complex integration of cerebellar functions with multiple sensory inputs (visual, vestibular, and somatosensory) and motor outputs [ 32 – 37 ], potentially making it more vulnerable to overall disease progression or less amenable to improvement due to the specific exercises emphasized in our program (e.g., ergometer cycling targeting limb coordination, likely benefiting SARA scores more directly [ 15 , 26 ]). Furthermore, the annual 4-week format, albeit effective for coordination for several years, might be insufficient in frequency or duration to fully counteract the decline in the multifaceted demands of balance control over such an extended period. Although the decline in BESTest scores indicates a need to explore complementary strategies specifically targeting balance [ 38 , 39 ], it does not diminish the significant finding regarding SARA scores. The sustained relative stability in coordination function over multiple years provides strong evidence for the clinical utility of annual intensive rehabilitation in the long-term management of pure cerebellar ataxia. This periodic approach appears valuable for preserving limb coordination, a critical aspect of daily function for these patients. Future research, including controlled trials with a larger patient cohort, is warranted to further delineate the effects on different functional domains and investigate optimal rehabilitation frequencies, durations, and components aimed at exploring integrated approaches to better address coordination and the challenging progressive decline in balance. Limitations This study has some limitations. First, as a retrospective study, complete standardization of rehabilitation content and evaluation periods was impossible. Second, the small sample size of seven participants does not allow generalization of results. Additionally, the absence of a control group prevents direct comparison with the natural history of the condition, and the linear mixed model analysis may not fully capture potential non-linear disease progression patterns. Future research should include large-scale prospective studies, multicenter collaborative research, and controlled intervention trials to verify the optimal rehabilitation frequency, duration, and effectiveness of additional approaches for maintaining balance function. Conclusions This 7-year longitudinal study provides significant evidence supporting the long-term benefits of annual 4-week intensive rehabilitation in managing coordination deficits in patients with pure cerebellar ataxia (SCA6/SCA31). SARA scores, reflecting coordination, demonstrated relative stability compared with the expected natural history of several years, suggesting that this periodic intervention effectively contributes to slowing the progression of core ataxic symptoms. However, balance function, as assessed by the BESTest, showed an earlier and more progressive decline, indicating that maintaining this complex function poses a greater challenge under the current annual intervention format. Thus, although annual rehabilitation strategies are valuable for coordination, preserving balance may require supplementary or more frequent therapeutic interventions. Overall, our findings strongly support the clinical utility of annual intensive rehabilitation for its demonstrated positive impact on coordination function over an extended period. Comprehensive long-term management should leverage these benefits while exploring tailored approaches to mitigate the concurrent decline in balance. Future research should focus on optimizing intervention protocols, potentially integrating balance-specific training, to address the full spectrum of motor impairments in these patients. Abbreviations SCA6 spinocerebellar ataxia type 6 SCA31 spinocerebellar ataxia type 31 SARA Scale for the Assessment and Rating of Ataxia (score range 0–40,higher scores indicate more significant impairment) BESTest Balance Evaluation Systems Test (score range 0–108,higher scores indicate better balance function). Declarations Acknowledgements We thank the patients and their families who participated in this study, as well as Kyoko Todoroki, Wakana Oba, and Yu Ogasawara, for their contributions to the organization and data collection. Disclosures Funding Sources This work was supported by the Practical Research Project for Rare and Intractable Diseases from the Japan Agency for Medical Research and Development (AMED) (grant JP23ek0109420h0003; Y.T.), Grants‑in‑Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS KAKENHI) (grant JP21K17485; K.B.), Intramural Research Grants for Neurological and Psychiatric Disorders of the National Center of Neurology and Psychiatry (grant nos. 3‑4 and 6‑5; Y.T.), and the Ministry of Health, Labour and Welfare Program (grant JPMH17933916; Y.T.). Disclosure of potential conflicts of interest The authors have no relevant financial or non-financial interests to disclose. Research involving Human Participants and/or Animals This study was performed in line with the principles of the Declaration of Helsinki. This study was approved by the local ethics committee of the National Centre of Neurology and Psychiatry (Approval No. A2018-104). We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines. Informed consent . Informed consent was obtained from all individual participants included in the study. Data availability statement The data that support the findings of this study are available from the corresponding author, K. B., upon reasonable request. Authors’ contributions K.B., Y.K., M.O., T.H, and Y.T. contributed to the conception and design of the study, statistical analyses, drafting of the text, and preparation of the figures. K.B., Y. K., Y.A., and T.K. performed data acquisition and analysis. References Diallo A, Jacobi H, Tezenas du Montcel S, Klockgether T. Natural history of most common spinocerebellar ataxia: a systematic review and meta-analysis. J Neurol. 2021;268:2749–56. Sun YM, Lu C, Wu ZY. Spinocerebellar ataxia: relationship between phenotype and genotype – a review. Clin Genet. 2016;90:305–14. 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Shah VV, Muzyka D, Jagodinsky A, et al. Digital measures of postural sway quantify balance deficits in spinocerebellar ataxia. Mov Disord. 2024;39:663–73. Heusel-Gillig LL, Hall CD. Effectiveness of vestibular rehabilitation for patients with degenerative cerebellar ataxia: A retrospective cohort study. Brain Sci. 2023;13:1520. Santos de Oliveira LA, Martins CP, Horsczaruk CHR, et al. Decreasing fall risk in spinocerebellar ataxia. J Phys Ther Sci. 2015;27:1223–5. Tables Table 1. Demographic and clinical characteristics of study participants at baseline Abbreviations: SCA6, spinocerebellar ataxia type 6; SCA31, spinocerebellar ataxia type 31; SARA, Scale for the Assessment and Rating of Ataxia (score range 0–40, higher scores indicate more significant impairment); BESTest, Balance Evaluation Systems Test (score range 0–108, higher scores indicate better balance function). Note: Age at study entry refers to the participant’s age at the start of the rehabilitation program. Age at onset represents the age at which the patient or family members noticed the first symptoms. Base SARA and Base BESTest scores were obtained at the initial assessment before the first rehabilitation intervention. Table 2. Linear mixed model analysis of changes in SARA score from baseline over the 7-year follow-up Abbreviations: SARA, Scale for the Assessment and Rating of Ataxia; SE, Standard Error; df, degrees of freedom; CI, Confidence Interval. Note: Estimates represent changes from baseline (year 1) scores. Positive values indicate worsening, and negative values indicate improvement. Analysis was performed using a linear mixed-effects model with fixed effects for year and disease type and random effects for individual participants. *P < 0.05, **P < 0.01 Table 3. Linear mixed model analysis of changes in the BESTest score from baseline over the 7-year follow-up Abbreviations: BESTest, Balance Evaluation Systems Test; SE, Standard Error; df, degrees of freedom; CI, Confidence Interval. Note: Estimates represent changes from baseline (year 1) scores. Negative values indicate deterioration in balance function, as BESTest scores range from 0 to 108, with higher scores indicating better balance function. Analysis was performed using a linear mixed-effects model with fixed effects for year and disease type and random effects for individual participants. *P < 0.05, **P < 0.01 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Published Journal Publication published 04 Sep, 2025 Read the published version in The Cerebellum → Version 1 posted Editorial decision: Revision requested 01 Jun, 2025 Reviews received at journal 27 May, 2025 Reviewers agreed at journal 14 May, 2025 Reviewers invited by journal 13 May, 2025 Editor assigned by journal 12 May, 2025 Submission checks completed at journal 12 May, 2025 First submitted to journal 09 May, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-6630053","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":457321534,"identity":"7ed4ecd1-5e7b-4865-9388-412b1a09e51c","order_by":0,"name":"Kyota Bando","email":"","orcid":"","institution":"National Center Hospital, National Center of Neurology and Psychiatry","correspondingAuthor":false,"prefix":"","firstName":"Kyota","middleName":"","lastName":"Bando","suffix":""},{"id":457321535,"identity":"2d866166-ca66-45f8-9682-ab006afa15bb","order_by":1,"name":"Yuki Kondo","email":"","orcid":"","institution":"Kanto Gakuin University","correspondingAuthor":false,"prefix":"","firstName":"Yuki","middleName":"","lastName":"Kondo","suffix":""},{"id":457321537,"identity":"df14b5e8-8dc2-493c-966e-d3a5feba481a","order_by":2,"name":"Yosuke Ariake","email":"","orcid":"","institution":"National Center Hospital, National Center of Neurology and Psychiatry","correspondingAuthor":false,"prefix":"","firstName":"Yosuke","middleName":"","lastName":"Ariake","suffix":""},{"id":457321538,"identity":"878640de-2444-4e2d-9941-da09a2b2e900","order_by":3,"name":"Taro Kato","email":"","orcid":"","institution":"National Center Hospital, National Center of Neurology and Psychiatry","correspondingAuthor":false,"prefix":"","firstName":"Taro","middleName":"","lastName":"Kato","suffix":""},{"id":457321539,"identity":"ce7b9ff3-14a7-4dae-b059-c062eeb40979","order_by":4,"name":"Mari S. Oba","email":"","orcid":"","institution":"National Center of Neurology and Psychiatry","correspondingAuthor":false,"prefix":"","firstName":"Mari","middleName":"S.","lastName":"Oba","suffix":""},{"id":457321540,"identity":"095aa601-e278-488a-9031-ba948b76c04e","order_by":5,"name":"Takatoshi Hara","email":"","orcid":"","institution":"National Center Hospital, National Center of Neurology and Psychiatry","correspondingAuthor":false,"prefix":"","firstName":"Takatoshi","middleName":"","lastName":"Hara","suffix":""},{"id":457321541,"identity":"426d053f-01d5-443f-8cb3-beb8348d76ad","order_by":6,"name":"Yuji Takahashi","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA9ElEQVRIiWNgGAWjYJACxgaGAwwMEoyND+BCEng1MMO1NBuQqoWBDb9CGDC4kX/w44yaO/Lys5vbqgtq7uQx8C8+wGC5A5+WZGbJDceeGW64c7Dt9oxjz4oZJJ4lMEiewauFQfIB22HGDRKJbbd5Gw4nNkicMWCQbMNvy88H/w7bz5+R2FZMrBY2yY1tQJU3EtuYwVr4e/BrkTzz2MxyZt/h5A03EpuleY4dLmaTYEs4gM8vfMcTH9/s+XbYdv6M9IefeWoO5/HzHz74WBJPiCkcQBNIYJNIYDgs2YBbizy6XAID/wEGxo94tIyCUTAKRsGIAwCIxl3mXk9VOgAAAABJRU5ErkJggg==","orcid":"","institution":"National Center Hospital, National Center of Neurology and Psychiatry","correspondingAuthor":true,"prefix":"","firstName":"Yuji","middleName":"","lastName":"Takahashi","suffix":""}],"badges":[],"createdAt":"2025-05-09 15:38:25","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-6630053/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-6630053/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s12311-025-01899-8","type":"published","date":"2025-09-04T15:57:38+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":82898824,"identity":"19f5a675-7313-4876-95ca-c2570d80cfef","added_by":"auto","created_at":"2025-05-16 13:13:25","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":207668,"visible":true,"origin":"","legend":"\u003cp\u003eIndividual longitudinal changes in SARA and BESTest scores over the 7-year follow-up\u003c/p\u003e\n\u003cp\u003eNote: Values are shown as percentile-transformed scores comparing SARA and BESTest (SARA: 0–40 points; BESTest: 0–108 points). The y-axis for SARA scores is inverted because lower scores indicate better function, whereas higher BESTest scores indicate better balance performance. Graphs should be interpreted such that a downward trend indicates worsening of symptoms. SARA, Scale for the Assessment and Rating of Ataxia; BESTest, Balance Evaluation Systems Test\u003c/p\u003e","description":"","filename":"Fig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-6630053/v1/33c3fe614ed1bb0d9262fc9d.jpg"},{"id":90827957,"identity":"8dce6e1f-d1bd-439f-9fac-5650fa0369b9","added_by":"auto","created_at":"2025-09-08 16:04:05","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":911495,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-6630053/v1/84c66f26-33ab-4417-974e-1b5e9663f303.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Long-term Effects of Annual Intensive Rehabilitation in Patients with Hereditary Pure Cerebellar Ataxia: A 7-year Follow-up Study","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSpinocerebellar degeneration (SCD) encompasses a group of progressive neurodegenerative disorders that primarily affect the cerebellum [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Although hereditary SCDs comprise multiple subtypes with diverse clinical presentations based on their pathophysiology and causative genes, they share common cerebellar ataxia symptoms, including impaired coordination, intention tremor, dysarthria, and oculomotor abnormalities [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eSpinocerebellar ataxia types 6 (SCA6) and 31 (SCA31) are classified as pure cerebellar types, characterized by the predominant degeneration of Purkinje cells in the cerebellar cortex [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. These subtypes typically present with coordination deficits and intention tremor, followed by progressive deterioration of balance function. Pure cerebellar types generally exhibit slower disease progression than other genetic variants, necessitating treatment interventions with that consider long-term efficacy [\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eRecent studies have suggested that intensive rehabilitation may lead to short-term improvements in coordination deficits and gait ability [\u003cspan additionalcitationids=\"CR8\" citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Intensive and repetitive motor learning programs are considered practical approaches, potentially promoting neuroplasticity at cerebellar and cerebral cortical levels [\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, studies investigating the long-term effects of continuous intervention over multiple years remain scarce, with no long-term intervention studies specifically targeting patients with SCA6 and SCA31 types [\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eFurthermore, understanding which symptoms show sustained improvements following intensive rehabilitation is crucial. Aerobic exercise using ergometers may improve coordination deficits, whereas balance training may be more effective for improving balance function than for coordination deficits [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e]. The cerebellar cortex exhibits functional segregation, with the vermis primarily controlling standing balance and the intermediate portion regulating limb coordination [\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e]. Thus, the effects of long-term interventions should be evaluated from perspectives of coordination and balance function.\u003c/p\u003e \u003cp\u003eIn this study, we conducted annual intensive rehabilitation sessions for up to 7 years in patients with SCA6 and SCA31. We assessed yearly progression using the Scale for the Assessment and Rating of Ataxia (SARA) for ataxic symptoms and Balance Evaluation Systems Test (BESTest) for balance function [\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e]. Our objective was to elucidate the differential progression patterns of ataxic symptoms versus balance function and to determine the potential role of annual interventions. The findings of this study may contribute to establishing comprehensive long-term rehabilitation strategies for pure cerebellar-type ataxia.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\n\u003ch2\u003eStudy design and participants\u003c/h2\u003e\n\u003cp\u003eThis retrospective cohort study was conducted at the National Center of Neurology and Psychiatry between June 2015 and April 2021. The study included patients with SCD who participated in an intensive rehabilitation program. Eligible participants could walk independently (with or without assistive devices) and preserve community living with minimal or no assistance. We analyzed seven patients with SCA6 and SCA31 who participated in the annual program at least three times. The demographic and clinical characteristics of the participants are presented in Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e. The cohort included two patients with SCA6 and five patients with SCA31. The mean age of onset was 53.9 years and at study entry was 66.4 years.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cp\u003eThe study was conducted in accordance with the Declaration of Helsinki and was approved by the Ethics Committee of the National Center of Neurology and Psychiatry (approval number A2018-104). All participants provided informed consent after receiving verbal explanation of the purpose, methods, anticipated benefits, and potential risks of the study.\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eRehabilitation Intervention Program\u003c/h3\u003e\n\u003cp\u003eParticipants underwent rehabilitation 5 days per week over a 4-week period while hospitalized. The daily program consisted of three 1-hour sessions, consisting of individualized physical therapy, occupational or speech therapy, and self-directed balance training. The physical therapy sessions incorporated balance training and ergometer exercises for lower limb ataxia, following the rehabilitation guidelines established by the Research Committee on Ataxia of the Ministry of Health, Labour and Welfare of Japan (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttp://ataxia.umin.ne.jp/rehabilitation/\u003c/span\u003e\u003c/span\u003e). Occupational therapy focused on fine motor skills, whereas speech therapy provided articulation training for patients with dysarthria. Self-directed training sessions included safety-monitored mat exercises, kneeling, and quadruped positions, as prescribed by physical therapists for individual practice.\u003c/p\u003e\n\u003ch3\u003eOutcome Measures\u003c/h3\u003e\n\u003cp\u003eAssessments were conducted annually at three-time points: pre-intervention (pre), post-intervention (post), and at 6 months post-intervention (follow-up). The primary outcome measure was the SARA scale, with scores ranging from 0 to 40 points and higher scores indicating greater severity of ataxia [\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e]. The balance function was evaluated using the BESTest, which was scored from 0 to 108 points, with higher scores indicating better balance function [\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e]. To minimize measurement bias, evaluations were conducted by physical therapists who were not involved in the intervention and had received comprehensive training in assessment procedures.\u003c/p\u003e\n\u003cdiv id=\"Sec6\" class=\"Section2\"\u003e\n\u003ch2\u003eStatistical Analysis\u003c/h2\u003e\n\u003cp\u003eTo analyze the yearly changes in SARA and BESTest scores, we employed a linear mixed-effect model (LMM) using R (v.4.0.2; R Foundation for Statistical Computing, Vienna, Austria) with the lme4 and lmerTest packages [\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e]. The dependent variables were changes in SARA and BESTest scores from baseline (year 1), fixed effects for evaluation year and disease type (SCA31 and SCA6), and random effects for individual ID. Analyses were conducted separately for pre-intervention (to investigate yearly changes), for post-intervention (to assess intervention effects), and at the follow-up (to evaluate effect retention) time points.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec8\" class=\"Section2\"\u003e\n\u003ch2\u003eChanges in SARA Scores\u003c/h2\u003e\n\u003cp\u003eThe linear mixed model analysis of SARA scores revealed several significant temporal changes (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). Analysis of yearly changes from baseline pre-intervention scores showed estimated changes of -1.34 (95% confidence intervals [CI] [-4.24, 1.56], p\u0026thinsp;=\u0026thinsp;0.37) at year 2 and 0.16 (95% CI [-2.74, 3.06], p\u0026thinsp;=\u0026thinsp;0.92) at year 3. The 95% CI continued to cross zero through year 6. A significant increase of 5.78 (95% CI [1.54, 10.03], p\u0026thinsp;=\u0026thinsp;0.01) was observed at year 7.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cp\u003ePost-intervention evaluation revealed significant improvement at year 2 (-2.68, 95% CI [-5.01, -0.35], p\u0026thinsp;=\u0026thinsp;0.04). The estimated change in year 3 was \u0026minus;\u0026thinsp;0.11; at year 4, it was \u0026minus;\u0026thinsp;0.02. Although estimates showed an increasing trend from year 5 onward, all 95% CI values crossed zero.\u003c/p\u003e\n\u003cp\u003eAt the 6-month follow-up, despite no significant differences at year 2 (0.47, 95% CI [-0.95, 1.89], p\u0026thinsp;=\u0026thinsp;0.52), significant increases were observed in year 3 (1.90, 95% CI [0.39, 3.41], p\u0026thinsp;=\u0026thinsp;0.02) and year 4 (2.07, 95% CI [0.55, 3.58], p\u0026thinsp;=\u0026thinsp;0.02), with evidence of more pronounced deterioration in years 6 to 7.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003c/div\u003e\n\u003ch3\u003eChanges in BESTest Scores\u003c/h3\u003e\n\u003cp\u003eThe analysis of BESTest scores demonstrated a more pronounced pattern of decline (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e and Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). Pre-intervention BESTest scores showed no significant differences at year 2 (-3.71, 95% CI [-10.24, 2.81], p\u0026thinsp;=\u0026thinsp;0.28), but a significant decline was observed from year 3 (-7.14, 95% CI [-13.66, -0.62], p\u0026thinsp;=\u0026thinsp;0.04) onward, reaching \u0026minus;\u0026thinsp;32.04 (95% CI [-42.30, -21.79], p\u0026thinsp;\u0026lt;\u0026thinsp;0.01) by year 7.\u003c/p\u003e\n\u003cdiv class=\"gridtable\"\u003e\u0026nbsp;\u003c/div\u003e\n\u003cp\u003ePost-intervention assessments demonstrated a consistent significant decline from year 3 onward, with follow-up evaluations showing significant balance deterioration from year 4 (-8.50, 95% CI [-16.01, -1.00], p\u0026thinsp;=\u0026thinsp;0.04) onward. Notably, years 5 to 7 showed decreases exceeding 19 points in BESTest scores, suggesting a relatively faster progression of balance dysfunction compared to that observed with the SARA scores.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eTo the best of our knowledge this study represents the first longitudinal investigation of annual intensive rehabilitation programs in patients with hereditary pure cerebellar ataxia (SCA6 and SCA31) over an extended follow-up period of up to 7 years. The study examined ataxic symptoms (SARA) and balance function (BESTest). The findings indicate that annual intensive rehabilitation can slow the progression of coordination deficits, as indicated by SARA, over several years, providing valuable long-term benefits. However, balance function, assessed by the BESTest, showed a different trajectory, highlighting potential areas for refinement of long-term management strategies.\u003c/p\u003e \u003cp\u003eExamining the effects on coordination, assessed using the SARA scale, the primary goal of rehabilitation intervention in patients with SCD is to minimize disease progression [\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e]. The natural history of SARA scores in patients with SCA6 and SCA31 typically presents an average annual deterioration of 0.8 points [\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e]. Our results demonstrated that the pre-intervention SARA estimates remained relatively stable compared with the reported natural history through year 6, suggesting that the annual intervention may have contributed to slowing disease progression in terms of coordination. Although year 7 showed a significant increase in the pre-intervention score compared to baseline, this finding may be influenced by the smaller sample size in the final year. Intervention effects, assessed post-intervention, showed significant improvement in year 2 (-2.68, p\u0026thinsp;=\u0026thinsp;0.04) and remained relatively stable through years 3 and 4 (-0.11 and \u0026minus;\u0026thinsp;0.02, respectively), with a trend towards deterioration from year 5 onward. However, the 95% CIs for post-intervention change continued to cross zero through year 7, which indicated that the annual rehabilitation program had a lasting, albeit diminishing, effect on coordination deficits even after 7 years. One contributing factor may have been our program's emphasis on aerobic exercise using ergometers, which targets limb coordination and is effective in improving SARA scores [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]. These findings underscore the long-term value of periodic intensive rehabilitation for maintaining coordination.\u003c/p\u003e \u003cp\u003eThe retention effect at the 6-month follow-up showed a decreasing trend over the years, becoming significantly worse than baseline from year 3 onwards. The cerebellum plays a crucial role in motor learning [\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e], and intensive motor programs in patients with SCD induce plastic changes in the cerebellum and in functionally connected cerebral cortical areas [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. However, SCD causes progressive reduction in cerebellar cortical volume over time [\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e], and motor learning capacity reportedly declines with increasing disease duration [\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e]. These factors likely contributed to the observed decline in the retention of intervention effects, suggesting that although short-term motor learning remains possible, long-term retention capacity may be compromised by disease progression. This highlights the importance of the annual repetition of the intensive program to reinforce benefits.\u003c/p\u003e \u003cp\u003eA key finding of this long-term study is the positive impact of annual intensive rehabilitation on coordination function, as assessed by the SARA scale. Our results suggest that this periodic intervention helped to stabilize SARA scores compared with the expected natural history for up to six years, demonstrating valuable long-term benefits in managing core ataxic symptoms in patients with SCA6 and SCA31. This underscores the potential of structured, repeated rehabilitation efforts to mitigate disease progression in specific functional domains.\u003c/p\u003e \u003cp\u003eIn contrast, balance function, measured by the BESTest, showed a significant decline starting from years 3 to 4, a trend observed across all assessment time points. This earlier deterioration highlights a divergence in the long-term response between coordination and balance under this specific annual intervention protocol. Several factors may contribute to this difference. Balance control relies on a more complex integration of cerebellar functions with multiple sensory inputs (visual, vestibular, and somatosensory) and motor outputs [\u003cspan additionalcitationids=\"CR33 CR34 CR35 CR36\" citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e], potentially making it more vulnerable to overall disease progression or less amenable to improvement due to the specific exercises emphasized in our program (e.g., ergometer cycling targeting limb coordination, likely benefiting SARA scores more directly [\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e]). Furthermore, the annual 4-week format, albeit effective for coordination for several years, might be insufficient in frequency or duration to fully counteract the decline in the multifaceted demands of balance control over such an extended period.\u003c/p\u003e \u003cp\u003eAlthough the decline in BESTest scores indicates a need to explore complementary strategies specifically targeting balance [\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e], it does not diminish the significant finding regarding SARA scores. The sustained relative stability in coordination function over multiple years provides strong evidence for the clinical utility of annual intensive rehabilitation in the long-term management of pure cerebellar ataxia. This periodic approach appears valuable for preserving limb coordination, a critical aspect of daily function for these patients.\u003c/p\u003e \u003cp\u003eFuture research, including controlled trials with a larger patient cohort, is warranted to further delineate the effects on different functional domains and investigate optimal rehabilitation frequencies, durations, and components aimed at exploring integrated approaches to better address coordination and the challenging progressive decline in balance.\u003c/p\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003eLimitations\u003c/h2\u003e \u003cp\u003eThis study has some limitations. First, as a retrospective study, complete standardization of rehabilitation content and evaluation periods was impossible. Second, the small sample size of seven participants does not allow generalization of results. Additionally, the absence of a control group prevents direct comparison with the natural history of the condition, and the linear mixed model analysis may not fully capture potential non-linear disease progression patterns. Future research should include large-scale prospective studies, multicenter collaborative research, and controlled intervention trials to verify the optimal rehabilitation frequency, duration, and effectiveness of additional approaches for maintaining balance function.\u003c/p\u003e \u003c/div\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis 7-year longitudinal study provides significant evidence supporting the long-term benefits of annual 4-week intensive rehabilitation in managing coordination deficits in patients with pure cerebellar ataxia (SCA6/SCA31). SARA scores, reflecting coordination, demonstrated relative stability compared with the expected natural history of several years, suggesting that this periodic intervention effectively contributes to slowing the progression of core ataxic symptoms. However, balance function, as assessed by the BESTest, showed an earlier and more progressive decline, indicating that maintaining this complex function poses a greater challenge under the current annual intervention format. Thus, although annual rehabilitation strategies are valuable for coordination, preserving balance may require supplementary or more frequent therapeutic interventions. Overall, our findings strongly support the clinical utility of annual intensive rehabilitation for its demonstrated positive impact on coordination function over an extended period. Comprehensive long-term management should leverage these benefits while exploring tailored approaches to mitigate the concurrent decline in balance. Future research should focus on optimizing intervention protocols, potentially integrating balance-specific training, to address the full spectrum of motor impairments in these patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSCA6\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003espinocerebellar ataxia type 6\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSCA31\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003espinocerebellar ataxia type 31\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSARA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eScale for the Assessment and Rating of Ataxia (score range 0\u0026ndash;40,higher scores indicate more significant impairment)\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eBESTest\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eBalance Evaluation Systems Test (score range 0\u0026ndash;108,higher scores indicate better balance function).\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank the patients and their families who participated in this study, as well as Kyoko Todoroki, Wakana Oba, and Yu Ogasawara, for their contributions to the organization and data collection.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eFunding Sources\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis work was supported by the Practical Research Project for Rare and Intractable Diseases from the Japan Agency for Medical Research and Development (AMED) (grant JP23ek0109420h0003; Y.T.), Grants‑in‑Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS KAKENHI) (grant JP21K17485; K.B.), Intramural Research Grants for Neurological and Psychiatric Disorders of the National Center of Neurology and Psychiatry (grant nos. 3‑4 and 6‑5; Y.T.), and the Ministry of Health, Labour and Welfare Program (grant JPMH17933916; Y.T.).\u0026nbsp;\u003c/p\u003e\n\n\u003cp\u003e\u003cstrong\u003eDisclosure of potential conflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eResearch involving Human Participants and/or Animals\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study was performed in line with the principles of the Declaration of Helsinki. This study was approved by the local ethics committee of the National Centre of Neurology and Psychiatry (Approval No. A2018-104). We confirm that we have read the Journal’s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eInformed consent\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e. Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe data that support the findings of this study are available from the corresponding author, K. B., upon reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors’ contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eK.B., Y.K., M.O., T.H, and Y.T. contributed to the conception and design of the study, statistical analyses, drafting of the text, and preparation of the figures. K.B., Y. K., Y.A., and T.K. performed data acquisition and analysis.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eDiallo A, Jacobi H, Tezenas du Montcel S, Klockgether T. Natural history of most common spinocerebellar ataxia: a systematic review and meta-analysis. J Neurol. 2021;268:2749\u0026ndash;56.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSun YM, Lu C, Wu ZY. Spinocerebellar ataxia: relationship between phenotype and genotype \u0026ndash; a review. Clin Genet. 2016;90:305\u0026ndash;14.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSato N, Amino T, Kobayashi K, et al. 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Digital measures of postural sway quantify balance deficits in spinocerebellar ataxia. Mov Disord. 2024;39:663\u0026ndash;73.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eHeusel-Gillig LL, Hall CD. Effectiveness of vestibular rehabilitation for patients with degenerative cerebellar ataxia: A retrospective cohort study. Brain Sci. 2023;13:1520.\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSantos de Oliveira LA, Martins CP, Horsczaruk CHR, et al. Decreasing fall risk in spinocerebellar ataxia. J Phys Ther Sci. 2015;27:1223\u0026ndash;5.\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e Demographic and clinical characteristics of study participants at baseline\u003c/p\u003e\n\u003cp\u003e\u003cimg width=\"562\" height=\"161\" 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alt=\"image\"\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAbbreviations: SCA6, spinocerebellar ataxia type 6; SCA31, spinocerebellar ataxia type 31; SARA, Scale for the Assessment and Rating of Ataxia (score range 0\u0026ndash;40, higher scores indicate more significant impairment); BESTest, Balance Evaluation Systems Test (score range 0\u0026ndash;108, higher scores indicate better balance function).\u003c/p\u003e\n\u003cp\u003eNote: Age at study entry refers to the participant\u0026rsquo;s age at the start of the rehabilitation program. Age at onset represents the age at which the patient or family members noticed the first symptoms. Base SARA and Base BESTest scores were obtained at the initial assessment before the first rehabilitation intervention.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 2.\u003c/strong\u003e Linear mixed model analysis of changes in SARA score from baseline over the 7-year follow-up\u003c/p\u003e\n\u003cp\u003e\u003cimg width=\"512\" height=\"517\" 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alt=\"image\"\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviations: SARA, Scale for the Assessment and Rating of Ataxia; SE, Standard Error; df, degrees of freedom; CI, Confidence Interval.\u003c/p\u003e\n\u003cp\u003eNote: Estimates represent changes from baseline (year 1) scores. Positive values indicate worsening, and negative values indicate improvement. Analysis was performed using a linear mixed-effects model with fixed effects for year and disease type and random effects for individual participants. *P \u0026lt; 0.05, **P \u0026lt; 0.01\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTable 3.\u003c/strong\u003e Linear mixed model analysis of changes in the BESTest score from baseline over the 7-year follow-up\u003c/p\u003e\n\u003cp\u003e\u003cimg width=\"524\" height=\"529\" 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alt=\"image\"\u003e\u003c/p\u003e\n\u003cp\u003eAbbreviations: BESTest, Balance Evaluation Systems Test; SE, Standard Error; df, degrees of freedom; CI, Confidence Interval.\u003c/p\u003e\n\u003cp\u003eNote: Estimates represent changes from baseline (year 1) scores. Negative values indicate deterioration in balance function, as BESTest scores range from 0 to 108, with higher scores indicating better balance function. Analysis was performed using a linear mixed-effects model with fixed effects for year and disease type and random effects for individual participants. *P \u0026lt; 0.05, **P \u0026lt; 0.01\u003c/p\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"the-cerebellum","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cere","sideBox":"Learn more about [The Cerebellum](http://link.springer.com/journal/12311)","snPcode":"12311","submissionUrl":"https://submission.nature.com/new-submission/12311/3","title":"The Cerebellum","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Spinocerebellar Ataxia, Rehabilitation, Postural Balance, Ataxia, Longitudinal Studies","lastPublishedDoi":"10.21203/rs.3.rs-6630053/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6630053/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground\u003c/strong\u003e: Although intensive rehabilitation has achieved short-term benefits in patients with spinocerebellar degeneration, long-term outcomes of periodic intervention remain unclear, particularly in patients with pure spinocerebellar ataxia types 6 (SCA6) and 31 (SCA31).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObjective\u003c/strong\u003e: To investigate the longitudinal effects of annual intensive rehabilitation on ataxic symptoms and balance function in patients with pure cerebellar type SCA6 and SCA31.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMethods\u003c/strong\u003e: Seven patients with genetically confirmed SCA6 or SCA31 participated in annual 4-week intensive rehabilitation programs. Each program consisted of daily physical therapy, occupational/speech therapy, and self-directed balance training. The participants were assessed annually at pre-intervention, post-intervention, and the 6-month follow-up using the Scale for the Assessment and Rating of Ataxia (SARA) and Balance Evaluation Systems Test (BESTest). Changes were analyzed using linear mixed-effect models.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eResults\u003c/strong\u003e: SARA scores were stable, indicating slower progression than the expected natural history, through year 6, with significant improvement observed post-intervention in year 2 (p=0.04). Significant deterioration occurred at year 7 based on pre-intervention scores (p=0.01), suggesting prolonged sustained benefits for coordination. The BESTest scores revealed an earlier decline, with significant deterioration from year 3 (p=0.04), which progressed until year 7 (p\u0026lt;0.01).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConclusions\u003c/strong\u003e: Annual intensive rehabilitation demonstrated potential long-term benefits on motor functions in patients with pure cerebellar-type ataxia. Coordination function improved, suggesting prolonged slowing of progression. However, maintaining balance function may be more challenging under an annual intervention schedule. More frequent or comprehensive approaches, specifically targeting balance, may be necessary to complement the observed benefits in coordination and address the progressive decline in balance function.\u003c/p\u003e","manuscriptTitle":"Long-term Effects of Annual Intensive Rehabilitation in Patients with Hereditary Pure Cerebellar Ataxia: A 7-year Follow-up Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-05-16 13:13:20","doi":"10.21203/rs.3.rs-6630053/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-06-01T16:01:17+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-05-27T06:25:29+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"160648161386636010890026249243499903652","date":"2025-05-14T06:59:11+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-05-13T17:14:36+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-05-13T02:49:40+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-05-13T02:48:48+00:00","index":"","fulltext":""},{"type":"submitted","content":"The Cerebellum","date":"2025-05-09T15:32:17+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"the-cerebellum","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"cere","sideBox":"Learn more about [The Cerebellum](http://link.springer.com/journal/12311)","snPcode":"12311","submissionUrl":"https://submission.nature.com/new-submission/12311/3","title":"The Cerebellum","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"f25b51bc-7e3e-48fc-a588-5e05cb8663df","owner":[],"postedDate":"May 16th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-09-08T16:00:41+00:00","versionOfRecord":{"articleIdentity":"rs-6630053","link":"https://doi.org/10.1007/s12311-025-01899-8","journal":{"identity":"the-cerebellum","isVorOnly":false,"title":"The Cerebellum"},"publishedOn":"2025-09-04 15:57:38","publishedOnDateReadable":"September 4th, 2025"},"versionCreatedAt":"2025-05-16 13:13:20","video":"","vorDoi":"10.1007/s12311-025-01899-8","vorDoiUrl":"https://doi.org/10.1007/s12311-025-01899-8","workflowStages":[]},"version":"v1","identity":"rs-6630053","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6630053","identity":"rs-6630053","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}