The Association Between Diplopia and Clinical Phenotypes in Spinocerebellar Ataxia Type 3

The Association Between Diplopia and Clinical Phenotypes in Spinocerebellar Ataxia Type 3 | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The Association Between Diplopia and Clinical Phenotypes in Spinocerebellar Ataxia Type 3 mei zheng, Mao-lin Cui, wei Lin, Zhuo-Ying Huang, bin Cai, Shirui Gan This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7967632/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 10 Apr, 2026 Read the published version in BMC Neurology → Version 1 posted 12 You are reading this latest preprint version Abstract Background: Spinocerebellar ataxia type 3 (SCA3) is a rare monogenic hereditary neurodegenerative disease. It is the most common form of spinocerebellar ataxia worldwide, with diplopia being one of its most frequent symptoms. Diplopia has been reported to be associated with clinical phenotypes and daily living activities in various neurodegenerative diseases. Objectives: Our objective is to investigate the association between diplopia and the clinical phenotype of SCA3. Methods: We conducted a retrospective analysis of 182 patients with SCA3. Participants were categorized into two groups based on the presence or absence of diplopia: the diplopia group and the non-diplopia group. We used the Mann-Whitney U test to analyze phenotypic differences between the groups. We performed univariate and multivariate logistic regression analyses to identify risk factors for the development of diplopia. Additionally, we conducted a multivariate linear regression analysis to determine the association of diplopia with age at onset (AAO), severity of ataxia, and disease progression. Results: In this study, the frequency of diplopia among subjects was 45.6%, while 54.4% of subjects did not experience diplopia. The diplopia group exhibited significantly higher ICARS scores (p = 0.002) . We found that visual impairment (p = 0.027, OR = 2.22) was a risk factor for diplopia and diplopia significantly affected the severity of ataxia (β = 7.77, p = 0.003). Conclusion: Diplopia is common in patients with SCA3. Visual impairment has been identified as a risk factor for developing diplopia. Additionally, diplopia is associated with the severity of ataxia, necessitating intensive focus and interventions in the care of SCA3 patients. Diplopia Phenotypes spinocerebellar ataxia type 3 ataxia Introduction Spinocerebellar ataxia type 3 (SCA3) constitutes a rare, monogenic, hereditary neurodegenerative disorder, representing the most prevalent form of spinocerebellar ataxia globally 1 . The onset ofSCA3 is linked to a pathological expansion of CAG repeats within exon 10 of the ATXN3 gene, positioned at the 14q32.1 locus on chromosome 14. This expansion induces an elongation of the polyglutamine tract within the ataxin-3 protein 2 . The resultant abnormal expansion of polyglutamine (polyQ) leads to an anomalous protein conformation, thereby facilitating its aggregation and cytotoxicity and ultimately culminating in neuronal damage and subsequent loss 3 . The pathology of SCA3 manifests across multiple systems and regions, predominantly impacting the cerebellum and pons, while also potentially involving the substantia nigra and striatum 4 . Such damage yields a spectrum of outward symptoms, notably encompassing ataxic gait, limb incoordination, dysarthria, dysphagia, impaired proprioception, nystagmus, and diplopia 5 . Diplopia, characterized by the perception of a single object as two separate images, presents in various forms, ranging from equal intensity images to ghost images or shadows. These duplicates may appear side by side, vertically aligned, or at differing angles, contingent upon gaze direction, and may manifest either monocularly or binocularly 6 . Within the spectrum of neurodegenerative diseases, diplopia emerges as a relatively common occurrence 7 . In Parkinson's disease (PD), diplopia prevails with an estimated frequency ranging between 10% to 38% 8,9,10, 11 . Those afflicted with diplopia tend to exhibit poorer motor and non-motor functions, heightened dependence on activities of daily living (ADL), and increased susceptibility to cognitive impairments and emotional blunting 12 – 15 . Moreover, in Progressive Supranuclear Palsy (PSP), diplopia stands as a primary complaint, particularly among individuals diagnosed with the Wall-eyed Bilateral Internuclear Ophthalmoplegia (WEBINO) variant 16 , 17 .Among patients with SCA3, diplopia emerges as a prevalent clinical manifestation 5 , 18 – 21 . Building upon these observations, we propose that delving into the association of diplopia with the clinical phenotype of SCA3 patients can deepen our comprehension of disease progression, thereby facilitating more targeted interventions and treatments. However, the current body of literature lacks systematic investigations on diplopia in SCA3 patients. Hence, in this study, we retrospectively included 182 SCA3 patients from our cerebellar ataxia cohort to explore the frequency of diplopia, identify risk factors, and determine whether diplopia is associated with age at onset (AAO), severity, and progression of ataxia. Methods Study subjects We included a total of 182 molecular-confirmed SCA3 patients from the Organization in South-East China for Cerebellar Ataxia Research (OSCCAR) database, situated within the neurology department of the First Affiliated Hospital of Fujian Medical University. Recruitment occurred between October 2014 and May 2019, with subsequent retrospective analysis conducted on this patient cohort. Inclusion criteria comprised (a) the genetic diagnosis is SCA3, (b) presence of ataxia, (c) the relevant clinical evaluation was conducted, and (d) age of 14 years and older. Exclusion criteria encompassed (a) lacking data on CAG repeats, (b) homozygous individuals, and (c) a history of ocular trauma is present. Genotype and phenotype analyses We requested each patient to provide a peripheral blood sample, from which genomic DNA extraction was conducted using a QIAamp DNA Blood MiniKit (Qiagen, Hilden, Germany). Polymerase chain reaction (PCR) and subsequent Sanger sequencing were undertaken to ascertain the number of CAG repeats within the ATXN3 gene, as detailed in prior reports 22 . Furthermore, face-to-face interviews were conducted by ataxia specialists with each patient to gather all requisite information for the current study. Diplopia denotes a symptom wherein a patient perceives a single object as double, while visual impairment entails symptoms such as blurred vision and diminished visual acuity. AAO denotes the age when symptoms were initially noticed by the patient, close relative, or caregiver. Disease duration is defined as the time interval between AAO and the age at which the clinical evaluation was conducted. The severity of a patient's condition is evaluated using the ICARS, ranging from 0 (indicative of no ataxia) to 100 (representing the most severe ataxia). This scale comprises four components: postural and gait abnormalities, limb ataxia, dysarthria, and oculomotor irregularities, collectively constituting the entirety of the scale 23 , 24 . Additionally, the progression of ataxia is assessed through the following calculation: the ICARS score divided by the duration (in years). Statistical analyses Subjects were categorized into two groups based on the presence or absence of diplopia: the diplopia group and the non-diplopia group. For comparative demographic analysis between the two groups, the chi-square test was employed to assess gender distribution and visual impairment. The independent samples t-test was utilized for normally distributed variables, while the Mann-Whitney U test was applied for variables demonstrating non-normal distributions, with confirmation of normality conducted via the Kolmogorov-Smirnov test. Statistical significance was determined at p < 0.05. Normally distributed variables were expressed as mean ± SD (range), whereas non-normally distributed variables were presented as median (1st Quartile, 3rd Quartile). To discern potential factors associated with diplopia, a two-step logistic regression analysis was undertaken. Initially, a univariate logistic regression analysis was executed to evaluate the association between each variable and the occurrence of diplopia. Subsequently, a multivariate logistic regression analysis was conducted to assess the association of these variables with diplopia while adjusting for intercorrelations among them. Diplopia (binary) was designated as the dependent variable, with AAO, gender (binary), visual impairment (binary), length of the normal CAG repeat sequence, and length of the expanded CAG repeat sequence serving as independent variables. We conducted separate multivariate linear regression analyses to assess the impact of diplopia AAO, severity of ataxia, and disease progression. When evaluating the influence of diplopia on AAO, we utilized AAO as the dependent variable, with diplopia (binary), visual impairment (binary), gender (binary), and normal versus expanded CAG repeat length as independent variables. For analyzing the effect of diplopia on the severity of ataxia, the ICARS score served as the dependent variable, with diplopia (binary), visual impairment (binary), gender (binary), AAO, and the number of normal and expanded CAG repeat lengths as independent variables. Furthermore, to assess the impact of diplopia on the progression of ataxia, we employed the progression value as the dependent variable, with diplopia (binary), visual impairment (binary), gender (binary), AAO, and the length of normal and expanded CAG repeat sequences as independent variables. All statistical analyses were conducted using SPSS version 25.0 (SPSS Inc., Chicago, IL, USA). Results In this study, we observed diplopia in 45.6% of subjects, while 54.4% reported no occurrence of diplopia. Gender distribution did not show significant differences between the diplopia and non-diplopia groups (p = 0.578, χ²=0.31), nor did age at onset (p = 0.841, Z=-0.20), progression of ataxia (p = 0.262, Z=-1.12), length of the normal CAG repeat sequence (p = 0.098, Z=-1.65), or length of the expanded CAG repeat sequence (p = 0.597, Z=-0.53). However, the diplopia group exhibited significantly higher ICARS scores compared to the non-diplopia group (Diplopia group: 32.00 (18.50, 47.50) vs. Non-diplopia group: 22.00 (15.50, 33.00), p = 0.002), and a markedly longer disease duration (Diplopia group: 8.00 (6.00, 12.00) vs. Non-diplopia group: 6.00 (3.00, 9.00), p < 0.001). Furthermore, the diplopia group showed a higher incidence of visual impairment (Visual impairment: χ²=10.03, p = 0.002). Table 1 presents the demographic characteristics of the SCA3 subjects. Table 1 Demographic features of the SCA3 participants Variables Non-Diplopia (n = 99) Diplopia (n = 83) Statistic P Age of first visit, Year, Mean ± SD 41.39 ± 12.95 43.47 ± 10.46 t=-1.17 0.242 Age at onset, Year, M (Q₁, Q₃) 34.00 (25.50, 43.50) 36.00 (27.00, 41.00) Z=-0.20 0.841 Disease duration, Year, M (Q₁, Q₃) 6.00 (3.00, 9.00) 8.00 (6.00, 12.00) Z=-3.66 0.000 Length of normal CAG repeats, N, M (Q₁, Q₃) 19.00 (14.00, 27.00) 14.00 (14.00, 27.00) Z=-1.65 0.098 Length of expanded CAG repeats, N, M (Q₁, Q₃) 75.00 (72.00, 78.00) 75.00 (73.00, 77.00) Z=-0.53 0.597 ICARS, M (Q₁, Q₃) 22.00 (15.50, 33.00) 32.00 (18.50, 47.50) Z=-3.12 0.002 Progression of ataxia, M (Q₁, Q₃) 3.78 (2.67, 6.00) 3.86 (2.57, 5.08) Z=-1.12 0.262 Gender (Man/Female) 53/46 41/42 χ²=0.31 0.578 Visual damage (P/ Ne) 50/49 61/22 χ²=10.03 0.002 t: t-test, Z: Mann-Whitney test, χ²: Chi-square test Bold represents p-values < 0.05 were considered significant. Abbreviations: F, female; M, male; ICARS, International Cooperative Ataxia Rating Scale; N, number; SD: standard deviation; M: Median; Q₁: 1st Quartile, Q₃: 3st Quartile; P: Positive; Ne: Negative. We employed logistic regression analysis (Table 2 ) to investigate the risk factors associated with diplopia in SCA3 patients. In the univariate logistic analysis, we found that disease duration (p < 0.001; OR = 1.14, 95% CI = 1.06 to 1.21), ICARS score (p < 0.001; OR = 1.03, 95% CI = 1.01 to 1.05), progression of ataxia (p = 0.044; OR = 0.91, 95% CI = 0.83 to 0.99), and visual impairment (p = 0.002; OR = 2.72, 95% CI = 1.45 to 5.09) were all identified as risk factors for diplopia. In the multivariate logistic analysis, which accounted for intercorrelations between variables, visual impairment (p = 0.027; OR = 2.22, 95% CI = 1.09 to 4.49) remained a significant risk factor for diplopia. However, no statistically significant associations were found for AAO, disease duration, normal CAG repeats, expanded CAG repeats, ICARS, or progression of ataxia in relation to the onset of diplopia (all p > 0.05). Table 2 Risk factors of diplopia. Variables Univariate Multivariate β S.E Z P OR (95%CI) β S.E Z P OR (95%CI) Age at onset, Year -0.01 0.01 -0.58 0.565 0.99(0.97 ~ 1.02) -0.51 1.10 -0.46 0.644 0.60(0.07 ~ 5.17) Disease duration, Year 0.13 0.03 3.77 < .001 1.14(1.06 ~ 1.21) -0.46 1.09 -0.42 0.673 0.63(0.07 ~ 5.38) Length of normal CAG repeats, N -0.04 0.02 -1.66 0.096 0.96(0.92 ~ 1.01) -0.04 0.03 -1.40 0.161 0.96(0.92 ~ 1.01) Length of expanded CAG repeats, N 0.03 0.04 0.77 0.442 1.03(0.95 ~ 1.12) 0.00 0.07 0.01 0.993 1.00(0.87 ~ 1.15) ICARS 0.03 0.01 3.31 < .001 1.03(1.01 ~ 1.05) 0.03 0.02 1.51 0.130 1.03(0.99 ~ 1.06) Progression of ataxia -0.09 0.05 -2.02 0.044 0.91(0.83 ~ 0.99) -0.08 0.08 -1.07 0.284 0.92(0.79 ~ 1.07) Visual damage 1.00 0.32 3.13 0.002 2.72(1.45 ~ 5.09) 0.80 0.36 2.21 0.027 2.22(1.09 ~ 4.49) OR: Odds Ratio, CI: Confidence Interval To further explore the potential impact of diplopia on AAO, severity, and progression of ataxia (Table 3 ), we conducted a multivariate linear regression analysis. After adjusting for AAO, gender, and the lengths of normal and expanded CAG repeat numbers, we observed that the severity of ataxia in the diplopia group was significantly greater than that in the non-diplopia group (β = 7.77, p = 0.003). However, diplopia did not exert a significant influence on AAO (β = -0.96, p = 0.567) or on the progression of ataxia (β = -1.558, p = 0.075) in patients with SCA3. Table 3 Influence of diplopia on the AAO, severity, and progression of ataxia. Coefficient Estimate Standard Error p-value Influence of diplopia on AAO Gender b -3.08 1.05 0.005 Expanded CAG repeats -2.29 0.15 0.000 Normal CAG repeats -0.07 0.08 0.403 Diplopia a -0.96 1.67 0.567 Visual damage 1.68 1.14 0.144 Influence of diplopia on ataxia severity Gender b 3.21 2.55 0.210 Expanded CAG repeats 1.911 0.526 0.000 Normal CAG repeats -0.341 0.187 0.069 Diplopia a 7.768 2.591 0.003 Visual damage 3.622 2.637 0.171 AAO 0.687 0.173 0.000 Influence of diplopia on ataxia progression c Gender b 0.638 0.857 0.457 Expanded CAG repeats 0.067 0.177 0.706 Normal CAG repeats 0.001 0.063 0.986 Diplopia a -1.558 0.871 0.075 Visual damage -0.524 0.886 0.555 AAO 0.153 0.058 0.009 Bold values show statistical significance. Abbreviations: AAO, age at onset; ICARS, International Cooperative Ataxia Rating Scale. a Diplopia-onset versus non‐diplopia t‐onset. b Female versus male. c Ataxia progression: the ICARS scores divided by disease duration (in years) Discussion In our investigation, we observed that about fifty percent of the SCA3 patients within our study cohort experienced diplopia, indicating its common occurrence in SCA3 cases. Our findings highlight visual impairment as a significant risk factor for diplopia onset, underscoring that this symptom is not merely an isolated ocular manifestation but rather part of a spectrum of ocular abnormalities 19 , 25 . Additionally, our research revealed a correlation between the presence of diplopia and the severity of ataxia in patients, suggesting a potential link between diplopia and heightened neurological impairment. The etiology of diplopia is complex and multifaceted. Ophthalmoplegia and diplopia are both common ocular motor manifestations in patients with SCA3, and they frequently occur together 26 , 27 . Damage to the oculomotor nerve can lead to ophthalmoplegia, which in turn can cause diplopia 6 . Other studies suggest that diplopia pathogenesis is more likely due to degeneration of brainstem-cerebellar pathways 25 , 26 , 28 . Additionally, damage to the vestibular complex may impair the ocular vestibular reflex, contributing to diplopia 6 , 29 , 30 . Finally, damage to the NRTP affects vergence control, leading to diplopia 26 , 31 . In summary, diplopia in SCA3 differs from simple ophthalmoparesis or abducens nerve palsy. It results not from ocular muscle weakness but from damage to higher-level neural pathways involving the cerebellum, brainstem, and premotor command circuits 25 , 26 , 28 , 29 , 32 . Therefore, we hypothesize that diplopia in SCA3 stems from injuries to these specific areas closely associated with diplopia. Furthermore, these structures are closely connected to the cerebellum 33 – 36 , potentially leading to abnormalities in balance and motor control. Consequently, SCA3 patients with diplopia may present with more severe ataxia. However, these hypotheses are speculative, and further experimental research is necessary to elucidate the specific underlying mechanisms Our study also presents several limitations. Firstly, we lack pathological evidence regarding diplopia in SCA3 patients. Secondly, we relied on patient interviews rather than utilizing a standardized scale to determine the presence of diplopia. Additionally, our method for assessing disease progression requires refinement; as we only have baseline visit data, we calculated disease progression by dividing the ICARS score by disease duration. Therefore, follow-up assessments are necessary to establish a more precise relationship between initial symptoms and disease progression. Lastly, we assessed the reduction in patients' visual acuity solely through interviews, without quantifying this impairment through additional ophthalmic examination. This approach may have led to mild diplopia being misclassified as visual impairment, potentially resulting in an underestimation of the prevalence of diplopia. In conclusion, our study statistically quantified the frequency of diplopia in SCA3 and identifies visual impairment as a risk factor for its development in SCA3 patients. Furthermore, we found that diplopia is associated with the severity of ataxic symptoms, highlighting its significance in the therapeutic management of SCA3 patients and underscoring the need for specific attention and intervention. Declarations Ethics approval and consent to participate We confirm that this study was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from the Ethics Committee of the First Affiliated Hospital of Fujian Medical University (Approval No.: MRCTA, ECFAH FMU [2006]119). Written informed consent was provided by all participants, and for those under the age of 18, parental consent was obtained. We have read the Journal’s policy on ethical publication and affirm that this manuscript is consistent with those guidelines. Consent for publication Not applicable Competing interests The authors report no relevant disclosures. All authors report no conflict of interest. Funding This work was supported by the National Natural Science Foundation of China (82371879, Beijing, S-R-G; 82071277, Beijing, B-C). This work was also supported by the Joint Funds for the Innovation of Science and Technology of Fujian Province (2021Y9128, Fujian, S-R-G). Author Contribution SRG and BC formulated and designed the study concept; MZ, MLC and SRG analyzed the data and manuscript drafting or manuscript revision for important intellectual content; MZ, MLC, WL and ZYH enrolled the patients and conducted clinical assessments, all authors; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors. Acknowledgments The authors would like to thank the kind patients, families, caregivers, and members who participated in this research. Data Availability The data that support the findings of this study are not publicly available due to containing information that could compromise the privacy of research participants but are available from corresponding author [GSR] upon reasonable request References Paulino R, Nóbrega C. Autophagy in Spinocerebellar Ataxia Type 3: From Pathogenesis to Therapeutics. Int J Mol Sci 2023;24. 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Cite Share Download PDF Status: Published Journal Publication published 10 Apr, 2026 Read the published version in BMC Neurology → Version 1 posted Editorial decision: Revision requested 09 Feb, 2026 Reviews received at journal 07 Feb, 2026 Reviewers agreed at journal 01 Feb, 2026 Reviews received at journal 05 Jan, 2026 Reviewers agreed at journal 25 Dec, 2025 Reviews received at journal 11 Dec, 2025 Reviewers agreed at journal 04 Dec, 2025 Reviewers invited by journal 18 Nov, 2025 Editor invited by journal 17 Nov, 2025 Editor assigned by journal 04 Nov, 2025 Submission checks completed at journal 04 Nov, 2025 First submitted to journal 28 Oct, 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. 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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-7967632","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":549921477,"identity":"2aa4be3c-6196-41cc-9d05-231e7260993f","order_by":0,"name":"mei zheng","email":"","orcid":"","institution":"Department of Neurology, The First Affiliated Hospital of fujian University","correspondingAuthor":false,"prefix":"","firstName":"mei","middleName":"","lastName":"zheng","suffix":""},{"id":549921478,"identity":"e76a3dea-a0df-4c31-839d-1588e5d94c2d","order_by":1,"name":"Mao-lin Cui","email":"","orcid":"","institution":"Department of Neurology, 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fujian University","correspondingAuthor":false,"prefix":"","firstName":"bin","middleName":"","lastName":"Cai","suffix":""},{"id":549921482,"identity":"de4bd46c-6a78-4712-b41c-4172a7308d42","order_by":5,"name":"Shirui Gan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA40lEQVRIiWNgGAWjYJACZgYDBgY29sYHBmDuAaK18Bw2IEULCEgkQ3QQ1CLvfvbw54KCe4l9ko8Zim62Mcjx3Uhg/FyAR4vhmbw06RkGxYlt0skMxrltDMaSNxKYpWfg09KQY8bMY5AA1JJ/AKQlccONBDZmHnxa+t8YfwZrkTwMtqWeoBZ5iRwDabAWCWawlgQDQloMJN6YgbQYt/EA/ZJzTsJw5pmHzdJ4benPATrsT4Ls/PbDbMY5ZTbyfMeTD37Ga8sBBJsNGDESQJqxAY8GoC1I0swP8CodBaNgFIyCEQsAjIxElEENcxYAAAAASUVORK5CYII=","orcid":"","institution":"Department of Neurology, The First Affiliated Hospital of fujian University","correspondingAuthor":true,"prefix":"","firstName":"Shirui","middleName":"","lastName":"Gan","suffix":""}],"badges":[],"createdAt":"2025-10-28 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13:13:03","extension":"html","order_by":7,"title":"","display":"","copyAsset":false,"role":"acdc-reference","size":97301,"visible":true,"origin":"","legend":"","description":"","filename":"earlyproof.html","url":"https://assets-eu.researchsquare.com/files/rs-7967632/v1/fb3b02048324c095acfea4b9.html"},{"id":106809567,"identity":"fad9f07a-5d95-4127-8b44-c0874a77638b","added_by":"auto","created_at":"2026-04-13 16:11:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":669122,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7967632/v1/34e955f2-6a8a-48f6-9de5-7254bdbaab1b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Association Between Diplopia and Clinical Phenotypes in Spinocerebellar Ataxia Type 3","fulltext":[{"header":"Introduction","content":"\u003cp\u003eSpinocerebellar ataxia type 3 (SCA3) constitutes a rare, monogenic, hereditary neurodegenerative disorder, representing the most prevalent form of spinocerebellar ataxia globally \u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. The onset ofSCA3 is linked to a pathological expansion of CAG repeats within exon 10 of the ATXN3 gene, positioned at the 14q32.1 locus on chromosome 14. This expansion induces an elongation of the polyglutamine tract within the ataxin-3 protein \u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. The resultant abnormal expansion of polyglutamine (polyQ) leads to an anomalous protein conformation, thereby facilitating its aggregation and cytotoxicity and ultimately culminating in neuronal damage and subsequent loss \u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. The pathology of SCA3 manifests across multiple systems and regions, predominantly impacting the cerebellum and pons, while also potentially involving the substantia nigra and striatum \u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e. Such damage yields a spectrum of outward symptoms, notably encompassing ataxic gait, limb incoordination, dysarthria, dysphagia, impaired proprioception, nystagmus, and diplopia \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e. Diplopia, characterized by the perception of a single object as two separate images, presents in various forms, ranging from equal intensity images to ghost images or shadows. These duplicates may appear side by side, vertically aligned, or at differing angles, contingent upon gaze direction, and may manifest either monocularly or binocularly \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Within the spectrum of neurodegenerative diseases, diplopia emerges as a relatively common occurrence \u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn Parkinson's disease (PD), diplopia prevails with an estimated frequency ranging between 10% to 38% \u003csup\u003e8,9,10, 11\u003c/sup\u003e. Those afflicted with diplopia tend to exhibit poorer motor and non-motor functions, heightened dependence on activities of daily living (ADL), and increased susceptibility to cognitive impairments and emotional blunting \u003csup\u003e\u003cspan additionalcitationids=\"CR13 CR14\" citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Moreover, in Progressive Supranuclear Palsy (PSP), diplopia stands as a primary complaint, particularly among individuals diagnosed with the Wall-eyed Bilateral Internuclear Ophthalmoplegia (WEBINO) variant \u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e.Among patients with SCA3, diplopia emerges as a prevalent clinical manifestation \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e, \u003cspan additionalcitationids=\"CR19 CR20\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Building upon these observations, we propose that delving into the association of diplopia with the clinical phenotype of SCA3 patients can deepen our comprehension of disease progression, thereby facilitating more targeted interventions and treatments. However, the current body of literature lacks systematic investigations on diplopia in SCA3 patients. Hence, in this study, we retrospectively included 182 SCA3 patients from our cerebellar ataxia cohort to explore the frequency of diplopia, identify risk factors, and determine whether diplopia is associated with age at onset (AAO), severity, and progression of ataxia.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e\u003ch2\u003eStudy subjects\u003c/h2\u003e\u003cp\u003eWe included a total of 182 molecular-confirmed SCA3 patients from the Organization in South-East China for Cerebellar Ataxia Research (OSCCAR) database, situated within the neurology department of the First Affiliated Hospital of Fujian Medical University. Recruitment occurred between October 2014 and May 2019, with subsequent retrospective analysis conducted on this patient cohort. Inclusion criteria comprised (a) the genetic diagnosis is SCA3, (b) presence of ataxia, (c) the relevant clinical evaluation was conducted, and (d) age of 14 years and older. Exclusion criteria encompassed (a) lacking data on CAG repeats, (b) homozygous individuals, and (c) a history of ocular trauma is present.\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eGenotype and phenotype analyses\u003c/h3\u003e\n\u003cp\u003eWe requested each patient to provide a peripheral blood sample, from which genomic DNA extraction was conducted using a QIAamp DNA Blood MiniKit (Qiagen, Hilden, Germany). Polymerase chain reaction (PCR) and subsequent Sanger sequencing were undertaken to ascertain the number of CAG repeats within the ATXN3 gene, as detailed in prior reports \u003csup\u003e\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eFurthermore, face-to-face interviews were conducted by ataxia specialists with each patient to gather all requisite information for the current study. Diplopia denotes a symptom wherein a patient perceives a single object as double, while visual impairment entails symptoms such as blurred vision and diminished visual acuity. AAO denotes the age when symptoms were initially noticed by the patient, close relative, or caregiver. Disease duration is defined as the time interval between AAO and the age at which the clinical evaluation was conducted. The severity of a patient's condition is evaluated using the ICARS, ranging from 0 (indicative of no ataxia) to 100 (representing the most severe ataxia). This scale comprises four components: postural and gait abnormalities, limb ataxia, dysarthria, and oculomotor irregularities, collectively constituting the entirety of the scale \u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e, \u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. Additionally, the progression of ataxia is assessed through the following calculation: the ICARS score divided by the duration (in years).\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eSubjects were categorized into two groups based on the presence or absence of diplopia: the diplopia group and the non-diplopia group. For comparative demographic analysis between the two groups, the chi-square test was employed to assess gender distribution and visual impairment. The independent samples t-test was utilized for normally distributed variables, while the Mann-Whitney U test was applied for variables demonstrating non-normal distributions, with confirmation of normality conducted via the Kolmogorov-Smirnov test. Statistical significance was determined at p\u0026thinsp;\u0026lt;\u0026thinsp;0.05. Normally distributed variables were expressed as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD (range), whereas non-normally distributed variables were presented as median (1st Quartile, 3rd Quartile).\u003c/p\u003e\u003cp\u003eTo discern potential factors associated with diplopia, a two-step logistic regression analysis was undertaken. Initially, a univariate logistic regression analysis was executed to evaluate the association between each variable and the occurrence of diplopia. Subsequently, a multivariate logistic regression analysis was conducted to assess the association of these variables with diplopia while adjusting for intercorrelations among them. Diplopia (binary) was designated as the dependent variable, with AAO, gender (binary), visual impairment (binary), length of the normal CAG repeat sequence, and length of the expanded CAG repeat sequence serving as independent variables.\u003c/p\u003e\u003cp\u003eWe conducted separate multivariate linear regression analyses to assess the impact of diplopia AAO, severity of ataxia, and disease progression. When evaluating the influence of diplopia on AAO, we utilized AAO as the dependent variable, with diplopia (binary), visual impairment (binary), gender (binary), and normal versus expanded CAG repeat length as independent variables. For analyzing the effect of diplopia on the severity of ataxia, the ICARS score served as the dependent variable, with diplopia (binary), visual impairment (binary), gender (binary), AAO, and the number of normal and expanded CAG repeat lengths as independent variables. Furthermore, to assess the impact of diplopia on the progression of ataxia, we employed the progression value as the dependent variable, with diplopia (binary), visual impairment (binary), gender (binary), AAO, and the length of normal and expanded CAG repeat sequences as independent variables. All statistical analyses were conducted using SPSS version 25.0 (SPSS Inc., Chicago, IL, USA).\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003eIn this study, we observed diplopia in 45.6% of subjects, while 54.4% reported no occurrence of diplopia. Gender distribution did not show significant differences between the diplopia and non-diplopia groups (p\u0026thinsp;=\u0026thinsp;0.578, χ\u0026sup2;=0.31), nor did age at onset (p\u0026thinsp;=\u0026thinsp;0.841, Z=-0.20), progression of ataxia (p\u0026thinsp;=\u0026thinsp;0.262, Z=-1.12), length of the normal CAG repeat sequence (p\u0026thinsp;=\u0026thinsp;0.098, Z=-1.65), or length of the expanded CAG repeat sequence (p\u0026thinsp;=\u0026thinsp;0.597, Z=-0.53). However, the diplopia group exhibited significantly higher ICARS scores compared to the non-diplopia group (Diplopia group: 32.00 (18.50, 47.50) vs. Non-diplopia group: 22.00 (15.50, 33.00), p\u0026thinsp;=\u0026thinsp;0.002), and a markedly longer disease duration (Diplopia group: 8.00 (6.00, 12.00) vs. Non-diplopia group: 6.00 (3.00, 9.00), p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Furthermore, the diplopia group showed a higher incidence of visual impairment (Visual impairment: χ\u0026sup2;=10.03, p\u0026thinsp;=\u0026thinsp;0.002). Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e presents the demographic characteristics of the SCA3 subjects.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eDemographic features of the SCA3 participants\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"5\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eNon-Diplopia (n\u0026thinsp;=\u0026thinsp;99)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eDiplopia (n\u0026thinsp;=\u0026thinsp;83)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eStatistic\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge of first visit, Year, Mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e41.39\u0026thinsp;\u0026plusmn;\u0026thinsp;12.95\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e43.47\u0026thinsp;\u0026plusmn;\u0026thinsp;10.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003et=-1.17\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.242\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge at onset, Year, M (Q₁, Q₃)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e34.00 (25.50, 43.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e36.00 (27.00, 41.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eZ=-0.20\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.841\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisease duration, Year, M (Q₁, Q₃)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6.00 (3.00, 9.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e8.00 (6.00, 12.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eZ=-3.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLength of normal CAG repeats, N, M (Q₁, Q₃)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e19.00 (14.00, 27.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e14.00 (14.00, 27.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eZ=-1.65\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.098\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLength of expanded CAG repeats, N, M (Q₁, Q₃)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e75.00 (72.00, 78.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e75.00 (73.00, 77.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eZ=-0.53\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.597\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eICARS, M (Q₁, Q₃)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e22.00 (15.50, 33.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e32.00 (18.50, 47.50)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eZ=-3.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProgression of ataxia, M (Q₁, Q₃)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.78 (2.67, 6.00)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e3.86 (2.57, 5.08)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eZ=-1.12\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.262\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender (Man/Female)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e53/46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e41/42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eχ\u0026sup2;=0.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.578\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVisual damage (P/ Ne)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e50/49\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e61/22\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003eχ\u0026sup2;=10.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"5\" nameend=\"c5\" namest=\"c1\"\u003e\u003cp\u003et: t-test, Z: Mann-Whitney test, χ\u0026sup2;: Chi-square test\u003c/p\u003e\u003cp\u003eBold represents p-values\u0026thinsp;\u0026lt;\u0026thinsp;0.05 were considered significant.\u003c/p\u003e\u003cp\u003eAbbreviations: F, female; M, male; ICARS, International Cooperative Ataxia Rating Scale; N, number; SD: standard deviation; M: Median; Q₁: 1st Quartile, Q₃: 3st Quartile; P: Positive; Ne: Negative.\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eWe employed logistic regression analysis (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e) to investigate the risk factors associated with diplopia in SCA3 patients. In the univariate logistic analysis, we found that disease duration (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; OR\u0026thinsp;=\u0026thinsp;1.14, 95% CI\u0026thinsp;=\u0026thinsp;1.06 to 1.21), ICARS score (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001; OR\u0026thinsp;=\u0026thinsp;1.03, 95% CI\u0026thinsp;=\u0026thinsp;1.01 to 1.05), progression of ataxia (p\u0026thinsp;=\u0026thinsp;0.044; OR\u0026thinsp;=\u0026thinsp;0.91, 95% CI\u0026thinsp;=\u0026thinsp;0.83 to 0.99), and visual impairment (p\u0026thinsp;=\u0026thinsp;0.002; OR\u0026thinsp;=\u0026thinsp;2.72, 95% CI\u0026thinsp;=\u0026thinsp;1.45 to 5.09) were all identified as risk factors for diplopia. In the multivariate logistic analysis, which accounted for intercorrelations between variables, visual impairment (p\u0026thinsp;=\u0026thinsp;0.027; OR\u0026thinsp;=\u0026thinsp;2.22, 95% CI\u0026thinsp;=\u0026thinsp;1.09 to 4.49) remained a significant risk factor for diplopia. However, no statistically significant associations were found for AAO, disease duration, normal CAG repeats, expanded CAG repeats, ICARS, or progression of ataxia in relation to the onset of diplopia (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eRisk factors of diplopia.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"11\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c8\" colnum=\"8\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c9\" colnum=\"9\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c10\" colnum=\"10\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c11\" colnum=\"11\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e\u003cp\u003eVariables\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"5\" nameend=\"c6\" namest=\"c2\"\u003e\u003cp\u003eUnivariate\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colspan=\"5\" nameend=\"c11\" namest=\"c7\"\u003e\u003cp\u003eMultivariate\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eβ\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eS.E\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eZ\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c6\"\u003e\u003cp\u003eOR (95%CI)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c7\"\u003e\u003cp\u003eβ\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c8\"\u003e\u003cp\u003eS.E\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c9\"\u003e\u003cp\u003eZ\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cem\u003eP\u003c/em\u003e\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c11\"\u003e\u003cp\u003eOR (95%CI)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAge at onset, Year\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-0.58\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.565\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.99(0.97\u0026thinsp;~\u0026thinsp;1.02)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.10\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-0.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.644\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.60(0.07\u0026thinsp;~\u0026thinsp;5.17)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDisease duration, Year\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.14(1.06\u0026thinsp;~\u0026thinsp;1.21)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.46\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e1.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-0.42\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.673\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.63(0.07\u0026thinsp;~\u0026thinsp;5.38)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLength of normal CAG repeats, N\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-1.66\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.096\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.96(0.92\u0026thinsp;~\u0026thinsp;1.01)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-1.40\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.161\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.96(0.92\u0026thinsp;~\u0026thinsp;1.01)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eLength of expanded CAG repeats, N\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.04\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.77\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e0.442\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.03(0.95\u0026thinsp;~\u0026thinsp;1.12)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.993\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.00(0.87\u0026thinsp;~\u0026thinsp;1.15)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eICARS\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.01\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.31\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e\u0026lt;\u0026thinsp;.001\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e1.03(1.01\u0026thinsp;~\u0026thinsp;1.05)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.03\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e1.51\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.130\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e1.03(0.99\u0026thinsp;~\u0026thinsp;1.06)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eProgression of ataxia\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.09\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e-2.02\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.044\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e0.91(0.83\u0026thinsp;~\u0026thinsp;0.99)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e-0.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e-1.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e0.284\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e0.92(0.79\u0026thinsp;~\u0026thinsp;1.07)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVisual damage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.00\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.32\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e3.13\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c5\"\u003e\u003cp\u003e\u003cb\u003e0.002\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c6\"\u003e\u003cp\u003e2.72(1.45\u0026thinsp;~\u0026thinsp;5.09)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c7\"\u003e\u003cp\u003e0.80\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c8\"\u003e\u003cp\u003e0.36\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c9\"\u003e\u003cp\u003e2.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c10\"\u003e\u003cp\u003e\u003cb\u003e0.027\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c11\"\u003e\u003cp\u003e2.22(1.09\u0026thinsp;~\u0026thinsp;4.49)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"11\" nameend=\"c11\" namest=\"c1\"\u003e\u003cp\u003eOR: Odds Ratio, CI: Confidence Interval\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eTo further explore the potential impact of diplopia on AAO, severity, and progression of ataxia (Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e), we conducted a multivariate linear regression analysis. After adjusting for AAO, gender, and the lengths of normal and expanded CAG repeat numbers, we observed that the severity of ataxia in the diplopia group was significantly greater than that in the non-diplopia group (β\u0026thinsp;=\u0026thinsp;7.77, p\u0026thinsp;=\u0026thinsp;0.003). However, diplopia did not exert a significant influence on AAO (β = -0.96, p\u0026thinsp;=\u0026thinsp;0.567) or on the progression of ataxia (β = -1.558, p\u0026thinsp;=\u0026thinsp;0.075) in patients with SCA3.\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eInfluence of diplopia on the AAO, severity, and progression of ataxia.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eCoefficient Estimate\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003eStandard Error\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003ep-value\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInfluence of diplopia on AAO\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-3.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.05\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.005\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExpanded CAG repeats\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-2.29\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.15\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNormal CAG repeats\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.07\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.08\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.403\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiplopia\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.96\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.67\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.567\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVisual damage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.68\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e1.14\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.144\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInfluence of diplopia on ataxia severity\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.21\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.55\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.210\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExpanded CAG repeats\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.911\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.526\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNormal CAG repeats\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.341\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.187\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.069\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiplopia\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e7.768\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.591\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.003\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVisual damage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3.622\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e2.637\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.171\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAAO\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.687\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.173\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.000\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eInfluence of diplopia on ataxia progression\u003csup\u003ec\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eGender\u003csup\u003eb\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.638\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.857\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.457\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eExpanded CAG repeats\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.067\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.177\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.706\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eNormal CAG repeats\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.001\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.063\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.986\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eDiplopia\u003csup\u003ea\u003c/sup\u003e\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-1.558\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.871\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.075\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVisual damage\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e-0.524\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.886\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e0.555\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eAAO\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e0.153\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c3\"\u003e\u003cp\u003e0.058\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c4\"\u003e\u003cp\u003e\u003cb\u003e0.009\u003c/b\u003e\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colspan=\"4\" nameend=\"c4\" namest=\"c1\"\u003e\u003cp\u003eBold values show statistical significance.\u003c/p\u003e\u003cp\u003eAbbreviations: AAO, age at onset; ICARS, International Cooperative Ataxia Rating Scale.\u003c/p\u003e\u003cp\u003e\u003csup\u003ea\u003c/sup\u003eDiplopia-onset versus non‐diplopia t‐onset.\u003c/p\u003e\u003cp\u003e\u003csup\u003eb\u003c/sup\u003eFemale versus male.\u003c/p\u003e\u003cp\u003e\u003csup\u003ec\u003c/sup\u003eAtaxia progression: the ICARS scores divided by disease duration (in years)\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eIn our investigation, we observed that about fifty percent of the SCA3 patients within our study cohort experienced diplopia, indicating its common occurrence in SCA3 cases. Our findings highlight visual impairment as a significant risk factor for diplopia onset, underscoring that this symptom is not merely an isolated ocular manifestation but rather part of a spectrum of ocular abnormalities\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. Additionally, our research revealed a correlation between the presence of diplopia and the severity of ataxia in patients, suggesting a potential link between diplopia and heightened neurological impairment.\u003c/p\u003e\u003cp\u003eThe etiology of diplopia is complex and multifaceted. Ophthalmoplegia and diplopia are both common ocular motor manifestations in patients with SCA3, and they frequently occur together \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e. Damage to the oculomotor nerve can lead to ophthalmoplegia, which in turn can cause diplopia \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Other studies suggest that diplopia pathogenesis is more likely due to degeneration of brainstem-cerebellar pathways \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. Additionally, damage to the vestibular complex may impair the ocular vestibular reflex, contributing to diplopia \u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e. Finally, damage to the NRTP affects vergence control, leading to diplopia \u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\u003cp\u003eIn summary, diplopia in SCA3 differs from simple ophthalmoparesis or abducens nerve palsy. It results not from ocular muscle weakness but from damage to higher-level neural pathways involving the cerebellum, brainstem, and premotor command circuits \u003csup\u003e\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e, \u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e, \u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e, \u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e. Therefore, we hypothesize that diplopia in SCA3 stems from injuries to these specific areas closely associated with diplopia. Furthermore, these structures are closely connected to the cerebellum \u003csup\u003e\u003cspan additionalcitationids=\"CR34 CR35\" citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e, potentially leading to abnormalities in balance and motor control. Consequently, SCA3 patients with diplopia may present with more severe ataxia. However, these hypotheses are speculative, and further experimental research is necessary to elucidate the specific underlying mechanisms\u003c/p\u003e\u003cp\u003eOur study also presents several limitations. Firstly, we lack pathological evidence regarding diplopia in SCA3 patients. Secondly, we relied on patient interviews rather than utilizing a standardized scale to determine the presence of diplopia. Additionally, our method for assessing disease progression requires refinement; as we only have baseline visit data, we calculated disease progression by dividing the ICARS score by disease duration. Therefore, follow-up assessments are necessary to establish a more precise relationship between initial symptoms and disease progression. Lastly, we assessed the reduction in patients' visual acuity solely through interviews, without quantifying this impairment through additional ophthalmic examination. This approach may have led to mild diplopia being misclassified as visual impairment, potentially resulting in an underestimation of the prevalence of diplopia.\u003c/p\u003e\u003cp\u003eIn conclusion, our study statistically quantified the frequency of diplopia in SCA3 and identifies visual impairment as a risk factor for its development in SCA3 patients. Furthermore, we found that diplopia is associated with the severity of ataxic symptoms, highlighting its significance in the therapeutic management of SCA3 patients and underscoring the need for specific attention and intervention.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\n\u003cp\u003eWe confirm that this study was conducted in accordance with the Declaration of Helsinki. Ethical approval was obtained from the Ethics Committee of the First Affiliated Hospital of Fujian Medical University (Approval No.: MRCTA, ECFAH FMU [2006]119). Written informed consent was provided by all participants, and for those under the age of 18, parental consent was obtained. We have read the Journal\u0026rsquo;s policy on ethical publication and affirm that this manuscript is consistent with those guidelines.\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003eNot applicable\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors report no relevant disclosures. All authors report no conflict of interest.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eThis work was supported by the National Natural Science Foundation of China (82371879, Beijing, S-R-G; 82071277, Beijing, B-C). This work was also supported by the Joint Funds for the Innovation of Science and Technology of Fujian Province (2021Y9128, Fujian, S-R-G).\u003c/p\u003e\n\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\n\u003cp\u003eSRG and BC formulated and designed the study concept; MZ, MLC and SRG analyzed the data and manuscript drafting or manuscript revision for important intellectual content; MZ, MLC, WL and ZYH enrolled the patients and conducted clinical assessments, all authors; approval of final version of submitted manuscript, all authors; agrees to ensure any questions related to the work are appropriately resolved, all authors.\u003c/p\u003e\n\u003ch2\u003eAcknowledgments\u003c/h2\u003e\n\u003cp\u003eThe authors would like to thank the kind patients, families, caregivers, and members who participated in this research.\u003c/p\u003e\n\u003ch2\u003eData Availability\u003c/h2\u003e\n\u003cp\u003eThe data that support the findings of this study are not publicly available due to containing information that could compromise the privacy of research participants but are available from corresponding author [GSR] upon reasonable request\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003ePaulino R, N\u0026oacute;brega C. 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Lancet Neurol. 2010;9:885\u0026ndash;94.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKedar S, Ghate D, Murray EL, Corbett JJ, Subramony SH. Vision related quality of life in spinocerebellar ataxia. J Neurol Sci. 2015;358:404\u0026ndash;8.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLin MT, Yang JS, Chen PP, et al. Bidirectional Connections between Depression and Ataxia Severity in Spinocerebellar Ataxia Type 3 Patients. Eur Neurol. 2018;79:266\u0026ndash;71.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eLuo L, Wang J, Lo RY, et al. The Initial Symptom and Motor Progression in Spinocerebellar Ataxias. Cerebellum. 2017;16:615\u0026ndash;22.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eGan S-R, Shi S-S, Wu J-J et al. High frequency of Machado-Joseph disease identified in Southeastern Chinese kindreds with spinocerebellar ataxia. BMC Med Genet 2010;11.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eStorey E, Tuck K, Hester R, Hughes A, Churchyard A. Inter-rater reliability of the International Cooperative Ataxia Rating Scale (ICARS). Mov Disord. 2003;19:190\u0026ndash;2.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eTrouillas P, Takayanagi T, Hallett M, et al. International Cooperative Ataxia Rating Scale for pharmacological assessment of the cerebellar syndrome. J Neurol Sci. 1997;145:205\u0026ndash;11.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eB\u0026uuml;rk K, Fetter M, Abele M, et al. Autosomal dominant cerebellar ataxia type I: oculomotor abnormalities in families with SCA1, SCA2, and SCA3. J Neurol. 1999;246:789\u0026ndash;97.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eKang SL, Shaikh AG, Ghasia FF. Vergence and Strabismus in Neurodegenerative Disorders. 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Brain Res Bull. 2003;60:511\u0026ndash;41.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eOhyagi Y, Yamada T, Okayama A, et al. Vergence disorders in patients with spinocerebellar ataxia 3/Machado-Joseph disease: a synoptophore study. J Neurol Sci. 2000;173:120\u0026ndash;3.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eRub U, Burk K, Schols L, et al. Damage to the reticulotegmental nucleus of the pons in spinocerebellar ataxia type 1, 2, and 3. Neurology. 2004;63:1258\u0026ndash;63.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBeh SC, Frohman TC, Frohman EM. Cerebellar Control of Eye Movements. J Neuroophthalmol. 2017;37:87\u0026ndash;98.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBalaban CD. Neurotransmitters in the vestibular system. Handb Clin Neurol. 2016;137:41\u0026ndash;55.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eSeidel K, Siswanto S, Brunt ER, den Dunnen W, Korf HW, Rub U. Brain pathology of spinocerebellar ataxias. Acta Neuropathol. 2012;124:1\u0026ndash;21.\u003c/span\u003e\u003c/li\u003e\u003cli\u003e\u003cspan\u003eBodranghien F, Bastian A, Casali C, et al. Consensus Paper: Revisiting the Symptoms and Signs of Cerebellar Syndrome. Cerebellum. 2016;15:369\u0026ndash;91.\u003c/span\u003e\u003c/li\u003e\u003c/ol\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":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Diplopia, Phenotypes, spinocerebellar ataxia type 3, ataxia","lastPublishedDoi":"10.21203/rs.3.rs-7967632/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7967632/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e\u003c/em\u003e Spinocerebellar ataxia type 3 (SCA3) is a rare monogenic hereditary neurodegenerative disease. It is the most common form of spinocerebellar ataxia worldwide, with diplopia being one of its most frequent symptoms. Diplopia has been reported to be associated with clinical phenotypes and daily living activities in various neurodegenerative diseases.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eObjectives: \u003c/strong\u003e\u003c/em\u003eOur objective is to investigate the association between diplopia and the clinical phenotype of SCA3.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e \u003c/strong\u003eWe conducted a retrospective analysis of 182 patients with SCA3. Participants were categorized into two groups based on the presence or absence of diplopia: the diplopia group and the non-diplopia group. We used the Mann-Whitney U test to analyze phenotypic differences between the groups. We performed univariate and multivariate logistic regression analyses to identify risk factors for the development of diplopia. Additionally, we conducted a multivariate linear regression analysis to determine the association of diplopia with age at onset (AAO), severity of ataxia, and disease progression.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eResults:\u003c/strong\u003e\u003c/em\u003e In this study, the frequency of diplopia among subjects was 45.6%, while 54.4% of subjects did not experience diplopia. The diplopia group exhibited significantly higher ICARS scores (p = 0.002) . We found that visual impairment (p = 0.027, OR = 2.22) was a risk factor for diplopia and diplopia significantly affected the severity of ataxia (β = 7.77, p = 0.003).\u003c/p\u003e\n\u003cp\u003e\u003cem\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e\u003c/em\u003e\u003cstrong\u003e \u003c/strong\u003eDiplopia is common in patients with SCA3. Visual impairment has been identified as a risk factor for developing diplopia. Additionally, diplopia is associated with the severity of ataxia, necessitating intensive focus and interventions in the care of SCA3 patients.\u003c/p\u003e","manuscriptTitle":"The Association Between Diplopia and Clinical Phenotypes in Spinocerebellar Ataxia Type 3","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-12-01 20:16:51","doi":"10.21203/rs.3.rs-7967632/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-02-09T07:02:47+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-02-08T03:24:12+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"339697437258221636639342703868805890640","date":"2026-02-02T01:54:22+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-01-05T05:52:24+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"296897483755945204930796447562527276755","date":"2025-12-25T05:36:52+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-12-12T00:38:26+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"174382228732404922339719413429075909671","date":"2025-12-04T15:41:26+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-11-18T05:28:27+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2025-11-17T10:56:23+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-11-04T07:11:20+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-11-04T07:11:08+00:00","index":"","fulltext":""},{"type":"submitted","content":"BMC Neurology","date":"2025-10-28T09:37:32+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-neurology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"nurl","sideBox":"Learn more about [BMC Neurology](http://bmcneurol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/nurl","title":"BMC Neurology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"20b2117b-7e6b-4b16-9941-84b17290f5be","owner":[],"postedDate":"December 1st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2026-04-13T16:07:34+00:00","versionOfRecord":{"articleIdentity":"rs-7967632","link":"https://doi.org/10.1186/s12883-026-04848-y","journal":{"identity":"bmc-neurology","isVorOnly":false,"title":"BMC Neurology"},"publishedOn":"2026-04-10 15:57:28","publishedOnDateReadable":"April 10th, 2026"},"versionCreatedAt":"2025-12-01 20:16:51","video":"","vorDoi":"10.1186/s12883-026-04848-y","vorDoiUrl":"https://doi.org/10.1186/s12883-026-04848-y","workflowStages":[]},"version":"v1","identity":"rs-7967632","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7967632","identity":"rs-7967632","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}