Clinical validation of the 2008 and 2022 diagnostic criteria for early multiple system atrophy

Clinical validation of the 2008 and 2022 diagnostic criteria for early multiple system atrophy | 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 Clinical validation of the 2008 and 2022 diagnostic criteria for early multiple system atrophy Seoyeon Kim, Kyung Ah Woo, Jung Hwan Shin, Han-Joon Kim, Beomseok Jeon This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3931416/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 11 Sep, 2024 Read the published version in Clinical Autonomic Research → Version 1 posted 3 You are reading this latest preprint version Abstract Purpose The Movement Disorders Society criteria for multiple system atrophy (MDS-MSA) was recently proposed to improve the diagnostic accuracy, particularly the lack of sensitivity at early stages. We aimed to seek consistencies and discrepancies between the old and new criteria in early MSA-C. Methods Fifty patients with a cerebellar syndrome with duration less than two years were recruited. Either MSA or cerebellar ataxia (CA) was diagnosed according to the second consensus criteria and MDS-MSA criteria, respectively. Results Among the forty-one MSA-C patients diagnosed by the second consensus criteria, sixteen patients were diagnosed with CA by the MDS-MSA criteria due to lack of supportive clinical features. Eleven probable MSA patients were diagnosed with clinically probable MSA by the MDS-MSA criteria, due to absence of MRI biomarkers. Conclusion The MDS-MSA criteria seems to be stricter compared with the second consensus criteria, and modest sensitivity still proposes a challenge for early detection of MSA-C. ataxia multiple system atrophy cerebellar ataxia Introduction The clinical presentation of multiple system atrophy (MSA) commonly overlaps with other disorders similarly presenting with autonomic failure, parkinsonism, or cerebellar ataxia which leads to frequent misdiagnosis 1 . Although the second consensus criteria published in 2008 2 was widely used for the diagnosis of MSA until recently, several issues leading to its poor sensitivity have been raised throughout the years 3 . In order to overcome the suboptimal accuracy and low sensitivity of the second consensus criteria 4 , 5 , the Movement Disorders Society criteria for multiple system atrophy (MDS-MSA) was newly proposed in 2022. Notably, the term clinically established MSA and clinically probable MSA was introduced among other modifications. According to the new diagnostic criteria, clinically established MSA now requires magnetic resonance imaging (MRI) markers for diagnosis, and clinically probable MSA has been somewhat simplified compared with the previous criteria 6 . A recent pathological validation study was conducted soon after based on this new diagnostic criteria, and although the MDS-MSA criteria showed excellent diagnostic performance compared to previous standards, low sensitivity in early diagnosis still remains a challenge 7 . Therefore, we aimed to seek how the level of diagnostic certainty specifically differs between the two diagnostic criteria, especially in early MSA-cerebellar type (MSA-C) patients. Methods Participants and study design We enrolled consecutive patients presenting with a cerebellar syndrome admitted at the Department of Neurology at Seoul National University Hospital for evaluation between 2019 and 2022, with symptom duration less than 2 years. The presumptive diagnosis was either MSA or cerebellar ataxia (CA). Patients with clinical or laboratory evidence suggestive of an alternative diagnosis were excluded from the study. Similarly, patients with non-supporting features of MSA from the second consensus criteria or features listed in the exclusion criteria of the MDS-MSA criteria were also excluded. Patients were classified according to the second consensus criteria as probable or possible MSA, and to the MDS-MSA criteria as clinically established or clinically probable MSA. Those who did not meet either criteria were classified as CA. This study followed the tenets of the Declaration of Helsinki and informed consent was waived because of the retrospective nature of the study. The study protocol was approved by the Institutional Review Board of Seoul National University Hospital (IRB no. 2306-107-1438). Data analysis Since diagnosis was based on clinical grounds and pathologic evidence was not available, sensitivity and specificity could not be measured. Instead, consistencies and discrepancies between the clinical diagnoses derived from each criteria were evaluated. Although the level of diagnostic certainty is not identical between the two criteria, we assumed probable MSA from the second consensus criteria as the equivalent of clinically established MSA from the MDS-MSA criteria, and possible MSA as clinically probable MSA. Cohen’s kappa co-efficient was calculated to measure agreement. The prevalence of individual additional or supportive features from each diagnostic criteria was additionally obtained. Statistical analyses were performed using IBM SPSS Statistical software version 26. Results Fifty patients, comprising thirty-four men and sixteen women, were included in this study. The mean age was 62.1 ± 8.7 years. Based on the second consensus criteria, forty-one patients were diagnosed as MSA, regardless of probable or possible, and nine patients as CA. Among the forty-one MSA patients, only twenty-five patients were still classified as MSA when the MDS-MSA criteria was applied. Seven out of nine patients were diagnosed as CA by both diagnostic criteria (Table 1 A). There was fair agreement between the two criteria based on Cohen’s κ (κ = 0.241, p = 0.035). Of the sixteen patients classified as MSA by the second consensus criteria but did not meet requirements of the MDS-MSA criteria, thus classified as CA, the dropout was mainly due to lack of supportive clinical features. Thirteen patients fulfilled additional features of possible MSA from the second consensus criteria by atrophy on MRI of putamen, middle cerebellar peduncle, or pons, but did not show any supportive motor or non-motor features definite enough to meet the MDS-MSA criteria. The remaining three patients did not meet any additional or supportive features in both criteria, but were diagnosed as probable MSA by the second consensus criteria by presenting with a cerebellar syndrome and autonomic failure. From the twenty-five patients diagnosed with MSA by both criteria, eleven patients were classified as probable MSA by the second consensus criteria but were categorized as clinically probable MSA by the MDS-MSA criteria (Table 1 B), showing a relatively lower level of diagnostic certainty in the latter. The reason for this was due to the lack of MRI biomarkers in six patients, and an inadequate number of supportive clinical features in five patients, who showed only one supportive feature (mainly stridor). Discussion The purpose of the MDS-MSA criteria was to enhance specificity with acceptable sensitivity in clinically established MSA, and to balance specificity and sensitivity in clinically probable MSA 6 . We attempted to validate diagnostic performance in early MSA-C patients based on clinical information and identify factors contributing to the difference between the old and new criteria. Overall, a large number of patients presenting with a cerebellar syndrome who were diagnosed as MSA by the second consensus criteria did not meet requirements of the MDS-MSA criteria, and were diagnosed as CA. Although this may help in improving diagnostic accuracy, as was demonstrated by the high specificity (100% for clinically established MSA, and 94.0% for clinically probable MSA) reported from a pathologic validation study 7 , it seems to show limited improvement in terms of sensitivity and even a detrimental effect in diagnosing early MSA-C patients. In contrast to the second consensus criteria, which included MRI biomarkers as part of additional features, the new MDS-MSA criteria separated MRI markers and supportive clinical features as independent categories. As a result, when the MDS diagnostic criteria was applied, neither patients with subtle clinical manifestations nor those without discernible atrophic changes on MRI were diagnosed as MSA. In addition, mandatory inclusion of MRI markers to diagnose clinically established MSA might be problematic in regions where MRI is not readily accessible or in circumstances where MRI is not affordable. These factors may contribute to low sensitivity which in turn presents a challenge for potential clinical trials, where early detection and enrollment is crucial for disease modifying therapies. If the revised diagnostic criteria is still insufficient to detect MSA-C at its early stages, additional biomarkers which were not included in the MDS-MSA criteria might be necessary to complement its weaknesses. To overcome these pitfalls, increasing attention is being paid on the development of more sensitive biomarkers that may detect abnormalities from earlier stages 8 , such as α-synuclein seed amplification assays 9 , serum neurofilament light chain 10 , or abnormalities on structural MRI 11 . The Unified MSA Rating Scale (UMSARS) is also under revision to enhance sensitivity 12 , 13 . Incorporation of these additional advances in MSA diagnosis may increase the sensitivity in early diagnosis. Several limitations are noted in this study. This was designed as a single center study with a relatively small number of patients, and as mentioned before, pathological diagnosis was not available which prevented from deriving sensitivity and specificity. We attempted to make clinical diagnoses based on the diagnostic criteria as objectively as possible, but ambiguity in certain categories (such as determining ‘rapid’ progression or the range of ‘moderate to severe’ postural instability) may have resulted in inaccurate diagnosis interfering with our outcomes. The fact that clinical diagnosis was made by a single clinician, although beneficial in terms of diagnostic consistency, is another limitation. Further clinicopathological validation studies conducted with increasing experience of the new diagnostic criteria may address this issue in the future. In conclusion, although the new diagnostic criteria for MSA has its strengths, modest sensitivity in early stages still proposes a diagnostic challenge for early detection of MSA-C and should be considered in future criteria revision. Declarations Data availability statement The data that supports the findings of this study are available on request from the corresponding author. Ethical compliance Statement The study protocol was approved by the Institutional Review Board of Seoul National University Hospital (2306-107-1438). Informed consent was waived because of the retrospective nature of the study. 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. Author contributions 1) Research project : A. Conception, B. Organization, C. Execution; 2) Statistical analysis : A. Design, B. Execution, C. Review and critique; 3) Manuscript : A. Writing of the first draft, B. Review and Critique. S Kim : 1B, 1C, 2A, 2B, 3A. KA Woo : 2C, 3B. JH Shin : 2C, 3B. HJ Kim : 1A, 1B, 2A, 2C, 3A, 3B. B Jeon : 3B. Conflicts of interest The authors have no potential conflicts of interest to disclose. Funding statement The authors have nothing to disclose. Full financial disclosure for the previous 12 months S Kim and KA Woo received travel grant from International Parkinson and Movement Disorder Society. HJ Kim received research grants from Seoul National University Hospital, National Information Society Agency, Ministry of Science and ICT, Ministry of Health and Welfare, Samil Pharmaceutical, Emocog, and Bukwang Pharm Co Ltd; travel grant from International Parkinson and Movement Disorder Society. Other authors have nothing to disclose. References Kim HJ, Stamelou M, Jeon B. Multiple system atrophy-mimicking conditions: Diagnostic challenges. Parkinsonism Relat Disord 2016;22 Suppl 1:S12-15. Gilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al. Second consensus statement on the diagnosis of multiple system atrophy. Neurology 2008;71:670-676. Stankovic I, Quinn N, Vignatelli L, Antonini A, Berg D, Coon E, et al. A critique of the second consensus criteria for multiple system atrophy. Mov Disord 2019;34:975-984. Miki Y, Foti SC, Asi YT, Tsushima E, Quinn N, Ling H, et al. Improving diagnostic accuracy of multiple system atrophy: a clinicopathological study. Brain 2019;142:2813-2827. Lamotte G, Kaufmann H. Movement disorder society criteria for the diagnosis of multiple system atrophy-what's new? Clin Auton Res 2022;32:163-165. Wenning GK, Stankovic I, Vignatelli L, Fanciulli A, Calandra-Buonaura G, Seppi K, et al. The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy. Mov Disord 2022;37:1131-1148. Virameteekul S, Revesz T, Jaunmuktane Z, Warner TT, De Pablo-Fernandez E. Pathological Validation of the MDS Criteria for the Diagnosis of Multiple System Atrophy. Mov Disord 2023;38:444-452. Watanabe H, Shima S, Mizutani Y, Ueda A, Ito M. Multiple System Atrophy: Advances in Diagnosis and Therapy. J Mov Disord 2023;16:13-21. Poggiolini I, Gupta V, Lawton M, Lee S, El-Turabi A, Querejeta-Coma A, et al. Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies. Brain 2022;145:584-595. Chelban V, Nikram E, Perez-Soriano A, Wilke C, Foubert-Samier A, Vijiaratnam N, et al. Neurofilament light levels predict clinical progression and death in multiple system atrophy. Brain 2022;145:4398-4408. Krismer F, Seppi K, Wenning GK, Papapetropoulos S, Abler V, Goebel G, et al. Abnormalities on structural MRI associate with faster disease progression in multiple system atrophy. Parkinsonism Relat Disord 2019;58:23-27. Poewe W, Stankovic I, Halliday G, Meissner WG, Wenning GK, Pellecchia MT, et al. Multiple system atrophy. Nat Rev Dis Primers 2022;8:56. Krismer F, Palma JA, Calandra-Buonaura G, Stankovic I, Vignatelli L, Berger AK, et al. The Unified Multiple System Atrophy Rating Scale: Status, Critique, and Recommendations. Mov Disord 2022;37:2336-2341. Table 1 Table 1. 2022 MDS-MSA criteria MSA CA Total 2008 second consensus criteria MSA 25 16 41 CA 2 7 9 Total 27 23 50 (A) Classification of patients (n=50 cases) according to the MDS-MSA criteria and second consensus criteria as either multiple system atrophy (MSA) or cerebellar ataxia (CA). Values indicate the number of patients. 2022 MDS-MSA criteria Clinically established Clinically probable Total 2008 second consensus criteria Probable 9 11 20 Possible 3 2 5 Total 12 13 25 (B) Classification of patients diagnosed with multiple system atrophy (MSA) by both criteria (n=25 cases). Patients were further diagnosed as clinically established MSA or clinically probable MSA by the MDS-MSA criteria, and probable MSA or possible MSA by the second consensus criteria. Values indicate the number of patients. Cite Share Download PDF Status: Published Journal Publication published 11 Sep, 2024 Read the published version in Clinical Autonomic Research → Version 1 posted Reviewers agreed at journal 22 Apr, 2024 Reviewers invited by journal 22 Apr, 2024 First submitted to journal 05 Feb, 2024 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. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-3931416","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":294243453,"identity":"408ea9c8-6455-48f9-a69c-3addf5f05727","order_by":0,"name":"Seoyeon Kim","email":"","orcid":"","institution":"Seoul National University Hospital Department of Neurology","correspondingAuthor":false,"prefix":"","firstName":"Seoyeon","middleName":"","lastName":"Kim","suffix":""},{"id":294243454,"identity":"c5641b35-6137-4fef-8f62-a0195aad883b","order_by":1,"name":"Kyung Ah Woo","email":"","orcid":"","institution":"Seoul National University Hospital Department of Neurology","correspondingAuthor":false,"prefix":"","firstName":"Kyung","middleName":"Ah","lastName":"Woo","suffix":""},{"id":294243455,"identity":"88bf704f-48ef-4ace-bb2e-b69123bbee9d","order_by":2,"name":"Jung Hwan Shin","email":"","orcid":"","institution":"Seoul National University Hospital Department of Neurology","correspondingAuthor":false,"prefix":"","firstName":"Jung","middleName":"Hwan","lastName":"Shin","suffix":""},{"id":294243456,"identity":"5173aa0f-29e9-4b19-9670-0c9c31ae820c","order_by":3,"name":"Han-Joon Kim","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAxklEQVRIiWNgGAWjYDADfhhDglgdEpINJGsxOECsFt32HsNHNyru1BmfP3tMgqHGjkFy9gH8WszOnDE2zjnzTMLsRl6aBMOxZAZpvgQCWm6kpUnnth0GauExk2BgO8Agx0PAYUAt6b9z/x2WMO4/A9TyjygtyceYcxsOSxgw5JhJMLYdYJAmqOXM4cPSOccOS864kWNskdiXzCPZQ0jL8cbGzzk1h/n5+88Y3vjwzU5O4gwBLagggYGBkLNGwSgYBaNgFBADAC3BPQArLSNQAAAAAElFTkSuQmCC","orcid":"https://orcid.org/0000-0001-8219-9663","institution":"Seoul National University Hospital Department of Neurology","correspondingAuthor":true,"prefix":"","firstName":"Han-Joon","middleName":"","lastName":"Kim","suffix":""},{"id":294243457,"identity":"9c0b6a67-cc2e-490b-9890-2f0f83c51201","order_by":4,"name":"Beomseok Jeon","email":"","orcid":"","institution":"Seoul National University Hospital Department of Neurology","correspondingAuthor":false,"prefix":"","firstName":"Beomseok","middleName":"","lastName":"Jeon","suffix":""}],"badges":[],"createdAt":"2024-02-05 15:56:23","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3931416/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3931416/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1007/s10286-024-01061-0","type":"published","date":"2024-09-11T15:56:52+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":64618893,"identity":"ace41318-96b8-4308-8996-2f15fb79f324","added_by":"auto","created_at":"2024-09-16 16:06:40","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":285759,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3931416/v1/b3c0a0d1-dcbe-4797-8166-33fd90f3f679.pdf"}],"financialInterests":"","formattedTitle":"Clinical validation of the 2008 and 2022 diagnostic criteria for early multiple system atrophy","fulltext":[{"header":"Introduction","content":"\u003cp\u003eThe clinical presentation of multiple system atrophy (MSA) commonly overlaps with other disorders similarly presenting with autonomic failure, parkinsonism, or cerebellar ataxia which leads to frequent misdiagnosis\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. Although the second consensus criteria published in 2008\u003csup\u003e2\u003c/sup\u003e was widely used for the diagnosis of MSA until recently, several issues leading to its poor sensitivity have been raised throughout the years\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eIn order to overcome the suboptimal accuracy and low sensitivity of the second consensus criteria\u003csup\u003e\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u003c/sup\u003e, the Movement Disorders Society criteria for multiple system atrophy (MDS-MSA) was newly proposed in 2022. Notably, the term \u003cem\u003eclinically established\u003c/em\u003e MSA and \u003cem\u003eclinically probable\u003c/em\u003e MSA was introduced among other modifications. According to the new diagnostic criteria, clinically established MSA now requires magnetic resonance imaging (MRI) markers for diagnosis, and clinically probable MSA has been somewhat simplified compared with the previous criteria\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eA recent pathological validation study was conducted soon after based on this new diagnostic criteria, and although the MDS-MSA criteria showed excellent diagnostic performance compared to previous standards, low sensitivity in early diagnosis still remains a challenge\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e. Therefore, we aimed to seek how the level of diagnostic certainty specifically differs between the two diagnostic criteria, especially in early MSA-cerebellar type (MSA-C) patients.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eParticipants and study design\u003c/h2\u003e \u003cp\u003eWe enrolled consecutive patients presenting with a cerebellar syndrome admitted at the Department of Neurology at Seoul National University Hospital for evaluation between 2019 and 2022, with symptom duration less than 2 years. The presumptive diagnosis was either MSA or cerebellar ataxia (CA). Patients with clinical or laboratory evidence suggestive of an alternative diagnosis were excluded from the study. Similarly, patients with non-supporting features of MSA from the second consensus criteria or features listed in the exclusion criteria of the MDS-MSA criteria were also excluded. Patients were classified according to the second consensus criteria as probable or possible MSA, and to the MDS-MSA criteria as clinically established or clinically probable MSA. Those who did not meet either criteria were classified as CA. This study followed the tenets of the Declaration of Helsinki and informed consent was waived because of the retrospective nature of the study. The study protocol was approved by the Institutional Review Board of Seoul National University Hospital (IRB no. 2306-107-1438).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eData analysis\u003c/h2\u003e \u003cp\u003eSince diagnosis was based on clinical grounds and pathologic evidence was not available, sensitivity and specificity could not be measured. Instead, consistencies and discrepancies between the clinical diagnoses derived from each criteria were evaluated. Although the level of diagnostic certainty is not identical between the two criteria, we assumed probable MSA from the second consensus criteria as the equivalent of clinically established MSA from the MDS-MSA criteria, and possible MSA as clinically probable MSA. Cohen\u0026rsquo;s kappa co-efficient was calculated to measure agreement. The prevalence of individual additional or supportive features from each diagnostic criteria was additionally obtained. Statistical analyses were performed using IBM SPSS Statistical software version 26.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eFifty patients, comprising thirty-four men and sixteen women, were included in this study. The mean age was 62.1\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7 years. Based on the second consensus criteria, forty-one patients were diagnosed as MSA, regardless of probable or possible, and nine patients as CA. Among the forty-one MSA patients, only twenty-five patients were still classified as MSA when the MDS-MSA criteria was applied. Seven out of nine patients were diagnosed as CA by both diagnostic criteria (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003eA). There was fair agreement between the two criteria based on Cohen\u0026rsquo;s κ (κ\u0026thinsp;=\u0026thinsp;0.241, p\u0026thinsp;=\u0026thinsp;0.035). Of the sixteen patients classified as MSA by the second consensus criteria but did not meet requirements of the MDS-MSA criteria, thus classified as CA, the dropout was mainly due to lack of supportive clinical features. Thirteen patients fulfilled additional features of possible MSA from the second consensus criteria by atrophy on MRI of putamen, middle cerebellar peduncle, or pons, but did not show any supportive motor or non-motor features definite enough to meet the MDS-MSA criteria. The remaining three patients did not meet any additional or supportive features in both criteria, but were diagnosed as probable MSA by the second consensus criteria by presenting with a cerebellar syndrome and autonomic failure.\u003c/p\u003e \u003cp\u003eFrom the twenty-five patients diagnosed with MSA by both criteria, eleven patients were classified as probable MSA by the second consensus criteria but were categorized as clinically probable MSA by the MDS-MSA criteria (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003eB), showing a relatively lower level of diagnostic certainty in the latter. The reason for this was due to the lack of MRI biomarkers in six patients, and an inadequate number of supportive clinical features in five patients, who showed only one supportive feature (mainly stridor).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe purpose of the MDS-MSA criteria was to enhance specificity with acceptable sensitivity in clinically established MSA, and to balance specificity and sensitivity in clinically probable MSA\u003csup\u003e\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. We attempted to validate diagnostic performance in early MSA-C patients based on clinical information and identify factors contributing to the difference between the old and new criteria.\u003c/p\u003e \u003cp\u003eOverall, a large number of patients presenting with a cerebellar syndrome who were diagnosed as MSA by the second consensus criteria did not meet requirements of the MDS-MSA criteria, and were diagnosed as CA. Although this may help in improving diagnostic accuracy, as was demonstrated by the high specificity (100% for clinically established MSA, and 94.0% for clinically probable MSA) reported from a pathologic validation study\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e\u003c/sup\u003e, it seems to show limited improvement in terms of sensitivity and even a detrimental effect in diagnosing early MSA-C patients.\u003c/p\u003e \u003cp\u003eIn contrast to the second consensus criteria, which included MRI biomarkers as part of additional features, the new MDS-MSA criteria separated MRI markers and supportive clinical features as independent categories. As a result, when the MDS diagnostic criteria was applied, neither patients with subtle clinical manifestations nor those without discernible atrophic changes on MRI were diagnosed as MSA. In addition, mandatory inclusion of MRI markers to diagnose clinically established MSA might be problematic in regions where MRI is not readily accessible or in circumstances where MRI is not affordable. These factors may contribute to low sensitivity which in turn presents a challenge for potential clinical trials, where early detection and enrollment is crucial for disease modifying therapies. If the revised diagnostic criteria is still insufficient to detect MSA-C at its early stages, additional biomarkers which were not included in the MDS-MSA criteria might be necessary to complement its weaknesses. To overcome these pitfalls, increasing attention is being paid on the development of more sensitive biomarkers that may detect abnormalities from earlier stages\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e, such as α-synuclein seed amplification assays\u003csup\u003e\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e\u003c/sup\u003e, serum neurofilament light chain\u003csup\u003e\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e, or abnormalities on structural MRI\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. The Unified MSA Rating Scale (UMSARS) is also under revision to enhance sensitivity\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. Incorporation of these additional advances in MSA diagnosis may increase the sensitivity in early diagnosis.\u003c/p\u003e \u003cp\u003eSeveral limitations are noted in this study. This was designed as a single center study with a relatively small number of patients, and as mentioned before, pathological diagnosis was not available which prevented from deriving sensitivity and specificity. We attempted to make clinical diagnoses based on the diagnostic criteria as objectively as possible, but ambiguity in certain categories (such as determining ‘rapid’ progression or the range of ‘moderate to severe’ postural instability) may have resulted in inaccurate diagnosis interfering with our outcomes. The fact that clinical diagnosis was made by a single clinician, although beneficial in terms of diagnostic consistency, is another limitation. Further clinicopathological validation studies conducted with increasing experience of the new diagnostic criteria may address this issue in the future.\u003c/p\u003e \u003cp\u003eIn conclusion, although the new diagnostic criteria for MSA has its strengths, modest sensitivity in early stages still proposes a diagnostic challenge for early detection of MSA-C and should be considered in future criteria revision.\u003c/p\u003e "},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eData availability statement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; The data that supports the findings of this study are available on request from the corresponding author.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eEthical compliance Statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study protocol was approved by the Institutional Review Board of Seoul National University Hospital (2306-107-1438). Informed consent was waived because of the retrospective nature of the study. We confirm that we have read the Journal\u0026rsquo;s position on issues involved in ethical publication and affirm that this work is consistent with those guidelines.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eAuthor contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e1) Research project : A. Conception, B. Organization, C. Execution; 2) Statistical analysis : A. Design, B. Execution, C. Review and critique; 3) Manuscript : A. Writing of the first draft, B. Review and Critique.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; S Kim : 1B, 1C, 2A, 2B, 3A. KA Woo : 2C, 3B. JH Shin : 2C, 3B. HJ Kim : 1A, 1B, 2A, 2C, 3A, 3B. B Jeon : 3B.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eConflicts of interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have no potential conflicts of interest to disclose.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eFunding statement\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors have nothing to disclose.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003cstrong\u003eFull financial disclosure for the previous 12 months\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eS Kim and KA Woo received travel grant from International Parkinson and Movement Disorder Society. HJ Kim received research grants from Seoul National University Hospital, National Information Society Agency, Ministry of Science and ICT, Ministry of Health and Welfare, Samil Pharmaceutical, Emocog, and Bukwang Pharm Co Ltd; travel grant from International Parkinson and Movement Disorder Society. Other authors have nothing to disclose.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eKim HJ, Stamelou M, Jeon B. Multiple system atrophy-mimicking conditions: Diagnostic challenges. \u003cem\u003eParkinsonism Relat Disord\u003c/em\u003e 2016;22 Suppl 1:S12-15.\u003c/li\u003e\n\u003cli\u003eGilman S, Wenning GK, Low PA, Brooks DJ, Mathias CJ, Trojanowski JQ, et al. Second consensus statement on the diagnosis of multiple system atrophy. \u003cem\u003eNeurology\u003c/em\u003e 2008;71:670-676.\u003c/li\u003e\n\u003cli\u003eStankovic I, Quinn N, Vignatelli L, Antonini A, Berg D, Coon E, et al. A critique of the second consensus criteria for multiple system atrophy. \u003cem\u003eMov Disord\u003c/em\u003e 2019;34:975-984.\u003c/li\u003e\n\u003cli\u003eMiki Y, Foti SC, Asi YT, Tsushima E, Quinn N, Ling H, et al. Improving diagnostic accuracy of multiple system atrophy: a clinicopathological study. \u003cem\u003eBrain\u003c/em\u003e 2019;142:2813-2827.\u003c/li\u003e\n\u003cli\u003eLamotte G, Kaufmann H. Movement disorder society criteria for the diagnosis of multiple system atrophy-what\u0026apos;s new? \u003cem\u003eClin Auton Res\u003c/em\u003e 2022;32:163-165.\u003c/li\u003e\n\u003cli\u003eWenning GK, Stankovic I, Vignatelli L, Fanciulli A, Calandra-Buonaura G, Seppi K, et al. The Movement Disorder Society Criteria for the Diagnosis of Multiple System Atrophy. \u003cem\u003eMov Disord\u003c/em\u003e 2022;37:1131-1148.\u003c/li\u003e\n\u003cli\u003eVirameteekul S, Revesz T, Jaunmuktane Z, Warner TT, De Pablo-Fernandez E. Pathological Validation of the MDS Criteria for the Diagnosis of Multiple System Atrophy. \u003cem\u003eMov Disord\u003c/em\u003e 2023;38:444-452.\u003c/li\u003e\n\u003cli\u003eWatanabe H, Shima S, Mizutani Y, Ueda A, Ito M. Multiple System Atrophy: Advances in Diagnosis and Therapy. \u003cem\u003eJ Mov Disord\u003c/em\u003e 2023;16:13-21.\u003c/li\u003e\n\u003cli\u003ePoggiolini I, Gupta V, Lawton M, Lee S, El-Turabi A, Querejeta-Coma A, et al. Diagnostic value of cerebrospinal fluid alpha-synuclein seed quantification in synucleinopathies. \u003cem\u003eBrain\u003c/em\u003e 2022;145:584-595.\u003c/li\u003e\n\u003cli\u003eChelban V, Nikram E, Perez-Soriano A, Wilke C, Foubert-Samier A, Vijiaratnam N, et al. Neurofilament light levels predict clinical progression and death in multiple system atrophy. \u003cem\u003eBrain\u003c/em\u003e 2022;145:4398-4408.\u003c/li\u003e\n\u003cli\u003eKrismer F, Seppi K, Wenning GK, Papapetropoulos S, Abler V, Goebel G, et al. Abnormalities on structural MRI associate with faster disease progression in multiple system atrophy. \u003cem\u003eParkinsonism Relat Disord\u003c/em\u003e 2019;58:23-27.\u003c/li\u003e\n\u003cli\u003ePoewe W, Stankovic I, Halliday G, Meissner WG, Wenning GK, Pellecchia MT, et al. Multiple system atrophy. \u003cem\u003eNat Rev Dis Primers\u003c/em\u003e 2022;8:56.\u003c/li\u003e\n\u003cli\u003eKrismer F, Palma JA, Calandra-Buonaura G, Stankovic I, Vignatelli L, Berger AK, et al. The Unified Multiple System Atrophy Rating Scale: Status, Critique, and Recommendations. \u003cem\u003eMov Disord\u003c/em\u003e 2022;37:2336-2341.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 1","content":"\u003cp\u003eTable 1.\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"22%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.666666666666666%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"62.333333333333336%\" colspan=\"3\"\u003e\n \u003cp\u003e2022 MDS-MSA criteria\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.666666666666666%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.166666666666668%\"\u003e\n \u003cp\u003eMSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.666666666666668%\"\u003e\n \u003cp\u003eCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.5%\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22%\" rowspan=\"3\"\u003e\n \u003cp\u003e2008 second consensus criteria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.666666666666666%\"\u003e\n \u003cp\u003eMSA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.166666666666668%\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.666666666666668%\"\u003e\n \u003cp\u003e16\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.5%\"\u003e\n \u003cp\u003e41\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.085470085470085%\"\u003e\n \u003cp\u003eCA\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.26495726495727%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.34188034188034%\"\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.307692307692307%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.085470085470085%\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.26495726495727%\"\u003e\n \u003cp\u003e27\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.34188034188034%\"\u003e\n \u003cp\u003e23\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.307692307692307%\"\u003e\n \u003cp\u003e50\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e(A) Classification of patients (n=50 cases) according to the MDS-MSA criteria and second consensus criteria as either multiple system atrophy (MSA) or cerebellar ataxia (CA). Values indicate the number of patients.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"0\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd width=\"22%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.666666666666666%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"62.333333333333336%\" colspan=\"3\"\u003e\n \u003cp\u003e2022 MDS-MSA criteria\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.666666666666666%\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.166666666666668%\"\u003e\n \u003cp\u003eClinically established\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.666666666666668%\"\u003e\n \u003cp\u003eClinically probable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.5%\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"22%\" rowspan=\"3\"\u003e\n \u003cp\u003e2008 second consensus criteria\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"15.666666666666666%\"\u003e\n \u003cp\u003eProbable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"25.166666666666668%\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"23.666666666666668%\"\u003e\n \u003cp\u003e11\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"13.5%\"\u003e\n \u003cp\u003e20\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.085470085470085%\"\u003e\n \u003cp\u003ePossible\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.26495726495727%\"\u003e\n \u003cp\u003e3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.34188034188034%\"\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.307692307692307%\"\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd width=\"20.085470085470085%\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"32.26495726495727%\"\u003e\n \u003cp\u003e12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"30.34188034188034%\"\u003e\n \u003cp\u003e13\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd width=\"17.307692307692307%\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e(B) Classification of patients diagnosed with multiple system atrophy (MSA) by both criteria (n=25 cases). Patients were further diagnosed as \u003cem\u003eclinically established MSA\u003c/em\u003e or \u003cem\u003eclinically probable MSA\u003c/em\u003e by the MDS-MSA criteria, and \u003cem\u003eprobable MSA\u003c/em\u003e or \u003cem\u003epossible MSA\u003c/em\u003e by the second consensus criteria. Values indicate the number of patients.\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":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"clinical-autonomic-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"autr","sideBox":"Learn more about [Clinical Autonomic Research](http://link.springer.com/journal/10286)","snPcode":"10286","submissionUrl":"https://www.editorialmanager.com/autr/default2.aspx","title":"Clinical Autonomic Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"ataxia, multiple system atrophy, cerebellar ataxia","lastPublishedDoi":"10.21203/rs.3.rs-3931416/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3931416/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eThe Movement Disorders Society criteria for multiple system atrophy (MDS-MSA) was recently proposed to improve the diagnostic accuracy, particularly the lack of sensitivity at early stages. We aimed to seek consistencies and discrepancies between the old and new criteria in early MSA-C.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eFifty patients with a cerebellar syndrome with duration less than two years were recruited. Either MSA or cerebellar ataxia (CA) was diagnosed according to the second consensus criteria and MDS-MSA criteria, respectively.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eAmong the forty-one MSA-C patients diagnosed by the second consensus criteria, sixteen patients were diagnosed with CA by the MDS-MSA criteria due to lack of supportive clinical features. Eleven probable MSA patients were diagnosed with clinically probable MSA by the MDS-MSA criteria, due to absence of MRI biomarkers.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eThe MDS-MSA criteria seems to be stricter compared with the second consensus criteria, and modest sensitivity still proposes a challenge for early detection of MSA-C.\u003c/p\u003e","manuscriptTitle":"Clinical validation of the 2008 and 2022 diagnostic criteria for early multiple system atrophy","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-04-25 04:39:02","doi":"10.21203/rs.3.rs-3931416/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2024-04-22T19:46:29+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2024-04-22T19:34:07+00:00","index":"","fulltext":""},{"type":"submitted","content":"Clinical Autonomic Research","date":"2024-02-05T20:31:01+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"clinical-autonomic-research","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"autr","sideBox":"Learn more about [Clinical Autonomic Research](http://link.springer.com/journal/10286)","snPcode":"10286","submissionUrl":"https://www.editorialmanager.com/autr/default2.aspx","title":"Clinical Autonomic Research","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b5c919a2-0b9e-449b-9177-e35d7285d63b","owner":[],"postedDate":"April 25th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2024-09-16T15:58:53+00:00","versionOfRecord":{"articleIdentity":"rs-3931416","link":"https://doi.org/10.1007/s10286-024-01061-0","journal":{"identity":"clinical-autonomic-research","isVorOnly":false,"title":"Clinical Autonomic Research"},"publishedOn":"2024-09-11 15:56:52","publishedOnDateReadable":"September 11th, 2024"},"versionCreatedAt":"2024-04-25 04:39:02","video":"","vorDoi":"10.1007/s10286-024-01061-0","vorDoiUrl":"https://doi.org/10.1007/s10286-024-01061-0","workflowStages":[]},"version":"v1","identity":"rs-3931416","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3931416","identity":"rs-3931416","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}