Prognostic Factors in Sporadic Bulbar Onset Motor Neuron Disease

Prognostic Factors in Sporadic Bulbar Onset Motor Neuron Disease | 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 Prognostic Factors in Sporadic Bulbar Onset Motor Neuron Disease Jianfeng Ding, Nan Hu, Ming Qi, Huihong Tian, Liying Cui, Jingwen Niu, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7056346/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Objective To identify possible prognostic factors of sporadic bulbar onset motor neuron disease (MND). Methods Our study involved bulbar onset MND patients between January 2014 and December 2023. Decease, tracheotomy and permanent non-invasive positive pressure ventilation were defined as endpoint events. Clinical data were retrospectively collected, cut-off values of duration from onset to next region were calculated for further evaluation of its prognostic effect and disease classification. Results A total of 537 patients initially met eligibility and 441 of them were routinely followed up, 213 cases reached endpoint events. Female versus male ratio was 1.22, and median age at onset was 57 years. Median duration from onset to next region and onset to endpoint events were 6 months and 29 months respectively. Lower age at onset, slower ALSFRS-R decreasing rate, longer duration from onset to next region and pure upper motor neuron (UMN) involvement at first visit were associated with favorite prognosis. Cut-off values of duration from onset to next region were defined as 7 and 10 months respectively for patients with and without lower motor neuron (LMN) involved. Conclusions We identified age at onset, duration from onset to next region, ALSFRS-R decreasing rate and exclusive UMN involvement at first assessment as possible prognostic factors. A classification diagram for bulbar onset MND was proposed based on patterns of UMN and LMN involvement and duration from onset to next region. Motor neuron disease bulbar palsy prognostic analysis classifications Figures Figure 1 Figure 2 Figure 3 Introduction Motor neuron disease (MND) includes a wide category of neurodegenerative diseases mainly represented by amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA) and progressive bulbar palsy (PBP). Bulbar onset and spinal onset MND are the two most common presentations, with bulbar onset MND accounting for approximately 20%-30% of the overall cases [ 1 , 2 ]. Considering the irreversible nature of MND, early prediction of disease progression and prognosis remains a hotspot and challenge for relevant studies. Generally, median survival time of MND patients is 2 to 4 years, and those with bulbar onset portend rapid disease progression and inferior prognosis than those with spinal onset [ 2 – 4 ]. However, some bulbar onset patients were reported to survive for more than 10 years, indicating its great heterogeneity [ 3 – 5 ]. In this retrospective study, we aim to explore the characteristics of sporadic bulbar onset MND patients and to identify possible indicators for prognosis. Methods Compliance with ethical standards The institutional ethics committee of Peking Union Medical College Hospital (PUMCH) approved this study (K22C2349). Informed consents were obtained from each individual. Patient selection and definitions This was a retrospective study based on the MND database of PUMCH in China. Patients were recruited from January 2014 to December 2023 and received routine follow-up at least every six months by clinic, telephone or social media (WeChat) until March 2024. Demographic and clinical information were collected at first consultation and updated during follow-up. Endpoint events referred to any causes of decease, tracheotomy and permanent non-invasive positive pressure ventilation (NIPPV) (>22 hours daily for >7days). Patients were diagnosed according to the revised EI Escorial criteria,[6] patients who only met the EI Escorial criteria (1994) for ‘suspected’ were categorized into ‘unclassified’ [7]. Familial MND, amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD), facial onset sensory and motor neuronopathy (FOSMN) syndrome were excluded in this study. ALSFRS-R scores and duration from onset to first visit (DOFV) were recorded at first assessment at our facility. ALSFRS-R was further transformed to FRS [(ALSFRS-R at first assessment - 48) / DOFV] [8]. Duration from onset to next region (DNR) was defined as time from symptoms onset to first notice of limb weakness, atrophy, fasciculation, stiffness or dyspnea verified by either physical examination or neurogenic changes detected by electromyography (EMG). According to variant physical signs presented at first assessment, bulbar onset MND patients were divided into upper motor neuron (UMN), lower motor neuron (LMN) and UMN+LMN phenotypes. UMN signs of bulbar region referred to pseudobulbar affect (PBA), positive palmomental or sucking reflex, pharyngeal hyperreflexia, while LMN signs referred to tongue atrophy or fasciculation, neurogenic changes of sternocleidomastoid muscle or lingua in EMG. Statistics analysis Data were analyzed in SPSS version 21 and R software 4.4.0. Significance was tested at the 5% level. Kolmogorov-Smirnov test was utilized to examine whether data were normally distributed, and data were presented as median (minimum, maximum) for skewed distribution or mean±SD for normal distribution. Continuous variables were analyzed by independent t-test, one-way analysis of variance (ANOVA), Mann-Whitney U test, or Kruskal-Wallis H test. Pairwise comparisons between groups were performed by Students Newman Keuls or Kruskal-Wallis one-way ANOVA test. Categorical variables were analyzed by χ2 test or Fisher’s exact test. Cut-off values of DNR and age at onset were determined by maximum selected log-rank statistics in R software (packages: maxstat, minprop=0.2, maxprop=0.8). Survival curves were performed by Kaplan-Meier analysis in R software (packages: survival, survminer), covariates were analyzed by log-rank test and COX regression model. Results Demographic and clinical features of bulbar onset MND patients A total of 2507 MND patients were registered in our MND center (PUMCH) between Jan 01 2014 and Dec 31 2023, of these, 616 cases (24.6%) were bulbar onset and 441 of them were included in final analysis according to the selection criteria (figure 1). The demographic and clinical characteristics of study subjects were summarized in table 1. Amongst the 441 patients, 213 cases reached endpoint events during the entire follow-up and 37 (17.4%) of them reached endpoint events at least four years from symptom onset, detailed distribution of duration from onset to endpoint events was shown in figure S1. The clinical features and prognostic factors of patients reaching endpoint events The 213 patients were divided into two groups based on whether endpoint events occurred within four years from onset (table2). From table 2, we could see that patients who reached endpoint events within four years had older onset age, faster ALSFRS-R decreasing rate (FRS) and shorter duration from onset to next region (DNR), proportions of clinical phenotypes were also different between groups. Correlations between duration from onset to endpoint events (DOE) and candidate variables were shown in scatter plots in figure S2. Slower FRS and longer DNR were associated with better prognosis. UMN phenotype generally possessed the best prognosis followed by LMN and UMN+LMN groups, with one exception in the UMN+LMN phenotype. Patients with early onset also reached endpoint events at earlier age than those with late onset (figure S3). Gender ratio was not significantly different between patients who reached endpoint events beyond and within 4 years (table2), nevertheless median DOE was still shorter in male than that in female patients [27.5 (6, 67) vs 32 (8, 89) months, p=0.042, figure S2 e]. Comparisons among patients with different patterns of upper and lower motor neuron involvement In the 441 patients with routine follow-up, data of physical signs was missing in 3 patients, the rest 438 patients were classified into three groups based on different combinations of UMN and LMN signs at first assessment (table 3). The majority of patients had both UMN and LMN involved. There was no significant difference in gender ratio and onset age among three phenotypes. Duration from onset to endpoint events or last visit was longest in UMN phenotype, followed by LMN and UMN+LMN group. There were differences in duration from onset to first visit (DOFV), FRS and DNR among three phenotypes, however, no significant difference was identified between UMN and LMN group in multiple comparisons (table 3). Analysis of prognostic factors in all MND patients In our cohort, 441 patients had been followed up regularly. Of the 228 cases who had not reached endpoint events, 79 (18.0%) of them had a disease duration of at least 4 years, of which the longest was 125 months (detailed distribution seen in figure S1). In univariate survival analysis, younger age at onset, slower FRS, longer DNR and pure UMN or LMN involvement at first assessment were predictive of favorite prognosis. In multivariate survival analysis, age at onset, FRS, DNR and pure UMN involvement were proved to be independent prognostic factors, older onset age, slower FRS, longer DNR and exclusive UMN involvement at first assessment led to better prognosis (table S1, figure 2d). Maximum selected log-rank statistics for age at onset showed a best cut-off value of 58 years, and the commonly used value of 65 years was also presented (figure 2 a-b). Results for pure LMN involvement were inconsistent between univariate and multivariate analysis, and DNR was found to be the most important influential factor (if DNR removed, p values were 0.060 for LMN in multivariate analysis). Combined analyses of duration from onset to next region (DNR) and patterns of UMN and LMN involvement Few patients had DNR for more than two years and the longest reported duration was 48 months. DNR cut-off values for overall cases and each phenotype were calculated by maximum selected log-rank statistics method, and a common cut-off value of 7 months was used for simplification in patients with LMN features (figure S4). DNR for at least 7 months generally indicated favorite survival prognosis, in patients with DNR for less than 7 months, additional UMN involvement was associated with poor prognosis (p=0.002) (figure 2c, table 4). Patients in the UMN group generally had the most favorite prognosis, nevertheless internal variances were still observed (table 3). 25 patients presented LMN signs in later disease course, 4 cases did not show LMN signs for at least 9, 28, 57 and 89 months respectively, while the rest 10 cases were unable to be determined. In univariate survival analysis, prognostic factors included DNR (p=0.023), but not gender (p=0.175), age at onset (p=0.092), FRS (p=0.146) and later LMN involvement (p=0.314). Discussion On the basis of a large scale of patients, our retrospective study depicted the general picture of bulbar onset MND and confirmed its long-recognized heterogeneity especially in the aspect of endpoint events. Detailed comparisons with previous studies were summarized in table S2 [3-5, 9-15]. In the perspective of overall MND patients, advanced age was linked to severe decline in ALSFRS-R bulbar scores and faster disease progression [3, 4, 12, 16-19]. Our study confirmed that bulbar onset patients with early onset generally had better survival prognosis than those with late onset, but their actual age at endpoint events was still earlier than those with late onset. The underlying mechanisms by which age at onset influenced prognosis remained elusive, probably due to higher burden of comorbidities (e.g. cardiovascular diseases, diabetes mellitus), reduced reserves of motor neurons and down-regulated enzyme activities in older population, or innate disease heterogeneity [17, 18]. Steeper FRS was widely acknowledged to be associated with inferior prognosis, and it was reliable whether from onset to first assessment or during the whole disease course [8, 20, 21]. However, the credibility of FRS reduced in the UMN phenotype, revealing its limitation in patients with minor changes in ALSFRS-R during an extended time period. As for DNR, interval from onset to next region was also proved to be significantly relevant to prognosis, independent of varied combinations of affected regions [22]. In studies related to bulbar onset MND, DNR and its cut-off values were used to distinguish between isolated bulbar palsy (IBP) and progressive bulbar palsy (PBP), and subjects with DNR for more than 6 months were commonly considered as IBP that led to relatively benign prognosis [15, 23, 24]. UMN and LMN lesions were generally independent of each other in disease severity and progression[25]. Our study demonstrated the detrimental effects of LMN involvement on prognosis, and various factors might lead to the different roles of UMN and LMN lesions. Patients with pure or predominantly UMN features mainly presented with stiffness, spasticity or active deep tendon reflexes, in which motor function was commonly preserved. By contrast, patients with pure or predominantly LMN involvement usually had muscle weakness, atrophy and complaints on dysphagia and choking, which increased the risk of aspiration and malnutrition and eventually led to adverse prognosis. Besides, drugs such as baclofen and benzodiazepines can be used to relieve stiffness and spasticity, while no medicines were currently available for muscle atrophy and weakness. Based on the combined effects of DNR and patterns of UMN and LMN involvement, we proposed several classifications and established a diagnostic flow chart for bulbar onset MND. As shown in figure 3, the first step was to determine whether LMN features were presented at first assessment. For patients with LMN involvement, there were then three important time points in DNR, namely 7, 24 and 48 months, which led to different classifications. On the other hand, theoretically, patients with pure UMN signs were preferred to be classified by whether LMN signs were later involved. Surprisingly, later involvement of LMN or not had not been proved to be a prognostic factor, this might result from the few numbers of patients with pure UMN signs, limited follow-up duration to reach enough endpoint events and the fact that some patients developed LMN features soon after onset so that they were initially assigned into the UMN+LMN group. There were several limitations in our study. First, this was a retrospective study, certain data including diagnostic delay, forced vital capacity were missing. Second, regular follow-up of physical examination or electromyography examination were required to judge whether lesions had extended beyond the bulbar region, while it was difficult to ensure that the follow-up time interval of different patients were completely consistent, which could lead to a certain bias in the results of DNR, but this was unavoidable in clinical studies. Third, this was a single center study based on a tertiary center, which might lead to potential selection bias. In summary, our study identified age at onset, FRS, DNR and pure UMN involvement at first assessment as possible prognostic factors for sporadic bulbar onset MND. DNR and patterns of UMN and LMN involvement might be applied for disease classifications. Declarations Funding CAMS Innovation Fund for Medical Sciences (CIFMS 2021-I2M-1-003), National High Level Hospital Clinical Research Funding (2022-PUMCH-B-017 and 2022-PUMCH-D-002), National Science and Technology Major Project (2022ZD0118003), The Strategic Priority Research Program (Pilot study) “Biological basis of aging and therapeutic strategies” of the Chinese Academy of Sciences (XDB39040000). The authors report there are no competing interests to declare. Statements of Authorship Jianfeng Ding: drafting on the manuscript, data collection and analysis; Nan Hu, Ming Qi and Huihong Tian: data collection; Liying Cui: study design and supervision; Mingsheng Liu and Jingwen Niu: study design, supervision and revision of the manuscript. All authors have read and approved the manuscript. Compliance with Ethical Standards The institutional ethics committee of Peking Union Medical College Hospital (PUMCH) approved this study (K22C2349). Informed consents were obtained from involved participants. Author Contribution Jianfeng Ding: drafting on the manuscript, data collection and analysis; Nan Hu, Ming Qi and Huihong Tian: data collection; Liying Cui: study design and supervision; Mingsheng Liu and Jingwen Niu: study design, supervision and revision of the manuscript. All authors reviewed the manuscript. Acknowledgement Authors thank all contributors and participants in this study. 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Tables Table 1 Demographic and clinical characteristics of bulbar onset MND patients with follow-up (Total n = 441) Variables Patients reaching endpoint events n = 213 Patients not reaching endpoint events n = 228 Overall n = 441 Gender Male Female 104 (48.8) 109 (51.2) 95 (41.7) 133 (58.3) 199 (45.1) 242 (54.9) Age at onset (years) 59 (29, 78) 56 (27, 77) 57 (27, 78) DOFV (months) 11 (2, 75) 12 (3, 89) 12 (2, 89) ALSFRS-R at first assessment (points) 39 (21, 47) n = 186 39 (21, 47) n = 221 39 (21, 47) n = 407 FRS (points/month) -0.67 (-3.50, -0.10) -0.60 (-4.00, -0.03) -0.64 (-4.00, -0.03) Duration to next region (months) DNR≤12 12 ＜ DNR≤24 24 ＜ DNR≤36 36 ＜ DNR≤48 Undetermined or missing 6 (1, 37) 105 (49.3) 21 (9.9) 1 (0.5) 1 (0.5) 85 (39.9) 8 (1, 48) 105 (46.1) 26 (11.4) 7 (3.1) 1 (0.4) 89 (39.0) 6 (1, 48) 210 (47.6) 47 (10.7) 8 (1.8) 2 (0.5) 174 (39.4) Clinical phenotypes UMN LMN UMN+LMN Unable to determine 18 (8.5) 53 (24.9) 142 (66.7) - 21 (9.2) 59 (25.9) 145 (63.6) 3 (1.3) 39 (8.8) 112 (25.4) 287 (65.1) 3 (0.7) Revised EI Escorial category at first assessment Clinically definite Clinically probable Lab-supported probable Clinically possible Unclassified* 36 (16.9) 53 (24.9) 44 (20.7) 64 (30.0) 16 (7.5) 35 (15.4) 61 (26.8) 39 (17.1) 60 (26.3) 33 (14.5) 71 (16.1) 114 (25.9) 83 (18.8) 124 (28.1) 49 (11.1) Duration from onset to endpoint events or last visit (months) 29 (6, 89) 30 (9, 125) - Abbreviations: DOFV, duration from onset to first visit; FRS = (ALSFRS-R at assessment– 48) / DOFV; UMN, upper motor neuron; LMN, lower motor neuron; DNR, duration from onset to next region. Note: Data were presented as n (%) or median (minimum, maximum) *Category of ‘suspected’ in EI Escorial criteria (3 cases missing). Table 2 Comparisons between groups within and beyond 4 years to endpoint events (Total n = 213) Variables Duration from onset to endpoint events ≥4 years n = 37 <4 years n = 176 P value * Gender Male Female 14 23 90 86 0.141 Age at onset (years) 53.03 ± 10.67 55 (29, 75) 58.47 ± 9.65 59.5 (32, 78) 0.003 DOFV (months) 18 (2, 75) 10 (3, 42) <0.001 ALSFRS-R at first assessment (points) 39 (25, 47) 39 (21, 47) 0.455 FRS (points/month) -0.41 (-1.07, -0.14) -0.71 (-3.50, -0.1) <0.001 DNR (months) 14 (2, 37) n = 21 5 (1, 22) n = 107 <0.001 Clinical phenotypes UMN LMN UMN+LMN 8 10 19 10 43 123 0.004 Revised EI Escorial category at first assessment Clinically definite Clinically probable Lab-supported probable Clinically possible 6 7 4 17 30 46 40 47 0.171 Abbreviations: DOFV, duration from onset to first visit; FRS = (ALSFRS-R at assessment– 48) / DOFV; UMN, upper motor neuron; LMN, lower motor neuron; DNR, duration from onset to next region. Note: Data were presented as median (minimum, maximum) or mean±SD; *χ2 test for gender, clinical phenotypes; Fisher’s exact test for revised EI Escorial category; Mann-Whitney U test for TOFV, ALSFRS-R, FRS and DNR; independent t-test for age at onset. Table 3 Comparisons among clinical phenotypes in bulbar onset MND patients with follow-up (Total n = 438) Variables Clinical phenotypes P value * Adjusted p value † UMN (U) n = 39 LMN (L) n = 112 UMN+LMN (U+L) n = 287 U vs L U vs U+L L vs U+L Gender Female Male 27 (69.2) 12 (30.8) 56 (50.0) 56 (50.0) 157 (54.7) 130 (45.3) 0.115 Age at onset (years) 57 (31, 78) 56.1±10.8 58 (27, 77) 57.0±10.2 57 (31, 78) 56.6±10.2 0.842 DOFV (months) 17 (4, 89) 13.5 (3, 81) 11 (2, 70) <0.001 0.999 0.005 <0.001 FRS (points/month) -0.40 (-1.45, -0.03) -0.50 (-3.50, -0.04) -0.71 (-4.00, -0.06) <0.001 0.080 <0.001 0.002 DNR (months) No. of known DNR 15 (6, 36) 21 10.5 (1, 48) 58 5 (1, 30) 188 <0.001 0.134 <0.001 <0.001 Status at last visit No. of endpoint events Duration from onset to endpoint events (months) Duration from onset to last visit ‡ (months) 18 45.50 (27, 82) 52 (22, 125) 53 35 (12, 69) 34 (9, 94) 142 25.50 (6, 89) 25 (9, 84) <0.001 0.028 <0.001 0.006 <0.001 0.019 <0.001 0.011 Abbreviations: DOFV, duration from onset to first visit; FRS = (ALSFRS-R at assessment– 48) / DOFV; UMN, upper motor neuron; LMN, lower motor neuron; DNR, duration from onset to next region. Note: Data were presented as n (%) or median (minimum, maximum) or mean±SD; * χ2 test for Gender, Kruskal-Wallis H test for the rest, † Kruskal-Wallis one-way ANOVA test for pairwise comparisons; ‡ in patients not reaching endpoint events. Table 4 Combined analyses of duration from onset to next region and patterns of UMN and LMN involvement. (Total n = 211) Clinical phenotype Duration from onset to endpoint events (months) DNR <7months No. of events DNR ≥7months No. of events P value LMN UMN+LMN 29 (12, 52) 22 (6, 61) 28 94 43 (16, 69) 40 (17, 89) 25 46 0.003 <0.001 Total* 24 (6, 61) 125 41 (16, 89) 86 <0.001 Abbreviations: UMN, upper motor neuron; LMN, lower Motor neuron; DNR, duration from onset to next region. Note: Data were presented as n or median (minimum, maximum), within-group p value for LMN and UMN+LMN phenotypes: 1) DNR≥7months, p=0.470; 2) DNR <7 months, p=0.002 *UMN, LMN and UMN+LMN phenotypes; Additional Declarations No competing interests reported. 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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-7056346","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":491497787,"identity":"e750db56-a678-4614-93e8-40e08be9a57f","order_by":0,"name":"Jianfeng Ding","email":"","orcid":"","institution":"Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Jianfeng","middleName":"","lastName":"Ding","suffix":""},{"id":491497788,"identity":"0d50f2e5-09db-4fd7-bb47-b3ebf88b55e1","order_by":1,"name":"Nan Hu","email":"","orcid":"","institution":"Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Nan","middleName":"","lastName":"Hu","suffix":""},{"id":491497789,"identity":"bb352c6c-88ef-44fe-b710-ea5f55f06fb8","order_by":2,"name":"Ming Qi","email":"","orcid":"","institution":"Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Ming","middleName":"","lastName":"Qi","suffix":""},{"id":491497790,"identity":"21ce4093-0063-4958-a50c-c785cd757d54","order_by":3,"name":"Huihong Tian","email":"","orcid":"","institution":"Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Huihong","middleName":"","lastName":"Tian","suffix":""},{"id":491497791,"identity":"0a37cec3-3318-40fe-ae9d-f41131bbe32b","order_by":4,"name":"Liying Cui","email":"","orcid":"","institution":"Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Liying","middleName":"","lastName":"Cui","suffix":""},{"id":491497792,"identity":"624e2523-3f31-4a9e-b304-b231ec65f3fb","order_by":5,"name":"Jingwen Niu","email":"","orcid":"","institution":"Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":false,"prefix":"","firstName":"Jingwen","middleName":"","lastName":"Niu","suffix":""},{"id":491497793,"identity":"b8504c0c-24da-4cb6-ade5-d1d566261aa4","order_by":6,"name":"Mingsheng Liu","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABCUlEQVRIiWNgGAWjYBACPmYgkQDEBnAhCeYDBz78wK2FDYsWtsSDM3vwaIExkLTwGB/mYMOqGqKFncd0w8Mdtfbm7L2HXzDuOBzNP7vnw2EGHgZ5frEDOBzGY3Yj8czxxJ0959IsGM8czp1x5+yGwwUWDIYzZyfg0dJ2LMHgRo6ZAWPb4dwNErkbDs/gYUgwuI1fi73B/TcwLTkPDvOwEdRSw7jhBo/xA6gWBgJa2MqAWg4kbjiTY8bAeCY9d8aNNANgIEvg9As//+FtN3+21dkbHD9j/IFxh3Vu/4zkxx8+/LCR55fGrgUKDoNtlP7bABeRwKccBOpABPMHxgYC6kbBKBgFo2BEAgB8H2VC4SakDwAAAABJRU5ErkJggg==","orcid":"","institution":"Department of Neurology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College","correspondingAuthor":true,"prefix":"","firstName":"Mingsheng","middleName":"","lastName":"Liu","suffix":""}],"badges":[],"createdAt":"2025-07-06 07:23:11","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7056346/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7056346/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87899467,"identity":"e743d4b2-908e-4147-ae04-0c310e095ba9","added_by":"auto","created_at":"2025-07-30 08:03:16","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":105148,"visible":true,"origin":"","legend":"\u003cp\u003eStudy flowchart.\u003c/p\u003e","description":"","filename":"floatimage1.png","url":"https://assets-eu.researchsquare.com/files/rs-7056346/v1/03a65ab6939e197ffab70b4b.png"},{"id":87901535,"identity":"a953a38c-9f4a-4e4c-8ae8-13d007660286","added_by":"auto","created_at":"2025-07-30 08:19:17","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":439163,"visible":true,"origin":"","legend":"\u003cp\u003eKaplan Meier survival curves for patients with follow-up.\u003c/p\u003e","description":"","filename":"floatimage2.png","url":"https://assets-eu.researchsquare.com/files/rs-7056346/v1/6d02a0ba300cc8d2649aa975.png"},{"id":87900710,"identity":"22b6d37b-dc02-4f2b-b836-00ea87bcaf8c","added_by":"auto","created_at":"2025-07-30 08:11:16","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":102363,"visible":true,"origin":"","legend":"\u003cp\u003eSuggested classifications of bulbar onset MND.\u003c/p\u003e","description":"","filename":"floatimage3.png","url":"https://assets-eu.researchsquare.com/files/rs-7056346/v1/f494cedff35bf375dfb0a0b6.png"},{"id":90341182,"identity":"accdbfef-3701-4157-a045-311c2eda3d65","added_by":"auto","created_at":"2025-09-01 15:17:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1898652,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7056346/v1/234c36a3-8cea-4c42-8457-d545f3ba46d2.pdf"},{"id":87900714,"identity":"354aa550-9c1c-4638-95e2-c4a65547a5fb","added_by":"auto","created_at":"2025-07-30 08:11:17","extension":"docx","order_by":0,"title":"","display":"","copyAsset":false,"role":"supplement","size":1302081,"visible":true,"origin":"","legend":"","description":"","filename":"Supplementalmaterials.docx","url":"https://assets-eu.researchsquare.com/files/rs-7056346/v1/f144e0c192fbddeb13cd668b.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Prognostic Factors in Sporadic Bulbar Onset Motor Neuron Disease","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMotor neuron disease (MND) includes a wide category of neurodegenerative diseases mainly represented by amyotrophic lateral sclerosis (ALS), primary lateral sclerosis (PLS), progressive muscular atrophy (PMA) and progressive bulbar palsy (PBP). Bulbar onset and spinal onset MND are the two most common presentations, with bulbar onset MND accounting for approximately 20%-30% of the overall cases [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. Considering the irreversible nature of MND, early prediction of disease progression and prognosis remains a hotspot and challenge for relevant studies.\u003c/p\u003e\u003cp\u003eGenerally, median survival time of MND patients is 2 to 4 years, and those with bulbar onset portend rapid disease progression and inferior prognosis than those with spinal onset [\u003cspan additionalcitationids=\"CR3\" citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. However, some bulbar onset patients were reported to survive for more than 10 years, indicating its great heterogeneity [\u003cspan additionalcitationids=\"CR4\" citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e]. In this retrospective study, we aim to explore the characteristics of sporadic bulbar onset MND patients and to identify possible indicators for prognosis.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003e\u003cstrong\u003eCompliance with ethical standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe institutional ethics committee of Peking Union Medical College Hospital (PUMCH) approved this study (K22C2349). Informed consents were obtained from each individual.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePatient selection and definitions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis was a retrospective study based on the MND database of PUMCH in China. Patients were recruited from January 2014 to December 2023 and received routine follow-up at least every six months by clinic, telephone or social media (WeChat) until March 2024. Demographic and clinical information were collected at first consultation and updated during follow-up. Endpoint events referred to any causes of decease, tracheotomy and permanent non-invasive positive pressure ventilation (NIPPV) (\u0026gt;22 hours daily for \u0026gt;7days).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;Patients were diagnosed according to the revised EI Escorial criteria,[6] patients who only met the EI Escorial criteria (1994) for \u0026lsquo;suspected\u0026rsquo; were categorized into \u0026lsquo;unclassified\u0026rsquo; [7]. Familial MND, amyotrophic lateral sclerosis and frontotemporal dementia (ALS-FTD), facial onset sensory and motor neuronopathy (FOSMN) syndrome were excluded in this study.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;ALSFRS-R scores and duration from onset to first visit (DOFV) were recorded at first assessment at our facility. ALSFRS-R was further transformed to FRS [(ALSFRS-R at first assessment - 48) / DOFV] [8]. Duration from onset to next region (DNR) was defined as time from symptoms onset to first notice of limb weakness, atrophy, fasciculation, stiffness or dyspnea verified by either physical examination or neurogenic changes detected by electromyography (EMG).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; \u0026nbsp;According to variant physical signs presented at first assessment, bulbar onset MND patients were divided into upper motor neuron (UMN), lower motor neuron (LMN) and UMN+LMN phenotypes. UMN signs of bulbar region referred to pseudobulbar affect (PBA), positive palmomental or sucking reflex, pharyngeal hyperreflexia, while LMN signs referred to tongue atrophy or fasciculation, neurogenic changes of sternocleidomastoid muscle or lingua in EMG.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatistics analysis\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eData were analyzed in SPSS version 21 and R software 4.4.0. Significance was tested at the 5% level. Kolmogorov-Smirnov test was utilized to examine whether data were normally distributed, and data were presented as median (minimum, maximum) for skewed distribution or mean\u0026plusmn;SD for normal distribution. Continuous variables were analyzed by independent t-test, one-way analysis of variance (ANOVA), Mann-Whitney U test, or Kruskal-Wallis H test. Pairwise comparisons between groups were performed by Students Newman Keuls or Kruskal-Wallis one-way ANOVA test. Categorical variables were analyzed by \u0026chi;2 test or Fisher\u0026rsquo;s exact test. Cut-off values of DNR and age at onset were determined by maximum selected log-rank statistics in R software (packages: maxstat, minprop=0.2, maxprop=0.8). Survival curves were performed by Kaplan-Meier analysis in R software (packages: survival, survminer), covariates were analyzed by log-rank test and COX regression model.\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eDemographic and clinical features of bulbar onset MND patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; A total of 2507 MND patients were registered in our MND center (PUMCH) between Jan 01 2014 and Dec 31 2023, of these, 616 cases (24.6%) were bulbar onset and 441 of them were included in final analysis according to the selection criteria (figure 1). The demographic and clinical characteristics of study subjects were summarized in table 1. Amongst the 441 patients, 213 cases reached endpoint events during the entire follow-up and 37 (17.4%) of them reached endpoint events at least four years from symptom onset, detailed distribution of duration from onset to endpoint events was shown in\u0026nbsp;figure S1.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe clinical features and prognostic factors of patients reaching endpoint events\u0026nbsp;\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe 213 patients were divided into two groups based on whether endpoint events occurred within four years from onset (table2). From table 2, we could see that patients who reached endpoint events within four years had older onset age, faster ALSFRS-R decreasing rate (FRS) and shorter duration from onset to next region (DNR), proportions of clinical phenotypes were also different between groups.\u003c/p\u003e\n\u003cp\u003eCorrelations between duration from onset to endpoint events (DOE) and candidate variables were shown in scatter plots in figure S2. Slower FRS and longer DNR were associated with better prognosis. UMN phenotype generally possessed the best prognosis followed by LMN and UMN+LMN groups, with one exception in the UMN+LMN phenotype. Patients with early onset also reached endpoint events at earlier age than those with late onset (figure S3).\u003c/p\u003e\n\u003cp\u003eGender ratio was not significantly different between patients who reached endpoint events beyond and within 4 years (table2), nevertheless median DOE was still shorter in male than that in female patients [27.5 (6, 67) vs 32 (8, 89) months, p=0.042, figure S2 e].\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eComparisons among patients with different patterns of upper and lower motor neuron involvement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; In the 441 patients with routine follow-up, data of physical signs was missing in 3 patients, the rest 438 patients were classified into three groups based on different combinations of UMN and LMN signs at first assessment (table 3). The majority of patients had both UMN and LMN involved.\u003c/p\u003e\n\u003cp\u003eThere was no significant difference in gender ratio and onset age among three phenotypes.\u0026nbsp;Duration from onset to endpoint events or last visit was longest in UMN phenotype, followed by LMN and UMN+LMN group.\u0026nbsp;There were differences in duration from onset to first visit (DOFV), FRS and DNR among three phenotypes, however, no significant difference was identified between UMN and LMN group in multiple comparisons (table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAnalysis of prognostic factors in all MND patients\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eIn our cohort, 441 patients had been followed up regularly. Of the 228 cases who had not reached endpoint events, 79 (18.0%) of them had a disease duration of at least 4 years, of which the longest was 125 months\u0026nbsp;(detailed distribution seen in figure S1).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn univariate survival analysis, younger age at onset, slower FRS, longer DNR and pure UMN or LMN involvement at first assessment were predictive of favorite prognosis. In multivariate survival analysis, age at onset, FRS, DNR and pure UMN involvement were proved to be independent prognostic factors, older onset age, slower FRS, longer DNR and exclusive UMN involvement at first assessment led to better prognosis (table S1, figure 2d).\u003c/p\u003e\n\u003cp\u003eMaximum selected log-rank statistics for age at onset showed a best cut-off value of 58 years, and the commonly used value of 65 years was also presented (figure 2 a-b). Results for pure LMN involvement were inconsistent between univariate and multivariate analysis, and DNR was found to be the most important influential factor (if DNR removed, p values were 0.060 for LMN in multivariate analysis).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCombined analyses of duration from onset to next region (DNR) and patterns of UMN and LMN involvement\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFew patients had DNR for more than two years and the longest reported duration was 48 months. DNR cut-off values for overall cases and each phenotype were calculated by maximum selected log-rank statistics method, and a common cut-off value of 7 months was used for simplification in patients with LMN features (figure S4). DNR for at least 7 months generally indicated favorite survival prognosis, in patients with DNR for less than 7 months, additional UMN involvement was associated with poor prognosis (p=0.002) (figure 2c, table 4).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; Patients in the UMN group generally had the most favorite prognosis, nevertheless internal variances were still observed (table 3). 25 patients presented LMN signs in later disease course, 4 cases did not show LMN signs for at least 9, 28, 57 and 89 months respectively, while the rest 10 cases were unable to be determined. In univariate survival analysis, prognostic factors included DNR (p=0.023), but not gender (p=0.175), age at onset (p=0.092), FRS (p=0.146) and later LMN involvement (p=0.314).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eOn the basis of a large scale of patients, our retrospective study depicted the general picture of bulbar onset MND and confirmed its long-recognized heterogeneity especially in the aspect of endpoint events. Detailed comparisons with previous studies were summarized in table S2 [3-5, 9-15].\u003c/p\u003e\n\u003cp\u003eIn the perspective of overall MND patients, advanced age was linked to severe decline in ALSFRS-R bulbar scores and faster disease progression [3, 4, 12, 16-19]. Our study confirmed that bulbar onset patients with early onset generally had better survival prognosis than those with late onset, but their actual age at endpoint events was still earlier than those with late onset. The underlying mechanisms by which age at onset influenced prognosis remained elusive, probably due to higher burden of comorbidities (e.g. cardiovascular diseases, diabetes mellitus), reduced reserves of motor neurons and down-regulated enzyme activities in older population, or innate disease heterogeneity [17, 18].\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; Steeper FRS was widely acknowledged to be associated with inferior prognosis, and it was reliable whether from onset to first assessment or during the whole disease course [8, 20, 21]. However, the credibility of FRS reduced in the UMN phenotype, revealing its limitation in patients with minor changes in ALSFRS-R during an extended time period. As for DNR, interval from onset to next region was also proved to be significantly relevant to prognosis, independent of varied combinations of affected regions [22]. In studies related to bulbar onset MND, DNR and its cut-off values were used to distinguish between isolated bulbar palsy (IBP) and progressive bulbar palsy (PBP), and subjects with DNR for more than 6 months were commonly considered as IBP that led to relatively benign prognosis [15, 23, 24].\u003c/p\u003e\n\u003cp\u003eUMN and LMN lesions were generally independent of each other in disease severity and progression[25]. Our study demonstrated the detrimental effects of LMN involvement on prognosis, and various factors might lead to the different roles of UMN and LMN lesions. Patients with pure or predominantly UMN features mainly presented with stiffness, spasticity or active deep tendon reflexes, in which motor function was commonly preserved. By contrast, patients with pure or predominantly LMN involvement usually had muscle weakness, atrophy and complaints on dysphagia and choking, which increased the risk of aspiration and malnutrition and eventually led to adverse prognosis. Besides, drugs such as baclofen and benzodiazepines can be used to relieve stiffness and spasticity, while no medicines were currently available for muscle atrophy and weakness.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp; Based on the combined effects of DNR and patterns of UMN and LMN involvement, we proposed several classifications and established a diagnostic flow chart for bulbar onset MND. As shown in figure 3, the first step was to determine whether LMN features were presented at first assessment. For patients with LMN involvement, there were then three important time points in DNR, namely 7, 24 and 48 months, which led to different classifications. On the other hand, theoretically, patients with pure UMN signs were preferred to be classified by whether LMN signs were later involved. Surprisingly, later involvement of LMN or not had not been proved to be a prognostic factor, this might result from the few numbers of patients with pure UMN signs, limited follow-up duration to reach enough endpoint events and the fact that some patients developed LMN features soon after onset so that they were initially assigned into the UMN+LMN group.\u003c/p\u003e\n\u003cp\u003eThere were several limitations in our study. First, this was a retrospective study, certain data including diagnostic delay, forced vital capacity were missing. Second, regular follow-up of physical examination or electromyography examination were required to judge whether lesions had extended beyond the bulbar region, while it was difficult to ensure that the follow-up time interval of different patients were completely consistent, which could lead to a certain bias in the results of DNR, but this was unavoidable in clinical studies. Third, this was a single center study based on a tertiary center, which might lead to potential selection bias.\u003c/p\u003e\n\u003cp\u003eIn summary, our study identified age at onset, FRS, DNR and pure UMN involvement at first assessment as possible prognostic factors for sporadic bulbar onset MND. DNR and patterns of UMN and LMN involvement might be applied for disease classifications.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eFunding\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eCAMS Innovation Fund for Medical Sciences (CIFMS 2021-I2M-1-003), National High Level Hospital Clinical Research Funding (2022-PUMCH-B-017 and 2022-PUMCH-D-002), National Science and Technology Major Project (2022ZD0118003), The Strategic Priority Research Program (Pilot study) \u0026ldquo;Biological basis of aging and therapeutic strategies\u0026rdquo; of the Chinese Academy of Sciences (XDB39040000).\u003c/p\u003e\n\u003cp\u003eThe authors report there are no competing interests to declare.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eStatements of Authorship\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eJianfeng Ding: drafting on the manuscript, data collection and analysis; Nan Hu, Ming Qi and Huihong Tian: data collection; Liying Cui: study design and supervision; Mingsheng Liu and Jingwen Niu: study design, supervision and revision of the manuscript. All authors have read and approved the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompliance with Ethical Standards\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe institutional ethics committee of Peking Union Medical College Hospital (PUMCH) approved this study (K22C2349). Informed consents were obtained from involved participants.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eJianfeng Ding: drafting on the manuscript, data collection and analysis; Nan Hu, Ming Qi and Huihong Tian: data collection; Liying Cui: study design and supervision; Mingsheng Liu and Jingwen Niu: study design, supervision and revision of the manuscript. All authors reviewed the manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eAuthors thank all contributors and participants in this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eFoster LA and Salajegheh MK (2019) Motor Neuron Disease: Pathophysiology, Diagnosis, and Management\u003cem\u003e.\u003c/em\u003e Am J Med 132: 32-37 https://doi.org/10.1016/j.amjmed.2018.07.012.\u003c/li\u003e\n\u003cli\u003eFeldman EL, Goutman SA, Petri S, Mazzini L, Savelieff MG, Shaw PJ, and Sobue G (2022) Amyotrophic lateral sclerosis\u003cem\u003e.\u003c/em\u003e Lancet 400: 1363-1380 https://doi.org/10.1016/s0140-6736(22)01272-7.\u003c/li\u003e\n\u003cli\u003eCalvo A, Moglia C, Lunetta C, Marinou K, Ticozzi N, Ferrante GD, Scialo C, Sorar\u0026ugrave; G, Trojsi F, Conte A, Falzone YM, Tortelli R, Russo M, Chi\u0026ograve; A, Sansone VA, Mora G, Silani V, Volanti P, Caponnetto C, Querin G, Monsurr\u0026ograve; MR, Sabatelli M, Riva N, Logroscino G, Messina S, Fini N, and Mandrioli J (2017) Factors predicting survival in ALS: a multicenter Italian study\u003cem\u003e.\u003c/em\u003e J Neurol 264: 54-63 https://doi.org/10.1007/s00415-016-8313-y.\u003c/li\u003e\n\u003cli\u003eChen L, Zhang B, Chen R, Tang L, Liu R, Yang Y, Yang Y, Liu X, Ye S, Zhan S, and Fan D (2015) Natural history and clinical features of sporadic amyotrophic lateral sclerosis in China\u003cem\u003e.\u003c/em\u003e J Neurol Neurosurg Psychiatry 86: 1075-81 https://doi.org/10.1136/jnnp-2015-310471.\u003c/li\u003e\n\u003cli\u003eChi\u0026ograve; A, Calvo A, Moglia C, Mazzini L, and Mora G (2011) Phenotypic heterogeneity of amyotrophic lateral sclerosis: a population based study\u003cem\u003e.\u003c/em\u003e J Neurol Neurosurg Psychiatry 82: 740-6 https://doi.org/10.1136/jnnp.2010.235952.\u003c/li\u003e\n\u003cli\u003eBrooks BR, Miller RG, Swash M, and Munsat TL (2000) El Escorial revisited: revised criteria for the diagnosis of amyotrophic lateral sclerosis\u003cem\u003e.\u003c/em\u003e Amyotroph Lateral Scler Other Motor Neuron Disord 1: 293-9 https://doi.org/10.1080/146608200300079536.\u003c/li\u003e\n\u003cli\u003eBrooks BR (1994) El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis. Subcommittee on Motor Neuron Diseases/Amyotrophic Lateral Sclerosis of the World Federation of Neurology Research Group on Neuromuscular Diseases and the El Escorial \u0026quot;Clinical limits of amyotrophic lateral sclerosis\u0026quot; workshop contributors\u003cem\u003e.\u003c/em\u003e J Neurol Sci 124 Suppl: 96-107 https://doi.org/10.1016/0022-510x(94)90191-0.\u003c/li\u003e\n\u003cli\u003eWesteneng HJ, Debray TPA, Visser AE, van Eijk RPA, Rooney JPK, Calvo A, Martin S, McDermott CJ, Thompson AG, Pinto S, Kobeleva X, Rosenbohm A, Stubendorff B, Sommer H, Middelkoop BM, Dekker AM, van Vugt J, van Rheenen W, Vajda A, Heverin M, Kazoka M, Hollinger H, Gromicho M, K\u0026ouml;rner S, Ringer TM, R\u0026ouml;diger A, Gunkel A, Shaw CE, Bredenoord AL, van Es MA, Corcia P, Couratier P, Weber M, Grosskreutz J, Ludolph AC, Petri S, de Carvalho M, Van Damme P, Talbot K, Turner MR, Shaw PJ, Al-Chalabi A, Chi\u0026ograve; A, Hardiman O, Moons KGM, Veldink JH, and van den Berg LH (2018) Prognosis for patients with amyotrophic lateral sclerosis: development and validation of a personalised prediction model\u003cem\u003e.\u003c/em\u003e Lancet Neurol 17: 423-433 https://doi.org/10.1016/s1474-4422(18)30089-9.\u003c/li\u003e\n\u003cli\u003eNalini A, Thennarasu K, Gourie-Devi M, Shenoy S, and Kulshreshtha D (2008) Clinical characteristics and survival pattern of 1,153 patients with amyotrophic lateral sclerosis: experience over 30 years from India\u003cem\u003e.\u003c/em\u003e J Neurol Sci 272: 60-70 https://doi.org/10.1016/j.jns.2008.04.034.\u003c/li\u003e\n\u003cli\u003eHe Z, Sun B, Feng F, Bai J, Wang H, Wang H, Yang F, Cui F, and Huang X (2022) Time of symptoms beyond the bulbar region predicts survival in bulbar onset amyotrophic lateral sclerosis\u003cem\u003e.\u003c/em\u003e Neurol Sci 43: 1817-1822 https://doi.org/10.1007/s10072-021-05556-w.\u003c/li\u003e\n\u003cli\u003eTalman P, Duong T, Vucic S, Mathers S, Venkatesh S, Henderson R, Rowe D, Schultz D, Edis R, Needham M, Macdonnell R, McCombe P, Birks C, and Kiernan M (2016) Identification and outcomes of clinical phenotypes in amyotrophic lateral sclerosis/motor neuron disease: Australian National Motor Neuron Disease observational cohort\u003cem\u003e.\u003c/em\u003e BMJ Open 6: e012054 https://doi.org/10.1136/bmjopen-2016-012054.\u003c/li\u003e\n\u003cli\u003eMcCluskey G, Duddy W, Haffey S, Morrison K, Donaghy C, and Duguez S (2022) Epidemiology and survival trends of motor neurone disease in Northern Ireland from 2015 to 2019\u003cem\u003e.\u003c/em\u003e Eur J Neurol 29: 707-714 https://doi.org/10.1111/ene.15172.\u003c/li\u003e\n\u003cli\u003eZhang H, Chen L, Tian J, and Fan D (2021) Disease duration of progression is helpful in identifying isolated bulbar palsy of amyotrophic lateral sclerosis\u003cem\u003e.\u003c/em\u003e BMC Neurol 21: 405 https://doi.org/10.1186/s12883-021-02438-8.\u003c/li\u003e\n\u003cli\u003eTurner MR, Scaber J, Goodfellow JA, Lord ME, Marsden R, and Talbot K (2010) The diagnostic pathway and prognosis in bulbar-onset amyotrophic lateral sclerosis\u003cem\u003e.\u003c/em\u003e J Neurol Sci 294: 81-5 https://doi.org/10.1016/j.jns.2010.03.028.\u003c/li\u003e\n\u003cli\u003eZhang HG, Chen L, Tang L, Zhang N, and Fan DS (2017) Clinical Features of Isolated Bulbar Palsy of Amyotrophic Lateral Sclerosis in Chinese Population\u003cem\u003e.\u003c/em\u003e Chin Med J (Engl) 130: 1768-1772 https://doi.org/10.4103/0366-6999.211538.\u003c/li\u003e\n\u003cli\u003eKihira T, Yoshida S, Okamoto K, Kazimoto Y, Ookawa M, Hama K, Miwa H, and Kondo T (2008) Survival rate of patients with amyotrophic lateral sclerosis in Wakayama Prefecture, Japan, 1966 to 2005\u003cem\u003e.\u003c/em\u003e J Neurol Sci 268: 95-101 https://doi.org/10.1016/j.jns.2007.11.011.\u003c/li\u003e\n\u003cli\u003eYokoi D, Atsuta N, Watanabe H, Nakamura R, Hirakawa A, Ito M, Watanabe H, Katsuno M, Izumi Y, Morita M, Taniguchi A, Oda M, Abe K, Mizoguchi K, Kano O, Kuwabara S, Kaji R, and Sobue G (2016) Age of onset differentially influences the progression of regional dysfunction in sporadic amyotrophic lateral sclerosis\u003cem\u003e.\u003c/em\u003e J Neurol 263: 1129-36 https://doi.org/10.1007/s00415-016-8109-0.\u003c/li\u003e\n\u003cli\u003eAtsuta N, Watanabe H, Ito M, Tanaka F, Tamakoshi A, Nakano I, Aoki M, Tsuji S, Yuasa T, Takano H, Hayashi H, Kuzuhara S, and Sobue G (2009) Age at onset influences on wide-ranged clinical features of sporadic amyotrophic lateral sclerosis\u003cem\u003e.\u003c/em\u003e J Neurol Sci 276: 163-9 https://doi.org/10.1016/j.jns.2008.09.024.\u003c/li\u003e\n\u003cli\u003eSu WM, Cheng YF, Jiang Z, Duan QQ, Yang TM, Shang HF, and Chen YP (2021) Predictors of survival in patients with amyotrophic lateral sclerosis: A large meta-analysis\u003cem\u003e.\u003c/em\u003e EBioMedicine 74: 103732 https://doi.org/10.1016/j.ebiom.2021.103732.\u003c/li\u003e\n\u003cli\u003eKollewe K, Mauss U, Krampfl K, Petri S, Dengler R, and Mohammadi B (2008) ALSFRS-R score and its ratio: a useful predictor for ALS-progression\u003cem\u003e.\u003c/em\u003e J Neurol Sci 275: 69-73 https://doi.org/10.1016/j.jns.2008.07.016.\u003c/li\u003e\n\u003cli\u003eKimura F, Fujimura C, Ishida S, Nakajima H, Furutama D, Uehara H, Shinoda K, Sugino M, and Hanafusa T (2006) Progression rate of ALSFRS-R at time of diagnosis predicts survival time in ALS\u003cem\u003e.\u003c/em\u003e Neurology 66: 265-7 https://doi.org/10.1212/01.wnl.0000194316.91908.8a.\u003c/li\u003e\n\u003cli\u003eFujimura-Kiyono C, Kimura F, Ishida S, Nakajima H, Hosokawa T, Sugino M, and Hanafusa T (2011) Onset and spreading patterns of lower motor neuron involvements predict survival in sporadic amyotrophic lateral sclerosis\u003cem\u003e.\u003c/em\u003e J Neurol Neurosurg Psychiatry 82: 1244-9 https://doi.org/10.1136/jnnp-2011-300141.\u003c/li\u003e\n\u003cli\u003eBurrell JR, Vucic S, and Kiernan MC (2011) Isolated bulbar phenotype of amyotrophic lateral sclerosis\u003cem\u003e.\u003c/em\u003e Amyotroph Lateral Scler 12: 283-9 https://doi.org/10.3109/17482968.2011.551940.\u003c/li\u003e\n\u003cli\u003eJawdat O, Statland JM, Barohn RJ, Katz JS, and Dimachkie MM (2015) Amyotrophic Lateral Sclerosis Regional Variants (Brachial Amyotrophic Diplegia, Leg Amyotrophic Diplegia, and Isolated Bulbar Amyotrophic Lateral Sclerosis)\u003cem\u003e.\u003c/em\u003e Neurol Clin 33: 775-85 https://doi.org/10.1016/j.ncl.2015.07.003.\u003c/li\u003e\n\u003cli\u003eRavits J, Paul P, and Jorg C (2007) Focality of upper and lower motor neuron degeneration at the clinical onset of ALS\u003cem\u003e.\u003c/em\u003e Neurology 68: 1571-5 https://doi.org/10.1212/01.wnl.0000260965.20021.47.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 Demographic and clinical characteristics of bulbar onset MND patients with follow-up (Total n = 441)\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"680\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatients reaching\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eendpoint events\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en = 213\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u003cstrong\u003ePatients not reaching endpoint events\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en = 228\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eOverall\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en = 441\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eFemale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e104 (48.8)\u003c/p\u003e\n \u003cp\u003e109 (51.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e95 (41.7)\u003c/p\u003e\n \u003cp\u003e133 (58.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e199 (45.1)\u003c/p\u003e\n \u003cp\u003e242 (54.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at onset (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e59 (29, 78)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e56 (27, 77)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e57 (27, 78)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDOFV (months)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e11 (2, 75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e12 (3, 89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e12 (2, 89)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eALSFRS-R at first assessment (points)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e39 (21, 47)\u003c/p\u003e\n \u003cp\u003en = 186\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e39 (21, 47)\u003c/p\u003e\n \u003cp\u003en = 221\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e39 (21, 47)\u003c/p\u003e\n \u003cp\u003en = 407\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFRS (points/month)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e-0.67 (-3.50, -0.10)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e-0.60 (-4.00, -0.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e-0.64 (-4.00, -0.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuration to next region (months)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; DNR\u0026le;12\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;12\u003c/strong\u003e\u003cstrong\u003e＜\u003c/strong\u003e\u003cstrong\u003eDNR\u0026le;24\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;24\u003c/strong\u003e\u003cstrong\u003e＜\u003c/strong\u003e\u003cstrong\u003eDNR\u0026le;36\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp;36\u003c/strong\u003e\u003cstrong\u003e＜\u003c/strong\u003e\u003cstrong\u003eDNR\u0026le;48\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026nbsp; Undetermined or missing\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e6 (1, 37)\u003c/p\u003e\n \u003cp\u003e105 (49.3)\u003c/p\u003e\n \u003cp\u003e21 (9.9)\u003c/p\u003e\n \u003cp\u003e1 (0.5)\u003c/p\u003e\n \u003cp\u003e1 (0.5)\u003c/p\u003e\n \u003cp\u003e85 (39.9)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e8 (1, 48)\u003c/p\u003e\n \u003cp\u003e105 (46.1)\u003c/p\u003e\n \u003cp\u003e26 (11.4)\u003c/p\u003e\n \u003cp\u003e7 (3.1)\u003c/p\u003e\n \u003cp\u003e1 (0.4)\u003c/p\u003e\n \u003cp\u003e89 (39.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e6 (1, 48)\u003c/p\u003e\n \u003cp\u003e210 (47.6)\u003c/p\u003e\n \u003cp\u003e47 (10.7)\u003c/p\u003e\n \u003cp\u003e8 (1.8)\u003c/p\u003e\n \u003cp\u003e2 (0.5)\u003c/p\u003e\n \u003cp\u003e174 (39.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical phenotypes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eUMN\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLMN\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eUMN+LMN\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eUnable to determine\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18 (8.5)\u003c/p\u003e\n \u003cp\u003e53 (24.9)\u003c/p\u003e\n \u003cp\u003e142 (66.7)\u003c/p\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e21 (9.2)\u003c/p\u003e\n \u003cp\u003e59 (25.9)\u003c/p\u003e\n \u003cp\u003e145 (63.6)\u003c/p\u003e\n \u003cp\u003e3 (1.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e39 (8.8)\u003c/p\u003e\n \u003cp\u003e112 (25.4)\u003c/p\u003e\n \u003cp\u003e287 (65.1)\u003c/p\u003e\n \u003cp\u003e3 (0.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 236px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRevised EI Escorial category\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eat first assessment\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eClinically definite\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eClinically probable\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLab-supported probable\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eClinically possible\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eUnclassified*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e36 (16.9)\u003c/p\u003e\n \u003cp\u003e53 (24.9)\u003c/p\u003e\n \u003cp\u003e44 (20.7)\u003c/p\u003e\n \u003cp\u003e64 (30.0)\u003c/p\u003e\n \u003cp\u003e16 (7.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 161px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e35 (15.4)\u003c/p\u003e\n \u003cp\u003e61 (26.8)\u003c/p\u003e\n \u003cp\u003e39 (17.1)\u003c/p\u003e\n \u003cp\u003e60 (26.3)\u003c/p\u003e\n \u003cp\u003e33 (14.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e71 (16.1)\u003c/p\u003e\n \u003cp\u003e114 (25.9)\u003c/p\u003e\n \u003cp\u003e83 (18.8)\u003c/p\u003e\n \u003cp\u003e124 (28.1)\u003c/p\u003e\n \u003cp\u003e49 (11.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 0px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuration from onset to endpoint events or last visit (months)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e29 (6, 89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e30 (9, 125)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 0px;\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: DOFV, duration from onset to first visit; FRS = (ALSFRS-R at assessment\u0026ndash; 48) / DOFV; UMN, upper motor neuron; LMN, lower motor neuron; DNR, duration from onset to next region.\u003c/p\u003e\n\u003cp\u003eNote: Data were presented as n (%) or median (minimum, maximum)\u003c/p\u003e\n\u003cp\u003e*Category of \u0026lsquo;suspected\u0026rsquo; in EI Escorial criteria (3 cases missing).\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2 Comparisons between groups within and beyond 4 years to endpoint events (Total n = 213)\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"603\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 385px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuration from onset to endpoint events\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026ge;4 years\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en = 37\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;4 years\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003en = 176\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value *\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender \u0026nbsp; \u0026nbsp; \u0026nbsp;Male\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eFemale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e14\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e23\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e90\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e86\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.141\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at onset (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e53.03\u003c/strong\u003e \u003cstrong\u003e\u0026plusmn;\u003c/strong\u003e \u003cstrong\u003e10.67\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e55 (29, 75)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e58.47\u003c/strong\u003e \u003cstrong\u003e\u0026plusmn;\u003c/strong\u003e \u003cstrong\u003e9.65\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e59.5 (32, 78)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.003\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDOFV (months)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e18 (2, 75)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e10 (3, 42)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eALSFRS-R at first assessment (points)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e39 (25, 47)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e39 (21, 47)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.455\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFRS (points/month)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-0.41 (-1.07, -0.14)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e-0.71 (-3.50, -0.1)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDNR (months)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e14 (2, 37)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003en = 21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e5 (1, 22)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003en = 107\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e\u0026lt;0.001\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical phenotypes\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eUMN\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLMN\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eUMN+LMN\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e8\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e10\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e19\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e10\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e43\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e123\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.004\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 217px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eRevised EI Escorial category at first assessment\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eClinically definite\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eClinically probable\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eLab-supported probable\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eClinically possible\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 142px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e6\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e7\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e4\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e17\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e30\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e46\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e40\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003e47\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 111px;\"\u003e\n \u003cp\u003e\u003cstrong\u003e0.171\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: DOFV, duration from onset to first visit; FRS = (ALSFRS-R at assessment\u0026ndash; 48) / DOFV; UMN, upper motor neuron; LMN, lower motor neuron; DNR, duration from onset to next region.\u003c/p\u003e\n\u003cp\u003eNote: Data were presented as median (minimum, maximum) or mean\u0026plusmn;SD;\u003c/p\u003e\n\u003cp\u003e*\u0026chi;2 test for gender, clinical phenotypes; Fisher\u0026rsquo;s exact test for revised EI Escorial category; Mann-Whitney U test for TOFV, ALSFRS-R, FRS and DNR; independent t-test for age at onset.\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 3 Comparisons among clinical phenotypes in bulbar onset MND patients with follow-up (Total n = 438)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"933\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 221px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eVariables\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"3\" valign=\"top\" style=\"width: 418px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical phenotypes\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" rowspan=\"2\" style=\"width: 80px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eP value *\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"4\" style=\"width: 215px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAdjusted p value \u003csup\u003e\u0026dagger;\u003c/sup\u003e\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eUMN (U)\u003c/p\u003e\n \u003cp\u003en =\u0026nbsp;39\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eLMN (L)\u003c/p\u003e\n \u003cp\u003en = 112\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003eUMN+LMN (U+L)\u003c/p\u003e\n \u003cp\u003en = 287\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003eU vs L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 79px;\"\u003e\n \u003cp\u003eU vs U+L\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\n \u003cp\u003eL vs U+L\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 221px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eGender \u0026nbsp; \u0026nbsp;Female\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eMale\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e27 (69.2)\u003c/p\u003e\n \u003cp\u003e12 (30.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e56 (50.0)\u003c/p\u003e\n \u003cp\u003e56 (50.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e157 (54.7)\u003c/p\u003e\n \u003cp\u003e130 (45.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"6\" style=\"width: 295px;\"\u003e\n \u003cp\u003e0.115\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 221px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eAge at onset (years)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e57 (31, 78)\u003c/p\u003e\n \u003cp\u003e56.1\u0026plusmn;10.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e58 (27, 77)\u003c/p\u003e\n \u003cp\u003e57.0\u0026plusmn;10.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e57 (31, 78)\u003c/p\u003e\n \u003cp\u003e56.6\u0026plusmn;10.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"6\" valign=\"top\" style=\"width: 295px;\"\u003e\n \u003cp\u003e0.842\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 221px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDOFV (months)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 139px;\"\u003e\n \u003cp\u003e17 (4, 89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 139px;\"\u003e\n \u003cp\u003e13.5 (3, 81)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 139px;\"\u003e\n \u003cp\u003e11 (2, 70)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 87px;\"\u003e\n \u003cp\u003e0.999\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e0.005\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eFRS (points/month)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e-0.40 (-1.45, -0.03)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e-0.50 (-3.50, -0.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e-0.71 (-4.00, -0.06)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 87px;\"\u003e\n \u003cp\u003e0.080\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" style=\"width: 70px;\"\u003e\n \u003cp\u003e0.002\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDNR (months)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNo. of known DNR\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e15 (6, 36)\u003c/p\u003e\n \u003cp\u003e21\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e10.5 (1, 48)\u003c/p\u003e\n \u003cp\u003e58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e5 (1, 30)\u003c/p\u003e\n \u003cp\u003e188\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026lt;0.001 \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e0.134\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 221px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eStatus at last visit\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eNo. of endpoint events\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDuration from onset to\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eendpoint events (months)\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eDuration from onset to\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003elast visit \u003csup\u003e\u0026Dagger;\u003c/sup\u003e (months)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e18\u003c/p\u003e\n \u003cp\u003e45.50 (27, 82)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e52 (22, 125)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e53\u003c/p\u003e\n \u003cp\u003e35 (12, 69)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e34 (9, 94)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 139px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e142\u003c/p\u003e\n \u003cp\u003e25.50 (6, 89)\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e25 (9, 84)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.028\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.006\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 61px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 87px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.019\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 70px;\"\u003e\n \u003cp\u003e\u0026nbsp;\u003c/p\u003e\n \u003cp\u003e0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd style=\"width: 221px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 139px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 139px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 139px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 61px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 19px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 77px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 2px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003ctd style=\"width: 68px;\"\u003e\u003cbr\u003e\u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: DOFV, duration from onset to first visit; FRS = (ALSFRS-R at assessment\u0026ndash; 48) / DOFV; UMN, upper motor neuron; LMN, lower motor neuron; DNR, duration from onset to next region.\u003c/p\u003e\n\u003cp\u003eNote: Data were presented as n (%) or median (minimum, maximum) or mean\u0026plusmn;SD; *\u003csup\u003e\u0026nbsp;\u003c/sup\u003e\u0026chi;2 test for Gender, Kruskal-Wallis H test for the rest, \u003csup\u003e\u0026dagger;\u003c/sup\u003e Kruskal-Wallis one-way ANOVA test for pairwise comparisons; \u003csup\u003e\u0026Dagger;\u003c/sup\u003e in patients not reaching endpoint events.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 4 Combined analyses of duration from onset to next region and patterns of UMN and LMN involvement. (Total n = 211)\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\" width=\"576\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eClinical phenotype\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"5\" valign=\"top\" style=\"width: 472px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eDuration from onset to endpoint events (months)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003eDNR\u003c/p\u003e\n \u003cp\u003e\u0026lt;7months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003eNo. of events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003eDNR\u003c/p\u003e\n \u003cp\u003e\u0026ge;7months\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003eNo. of events\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eLMN\u003c/strong\u003e\u003c/p\u003e\n \u003cp\u003e\u003cstrong\u003eUMN+LMN\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e29 (12, 52)\u003c/p\u003e\n \u003cp\u003e22 (6, 61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e28\u003c/p\u003e\n \u003cp\u003e94\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e43 (16, 69)\u003c/p\u003e\n \u003cp\u003e40 (17, 89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e25\u003c/p\u003e\n \u003cp\u003e46\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e0.003\u003c/p\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u003cstrong\u003eTotal*\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 117px;\"\u003e\n \u003cp\u003e24 (6, 61)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 83px;\"\u003e\n \u003cp\u003e125\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 92px;\"\u003e\n \u003cp\u003e41 (16, 89)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 77px;\"\u003e\n \u003cp\u003e86\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 104px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eAbbreviations: UMN, upper motor neuron; LMN, lower Motor neuron; DNR, duration from onset to next region.\u003c/p\u003e\n\u003cp\u003eNote: Data were presented as n or median (minimum, maximum), within-group p value for LMN and UMN+LMN phenotypes: 1) DNR\u0026ge;7months, p=0.470; 2) DNR \u0026lt;7 months, p=0.002\u003c/p\u003e\n\u003cp\u003e*UMN, LMN and UMN+LMN phenotypes;\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Motor neuron disease, bulbar palsy, prognostic analysis, classifications","lastPublishedDoi":"10.21203/rs.3.rs-7056346/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7056346/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eObjective\u003c/h2\u003e\u003cp\u003eTo identify possible prognostic factors of sporadic bulbar onset motor neuron disease (MND).\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eOur study involved bulbar onset MND patients between January 2014 and December 2023. Decease, tracheotomy and permanent non-invasive positive pressure ventilation were defined as endpoint events. Clinical data were retrospectively collected, cut-off values of duration from onset to next region were calculated for further evaluation of its prognostic effect and disease classification.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eA total of 537 patients initially met eligibility and 441 of them were routinely followed up, 213 cases reached endpoint events. Female versus male ratio was 1.22, and median age at onset was 57 years. Median duration from onset to next region and onset to endpoint events were 6 months and 29 months respectively. Lower age at onset, slower ALSFRS-R decreasing rate, longer duration from onset to next region and pure upper motor neuron (UMN) involvement at first visit were associated with favorite prognosis. Cut-off values of duration from onset to next region were defined as 7 and 10 months respectively for patients with and without lower motor neuron (LMN) involved.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eWe identified age at onset, duration from onset to next region, ALSFRS-R decreasing rate and exclusive UMN involvement at first assessment as possible prognostic factors. A classification diagram for bulbar onset MND was proposed based on patterns of UMN and LMN involvement and duration from onset to next region.\u003c/p\u003e","manuscriptTitle":"Prognostic Factors in Sporadic Bulbar Onset Motor Neuron Disease","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-30 08:03:12","doi":"10.21203/rs.3.rs-7056346/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"b222e8e8-f918-4063-8777-b6412d64ad29","owner":[],"postedDate":"July 30th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-09-01T15:09:00+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-30 08:03:12","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7056346","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7056346","identity":"rs-7056346","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}