Time Of Spread And Survival In Bulbar-onset Amyotrophic Lateral Sclerosis:a Clinical Study In 159 Cases

Background:Amyotrophic lateral sclerosis(ALS)is a progressive neurodegenerative disorder that involves both upper and lower motor neurons.Bulbar-onset patients constitute 25%-35%of most ALS clinic populations.Etiology and pathogenesis of ALS are not well understood,and heterogeneity lies in disease spread pattern and survival.There is constant debating over characteristics of disease spread in ALS.Results are limited and conclusions are yet reach in regard of clinical characteristics and survival in bulbar-onset ALS patients based on Chinese population.Objective:This study aimed to explore the clinical characteristics and disease spread pattern in sporadic bulbar-onset ALS patients and their effects on survival.Method:Sporadic ALS patients seen at Peking Union Medical College Hospital from January 2013 to November 2017 were prospectively recorded in a database as part of clinical care.Patients with bulbar-onset disease were included in this study.Age at onset,gender,diagnostic delay,site of next involvement,interval for spread to site of next involvement,nutritional status and ALS Functional Rating Scale(ALSFRS-R)were collected at baseline.Death or tracheotomy was used as composite endpoint to study mortality.Survival data was analyzed using Kaplan-Meier survival curve and Cox regression analysis.Result:Of all 159 bulbar-onset ALS patients,mean age at onset was 56.0±10.4 years old;ratio of male to female was 0.87:1.Diagnostic delay was 13.9±9.8 months on average and 12 months in median.Till last follow-up in April 2019,100 of 159 patients(62.9%)reached composite endpoint with a median survival time of 28.0 months.Three-year survival rate was estimated as 37%and five-year 17%using K-M curve.Estimated median survival time from symptoms onset was 39(95%CI:32-46)months overall.Site of next involvement was determined in 156 patients,where it was upper-limb in 82.4%and lower-limb in 17.6%patients.Females were found prone to have upper-limb as site of next involvement.No significant differences were found in mortality rates after stratifying patients according to site of next involvement.The mean time interval for spread to site of next involvement was 11.3±9.9 months.Median survival time varied significantly after stratifying patients according to interval for spread to site of next involvement(≤6 months:26 months vs.>6 months,47 months,p<0.001).After adjustment for age at onset,gender and diagnostic delay,mortality rate in fast progression group was 2.8 of that in slow progression group(p<0.001).Positive correlation was established in survival without tracheotomy with interval for spread to site of next involvement in patients who reached composite endpoint(r=0.585,p<0.001),with adjusted R2 of 42.9%.Interval for spread to site of next involvement was found prone to be positively correlated with age at onset(r=0.133,p=0.095).Patients with early onset(Age at onset:≤60 years old)had higher bulbar points of ALSFRS-R than those with late onset(9 vs.8,p=0.022);though whole points of ALSFRS-R did not vary significantly between two groups.After adjustment of gender,diagnostic delay and interval for spread to site of next involvement,mortality rate in late onset group was 2.1 of that in early onset group(p=0.001);mortality rate increases with age at onset(p=0.003).Interval for spread to site of next involvement was found to be positively correlated with diagnostic delay(r=0.674,p<0.001).After adjustment of gender,age at onset and interval for spread to site of next involvement,mortality rate and median survival time were not significantly influenced by diagnostic delay.Conclusion:1.Interval for spread to site of next involvement had a strong association with survival and mortality increases with the decrease of interval for spread to site of next involvement.Overall survival in months from symptom onset approximated to two years plus interval for spread to site of next involvement.2.Age at onset was a significant prognostic factor,and independent of interval for spread to site of next involvement.Mortality rate increases with age at onset.3.Site of next involvement was upper-limb in 82.4%and lower-limb in 17.6%patients.No significant differences were found in mortality rates in patients with different site of next involvement.4.Diagnostic delay was positively correlated with interval for spread to site of next involvement.