Prognostic Value of Time to Generalization in 71 Chinese Patients with Sporadic Amyotrophic Lateral Sclerosis
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that affects both upper and lower motor neurons. Despite extensive research, the underlying cause of ALS remains unclear, and most patients succumb to respiratory failure within 3 to 5 years of symptom onset, although a small percentage may survive for 10 years or more. Early identification of prognostic factors is crucial for patient care, resource allocation, and clinical trial stratification. One such factor is the time taken for symptoms to spread from spinal or bulbar regions to both, known as the time to generalization (TTG). This retrospective study aimed to evaluate the prognostic value of TTG in Chinese patients with sporadic ALS.
The study included 71 patients diagnosed with definite, probable, or possible ALS at the Chinese People’s Liberation Army (PLA) General Hospital between July 2009 and November 2016. The diagnosis was based on the revised El Escorial criteria, and all patients exhibited sporadic ALS. Clinical variables recorded included age at symptom onset, gender, site of symptom onset, diagnostic latency (time from symptom onset to diagnosis), TTG, diagnostic category, ALS Functional Rating Scale-revised (ALSFRS-r) score, percent predicted forced vital capacity (FVC%), and disease progression rate (DPR) at diagnosis. Follow-up for survival was conducted every 3 months via phone until December 2017, with survival time defined as the period from symptom onset to death or tracheotomy.
The mean age at symptom onset was 54.12 years, with a standard deviation of 10.20 years, ranging from 25 to 72 years. The cohort comprised 37 males (52%) and 34 females (48%), with a male-to-female ratio of 1.09. Among the patients, 18 (25%) had bulbar onset, and 53 (75%) had limb onset ALS. The median diagnostic latency was 11 months, ranging from 2 to 77 months. Of the 71 patients, 51 were classified as definite, 12 as probable, and eight as possible ALS. The mean ALSFRS-r score was 38, with a standard deviation of 6, and the mean DPR was 0.54. The FVC% ranged from 26.2% to 129.0%, with a mean value of 80.1%. The median TTG was 10 months, ranging from 1 to 69 months. By the end of the follow-up period, 45 patients (63%) had died or undergone tracheostomy, while 26 (37%) were still alive. The median survival time from symptom onset was 41 months, with a 95% confidence interval of 34 to 47 months.
Univariate Kaplan-Meier analysis identified several factors independently affecting survival, including age at symptom onset, TTG, diagnostic latency, and DPR. Age at symptom onset significantly impacted survival, with a log-rank value of 15.652 and a p-value of less than 0.0001. Similarly, TTG showed a strong association with survival, with a log-rank value of 14.728 and a p-value of less than 0.0001. Diagnostic latency also significantly affected survival, with a log-rank value of 11.997 and a p-value of 0.001. DPR at diagnosis was another significant factor, with a log-rank value of 6.50 and a p-value of 0.011. In contrast, gender, site of onset, diagnostic category, ALSFRS-r score, and FVC% at diagnosis were not found to be significant prognostic factors.
Multivariate Cox proportional hazards analysis further confirmed the prognostic value of TTG and age at symptom onset. TTG had the strongest impact on survival time, with a hazard ratio of 0.926 and a p-value of 0.01. Age at symptom onset also significantly affected survival, with a hazard ratio of 1.079 and a p-value of 0.021. Diagnostic latency and DPR at diagnosis did not show significant independent effects on survival in the multivariate model.
Spearman rho correlation analysis was conducted to explore the relationships between TTG and other clinical variables. TTG was inversely correlated with ALSFRS-r score and DPR at diagnosis, with correlation coefficients of -0.288 and -0.620, respectively, and p-values of 0.004 and less than 0.0001. TTG was positively correlated with diagnostic latency, with a correlation coefficient of 0.705 and a p-value of less than 0.0001. No significant correlations were found between TTG and age at onset, gender, diagnostic category, or FVC% at diagnosis. Additionally, TTG was shorter in bulbar onset patients (mean: 9.29 months) compared to limb onset patients (mean: 14.19 months).
The study’s findings highlight the prognostic significance of TTG in Chinese patients with sporadic ALS. A shorter TTG was associated with a worse prognosis, as indicated by reduced survival times. This aligns with previous research suggesting that the time of disease spread reflects the progression rate of neuroaxonal damage. Neurofilament heavy chain and light chain levels in body fluids, such as cerebrospinal fluid (CSF) and plasma, have been recognized as biological markers of neuroaxonal degeneration, reflecting disease activity and progression in ALS. High levels of these markers have been associated with a short TTG, further supporting the role of TTG as an external expression of neuroaxonal degeneration in ALS.
The study also corroborated the prognostic value of other factors, such as age at symptom onset, diagnostic latency, and DPR at diagnosis. Older age at symptom onset and shorter diagnostic latency were associated with worse survival outcomes, consistent with findings from previous studies. Bulbar onset ALS was also linked to shorter survival times compared to limb onset ALS. However, gender, diagnostic category, ALSFRS-r score, and FVC% at diagnosis did not significantly impact survival in this cohort.
One of the strengths of this study is its focus on TTG as a prognostic factor, which has been less studied in Asian populations. The results suggest that TTG can serve as an effective early-stage prognostic marker, providing valuable information for patient care planning and clinical trial stratification. However, the study has some limitations, including the relatively small sample size and the reliance on patient recall for determining TTG. Future prospective population-based studies with larger cohorts are needed to validate these findings and further explore the prognostic value of TTG in ALS.
In conclusion, this study demonstrates that TTG is a significant predictor of survival in Chinese patients with sporadic ALS. A shorter TTG is associated with a worse prognosis, and TTG has the strongest impact on survival compared to other clinical variables. These findings underscore the importance of early identification of prognostic factors in ALS and highlight the potential of TTG as a valuable marker for disease progression and outcome.
doi.org/10.1097/CM9.0000000000000200
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