Rate of change in upper and lower motor neuron burden is associated with survival in amyotrophic lateral sclerosis

Background We hypothesize that the rate of change in upper (Delta UMN) and lower (Delta LMN) motor neuron signs from symptom onset to first clinical assessment represent best predictors of survival and disease progression in amyotrophic lateral sclerosis (ALS) compared to singular quantification of UMN and LMN involvement. Methods A retrospective inpatient cohort of 1000 ALS patients was evaluated. The burden of UMN and LMN signs was assessed using the Penn Upper Motor Neuron Score and Lower Motor Neuron Score, respectively. For 421 patients, we compute the ENCALS survival model.Univariate and regularized Cox regressions were conducted to estimate the effect of the aforementioned variables on survival. The ROC curve analysis was then employed to a training sub-cohort to identify a Delta LMN cut-off value discriminating ALS patients with prolonged vs short survival. This cut-off value was then cross validated on a test sub-cohort. A multinomial regression model was used to compare different Delta UMN and Delta LMN scores among ENCALS groups. Results Delta UMN and Delta LMN showed a negative association with survival (Delta UMN: HR = 1.30; Delta LMN: HR = 4.22). A cut-off value of 0.22 for Delta LMN was identified to predict patients with estimated short vs prolonged survival. ENCALS groups characterized by shorter survival presented significantly higher Delta UMN and Delta LMN scores compared to those with longer survival. No significant association of PUMNS or LMNS gross scores with the above-mentioned variables was observed. Conclusion By reflecting the progressing degeneration of the two distinct motor neuron subpopulations, Delta UMN and Delta LMN might represent reliable and easily measurable clinical indexes to estimate survival in ALS.