Heterogeneity in ALSFRS-R decline and survival: a population-based study in Italy

Abstract

Very few studies examined trend over time of the revised Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS-R) and factors influencing it; previous studies, then, included only patients attending tertiary ALS Centres. We studied ALSFRS-R decline, factors influencing this trend and survival in a population-based setting. From 2009 onwards, a prospective registry records all incident ALS cases among residents in Emilia Romagna (population: 4.4 million). For each patient, demographic and clinical details (including ALSFRS-R) are collected by caring physicians at each follow-up. Analysis was performed on 402 incident cases (1279 ALSFRS-R assessments). The average decline of the ALSFRS-R was 0.60 points/month during the first year after diagnosis and 0.34 points/month in the second year. ALSFRS-R decline was heterogeneous among subgroups. Repeated measures mixed model showed that ALSFRS-R score decline was influenced by age at onset (p < 0.01), phenotype (p = 0.01), body mass index (BMI) (p < 0.01), progression rate at diagnosis (ΔFS) (p < 0.01), El Escorial Criteria-Revised (p < 0.01), and FVC% at diagnosis (p < 0.01). Among these factors, at multivariate analysis, only age, site of onset and ΔFS independently influenced survival. In this first population-based study on ALSFRS-R trend, we confirm that ALSFRS-R decline is not homogeneous among ALS patients and during the disease. Factors influencing ALSFRS-R decline may not match with those affecting survival. These disease modifiers should be taken into consideration for trials design and in clinical practice during discussions with patients on prognosis.

Assessment of the factorial validity and reliability of the ALSFRS-R: a revision of its measurement model

“…Furthermore, the present study examined the measurement model in the ALS population. Given the heterogeneity of the disease [25], results might be different in subgroups of the population. Future studies should, therefore, assess measurement invariance of the ALSFRS-R between clinical subgroups of patients with ALS.…”

Patients with ALS show highly correlated progression rates in left and right limb muscles

“…This may appear contradictory with clinical observations that the disease starts in different regions and spreads. 10 However, it implies that irrespective of which muscle starts declining soonest or latest, their rates of decline following onset are more consistent. The subsequent PCs show differing contributions by each muscle, and sometimes in different directions.…”

What does the ALSFRS-R really measure? A longitudinal and survival analysis of functional dimension subscores in amyotrophic lateral sclerosis

“…This was later extended to the ALSFRS-R by including extra respiratory scores to better capture the respiratory functional domain 4. The longitudinal analysis of change in ALSFRS-R, which is generally considered to be linear for the majority of the illness, is complicated both by heterogeneity5 and by longitudinally informative censoring due to dropout of more ill patients, and/or the mortality of patients over time 6. This problem has led to the development of alternative measures, such as the Combined Assessment of Function and Survival, a non-parametric ranked score combining functional and survival outcomes for use in clinical trials in ALS 7…”