Regionality of disease progression predicts prognosis in amyotrophic lateral sclerosis

Abstract

Amyotrophic lateral sclerosis (ALS) is a devastating neurological syndrome in which motor neurons degenerate relentlessly. Although the site of onset and the rate of spread have been studied extensively, little is known about whether focal as opposed to diffuse disease affects prognosis. We therefore tested the hypothesis that regionality of disease burden is a prognostic factor in ALS. We analysed clinical data from two large multicentre, longitudinal trials. Regionality was defined as the difference in progression rates in three domains as measured by the revised ALS Functional Rating Scale, omitting the respiratory domain from analysis. We used death by trial end as the outcome variable and tested this by logistic regression against predictor variables including regionality and overall rate of disease progression. There were 561 patients. Regionality of disease was independently associated with significantly higher chance of death by study end (odds ratio most diffuse against most focal category 0.354 (0.191, 0.657), p = 0.001), with a direct relationship between degree of regionality and odds of death. We have shown using clinical trial data that focal disease is associated with a worse prognosis in ALS. Measures of regionality warrant further independent consideration in the development of future prognostic models.

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

“…Taken together, these results indicate that ALSFRS-R_bulb and ALSFRS-R_motor capture the divergent clinical and prognostic characteristics of patients with spinal and bulbar onset. The observed longitudinal trend in subscores may also explain observations that increased regionality (estimated from ALSFRS-R subscores) of disease was prognostic,22 since typically the bulbar score in patients with bulbar declines very rapidly (figure 2). …”

“…However, by compressing multidimensional domains into one combined score, information may be lost. ALSFRS-R subscores have previously been used to quantify regionality of disease, which was seen to be a prognostic factor 22. Furthermore, it has been suggested that cognitive impairment, particularly executive dysfunction at onset, predicts a bulbar subscore decline 23.…”

Amyotrophic lateral sclerosis regional progression intervals change according to time of involvement of different body regions

“…Despite the widespread interest in disease prediction modeling, the current literature about the progression rates in different body regions and the reaching of clinical milestones is still relatively sparse. One of the first attempts to distinguish between overall and regional progression was a study by van der Kleij et al [18]. Using the ALSFRS-r score, they produced a model to measure the regional burden of the disease and thus predict overall survival.…”