Motor unit number index (MUNIX) in the D50 disease progression model reflects disease accumulation independently of disease aggressiveness in ALS

Abstract

The neurophysiological technique motor unit number index (MUNIX) is increasingly used in clinical trials to measure loss of motor units. However, the heterogeneous disease course in amyotrophic lateral sclerosis (ALS) obfuscates robust correlations between clinical status and electrophysiological assessments. To address this heterogeneity, MUNIX was applied in the D50 disease progression model by analyzing disease aggressiveness (D50) and accumulation (rD50 phase) in ALS separately. 237 ALS patients, 45 controls and 22 ALS-Mimics received MUNIX of abductor pollicis brevis (APB), abductor digiti minimi (ADM) and tibialis anterior (TA) muscles. MUNIX significantly differed between controls and ALS patients and between ALS-Mimics and controls. Within the ALS cohort, significant differences between Phase I and II revealed in MUNIX, compound muscle action potential (CMAP) and motor unit size index (MUSIX) of APB as well as in MUNIX and CMAP of TA. For the ADM, significant differences occurred later in CMAP and MUNIX between Phase II and III/IV. In contrast, there was no significant association between disease aggressiveness and MUNIX. In application of the D50 disease progression model, MUNIX can demonstrate disease accumulation already in early Phase I and evaluate effects of therapeutic interventions in future therapeutic trials independent of individual disease aggressiveness.

Motor unit number index (MUNIX) loss of 50% occurs in half the time of 50% functional loss according to the D50 disease progression model of ALS

“…The cohort of those who volunteered to be controls (n = 45) was the same as in our recent published article on MUNIX 19 . They were all older than 40 years and had no clinical evidence of peripheral or central nervous system diseases that could affect the measurements.…”

“…Application of the D50 disease progression model. MUNIX parameters were analyzed using the framework of the D50 disease progression model which was described in detail previously [15][16][17][18][19] . In essence, the www.nature.com/scientificreports/ model fits an individual sigmoidal decay curve of ALS patients with all available ALSFRS-R scores in disease course to create a mathematical abstraction of ALSFRS-R progression.…”

“…Overall disease aggressiveness is then expressed by the parameter D50, which indicates the turning point of the sigmoid and equals the time in months patients take to lose 50% of their full clinical motor function (ALSFRS-R equals 24). The patient cohort can be divided into three subgroups of high (0 ≤ D50 < 20 months), intermediate (20 ≤ D50 < 40) and low (D50 ≥ 40) aggressiveness (see Table 1) as previously described 18,19 .…”

“…time of diagnosis 2 . Briefly, the D50 model of disease progression can be used to address this heterogeneity because the model allows individual disease aggressiveness and accumulation to be considered separately in ALS patients [15][16][17][18][19] .…”

Prognostic Usefulness of Motor Unit Number Index (MUNIX) in Patients Newly Diagnosed with Amyotrophic Lateral Sclerosis

“…The choice of limiting the analysis to one upper and one lower limb was taken for two reasons: first, because we wished to avoid a time-consuming examination, in view of its possible application in longitudinal designs, and second, in a few cases the choice was almost forced due to marked contralateral limb weakness, such that the examination was not possible, as minimal patient cooperation is required to effect the contraction. The choice of measuring just the limbs of one side, namely the less affected one, has already been carried out by some study groups [22,25,27,28,43].…”