Improvement of muscle strength in specific muscular regions in nusinersen-treated adult patients with 5q-spinal muscular atrophy

Abstract

Real-world data have shown mild improvement of overall motor function in adult patients treated with nusinersen, the first approved therapy for 5q-spinal muscular atrophy (SMA). However, knowledge about preferably targeted muscle functions is sparse. The aim of this study was to evaluate strength of distinct muscles and body regions in adult SMA patients in the early course of nusinersen therapy. 72 muscles of 15 patients were tested on the Medical Research Council (MRC) 0-10 scale (translated into MRC %) from nusinersen start to 14 months of treatment. The whole body muscular strength improved slightly or remained stable in 80% of SMA patients with a median improvement of + 2%. However, relevant increases of muscle strength of distinct regions were identified in the proximal upper limbs and shoulder girdle (median + 8%) and in muscle groups with a preserved function pre-treatment, even in more advanced diseased SMA patients. MRC grading was additionally performed in seven patients enrolled during ongoing treatment. Here, further improvement of muscle strength until month 18-26 was seen with the highest increases in the proximal upper and lower limbs. Our findings suggest that sole evaluation of the overall muscle strength might underestimate nusinersen therapy benefits.

Figure 1

Muscle function patterns of 15 assessed patients with SMA types 2–4. Individual values are presented as the mean of both sides (with the exception of neck flexion und extension) and sorted by maximum total MRC % at baseline (a) or month 14 (b). Patients are represented by columns on the x-axis. Patients with minor muscle strength grouped on the far left. Columns on the y-axis represent the impairment pattern of specific muscle functions through the study population. Green (100%) corresponds to the absence of muscle weakness and red (0%) to plegia. Lines underneath the heatmaps indicate the corresponding distribution of SMA subtypes, ambulatory status and SMN2 copies. (a) The impairment pattern at baseline shows a main involvement of proximal muscles, while distal muscle weakness was only visible in more progressed patients. (b) After 14 months on treatment, a trend towards regaining proximal muscle strength was seen, predominantly in the upper limbs.

Figure 2

Median pre-post-comparisons to baseline (Δ) at assessed time points for total MRC % and subdomains during nusinersen therapy. Error bars indicate the interquartile range. (a,b) Individual trajectories of assessed patients for non-ambulatory (a) and ambulatory (b) patients showed a marked variability of treatment responses. The n-number indicates the number of analysed individuals. Patients’ pseudonyms are listed alongside the graphs (e.g. S1). (c–f) Depiction of MRC % changes in subdomains over time in ambulatory vs non-ambulatory patients and the overall cohort. Numbers in brackets indicate the number of muscle functions included in that specific subdomain. Improvements in both patient subgroups were observed in the proximal muscles of the upper limb (c). Muscle strength showed no relevant changes in the lower limbs with temporary increases above the threshold of non-ambulatory patients shortly after the loading dosing (d,f) regressing during further therapy. At month two distal muscle strength of ambulatory patients worsened (e,f), but the initial decline lessened over time.

Figure 3

Individual MRC % trajectories of seven patients who were enrolled while ongoing nusinersen therapy. The first data point depicts the therapy month of enrolment; the last complies with the last assessment taken before data-cut. Individual variability of motor function in patients up to month 26 can be seen, with initial increases at the beginning of the observation period in five patients, succeeded by a predominantly stable period in three patients and a more variable trajectory in two patients. Comparing baseline to last assessment, improvement of motor function could be witnessed in most patients. Non-ambulatory patients presented with a total MRC % under 60% in the lower half of the graph.