Validation of motor and functional scales for the evaluation of adult patients with 5q spinal muscular atrophy

Abstract

Objective To assess in adult spinal muscular atrophy (SMA) patients the construct validity and responsiveness of several outcome measures. Methods Patients older than 15 years and followed-up at least for 6 months, between October 2015 and August 2020, with one motor function scale (Hammersmith Functional Motor Scale Expanded, HFMSE; Revised Upper Limb module, RULM) in five referral centers were included. Bedside functional scales (Egen Klassification, EK2; Revised Amyotrophic Lateral Sclerosis Functional Rating Scale, ALSFRS-R) were also collected when available. Correlations and regression models were performed to evaluate the construct validity. The monthly slopes of change were used to calculate their responsiveness. Results The study included 79 SMA patients, followed up for a mean of 16 months. All scales showed strong or very strong correlations with each other. A floor effect in motor function scales was found in weakest patients (HFMSE < 5 and RULM<10), and a ceiling effect in stronger patients (with HFMSE >55 and RULM > 35), when compared with other scales. ALSFRS-R (B=0.72) showed a strong discriminating ability between walkers, sitters, and non-sitters, and HFMSE (B=0.86) between walkers and sitters. The responsiveness was overall low, although in treated patients a moderate responsiveness was found for ALSFRS-R and HFMSE in walkers (0.69 and 0.61 respectively), and for EK2 in sitters (0.65) and non-sitters (0.60). Conclusions This study shows the validity in SMA adult patients of commonly used scales. Overall, bedside functional scales showed some advantages over motor function scales, although all scales showed low responsiveness in untreated patients.

Cerebrospinal Fluid and Clinical Profiles in Adult Type 2–3 Spinal Muscular Atrophy Patients Treated with Nusinersen: An 18-Month Single-Centre Experience

“…First, the small sample size of our cohort, which, moreover, was phenotypically heterogenous, could have reduced the power of our statistical analysis. On the other hand, the motor scales used may have underestimated the clinical improvements in weaker patients ('floor effect') and stronger patients ('ceiling effect'), as suggested by Vázquez-Costa et al [18]. Therefore, new outcome measures should probably be developed and/or validated in a larger cohort of adult SMA patients or at least different motor scales should be used after stratifying patients according to the functional subgroups (non-sitters, sitters, walkers) [18].…”

“…On the other hand, the motor scales used may have underestimated the clinical improvements in weaker patients ('floor effect') and stronger patients ('ceiling effect'), as suggested by Vázquez-Costa et al [18]. Therefore, new outcome measures should probably be developed and/or validated in a larger cohort of adult SMA patients or at least different motor scales should be used after stratifying patients according to the functional subgroups (non-sitters, sitters, walkers) [18]. Nevertheless, albeit minimal, in our patients the clinical improvement remained stable after 18 months of follow-up.…”

“…Clinical severity was evaluated by Hammersmith Functional Motor Scale Expanded (HFMSE), which consists of 33 items with a maximum of 66 points (higher scores indicating better function), and Revised Upper Limb Module for SMA (RULM), which includes 20 items with a maximum score of 37 (higher scores indicating better function). Although a recent study has questioned the validity of these scales in adult SMA patients [18], they were the most widely used motor scales in multicentre observational cohort studies of adult SMA The most severe phenotype is the type 0 SMA, with prenatal onset and death early after birth; the onset of type 1 SMA (namely Werdnig Hoffman syndrome) is within the first months of life and the death occurs within 2 years; type 2 and type 3 SMA (namely Kugelberg-Welander) usually display a highly variable phenotypic spectrum of disease, with life expectancy from infancy to adult age; finally type 4 SMA shows mild motor symptoms starting in the adult age with a very slow evolution over time [2]. The severity of the clinical phenotypes correlates inversely with the number of SMN2 copies, with 0-1 copies of SMN2 in the most severe type 0, or more than 4 copies in the mildest type 4 [1].…”

Predictive models in SMA II natural history trajectories using machine learning: A proof of concept study

“…The principal limitations of this study are that natural history data were drawn from a single center and that, even if there was a relatively large number of 6 month and 12 month follow-up intervals (>300 visits), the number of patients was much smaller (n = 30). Furthermore, it is known that the HFMSE is able to measure progression overtime but that can present floor/ceiling effect depending on age and functional status [ 15 , 16 , 19 , 21 , 22 ]. To address these concerns, additional work is in progress to establish external validity in separate datasets with a greater sample size.…”

Risdiplam in adult non-sitter patients with 5q spinal muscular atrophy: a non-interventional, single centre, observational cohort study

“…It is important to note that these domains are either difficult to measure or not measurable at all with most motor scales, which are currently used as the gold standard outcome measures in both clinical trials and clinical practice [5,8]. Specifically, in our series, half of patients could not perform or showed floor effects with both RULM and FVC, which are probably the most widely used measures in nonsitters [5,8]. Consequently, non-sitter adults have been systematically excluded from clinical trials and there is also a lack of real-world data on these patients, resulting in limited access to disease modifying treatments.…”