Rachel Salazar

Patterns of disease progression in type 2 and 3 SMA: Implications for clinical trials

Highlights • The paper reports for the first time patterns of progression in type 2 and 3 SMA.• Different trajectories can be identified in ambulant and non-ambulant patients.• Age appears to be an important factor in determining trajectories of progression.

Revised Hammersmith Scale for spinal muscular atrophy: A SMA specific clinical outcome assessment tool

Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are ‘fit for purpose’. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psychometric techniques and the application of clinical sensibility via expert panels. Specifically, we intended to develop a psychometrically and clinically robust functional clinician rated outcome measure to assess physical abilities in weak SMA type 2 through to strong ambulant SMA type 3 patients. The final scale, the Revised Hammersmith Scale (RHS) for SMA, consisting of 36 items and two timed tests, was piloted in 138 patients with type 2 and 3 SMA in an observational cross-sectional multi-centre study across the three national networks. Rasch analysis demonstrated very good fit of all 36 items to the construct of motor performance, good reliability with a high Person Separation Index PSI 0.98, logical and hierarchical scoring in 27/36 items and excellent targeting with minimal ceiling. The RHS differentiated between clinically different groups: SMA type, World Health Organisation (WHO) categories, ambulatory status, and SMA type combined with ambulatory status (all p < 0.001). Construct and concurrent validity was also confirmed with a strong significant positive correlation with the WHO motor milestones rs = 0.860, p < 0.001. We conclude that the RHS is a psychometrically sound and versatile clinical outcome assessment to test the broad range of physical abilities of patients with type 2 and 3 SMA. Further longitudinal testing of the scale with regards change in scores over 6 and 12 months are required prior to its adoption in clinical trials.

Developmental milestones in type I spinal muscular atrophy

Highlights • This paper reports patterns of natural progression in type I SMA.• The HINE is used to capture motor developmental milestones in SMA.• Motor developmental milestones are rarely acquired in type I SMA infants.

Six-minute walk test is reliable and valid in spinal muscular atrophy.

Introduction: The Six‐Minute Walk Test (6MWT) was adopted as a clinical outcome measure for ambulatory spinal muscular atrophy (SMA). However, a systematic review of measurement properties reported significant variation among chronic pediatric conditions. Our purpose was to assess the reliability/validity of the 6MWT in SMA. Methods: Thirty participants performed assessments, including the 6MWT, strength, and function. Reproducibility was evaluated by intraclass correlation coefficients. Criterion/convergent validity were determined using Pearson correlation coefficients. Results: Test–retest reliability was excellent. The 6MWT was associated positively with peak oxygen uptake, Hammersmith Functional Motor Scale Expanded (HFMSE), lower extremity manual muscle testing, knee flexion hand‐held dynamometry, and inversely with 10‐m walk/run. The 6MWT discriminates between disease severity, unlike the HFMSE. Conclusions: This study documents measurement properties of reproducibility, positive criterion validity, and convergent validity with established clinical assessments and reaffirms the value of the 6MWT as a pivotal outcome measure in SMA clinical trials. Muscle Nerve 54: 836–842, 2016

Revised upper limb module for spinal muscular atrophy: Development of a new module

There is a growing need for a robust clinical measure to assess upper limb motor function in spinal muscular atrophy (SMA), as the available scales lack sensitivity at the extremes of the clinical spectrum. We report the development of the Revised Upper Limb Module (RULM), an assessment specifically designed for upper limb function in SMA patients.

Content validity and clinical meaningfulness of the HFMSE in spinal muscular atrophy

BackgroundReports on the clinical meaningfulness of outcome measures in spinal muscular atrophy (SMA) are rare. In this two-part study, our aim was to explore patients’ and caregivers’ views on the clinical relevance of the Hammersmith Functional Motor Scale Expanded- (HFMSE).MethodsFirst, we used focus groups including SMA patients and caregivers to explore their views on the clinical relevance of the individual activities included in the HFMSE. Then we asked caregivers to comment on the clinical relevance of possible changes of HFMSE scores over time. As functional data of individual patients were available, some of the questions were tailored according to their functional level on the HFMSE.ResultsPart 1: Sixty-three individuals participated in the focus groups. This included 30 caregivers, 25 patients and 8 professionals who facilitated the discussion.The caregivers provided a comparison to activities of daily living for each of the HFMSE items.Part 2: One hundred and forty-nine caregivers agreed to complete the questionnaire: in response to a general question, 72% of the caregivers would consider taking part in a clinical trial if the treatment was expected to slow down deterioration, 88% if it would stop deterioration and 97% if the treatment was expected to produce an improvement.Caregivers were informed of the first three items that their child could not achieve on the HFMSE. In response 75% indicated a willingness to take part in a clinical trial if they could achieve at least one of these abilities, 89% if they could achieve two, and 100% if they could achieve more than 2.ConclusionsOur findings support the use of the HFMSE as a key outcome measure in SMA clinical trials because the individual items and the detected changes have clear content validity and clinical meaningfulness for patients and their caregivers.

Rasch analysis of the Pediatric Evaluation of Disability Inventory-computer adaptive test (PEDI-CAT) item bank for children and young adults with spinal muscular atrophy.

Introduction: In this study we evaluated the suitability of a caregiver‐reported functional measure, the Pediatric Evaluation of Disability Inventory–Computer Adaptive Test (PEDI‐CAT), for children and young adults with spinal muscular atrophy (SMA). Methods: PEDI‐CAT Mobility and Daily Activities domain item banks were administered to 58 caregivers of children and young adults with SMA. Rasch analysis was used to evaluate test properties across SMA types. Results: Unidimensional content for each domain was confirmed. The PEDI‐CAT was most informative for type III SMA, with ability levels distributed close to 0.0 logits in both domains. It was less informative for types I and II SMA, especially for mobility skills. Item and person abilities were not distributed evenly across all types. Conclusions: The PEDI‐CAT may be used to measure functional performance in SMA, but additional items are needed to identify small changes in function and best represent the abilities of all types of SMA. Muscle Nerve 54: 1097–1107, 2016

Gait assessment with solesound instrumented footwear in spinal muscular atrophy

Gait impairment is common in spinal muscular atrophy (SMA) and is described using clinical assessments and instrumented walkways. Continuous over‐ground walking has not been studied.

Old measures and new scores in spinal muscular atrophy patients

Introduction: A recent Rasch analysis performed on the Hammersmith Functional Motor Scale—Expanded (HFMSE) in patients with spinal muscular atrophy (SMA) identified issues impacting scale validity, redundant items, and disordered thresholds on some items. Methods: We modified the HMFSE scoring based on the Rasch analysis and on expert consensus to establish whether the traditional scoring overestimated the number of patients with changes within 2 points from baseline. Data were collected retrospectively from multicenter data sets in 255 type 2 and 3 SMA patients. Results: The mean 12‐month changes using the new and the traditional scoring system did not differ significantly (P > 0.05). The numbers of patients who improved or decreased by >2 points were also similar. Conclusions: The presence of outliers using the traditional scoring system was not due to overestimation of changes in activities that were tested bilaterally or to discrepancies in the scoring hierarchy of individual items. Muscle Nerve 52:435–437, 2015

Ambulatory function in spinal muscular atrophy: Age-related patterns of progression

Individuals with spinal muscular atrophy (SMA) type 3 are able to walk but they have weakness, gait impairments and fatigue. Our primary study objective was to examine longitudinal changes in the six-minute walk test (6MWT) and to evaluate whether age and SMA type 3 subtype are associated with decline in ambulatory function. Data from three prospective natural history studies were used. Seventy-three participants who performed the 6MWT more than once, at least 6 months apart, were included; follow-up ranged from 0.5–9 years. Only data from patients who completed the 6MWT were included. The mean age of the participants was 13.5 years (range 2.6–49.1), with 52 having disease onset before age 3 years (type 3A). At baseline, type 3A participants walked a shorter distance on average (257.1 m) than type 3B participants (390.2 m) (difference = 133.1 m, 95% confidence interval [CI] 71.8–194.3, p < 0.001). Distance walked was weakly associated with age (r = 0.25, p = 0.04). Linear mixed effects models were used to estimate the mean annual rate of change. The overall mean rate of change was -7.8 m/year (95% CI -13.6 –-2.0, p = 0.009) and this did not differ by subtype (type 3A: -8.5 m/year, type 3B: -6.6 m/year, p = 0.78), but it did differ by age group (< 6: 9.8 m/year; 6–10: -7.9 m/year; 11–19: -20.8 m/year; ≥ 20: -9.7 m/year; p = 0.005). Our results showed an overall decline on the 6MWT over time, but different trajectories were observed depending on age. Young ambulant SMA patients gain function but in adolescence, patients lose function. Future clinical trials in ambulant SMA patients should consider in their design the different trajectories of ambulatory function over time, based on age.