ABSTRACT
Introduction
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.
Methods
An international panel with specific neuromuscular expertise performed a thorough review of scales currently available to assess upper limb function in SMA. This review facilitated a revision of the existing upper limb function scales to make a more robust clinical scale.
Results
Multiple revisions of the scale included statistical analysis and captured clinically relevant changes to fulfill requirements by regulators and advocacy groups.
Conclusions
The resulting RULM scale shows good reliability and validity, making it a suitable tool to assess upper extremity function in the SMA population for multi‐center clinical research. Muscle Nerve 55: 869–874, 2017
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.
The aim of the study was to evaluate the spectrum of upper limb functional activities and imaging finding in a cohort of patients affected by Duchenne muscular dystrophy. Thirty-one patients of age ...between 5 and 29 years were included in the study (17 ambulant and 14 non-ambulant). They were all assessed using the Performance of Upper Limb (PUL) test and muscle MRI of shoulder, arm and forearm in order to establish if the functional scores obtained at shoulder, mid and distal level related to specific patterns of involvement in each upper limb segment on muscle MRI. At shoulder level, latissimus dorsi, serratus anterior, infraspinatus and subscapularis were always involved, even in patients with full functional scores at shoulder level. Diffuse and severe involvement of all muscles was found in the patients with a PUL shoulder functional score of ≤ 5. At arm level biceps brachii, brachialis and triceps were generally concordantly involved or spared. Some degree of involvement could already be detected in patients with reduced scores on the PUL mid domain. They were generally severely involved in patients with functional scores less than 6 at mid-level. At distal level supinator and pronator muscles were often involved, followed by brachioradialis and, less frequently, by the muscles of the flexor compartment. The extensor muscles were generally completely spared. A diffuse and severe involvement was found only in patients who had very low scores (8 or below) on the PUL distal domain. The integrated use of functional scales and imaging allowed to establish patterns of involvement at each level, and the functional scores that were more frequently associated with diffuse and severe involvement.
Background and Objectives: The aim of this study was to evaluate longitudinal changes using both upper limb muscle Magnetic Resonance Imaging (MRI) at shoulder, arm and forearm levels and Performance ...of upper limb (PUL) in ambulant and non-ambulant Duchenne Muscular Dystrophy (DMD) patients. We also wished to define whether baseline muscle MRI could help to predict functional changes after one year. Materials and Methods: Twenty-seven patients had both baseline and 12month muscle MRI and PUL assessments one year later. Results: Ten were ambulant (age range 5–16 years), and 17 non ambulant (age range 10–30 years). Increased abnormalities equal or more than 1.5 point on muscle MRI at follow up were found on all domains: at shoulder level 12/27 patients (44%), at arm level 4/27 (15%) and at forearm level 6/27 (22%). Lower follow up PUL score were found in 8/27 patients (30%) at shoulder level, in 9/27 patients (33%) at mid-level whereas no functional changes were found at distal level. There was no constant association between baseline MRI scores and follow up PUL scores at arm and forearm levels but at shoulder level patients with moderate impairment on the baseline MRI scores between 16 and 34 had the highest risk of decreased function on PUL over a year. Conclusions: Our results confirmed that the integrated use of functional scales and imaging can help to monitor functional and MRI changes over time.
To report the long-term progression in a cohort of patients with type II spinal muscular atrophy (SMA) assessed with the Hammersmith Functional Motor Scale-Expanded.
Seventy-three patients (age ...2.6-25 years) were included in the study. Twenty-eight of the 73 were first assessed before the age of 5 years and had been followed up for ≈5 years or longer. We observed an overall progression that was not linear. A piecewise regression analysis showed an improvement of scores in the younger patients with a point of slope change at ≈5 years of age, a decline between 5 and 13 years of age, and stability/slower decline after that.
Patients with the lowest scores at baseline had the earliest onset of scoliosis and a higher need for noninvasive ventilation compared to those with higher scores. Our results confirm that on the long-term follow-up all patients with type II SMA show a clear and progressive decline.
The severity of functional impairment at baseline can help to predict the magnitude of changes over time and the overall progression, including onset of scoliosis and need for noninvasive ventilation.
Type II spinal muscular atrophy (SMA) often leads to scoliosis in up to 90% of cases. While pharmacological treatments have shown improvements in motor function, their impact on scoliosis progression ...remains unclear. This study aims to evaluate potential differences in scoliosis progression between treated and untreated SMA II patients.
Treatment effect on Cobb's angle annual changes and on reaching a 50° Cobb angle was analysed in treated and untreated type II SMA patients with a minimum 1.5-year follow-up. A sliding cut-off approach identified the optimal treatment subpopulation based on age, Cobb angle and Hammersmith Functional Motor Scale Expanded at the initial visit. Mann-Whitney U-test assessed statistical significance.
There were no significant differences in baseline characteristics between the untreated (n=46) and treated (n=39) populations. The mean Cobb angle variation did not significantly differ between the two groups (p=0.4). Optimal cut-off values for a better outcome were found to be having a Cobb angle <26° or an age <4.5 years. When using optimal cut-off, the treated group showed a lower mean Cobb variation compared with the untreated group (5.61 (SD 4.72) degrees/year vs 10.05 (SD 6.38) degrees/year; p=0.01). Cox-regression analysis indicated a protective treatment effect in reaching a 50° Cobb angle, significant in patients <4.5 years old (p=0.016).
This study highlights that pharmacological treatment, if initiated early, may slow down the progression of scoliosis in type II SMA patients. Larger studies are warranted to further investigate the effectiveness of individual pharmacological treatment on scoliosis progression in this patient population.
Reports 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).
First, 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.
Part 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.
Our 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.
Introduction: The aim of the study was to assess 12 month changes in upper limb function in patients affected by spinal muscular atrophy type 2 and 3. Methods: Longitudinal 12 month data was ...collected in 114 patients, 60 type 2 and 54 type 3, using the Revised Upper Limb Module. Results: The 12 month changes ranged between ‐7 and 9 (mean: ‐0.41; SD: 2.93). The mean changes were not significantly different between the three spinal muscular atrophy groups (‐0.45 in type 2, ‐0.23 in non‐ambulant type 3 and ‐0.34 in ambulant type 3, p = 0.96) and the relationship between 12 month change and age classes was not significantly different among the three types of SMA patients. Discussion: Our results confirm that the Module explores a wide range of functional abilities and can be used in ambulant and non‐ambulant patients of different ages in conjunction with other functional scales. Muscle Nerve 59:426–430, 2019
Objective
To investigate ultrasound features of diaphragm motion and function in type 1 spinal muscular atrophy (SMA‐1) patients.
Design
Prospective study.
Patients
The study cohort included SMA‐1 ...children younger than 18‐year‐old. Control subjects included type 2 and type 3 SMA and other neuromuscular disorders younger than 18‐year‐old.
Methodology
Diaphragm ultrasound evaluating diaphragmatic excursion, speed of diaphragmatic contraction, duration of the respiratory cycle, inspiratory/expiratory relationship, end‐inspiratory and ‐expiratory thickness, thickening fraction, and pattern of contractility. The interrater reliability for each variable was established by calculation of Cohen's k coefficient.
Results
Twenty‐three SMA‐1 patients and 12 controls were evaluated. Diaphragm ultrasound values were within normal ranges in all study cohort patients and no difference was found with controls. There was a gradient of diaphragm function with SMA 1.9 subgroup having the best and SMA 1.1 having the worst parameters, particularly in end‐inspiratory thickness and diaphragmatic excursion (P = .031 and P = .041, respectively). Seventy‐four percent of SMA‐1 patients had a dysmotility pattern of diaphragm contraction, mostly represented in SMA 1.9 subgroup (P = .001). This pattern was observed in 92.8% of children on noninvasive ventilation (NIV) for less than 16 hours/d of and in 20% patients with invasive ventilation or NIV for more than 16 hours/d (P = .027). The dysmotility pattern was never observed in the control group. The levels of interobserver agreement were high for “diaphragm irregularities,” “inspiratory/expiratory relationship,” and “diaphragm thickness,” and good for the other variables.
Conclusions
Ultrasound can be used to evaluate diaphragm function and contractility in SMA‐1 children, providing additional information to the clinical examination and functional respiratory tests, describing a characteristic contractility pattern in these patients. Longitudinal studies are needed to understand the impact of diaphragm dysmotility and other parameters on long‐term outcome in SMA‐1 patients.
•The aim of this retrospective study was to assess functional changes using the CHOP INTEND scale in a cohort of type 1 infants.•Patients were classified according to the severity of the phenotype ...and age of onset. SMN2 copies were also assessed.•Our results suggest that the CHOP INTEND can help to identify trajectories of progression in type 1 SMA.
The advent of clinical trials has highlighted the need for natural history studies reporting disease progression in type 1 spinal muscular atrophy. The aim of this study was to assess functional changes using the Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP INTEND) scale in a cohort of type 1 infants. Nutritional and respiratory longitudinal data were also recorded. Patients were classified according to the severity of the phenotype and age of onset. SMN2 copies were also assessed. Twenty patients were included, eight with early onset most severe phenotype, eight with the more typical type 1 phenotype and 4, who achieved some head control, with a milder phenotype. Both baseline values and trajectories of progression were different in the three subgroups (p = 0.0001). Infants with the most severe phenotype had the lowest scores (below 20) on their first assessment and had the most rapid decline. Those with the typical phenotype had scores generally between 20 and 40 and also had a fast decline. The infants with the milder phenotype had the highest scores, generally above 35, and a much slower deterioration. Infants with three SMN2 copies had an overall milder phenotype and milder progression while two SMN2 copies were found in all three subgroups.
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