Disease Trajectories in the Revised Hammersmith Scale in a Cohort of Untreated Patients with Spinal Muscular Atrophy types 2 and 3.

Background: Spinal muscular atrophy (SMA) is a neuromuscular disorder characterised by progressive motor function decline. Motor function is assessed using several functional outcome measures including the Revised Hammersmith Scale (RHS). Objective: In this study, we present longitudinal trajectories for the RHS in an international cohort of 149 untreated paediatric SMA 2 and 3 patients (across 531 assessments collected between March 2015 and July 2019). Methods: We contextualise these trajectories using both the Hammersmith Functional Motor Scale Expanded (HFMSE) and Revised Upper Limb Module (RULM). At baseline, this cohort included 50% females and 15% of patients had undergone spinal fusion surgery. Patient trajectories were modelled using a natural cubic spline with age, sex, and random effects for each patient. Results: RHS and HFMSE scores show similar trends over time in this cohort not receiving disease modifying therapies. The results confirm the strong correlation between the RHS and RULM previously observed in SMA types 2 and 3a. Scoliosis surgery is associated with a reduction of 3 points in the RHS, 4.5 points in the HFMSE for the SMA 2 population, and a reduction of 11.8 points in the RHS, and 13.4 points in the HFMSE for the SMA 3a populations. When comparing the RHS and RULM, there is a lower correlation in the type 3a's than the type 2 patients. In the SMA 2 population, there is no significant difference between the sexes in either the RHS or HFMSE trajectories. There is no significant difference in the RULM trajectory in the SMA 2 or 3a participants by sex. Conclusions: This study demonstrates that the RHS could be used in conjunction with other functional measures such as the RULM to holistically detect SMA disease progression. This will assist with fully understanding changes that occur with treatments, further defining trajectories and therapy outcomes.

Assessment of the upper limb function, strength, and mobility in treatment-naive children with spinal muscular atrophy Types 2 and 3.

INTRODUCTION/AIMS: Current upper limb assessments in pediatric spinal muscular atrophy (SMA) may not adequately capture change with disease progression. Our aim was to examine the relationship between motor function, strength, and hand/finger mobility of the upper limb in treatment-naïve children with SMA Types 2 and 3 to assess new methods to supplement current outcomes. METHODS: The Revised Upper Limb Module (RULM), grip and pinch strength, and hand/finger mobility data were collected from 19 children with SMA Types 2 and 3 aged 5.2-16.9 years over a year. RESULTS: A median loss between 0.5 and 2.5 points in the RULM was seen across all SMA subgroups with the biggest median loss recorded between 10 and 14 years of age. The grip strength loss was -0.06 kg (-4.69 to 3.49; IQR, 1.21); pinch improvement of 0.05 (-0.65 to 1.27; IQR, 0.48); hand/finger mobility test improvement of 4 points (-24 to 14; IQR, 6.75) for the whole cohort. Significant correlations were found between the RULM and grip strength (p < .001), RULM and pinch strength (p < .001), RULM and revised Brooke (p < .001), grip strength and pinch strength (p < .001). DISCUSSION: The combined use of the RULM, dynamometry, and hand mobility provide insight about correlations between function and strength in children with SMA. The RULM and grip strength assessments captured a significant decline in upper limb function, whereas the pinch and finger/hand mobility showed an improvement over the course of 1 year and these results should be considered for future studies.

2-Year Change in Revised Hammersmith Scale Scores in a Large Cohort of Untreated Paediatric Type 2 and 3 SMA Participants.

The Revised Hammersmith Scale (RHS) is a 36-item ordinal scale developed using clinical expertise and sound psychometrics to investigate motor function in participants with Spinal Muscular Atrophy (SMA). In this study, we investigate median change in the RHS score up to two years in paediatric SMA 2 and 3 participants and contextualise it to the Hammersmith Functional Motor Scale-Expanded (HFMSE). These change scores were considered by SMA type, motor function, and baseline RHS score. We consider a new transitional group, spanning crawlers, standers, and walkers-with-assistance, and analyse that alongside non-sitters, sitters, and walkers. The transitional group exhibit the most definitive change score trend, with an average 1-year decline of 3 points. In the weakest patients, we are most able to detect positive change in the RHS in the under-5 age group, whereas in the stronger patients, we are most able to detect decline in the RHS in the 8-13 age group. The RHS has a reduced floor effect compared to the HFMSE, although we show that the RHS should be used in conjunction with the RULM for participants scoring less than 20 points on the RHS. The timed items in the RHS have high between-participant variability, so participants with the same RHS total can be differentiated by their timed test items.

Revised Hammersmith Scale for spinal muscular atrophy: Inter and intra-rater reliability and agreement.

The Revised Hammersmith Scale (RHS) for Spinal Muscular Atrophy (SMA) was designed as a psychometrically robust clinical outcome assessment to assess physical abilities of patients with type 2 and 3 SMA. The reliability properties of the RHS have not yet been reported. A prospective RHS reliability study was undertaken in a UK cohort of experienced neuromuscular paediatric Physiotherapists. Reliability testing was conducted via a virtual survey platform two weeks apart. Through the virtual platform participants scored videos of two RHS assessments, one of a child with SMA 2 and one of a child with SMA 3. Inter and intra-rater reliability was analysed using a type 3 Intraclass Correlation Coefficient (ICC). Intra-rater agreement was further analysed using Bland Altman (BA) Limits of Agreement (LOA) and plots. The acceptable inter and intra-rater variability was set as a change of ± 2 by the international team of expert physiotherapists who developed the RHS. Inter-rater agreement, n = 22 raters, type 3 ICC was 0.989 (95% CI 0.944 to 1.00), 97.7% of scores were within the acceptable limits of ± 2 points. Intra-rater agreement, n = 21 raters, type 3 ICC ranged from 0.922 to 1.0, with 97.6% of scores within the acceptable limits of ± 2 points. The mean SMA 2 intra-rater difference was -0.10 (-0.6 to 0.4), with lower LOA -2.24 and upper LOA +2.04. Intra-rater difference between tests for SMA 3 intra-rater difference was -0.05 (-0.6 to 0.5), with lower LOA -2.48 and upper LOA +2.38. Intra-rater scoring precision fell within BA agreement limits of ±2 points. The results demonstrate that the RHS is highly reliable when used by experienced UK physiotherapists, and variability of test scores regarding inter and intra-rater reliability was confirmed to lie within ±2 points.

Revised upper limb module for spinal muscular atrophy: 12 month changes.

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.

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.

Quantitative Evaluation of Lower Extremity Joint Contractures in Spinal Muscular Atrophy: Implications for Motor Function.

PURPOSE: To quantitatively describe passive lower extremity range of motion in participants with spinal muscular atrophy (SMA) types 2 and 3, and to establish preliminary thresholds to identify individuals at risk for performing poorly on disease-specific motor function outcome measures. METHODS: Eighty participants with SMA types 2 and 3, enrolled in an international multicenter natural history study, were evaluated with lower extremity range of motion testing and the Hammersmith Functional Motor Scale-Expanded. RESULTS: A hip extension joint angle of -7.5° or less for SMA type 2 and 0° or less for SMA type 3 identified diminished motor ability with good sensitivity. For knee extension, a joint angle of -9.0° or less for SMA type 2 or 0° or less for SMA type 3 was similarly sensitive. CONCLUSIONS: Minimal hip and knee joint contractures were associated with diminished motor ability. Clinical trial designs should consider the effect of contractures on motor function.

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.

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

BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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

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.

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

The aim of the study was to establish 12-month changes in the Hammersmith Functional motor scale in a large cohort of SMA patients, to identify patterns of disease progression and the effect of different variables. 268 patients were included in this multicentric study. Their age ranged between 2.5 and 55.5 years at baseline, 68 were ambulant and 200 non-ambulant. The baseline scores ranged between 0 and 66 (mean 23.91, SD 20.09). The 12-month change was between -14 and +9 (mean -0.56, SD 2.72). Of the 268 patients, 206 (76.86%) had changes between -2 and +2 points. Ambulant and non-ambulant subjects had a different relationship between baseline values and age (p for age X ambulation interaction = 0.007). There was no association with age in ambulant subjects, while there was a significant heterogeneity at different age for non-ambulant patients (p < 0.001). The 12-month change (adjusted for baseline) was not associated with age in ambulant patients (p = 0.34), but it was significantly different among various age groups in non-ambulant patients. Our results suggest that there are different profiles of progression in ambulant and non-ambulant patients, and that age may play an important role in the progression of non-ambulant patients.

Novel Bedside Phonetic Evaluation to Identify Dysphagia and Aspiration Risk.

BACKGROUND: There is a need for improved clinical identification of hospitalized patients at risk of aspiration. We evaluated our novel phonetic test in a broad spectrum of patients at risk of aspiration in the ICU or intermediate care unit. METHODS: We prospectively enrolled 60 hospitalized patients with aspiration risk, between December 2009 and September 2011, who subsequently underwent audio-recorded three-component phonetic bedside evaluation. The recordings were scored by two blinded speech-language pathologists. The institutional dysphagia admission screening test was performed by a bedside nurse. The primary outcomes, dysphagia and aspiration, were assessed by a videofluoroscopic swallowing study, fiber-optic endoscopic evaluation of swallowing, or both. We assessed the short- and long-term clinical outcomes (length of stay, subsequent aspiration pneumonia and respiratory failure, survival) and how these were associated with the phonetic and swallow assessments. RESULTS: Statistically significant linear associations with dysphagia were noted for all three individual phonetic components. Also, there were statistically significant linear associations with aspiration for diadochokinesis (P = .050) and consensus auditory-perceptual evaluation of voice (P = .025). Diadochokinesis alone predicted dysphagia (area under the curve [AUC], 0.74; P = .001) and aspiration (AUC, 0.67; P = .012). Its predictive ability improved when combined with normalized dysphagia admission screening test results (AUC, 0.79; P = .001). The short- and long-term clinical outcomes were adversely affected by the worse phonetic/swallowing scores, although they were not statistically different. CONCLUSIONS: Abnormal phonation among ICU and intermediate care unit patients is associated with dysphagia and aspiration. Future investigative efforts should uncover the most effective combination of evaluations for accurate bedside detection of dysphagia and aspiration risk in a broad spectrum of patients.

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.