Amy Pasternak

Cross-sectional Evaluation of Electrical Impedance Myography and Quantitative Ultrasound for the Assessment of Duchenne Muscular Dystrophy in a Clinical Trial Setting

BACKGROUND Electrical impedance myography and quantitative ultrasound are two noninvasive, painless, and effort-independent approaches for assessing neuromuscular disease. Both techniques have potential to serve as useful biomarkers in clinical trials in Duchenne muscular dystrophy. However, their comparative sensitivity to disease status and how they relate to one another are unknown. METHODS We performed a cross-sectional analysis of electrical impedance myography and quantitative ultrasound in 24 healthy boys and 24 with Duchenne muscular dystrophy, aged 2 to 14 years with trained research assistants performing all measurements. Three upper and three lower extremity muscles were studied unilaterally in each child, and the data averaged for each individual. RESULTS Both electrical impedance myography and quantitative ultrasound differentiated healthy boys from those with Duchenne muscular dystrophy (P < 0.001 for both). Quantitative ultrasound values correlated with age in Duchenne muscular dystrophy boys (rho = 0.45; P = 0.029), whereas electrical impedance myography did not (rho = -0.31; P = 0.14). However, electrical impedance myography phase correlated with age in healthy boys (rho = 0.51; P = 0.012), whereas quantitative ultrasound did not (rho = -0.021; P = 0.92). In Duchenne muscular dystrophy boys, electrical impedance myography phase correlated with the North Star Ambulatory Assessment (rho = 0.65; P = 0.022); quantitative ultrasound revealed a near-significant association (rho = -0.56; P = 0.060). The two technologies trended toward a moderate correlation with one another in the Duchenne muscular dystrophy cohort but not in the healthy group (rho = -0.40; P = 0.054 and rho = -0.32; P = 0.13, respectively). CONCLUSIONS Electrical impedance myography and quantitative ultrasound are complementary modalities for the assessment of boys with Duchenne muscular dystrophy; further study and application of these two modalities alone or in combination in a longitudinal fashion are warranted.

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.

An Aquatic Physical Therapy Program at a Pediatric Rehabilitation Hospital: A Case Series

Purpose: The purpose of this case series is to describe the implementation of an aquatic physical therapy (PT) program at a pediatric hospital and to document improvements in participants’ abilities after PT intervention. Methods: Four patients with cerebral palsy, juvenile idiopathic arthritis, or Prader-Willi syndrome participated in aquatic and land-based PT intervention. Three of the patients had orthopedic conditions which required limited weight-bearing or low-joint impact during motor activities. A wide range of outcomes were used to assess changes in participation, activity, and body function. When available, minimal detectable change and minimal important difference values were used to interpret data. Results: Clinically significant improvements were documented in functional mobility, walking endurance, range of motion, muscle strength, and/or pain reduction for all 4 patients. Conclusions: Aquatic PT used as an adjunct to land-based PT interventions may be effective in improving outcomes in patients with physical disabilities.

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.

Optimizing electrical impedance myography measurements by using a multifrequency ratio: A study in Duchenne muscular dystrophy

OBJECTIVE Electrical impedance myography (EIM) is an electrophysiological technique for neuromuscular evaluation that is impacted by subcutaneous fat (SF). Exploiting the differing frequency dependences of muscle and fat, we assessed a 2-frequency EIM phase ratio in Duchenne muscular dystrophy (DMD) boys. METHODS Twenty-eight DMD boys aged 2-13years underwent EIM and the 6-minute walk test (6MWT). For each subject, 50kHz phase data was input into the numerator while 20-500kHz phase values were input into the denominator. We then performed correlation analyses seeking to identify the denominator frequency that simultaneously optimized SF and 6MWT correlations. This optimized ratio was then tested in 24 healthy boys. RESULTS 50kHz phase correlated to 6MWT in DMD boys with R=0.52, p=0.0066, and to SF thickness with R=-0.67, p<0.001. An optimized ratio of 50/200kHz phase reduced the correlation of SF thickness to R=-0.075, p=0.45 while improving the relationship to the 6MWT (R=0.60, p=0.001). In normal subjects, the optimization decreased SF correlation from R=0.61 from R=0.16 with 6MWT correlation remaining unchanged. CONCLUSIONS The 50/200kHz EIM phase ratio removes the impact of SF while maintaining EIMs association with function. SIGNIFICANCE The use of a phase ratio may enhance EIMs application for evaluation of neuromuscular disease.

Spinal muscular atrophy functional composite score: A functional measure in spinal muscular atrophy.

Introduction: With clinical trials underway, our objective was to construct a composite score of global function that could discriminate among people with spinal muscular atrophy (SMA). Methods: Data were collected from 126 participants with SMA types 2 and 3. Scores from the Hammersmith Functional Motor Scale—Expanded and Upper Limb Module were expressed as a percentage of the maximum score and 6‐minute walk test as percent of predicted normal distance. A principal component analysis was performed on the correlation matrix for the 3 percentage scores. Results: The first principal component yielded a composite score with approximately equal weighting of the 3 components and accounted for 82% of the total variability. The SMA functional composite score, an unweighted average of the 3 individual percentage scores, correlated almost perfectly with the first principal component. Conclusions: This combination of measures broadens the spectrum of ability that can be quantified in type 2 and 3 SMA patients. Muscle Nerve 52: 942–947, 2015

Composite Biomarkers for Assessing Duchenne Muscular Dystrophy: An Initial Assessment

BACKGROUND Compared with individual parameters, composite biomarkers may provide a more effective means for monitoring disease progression and the effects of therapy in clinical trials than single measures. In this study, we built composite biomarkers for use in Duchenne muscular dystrophy by combining values from two objective measures of disease severity: electrical impedance myography and quantitative ultrasound and evaluating how well they correlated to standard functional measures. METHODS Using data from an ongoing study of electrical impedance myography and quantitative ultrasound in 31 Duchenne muscular dystrophy and 26 healthy boys aged 2-14 years, we combined data sets by first creating z scores based on the normal subject data and then using simple mathematical operations (addition and multiplication) to create composite measures. These composite scores were then correlated to age and standard measures of function including the 6-minute walk test, the North Star Ambulatory Assessment, and handheld dynamometry. RESULTS Combining data sets resulted in stronger correlations with all four outcomes than for either electrical impedance myography or quantitative ultrasound alone in six of eight instances. These improvements reached statistical significance (P < 0.05) in several cases. For example, the correlation coefficient for the composite measure with the North Star Ambulatory Assessment was 0.79 but was only 0.66 and 0.67 (respectively) for gray scale level and electrical impedance myography separately. CONCLUSIONS Arithmetically derived composite scores can provide stronger correlations to functional measures than isolated biomarkers. Longitudinal study of such composite markers in Duchenne muscular dystrophy clinical trials is warranted.

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.

Quantitative muscle ultrasound detects disease progression in Duchenne muscular dystrophy

We assessed changes in quantitative muscle ultrasound data in boys with Duchenne muscular dystrophy (DMD) and healthy controls to determine whether ultrasound can serve as a biomarker of disease progression. Two approaches were used: gray scale level (GSL), measured from the ultrasound image, and quantitative backscatter analysis (QBA), measured directly from the received echoes.