Alina Nicorici

The 6-minute walk test as a new outcome measure in Duchenne muscular dystrophy.

Walking abnormalities are prominent in Duchenne muscular dystrophy (DMD). We modified the 6‐minute walk test (6MWT) for use as an outcome measure in patients with DMD and evaluated its performance in 21 ambulatory boys with DMD and 34 healthy boys, ages 4 to 12 years. Boys with DMD were tested twice, ∼1 week apart; controls were tested once. The groups had similar age, height, and weight. All tests were completed. Boys who fell recovered rapidly from falls without injury. Mean ± SD [range] 6‐minute walk distance (6MWD) was lower in boys with DMD than in controls (366 ± 83 [125–481] m vs. 621 ± 68 [479–754] m; P < 0.0001; unpaired t‐test). Test‐retest correlation for boys with DMD was high (r = 0.91). Stride length (R2 = 0.89; P < 0.0001) was the major determinant of 6MWD for both boys with DMD and controls. A modified 6MWT is feasible and safe, documents disease‐related limitations on ambulation, is reproducible, and offers a new outcome measure for DMD natural history and therapeutic trials. Muscle Nerve, 2010

The 6-minute walk test in Duchenne/Becker muscular dystrophy: Longitudinal observations

In this study we used the 6‐minute walk distance (6MWD) to characterize ambulation over time in Duchenne/Becker muscular dystrophy (DBMD). The 6MWD was assessed in 18 boys with DBMD and 22 healthy boys, ages 4–12 years, over mean [range] intervals of 58 [39–87] and 69 [52–113] weeks, respectively. Height and weight increased similarly in both groups. At 52 weeks, 6MWD decreased in 12 of 18 (67%) DBMD subjects (overall mean [range]: 357 [125–481] to 300 [0–510] meters; Δ −57 meters, −15.9%), but increased in 14 of 22 (64%) healthy subjects (overall mean [range]: 623 [479–754] to 636 [547–717] meters; Δ +13 meters, +2.1%). Two DBMD subjects lost ambulation. Changes in 6MWD depended on stride length and age; improvements usually occurred by 7–8 years of age; older DBMD subjects worsened, whereas older healthy subjects were stable. The 6MWD changes at 1 year confirm the validity of this endpoint and emphasize that preserving ambulation must remain a major goal of DBMD therapy. Muscle Nerve, 2010

The 6-Minute Walk Test and Person-Reported Outcomes in Boys with Duchenne Muscular Dystrophy and Typically Developing Controls: Longitudinal Comparisons and Clinically-Meaningful Changes Over One Year.

Introduction: Data is currently lacking anchoring a 30-meter longitudinal change in walking ability by 6-minute walk test (6MWT) in Duchenne muscular dystrophy as a minimal clinically important difference and “clinically meaningful” person-reported outcomes (PROs) at differing levels of ambulatory ability. Methods: We describe correlation between measures, 1-year change in measures, and correlation of 1-year changes between measures for the six-minute walk test (6MWT), 10-meter run/walk velocity, PedsQL and POSNA Pediatric Outcomes Data Collection Instrument (PODCI) in 24 4-12 year old. ambulatory DMD and 36 typical controls, and determine if minimal clinically important differences (MCID) of PROs contribute to different estimates of 6-minute walk distance (6MWD) change at differing levels of ability. Results: PedsQL total and physical function and PODCI global, transfer/mobility and sports/physical function PROs demonstrated significant differences between DMD and controls (p<0.00001). In DMD, 6MWD and 10-meter run/walk velocity were correlated with PODCI domain scores, with the transfer/mobility scale showing the strongest relationship (r=0.79 and r=0.76). In DMD, 6MWD distance and 10-meter run/walk velocity weakly correlated with PedsQL domain scores. In DMD, 6MWD, 10-meter run/walk velocity, and PODCI global and transfer and basic mobility demonstrated significant one-year change and exceeded the amount of change representing MCID. In DMD, 6MWD change highly correlated with change in PODCI global and PODCI transfer/mobility scores (r=0.76 and r=0.93). PODCI global and PODCI transfer/mobility scales provided the best estimates of 6MWT performance. A “meaningful” 4.5 point change in a low PODCI transfer / basic mobility score of 30 to 34.5 was associated with a 5.6m 6MWD change from 150.3 to 155.9m. At PODCI levels closer to normative levels for healthy controls, the change in 6MWD distance associated with a “meaningful” change in PODCI scores was almost 46m. Discussion: At lower levels of function, smaller increases in 6MWD result in meaningful change in quality of life (QoL) instrument scores. At higher levels of function, larger increases may be necessary to achieve the same QoL change score.

Percent-predicted 6-minute walk distance in duchenne muscular dystrophy to account for maturational influences.

We recently described a modified version of the 6-minute walk test (6MWT) for Duchenne muscular dystrophy (DMD) based partly on the American Thoracic Society (ATS) guidelines. This measure has shown reliability, validity and utility as a primary outcome measure in DMD clinical trials. Because loss of muscle function in DMD occurs against the background of normal childhood growth and development, younger children with DMD can show increase in distance walked during 6MWT over ~1 year despite progressive muscular impairment. In this study, we compare 6-minute walk distance (6MWD) data from DMD boys (n=17) and typically developing control subjects (n=22) to existing normative data from age- and sex-matched children and adolescents. An age- and height-based equation fitted to normative data by Geiger and colleagues was used to convert 6MWD to a percent-predicted (%-predicted) value in boys with DMD. Analysis of %-predicted 6MWD data represents a method to account for normal growth and development, and shows that gains in function at early ages represents stable rather than improving abilities in boys with DMD. Boys with DMD from 4-7 years of age maintain a stable 6MWD approximately 80% of that of typically developing peers, with the deficit progressing at a variable rate thereafter.

Motor and cognitive assessment of infants and young boys with Duchenne Muscular Dystrophy: results from the Muscular Dystrophy Association DMD Clinical Research Network

Therapeutic trials in Duchenne Muscular Dystrophy (DMD) exclude young boys because traditional outcome measures rely on cooperation. The Bayley III Scales of Infant and Toddler Development (Bayley III) have been validated in developing children and those with developmental disorders but have not been studied in DMD. Expanded Hammersmith Functional Motor Scale (HFMSE) and North Star Ambulatory Assessment (NSAA) may also be useful in this young DMD population. Clinical evaluators from the MDA-DMD Clinical Research Network were trained in these assessment tools. Infants and boys with DMD (n = 24; 1.9 ± 0.7 years) were assessed. The mean Bayley III motor composite score was low (82.8 ± 8; p ≤ .0001) (normal = 100 ± 15). Mean gross motor and fine motor function scaled scores were low (both p ≤ .0001). The mean cognitive comprehensive (p=.0002), receptive language (p ≤ .0001), and expressive language (p = .0001) were also low compared to normal children. Age was negatively associated with Bayley III gross motor (r = -0.44; p = .02) but not with fine motor, cognitive, or language scores. HFMSE (n=23) showed a mean score of 31 ± 13. NSAA (n = 18 boys; 2.2 ± 0.4 years) showed a mean score of 12 ± 5. Outcome assessments of young boys with DMD are feasible and in this multicenter study were best demonstrated using the Bayley III.

Relationship Between Clinical Outcome Measures and Parent Proxy Reports of Health-Related Quality of Life in Ambulatory Children With Duchenne Muscular Dystrophy

In Duchenne muscular dystrophy, data directly linking changes in clinical outcome measures to patient-perceived well-being are lacking. This study evaluated the relationship between clinical outcome measures used in clinical trials of ambulatory Duchenne muscular dystrophy (Vignos functional grade, quantitative knee extension strength, timed functional performance measures, and gait velocity) and 2 health-related quality of life measures—the Pediatric Outcomes Data Collection Instrument and Pediatric Quality of Life Inventory—in 52 ambulatory Duchenne muscular dystrophy subjects and 36 controls. Those with the disease showed significant decrements in parent proxy-reported health-related quality of life measures versus controls across all domains. The Pediatric Outcomes Data Collection Instrument transfers/basic mobility and sports/ physical function and the Pediatric Quality of Life Inventory physical functioning domains had significant associations with age (and hence disease progression) and traditional clinical outcome measures employed in clinical trials of ambulatory boys with Duchenne muscular dystrophy. Selected domains of the Pediatric Outcomes Data Collection Instrument and generic Pediatric Quality of Life Inventory are potential patient-reported outcome measures for clinical trials in ambulatory individuals with the disease.

Development and application of stereo camera-based upper extremity workspace evaluation in patients with neuromuscular diseases.

Background The concept of reachable workspace is closely tied to upper limb joint range of motion and functional capability. Currently, no practical and cost-effective methods are available in clinical and research settings to provide arm-function evaluation using an individual’s three-dimensional (3D) reachable workspace. A method to intuitively display and effectively analyze reachable workspace would not only complement traditional upper limb functional assessments, but also provide an innovative approach to quantify and monitor upper limb function. Methodology/Principal Findings A simple stereo camera-based reachable workspace acquisition system combined with customized 3D workspace analysis algorithm was developed and compared against a sub-millimeter motion capture system. The stereo camera-based system was robust, with minimal loss of data points, and with the average hand trajectory error of about 40 mm, which resulted to ∼5% error of the total arm distance. As a proof-of-concept, a pilot study was undertaken with healthy individuals (n = 20) and a select group of patients with various neuromuscular diseases and varying degrees of shoulder girdle weakness (n = 9). The workspace envelope surface areas generated from the 3D hand trajectory captured by the stereo camera were compared. Normalization of acquired reachable workspace surface areas to the surface area of the unit hemi-sphere allowed comparison between subjects. The healthy group’s relative surface areas were 0.618±0.09 and 0.552±0.092 (right and left), while the surface areas for the individuals with neuromuscular diseases ranged from 0.03 and 0.09 (the most severely affected individual) to 0.62 and 0.50 (very mildly affected individual). Neuromuscular patients with severe arm weakness demonstrated movement largely limited to the ipsilateral lower quadrant of their reachable workspace. Conclusions/Significance The findings indicate that the proposed stereo camera-based reachable workspace analysis system is capable of distinguishing individuals with varying degrees of proximal upper limb functional impairments.

Outcome reliability in non-Ambulatory Boys/Men with duchenne muscular dystrophy

Introduction: Therapeutic trials in Duchenne muscular dystrophy (DMD) often exclude non‐ambulatory individuals. Here we establish optimal and reliable assessments in a multicenter trial. Methods: Non‐ambulatory boys/men with DMD (N = 91; 16.7 ± 4.5 years of age) were assessed by trained clinical evaluators. Feasibility (percentage completing task) and reliability [intraclass correlation coefficients (ICCs) between morning and afternoon tests] were measured. Results: Forced vital capacity (FVC), assessed in all subjects, showed a mean of 47.8 ± 22% predicted (ICC 0.98). Brooke Upper Extremity Functional Rating (Brooke) and Egen Klassifikation (EK) scales in 100% of subjects showed ICCs ranging from 0.93 to 0.99. Manual muscle testing, range of motion, 9‐hole peg test, and Jebsen‐Taylor Hand Function Test (JHFT) demonstrated varied feasibility (99% to 70%), with ICCs ranging from 0.99 to 0.64. We found beneficial effects of different forms of corticosteroids for the Brooke scale, percent predicted FVC, and hand and finger strength. Conclusions: Reliable assessment of non‐ambulatory boys/men with DMD is possible. Clinical trials will have to consider corticosteroid use. Muscle Nerve 51: 522–532, 2015

Reachable workspace in facioscapulohumeral muscular dystrophy (FSHD) by kinect

Introduction: A depth‐ranging sensor (Kinect) based upper extremity motion analysis system was applied to determine the spectrum of reachable workspace encountered in facioscapulohumeral muscular dystrophy (FSHD). Methods: Reachable workspaces were obtained from 22 individuals with FSHD and 24 age‐ and height‐matched healthy controls. To allow comparison, total and quadrant reachable workspace relative surface areas (RSAs) were obtained by normalizing the acquired reachable workspace by each individuals arm length. Results: Significantly contracted reachable workspace and reduced RSAs were noted for the FSHD cohort compared with controls (0.473 ± 0.188 vs. 0.747 ± 0.082; P < 0.0001). With worsening upper extremity function as categorized by the FSHD evaluation subscale II + III, the upper quadrant RSAs decreased progressively, while the lower quadrant RSAs were relatively preserved. There were no side‐to‐side differences in reachable workspace based on hand‐dominance. Conclusions: This study demonstrates the feasibility and potential of using an innovative Kinect‐based reachable workspace outcome measure in FSHD. Muscle Nerve 51: 168–175, 2015

Upper extremity reachable workspace evaluation with Kinect.

We propose a novel low-cost method for quantitative assessment of upper extremity workspace envelope using Microsoft Kinect camera. In clinical environment there are currently no practical and cost-effective methods available to provide arm-function evaluation in three-dimensional space. In this paper we examine the accuracy of the proposed technique for workspace estimation using Kinect in comparison with a motion capture system. The experimental results show that the developed system is capable of capturing the workspace with sufficient accuracy and robustness.