Characterizing Expiratory Respiratory Muscle Degeneration in Duchenne Muscular Dystrophy Using MRI

Abstract

Background: Expiratory muscle weakness and impaired airway clearance are early signs of respiratory dysfunction in Duchenne muscular dystrophy (DMD), a degenerative muscle disorder in which muscle cells are damaged and replaced by fibrofatty tissue. Little is known about expiratory muscle pathology and its relationship to cough and airway clearance capacity; however, the level of muscle replacement by fat can be estimated using MRI and expressed as a fat fraction (FF).

Research question: How does abdominal expiratory muscle fatty infiltration change over time in DMD and relate to clinical expiratory function?

Study design and methods: Individuals with DMD underwent longitudinal MRI of the abdomen to determine FF in the internal oblique, external oblique, and rectus abdominis expiratory muscles. FF data were used to estimate a model of expiratory muscle degeneration by using nonlinear mixed effects and a cumulative distribution function. FVC, maximal inspiratory and expiratory pressures, and peak cough flow were collected as clinical correlates to MRI.

Results: Forty individuals with DMD (aged 6-18 years at baseline) participated in up to five visits over 36 months. Modeling estimated the internal oblique progresses most quickly and reached 50% replacement by fat at a mean patient age of 13.0 years (external oblique, 14.0 years; rectus abdominis, 16.2 years). Corticosteroid-untreated individuals (n = 4) reached 50% muscle replacement by fat 3 to 4 years prior to treated individuals. Individuals with mild clinical dystrophic phenotypes (n = 3) reached 50% muscle replacement by fat 4 to 5 years later than corticosteroid-treated individuals. Internal and external oblique FFs near 50% were associated with maximal expiratory pressures < 60 cm H₂O and peak cough flows < 270 L/min.

Interpretation: These data improve understanding of the early phase of respiratory compromise in DMD, which typically presents as airway clearance dysfunction prior to the onset of hypoventilation, and links expiratory muscle fatty infiltration to pulmonary function measures.

Keywords: Duchenne muscular dystrophy; MRI; airway clearance; cough; expiratory muscles.

Graphical abstract

Figure 1

A-G, Pulmonary function characteristics of the study cohort. A, FVC. B, Percent predicted FVC. C, MEP. D, Percent predicted MEP. E, MIP. F, Percent predicted MIP. G, Peak cough flow values for the study cohort. Dots indicate test values at a single visit, and lines connect data from a single participant. Filled dots denote ambulatory time points, and open dots denote nonambulatory time points. When participants lost ambulation during the study, this is noted with a blue line. Note that percent predicted FVC uses height in estimation equations, and height measurement methods changed once a participant became nonambulatory. MEP = maximal expiratory pressure; MIP = maximal inspiratory pressure.

Figure 2

Expiratory muscle fatty infiltration over time. Axial fat-water fusion images from two participants at four time points illustrate the progressive fatty infiltration of the internal oblique, external oblique, and rectus abdominis muscles over time. The individual detailed in the top row was 12.3 years old at baseline and nonambulatory throughout the study; the individual detailed in the bottom row was 12.7 years old at baseline and remained ambulatory throughout. Abd = abdominis.

Figure 3

A-F, Raw data and modeled trajectories of expiratory muscle fatty infiltration. A, C, E, Trajectories of expiratory muscle FF from each participant. Dots indicate FF at a single visit, and lines connect data from a single participant. The internal oblique had the fastest degeneration and increase in FF of the three muscles. Although the majority of participants were corticosteroid treated (Steroid +, blue dots), there were four corticosteroid-negative (Steroid -, red dots) participants. There was also three participants with mild clinical phenotypes (Mild Phenotype, gray dots). B, D, F, Modeled trajectories (solid line) and 25%/75% quartiles (dashed lines) for expiratory muscle FF changes with age. FF = fat fraction.

Figure 4

A-F, Estimated FF trajectories and parameters for subgroups. A-C, Mu values (age at muscle FF = 0.50) derived from modeled trajectories for each participant plotted as box and whisker plots with median and 25th and 75th percentile lines creating the box, and the minimum and maximum values creating the whiskers. The mu values of the corticosteroid-negative group (Steroid -, red dots), the corticosteroid-treated group (Steroid +, blue dots), and the mild clinical phenotype group (Mild Phenotype, gray dots) are plotted. D-F, Expiratory muscle trajectories were plotted by using the mean mu and sigma values from the participants in each group. For all three expiratory muscles, the corticosteroid-negative group (red line) was the most left shifted, denoting fatty infiltration reaching 50% at an earlier age, and the mild clinical phenotype group (gray line) was the most right shifted, reflecting an older age at 50% fatty infiltration (slower disease progression). FF = fat fraction.

Figure 5

A-G, Comparison of expiratory muscle FF vs pulmonary function test results. A-F, Box and whisker plots illustrate pulmonary function test values for each of five internal oblique and external oblique FF groups. The median and 25th and 75th percentile lines create the box, and the minimum and maximum values create the whiskers. The + symbol indicates mean. For percent predicted FVC and MEP, the red shaded area indicates values ≤ 80%, where 80% is generally accepted as the lower limit of normal for these tests. For PCF, the line indicates 270 L/min; the red shaded area indicates values ≤ 160 L/min. G, Bars indicate the percentage of the participant visits with MEP values < 60 cm H₂O (blue) and > 60 cm H₂O (red) for each FF group. FF = fat fraction; MEP = maximal expiratory pressure.