Abstract
Subjects with Duchenne Muscular Dystrophy (DMD) suffer from progressive muscle damage leading to diaphragmatic weakness that ultimately requires ventilation. Emerging treatments have generated interest in better characterizing the natural history of respiratory impairment in DMD and responses to therapy. Dynamic (cine) Magnetic Resonance Imaging (MRI) may provide a more sensitive measure of diaphragm function in DMD than the commonly used spirometry. This study presents an analysis pipeline for measuring parameters of diaphragmatic motion from dynamic MRI and its application to investigate MRI measures of respiratory function in both healthy controls and non-ambulant DMD boys. We scanned 13 non-ambulant DMD boys and 10 age-matched healthy male volunteers at baseline, with a subset (n = 10, 10, 8) of the DMD subjects also assessed 3, 6, and 12 months later. Spirometry-derived metrics including forced vital capacity were recorded. The MRI-derived measures included the lung cross-sectional area (CSA), the anterior, central, and posterior lung lengths in the sagittal imaging plane, and the diaphragm length over the time-course of the dynamic MRI. Regression analyses demonstrated strong linear correlations between lung CSA and the length measures over the respiratory cycle, with a reduction of these correlations in DMD, and diaphragmatic motions that contribute less efficiently to changing lung capacity in DMD. MRI measures of pulmonary function were reduced in DMD, controlling for height differences between the groups: at maximal inhalation, the maximum CSA and the total distance of motion of the diaphragm were 45% and 37% smaller. MRI measures of pulmonary function were correlated with spirometry data and showed relationships with disease progression surrogates of age and months non-ambulatory, suggesting that they provide clinically meaningful information. Changes in the MRI measures over 12 months were consistent with weakening of diaphragmatic and inter-costal muscles and progressive diaphragm dysfunction. In contrast, longitudinal changes were not seen in conventional spirometry measures during the same period. Dynamic MRI measures of thoracic muscle and pulmonary function are, therefore, believed to detect meaningful differences between healthy controls and DMD and may be sensitive to changes in function over relatively short periods of follow-up in non-ambulant boys with DMD.
Highlights
Duchenne Muscular Dystrophy (DMD) is a highly debilitating X-linked recessive disorder affecting 1 in 5,000 male births [1]
Baseline mean for the spirometry measures of FVC, %Pred, peak expiratory flow (PEF), peak cough flow (PCF), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) for Duchenne muscular dystrophy (DMD) subjects are given in Table 1, together with their percentage change from baseline at the follow-up visits 3, 6, and 12 months later
We have reported the respiratory profile of a cohort of glucocorticoids treated non-ambulant DMD subjects as recorded by spirometry, lung and diaphragm measures from dynamic Magnetic Resonance Imaging (MRI)
Summary
Duchenne Muscular Dystrophy (DMD) is a highly debilitating X-linked recessive disorder affecting 1 in 5,000 male births [1]. Mutations in the DMD gene preclude expression of the sarcolemmal protein dystrophin, which is found primarily in skeletal and cardiac muscle. This leads to progressive muscle damage, loss of function, and loss of ambulation (LOA) by their mid-teens [2]. Glucocorticoid therapy was the only pharmacological intervention proven to delay disease progression in muscles [5]; a phosphorodiamidate morpholino antisense oligonucleotide (PMO) that modulates splicing to restore semi-functional dystrophin has received conditional approval by the Food and Drug Administration to treat DMD [6] and a drug to induce read-through nonsense mutations has been approved within the European Union Member States [7]. Outcome measures in clinical trials currently rely on the assessment of motor function, such as the 6-minute-walk test (6-MWT), which has been utilized as a primary outcome end-point in phase II–III clinical trials [7,8,9]
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