Synopsis

This study presents both an analysis pipeline for measuring diaphragmatic motion from cine MRI data, and the application of this image processing technique to investigate exploratory MRI endpoints of respiratory function in both healthy controls and non-ambulant DMD boys. Cine-derived metrics of diaphragm motility and contractility correlated with sitting spirometry-derived forced vital capacity, and showed relationships with disease progression surrogates of age and months non-ambulatory, as well as a longitudinal change over 12 months. Longitudinal changes were not seen in spirometry measures.

Introduction

DMD involves progressive muscle damage including of the diaphragm, ultimately requiring ventilation¹. Recent studies have described the spirometry derived forced vital capacity (FVC) as a percentage of predicted normal values (%Pred) in both ambulant and non-ambulant DMD^2–4. Our aim was to explore whether image analysis of dynamic (cine) MRI can be used to provide an adjunctive measure of diaphragm mobility in DMD.

Patients and Methods

Thirteen non-ambulant DMD boys (mean age 13.2±2.1 years, 20.9±12.6 months since loss of ambulation) and 10 age- and gender-matched healthy volunteers (mean age 14.6±1.3 years; P=0.081) were recruited and scanned at baseline, with a subset (n=10) of the DMD subjects also assessed at follow-up visits 3, 6 and 12 months later.

Spirometry derived FVC, %Pred, peak expiratory flow (PEF), maximal inspiratory pressure (MIP), and maximal expiratory pressure (MEP) were recorded. 60 Cine MRI frames were acquired each 0.5s in sagittal acquisitions at the midline of each lung on a Siemens Skyra 3T using a TR of 250ms, TE of 1.39s, FA 8°, and 5mm slice thickness.

A schematic of the image analysis pipeline, including the lung and diaphragm measures extracted^5,7, is provided in Figure 1.

Results

Strong differences in almost all lung shape parameters were found between controls and DMD, controlling for height differences between the groups (Table 1). There was good correlation of most diaphragm motion measures with the spirometry measures of sitting FVC (Table 2). The end-expiratory lengths were shorter and a larger change in TDM is required in DMD patients for a unit change in CSA (Figure 2). The end-expiratory length for ANT and PST were numerically reduced at all follow-up visits, but only reached significance at 3 month follow-up (P=0.02 and 0.03, two-tailed).

Age and to a greater degree months of non-ambulation influence the observed longitudinal decrease in min CSA, min TDM and max TDM (Figure 7: left and middle plots). This is further supported by the statistically significant relationships found for the number of non-ambulatory months versus max CSA (R=-0.460, P=0.0042, N=37), delta CSA (R=-0.482, P=0.0025) and mean CSA (R=-0.368, P=0.025), both max TDM (R=-0.394, P=0.016) and delta TDM (R=-0.401, P=0.014), max DIA (R=-0.441, P=0.0062), delta DIA (R=-0.527, P=0.0008) and mean DIA (R=-0.391, P=0.017), delta CNT (R=-0.438, P=0.0066), max PST (R=-0.338, P=0.041) and delta PST (R=-0.358, P=0.030). In contrast, only the spirometry metric of %Pred correlated with the months of non-ambulation (R=-0.390, P=0.0299 (N=31)). There was a statistically significant decrease in min CSA at 12 months compared to baseline (-15.3% (19.3), P=0.03, Figure 3 top-right). No longitudinal changes were observed for FVC sitting or %Pred.

Discussion

Although spirometry is currently the most common test for pulmonary function in DMD as an outcome measure in clinical trials it requires a large number of subjects to account for the wide variability. Furthermore, measures can be heavily reliant on subject cooperation and motivation to perform the tests.

On the other hand, MRI appears to offer a sensitive and targeted measure of diaphragm function. While still requiring cooperation, the manoeuvres required for the MRI assessment are less dependent on coordination and following specific commands, and have been shown to be similar in prone and supine positions⁹. The MRI parameters may also offer a more extensive measurement and more flexibility to probe specific, individual contributions to pulmonary function (such as the lower contribution from the anterior part of the diaphragm to the CSA change) since multiple imaging planes and targeted regions-of-interest, on a slice-by-slice or volumetric basis, can be objectively explored with relative ease and accuracy.

Previous studies exploring MRI measures of pulmonary function have largely focused on healthy volunteers [^5–9]. Cluzel et al. showed good agreement between spirometry and MR values of lung volume. We have also demonstrated that many of the derived MRI summary measures correlate well with spirometry data but also other measures of disease progression/severity (such as months of non-ambulation) in DMD.

In this DMD cohort, the finding of a statistically significant decrease in min CSA at 12 months compared to baseline and a trending decrease in min TDM across visits, could possibly be due to a weakening of both the diaphragm and the intercostal muscles over the one year study period. In addition, the trending decrease in max TDM across visits could indicate progressive diaphragm dysfunction in this DMD cohort.

Acknowledgements

The financial support of L’Association Française contre les Myopathies (AFM) and European Commission (EU) are also acknowledged (VR). This study was supported by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London (FM). The MRC support to the Neuromuscular Translational Centre at UCL, and the support of the Muscular Dystrophy Campaign to the Neuromuscular Centres at GOSH and UCLH is also gratefully acknowledged.

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