23Na MRI and myometry to compare eplerenone vs. glucocorticoid treatment in Duchenne dystrophy

Abstract

In this pilot study we tested whether a low dose application of a mild diuretic substance such as eplerenone is beneficial in early stages of Duchenne muscular dystrophy using 23Na und 1H imaging, myometry, and clinical testing versus the glucocorticoid gold standard. Two 7-years old patients with DMD were examined on a 3T MRI system. 1H MRI and 23Na density-adapted 3-dimensional radial MRI sequences were performed both before and 1, 3 and 6 months after therapy with eplerenone respectively cortisone. We quantified fatty infiltration on T1-weighted images using subcutaneous fat as reference and fat fraction with a two-point DIXON sequence. Muscle oedema was quantified on STIR images and DIXON water maps with background noise as reference. We quantified Na+ by a muscular tissue concentration sequence with a 51.3mM Na+ with 5% agarose reference tube. A Na+ IR-sequence was used for determination of mainly myoplasmic Na+. Correspondingly myometry of muscles and tendons were assessed. Clinical tests (i.e. 4-steps-test) and blood counts (i.e. K+) were done by a pediatrician. Under eplerenone therapy we detected a reduction of muscular oedema, intracellular-weighted sodium IR signal and muscular sodium concentration. The oedema reduction in the DMD patient receiving eplerenone was more pronounced to the patient with cortisone. Myometric-measured tissue parameters such as muscle stiffness had a more pronounced effect in the child treated with eplerenone after a first increase in muscle stiffness both after eplerenone and cortisone treatment. Clinical abilities during both therapies were mostly constant. Eplerenone might be a possible new therapy option in DMD patients.

Keywords: 23Na MRI; Duchenne; eplerenone.

Figures

Figure 1.

MRI of calves of four 7-years old boys with DMD. T1-w (A-B), short tau inversion recovery (STIR, C-L). Development of fatty muscular infiltration (T1-w) and muscular oedema (STIR). Two DMD patients (A-D) without therapy at any time in 3 years' (first patient without therapy, A-B) and 7 months' time period (second patient without therapy, C-D). DMD patient before (E) and 1,3 and 6 months (F-H) after therapy with glucocorticoids (0,9mg Deflazacort/kg/day). DMD patient before (I) and 1,3 and 6 months (J-L) after therapy with eplerenone (25mg/day). Increasing fatty degeneration of the soleus muscle (A-B) and increasing oedema-like changes in the medial gastrocnemius muscle (C-D) in two patients without therapy. Prior to therapy, oedema-like changes especially in the anterior compartment (E; afterwards glucocorticoid treatment) respectively deep posterior compartment and medial gastrocnemius muscle (I, afterwards treatment with eplerenone). Following therapy with glucocorticoids (standard) and eplerenone, there are decreasing oedema-like changes.

Figure 2.

Analysis of 1H MR and 23Na image data, DMD patient, exemplary measurements. 1H-T1w (left) and 23Na- MR image (spin density image contrast, no inversion recovery); reference tubes (in each image): right-hand side of the patient (51.3 mM NaCl in 5% agarose, mentioned as 4) and left-hand side (51.3mM NaCl solution) reference tube. Exemplary measurement of fatty infiltration using a 1H T1w Ratio (ROImuscle/ROIsubcutaneus fat) of the left soleus muscle (ROI 1/ROI 2 in left image); accordingly measurement of muscular sodium concentration using a 23Na-MR sequence (no IR, ROI of Na+ value of respective muscle / ROI of signal intensity in the existing Na+ agarose control phantom) within the left soleus muscle (ROI 3/ROI 4 in right image).

Table 1.

Treatment effects of two 7-years old DMD boys under eplerenone and glucocorticoid treatment, respectively. There is a decrease of the 23Na IR signal and the muscular sodium concentration following both eplerenone and glucocorticoid treatment. The reduction of muscular water content (measured by the DIXON water mapping) was more pronounced in the boy with eplerenone treatment (especially in deep posterior muscle compartment and peroneus muscle compartment). A slighter change has been found for glucocorticoid treatment. Both the degree of fatty degeneration and the fat fraction (measured within the soleus muscle) remains constant over the 6 months' period.

Figure 3.

Illustration of declining muscular sodium concentration of four different muscle compartments comparing eplerenone vs. cortisone treatment in a graph according to Table 1. Both therapies showed a distinct effect.

Figure 4.

1H STIR Imaging: Illustration of the STIR ratio of four different muscle compartments comparing eplerenone vs. cortisone treatment. Symbols for the respective compartment as given in the legend of the figure. The oedema reduction for the patient following eplerenone treatment showed a higher oedema reduction especially in deep posterior and soleus muscle compartment. A slighter decrease is also shown for the patient receiving cortisone treatment (as showed in figures normed to 1).

Table 2.

Illustration of myometry: Myometric changes in stiffness of muscles and tendons were quantitatively assessed as described in the methods' section.

Figure 5.

Clinical testing (i.e. walking of 10 meters, 4-steps-test) for evaluation of muscle endurance and muscular abilities following the respective therapy. Both therapies (eplerenone and cortisone) showed no distinct changes in test results over a time-period of six months.

Figure 6.

Model illustrating the presumed pathophysiology in Duchenne muscular dystrophy. Dystrophin deficiency, nNOS and consecutive inaccurate sodium homeostasis as a major contributor in Duchenne muscular dystrophy.