Quantitative muscle ultrasound is a promising longitudinal follow-up tool in Duchenne muscular dystrophy

Abstract

Responsive outcome measures are needed to follow the disease status of Duchenne muscular dystrophy (DMD) patients, as new therapeutic approaches become available for affected boys. Quantitative muscle ultrasound (QMUS) is potentially an attractive follow up tool for DMD because it reflects the severity of the dystrophic process without the need for invasive procedures, by quantifying echo intensity (i.e. mean grey level of muscle images) and muscle thickness. We performed a longitudinal follow-up of lower and upper extremity QMUS in 18 DMD patients and compared this with physical functioning in 11 of these patients. QMUS could be performed in every patient, and no patient was subjected to more than a total of 20 min of ultrasound scanning time for this study. As expected we found a significant increase of echo intensity with age, reflecting increasing dystrophic muscle changes. This increase was related to ambulatory status, functional grading, muscle strength and motor ability. Our study establishes QMUS as a practical and child-friendly tool for the longitudinal follow up of DMD patients.

Introduction

Duchenne muscular dystrophy (DMD) is the most common debilitating neuromuscular disorder affecting young boys and their families. In the past decade new and promising therapeutic approaches have become available that need validation in practice. For this, responsive outcome measures are needed to quantify the disease status of boys with DMD. Such outcome measures also need to be practical, feasible in young children and patient friendly, and should therefore preferably be noninvasive.

The frequently used battery of clinical outcomes for DMD consists of quantitative muscle strength tests, the Six-Minute Walk Test [1], functional scales and timed function tests [2]. Although these outcome measures are clinically meaningful and have an immediate value to the boys and their parents, they also have their limitations. For example, sensitivity is often limited and ceiling effects exist for functional scales such as the Hammersmith Scale for Assessment of Motor Ability [2], [3]. Likewise, muscle strength tests have limited correlation with functionality because a small reduction in strength is often accompanied by a large reduction in functional ability when a paresis is already present [4]. Specific testing can be difficult in the younger children for whom new therapies will preferably be intended. Taken together with the increased risk for cognitive [5] and neurobehavioral problems [6] in DMD, measuring these boys’ physical and functional capacities can be challenging.

Quantitative muscle ultrasound (QMUS) is a child-friendly imaging technique that is fast, painless and does not require sedation or anaesthesia [7], [8]. It provides an accurate and reliable tool to distinguish children with and without a neuromuscular disorder with high predictive values and can visualize the intramuscular fibrosis and fatty infiltration in DMD as a homogeneous increase of muscle echo intensity (i.e. the muscle becomes more echogenic, so that its image appears more uniformly filled with grey speckles) [7], [9], [10], [11], [12].

Quantitative muscle imaging could be a relevant supplement to the current battery of clinical outcome measures, as it objectifies structural muscle changes without being influenced by fatigue, verbal understanding or cooperation, and can thus potentially quantify the pathology underlying deterioration of physical functioning without the need for muscle biopsy or sedated MR imaging. A recent cross-sectional study among 39 DMD patients has shown that the quantitatively determined muscle echo intensity of the elbow flexors linearly increased with age and correlated with physical functioning and disease severity [13]. Using grayscale analysis, the echo intensity in healthy children does not change with age until they reach adulthood [8], [12], although the use of another quantifying technique showed a possible increase in calibrated muscle backscatter in a plot of the elbow flexors over time [13]. Muscle echo intensity does increase significantly with age in healthy adults, probably as a result of age-related muscle replacement by fat and fibrous tissue [13], [14], [15], [16].

It is suspected but not yet investigated that echo intensity and muscle thickness of lower extremity muscles correlate with age and disease severity in DMD boys. It is also still unknown whether quantitatively assessed echo intensity and muscle thickness are sensitive enough to measure progressive changes in muscle structure over time or how strongly these changes are associated with clinical disease progression and loss of function. The aim of our study was therefore to perform a longitudinal follow up of the changes and relation of lower and upper extremity QMUS with age, disease severity and physical functioning in a cohort of DMD boys. The objective was to assess whether QMUS can be used as a responsive follow up tool in upcoming treatment trials for DMD.