Measurements of Motor Function and Other Clinical Outcome Parameters in Ambulant Children with Duchenne Muscular Dystrophy

Summary

The aim of this study is to present the most reliable clinical outcome measures and their correlations with quantitative muscle MRI in ambulant patients with Duchenne muscular dystrophy.

Abstract

While the number of new treatment options tested in patients with Duchenne muscular dystrophy (DMD) is increasing, there is still no defining of the most reliable assessments regarding therapeutic efficacy. We present clinical and radiological outcome measures used in ambulatory patients participating in our trial "Treatment with L-citrulline and metformin in Duchenne muscular dystrophy". The motor function measure is a validated test in patients with neuromuscular disorders that consists of 32 items and assesses all three dimensions of motor performance including standing and transfer (D1 subscore), axial and proximal motor function (D2 subscore), and distal motor function (D3 subscore). The test shows high intra- and inter-rater variability but only when strictly following guidelines of the materials, examination steps, and calculation of scores. The 6-minute walk test, timed 10-meter walk/run test, and supine-up time are commonly used timed functional tests that also sufficiently monitor changes in muscle function; however, they strongly depend on patient collaboration. Quantitative MRI is an objective and sensitive biomarker to detect subclinical changes, though the examination costs may be a reason for its limited use. In this study, a high correlation between all clinical assessments and quantitative MRI scans was found. The combinational use of these methods provides a better understanding about disease progression; however, longitudinal studies are needed to validate their reliability.

Introduction

Outcome measures that reliably reflect treatment response are an essential requirement of successful clinical trials. Due to the rapid development of new therapeutic strategies, stronger effort has been made to define reproducible as well as sensitive methods that monitor clinical outcomes.

Duchenne muscular dystrophy (DMD) is an X-linked recessive disorder and the most common type of muscular dystrophy in children. It is characterized by severe involvement of predominantly the skeletal and heart muscle and a progressive disease course, with loss of ambulation around 8-12 years old and premature death mainly before 30 years old

Protocol

Before recruitment, the study was approved by the local ethics committee [Ethics Committee of the two Basel Cantons (EKBB 63/13)] and the Swiss Drug Agency (Swissmedic 2013DR3151) and registered under ClinicalTrials.gov (NCT01995032).

1. Clinical Assessment of Muscle Function

1. Motor function measure (MFM)
   1. Have the patient perform each of the following tasks and score them as shown in Table 1.
      Note: The MFM contains 32 independent items that must be performed in the given order to avoid unnecessarily repositioning and exhaustion of the patient⁵. See

Results

Baseline data of 47 ambulatory male patients (aged 6.5 to 10.8 years) with DMD were analyzed. All patients participated previously in the "Treatment with L-citrulline and metformin in Duchenne muscular dystrophy" study. Patients were enrolled from the University Children's Hospital Basel and from the patient registries of Switzerland, Germany, and Austria. Except for one patient, who refused to take part in the scanning, MRI of all thigh muscles was performed¹³

Discussion

Several promising outcome measures have been used in clinical trials in patients with Duchenne muscular dystrophy (DMD). The MFM is a validated and reproducible functional test that involves a detailed examination of crucial motor functions in 32 steps⁴, while the 6MWT can provide useful information about the patient's endurance.

All currently validated tests have limitations due to inter- and intra-rater variabilities and all require cooperation of the patient and .......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Physiotherapy mat	-	-	should not be slippery; alternatively use a wide examination table
Cushions	-	-	-
Table	-	-	with adjustable height; it should allow the patient to rest forearms while seated and elbows flexed at 90°
Chair	-	-	with adjustable height if possible; it should allow the patient to touch the floor with the feet while seated with the hips and knees flexed at 90°
Stopwatch	-	-	-
CD or CD-ROM glued onto a piece of cardboard	-	-	-
10 coins	-	-	dimensions: 20 mm wide and 2 mm thick (10 euro cents or equivalent)
Lead pencil	-	-	-
Tennis ball	-	-	-
Sheets of A4 paper or equivalent	-	-	weight: 70-80g
Clipboard	-	-	-
Two small traffic cones	-	-	-
Tape	-	-	for marking arrows and stop
Line traced on the floor	-	-	2 centimeters wide and 6 meters long
Corridor	-	-	indoor, straight, up to 30 meters long