No use is disuse. Physical training in Duchenne muscular dystrophy. (2014)

General introductionDuchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy in childhood.Boys with DMD suffer from progressive loss of muscle strength and loss of functional abilities from a very young age.They lose the ability to ambulate in their early teenage years and the ability to lift their arms soon after the onset of wheelchair dependency.Because there is no cure for DMD, patient management is symptomatic directed at relieving complaints, supporting bodily functions and activities, and optimizing social participation and quality of life.Recommendations on physical training in boys with DMD are focused on avoiding disuse atrophy and other secondary complications of physical inactivity.However, these recommendations are based on limited evidence.This thesis describes the development and results of the No Use is Disuse (NUD) study, an assisted physical training program for boys with DMD that aimed to delay the loss of functional abilities secondary to disuse.Furthermore, this thesis describes the validation of three specific outcome measures (i.e., quantitative skeletal muscle ultrasound (QMUS) to assess the muscle histology, the Assisted 6-Minute Cycling Test (A6MCT) to assess physical endurance, and the Kidscreen-52 to assess Health Related Quality of Life (HRQoL)) for monitoring disease progression and the effects of interventions. Duchenne muscular dystrophy PathophysiologyDMD affects approximately 1 in 5000 newborn boys. 1 Girls who inherit a DMD mutation usually do not develop the disease, because the pattern of inheritance is X-linked recessive.DMD is caused by mutations in the DMD gene, resulting in an absence, or near-absence (<3%), of the functional protein dystrophin. 2 Dystrophin forms a mechanical link between the actin filaments inside the muscle cells and the extracellular matrix, and it provides mechanical stability during muscle contractions (Figure 1).Absence of dystrophin results in fragile muscle fibers that are prone to contraction-induced injury, leading to ongoing cycles of degeneration and regeneration.These ongoing degenerative cycles cause chronic inflammation, impaired muscle tissue repair, and eventually a replacement of muscle fibers by fat and connective tissue. 31 15 General introduction Chapter 1 Aim of this thesisThe main aim of the research presented in this thesis was to increase insight into the feasibility, safety and effectiveness of assisted physical training in boys with DMD who are ambulatory or wheelchair-dependent.In order to evaluate the effectiveness of the assisted physical training, three specific outcome measures were developed and/or validated.These aims led to the following main research questions that are addressed in this thesis: 1) Are QMUS, the Assisted Six-Minute Cycling Test (A6MCT) and HRQoL valid and/or responsive outcome measures to evaluate the effects of a physical training intervention in boys with DMD? 2) Is assisted physical training feasible, safe and effective to delay the functional deterioration in ambulatory and wheelchair-dependent children with DMD?It was hypothesized that assisted physical training would delay the secondary functional deterioration due to disuse in DMD and that this delay could be assessed with QMUS, the A6MCT and HRQoL. Outline of this thesisThis thesis is divided into two parts addressing the previously specified main research questions.Part one encompasses the studies on outcome measures, whereas part two addresses the effectiveness of two assisted physical training programs. Part 1 Outcome measuresChapter 2 starts with the investigation of the validity and responsiveness of QMUS by means of a longitudinal follow-up of 18 boys with DMD.In chapter 3, the development of the assisted 6-minute cycling test (A6MCT) meant to assess physical endurance is described.Its validity was examined in both healthy boys and boys with DMD.Chapter 4 describes the HRQoL of boys with DMD who are either ambulant or wheelchair-dependent as well as the HRQoL perception of the boys' parents as assessed with the KIDSCREEN-52 questionnaire. Part 2 Physical trainingChapter 5 describes the protocol of the No Use is Disuse (NUD) study.The NUD study is the first study in boys with DMD that examines whether assisted physical training is safe and beneficial to preserve muscle endurance and functional abilities.The study consists of two assisted physical training programs: study 1 "Dynamic leg and arm training for ambulant and recently wheelchair-dependent boys with DMD" (an RCT), and study 2 "Functional training with arm-support for boys with DMD who have been confined to a wheelchair for several years" (a feasibility study).The results of these two physical training programs are described in chapter 6 and chapter 7, respectively.