Verbeterd inzicht in gangcompensaties bij groeiende kinderen met Duchenne spierdystrofie: kader om nieuwe wegen van gangrevalidatie te verkennen

Gait becomes increasingly difficult for growing children with Duchenne muscular dystrophy (DMD), eventually leading to loss of ambulation and reliance on wheelchair in late childhood or early adolescence. DMD is a disorder characterized by progressive muscle damage, resulting in increasing muscle weakness, muscle stiffness, contractures, and altered muscle size. Consequently, children with DMD must adjust their gait to compensate for these underlying muscle impairments. As these impairments continue to increase during growth, gait pathology becomes more pronounced. The contributions of these muscle impairments to gait pathology are still poorly understood. Therefore, the general aim of this doctoral dissertation was to improve the understanding of compensation mechanisms in pathological gait of growing children with DMD, creating the foundation to explore new pathways of gait rehabilitation. To achieve the general aim, two main objectives were defined, which were addressed in STUDIES 1-8. Objective 1: To delineate gait pathology and the underlying muscle impairments in growing children with DMD Objective 1 was addressed in STUDIES 1-5. To better understand why boys with DMD walk the way they do, it should first be clear how they walk (STUDIES 1-2). Some studies tried to characterize DMD gait, but results were not homogeneous nor univocal. Moreover, longitudinal studies examining the changes in the gait pattern over time in DMD were lacking. Therefore, STUDY 1 provided a full longitudinal delineation of the progressive gait pathology in growing children with DMD. Repeated measures of the same boys over a period of five years highlighted an initial period characterized by maturational improvements of DMD gait (i.e., "honeymoon" period) followed by progressive divergence from typically developing (TD) gait. The progressive trajectory involved increasing anterior pelvic tilt, hip flexion, hip abduction, internal foot progression, pelvic obliquity motion, pelvic rotation motion, step width, and decreasing cadence, step length, and dorsiflexion at initial contact and in swing. This study provided statistically modelled individual trajectories of gait decline and revealed promising outcome measures, which could be used for patient-tailored monitoring and treatment planning in both clinical practice and clinical trials. STUDY 1 also highlighted a high variability in individual progression rates. Hence, classifying gait deviations into homogeneous groups, regardless of individual progression rates, could enhance the interpretability of the progressive gait pathology. More than 40 years ago, Sutherland et al. developed a DMD gait classification including three progressive stages, which remained the standard reference in the gait community. However, since then, advancements in medical care, particularly the long-term use of glucocorticoids, had significantly altered the natural history of DMD. Therefore, STUDY 2 developed an up-to-date DMD gait classification. Through a data-driven approach, three gait patterns were distinguished, which only partly reflected the increasing severity of gait deviations. Apart from the mildly affected pattern, two more severely affected gait patterns were found, namely the tiptoeing gait pattern and the flexion gait pattern with distinct anterior pelvic tilt and posterior trunk leaning, which showed most severe deviations at the ankle or at the proximal joints, respectively. The agreement between Sutherland's and the current classification was low, suggesting that gait pathology with the current state-of-the-art medical care has changed. However, because of overlap between gait patterns, careful consideration remains necessary when classifying individual boys with DMD. To better understand how underlying muscle impairments contribute to gait compensations, there is the need to first delineate these underlying muscle impairments (STUDIES 3-5). Our research group previously developed a new instrumented strength assessment. This assessment involves maximal isometric voluntary contractions performed in a custom-made chair with the hand-held dynamometer and participants securely fixated. However, its clinimetric properties were only partially defined, necessitating a thorough examination before utilizing this assessment to outline progressive muscle weakness in children with DMD. Therefore, STUDY 3 investigated the reliability, validity, and responsiveness of this instrumented strength assessment in TD children, as well as in children with a neural or neuromuscular disorder. The instrumented strength assessment was found to be reliable to confirm know-group validity for DMD. Moreover, several trends indicated that strength slowly decreased over time in DMD. However, due to the small sample size (n=8) the responsiveness of this assessment could not yet be entirely determined and more research with larger sample sizes is necessary. Growth and maturation effects often complicate the interpretation of pathological changes in muscle size and strength, such as in DMD. Therefore, STUDY 4 developed anthropometric-related percentile curves for muscle size and strength (measured with the instrumented strength assessment from STUDY 3) in a cohort of TD children and demonstrated their utility on individual patients. Overall, muscle size and strength, along with their inter-subject variation, increased with increasing anthropometric values. Individual patients (including boys with DMD) exhibited negative z-scores, indicating deficits in muscle size and strength in reference to TD peers. The established anthropometric-related TD percentile curves are ready to be used to express patient outcomes in reference to TD. This facilitates the interpretation of muscle size and weakness in children with a motor disability and allows for the evaluation of the disease progression and treatment impact during growth. Although multiple studies have examined changes in muscle impairments over time or with age in DMD, inconsistencies remained due to varied study designs, assessment methods, heterogeneous study samples, and normalization techniques. Therefore, STUDY 5 established longitudinal trajectories for a comprehensive set of muscle impairments in DMD, while accounting for normal maturation and growth effects. Muscle weakness, contractures and muscle size alterations were repeatedly measured over a seven year follow-up with the established instrumented strength assessment (STUDY 3), goniometry and 3D freehand ultrasound. These outcomes were standardized into unit-less z-scores using the anthropometric-related TD percentile curves that were developed in STUDY 4, enabling the interpretation of muscle impairments as alterations (most often deficits) relative to TD peers. At 4.3-4.9 years of age, all muscle strength outcomes and several range of motions (i.e., dorsiflexion, knee extension with hip flexed, and hip extension) showed deficits relative to TD, while m. medial gastrocnemius muscle size was increased. Most muscle impairments remained stable or slightly improved until the ages of 6.6-9.4 years (except knee flexion strength), likely reflecting the "honeymoon" period in DMD. After this period, muscle strength, dorsiflexion range of motion, and m. medial gastrocnemius and m. rectus femoris muscle size declined. This study provided statistically modelled individual trajectories of decline in muscle outcomes and revealed promising outcome measures, which could be used for patient-tailored monitoring and treatment planning in both clinical practice and clinical trials. Objective 2: To unravel the complex interactions between the underlying muscle impairments and gait pathology in children with DMD Objective 2 was addressed in STUDIES 6-8. Despite the clinical assumptions that muscle impairments influence gait, these associations have been lacking objective evidence. So far, only one cross-sectional study previously explored the relationship between muscle weakness and the gait pattern and did not find significant associations. Since the amount and timing of muscle activity is altered in DMD, muscle weakness could be considered a constraint for muscle control of gait in DMD. Therefore, STUDY 6 investigated the relationship between muscle weakness and muscle control during gait in DMD. We found that muscle control was not altered and not linked to the apparent muscle weakness in boys with DMD. The longitudinal delineations of the progressive gait pathology in STUDY 1 and muscle impairments in STUDY 5, created the foundations to comprehensively analyze their longitudinal interaction. There was a high inter-subject variability in the longitudinal trajectories of both muscle impairments and gait features, and it remained unclear which muscle impairments are related to which gait features and how their progression rates relate. Therefore, STUDY 7 investigated the interaction between the longitudinal individual trajectories of muscle impairments and gait pathology in DMD. Specifically, we first determined whether the starting levels of muscle impairments were related to the starting levels of gait features and subsequently whether their progression rates were related. Specific muscle impairments were related to specific gait features, in terms of both starting levels and progression rates. This study improved insights into how specific muscle impairments may contribute to specific gait features in DMD. Additionally, this study provided statistically modelled individual trajectories of the longitudinal interaction between specific muscle impairments and specific gait features, which could be used for patient-tailored monitoring and treatment planning in both clinical practice and clinical trials. However, these interactions do not prove any causality and do not provide insights into the relative contribution of muscle weakness and contractures to gait pathology in DMD. Therefore, STUDY 8 aimed to differentiate the causal e