Evaluation of Macroscopic Muscle Growth in Infants and Young Children With Spastic Cerebral Palsy

The Integration of Macroscopic and Microscopic Muscle Properties With Cell Modelling to Feature Altered Neuromuscular Behavior in Cerebral Palsy: 3D-Macroscopic Muscle Architecture in Cerebral Palsy

A mixed longitudinal design study will be carried out to explore the onset and time course of morphological muscle changes on a macroscopic level in children with spastic cerebral palsy (SCP). Therefore, this project aims to (1) describe the macroscopic morphological muscle changes with increasing age and (2) evaluate the onset and development of muscle alterations in relation to the brain lesion (e.g., timing, extent and location), to the neuromuscular impairments and to treatment. Overall, this project will evaluate the macroscopic muscle properties by means of 3D freehand ultrasound (3DfUS).

Background:

Recent literature reviews have emphasized the need for longitudinal studies with multiple measurement time- points to properly identify the natural course of muscle growth in young children with SCP, compared to typically developing (TD) children. The etiology of SCP, including the underlying brain lesion, may also be relevant to understand the onset and early development of altered muscle growth. Since the perinatal brain lesion in congenital SCP results in early abnormal neuronal input to the muscle, the process of muscle formation and maturation is likely to be disturbed. Because the overall treatment goal is to improve and maintain the functional abilities of children with SCP, there is a growing interest in the relation between the brain lesions (defined by MRI) and motor outcomes. However, no studies have systematically explored the relation between intrinsic muscle alterations and the brain lesion characteristics.

Improved understanding of morphologically muscle changes during growth, and how the participants relate to the timing of the brain lesion, to clinical neuromuscular impairments and to treatment, has potential to classify SCP muscles into sub-groups, or phenotypes. Moreover, these insights can reveal new markers to optimize treatment protocols or develop new treatments, leading to patient-tailored treatment management and new avenues for improving function in children with SCP.

Aim:

The focus of this study is to improve insights in the onset, development and progression of morphological macroscopic muscle changes for growing children with spastic cerebral palsy. The diversity in macroscopic muscle growth will thereby be considered in longitudinal studies, starting shortly after the occurrence of the brain injury.

To achieve this general research goal, this project plans two main studies. In study 1, the aim is to evaluate macroscopic morphological muscle changes with age. In study 2, the aim is to evaluate these muscle alterations in relation to the brain lesion characteristics.

The first study is focused on longitudinal evaluation of macroscopic muscle properties with age. This project generally aim to define changes in muscle properties over 2 years of time in children with SCP of different age-groups and to compare the differences between children with SCP and TD children in these specific age-groups. This project hypothesizes that the development of macroscopic muscle properties is significantly altered between CP age-groups and between CP and TD children. As a sub-goal of the first study, this project will describe the rate of muscle specific changes in SCP (for two lower limb muscles), the differences in rate of changes between three GFMCS levels and the impact of the number of previous Botulinum neurotoxin A (BoNT-A) injections on the rate of changes.

The second study is focused on the longitudinal muscle changes started from the early years of life. This altered muscle growth will be related to the brain lesion characteristics (i.e., timing, extent and location). This project hypothesizes that the onset and progress of these muscle changes is different between patient groups, which are defined by the age of the patients at the event of the brain lesion. With the majority of SCP brain lesions occurring during the last trimester of pregnancy, it can be hypothesized that the early timing of brain lesion and thus an early abnormal neuronal input to the muscle influences muscle development, suggesting a primary nature of altered muscle growth.

The main outcome of this research project is the evaluation of muscle changes in children with brain lesion. The primary muscle parameters are muscle volume, muscle belly length and echo-intensity of two lower limb muscles.

Methods/design:

Study 1: Children will enter at different ages, ranging from 2 till 9 years of age, and will participate in a 2-years follow-up with one year time interval. The children with SCP will be equally distributed between age-groups (2-5 and 6-9 years). Only children with a gross motor function level of one, two or three will be included. For this study, 80 children with congenital CP and 60 aged-matched TD children will be included.

Study 2: Two patient groups of children will be included (1) children with congenital CP (aged between 6 months and 3 years) with a brain lesion that occurred before or around birth and (2) children with acquired brain injury (ABI) (aged between 1,5 and 9 years), with a brain lesion that occurred at least one year after birth. All children will be enrolled at least 6 months after the occurrence of the brain injury and will be assessed over a 2-year period with 5 measurement time points (every 6 months). This project aims to include 48 children with congenital CP, 16 children with ABI and 25 TD children.

Participants will be evaluated at the University Hospitals Leuven (UZ Leuven) at campus Gasthuisberg or campus Pellenberg and the rehabilitation centers of Pulderbos and Inkendaal. Data will be collected during a hospital visit and every participant will undergo at least a 3DfUS measurement of the medial gastrocnemius and the semitendinosus muscle. Other information that will be collected out of the available medical records includes the results of the structural brain MRI, the use of medication, treatment details (physiotherapy, orthotics and/or orthopedic interventions), anthropometric measures (body weight and length and leg lengths), data of a standard clinical examination (joint range of motion, spasticity, muscle selectivity and strength), data of a neurological examination more specific the Hammersmith Infant Neurological Examination (HINE) and the motor development by using the Motor Scales of the Bayley-III-NL.

Inclusion Criteria:

• Confirmed diagnosis of spastic cerebral palsy or patients at high-risk for spastic cerebral palsy
• Suspected GMFCS levels I-III (GMFCS = Gross Motor Function Classification Scale, expressing the overall functional level of impairment)

Exclusion Criteria:

• Non-ambulatory
• Botulinum neurotoxin type-A injections six months prior to enrollment
• Lower limb surgery two years prior to enrollment
• Muscle surgery at the muscles in the lower limb
• Selective dorsal rhizotomy as treatment history
• Presence of ataxia or dystonia
• Severe co-morbidities (severe epilepsy, severe behavior problems that impede the cooperation)