Muscle composition, reach, physical activity and botulinum toxin treatment in children with cerebral palsy

Sammanfattning: Cerebral palsy (CP), the most common cause of movement disorders and physical disability in children all over the world, is caused by an injury to the developing brain. Although this injury is not progressive, the manifestations of the disorder change as the child ages. Spasticity and altered viscoelastic properties of the muscle often enhance muscle resistance to stretch and the peak spasticity of the calf muscles in children with CP observed at four years of age declines thereafter until twelve years of age. The cause of muscle contractures, which appear early and progress throughout childhood and adolescence is unclear and needs to be elucidated further to help design more effective preventive measures. Therefore, the first aim of this thesis was to further characterize muscle pathophysiology in children with CP with fixed contractures. Treatment of patients with CP involves a wide variety of efforts. Standardized and objective follow-up, as well as cost effectiveness are of considerable importance. Therefore, the second aim here focused on novel tools for clinical evaluation, as well as assessment of the economics of switching between two botulinum toxins (BoNT-A) in treatment of children with CP. We developed further a three-dimensional test of arm reach in typically developing (TD) children and tested the feasibility of this test in young adults with CP. We also developed a new approach evaluating the effects of BoNT-A treatment involving monitoring the child ́s home and school environments with four accelerometers. Moreover, we made a controlled switch from one brand of BoNT-A to another in attempt to reduce the drug cost without reducing efficacy or duration or exacerbating side-effects. The major novel findings with respect to muscle pathophysiology are that impaired production of ribosomes probably explains, at least in part, the deficient growth of skeletal muscle observed in children with CP and that levels of pro-inflammatory cytokines are elevated in their muscles. The latter alteration contributes to both inhibition of growth and expansion of the extracellular matrix and perhaps to the development of muscle contractures as well in children with CP. In addition, in the muscles of these children the number of satellite cells was reduced, the amount of intramuscular collagen situated around bundles of muscle fibers elevated and expression of the fatigable and fast Myosin Heavy Chain IIx isoform in wrist flexors higher in comparison to TD children. The major findings with respect to the development of novel tools for assessment and cost- effectiveness are that the 3D Reach Test for the arms exhibits excellent inter- and intra- session reliability in TD children, as well as excellent feasibility and reliability in a pilot study on young adults with CP. Moreover, monitoring children with CP in their own environment with four accelerometers following BoNT-A treatment reveals previously unknown effects on physical activity, effects not detected by routine clinical follow-up, such as a decline in ambulatory activity after injection into the legs. When the BoNT-A preparation used previously was replaced by another commercial BoNT-A product, the parents reported the treatment of their children with CP to be equally effective, while the cost was 41% lower with few, similar and transient side-effects. In conclusion, the present investigations provide new information on the pathophysiology of muscle in children with cerebral palsy that can help improve our understanding of contracture formation. The 3D Reach Test and post treatment monitoring with accelerometers are promising new tools for evaluation of the effects of treatment on reach and everyday movement. The cost of BoNT-A treatment can be reduced considerably by switching to another brand without compromising either the effect or patient safety.