Evaluation of Microscopic Muscle Properties in Growing Children With Cerebral Palsy and Their Relation to Macroscopic Muscle Properties

Background:

Altered muscle properties in CP have been reported by our own as well as other research groups, macroscopically and microscopically. Hence, key experts in the field acknowledge that further progress in the understanding of the pathogenesis of altered muscle properties will be gained by performing studies that combine macro- and microscopic evaluations of muscle structures, to define different disease presentations. Previous research also showed that a variety of treatment modalities, such as muscle stretching, strengthening, or tone reduction, have beneficial effects on neuromuscular symptoms and on certain muscle properties. However, treatment outcomes are not always satisfying and seem to be muscle and patient-specific. Recent developments in instrumented assessment of these clinical symptoms highlighted their heterogeneity. By applying these novel instrumented assessments, we found that the emergence of different neuromuscular phenotypes was found, such as distinct classes of spasticity based on muscle activation patterns measured during passive stretches at different velocities. While our results highlight that these phenotypes react differently to treatment, their etiology remains unknown. These findings suggest that patient-specific treatment can be improved when tuned to more entirely defined phenotypes. A comprehensive description of the intrinsic muscle properties, including microscopic as well as macroscopic features, is an important next step to further delineate the phenotypes, such that they can support the clinical decision making.

The pathogenesis of altered muscle growth in CP children remains inconclusive. There is no doubt that mature muscles adapt in response to altered use patterns30, suggesting that hampered muscle growth is a secondary process. However, many studies were restricted to children older than 2 to 4 years, and are therefore unable to systematically address the etiology of muscle deformities31. There is an urgent need to study microscopic muscle properties in young children with CP, at different ages. Also, a complete longitudinal delineation of altered muscle growth, covering an extended malleable period of childhood, is still missing.

Moreover, therapy for children with CP in Western countries generally starts at a very young age and includes physiotherapy, stretching casts, orthoses and BTX injections, which are all directed at the muscle. The diverse treatment histories of the participants from previous studies most likely influenced the development of certain muscles. Of particular interest is treatment with BTX injections, which became a first-line CP therapeutic intervention to treat focal spasticity, by means of chemodenervation. While BTX treatment results in reduced muscle tone, increased joint Range Of Motion [ROM] and improved gait, an increasing number of publications have raised concern that BTX may compromise muscle growth. Human studies on microscopic properties post BTX are rare. So far, there are no in vitro studies on CP muscles that have investigated the direct action of BTX on adult muscle stem cells. This is actually needed, since stroke and CP patients are different (in age, growth impact and number of BTX sessions) and animal studies suggest different mechanisms of intramuscular changes post BTX between juvenile and mature muscles. Hence, there is an urgent need to thoroughly investigate the potential impact of BTX on muscle atrophy and integrity in CP using a prospective study design. Indeed, research and clinics could benefit from a more detailed and longitudinal analysis of muscle samples, where it would be possible to characterize the short- and long-term effects of BTX injections on muscle tissue and on muscle adult stem cells.

Furthermore, different mechanisms underlying the altered muscle growth may also interact. Whilst the diversity of phenotypes is likely to reflect the interplay of several factors, and different pathways have been suggested as presumed key players in the pathogenesis of altered muscle properties and neuromuscular symptoms, little understanding remains on the predominant effect in specific circumstances. Literature suggests a close interplay between the ECM and SCs, such that the composition and mechanical properties of the ECM regulate SC activity and renewal; and conversely, SCs dictate ECM composition. More CP-related research is necessary to determine the importance of alterations in SCs, ICs, and ECM components, and their interplay.