Ignite Creation Date:
2024-10-26 @ 3:39 PM
Last Modification Date:
2024-10-26 @ 3:39 PM
Study NCT ID:
NCT06584851
Status:
RECRUITING
Last Update Posted:
None
First Post:
2024-05-24
Brief Title:
3D-Microscopic Muscle Architecture in Cerebral Palsy
Sponsor:
None
Organization:
None
Study Overview
Official Title:
Evaluation of Microscopic Muscle Properties in Growing Children With Cerebral Palsy and Their Relation to Macroscopic Muscle Properties
Status:
RECRUITING
Status Verified Date:
2024-09
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
No
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
3D-MMAP
Brief Summary:
The focus of this study is to understand and define the mechanisms of the altered muscle development and growth on a microscopic level within a long-term perspective in children with cerebral palsy and to relate these findings to muscle macroscopic properties defined by muscle imaging to neuromuscular symptoms and to treatment
This study aims to 1 evaluate intrinsic microscopic muscle properties of young growing children with CP and 2 to evaluate these muscle properties in relation to macroscopic properties neuromuscular symptoms and to treatment
Improved understanding of changes in microscopic muscle properties and how they relate to macroscopic properties and to the neuromuscular symptoms as well as how they are influenced by treatment has the potential to delineate CP phenotypes prone to intervention and to optimize treatment protocols or develop new treatments leading to new avenues for improving function in CP
The method to study microscopic muscle properties involves analysis of muscle biopsies histological immunohistochemistry analysis SC and IC culture gene expression Biopsies will be collected using the minimally invasive percutaneous needle microbiopsy technique suitable for collecting repeated samples over time in the same individual while still leading to sufficient tissue of good quality for subsequent analysis12 For the children with CP the local hospitals tradition of applying general anesthesia for delivering BTX injections will be exploited to collect the muscle samples prior to the BTX session and the one-year follow-up or general anesthesia planned for orthopedic surgery or diagnostic imaging such as MRI etc For the collection of the samples 3 months before the BTX session as well as 3 months and 6 months after BTX injections the common approach for microbiospy collection will be applied with local sedation on the skin Rapydan and fascia Xylocaine and local anesthesia by using Kalinox nitrous oxide in oxygen under supervision of the University Hospital PROSA team Biopsies of TD muscles will be collected in children with no history of neurological disorder nor musculoskeletal problems at the level of the gastrocnemius or semitendinosus at the time of upper limb orthopedic or trauma surgery and thus always under general anesthesia Ultrasound guided percutaneous muscle biopsy has been performed in children 2 months-18 years34 and has proven to be safe and well-tolerated A pilot study S61110 was conducted to confirm that the microbiopsy technique is suitable for the analysis of microscopic muscle properties and is well-tolerated in children with CP
Two specific research goals are planned with hypotheses emerging from literature
This study aims to 1 evaluate intrinsic microscopic muscle properties of young growing children with CP and 2 to evaluate these muscle properties in relation to macroscopic properties neuromuscular symptoms and to treatment
Improved understanding of changes in microscopic muscle properties and how they relate to macroscopic properties and to the neuromuscular symptoms as well as how they are influenced by treatment has the potential to delineate CP phenotypes prone to intervention and to optimize treatment protocols or develop new treatments leading to new avenues for improving function in CP
The method to study microscopic muscle properties involves analysis of muscle biopsies histological immunohistochemistry analysis SC and IC culture gene expression Biopsies will be collected using the minimally invasive percutaneous needle microbiopsy technique suitable for collecting repeated samples over time in the same individual while still leading to sufficient tissue of good quality for subsequent analysis12 For the children with CP the local hospitals tradition of applying general anesthesia for delivering BTX injections will be exploited to collect the muscle samples prior to the BTX session and the one-year follow-up or general anesthesia planned for orthopedic surgery or diagnostic imaging such as MRI etc For the collection of the samples 3 months before the BTX session as well as 3 months and 6 months after BTX injections the common approach for microbiospy collection will be applied with local sedation on the skin Rapydan and fascia Xylocaine and local anesthesia by using Kalinox nitrous oxide in oxygen under supervision of the University Hospital PROSA team Biopsies of TD muscles will be collected in children with no history of neurological disorder nor musculoskeletal problems at the level of the gastrocnemius or semitendinosus at the time of upper limb orthopedic or trauma surgery and thus always under general anesthesia Ultrasound guided percutaneous muscle biopsy has been performed in children 2 months-18 years34 and has proven to be safe and well-tolerated A pilot study S61110 was conducted to confirm that the microbiopsy technique is suitable for the analysis of microscopic muscle properties and is well-tolerated in children with CP
Two specific research goals are planned with hypotheses emerging from literature
Detailed Description:
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
The etiology of CP may also be relevant to understand the pathogenesis of altered muscle properties
Although prematurity and hypoxic-ischemic injury placental insufficiency and prenatal infection are well-recognized causes of CP more than 30 of the children lack traditional risk factors For many of these cases a genetic base to their condition is suspected Indeed current estimates indicate that as many as 30 of CP cases may be genetic in nature Hence for at least part of the CP children some muscle properties might also be genetically driven Moreover specific groups of patients with Hereditary Spastic Paraplegia HSP present with a very similar clinical picture as the bilaterally involved patients with CP ie similar symptoms of spasticity muscle weakness reduced muscle control and altered muscle structure
Aim
Objective 1 To study MICROSCOPIC MUSCLE PROPERTIES in CP and define their onset at an early disease stage and their progress with growth and pathology and to delineate their potential genetic nature WP 1
Firstly muscle biopsies will be collected to define microscopic properties of two age-groups of CP and TD children 2-5 versus 6-9 years It is hypothesized that 1 a lower percentage of contractile material increased collagen content reduced number of SCs and altered fiber size distribution are observed in CP compared to TD children and 2 these differences are age- and muscle-specific
Secondly since knowledge on early events and a follow-up of these events are lacking at the microscopic level repeated biopsies will be collected in two CP groups ie with and without BTX treatment history to study changes in the microscopic properties at different time-points pre- and post BTX injections The microbiopsies under general anaesthesia at the time of the BTX session and 12 year later ie at the time of the repeated BTX-session will be performed on the medial gastrocnemius and semitendinosus while the microbiopsies under locale aneasthesia at 3 months pre and 3 and 6 months post BTX will be performed only on the medial gastrocnemius It is hypothesized that 1 BTX-injection induce immediate altered structural muscle properties and molecular changes which partly recover within 12 year combined with 2 the trajectory of changes such as collagen content and persistence of inflammatory cells differs between BTX-naïve patients and patients with BTX treatment history during the 12-year follow-up
Thirdly while literature suggests a close interplay between the ECM SCs and ICs there is a lack of CP-related research on the interaction between microscopic properties A potential key regulatory factors that determine altered microscopic muscle properties will be defined in particular the relative importance of adult stem cell alterations by defining their interaction to ECM abnormalities It is hypothesized that 1 the misbalanced interplay between adult stem cells and ECM is related to altered muscle properties 2 the degree of misbalance evolves over time and 3 is muscle-specific
Fouthly recent literature suggests a genetic contribution to the pathology in about 30 of the children with CP and subgroups of patients with HSP SPG3a and SPG4 have identified genetic problems and present with similar clinical symptoms as the children with bilateral CP This triggers a novel research pathway on the multi-lineage differentiation of induced pluripotent stem cells in a select group of patients with proven genetic mutation It is hypothesized that that patient-specific cell modelling reflects genetic mutations influencing the patient phenotype
Objective 2 To delineate INTEGRATED CP PHENOTYPES prone to treatment by identifying relations between different levels of muscle alterations macro- and microscopic and neuromuscular symptoms The focus will be primarily on the symptom spasticity and on BTX treatment WP 2
Biopsy collection in the enrolled children of WP1 will always be preceded by ultrasound measures As part of their routine clinical follow-up these children also receive gait analysis and clinical assessments using standard clinical scales of neuromuscular symptoms before the treatment Additionally instrumented assessments of spasticity and strength will be performed This allows integrated analysis on multiple datasets to delineate integrated CP phenotypes Firstly relations between macro- and microscopic properties and spasticity will be explored It is hypothesized that 1 macroscopic growth is significantly related to the number and behavior of SCs ICs to fiber type properties and indirectly to ECM abnormalities 2 the macroscopic parameter EI is associated to microscopic muscular tissue integrity and 3 muscle properties are different between muscles classified by their spasticity patterns Secondly guidelines will be developed to fine-tune BTX treatment to the integrated phenotypes It is hypothesized that 1 BTX induces altered muscle volume and integrity but does not change the number of SCs and 2 BTX response is significantly correlated to specific baseline CP phenotype markers in particular to muscle integrity
Methodsdesign
To understand and define the mechanism and time course of muscle properties different studies with different study designs will be applied These studies are organized in two work packages each covering one of the two specific research goals
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
The etiology of CP may also be relevant to understand the pathogenesis of altered muscle properties
Although prematurity and hypoxic-ischemic injury placental insufficiency and prenatal infection are well-recognized causes of CP more than 30 of the children lack traditional risk factors For many of these cases a genetic base to their condition is suspected Indeed current estimates indicate that as many as 30 of CP cases may be genetic in nature Hence for at least part of the CP children some muscle properties might also be genetically driven Moreover specific groups of patients with Hereditary Spastic Paraplegia HSP present with a very similar clinical picture as the bilaterally involved patients with CP ie similar symptoms of spasticity muscle weakness reduced muscle control and altered muscle structure
Aim
Objective 1 To study MICROSCOPIC MUSCLE PROPERTIES in CP and define their onset at an early disease stage and their progress with growth and pathology and to delineate their potential genetic nature WP 1
Firstly muscle biopsies will be collected to define microscopic properties of two age-groups of CP and TD children 2-5 versus 6-9 years It is hypothesized that 1 a lower percentage of contractile material increased collagen content reduced number of SCs and altered fiber size distribution are observed in CP compared to TD children and 2 these differences are age- and muscle-specific
Secondly since knowledge on early events and a follow-up of these events are lacking at the microscopic level repeated biopsies will be collected in two CP groups ie with and without BTX treatment history to study changes in the microscopic properties at different time-points pre- and post BTX injections The microbiopsies under general anaesthesia at the time of the BTX session and 12 year later ie at the time of the repeated BTX-session will be performed on the medial gastrocnemius and semitendinosus while the microbiopsies under locale aneasthesia at 3 months pre and 3 and 6 months post BTX will be performed only on the medial gastrocnemius It is hypothesized that 1 BTX-injection induce immediate altered structural muscle properties and molecular changes which partly recover within 12 year combined with 2 the trajectory of changes such as collagen content and persistence of inflammatory cells differs between BTX-naïve patients and patients with BTX treatment history during the 12-year follow-up
Thirdly while literature suggests a close interplay between the ECM SCs and ICs there is a lack of CP-related research on the interaction between microscopic properties A potential key regulatory factors that determine altered microscopic muscle properties will be defined in particular the relative importance of adult stem cell alterations by defining their interaction to ECM abnormalities It is hypothesized that 1 the misbalanced interplay between adult stem cells and ECM is related to altered muscle properties 2 the degree of misbalance evolves over time and 3 is muscle-specific
Fouthly recent literature suggests a genetic contribution to the pathology in about 30 of the children with CP and subgroups of patients with HSP SPG3a and SPG4 have identified genetic problems and present with similar clinical symptoms as the children with bilateral CP This triggers a novel research pathway on the multi-lineage differentiation of induced pluripotent stem cells in a select group of patients with proven genetic mutation It is hypothesized that that patient-specific cell modelling reflects genetic mutations influencing the patient phenotype
Objective 2 To delineate INTEGRATED CP PHENOTYPES prone to treatment by identifying relations between different levels of muscle alterations macro- and microscopic and neuromuscular symptoms The focus will be primarily on the symptom spasticity and on BTX treatment WP 2
Biopsy collection in the enrolled children of WP1 will always be preceded by ultrasound measures As part of their routine clinical follow-up these children also receive gait analysis and clinical assessments using standard clinical scales of neuromuscular symptoms before the treatment Additionally instrumented assessments of spasticity and strength will be performed This allows integrated analysis on multiple datasets to delineate integrated CP phenotypes Firstly relations between macro- and microscopic properties and spasticity will be explored It is hypothesized that 1 macroscopic growth is significantly related to the number and behavior of SCs ICs to fiber type properties and indirectly to ECM abnormalities 2 the macroscopic parameter EI is associated to microscopic muscular tissue integrity and 3 muscle properties are different between muscles classified by their spasticity patterns Secondly guidelines will be developed to fine-tune BTX treatment to the integrated phenotypes It is hypothesized that 1 BTX induces altered muscle volume and integrity but does not change the number of SCs and 2 BTX response is significantly correlated to specific baseline CP phenotype markers in particular to muscle integrity
Methodsdesign
To understand and define the mechanism and time course of muscle properties different studies with different study designs will be applied These studies are organized in two work packages each covering one of the two specific research goals
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None