Gait classification for growing children with Duchenne muscular dystrophy.

Classifying gait patterns into homogeneous groups could enhance communication among healthcare providers, clinical decision making and clinical trial designs in boys with Duchenne muscular dystrophy (DMD). Sutherland's classification has been developed 40 years ago. Ever since, the state-of-the-art medical care has improved and boys with DMD are now longer ambulatory. Therefore, the gait classification requires an update. The overall aim was to develop an up-to-date, valid DMD gait classification. A total of 137 three-dimensional gait analysis sessions were collected in 30 boys with DMD, aged 4.6-17 years. Three classes were distinguished, which only partly aligned with increasing severity of gait deviations. Apart from the mildly affected pattern, two more severely affected gait patterns were found, namely the tiptoeing pattern and the flexion pattern with distinct anterior pelvic tilt and posterior trunk leaning, which showed most severe deviations at the ankle or at the proximal segments/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, overlap between classes, especially between the two more affected classes, highlights the complexity of the continuous gait changes. Therefore, caution is required when classifying individual boys with DMD into classes.

Histological analysis of the medial gastrocnemius muscle in young healthy children.

Introduction: Histological data on muscle fiber size and proportion in (very) young typically developing (TD) children is not well documented and data on capillarization and satellite cell content are also lacking. Aims: This study investigated the microscopic properties of the medial gastrocnemius muscle in growing TD children, grouped according to age and gender to provide normal reference values in healthy children. Methods: Microbiopsies of the medial gastrocnemius (MG) muscle were collected in 46 TD boys and girls aged 2-10 years subdivided into 4 age groups (2-4, 4-6, 6-8 and 8-10 years). Sections were immunostained to assess fiber type cross-sectional area (fCSA) and proportion, the number of satellite cells (SC), capillary to fiber ratio (C/F), capillary density for type I and II fiber (CFD), capillary domain, capillary-to-fiber perimeter exchange index (CFPE) and heterogeneity index. fCSA was normalized to fibula length2 and the coefficient of variation (CV) was calculated to reflect fCSA intrasubject variability. Results: Absolute fCSA of all fibers increased with age (r = 0.72, p < 0.001) but more in boys (+112%, p < 0.05) than in girls (+48%, p > 0.05) Normalized fCSA, CV and fiber proportion did not differ between age groups and gender. C/F was strongly correlated with age in boys (r = 0.83, p < 0.001), and to a lesser extent in girls (r = 0.37, p = 0.115), while other capillary parameters as well as the number of SC remained stable with increasing age in boys and girls. Discussion: This study provides reference values of histological measures in MG according to age in normally growing boys and girls. These data may be used as a reference to determine disease impact and efficacy of therapeutic approach on the muscle.

Short-Term Effects of Botulinum Toxin-A Injection on the Medial Gastrocnemius Histological Features in Ambulant Children with Cerebral Palsy: A Longitudinal Pilot Study.

Botulinum toxin-A (BoNT-A) injection is known to exert beneficial effects on muscle tone, joint mobility and gait in children with cerebral palsy (CP). However, recent animal and human studies have raised the concern that BoNT-A might be harmful to muscle integrity. In CP-children, the impact of BoNT-A on muscle structure has been poorly studied, and inconsistent results have been reported. This study was aimed at determining the time course effect of a single BoNT-A administration on medial gastrocnemius (MG) morphology in CP-children. MG microbiopsies from 12 ambulant and BoNT-A-naïve CP-children (age, 3.4 (2.3) years, ranging from 2.5 to 7.8 years; seven boys and five girls; GMFCS I = 5, II = 4 and III = 3) were collected before and 3 and 6 months after BoNT-A treatment to analyze the fiber cross-sectional area (fCSA) and proportion; capillarization; and satellite cell (SC) content. Compared with the baseline, the fCSA decreased at 3 months (-14%, NS) and increased at 6 months (+13%, NS). Fiber size variability was significantly higher at 3 months (type I: +56%, p = 0.032; type IIa: +37%, p = 0.032) and 6 months (type I: +69%, p = 0.04; type IIa: +121%, p = 0.032) compared with the baseline. The higher type I proportion seen at 3 months was still present and more pronounced at 6 months (type I: +17%, p = 0.04; type IIx: -65%, p = 0.032). The capillary fiber density was reduced at 3 months (type I: -43%, NS; type II: -44%, p = 0.0320) but normalized at 6 months. There was a non-significant increase in SC/100 fibers at 3 months (+75%, NS) and 6 months (+40%, NS) compared with the baseline. These preliminary data suggest that BoNT-A induced alterations in the MG of children with CP, which were still present 6 months after BoNT-A injection but with signs of muscle recovery.

Longitudinal trajectory of medial gastrocnemius muscle growth in the first years of life.

AIM: To define the longitudinal trajectory of gastrocnemius muscle growth in 6- to 36-month-old children with and without spastic cerebral palsy (SCP) and to compare trajectories by levels of gross motor function (Gross Motor Function Classification System, GMFCS) and presumed brain-lesion timing. METHOD: Twenty typically developing children and 24 children with SCP (GMFCS levels I-II/III-IV = 15/9), were included (28/16 females/males; mean age at first scan 15.4 months [standard deviation 4.93, range 6.24-23.8]). Three-dimensional freehand ultrasound was used to repeatedly assess muscle volume, length, and cross-sectional area (CSA), resulting in 138 assessments (mean interval 7.9 months). Brain lesion timing was evaluated with magnetic resonance imaging classification. Linear mixed-effects models defined growth rates, adjusted for GMFCS levels and presumed brain-lesion timing. RESULTS: At age 12 months, children with SCP showed smaller morphological muscle size than typically developing children (5.8 mL vs 9.8 mL, p < 0.001), while subsequently no differences in muscle growth were found between children with and without SCP (muscle volume: 0.65 mL/month vs 0.74 mL/month). However, muscle volume and CSA growth rates were lower in children classified in GMFCS levels III and IV than typically developing children and those classified in GMFCS levels I and II, with differences ranging from -56% to -70% (p < 0.001). INTERPRETATION: Muscle growth is already hampered during infancy in SCP. Muscle size growth further reduces with decreasing functional levels, independently from the brain lesion. Early monitoring of muscle growth combined with early intervention is needed.

Histological analysis of the gastrocnemius muscle in preschool and school age children with cerebral palsy compared with age-matched typically developing children.

Inconsistent alterations in skeletal muscle histology have been reported in adolescents with cerebral palsy (CP) and whether alterations are present in young children and differ from older children is not yet known. This study aimed to define histological alterations in the medial gastrocnemius (MG) of ambulant CP (gross-motor classification system, GMFCS I-III) stratified in two age groups (preschool children, PS: 2-5 and school age children, SA: 6-9-yr old) compared with age-matched typically developing (TD) children. We hypothesized that alterations in muscle microscopic properties are already present in PS-CP and are GMFCS level specific. Ultrasound guided percutaneous microbiopsies were collected in 46 CP (24-PS) and 45 TD (13-PS) children. Sections were stained to determine fiber cross-sectional area (fCSA) and proportion, capillary, and satellite cell amount. Average absolute and normalized fCSA were similar in CP and TD, but a greater percentage of smaller fibers was found in CP. Coefficient of variation (CV) was significantly larger in PS-CP-GMFCS I-II and for type I fiber. In SA-CP, all fiber types contributed to the higher CV. Type IIx proportion was higher and type I was lower in PS-CP-GMFCS-III and for all SA-CP. Reduced capillary-to-fiber ratio was present in PS-CP-GMFCS II-III and in all SA-CP. Capillary fiber density was lower in SA-CP. Capillary domain was enhanced in all CP, but capillary spatial distribution was maintained as was satellite cell content. We concluded that MG histological alterations are already present in very young CP but are only partly specific for GMFCS level and age.NEW & NOTEWORTHY Inconsistent histological alterations have been reported in children with cerebral palsy (CP) but whether they are present in very young and ambulant CP children and differ from those reported in old CP children is not known. This study highlighted for the first time that enhanced muscle fiber size variability and loss of capillaries are already present in very young CP children, even in the most ambulant ones, and these alterations seem to extend with age.

Botulinum Toxin Treatment of Adult Muscle Stem Cells from Children with Cerebral Palsy and hiPSC-Derived Neuromuscular Junctions.

Botulinum neurotoxin type-A (BoNT) injections are commonly used as spasticity treatment in cerebral palsy (CP). Despite improved clinical outcomes, concerns regarding harmful effects on muscle morphology have been raised, and the BoNT effect on muscle stem cells remains not well defined. This study aims at clarifying the impact of BoNT on growing muscles (1) by analyzing the in vitro effect of BoNT on satellite cell (SC)-derived myoblasts and fibroblasts obtained from medial gastrocnemius microbiopsies collected in young BoNT-naïve children (t0) compared to age ranged typically developing children; (2) by following the effect of in vivo BoNT administration on these cells obtained from the same children with CP at 3 (t1) and 6 (t2) months post BoNT; (3) by determining the direct effect of a single and repeated in vitro BoNT treatment on neuromuscular junctions (NMJs) differentiated from hiPSCs. In vitro BoNT did not affect myogenic differentiation or collagen production. The fusion index significantly decreased in CP at t2 compared to t0. In NMJ cocultures, BoNT treatment caused axonal swelling and fragmentation. Repeated treatments impaired the autophagic-lysosomal system. Further studies are warranted to understand the long-term and collateral effects of BoNT in the muscles of children with CP.

Morphological Medial Gastrocnemius Muscle Growth in Ambulant Children with Spastic Cerebral Palsy: A Prospective Longitudinal Study.

Only cross-sectional studies have demonstrated muscle deficits in children with spastic cerebral palsy (SCP). The impact of gross motor functional limitations on altered muscle growth remains unclear. This prospective longitudinal study modelled morphological muscle growth in 87 children with SCP (age range 6 months to 11 years, Gross Motor Function Classification System [GMFCS] level I/II/III = 47/22/18). Ultrasound assessments were performed during 2-year follow-up and repeated for a minimal interval of 6 months. Three-dimensional freehand ultrasound was applied to assess medial gastrocnemius muscle volume (MV), mid-belly cross-sectional area (CSA) and muscle belly length (ML). Non-linear mixed models compared trajectories of (normalized) muscle growth between GMFCS-I and GMFCS-II&III. MV and CSA growth trajectories showed a piecewise model with two breakpoints, with the highest growth before 2 years and negative growth rates after 6-9 years. Before 2 years, children with GMFCS-II&III already showed lower growth rates compared to GMFCS-I. From 2 to 9 years, the growth rates did not differ between GMFCS levels. After 9 years, a more pronounced reduction in normalized CSA was observed in GMFCS-II&III. Different trajectories in ML growth were shown between the GMFCS level subgroups. These longitudinal trajectories highlight monitoring of SCP muscle pathology from early ages and related to motor mobility. Treatment planning and goals should stimulate muscle growth.

A comprehensive normative reference database of muscle morphology in typically developing children aged 3-18 years-a cross-sectional ultrasound study.

During childhood, muscle growth is stimulated by a gradual increase in bone length and body mass, as well as by other factors, such as physical activity, nutrition, metabolic, hormonal, and genetic factors. Muscle characteristics, such as muscle volume, anatomical cross-sectional area, and muscle belly length, need to continuously adapt to meet the daily functional demands. Pediatric neurological and neuromuscular disorders, like cerebral palsy and Duchenne muscular dystrophy, are characterized by impaired muscle growth, which requires treatment and close follow-up. Nowadays ultrasonography is a commonly used technique to evaluate muscle morphology in both pediatric pathologies and typically developing children, as it is a quick, easy applicable, and painless method. However, large normative datasets including different muscles and a large age range are lacking, making it challenging to monitor muscle over time and estimate the level of pathology. Moreover, in order to compare individuals with different body sizes as a result of age differences or pathology, muscle morphology is often normalized to body size. Yet, the usefulness and practicality of different normalization techniques are still unknown, and clear recommendations for normalization are lacking. In this cross-sectional cohort study, muscle morphology of four lower limb muscles (medial gastrocnemius, tibialis anterior, the distal compartment of the semitendinosus, rectus femoris) was assessed by 3D-freehand ultrasound in 118 typically developing children (mean age 10.35 ± 4.49 years) between 3 and 18 years of age. The development of muscle morphology was studied over the full age range, as well as separately for the pre-pubertal (3-10 years) and pubertal (11-18 years) cohorts. The assumptions of a simple linear regression were checked. If these assumptions were fulfilled, the cross-sectional growth curves were described by a simple linear regression equation. Additional ANCOVA analyses were performed to evaluate muscle- or gender-specific differences in muscle development. Furthermore, different scaling methods, to normalize muscle morphology parameters, were explored. The most appropriate scaling method was selected based on the smallest slope of the morphology parameter with respect to age, with a non-significant correlation coefficient. Additionally, correlation coefficients were compared by a Steiger's Z-test to identify the most efficient scaling technique. The current results revealed that it is valid to describe muscle volume (with exception of the rectus femoris muscle) and muscle belly length alterations over age by a simple linear regression equation till the age of 11 years. Normalizing muscle morphology data by allometric scaling was found to be most useful for comparing muscle volumes of different pediatric populations. For muscle lengths, normalization can be achieved by either allometric and ratio scaling. This study provides a unique normative database of four lower limb muscles in typically developing children between the age of 3 and 18 years. These data can be used as a reference database for pediatric populations and may also serve as a reference frame to better understand both physiological and pathological muscle development.

Associations between muscle morphology and spasticity in children with spastic cerebral palsy.

INTRODUCTION: Due to the heterogeneous clinical presentation of spastic cerebral palsy (SCP), which makes spasticity treatment challenging, more insight into the complex interaction between spasticity and altered muscle morphology is warranted. AIMS: We studied associations between spasticity and muscle morphology and compared muscle morphology between commonly observed spasticity patterns (i.e. different muscle activation patterns during passive stretches). METHODS: Spasticity and muscle morphology of the medial gastrocnemius (MG) and semitendinosus (ST) were defined in 74 children with SCP (median age 8 years 2 months, GMFCS I/II/III: 31/25/18, bilateral/unilateral: 46/27). Using an instrumented assessment, spasticity was quantified as the difference in muscle activation recorded during passive stretches at low and high velocities and was classified in mixed length-/velocity-dependent or pure velocity-dependent activation patterns. Three-dimensional freehand ultrasound was used to assess muscle morphology (volume and length) and echogenicity intensity (as a proxy for muscle quality). Spearman correlations and Mann-Whitney-U tests defined associations and group differences, respectively. RESULTS: A moderate negative association (r = -0.624, p < 0.001) was found between spasticity and MG muscle volume, while other significant associations between spasticity and muscle morphology parameters were weak. Smaller normalized muscle volume (MG p = 0.004, ST p=<0.001) and reduced muscle belly length (ST p = 0.015) were found in muscles with mixed length-/velocity-dependent patterns compared to muscles with pure velocity-dependent patterns. DISCUSSION: Higher spasticity levels were associated with smaller MG and ST volumes and shorter MG muscles. These muscle morphology alterations were more pronounced in muscles that activated during low-velocity stretches compared to muscles that only activated during high-velocity stretches.

Progressive resistance training for children with cerebral palsy: A randomized controlled trial evaluating the effects on muscle strength and morphology.

Children with spastic cerebral palsy often present with muscle weakness, resulting from neural impairments and muscular alterations. While progressive resistance training (PRT) improves muscle weakness, the effects on muscle morphology remain inconclusive. This investigation evaluated the effects of a PRT program on lower limb muscle strength, morphology and gross motor function. Forty-nine children with spastic cerebral palsy were randomized by minimization. The intervention group (nparticipants = 26, age: 8.3 ± 2.0 years, Gross Motor Function Classification System [GMFCS] level I/II/III: 17/5/4, nlegs = 41) received a 12-week PRT program, consisting of 3-4 sessions per week, with exercises performed in 3 sets of 10 repetitions, aiming at 60%-80% of the 1-repetition maximum. Training sessions were performed under supervision with the physiotherapist and at home. The control group (nparticipants = 22, age: 8.5 ± 2.1 year, GMFCS level I/II/III: 14/5/3, nlegs = 36) continued usual care including regular physiotherapy and use of orthotics. We assessed pre- and post-training knee extension, knee flexion and plantar flexion isometric strength, rectus femoris, semitendinosus and medial gastrocnemius muscle morphology, as well as functional strength, gross motor function and walking capacity. Data processing was performed blinded. Linear mixed models were applied to evaluate the difference in evolution over time between the control and intervention group (interaction-effect) and within each group (time-effect). The α-level was set at p = 0.01. Knee flexion strength and unilateral heel raises showed a significant interaction-effect (p ≤ 0.008), with improvements in the intervention group (p ≤ 0.001). Moreover, significant time-effects were seen for knee extension and plantar flexion isometric strength, rectus femoris and medial gastrocnemius MV, sit-to-stand and lateral step-up in the intervention group (p ≤ 0.004). Echo-intensity, muscle lengths and gross motor function showed limited to no changes. PRT improved strength and MV in the intervention group, whereby strength parameters significantly or close to significantly differed from the control group. Although, relative improvements in strength were larger than improvements in MV, important effects were seen on the maintenance of muscle size relative to skeletal growth. In conclusion, this study proved the effectiveness of a home-based, physiotherapy supervised, PRT program to improve isometric and functional muscle strength in children with SCP without negative effects on muscle properties or any serious adverse events. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03863197.

The Short-Term Impact of Botulinum Neurotoxin-A on Muscle Morphology and Gait in Children with Spastic Cerebral Palsy.

Children with spastic cerebral palsy (SCP) are often treated with intramuscular Botulinum Neurotoxin type-A (BoNT-A). Recent studies demonstrated BoNT-A-induced muscle atrophy and variable effects on gait pathology. This group-matched controlled study in children with SCP compared changes in muscle morphology 8-10 weeks post-BoNT-A treatment (n = 25, median age 6.4 years, GMFCS level I/II/III (14/9/2)) to morphological changes of an untreated control group (n = 20, median age 7.6 years, GMFCS level I/II/III (14/5/1)). Additionally, the effects on gait and spasticity were assessed in all treated children and a subgroup (n = 14), respectively. BoNT-A treatment was applied following an established integrated approach. Gastrocnemius and semitendinosus volume and echogenicity intensity were assessed by 3D-freehand ultrasound, spasticity was quantified through electromyography during passive muscle stretches at different velocities. Ankle and knee kinematics were evaluated by 3D-gait analysis. Medial gastrocnemius (p = 0.018, -5.2%) and semitendinosus muscle volume (p = 0.030, -16.2%) reduced post-BoNT-A, but not in the untreated control group, while echogenicity intensity did not change. Spasticity reduced and ankle gait kinematics significantly improved, combined with limited effects on knee kinematics. This study demonstrated that BoNT-A reduces spasticity and partly improves pathological gait but reduces muscle volume 8-10 weeks post-injections. Close post-BoNT-A follow-up and well-considered treatment selection is advised before BoNT-A application in SCP.

Longitudinal Alterations in Gait Features in Growing Children With Duchenne Muscular Dystrophy.

Prolonging ambulation is an important treatment goal in children with Duchenne muscular dystrophy (DMD). Three-dimensional gait analysis (3DGA) could provide sensitive parameters to study the efficacy of clinical trials aiming to preserve ambulation. However, quantitative descriptions of the natural history of gait features in DMD are first required. The overall goal was to provide a full delineation of the progressive gait pathology in children with DMD, covering the entire period of ambulation, by performing a so-called mixed cross-sectional longitudinal study. Firstly, to make our results comparable with previous literature, we aimed to cross-sectionally compare 31 predefined gait features between children with DMD and a typically developing (TD) database (1). Secondly, we aimed to explore the longitudinal changes in the 31 predefined gait features in growing boys with DMD using follow-up 3DGA sessions (2). 3DGA-sessions (n = 124) at self-selected speed were collected in 27 boys with DMD (baseline age: 4.6-15 years). They were repeatedly measured over a varying follow-up period (range: 6 months-5 years). The TD group consisted of 27 children (age: 5.4-15.6 years). Per measurement session, the spatiotemporal parameters, and the kinematic and kinetic waveforms were averaged over the selected gait cycles. From the averaged waveforms, discrete gait features (e.g., maxima and minima) were extracted. Mann-Whitney U tests were performed to cross-sectionally analyze the differences between DMD at baseline and TD (1). Linear mixed effect models were performed to assess the changes in gait features in the same group of children with DMD from both a longitudinal (i.e., increasing time) as well as a cross-sectional perspective (i.e., increasing baseline age) (2). At baseline, the boys with DMD differed from the TD children in 17 gait features. Additionally, 21 gait features evolved longitudinally when following-up the same boys with DMD and 25 gait features presented a significant cross-sectional baseline age-effect. The current study quantitatively described the longitudinal alterations in gait features in boys with DMD, thereby providing detailed insight into how DMD gait deteriorates. Additionally, our results highlight that gait features extracted from 3DGA are promising outcome measures for future clinical trials to quantify the efficacy of novel therapeutic strategies.

Reduced Cross-Sectional Muscle Growth Six Months after Botulinum Toxin Type-A Injection in Children with Spastic Cerebral Palsy.

Botulinum Neurotoxin type-A (BoNT-A) injections are widely used as first-line spasticity treatment in spastic cerebral palsy (SCP). Despite improved clinical outcomes, concerns regarding harmful effects on muscle morphology have been raised. Yet, the risk of initiating BoNT-A to reduce muscle growth remains unclear. This study investigated medial gastrocnemius (MG) morphological muscle growth in children with SCP (n = 26, median age of 5.2 years (3.5)), assessed by 3D-freehand ultrasound prior to and six months post-BoNT-A injections. Post-BoNT-A MG muscle growth of BoNT-A naive children (n = 11) was compared to (a) muscle growth of children who remained BoNT-A naive after six months (n = 11) and (b) post-BoNT-A follow-up data of children with a history of BoNT-A treatment (n = 15). Six months after initiating BoNT-A injection, 17% decrease in mid-belly cross-sectional area normalized to skeletal growth and 5% increase in echo-intensity were illustrated. These muscle outcomes were only significantly altered when compared with children who remained BoNT-A naive (+4% and -3%, respectively, p < 0.01). Muscle length growth persevered over time. This study showed reduced cross-sectional growth post-BoNT-A treatment suggesting that re-injections should be postponed at least beyond six months. Future research should extend follow-up periods investigating muscle recovery in the long-term and should include microscopic analysis.

The Contribution of Decreased Muscle Size to Muscle Weakness in Children With Spastic Cerebral Palsy.

Muscle weakness is a common clinical symptom in children with spastic cerebral palsy (SCP). It is caused by impaired neural ability and altered intrinsic capacity of the muscles. To define the contribution of decreased muscle size to muscle weakness, two cohorts were recruited in this cross-sectional investigation: 53 children with SCP [median age, 8.2 (IQR, 4.1) years, 19/34 uni/bilateral] and 31 children with a typical development (TD) [median age, 9.7 (IQR, 2.9) years]. Muscle volume (MV) and muscle belly length for m. rectus femoris, semitendinosus, gastrocnemius medialis, and tibialis anterior were defined from three-dimensional freehand ultrasound acquisitions. A fixed dynamometer was used to assess maximal voluntary isometric contractions for knee extension, knee flexion, plantar flexion, and dorsiflexion from which maximal joint torque (MJT) was calculated. Selective motor control (SMC) was assessed on a 5-point scale for the children with SCP. First, the anthropometrics, strength, and muscle size parameters were compared between the cohorts. Significant differences for all muscle size and strength parameters were found (p ≤ 0.003), except for joint torque per MV for the plantar flexors. Secondly, the associations of anthropometrics, muscle size, gross motor function classification system (GMFCS) level, and SMC with MJT were investigated using univariate and stepwise multiple linear regressions. The associations of MJT with growth-related parameters like age, weight, and height appeared strongest in the TD cohort, whereas for the SCP cohort, these associations were accompanied by associations with SMC and GMFCS. The stepwise regression models resulted in ranges of explained variance in MJT from 29.3 to 66.3% in the TD cohort and from 16.8 to 60.1% in the SCP cohort. Finally, the MJT deficit observed in the SCP cohort was further investigated using the TD regression equations to estimate norm MJT based on height and potential MJT based on MV. From the total MJT deficit, 22.6-57.3% could be explained by deficits in MV. This investigation confirmed the disproportional decrease in muscle size and muscle strength around the knee and ankle joint in children with SCP, but also highlighted the large variability in the contribution of muscle size to muscle weakness.

Early interventions in infants with unilateral cerebral palsy: A systematic review and narrative synthesis.

BACKGROUND: Recent systematic reviews have already provided an overview of the impact of early interventions on developmental outcomes in infants at risk for cerebral palsy. However, none has thus far focused specifically on how early interventions might improve motor outcome in infants diagnosed with unilateral cerebral palsy (uCP). Hence, the aim of this systematic review was to provide an overview of early intervention programs used in infants with uCP to improve motor outcome. METHODS: A systematic literature search was performed in PubMed, Embase, Cochrane Central Register of Controlled trials, CINAHL and Web of Science following the PRISMA-statement guidelines. Risk of bias was assessed using the Cochrane risk-of-bias 2 tool. RESULTS: Three single-blinded randomized controlled trials (RCTs) were identified, including 88 infants with uCP. These RCTs suggest that modified constraint-induced movement therapy (mCIMT) is effective and safe for improving upper limb function in infants with uCP. Bimanual training compared to mCIMT was found to be equally effective in one study. No clinical or neurological predictors of treatment response could be identified yet. CONCLUSION: Although more high-quality RCTs are urgently needed, early interventions seem effective, safe and feasible to apply in infants with uCP for improving upper limb motor function. This underlines the importance of prompt referral to diagnostic-specific centres to start up such early interventions.

Reliability of Processing 3-D Freehand Ultrasound Data to Define Muscle Volume and Echo-intensity in Pediatric Lower Limb Muscles with Typical Development or with Spasticity.

This investigation assessed the processer reliability of estimating muscle volume and echo-intensity of the rectus femoris, tibialis anterior and semitendinosus. The muscles of 10 typically developing children (8.15 [1.40] y) and 15 children with spastic cerebral palsy (7.67 [3.80] y; Gross Motor Function Classification System I = 5, II = 5, III = 5) were scanned with 3-D freehand ultrasonography. For the intra-processer analysis, the intra-class correlations coefficients (ICCs) for muscle volume ranged from 0.943-0.997, with relative standard errors of measurement (SEM%) ranging from 1.24%-8.97%. For the inter-processer analysis, these values were 0.853 to 0.988 and 3.47% to 14.02%, respectively. Echo-intensity had ICCs >0.947 and relative SEMs <4% for both analyses. Muscle volume and echo-intensity can be reliably extracted for the rectus femoris, semitendinosus and tibialis anterior in typically developing children and children with cerebral palsy. The need for a single processer to analyze all data is dependent on the size of the expected changes or differences.

Muscle Characteristics in Pediatric Hereditary Spastic Paraplegia vs. Bilateral Spastic Cerebral Palsy: An Exploratory Study.

Hereditary spastic paraplegia (HSP) is a neurological, genetic disorder that predominantly presents with lower limb spasticity and muscle weakness. Pediatric pure HSP types with infancy or childhood symptom onset resemble in clinical presentation to children with bilateral spastic cerebral palsy (SCP). Hence, treatment approaches in these patient groups are analogous. Altered muscle characteristics, including reduced medial gastrocnemius (MG) muscle growth and hyperreflexia have been quantified in children with SCP, using 3D-freehand ultrasound (3DfUS) and instrumented assessments of hyperreflexia, respectively. However, these muscle data have not yet been studied in children with HSP. Therefore, we aimed to explore these MG muscle characteristics in HSP and to test the hypothesis that these data differ from those of children with SCP and typically developing (TD) children. A total of 41 children were retrospectively enrolled including (1) nine children with HSP (ages of 9-17 years with gross motor function levels I and II), (2) 17 age-and severity-matched SCP children, and (3) 15 age-matched typically developing children (TD). Clinically, children with HSP showed significantly increased presence and severity of ankle clonus compared with SCP (p = 0.009). Compared with TD, both HSP and SCP had significantly smaller MG muscle volume normalized to body mass (p ≤ 0.001). Hyperreflexia did not significantly differ between the HSP and SCP group. In addition to the observed pathological muscle activity for both the low-velocity and the change in high-velocity and low-velocity stretches in the two groups, children with HSP tended to present higher muscle activity in response to increased stretch velocity compared with those with SCP. This exploratory study is the first to reveal MG muscle volume deficits in children with HSP. Moreover, high-velocity-dependent hyperreflexia and ankle clonus is observed in children with HSP. Instrumented impairment assessments suggested similar altered MG muscle characteristics in pure HSP type with pediatric onset compared to bilateral SCP. This finding needs to be confirmed in larger sample sizes. Hence, the study results might indicate analogous treatment approaches in these two patient groups.

Muscle and tendon properties of the spastic lower leg after stroke defined by ultrasonography: a systematic review.

INTRODUCTION: Peripheral muscle and tendon changes after stroke can influence the functional outcome of patients. The aim of this systematic review was to summarize the evidence of ultrasonographic changes in morphological muscle and tendon properties of the spastic hemiparetic lower leg in patients with first ever stroke. EVIDENCE ACQUISITION: A systematic search was conducted through PubMed, Embase, Scopus, Cinahl, Cochrane Library, and manual searches from inception until May 1, 2020. Observational case control or cohort studies were included. Risk of bias was evaluated by using the Newcastle-Ottawa Quality Assessment Scale. Outcome parameters of interest included muscle thickness, muscle and tendon length, fascicle length, pennation angle and echo-intensity. EVIDENCE SYNTHESIS: Nine studies investigated outcome parameters beyond one-month after stroke. We are unable to make a comprehensive statement. Nevertheless, there are some arguments for reduced muscle thickness and reduced fascicle length of the hemiplegic, spastic leg. CONCLUSIONS: Despite the fact that objective assessment by ultrasonography holds promise for diagnosis and follow-up of spastic hemiparesis after stroke, more evidence is needed to determine how changes in morphological muscle and tendon properties are related to muscle weakness, severity of spasticity and compensation strategies such as disuse or overuse in longitudinal studies starting early after stroke.

Muscle weakness has a limited effect on motor control of gait in Duchenne muscular dystrophy.

AIM: Our aim was to determine if synergy weights and activations are altered in Duchenne muscular dystrophy (DMD) and if these alterations could be linked to muscle weakness. METHODS: In 22 children with DMD and 22 typical developing (TD) children of a similar age, surface electromyography (sEMG) of the gluteus medius, rectus femoris (REF), medial hamstrings, tibialis anterior, and medial gastrocnemius (GAS) were recorded during gait. Muscle weakness was assessed with maximal voluntary isometric contractions (MVIC). Synergies were calculated with non-negative matrix factorization. The number of synergies explaining ≥90% of the variance in the sEMG signals (N90), were extracted and grouped with k-means cluster analysis. We verified differences in weights with a Mann-Whitney U test. Statistical non-parametric mapping (Hotelling's T2 test and two-tailed t-test) was used to assess group differences in synergy activations. We used Spearman's rank correlation coefficients and canonical correlation analysis to assess if weakness was related to modifications in weights and activations, respectively. RESULTS: For both groups, average N90 was three. In synergy one, characterized by activity at the beginning of stance, the DMDs showed an increased REF weight (p = 0.001) and decreased GAS weight (p = 0.007). Synergy activations were similar, with only a small difference detected in mid-swing in the combined activations (p<0.001). Weakness was not associated with these differences. CONCLUSION: Despite the apparent weakness in DMD, synergy weights and activations were similar between the two groups. Our findings are in line with previous research suggesting non-neural alterations have limited influence on muscle synergies.

Muscle Microbiopsy to Delineate Stem Cell Involvement in Young Patients: A Novel Approach for Children With Cerebral Palsy.

Cerebral palsy (CP), the single largest cause of childhood physical disability, is characterized firstly by a lesion in the immature brain, and secondly by musculoskeletal problems that progress with age. Previous research reported altered muscle properties, such as reduced volume and satellite cell (SC) numbers and hypertrophic extracellular matrix compared to typically developing (TD) children (>10 years). Unfortunately, data on younger CP patients are scarce and studies on SCs and other muscle stem cells in CP are insufficient or lacking. Therefore, it remains difficult to understand the early onset and trajectory of altered muscle properties in growing CP children. Because muscle stem cells are responsible for postnatal growth, repair and remodeling, multiple adult stem cell populations from young CP children could play a role in altered muscle development. To this end, new methods for studying muscle samples of young children, valid to delineate the features and to elucidate the regenerative potential of muscle tissue, are necessary. Using minimal invasive muscle microbiopsy, which was applied in young subjects under general anaesthesia for the first time, we aimed to isolate and characterize muscle stem cell-derived progenitors of TD children and patients with CP. Data of 15 CP patients, 3-9 years old, and 5 aged-matched TD children were reported. The muscle microbiopsy technique was tolerated well in all participants. Through the explant technique, we provided muscle stem cell-derived progenitors from the Medial Gastrocnemius. Via fluorescent activated cell sorting, using surface markers CD56, ALP, and PDGFRa, we obtained SC-derived progenitors, mesoangioblasts and fibro-adipogenic progenitors, respectively. Adipogenic, skeletal, and smooth muscle differentiation assays confirmed the cell identity and ability to give rise to different cell types after appropriate stimuli. Myogenic differentiation in CP SC-derived progenitors showed enhanced fusion index and altered myotube formation based on MYOSIN HEAVY CHAIN expression, as well as disorganization of nuclear spreading, which were not observed in TD myotubes. In conclusion, the microbiopsy technique allows more focused muscle research in young CP patients. Current results show altered differentiation abilities of muscle stem cell-derived progenitors and support the hypothesis of their involvement in CP-altered muscle growth.