Using the gross motor function measure evolution ratio to compare different dosage of hyperbaric treatment with conventional therapies in children with cerebral palsy - could it end the controversy?

The Gross Motor Function Measure is used in most studies measuring gross motor function in children with cerebral palsy. In many studies, including those evaluating the effect of hyperbaric treatment, the Gross Motor Function Measure variations were potentially misinterpreted because of the lack of control groups. The Gross Motor Function Measure Evolution Ratio (GMFMER) uses historical data from the Gross Motor Function Classification System curves and allows to re-analyze previous published studies which used the Gross Motor Function Measure by considering the natural expected evolution of the Gross Motor Function Measure. As the GMFMER is defined by the ratio between the recorded Gross Motor Function Measure score increase and the expected increase attributed to natural evolution during the duration of the study (natural evolution yields a GMFMER of 1), it becomes easy to assess and compare the efficacy of different treatments. Objective: The objective of this study is to revisit studies done with different dosage of hyperbaric treatment and to compare the GMFMER measured in these studies with those assessing the effects of various recommended treatments in children with cerebral palsy. Methods: PubMed Searches were conducted to included studies that used the Gross Motor Function Measure to evaluate the effect of physical therapy, selective dorsal rhizotomy, botulinum toxin injection, hippotherapy, stem cell, or hyperbaric treatment. The GMFMER were computed for each group of the included studies. Results: Forty-four studies were included, counting 4 studies evaluating the effects of various dosage of hyperbaric treatment in children with cerebral palsy. Since some studies had several arms, the GMFMER has been computed for 69 groups. The average GMFMER for the groups receiving less than 2 h/week of physical therapy was 2.5 ± 1.8 whereas in context of very intensive physical therapy it increased to 10.3 ± 6.1. The GMFMER of stem cell, selective dorsal rhizotomy, hippotherapy, and botulinum toxin treatment was, 6.0 ± 5.9, 6.5 ± 2.0, 13.3 ± 0.6, and 5.0 ± 2.9, respectively. The GMFMER of the groups of children receiving hyperbaric treatment were 28.1 ± 13.0 for hyperbaric oxygen therapy and 29.8 ± 6.8 for hyperbaric air. Conclusion: The analysis of the included studies with the GMFMER showed that hyperbaric treatment can result in progress of gross motor function more than other recognized treatments in children with cerebral palsy.

Glycopyrronium 320 µg/mL in children and adolescents with severe sialorrhoea and neurodisabilities: A randomized, double-blind, placebo-controlled trial.

AIM: To investigate the efficacy, safety, and impact on quality of life (QoL) of an oral formulation of 320 µg/mL glycopyrronium designed for children. METHOD: A double-blind, placebo-controlled SALIVA (Sialanar plus orAl rehabiLitation against placebo plus oral rehabilitation for chIldren and adolescents with seVere sialorrhoeA and neurodisabilities) trial was conducted. Children (3-17 years) with neurodisabilities and severe sialorrhoea (modified Teachers Drooling Scale ≥6) were randomized to 320 µg/mL glycopyrronium or placebo, in addition to non-pharmacological standard care. RESULTS: Of 87 participants, 44 were aged 10 years or under and 43 had cerebral palsy. The primary endpoint, change in total Drooling Impact Scale (DIS) score from baseline to day 84, was significantly greater (improved) with 320 µg/mL glycopyrronium versus placebo (median [quartile 1, quartile 3] -29.5 [-44.5, 0] vs -1 [-16, 5]; p < 0.001), an effect also observed at day 28 (median - 25 vs -2; p < 0.01). Significant reduction in bibs/clothes used per day was seen with glycopyrronium versus placebo at day 84 (median - 2 vs 0; p < 0.01). Glycopyrronium significantly improved DIS items 9 and 10 related to the extent that drooling affects the child's and family's life (p ≤ 0.03). Adverse events were reported by 77.3% and 69.8% of children with glycopyrronium and placebo respectively; the most common treatment-related adverse event was constipation (20.5% and 16.3%). INTERPRETATION: The formulation of 320 µg/mL glycopyrronium significantly improved drooling and reduced its impact on QoL, with good tolerability in children with neurodisabilities. WHAT THIS PAPER ADDS: The formulation of 320 µg/mL glycopyrronium significantly improved Drooling Impact Scale score versus placebo at day 84. The formulation reduced the impact of drooling on the child's and family's quality of life. There were no safety or tolerability concerns with this specific formulation.

Safety and adherence of pressure garment therapy in children with upper limb unilateral cerebral palsy. Results from a randomized clinical trial ancillary analysis.

Background: This study was conducted to assess the safety and adherence of the use of a PGT (Pressure Garment Therapy) Lycra® sleeve to treat upper limb unilateral cerebral palsy (UCP) in children. Methods: This study was conducted as a prospective, placebo-controlled, double-blinded, randomized monocenter study. Included in the study were 58 UCP children, 49 of whom were analyzed. 25 children (mean age 6.6 ± 1.6 years; 12 girls) were allocated to the active group vs. 24 (mean age 6.7 ± 1.6 years; 10 girls) in the placebo group. The intervention consisted of an active PGT Lycra® arm sleeve manufactured to generate a homogeneous pressure ranging from 15 to 25 mmHg. The placebo PGT Lycra® sleeve was manufactured to generate a homogeneous pressure under 7 mmHg. The time of wearing period was set at 3 h/day at minimum and 6 h/day at maximum, over the course of 6 months. The main outcome measures were safety outcomes including the number and intensity of Adverse Events of Special Interest (AESIs). AESIs were defined as adverse events imputable to compressive therapy and Lycra® wearing. Level of adherence was expressed in percentage of number of days when the sleeve was worn for at least 3 h per day compared to length of duration in days (start and end date of wearing period). Results: Frequency of AESIs were very low and no different between groups (4.12 ± 11.32% vs. 1.83 ± 3.38%; p = 0.504). There were no differences in adherence (91.86 ± 13.86% vs. 94.30 ± 9.95%; p = 0.425). Conclusion: The use of PGT Lycra® arm sleeve in children with UCP is safe and well-tolerated with a very good adherence. The low rate of AESIs is promising for further randomized clinical trials on efficacy.

Assistive Products and Technology to Facilitate Activities and Participation for Children with Disabilities.

We aimed to identify activity limitations and participation restrictions encountered by children and youth with disabilities for which assistive products and technology could be helpful. We used a convergent, parallel, mixed-methods design involving a nationwide, French survey composed of closed questions (quantitative) and open questions (qualitative) that enlightened the quantitative data. A total of 1055 responses were received, and 962 included: 92 from children and youth with disabilities, 493 from relatives and 377 from professionals. Difficulties frequently checked and described in detail were participation in recreational activities, leaving the house and traveling, participating in a group, and getting ready. Transversal explanations for difficulties were spontaneously provided (e.g., lack of accessibility and mobility). Solutions proposed included personal assistive devices to facilitate home life, high-tech devices, devices to compensate for impaired body functions, and adaptation of the familiar environment and daily activities. Few public solutions were proposed. The necessity of human assistance was emphasized. The mixed-methods design and involvement of different stakeholders identified common, macroscopic trends in difficulties encountered and desired solutions. Products and technology are required in the following domains: the familiar environment, accessibility and mobility, sports and leisure, high-technology, and family support. We provide suggestions to facilitate the development of innovative solutions.

Hyperbaric oxygen in children with cerebral palsy: A systematic review of effectiveness and safety.

PURPOSE: To report current evidence regarding the effectiveness of hyperbaric oxygen therapy (HBOT) on the impairments presented by children with cerebral palsy (CP), and its safety. MATERIALS AND METHODS: PUBMED, The Cochrane Library, Google Scholar, and the Undersea and Hyperbaric Medical Society database were searched by two reviewers. Methodological quality was graded independently by 2 reviewers using the Physiotherapy Evidence Database assessment scale for randomized controlled trials (RCTs) and the modified Downs and Black (m-DB) evaluation tool for non RCTs. A meta-analysis was performed where applicable for RCTs. RESULTS: Five RCTs were identified. Four had a high level of evidence. Seven other studies were observational studies of low quality. All RCTs used 100% O2, 1.5 to 1.75 ATA, as the treatment intervention. Pressurized air was the control intervention in 3 RCTs, and physical therapy in 2. In all but one RCTs, similar improvements were observed regarding motor and/or cognitive functions, in the HBOT and control groups. Adverse events were mostly of mild severity, the most common being middle ear barotrauma (up to 50% of children). CONCLUSION: There is high-level evidence that HBOT is ineffective in improving motor and cognitive functions, in children with CP. There is moderate-level evidence that HBOT is associated with a higher rate of adverse events than pressurized air in children.

Starting from the needs: what are the appropriate sources to co-create innovative solutions for persons with disabilities?

PURPOSE: Technical solutions could facilitate activities and participation in individuals with disabilities. For the development of solutions, hackathons are a method of interdisciplinary collaboration. For hackathon, the definition of pain points that require solutions is crucial. We aimed to determine engineers' preferences and expectations regarding pain point qualities. METHODS: We used a collaborative approach involving individuals with disability, families, and healthcare professionals to determine pain points for use by engineering students during a disability Hackathon. A pain point bank was built using 3 upstream sources: a survey (350 responses, 20 pain points selected), interviews (8 children, 13 pain points), and a multidisciplinary workshop based on design thinking methods (45 people, 32 pain points). A fourth source was 20 adults with disabilities present during the Hackathon. Engineering students rated pain point qualities from each source in a questionnaire that included closed questions relating to predefined criteria: achievability, specificity, relevance and attractiveness and open questions to collect non-predefined quality criteria. RESULTS: Pain points from the workshop were most frequently used (48%); followed by on-site discussions with mentors (43%), the survey (38%), and interviews (31%). On-site discussions received the highest quality ratings followed by the workshop, survey, and interviews. Three quality criteria emerged from the responses to open questions: "representative", "empathy", and "real-need". CONCLUSIONS: To be actionable by engineers, pain points must relate to real needs, be achievable, specific, relevant and attractive but also representative and arouse empathy. We devised a checklist of qualities along with a toolbox of methods to achieve each.Implications For RehabilitationThe first step of the development of technical solutions for children and individuals with disabilities is the identification of their needs and their adequate formulation to be submitted to technical solutions providers.Daily life needs of individuals with disability were gathered for an engineering hackathon and proposed as pain points to 400 engineering students.To facilitate the development of solutions by engineers, pain points must relate to real needs, be specific, relevant, achievable and attractive; be representative and arouse empathy; a toolbox of needs collection methods is proposed to achieve each of those qualities.Discussions with individuals with disability and health professionals should be provided.

Assessing the contribution of lower limb mobilization, in the supine position, on shoulder-pelvis girdles dissociation.

BACKGROUND: Several articular, muscular and neurological diseases generate mobility loss in the shoulder and pelvis girdles. Joint mobilization contributes to improving shoulder-pelvis girdles dissociation, but current mobilization techniques are not always successful and standardized. A robotic medical device, DPA Med®, by inducing trunk mobilization through lower limb oscillation has been developed for producing such a shoulder-pelvis girdles dissociation and is already used worldwide in rehabilitation hospitals. RESEARCH QUESTION: To determine the optimal lower limb oscillation frequency that generated the best shoulder-pelvis girdles dissociation using the DPA Med® device. METHODS: Thirty healthy adult volunteers (mean age: 38.6 [SD 15.2] years, mean height: 174 [SD 11.9] cm, mean body mass: 70.3 [SD 14.7] kg) participated in this prospective study. A kinematic analysis quantified pelvic and shoulder girdle mobility (rotation and lateral tilt) at different DPA Med® frequencies, from 0.5 Hz to 1 Hz. A visual analysis of the lower limb movement was also performed, using video sensors, to better understand the kinematics involved. RESULTS: All DPA Med® frequencies have shown significant shoulder-pelvis girdles dissociation (p < 0.05). This study established an optimal oscillation frequency with the minimal interindividual variability at 0.808 Hz. It induced pelvic mobility similar to that of normal gait, in the transverse and frontal planes (10.3°, SD 2.9°, and 12.0°, SD 2.2°, respectively). This trunk mobility was achieved by producing a lemniscate-shaped motion in the lower limbs (an eight-shaped motion in the transverse plane). SIGNIFICANCE: This study has shown that the DPA Med® device is able to induce shoulder-pelvis girdles dissociation similar to that of normal gait and allowed to establish the existence of an optimal DPA Med® oscillation frequency for lower limb mobility at 0.808 Hz. Further studies are required to evaluate its potentially benefits on gait disorders.

Detection of pronator muscle overactivity in children with unilateral spastic cerebral palsy: Development of a semi-automatic method using EMG data.

BACKGROUND: The pronator teres and pronator quadratus muscles are frequently injected with neuromuscular blocking agents to improve supination in children with spastic cerebral palsy and limited active elbow supination. However, determining by simple clinical examination whether these muscles are overactive during active movement is difficult. OBJECTIVE: This study aimed to develop a semi-automatic method to detect pronator muscle overactivity by using surface electromyography (EMG) during active supination movements in children with cerebral palsy. METHODS: In total, 25 children with unilateral spastic cerebral palsy (10 males; mean [SD] age 10.6 [3.0] years) and 12 typically developing children (7 males; mean age 11.0 [3.0] years) performed pronation-supination movements at 0.50Hz. Kinematic parameters and surface EMG signals were recorded for both pronator muscles. Three experts visually assessed muscle overactivity in the EMG signals of the children with cerebral palsy, in comparison with the reference group. The reliability and discrimination ability of the visual assessments were analysed. Overactivity detection thresholds for the semi-automatic method were adjusted by using the visual assessment by the EMG experts. The positive and negative predictive values of the semi-automatic detection method were calculated. RESULTS: Intra-rater reliability of visual assessment by EMG experts was excellent and inter-rater reliability was moderate. For the 25 children with unilateral spastic cerebral palsy, EMG experts could discriminate different profiles of pronator overactivity during active supination: no pronator overactivity, one overactive pronator, or overactivity of both pronators. The positive and negative predictive values were 96% and 91%, respectively, for this semi-automatic detection method. CONCLUSIONS: Detection of pronator overactivity by using surface EMG provides an important complement to the clinical examination. This method can be used clinically, with the condition that clinicians be aware of surface EMG limitations. We believe use of this method can increase the accuracy of treatment for muscle overactivity, resulting in improved motor function and no worsening of paresis.

Patterns of upper limb muscle activation in children with unilateral spastic cerebral palsy: Variability and detection of deviations.

BACKGROUND: The aim of this study was two-fold: (1) to quantify the variability of upper limb electromyographic patterns during elbow movements in typically developing children and children with unilateral spastic cerebral palsy, and to compare different amplitude normalization methods; (2) to develop a method using this variability to detect (a) deviations in the patterns of a child with unilateral spastic cerebral palsy from the average patterns of typically developing children, and (b) changes after treatment to reduce muscle activation. METHODS: Twelve typically developing children ([6.7-15.9yo]; mean 11.0 SD 3.0yo) and six children with unilateral spastic cerebral palsy ([7.9-17.4yo]; mean 12.4 SD 4.0yo) attended two sessions during which they performed elbow extension-flexion and pronation-supination movements. Surface electromyography of the biceps, triceps, brachioradialis, pronator teres, pronator quadratus, and brachialis muscles was recorded. The Likelihood method was used to estimate the inter-trial, inter-session, and inter-subject variability of the electromyography patterns for each time point in the movement cycle. Deviations in muscle patterns from the patterns of typically developing children and changes following treatment were evaluated in a case study of a child with cerebral palsy. FINDINGS: Normalization of electromyographic amplitude by the mean peak yielded the lowest variability. The variability data were then used in the case study. This method detected higher levels of activation in specific muscles compared with typically developing children, and a reduction in muscle activation after botulinum toxin A injections. INTERPRETATION: Upper limb surface electromyography pattern analysis can be used for clinical applications in children with cerebral palsy.

Effect of glutamine on glucose metabolism in children with Duchenne muscular dystrophy.

BACKGROUND & AIMS: Glutamine is a potent gluconeogenic precursor and stimulates insulin secretion. Glutamine's effect on glucose metabolism in Duchenne muscular dystrophy (DMD) has never been studied. To determine plasma glucose and insulin concentrations measured during and after glutamine administration in DMD boys. We hypothesized that glutamine can modulate whole body glutamine-glucose metabolism in DMD, a genetically determined disease. METHODS: As secondary endpoints of a randomized crossover trial in 30 prepubertal DMD boys, we measured fasting blood glucose, insulin and the Homeostasis Model Assessment (HOMA) index after daily oral glutamine (0.5 g kg(-1) d(-1)) for 4 months versus placebo. In a separate time series trial in 6 prepubertal DMD boys, we measured the same endpoints as well as plasma glutamine and whole body glucose turnover (Ra,glc) (primed continuous i.v. infusion of d-[6,6-(2)D]glucose), while participants received acute oral glutamine (0.5 g kg(-1) d(-1)) continuously for 5 h. RESULTS: In the randomized trial, baseline measurements of HOMA correlated with age (r = 0,51, p = 0.007) and percent fat estimated by bioelectrical impedance analysis (BIA) (r = 0.39, p = 0.047). After 4 months glutamine supplementation, we observed no treatment or order effect on HOMA or insulin. During acute glutamine for 5 h (time series trial), plasma glutamine doubled and was associated with increased plasma insulin concentration (10.42 ± 2.54 vs 7.32 ± 1.86, p = 0.05) with no effect on plasma glucose, HOMA or Ra,glc. CONCLUSIONS: Acute glutamine transiently stimulates insulin secretion in DMD boys, which could be mediated by plasma glutamine concentrations. Fasting insulin concentration and HOMA might provide quantifiable indices of disease progression.

Assessing change in body composition in children with Duchenne muscular dystrophy: anthropometry and bioelectrical impedance analysis versus dual-energy X-ray absorptiometry.

BACKGROUND & AIMS: To compare the ability of bioelectrical impedance analysis (BIA) and skinfold thickness (ST) measurements to estimate changes in body composition in Duchenne muscular dystrophy (DMD). METHODS: A secondary analysis was performed on 26 ambulatory DMD boys aged 3-11 y selected for a randomised trial of glutamine supplementation. We assessed fat free mass (FFM) and percentage fat mass (%FM) by BIA (monofrequency (50kHz) unit), ST measurements and a criterion method, dual-energy X-ray absorptiometry (DXA), and repeated these measures 5 mo later at 3 outpatient clinical investigation centers in France. RESULTS: When compared with DXA reference method, ST overestimated change in FFM (P<0.01), whereas BIA estimates did not differ from DXA. Concordance plots revealed that when compared with DXA, ST overestimated the increase in FFM (mean: 0.6 kg; 95% CI: 0.17 to 0.99) which led to an underestimation in %FM change (mean: -1.4%; 95% CI: -2.6 to -0.2), whereas BIA estimated change in FFM (mean: -0.05 kg; 95% CI: -0.39 to 0.29) and %FM (mean: 1.3%; 95% CI: -0.06 to 2.7) more accurately. CONCLUSIONS: BIA method can be used to follow changes in nutritional status of ambulatory DMD children or to evaluate treatment efficacy.

Lack of functional benefit with glutamine versus placebo in Duchenne muscular dystrophy: a randomized crossover trial.

BACKGROUND: Oral glutamine decreases whole body protein breakdown in Duchenne muscular dystrophy (DMD). We evaluated the functional benefit of 4 months oral glutamine in DMD. METHODOLOGY/PRINCIPAL FINDINGS: 30 ambulant DMD boys were included in this double-blind, randomized crossover trial with 2 intervention periods: glutamine (0.5 g/kg/d) and placebo, 4 months each, separated by a 1-month wash-out, at 3 outpatient clinical investigation centers in France. Functional benefit was tested by comparing glutamine versus placebo on change in walking speed at 4 months. Secondary outcome measures were: 2-minute walk test, work, power, muscle mass (urinary creatinine), markers of myofibrillar protein breakdown (urinary 3-methyl-histidine/creatinine), serum creatine phospho-kinase, body composition (fat free mass, fat mass percentage), safety and oral nutrient intake. There was no improvement in the primary end point (walking speed) or in secondary measures of muscle function (2-minute walk test, work, power) in the glutamine group compared with placebo. However, subjects receiving glutamine or placebo showed no deterioration in functional measures over the course of the 9-month trial. No differences in muscle mass, markers of protein breakdown or serum creatine phosho-kinase were observed, except for a blunted increase in fat free mass in the glutamine group which led to a greater increase in fat mass percentage. Glutamine was safe and well-tolerated. CONCLUSIONS: This trial did not identify additional benefit of 4 months oral glutamine over placebo on muscle mass or function in ambulatory DMD boys. Although apparently safe, current data cannot support routine supplementation in this population as a whole, until further research proves otherwise. TRIAL REGISTRATION: (ClinicalTrials.gov) NCT00296621.

Epithelial phenotypes in the developing human prostate.

An intermediate population has been identified among prostate glands called transiently amplifying (TA) cells, which are characterized by coexpression of basal and luminal cytokeratins (CKs), high proliferation, and lack of p27 expression. These cells are rare in the normal adult prostate and increase in pretumoral conditions, but their importance in the developing gland remains unknown. We analyzed fetal prostates for the expression of CKs (5/6, 18, 19) and factors involved in proliferation and apoptosis: p63, Ki67, p27, epidermal growth factor (EGFR), Bcl2, androgen receptor (AR). Immunostaining was performed on a tissue microarray, including 40 prostates from fetuses aged 13-42 weeks and normal prostate tissue from 10 adults. In both solid buds and the basal compartment of canalized glands, cells expressed p63, CK5/6, CK19, CK18, BCL2, EGFR and were p27 negative. Luminal cells of fetal canalized glands continue to express CK19, EGFR, and BCL2, without p27 expression. In contrast, adult epithelial luminal cells showed diffuse AR and p27 expression, without CK19, BCL2, and EGFR staining. Proliferation was high and diffuse in fetal glands and rare and restricted to basal cells in adult glands. These results indicate that most fetal epithelial prostatic cells exhibit the phenotype of TA cells, suggesting their regulatory function in prostate development.