Umbilical Cord Blood Cell Clearance Post-Infusion in Immune-Competent Children with Cerebral Palsy.

Umbilical cord blood cells have therapeutic potential for neurological disorders, through a paracrine mechanism of action. A greater understanding of the safety and immunological effects of allogeneic donor cord blood cells in the context of a healthy recipient immune system, such as in cerebral palsy, is needed. This study aimed to determine how quickly donor cord blood cells were cleared from the circulation in children with cerebral palsy who received a single intravenous infusion of 12/12 human leucocyte antigen (HLA)-matched sibling cord blood cells. Twelve participants with cerebral palsy aged 2-12 years received cord blood cell infusions as part of a phase I trial of umbilical blood infusion for cerebral palsy. Digital droplet PCR analysis of DNA copy number variants specific to donor and recipient was used to assess donor DNA clearance at five timepoints post-infusion, a surrogate measure of cell clearance. Donor cells were cleared by 3 months post-infusion in 11/12 participants. When detected, donor DNA was at a fraction of 0.01-0.31% of total DNA with no signs of graft-versus-host disease in any participant. The donor DNA clearance times provided by this study have important implications for understanding the safety of allogeneic cord blood cell infusion for cerebral palsy and translational tissue engineering or regenerative medicine research in other disorders.

Safety of sibling cord blood cell infusion for children with cerebral palsy.

Cerebral palsy (CP) is a nonprogressive neurological disorder and the most common physical disability of childhood. There is no cure for CP, but stem cells have the potential to improve brain injury and hence function. This phase 1 clinical trial investigated the safety of the intravenous infusion of full-matched sibling cord blood cells for children with CP aged 1 to 16 years. Preliminary efficacy outcomes were also investigated. Twelve participants received 12/12 HLA-matched sibling cord blood cell infusions. One treatable serious adverse reaction to cryoprotectant was observed, and no adverse reactions occurred beyond 24 h after infusion. Gross motor function measure (GMFM-66) scores did not improve compared with baseline beyond what could be expected from developmental levels, and participants had varied changes in the Quality of Upper Extremity Skills Test (QUEST) and Vineland Adaptive Behavior Scales (VABS-II) scores. In conclusion, matched sibling cord blood cell infusion for children with CP is relatively safe when conducted in an appropriate facility. Australian and New Zealand Clinical Trials Registry (ACTRN12616000403437) and Clinicaltrials.gov (NCT03087110).

Single group multisite safety trial of sibling cord blood cell infusion to children with cerebral palsy: study protocol and rationale.

INTRODUCTION: Cerebral palsy (CP) is the most common physical disability of childhood but has no cure. Stem cells have the potential to improve brain injury and are proposed as a therapy for CP. However, many questions remain unanswered about the most appropriate cell type, timing of infusions, dose required and associated risks. Therefore, human safety and efficacy trials are necessary to progress knowledge in the field. METHODS AND ANALYSIS: This is a single group study with sample size n=12 to investigate safety of single-dose intravenous 12/12 human leucocyte antigen-matched sibling cord blood cell infusion to children with CP aged 1-16 years without immune suppression. The study is similar to a 3+3 design, where the first two groups of participants have severe CP, and the final six participants include children with all motor severities. Children will be monitored for adverse events and the duration that donor cells are detected. Assessments at baseline, 3 and 12 months will investigate safety and preliminary evidence of change in gross motor, fine motor, cognitive and quality of life outcomes. ETHICS AND DISSEMINATION: Full approval was obtained from The Royal Children's Hospital Human Research Ethics Committee, and a clinical trial notification was accepted by Australia's Therapeutic Goods Administration. Participant guardian informed consent will be obtained before any study procedures. The main results of this study will be submitted for publication in a peer-reviewed journal. TRIAL REGISTRATION NUMBER: ACTRN12616000403437, NCT03087110.

Psychometric properties of parent and child reported sleep assessment tools in children with cerebral palsy: a systematic review.

AIM: To determine whether any parent and child report sleep measure tools have been validated in children aged 0-18 years with cerebral palsy (CP). METHOD: A systematic search of five databases was performed up to June 2017. Studies were included if a sleep measure tool was used to evaluate sleep in children 0-18 years with CP based on international classifications of sleep. Sleep measures were assessed for psychometric data in children with CP. RESULTS: Only one paper which used the Schlaffragebogen für Kinder mit Neurologischen und Anderen Komplexen Erkrankungen (SNAKE) questionnaire met the study criteria. The four other measures frequently used in children with CP had no psychometric data available for their use in children with CP. The SNAKE questionnaire has been validated only in children with CP in Gross Motor Function Classification System level V. The Sleep Disturbance Scale for Children and the Pediatric Sleep Questionnaire had the strongest psychometric properties in typically developing children, but has not yet been validated in children with CP. INTERPRETATION: Current sleep measures being administered in typically developing children are also often used in children with CP, but have not been well validated in this group of children. WHAT THIS PAPER ADDS: There are no condition specific measures of sleep in children with cerebral palsy (CP). The Schlaffragebogen für Kinder mit Neurologischen und Anderen Komplexen Erkrankungen (SNAKE) questionnaire is validated for children with CP in Gross Motor Function Classification System level V. A framework to design a CP specific sleep questionnaire is provided.

PREDICT-CP: study protocol of implementation of comprehensive surveillance to predict outcomes for school-aged children with cerebral palsy.

OBJECTIVES: Cerebral palsy (CP) remains the world's most common childhood physical disability with total annual costs of care and lost well-being of $A3.87b. The PREDICT-CP (NHMRC 1077257 Partnership Project: Comprehensive surveillance to PREDICT outcomes for school age children with CP) study will investigate the influence of brain structure, body composition, dietary intake, oropharyngeal function, habitual physical activity, musculoskeletal development (hip status, bone health) and muscle performance on motor attainment, cognition, executive function, communication, participation, quality of life and related health resource use costs. The PREDICT-CP cohort provides further follow-up at 8-12 years of two overlapping preschool-age cohorts examined from 1.5 to 5 years (NHMRC 465128 motor and brain development; NHMRC 569605 growth, nutrition and physical activity). METHODS AND ANALYSES: This population-based cohort study undertakes state-wide surveillance of 245 children with CP born in Queensland (birth years 2006-2009). Children will be classified for Gross Motor Function Classification System; Manual Ability Classification System, Communication Function Classification System and Eating and Drinking Ability Classification System. Outcomes include gross motor function, musculoskeletal development (hip displacement, spasticity, muscle contracture), upper limb function, communication difficulties, oropharyngeal dysphagia, dietary intake and body composition, participation, parent-reported and child-reported quality of life and medical and allied health resource use. These detailed phenotypical data will be compared with brain macrostructure and microstructure using 3 Tesla MRI (3T MRI). Relationships between brain lesion severity and outcomes will be analysed using multilevel mixed-effects models. ETHICS AND DISSEMINATION: The PREDICT-CP protocol is a prospectively registered and ethically accepted study protocol. The study combines data at 1.5-5 then 8-12 years of direct clinical assessment to enable prediction of outcomes and healthcare needs essential for tailoring interventions (eg, rehabilitation, orthopaedic surgery and nutritional supplements) and the projected healthcare utilisation. TRIAL REGISTRATION NUMBER: ACTRN: 12616001488493.

Safety of Botulinum Toxin Type A for Children With Nonambulatory Cerebral Palsy.

OBJECTIVE: To determine safety of intramuscular botulinum toxin A (BoNT-A) injections to reduce spasticity and improve care and comfort of nonambulatory children with cerebral palsy (CP). METHODS: Nonambulatory children with CP were randomly allocated to receive either BoNT-A (n = 23) or sham procedure (n = 18) in Cycle 1. In Cycle 2, the BoNT-A group received a second episode of BoNT-A (n = 20) and sham group received their first episode of BoNT-A (n = 17). A pediatric rehabilitation specialist masked to group allocation graded each adverse event (AE) according to system, severity (mild, moderate, serious, sentinel) and causality (unlikely/unrelated; possible; probable/definite). RESULTS: There was no difference for all moderate/serious AEs between the BoNT-A and sham/control groups in either Cycle 1 (incident rate ratio = 1.30, 95% confidence interval = 0.43-4.00; P = .64) or Cycle 2 (incident rate ratio = 0.72, 95% confidence interval = 0.30-1.75; P = .47). In Cycle 2, 1 serious, 3 moderate (single-episode group), and 24 mild (single-episode group n = 10; 2 episode group n = 14) AEs were probably/definitely related to BoNT-A. CONCLUSIONS: Children receiving BoNT-A were at no greater risk of moderate/serious AEs compared with a sham control procedure. There was no increased risk of moderate/serious AEs between one and two episodes of BoNT-A.

Optimal management of complications associated with achondroplasia.

Achondroplasia is the most common form of skeletal dysplasia, resulting in disproportionate short stature, and affects over 250,000 people worldwide. Individuals with achondroplasia demonstrate a number of well-recognized anatomical features that impact on growth and development, with a complex array of medical issues that are best managed through a multidisciplinary team approach. The complexity of this presentation, whereby individual impairments may impact upon multiple activity and participation areas, requires consideration and discussion under a broad framework to gain a more thorough understanding of the experience of this condition for individuals with achondroplasia. This paper examines the general literature and research evidence on the medical and health aspects of individuals with achondroplasia and presents a pictorial model of achondroplasia based on The International Classification of Functioning, Disability, and Health (ICF). An expanded model of the ICF will be used to review and present the current literature pertaining to the musculoskeletal, neurological, cardiorespiratory, and ear, nose, and throat impairments and complications across the lifespan, with discussion on the impact of these impairments upon activity and participation performance. Further research is required to fully identify factors influencing participation and to help develop strategies to address these factors.

Botulinum toxin A for nonambulatory children with cerebral palsy: a double blind randomized controlled trial.

OBJECTIVES: To examine the efficacy and safety of intramuscular botulinum toxin A (BoNT-A) to reduce spasticity and improve comfort and ease of care in nonambulant children with cerebral palsy (CP). STUDY DESIGN: Nonambulant children with CP (n = 41; Gross Motor Function Classification System level IV = 3, level V = 38; mean age 7.1 years, range 2.3-16 years, 66% male) were randomly allocated to receive either intramuscular BoNT-A injections (n = 23) or sham procedure (n = 18) combined with therapy. The analysis used generalized estimating equations with primary outcome the Canadian Occupational Performance Measure (COPM) at 4 weeks postintervention and retention of effects at 16 weeks. Adverse events (AE) were collected at 2, 4, and 16 weeks by a physician masked to group allocation. RESULTS: There were significant between group differences favoring the BoNT-A-treated group on COPM performance at 4 weeks (estimated mean difference 2.2, 95% CI 0.8, 3.5; P = .002) and for COPM satisfaction (estimated mean difference 2.2, 95% CI 0.5, 3.9; P = .01). These effects were retained at 16 weeks for COPM satisfaction (estimated mean difference 1.8, 95% CI 0.1, 3.5; P = .04). There were more mild AE at 4 weeks for the BoNT-A group (P = .002), however, there were no significant between-group differences in the reporting of moderate and serious AE. CONCLUSIONS: In a double-blind randomized sham-controlled trial, intramuscular BoNT-A and therapy were effective for improving ease of care and comfort for nonambulant children with CP. There was no increase in moderate and severe AE in the children who had BoNT-A injections compared with the sham group.

Salivary gland botulinum toxin injections for drooling in children with cerebral palsy and neurodevelopmental disability: a systematic review.

AIM: The aim of this paper was to systematically review the efficacy and safety of botulinum toxin (BoNT) injections to the salivary glands to treat drooling in children with cerebral palsy and neurodevelopmental disability. METHOD: A systematic search of The Cochrane Central Register of Controlled Trials, PubMed, CINAHL (Cumulative Index to Nursing and Allied Health Literature), EMBASE, and the Physiotherapy Evidence Database (PEDro) was conducted (up to 1 October 2011). Data sources included published randomized controlled trials (RCTs) and prospective studies. RESULTS: Sixteen studies met inclusion criteria. Three outcome measures support the effectiveness of BoNT for drooling. One RCT found an almost 30% reduction in the impact of drooling on patients' lives, as measured by the Drooling Impact Scale (mean difference -27.45; 95% confidence interval [CI] -35.28 to -19.62). There were sufficient data to pool results on one outcome measure, the Drooling Frequency and Severity Scale, which supports this result (mean difference -2.71; 95% CI -4.82 to -0.60; p<0.001). There was a significant reduction in the observed number of bibs required per day. The incidence of adverse events ranged from 2 to 41%, but was inconsistently reported. One trial was terminated early because of adverse events. INTERPRETATION: BoNT is an effective, temporary treatment for sialorrhoea in children with cerebral palsy. Benefits need to be weighed against the potential for serious adverse events. More studies are needed to address the safety of BoNT and to compare BoNT with other treatment options for drooling.

Evaluation of the effects of botulinum toxin A injections when used to improve ease of care and comfort in children with cerebral palsy whom are non-ambulant: a double blind randomized controlled trial.

BACKGROUND: Children with cerebral palsy (CP) whom are non-ambulant are at risk of reduced quality of life and poor health status. Severe spasticity leads to discomfort and pain. Carer burden for families is significant. This study aims to determine whether intramuscular injections of botulinum toxin A (BoNT-A) combined with a regime of standard therapy has a positive effect on care and comfort for children with CP whom are non-ambulant (GMFCS IV/V), compared with standard therapy alone (cycle I), and whether repeated injections with the same regime of adjunctive therapy results in greater benefits compared with a single injecting episode (cycle II). The regime of therapy will include serial casting, splinting and/or provision of orthoses, as indicated, combined with four sessions of goal directed occupational therapy or physiotherapy. METHOD/DESIGN: This study is a double blind randomized controlled trial. Forty participants will be recruited. In cycle I, participants will be randomized to either a treatment group who will receive BoNT-A injections into selected upper and/or lower limb muscles, or a control group who will undergo sham injections. Both groups will receive occupational therapy and /or physiotherapy following injections. Groups will be assessed at baseline then compared at 4 and 16 weeks following injections or sham control. Parents, treating clinicians and assessors will be masked to group allocation. In cycle II, all participants will undergo intramuscular BoNT-A injections to selected upper and/or lower limb muscles, followed by therapy.The primary outcome measure will be change in parent ratings in identified areas of concern for their child's care and comfort, using the Canadian Occupational Performance Measure (COPM). Secondary measures will include the Care and Comfort Hypertonicity Scale (ease of care), the Cerebral Palsy Quality of Life Questionnaire (CP QoL-Child) (quality of life), the Caregiver Priorities and Child Health Index of Life with Disabilities Questionnaire (CPCHILD©) (health status) and the Paediatric Pain Profile (PPP) (pain). Adverse events will be carefully monitored by a clinician masked to group allocation. DISCUSSION: This paper outlines the theoretical basis, study hypotheses and outcome measures for a trial of BoNT-A injections and therapy for children with non-ambulant CP. TRIAL REGISTRATION: Australia New Zealand Clinical Trials Registry:N12609000360213.