Aggregated n-of-1 trials of central nervous system stimulants versus placebo for paediatric traumatic brain injury--a pilot study.

BACKGROUND: In 2006 there were 432,700 people in Australia who had acquired brain injury (ABI) with some limitation of activities; 90% of these were traumatic brain injuries (TBIs) and nearly a third sustained injury below age 15 years. One to four years post injury, 20% to 46% of children with traumatic brain injury (TBI) have clinically significant disorders of attention. There is controversy as to whether central nervous system (CNS) stimulants can be an effective method of treating these.Objectives were to determine the efficacy of CNS stimulants for children with TBI, and to calculate the sample size for a larger trial using the Conners' 3 Parent Rating Scales Score as the primary endpoint. METHODS: Pilot series of aggregated prospective randomised, double-blind, n-of-1 trials of stimulant versus placebo within individual patients. SETTING: tertiary children's public hospital. PARTICIPANTS: ten children aged 6 to 16 years more than 12 months post TBI with attention, concentration and behavioral difficulties on stimulants. INTERVENTIONS: Three cycles of methylphenidate or dexamphetamine orally at doses titrated by physician compared to placebo. MAIN OUTCOME MEASURES: Conners 3 Parent (Conners 3-P) and Teacher (Conners 3-T) Rating Scales (Global Index), Behaviour Rating Inventory of Executive Function (BRIEF) and Eyberg Child Behaviour Inventory (ECBI). RESULTS: Five of ten patients completed the study. Data from 18 completed cycles from seven patients were analysed. The posterior mean difference between stimulant and placebo scores for the Conners 3-PS (Global Index) was 2.3 (SD 6.2; 95% credible region -1.0 to 6.1; posterior probability that this mean difference was greater than zero was 0.92), and for the Conners 3-T (Global Index) the posterior mean difference was 5.9 (SD 4.5; 95% credible region -3.1 to 14.9; posterior probability 0.93). Posterior mean differences suggest improvement in behaviour and executive function and a decrease in number and intensity of child behaviour problems when taking stimulants compared to placebo. Taken together these data are suggestive of a small benefit at group level. CONCLUSIONS: In this pilot study, there was sufficient evidence that stimulants may be useful in management of behavioral and cognitive sequelae following TBI, to warrant a larger trial. TRIAL REGISTRATION: he trial was registered with the Australian and New Zealand Clinical Trials Registry: registration number ACTRN12609000873224.

Evaluation of bone mineral density and morphology using pQCT in children after spinal cord injury.

OBJECTIVE: To evaluate the effects of spinal cord injury (SCI) on bone density and morphology in children using peripheral quantitative computer tomography (pQCT). DESIGN: Retrospective cohort study of 19 paediatric patients with SCI (9 paraplegics and 10 tetraplegics). RESULTS: There was significant reduction in tibial metaphysial volumetric bone mineral density (vBMD), diaphysial cortical cross-sectional area (CSA), cortical thickness and polar strength-strain index. There was a significant loss of calf muscle CSA. Those who were able to stand had greater trabecular vBMD, tibial cortical thickness and tibial muscle CSA Z-scores. Lower limb fractures did not occur if tibial trabecular vBMD was greater than 100 mg/cm³. Tibial geometry following SCI was more circular compared to controls. CONCLUSIONS: pQCT provides a valuable insight into the regional changes in bone and muscle development in children following SCI. Residual muscle function with the ability to weight bear provides a significant benefit to bone development.

Adverse events and health status following botulinum toxin type A injections in children with cerebral palsy.

AIM: The aim of this study was to assess changes in health status before and after, as well as adverse events after, botulinum toxin type A (BoNT-A) injections in children with cerebral palsy (CP). METHOD: A total of 334 children (190 male; 144 female) aged 1y 6mo to 19y 4mo (mean 9y 2mo, SD 4y) with CP who were undergoing BoNT-A injections (596 injection courses in total) were clinically audited over a 16-month period. Of the 334 children, 62 were classified at Gross Motor Function Classification System (GMFCS) level I, 52 of whom had unilateral CP and 10 of whom had bilateral CP. Eighty-six children were classified at GMFCS level II, 39 of whom had unilateral CP and 47 of whom had bilateral CP. Forty-four children were classified at GMFCS level III, two of whom had unilateral CP and 42 of whom had bilateral CP. Sixty-six of the 334 children were classified at GMFCS level IV and 76 as level V. All the children classified as level IV or V had bilateral involvement. The health status of the children in the month before and a prospective audit of health status and adverse events in the month after BoNT-A injections were examined in order to assess the effects of the toxin. RESULTS: The data gathered for the month before administration of BoNT-A indicated that children with CP had significant background morbidities. After injection of BoNT-A, adverse events occurred in 23.2% of children. All adverse events were temporary and there were no deaths. INTERPRETATION: The results of this audit indicate that there is insufficient evidence to warrant restriction of the administration of BoNT-A in children with CP at any GMFCS level in our service.

Regional changes in bone mineral density following spinal cord injury in children.

OBJECTIVE: To document the serial changes in bone mineral density (BMD) following paediatric spinal cord injury (SCI). DESIGN: Retrospective case series. SETTING: Paediatric tertiary care hospital. PATIENTS: Eighteen children (nine males) followed in an outpatient spinal cord injury service. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE: Serial bone mineral density (BMD) measurements using dual energy X-ray absorptiometry (DXA). RESULTS: Mean follow-up was 5.0 +/- 3.6 years (range 0.4-12.4 years). Three children sustained minimal trauma fractures, all femoral. For the cohort, BMD Z-scores were significantly less than zero in the legs (-2.7 +/- 2.0, p < 0.001), femoral neck (-2.1 +/- 1.4, p < 0.001), total body (-0.8 +/- 1.3, p=0.02) and lumbar spine (-0.8 +/- 1.6, p=0.04), but not in the arms (-0.2 +/- 1.0, p=0.5). Lean tissue mass (LTM) Z-scores were reduced in the legs (-1.9 +/- 1.3, p < 0.001). Longitudinal data showed an initial decline in lower extremity BMD, BMC and LTM aged-matched Z-scores in the 12 months following SCI, followed by an age appropriate increase thereafter. CONCLUSIONS: Lower extremity osteopenia and sarcopenia develop rapidly in the first 12 months following the SCI. The reduced bone strength increases the risk of low trauma fracture.

Functional outcomes of intramuscular botulinum toxin type a and occupational therapy in the upper limbs of children with cerebral palsy: a randomized controlled trial.

OBJECTIVE: To investigate the functional outcomes of botulinum toxin type A (BTX-A) injections to the upper limb in combination with occupational therapy (OT) in children with cerebral palsy (CP). DESIGN: Randomized controlled trial with follow-up at 2 weeks, 3 months, and 6 months. SETTING: Specialist outpatient physical disabilities clinic within a public pediatric teaching hospital. PARTICIPANTS: Eighty children with spastic quadriplegic, triplegic, or hemiplegic CP from these clinics were randomly assigned to BTX-A plus OT, BTX-A alone, OT alone, or a no-treatment control group. INTERVENTIONS: Single set of BTX-A (Botox) injections and 12 weeks of OT. MAIN OUTCOME MEASURES: Canadian Occupational Performance Measure (COPM) and Goal Attainment Scale (GAS). RESULTS: The combination of BTX-A and OT resulted in accelerated attainment of functional goals measured by the COPM and GAS. There were no differences between groups on the Melbourne Assessment of Unilateral Upper Limb Function, Quality of Upper Extremity Skills Test, Pediatric Evaluation of Disability Inventory, Child Health Questionnaire, or active and passive range of motion. As expected, there was a significant reduction in muscle tone at follow-up 2 weeks after injection, which returned to baseline level by 6 months. CONCLUSIONS: OT enhanced individualized functional outcomes following BTX-A injections in the upper limbs of children with CP.

Functional outcomes of intramuscular botulinum toxin type A in the upper limbs of children with cerebral palsy: a phase II trial.

OBJECTIVE: To describe the functional and family-centered assessment protocol and outcomes of a phase II trial evaluating upper-limb function after botulinum toxin injections in children with cerebral palsy (CP). DESIGN: Intervention study, case series, phase II trial, follow-up at 2 weeks and 3 and 6 months. SETTING: Specialist outpatient physical disabilities clinic within a public pediatric teaching hospital. PARTICIPANTS: Convenience sample of 16 children with CP (age range, 2-12y). INTERVENTIONS: Botulinum toxin type A (Botox) injections after electrical stimulation localization of appropriate muscle. MAIN OUTCOME MEASURES: The Canadian Occupational Performance Measure (COPM), Goal Attainment Scale (GAS), Melbourne Assessment of Unilateral Upper Limb Function, Child Health Questionnaire (CHQ), parent questionnaire, Modified Ashworth Scale (MAS), Tardieu scale, and active (AROM) and passive (PROM) range of motion. RESULTS: On the COPM, there was significant improvement at 3 months and 6 months. On the GAS, the T-scores were 42 and 47 at 3 and 6 months, respectively. On the Melbourne Assessment and CHQ, there was no significant change. The parent questionnaire indicated acceptability of injections and positive outcomes. On the MAS, there was a significant reduction in tone at 2 weeks, with a return to baseline by 6 months. On the Tardieu scale, there was a significant increase in angle of first catch at 2 weeks, but only the elbow maintained a significant difference at 3 and 6 months. No significant change was found for AROM or PROM. CONCLUSIONS: Sustained functional outcomes occurred after botulinum toxin injections despite increasing muscle tone after an initial reduction in tone. Randomized controlled trials are required.