Randomised controlled trial of an online cognitive training program in school-aged children with cerebral palsy.

BACKGROUND: Children with cerebral palsy (CP) experience deficits in nonverbal reasoning. The SMART online cognitive intervention has been associated with gains in IQ and nonverbal IQ in previous studies in typically developing school-aged children and children experiencing learning difficulties. AIM: To assess the efficacy of an online cognitive intervention in school-aged children with CP. METHODS AND PROCEDURES: 21 children with CP (male n = 17; 76.2%), mean age 9 y 8 m, SD 1 y 1 month (range 8 y 3 m to 12 y 6 m) were randomised into the intervention group (n = 9) or a waitlist control group. A mixed-methods approach with an explanatory sequential design was used, with a randomised controlled trial followed by qualitative interviews. Participants were assessed on measures of intelligence, academic ability, attention and executive functioning, and social-emotional functioning at baseline, then after completing the training, or the waitlist period. Analyses included ANCOVAs and paired samples t tests. Semi-structured interviews explored participants' experiences with the training. RESULTS AND OUTCOMES: Training completion was low with a mean of 16.9 modules completed out of 55 available. No significant effect of training was found for the primary outcome of intelligence, or for any secondary outcomes. Participants reported barriers and facilitators for accessing the program. IMPLICATIONS: Cognitive training programs addressing relational framing ability may require significant modifications before they can be effectively tested with children with CP.

Constructing validity evidence from a pilot key-features assessment of clinical decision-making in cerebral palsy diagnosis: application of Kane's validity framework to implementation evaluations.

BACKGROUND: Physician decision-making skills training is a priority to improve adoption of the cerebral palsy (CP) clinical guideline and, through this, lower the age of CP diagnosis. Clinical guideline implementation aims to improve physician practice, but evaluating meaningful change is complex. Limitations in the validity evidence of evaluation instruments impact the evidence base. Validity frameworks, such as Kane's, enable a targeted process to gather evidence for instrument scores, congruent to context and purpose. Yet, application of argument-based methodology to implementation validation is rare. Key-features examination methodology has established validity evidence supporting its use to measure decision-making skills, with potential to predict performance. We aimed to apply Kane's framework to evaluate a pilot key-features examination on physician decision-making in early CP diagnosis. METHODS: Following Kane's framework, we evaluated evidence across inferences of scoring, generalisation, extrapolation and implications in a study design describing the development and pilot of a CP diagnosis key-features examination for practising physicians. If found to be valid, we proposed to use the key-feature scores as an outcome measure of decision-making post education intervention to expedite CP diagnosis and to correlate with real-world performance data to predict physician practice. RESULTS: Supporting evidence for acceptance of scoring inferences was achieved through examination development with an expert group (n = 10) and pilot results (n = 10): (1) high internal consistency (0.82); (2) acceptable mean item-discrimination (0.34); and (3) acceptable reliability of examination scorers (95.2% congruence). Decreased physician acceptance of examination time (70%) was identified as a threat and prioritised in case reduction processes. Partial acceptance of generalisation, extrapolation and implications inferences were defensible with: (1) accumulated development evidence following established key-features methodology; (2) high pilot acceptance for authenticity (90%); and (3) plausibility of assumptions of score correlation with population register data. CONCLUSIONS: Kane's approach is beneficial for prioritising sources of validity evidence alongside the iterative development of a key-features examination in the CP field. The validity argument supports scoring assumptions and use of scores as an outcome measure of physician decision-making for CP guideline education implementation interventions. Scoring evidence provides the foundation to direct future studies exploring association of key-feature scores with real-world performance.

Cognition and learning difficulties in a representative sample of school-aged children with cerebral palsy.

BACKGROUND: Nearly half of all children with CP experience intellectual impairment, with impacts on academic achievement. AIMS: To assess cognitive and academic functioning for primary-school aged children with CP METHODS AND PROCEDURES: This population-based cohort study assessed 93 participants (male n = 62; mean = 9 years 9 months, SD 1 y 1.8 months) on measures of fluid and crystallised intelligence (Raven's Coloured Progressive Matrices, Peabody Picture Vocabulary Test) and academic achievement (Wechsler Individual Achievement Test). Analyses included t-tests, Pearson's chi-square and regression. OUTCOMES AND RESULTS: 41 (44.1%) children met criteria consistent with intellectual developmental disorder. Academic skills were significantly below population means on word reading (M= 85.4, SD = 19.3), t(66) = -6.2, p < .001; spelling (M=83.3, SD=19.7) t(65) = -6.87, p < .001; and numerical operations (M=72.9, SD=21.7) Z = 66.0, p < .001. Cognitive ability was associated with GMFCS level (χ² (1, N = 93) = 16.15, p < .001) and diagnosis of epilepsy (χ² (2, N = 93) = 11.51 p = .003). Crystallised and fluid intelligence together accounted for 65% of the variance in word reading, 56% in spelling and 52% in numerical operations. IMPLICATIONS: Many children with CP experience academic challenges. Screening is recommended for all children with CP and full psychoeducational assessment undertaken when children with CP experience academic difficulties.

Automating Quantitative Measures of an Established Conventional MRI Scoring System for Preterm-Born Infants Scanned between 29 and 47 Weeks' Postmenstrual Age.

BACKGROUND AND PURPOSE: Conventional MR imaging scoring is a valuable tool for risk stratification and prognostication of outcomes, but manual scoring is time-consuming, operator-dependent, and requires high-level expertise. This study aimed to automate the regional measurements of an established brain MR imaging scoring system for preterm neonates scanned between 29 and 47 weeks' postmenstrual age. MATERIALS AND METHODS: This study used T2WI from the longitudinal Prediction of PREterm Motor Outcomes cohort study and the developing Human Connectome Project. Measures of biparietal width, interhemispheric distance, callosal thickness, transcerebellar diameter, lateral ventricular diameter, and deep gray matter area were extracted manually (Prediction of PREterm Motor Outcomes study only) and automatically. Scans with poor quality, failure of automated analysis, or severe pathology were excluded. Agreement, reliability, and associations between manual and automated measures were assessed and compared against statistics for manual measures. Associations between measures with postmenstrual age, gestational age at birth, and birth weight were examined (Pearson correlation) in both cohorts. RESULTS: A total of 652 MRIs (86%) were suitable for analysis. Automated measures showed good-to-excellent agreement and good reliability with manual measures, except for interhemispheric distance at early MR imaging (scanned between 29 and 35 weeks, postmenstrual age; in line with poor manual reliability) and callosal thickness measures. All measures were positively associated with postmenstrual age (r = 0.11-0.94; R2 = 0.01-0.89). Negative and positive associations were found with gestational age at birth (r = -0.26-0.71; R2 = 0.05-0.52) and birth weight (r = -0.25-0.75; R2 = 0.06-0.56). Automated measures were successfully extracted for 80%-99% of suitable scans. CONCLUSIONS: Measures of brain injury and impaired brain growth can be automatically extracted from neonatal MR imaging, which could assist with clinical reporting.

Validation of an MRI Brain Injury and Growth Scoring System in Very Preterm Infants Scanned at 29- to 35-Week Postmenstrual Age.

BACKGROUND AND PURPOSE: The diagnostic and prognostic potential of brain MR imaging before term-equivalent age is limited until valid MR imaging scoring systems are available. This study aimed to validate an MR imaging scoring system of brain injury and impaired growth for use at 29 to 35 weeks postmenstrual age in infants born at <31 weeks gestational age. MATERIALS AND METHODS: Eighty-three infants in a prospective cohort study underwent early 3T MR imaging between 29 and 35 weeks' postmenstrual age (mean, 32+2 ± 1+3 weeks; 49 males, born at median gestation of 28+4 weeks; range, 23+6-30+6 weeks; mean birthweight, 1068 ± 312 g). Seventy-seven infants had a second MR scan at term-equivalent age (mean, 40+6 ± 1+3 weeks). Structural images were scored using a modified scoring system which generated WM, cortical gray matter, deep gray matter, cerebellar, and global scores. Outcome at 12-months corrected age (mean, 12 months 4 days ± 1+2 weeks) consisted of the Bayley Scales of Infant and Toddler Development, 3rd ed. (Bayley III), and the Neuro-Sensory Motor Developmental Assessment. RESULTS: Early MR imaging global, WM, and deep gray matter scores were negatively associated with Bayley III motor (regression coefficient for global score ß = -1.31; 95% CI, -2.39 to -0.23; P = .02), cognitive (ß = -1.52; 95% CI, -2.39 to -0.65; P < .01) and the Neuro-Sensory Motor Developmental Assessment outcomes (ß = -1.73; 95% CI, -3.19 to -0.28; P = .02). Early MR imaging cerebellar scores were negatively associated with the Neuro-Sensory Motor Developmental Assessment (ß = -5.99; 95% CI, -11.82 to -0.16; P = .04). Results were reconfirmed at term-equivalent-age MR imaging. CONCLUSIONS: This clinically accessible MR imaging scoring system is valid for use at 29 to 35 weeks postmenstrual age in infants born very preterm. It enables identification of infants at risk of adverse outcomes before the current standard of term-equivalent age.

Measurements of the T(t,2n)4He neutron spectrum at low reactant energies from inertial confinement implosions.

Measurements of the neutron spectrum from the T(t,2n)4He (tt) reaction have been conducted using inertial confinement fusion implosions at the OMEGA laser facility. In these experiments, deuterium-tritium (DT) gas-filled capsules were imploded to study the tt reaction in thermonuclear plasmas at low reactant center-of-mass (c.m.) energies. In contrast to accelerator experiments at higher c.m. energies (above 100 keV), these results indicate a negligible n + 5He reaction channel at a c.m. energy of 23 keV.

Evidence for stratification of deuterium-tritium fuel in inertial confinement fusion implosions.

Measurements of the D(d,p)T (dd) and T(t,2n)(4)He (tt) reaction yields have been compared with those of the D(t,n)(4)He (dt) reaction yield, using deuterium-tritium gas-filled inertial confinement fusion capsule implosions. In these experiments, carried out on the OMEGA laser, absolute spectral measurements of dd protons and tt neutrons were obtained. From these measurements, it was concluded that the dd yield is anomalously low and the tt yield is anomalously high relative to the dt yield, an observation that we conjecture to be caused by a stratification of the fuel in the implosion core. This effect may be present in ignition experiments planned on the National Ignition Facility.

Supernovae and the chirality of the amino acids.

A mechanism for creating amino acid enantiomerism that always selects the same large-scale chirality is identified, and subsequent chemical replication and galactic mixing that would populate the Galaxy with the predominant species is described. This involves (1) the spin of the 14N in the amino acids, or in precursor molecules from which amino acids might be formed, that couples to the chirality of the molecules; (2) the neutrinos emitted from the supernova, together with the magnetic field from the nascent neutron star or black hole formed from the supernova, which selectively destroy one orientation of the 14N and thus select the chirality associated with the other 14N orientation; (3) chemical evolution, by which the molecules replicate and evolve to more complex forms of a single chirality on a relatively short timescale; and (4) galactic mixing on a longer timescale that mixes the selected molecules throughout the Galaxy.

Hip surveillance in children with cerebral palsy. Impact on the surgical management of spastic hip disease.

We studied prospectively the impact of a hip surveillance clinic on the management of spastic hip disease in children with cerebral palsy in a tertiary referral centre. Using a combination of primary clinical and secondary radiological screening we were able to detect spastic hip disease at an early stage in most children and to offer early surgical intervention. The principal effect on surgical practice was that more preventive surgery was carried out at a younger age and at a more appropriate stage of the disease. The need for reconstructive surgery has decreased and that for salvage surgery has been eliminated. Displacement of the hip in children with cerebral palsy meets specific criteria for a screening programme. We recommend that hip surveillance should become part of the routine management of children with cerebral palsy. The hips should be examined radiologically at 18 months of age in all children with bilateral cerebral palsy and at six- to 12-monthly intervals thereafter. A co-ordinated approach by orthopaedic surgeons and physiotherapists may be the key to successful implementation of this screening programme.

Current evidence for the use of botulinum toxin type A in the management of children with cerebral palsy: a systematic review.

Management of children with cerebral palsy (CP) is the focus of considerable resources in many countries, so that evaluation of the efficacy for new and established treatments is imperative. Botulinum toxin type A (BTX-A) is a relatively new method of spasticity management in children with cerebral palsy. It has been the focus of extensive research since its application to cerebral palsy 10 years ago. In a systematic review relating to the management of the lower limb in cerebral palsy 156 papers were identified. These were categorized according to Sackett and the World Health Organisation International Classification of Impairments, Disabilities and Handicaps model. We identified 10 randomized trials evaluating the use of BTX-A in the lower limb in children with cerebral palsy in a systematic review. A meta-analysis showed the pooled risk difference between BTX-A and placebo in three trials was 0.25 (95% CI 0.13, 0.37) and 0.23 (95% CI -0.06, 0.53) for two trials of BTX-A and casting using the physicians rating scale. These represent moderate treatment effects that are dosage-dependent. Outcomes were also compared for function in five studies. The type of evidence for BTX-A was graded by each treatment indication and directions for future research were then drawn from the available evidence.

The effect of botulinum toxin type A and a variable hip abduction orthosis on gross motor function: a randomized controlled trial.

Hip displacement is the second most common deformity after equinus in children with cerebral palsy (CP), and may result in dislocation, pain, fixed deformity and loss of function. We studied the combined effects of intramuscular injections of botulinum toxin type A (BTX-A) to the adductors and hamstrings and a variable hip abduction orthosis (SWASH), on gross motor function, hip displacement and progression to surgery, in a randomized clinical trial. Thirty-nine children, with bilateral spastic cerebral palsy, and mean age 3 years + 2 months (range 1 year+7 months--4 years +10 months) entered the trial. Gross Motor Function Classification System (GMFCS) levels were as follows: one child was level II, 11 were level III, 13 were level IV and 14 were level V. After concealed randomization, 20 were allocated to the control group and 19 to the intervention group. Thirty-five children completed the follow up at 1 year. The novel intervention group received up to 4.0 U BOTOX/kg/muscle, 16 U/kg/body weight every 6 months plus the use of a SWASH brace. The control group received clinical best practice comprising physiotherapy but no hip abduction bracing. Both groups showed improvements in total Gross Motor Function Measure (GMFM) score [mean 6.0% BTX-A group; 6.1% Control; 95% CI -- 6.7, 6.5 (NS)], however, there was no additional treatment effect for the study group. There were similar improvements on GMFM goal scores and GMFM-66 scores, but again no additional treatment effect was observed. Multiple regression of change in total GMFM by GMFCS classification for each group showed greater improvement in the total scores from baseline in the BTX-A/SWASH treated group than the control group. In the first year, nine children (two in the intervention group and seven in the control group) required soft tissue surgery because of progressive hip migration in excess of 40%. A longer-term follow up of a larger cohort may be required to determine the effect of the combined treatment on hip displacement.

Management of upper limb dysfunction in children with cerebral palsy: a systematic review.

Effective use of the upper limb can impact on educational outcomes, participation in activities of daily living and vocational options for many children with cerebral palsy (CP). This article presents the results of a systematic review of the literature on the management of upper limb dysfunction in children with CP. The range of management options includes therapies such as physiotherapy, occupational therapy, neurodevelopmental therapy and conductive education; peripheral splinting and casting; focal or generalized pharmacotherapy; and surgery to improve upper limb function or correct deformity. A literature search identified 60 papers, of which four were randomized controlled trials and 44 were prospective studies with objective outcome measures. Principal studies undertaken for each type of treatment and the efficacy of the different types of treatment were critically evaluated. In addition, the current level of evidence for each study was evaluated according to Sackett's (1989) model and ICIDH-2 classification. A close examination of two relatively new treatments for upper limb spasticity, constraint induced movement therapy and botulinum toxin type A (BTX-A) was conducted with reference to more extensive data on the efficacy of BTX-A in the lower limb.

Outcome measurement of effectiveness of botulinum toxin type A in children with cerebral palsy: an ICIDH-2 approach.

The ICIDH-2 serves as a useful framework for differentiating measurement by dimensions of the disabling process. Such differentiation is important to achieve more valid measurement of health related outcomes. We have attempted to examine one intervention, treatment with botulinum toxin type A, for one patient population, children with cerebral palsy, and to describe the outcome measures used in the evaluation of that intervention using this evolving classification system. This process supports the concept that measurement of health outcomes should focus on the nature and extent of functional limitations in physical, social and psychological domains. The selection of measurement outcomes must be determined not only by the requirements of the scientific process but also by the needs of the patients who are the intended beneficiaries of the intervention.

Botulinum toxin type A in the management of equinus in children with cerebral palsy: an evidence-based economic evaluation.

INTRODUCTION: The aim of this study was to compare two methods of conservative management of calf spasticity and equinus gait--intramuscular injection of botulinum toxin type A (BTX-A) and serial casting. An economic evaluation framework was adopted to assess whether BTX-A offers value for money in the management of equinus gait due to calf spasticity in children with cerebral palsy. Short- to medium-term health care costs and outcomes were estimated for the comparison. This study was embarked upon to provide clinical and economic data as part of an application to the Pharmaceutical Benefits Advisory Committee (PBAC) for the reimbursement of BOTOX by the Australian Commonwealth Government. This is the primary mechanism for reimbursement of pharmaceuticals in Australia, as they are not routinely reimbursed through health insurance companies. The perspective of the analysis was that of the Australian health system. METHODOLOGY: Randomized controlled trials (RCTs) exist comparing one treatment cycle of BTX-A with serial casting (Corry et al., 1998; Flett et al., 1999). A long-term prospective study provided data on multiple cycles of BTX-A treatment in a more naturalistic setting (Boyd et al., 1999). A simple economic modelling approach was used to establish resource utilization by treatment arm. Only direct medical costs were considered (BTX-A, medical personnel time and medical consumables). MAIN MEASURES: Clinical efficacy was obtained from the randomized controlled trials (Corry et al., 1998; Flett et al., 1999). Patient/parent preference was obtained from long-term follow-up (Corry et al., 1998) and a preference questionnaire (Flett et al., 1999). Australian treatment patterns and patient demographics were obtained from the naturalistic study (Boyd et al., 1999). RESULTS: The RCTs demonstrated equivalent efficacy of BTX-A and serial casting; however, with BTX-A the effect lasted longer and was clearly the preferred treatment. For patients with hemiplegia the costs of an episode of treatment with BTX-A or serial casting are ($AUD) $595 and $435, respectively, and thus the additional costs associated with BTX-A are $160. The corresponding costs for patients with diplegia are $1045 for BTX-A treatment and $870 for serial casting and thus the additional cost associated with BTX-A is $175. With an overall treatment duration of 3.7 years and an average treatment interval of 10 months, patients would receive an average of 5.4 treatments. Thus, for patients with hemiplegia the total additional cost, discounted at 5% annually, for BTX-A is $793. For patients with diplegia the total additional cost for BTX-A is $867. CONCLUSIONS AND CLINICAL INTERPRETATIONS: BTX-A is an effective, safe and acceptable treatment modality and is associated with only a modest increase in direct medical costs per child per year. BTX-A can be considered a valuable and cost-effective treatment in the conservative management of equinus due to calf spasticity in children with cerebral palsy. This conclusion is supported by the acceptance of the Pharmaceutical Benefits Advisory Committee (PBAC) recommendation that BOTOX should attract a full Government subsidy in Australia.

Biomechanical transformation of the gastroc-soleus muscle with botulinum toxin A in children with cerebral palsy.

Objective measures (kinematics and kinetics) were used to study prospectively the effects of botulinum toxin A (BTX/A) on the gastro-soleus muscle in ambulant children with cerebral palsy. In this prospective before and after trial, 15 children with diplegia and 10 children with hemiplegia were studied (mean age 5 years 7 months, range 4 years to 9 years). A range of standardized clinical measures was undertaken but the emphasis for this report is on the three-dimensional gait analysis (3DGA) results. All children showed improvements in sagittal ankle kinematics, as has been previously reported. Two new measures of ankle kinetics were devised: ankle moment quotient (AMQ), and ankle power quotient (APQ). Before intervention, ankle moments were characterized by a 'double bump' ankle moment. A typical abnormal baseline ankle-power curve was triphasic with an initial trough of absorption followed by abnormal mid-stance power generation, instead of the usual A1 pattern, and reduced terminal stance power generation (A2). Three weeks after treatment with BTX/A alone there was a statistically significant improvement of AMQ and APQ; some patients required potentiation of BTX/A with a short period of serial casts. Both groups (BTX/A alone and BTX/A plus casting) continued to show improvement in ankle kinetics from baseline after 12 and 24 weeks. This is the first study to demonstrate improvements in the typical abnormal ankle kinetics which we believe provides evidence of the 'biomechanical transformation of muscle'.

Recommendations for the use of botulinum toxin type A in the management of cerebral palsy.

Botulinum toxin type A (BTX-A) is increasingly being used for the treatment of childhood spasticity, particularly cerebral palsy. However, until very recently, all such use in this indication has been unapproved with no generally accepted treatment protocols, resulting in considerable uncertainty and variation in its use as a therapeutic agent. In view of the increasing awareness of, and interest in, this approach to the treatment of spasticity, and also the recent licensing in a number of countries of a BTX-A preparation for treating equinus deformity in children, it would seem timely to establish a framework of guidelines for the safe and efficacious use of BTX-A for treating spasticity in children. This paper represents an attempt, by a group of 15 experienced clinicians and scientists from a variety of disciplines, to arrive at a consensus and produce detailed recommendations as to appropriate patient selection and assessment, dosage, injection technique and outcome measurement. The importance of adjunctive physiotherapy, orthoses and casting is also stressed.

Resonant Nuclear Fusion Processes and the Gamma Rays of SS 433.

Gamma-ray spectral lines have recently been reported coming from the celestial object SS 433, which is known to emit high-speed jets in opposite directions. The proposed identification of the lines as coming from fusion reactions on nitrogen nuclei as part of the carbon-nitrogen-oxygen cycle operating in the jets has now received observational support. Predictions of strengths and widths of additional lines which, if seen, would provide valuable new information about conditions giving rise to the jets are presented.