The effect of botulinum toxin-A on the functional ability of young children with spastic hemiplegia due to cerebral palsy

Abstract

The purpose of this thesis is to determine the impact of very early-start injection of botulinum toxin-A (BoNT-A) on the quality of movement and the functional ability of children with hemiplegic cerebral palsy (CP). Traditionally, physiotherapy either with or without orthotic management has always been the mainstay of attempts to reduce muscle tone and improve function in children with CP. Several studies have demonstrated that injections of BoNT-A were effective in reducing spasticity in children with CP, and perhaps effective in preventing or reducing fixed muscle contracture, yet the tendency in published studies has been to concentrate on the outcomes of impairment (spasticity and range of movement measures) rather than on disability or functional ability.Over an extended period of time (1997–2008) two longitudinal, matched-pair, randomised, controlled trials (RCTs) were conducted to investigate the effect of BoNT-A on functional ability in children with spastic CP. The first matched-pair RCT in ambulant children with spastic hemiplegia due to CP was conducted between 1997 and 1999, and published in 2001. The aim was to determine the impact of BoNT-A on functional ability and gait. The length of time of the response to BoNTA was measured using the Modified Ashworth Scale (MAS), and the ratio of dynamic range of movement (R1) to static muscle length (R2). Functional ability was measured using the 88-item Gross Motor Function Measure (GMFM-88) and parental report. Although the subjects were matched on three separate and distinct criteria, there was significant variation in the degree and type of disability between the matched pairs. To enable the reporting of absolute measures of change to be clinically meaningful, an adjunct method of reporting outcomes (proportional change) was developed. This allowed change following intervention to be expressed in a manner that is both individualised and generalisable.This RCT demonstrated that the reduction in spasticity brought about by BoNT-A appeared to lead to a clinically significant acceleration of motor progress and improvement in walking patterns in children with spastic hemiplegia, aged between three and 13 years. Satisfaction was greater in the parents of recipients than in the parents of controls, but this may have been a placebo effect since their satisfaction did not correlate with the amount of improvement in spasticity or function in their child. The significant functional improvement documented after the injection of BoNT-A lasted longer than the pharmacological effect and there were no adverse events related to BoNT-A.These findings were included in pivotal submissions by Allergan Pty Ltd, the manufacturer of BOTOX® (the brand of BoNT-A used in the studies) as evidence, firstly to the Therapeutic Goods Administration, requesting approval for the use of BoNT-A in spastic equinus in children with CP aged two years and older, and secondly to the Australian Government, requesting Pharmaceutical Benefits Schemelisting for BoNT-A. Both submissions were successful. The submissions have resulted in BoNT-A being a recommended clinical intervention in Australia for the treatment of spastic equinus in children with CP over two years of age and the provision of government rebate or subsidy for BoNT-A when used for this indication.The finding of functional improvement in this first study also provided the justification for the second study presented in this dissertation: an investigation into the use of BoNT-A to facilitate functional gain in children with CP younger than two years of age.A second matched-pair, RCT of six monthly injections of BoNT-A in infants as they initiated early ambulation by pulling to stand commenced in 2002. The objectives were to determine the impact on the development of upright independent ambulation, to evaluate improvements in the quality of any motor gains achieved and identify any adverse issues that may be associated with administering BoNT-A to the very young infant. This was identified as the ‘early-start’ project.The outcome measures included measures of local technical response (MAS, R1 and R2) along with measures of functional ability and quality of movement (Gross Motor Function Measure, Gross Motor Performance Measure, Assisting Hand Assessment and the Physician Rating Scale).Increased functional gain and increased quality of movement of the children in the intervention (early-start) group compared with those in the control (standard practice) group was detected at follow-up at both two and three years of age.The findings also revealed that BoNT-A in doses of up to 12 Ukg-1 (BOTOX®, Allergan Pty Ltd, Irvine USA) proved to be safe and efficacious in the 20 children in this study, the youngest of whom was 11 months of age at admission. The possibility of dystonia being a contributor to contracture development also emerged as an interesting element of this second study.One issue that became obvious through the progress of the studies was the difficulty associated with the clinical identification and quantification of spasticity. In fact, it became clear that community paediatricians and general practitioners were reluctant to diagnose spastic hemiplegia until well after twelve months of age, in part due to a lack of confidence in clinical measurement tools. This fact led to the development of the Australian Spasticity Assessment Scale (ASAS) which, while not available for use in the two studies described here, was initiated following completion of Study 1 and is included as Chapters 17 and 18 for completeness.The findings of these two RCTs add to the limited body of knowledge about the effects of botulinum toxin type-A on the functional ability of the child with spasticity due to CP. In particular, serial BoNT-A as employed in Study 2 was shown to be safe and effective in improving the speed of acquisition and quality of independent ambulation when commenced at an earlier age (early-start) than current clinical practice advocates. The outcome of these interventions has been examined and shown to be safe and efficacious at an earlier age than that used in current clinical practice.