Cerebral palsy (CP) is “a group of permanent disorders of the development of movement and posture, causing activity limitation, that are attributed to non-progressive disturbances that occurred in the developing fetal or infant brain”.
] p.9 Classification systems have been developed to indicate the severity of functional limitations in CP. The Gross Motor Function Classification System (GMFCS), developed by Palisano and colleagues in 1997, has become internationally accepted for the classification of gross motor abilities for children with CP
]. The GMFCS is comprised of 5 levels, with GMFCS I reflecting the highest level of gross motor function. Children who are classified GMFCS IV and V are the most functionally impaired. Children classified as GMFCS IV require supportive seating for trunk control and to maximize upper limb function, and assistance for transfers. Self-mobility is limited to possible use of a powered wheelchair. Children who are classified as GMFCS V are unable to sit without support and have difficulty maintaining antigravity head and neck control. Children classified as GMFCS IV and V comprise approximately one third of children with CP in Australia
The most common motor type of CP is the spastic type
]. Spasticity is “a velocity-dependent resistance of a muscle to stretch”.
] p.91 Spasticity commonly leads to muscle contractures and eventual bony deformities, which may result in decreased functional ability as a child’s development progresses
]. Children whose CP is classified GMFCS IV or V frequently suffer from pain
]. Pain is often associated with marked spasticity, spasms, skin breakdown, or postural positioning leading to an increased burden of care. Even simple tasks like dressing can become problematic when children have high levels of spasticity
]. Pain negatively impacts children’s quality of life
] and participation in schooling and family activities
]. Pain is associated with a higher risk of stress for parents of children with CP
]. Pain, discomfort and carer burden lead parents to seek treatments to reduce their child’s spasticity.
Spasticity can be reduced with intramuscular injections of botulinum toxin A (BoNT-A)
]. When injected into a target muscle, BoNT-A enters the presynaptic terminal, and prevents the exocytosis of acetylcholine, thus reducing spasticity. The clinical effects have been reported to last for approximately 3-6 months. Intramuscular injections of BoNT-A, using Botox®
(Allergan PLC) have been approved (March 2011) by the Therapeutic Goods Association Australia for treatment of focal spasticity in the upper and lower limbs, including dynamic equinus foot deformity, in children with juvenile CP from the age of two years. Dysport®
is an alternative preparation of BoNT-A which will not be used in this study. Research has demonstrated the ability of BoNT-A to improve function for children with CP whom are ambulant
]. When used with ambulatory children, BoNT-A is considered to be generally safe with relatively few and minor complications
There is limited evidence for using BoNT-A with children with CP whom are non-ambulant (GMFCS IV and V) to reduce pain and improve ease of care. A small double-blinded, placebo controlled randomized trial examined the use of Botox®
pre-operatively for pain management post hip adductor release surgery for children with severe CP
]. Compared with the placebo group, children who received Botox®
required significantly less pain relief, including morphine (p
0.03) and combined narcotic dose (p
0.009) after the first 48 hours post operatively. The study concluded that there is a role for BoNT-A in reducing pain post-surgically and that it may have further clinical applications with this population. A more recent report detailed the outcomes of a clinical cohort of 26 children with CP, GMFCS V with spasticity and pain in the hip region who had injections of BoNT-A (n
17 had Dysport®
9 had Botox®
) to improve comfort
]. Pain was measured pre and post treatment by parent report using the Paediatric Pain Profile
]. All children in the study had reduced pain at 3 months post BoNT-A, with a significant overall reduction in pain (p
0.001). Although not formally measured, improved sleep patterns, tolerance of seating and ease of care were reported. Another small pre post study of children with severe CP evaluated the effects of intramuscular BoNT-A injections on parent-proxy ratings of pain
]. The study did not report GMFCS levels of the participants; however 13 of the 34 children had non-ambulant (quadriplegic) CP. Twenty-one (62%) participants experienced pain reduction one month after BoNT-A injections, as measured by a telephone survey with each child’s parent. There were no obvious child-specific characteristics that separated those who had pain reduction and those who experienced persistent pain however this report suggested that BoNT-A injections may have analgesic effects.
The pain-relieving potential of BoNT-A has been more rigorously investigated in adults
]. In a randomized, double blinded placebo controlled trial, BoNT-A injections have been shown to improve shoulder pain associated with spasticity in adults following stroke
]. Similar results were reported following injections to the pectoralis major muscle in an adult population suggesting that upper limb injections of BoNT-A may provide pain relief
]. Further well designed studies are needed to validate the efficacy of BoNT-A when used to reduce pain, improve comfort and reduce burden of cares in children with non-ambulant CP.
Following reports of systemic adverse events,
] there has been increasing focus on the safety of BoNT-A when used with children with CP. A systematic review which included 20 randomized clinical trials of BoNT-A found a good safety profile when used short term, however called for more research into a possible association between BoNT-A, seizures and death
]. A review of the efficacy and safety of pharmacological treatments for spasticity in children and adolescents with CP reported that BoNT-A was an effective and generally safe treatment however warned that generalized weakness may occur
]. A retrospective review of 1,980 BoNT-A injection episodes in 1,147 children ranging from GMFCS I –V found a low incidence of systemic adverse events
]. Incontinence occurred in 1% of cases, and respiratory symptoms requiring hospitalization in 1.3%. Higher GMFCS levels (IV,V) and higher doses of BoNT-A were associated with increased incidence of adverse events, leading the authors to recommend conservative dosing for children classified GMFCS IV-V
A meta-analysis of the safety of BoNT-A using a variety of preparations included 37 randomized controlled trials across a range of indications including participants with dystonia, movement disorders, spasticity and CP, urological and gastrointestinal disorders and for cosmetic use
]. Data from 2,361 subjects of whom 1,447 had received BoNT-A were reviewed. The incidence of side effects was 25% in BoNT-A treated patients and 15% in the control group. Of the side-effects, only focal muscle weakness and ptosis occurred more frequently in the treatment group
]. Another retrospective review of 929 patient encounters from a large movement disorders centre reviewed the safety profile of high dose (15-25 units Botox®
per kilogram per episode) BoNT-A across domains such as the aetiology of CP, motor pattern, ambulatory potential and muscles injected
]. The review found adverse effects were randomly distributed across the range of phenotypes and doses. A single blind randomized controlled trial assigned 90 children with bilateral spastic CP, primarily GMFCS IV and V, to either three years of six monthly injections of BoNT-A (maximum dose Botox®
16 units/kg/body weight) combined with wearing a hip abduction brace for 6 hours/day, compared to standard therapy treatment (no brace or BoNT-A). In this study, two children in the treatment group died due to reasons thought not to be related to the BoNT-A injections
]. Including these two deaths, there were 12 serious adverse events out of 204 injection episodes (6%), including four episodes of respiratory infection, three episodes of transient urinary incontinence, two cases of bronchospasm during recovery from general anaesthesia and one flu-like episode.
Data from these studies suggest that, when used in trial conditions, BoNT-A is a relatively safe treatment for children with severe CP but a small proportion of children may be susceptible to adverse events.
Children with severe CP are at risk of significant comorbidities. O’Flaherty and colleagues conducted an audit of health status in children with CP prior to BoNT-A injections
]. The incidence of health issues was reported according to GMFCS levels. In the month prior to injections they reported an incidence of 64/178 (36%) of health related issues including respiratory infections and seizures in children classified GMFCS V who were booked for BoNT-A injections (including those whose injections were cancelled for any reason). Liptak and colleagues performed a multicentre study investigating the health status of children with GMFCS V and found those who used a feeding tube had the lowest mental age, required the most health care resources and medications, had the most respiratory problems and the lowest global health scores
]. The heterogeneity of clinical phenotypes in CP needs to be considered in assessing the efficacy and safety of BoNT-A.
Previous studies of BoNT-A with children with CP have largely focused on children classified GMFCS I – III
]. In these studies, assessments of motor function have been used to test the ability of BoNT-A to bring about functional improvements. In this study with children with CP who have limited voluntary movement, improvements in motor function are not widely expected and are not the focus of investigation. Children with CP whom are non-ambulant rely on their parents for performance of daily activities. Spasticity and contracture, with associated discomfort and pain, contribute to these tasks being difficult, time consuming and/or stressful for parents. In our clinical BoNT-A injecting program, parents of children with severe CP regularly set goals for intervention around improving ease of care (for example, parents may hope for it to be easier to get their child’s arm through a sleeve, quicker to apply lower limb orthoses, or easier to perform transfers), and improving their child’s comfort (for example, that their child will tolerate sitting in their wheelchair for longer periods, require less pain medication or have fewer night wakings due to discomfort). Efficacy will be determined through measurement of changes in parental perceptions of the ease of carrying out daily cares for their child, and their child’s comfort, pre and post treatment, using the Canadian Occupational Performance Measure (COPM)
Clinically, we observe that reduction of spasticity, improved comfort and easier performance of daily cares has the potential to improve a child’s quality of life, health status and pain. Secondary outcome measures will investigate the impact of injections of BoNT-A and therapy on these factors.
In clinical practice, children who undergo BoNT-A injections typically have repeat injections once the effects have worn off. The majority of studies of BoNT-A with children with CP have investigated a single injection episode however several have examined the efficacy of repeated injections. A study of 22 young children with hemiplegia compared three 16 week cycles of BoNT-A injections followed by occupational therapy, with occupational therapy alone. They found that the group who had BoNT-A had reduced spasticity and improvements in the performance scale of the COPM, compared to the therapy only group.
]. Another study of young children with hemiplegia included 42 children who had either two or three cycles of upper limb BoNT-A injections and occupational therapy over a 30 month period
]. First and second injections demonstrated significant effect sizes for quality of movement, goal attainment and functional skills improvement. The study concluded that repeated upper limb injections of BoNT-A are safe and effective for children with unilateral CP receiving occupational therapy. A study of lower limb BoNT-A included ambulant children with CP who were separated into three groups: BoNT-A alone, BoNT-A + casting and casting + placebo injection
]. Each group received three treatment cycles, with the study finding that the groups who received BoNT-A + casting and casting + placebo obtained successive improvement in ankle kinematics, spasticity, range of motion and strength.
To date, no study has evaluated the efficacy and safety of repeated injections of BoNT-A for children with non-ambulant CP. Cycle II of this study will address this gap through a second phase of treatments, in which all children will receive BoNT-A injections followed by a standard therapy regime, as per cycle I. Outcome measurement and monitoring of safety outcomes will be performed as per cycle I. This will enable testing of the efficacy of repeat injecting and the ability to determine the safety of two episodes compared to one episode of injecting.
Intramuscular BoNT-A is widely used clinically for children with CP whom are non-ambulant
]. Research is urgently needed in order to establish efficacy of intramuscular BoNT-A in meeting child and family goals for improving quality of life by reducing pain and improving care and comfort. This study aims to evaluate the efficacy of BoNT-A, while closely monitoring safety in children with CP whom are non-ambulant.