‘Why do children with cerebral palsy discontinue therapy with botulinum toxin A?’

‘Why do children with cerebral palsy discontinue therapy with botulinum toxin A? ’ SIR Since the early 1990s the intramuscular injection of botulinum toxin A (BTX-A) has emerged as a well-established treatment option in the interdisciplinary management of spasticity in children with cerebral palsy (CP). 1,2 Despite numerous reports confirming its efficacy and safety with regard to shortterm functional benefit, there is a current lack of studies assessing long-term outcome. It is only for adults treated with BTX-A for cervical dystonia, hemifacial spasm, or blepharospasm, that some clinical trials have been published evaluating long-term efficacy and reasons for discontinuation of treatment.3–6 The aim of the retrospective study presented here was to investigate when and why children with CP stop therapy with BTX-A. We conducted a review of medical records focusing on the clinical characteristics of 112 children with CP who had received at least one BTX-A injection between 1993 and 2002 in our movement disorders outpatient clinic, but who had stopped treatment at the time of this evaluation. Additionally, a standardized mail questionnaire was designed to assess the parents’ perception of treatment and to determine their reasons for discontinuation. Approval from the local ethics committee (University of Freiburg, Germany) and informed consent from all parents were obtained. The children had a mean age of 8 years and 8 months (SD 4y 8mo; range 1mo–18y 11mo); 106 patients had bilateral spastic CP and six were classified as having unilateral CP. Main indications were leg adductor spasticity (n=59) and pes equinus deformity (n=35). Eighteen children were treated for spasticity of other muscles (e.g. upper limb, M. rectus femoris). The mean treatment period was 14 months (range 3–74mo), with reinjection intervals of 3 to 6 months. The BTX-A dosages were determined according to body weight and size of target muscle. The mean dose per visit was 8.5 units Botox or 24.6 units Dysport per kg body weight. Initial treatment response was measured by goal attainment scaling (GAS). 7 Twenty-seven of the 112 children (24%) did not show a satisfactory local or functional benefit after the first injection (GAS score 0: no change to status before treatment), so treatment was immediately discontinued. Among those patients we found a high proportion of children with structural changes of muscle, determined by clinical examination using the Tardieu Scale, (n=14, mean age 13y 11mo [SD 3y 10mo]; range 7y 10mo – 18y 11mo) as well as younger patients with relatively mild functional impairment who did not improve on motor performance (n=5, mean age 4y 4mo [SD 1y 6mo]; range 2y 1mo – 6y 4mo). In eight children with early treatment discontinutation we did not have a satisfactory explanation for their lack of benefit. Apart from musculoskeletal changes or extremely mild motor impairment, other factors such as mismatch between cognitive function and aimed functional therapy goal or inappropriate muscle selection might have attributed to the initial therapy failure. In 85 patients (76%) with an initially good response to BTXA (GAS score +1 / +2: reaching partly/completely the individual treatment goal), treatment was stopped after having received two or more injections. The reasons for discontinuation varied: nine children (11%) did not need any further treatment with BTX-A because of lasting functional benefits; 15 children (18%) underwent elective orthopaedic surgery. Forty children (47%) showed a secondary non-response: 30 had developed neutralizing anti-BTX-A antibodies and 10 were antibody negative. Side effects such as excessive local weakening of the muscle or emotional stress due to repeated injections led, in seven patients (8%), to termination of therapy. Other rationales for treatment discontinuation were non-compliance (10%) and non-medical reasons, e.g. relocation (6%). Seventy of 112 parents completed the questionnaire (response-rate 63%). In general, parent satisfaction with initial treatment effect was high: 79% reported a significant reduction of muscular hyperactivity, 68% also stated a beneficial functional improvement with positive impact on activities of daily living. Although basic limitations of the retrospective study design have to be taken into account, the following conclusions could be drawn: (1) even in a pure ‘dropout’ population, side effects are rarely the cause of patients discontinuing therapy; (2) upon examining the group of children who failed to show a satisfactory benefit from treatment initially, it becomes obvious that appropriate patient selection and the definition of realistic therapy goals are crucial to optimize treatment outcome; and (3) a large proportion of children with spastic CP stop BTX-A injections due to secondary lack of benefit after a good initial treatment response. In 75% secondary non-response could be attributed to the formation of anti-BTX-A antibodies, which is in concordance with the observed incidence of antibodies described in a recently published study.8 Besides antibody formation, the natural course of CP with the development of musculoskeletal changes as well as the lack of definition of longterm therapy goals might be relevant to discontinuation of therapy. Recent developments might influence the secondary loss of therapy gain in the following ways: (1) since one of the BTX-A preparations has been reformulated clinical trial data of adults treated with this preparation have shown a significantly reduced antigenicity rate;9 and (2) developments in BTX-A treatment strategies such as multilevel treatment and evidence based combinations of treatment options (e.g. casting, treadmill training, constraint-induced movement therapy) may also have an impact upon improving long-term outcome in children with spastic CP.