Safety of Botulinum toxin a in cerebral palsy

Abstract

The use of Botulinum toxin (BoNT) in the treatment of focal spasticity in adults and children has become well established worldwide. Since the first use of BoNT in children with spastic equinus over 10 years ago, there have been no serious or unexpected safety concerns for this indication. However, within the last year, there has been media attention as well as reviews by European and US regulatory agencies about the safety of all marketed Botulinum toxin products for the way in which they are used currently. Following the pioneering studies by Koman in the US and Graham in Europe, the initial publications recommended utilizing doses of 1–4 U BOTOX/kg body weight (BW) per muscle in the gastrocnemius and soleus and a total dose of not more than 8 units BOTOX/kg BW. For Dysport, the recommended dosing was up to 30 U/kg BW up to a maximum of 1000 U. In a consensus statement published in 2000, Graham and colleagues recommended a maximum dose of 50 U of the BOTOX formulation in any one site, a maximum total dose of 12 U/kg BW or 400 units at an injection session. This was based on clinical experience current at that time. Recognizing the multilevel nature of spasticity in children with spastic diplegia, firstly Graham and colleagues, followed by Molenaers and colleagues, extended existing protocols to expand the muscle groups injected to include the hamstrings, adductors and iliopsoas. Although the dose per muscle was not altered, this resulted in a stepwise increase in total dose administered. Subsequently, there have been numerous publications on outcomes and safety of BOTOX when used in a multi-level approach. The most common, obvious treated related side effects are pain at the site of injection, excess weakness of the targeted muscle, and weakness of adjacent muscle. The 2000 consensus statement anticipated that the risk of adverse events in children with cerebral palsy could be related to the type of cerebral palsy than the dose of toxin administered. Specifically, it is anticipated that children at GMFCS level V, who are non-ambulatory and often debilitated with impaired attention and cognition; have comorbidities of epilepsy and other cardiac, pulmonary or neurologic conditions; and have symptoms of pseudo-bulbar palsy, might be specifically at risk for complications of BoNT and/or the procedure including the use of sedative agents and anaesthesia. In a recent randomized trial, Graham and colleagues carefully studied adverse events in a large number of children with cerebral palsy treated with an average dose of 14 U BOTOX/kg BW. There was evidence of possible systemic spread and adverse events in some children, but no fatalities directly related to the administration of the toxin. This experience is consistent with the literature. In a recent review of our BoNT database, we have identified the following risk factors for adverse events in the administration of BoNT. In order of importance these are: (1) the child's GMFCS level; (2) the total dose administered; (3) method of sedation/anaesthesia. Secondary factors for further investigation include: (1) current and past medical history, specifically dysphagia, aspiration, cardiopulmonary events, concomitant medications; (2) reconstitution volume; (3) total number of muscles injected; (4) single or divided dose per muscle; (5) method of muscle targeting, e.g. muscle stimulation versus ultrasound.