Injection frequency of botulinum toxin A for spastic equinus : a randomized clinical trial

AIM: We compared two botulinum toxin A (BoNT-A) injection frequency regimens, 12-monthly versus 4-monthly, for spastic equinus in a randomized clinical trial. The primary outcome measure was passive ankle dorsiflexion. METHOD: Forty-two ambulant children with spastic equinus, secondary to cerebral palsy (23 males and 19 females; mean age 3y 6mo, SD 13mo; GMFCS levels I [n=20], II [n=19], III [n=3]) were randomized to receive either 12-monthly or 4-monthly BoNT-A injections to the calf, over a 26-month period. Twenty-one children had spastic hemiplegia, 21 children had spastic diplegia. A fixed 6U/kg dose of Botox was injected into the gastrocnemius muscle of both limbs in children with diplegia and the gastrocsoleus of the affected limb in children with hemiplegia, under mask anaesthesia. RESULTS: Forty-two children entered the trial with 21 participants randomized to each group. There were three withdrawals and two children received serial casting midway through the trial. There was no significant difference in passive dorsiflexion between 12-monthly and 4-monthly regimens (p=0.41). There were also no significant between group differences on secondary outcome measures. There were no serious adverse events - the rate was 1.2 adverse events per child per year in the 12-monthly group and 2.2 adverse events per child per year in the 4-monthly group. Subgroup analysis revealed a significant difference in passive dorsiflexion between children with hemiplegia and diplegia (p=0.01). INTERPRETATION: There was no significant difference between 12-monthly and 4-monthly injection regimens on passive dorsiflexion or secondary outcome measures. BoNT-A injections for spastic equinus may be recommended on a 12-monthly basis

Botulinum Toxin in the Management of Children with Cerebral Palsy

During the past 25 years, botulinum toxin type A (BoNT-A) has become the most widely used medical intervention in children with cerebral palsy. In this review we consider the gaps in our knowledge in the use of BoNT-A and reasons why muscle morphology and function in children with cerebral palsy are impaired. We review limitations in our knowledge regarding the mechanisms underlying the development of contractures and the difficulty in preventing them. It is clear from this review that injection of BoNT-A in the large muscles of both the upper and lower limbs of children with cerebral palsy will result in a predictable decrease in muscle activity, which is usually reported as a reduction in spasticity, for between 3 and 6 months. These changes are noted by the use of clinical tools such as the Modified Ashworth Scale and the Modified Tardieu Scale. Decreased muscle over-activity usually results in improved range of motion in distal joints. Injection of the gastrocnemius muscle for toe-walking in a child with hemiplegia or diplegia usually has the effect of increasing the passive range of dorsiflexion at the ankle. In our review, we found that this may result in a measurable improvement in gait by the use of observational gait scales or gait analysis, in some children. However, improvements in gait function are not always achieved and are small in magnitude and short lived. We found that some of the differences in outcomes in clinical trials may relate to the use of adjunctive interventions such as serial casting, orthoses, night splints and intensive therapy. We note that the majority of clinical trials of the use of BoNT-A in children with cerebral palsy have focussed on a single injection cycle and this is insufficient to understand the balance between benefit and harm. Most outcomes were reported in terms of changes in muscle tone and there were fewer studies with robust methodology that reported improvements in function. Changes in the domains of activities and participation have rarely been reported in studies to date. There were no clinical reviews to date that consider the findings of studies in human volunteers and in experimental animals and their relevance to clinical protocols. In this review we found that studies in human volunteers and in experimental animals show muscle atrophy after an injection of BoNT-A for at least 12 months. Muscle atrophy was accompanied by loss of contractile elements in muscle and replacement with fat and connective tissue. It is not currently known if these changes, mediated at a molecular level, are reversible. We conclude that there is a need to revise clinical protocols by using BoNT-A more thoughtfully, less frequently and with greatly enhanced monitoring of the effects on injected muscle for both short-term and long-term benefits and harms

Onabotulinum toxin-A (Botox) for spastic equinus in cerebral palsy: a prospective kinematic study

Purpose Botulinum toxin-A (or Botox) is widely used for the management of equinus gait in children with cerebral palsy but few recent studies have included instrumented gait analysis. Methods This was a prospective cohort study. Gait analysis was performed four weeks before and four weeks after Botulinum toxin-A injection for spastic equinus to detect the maximum effects on gait kinematics. Outcome measures included the Gait Profile Score (GPS), the Gait Variable Score (GVS) for the ankle, maximal ankle dorsiflexion and maximal knee extension at midstance. Results In all, 37 children participated (20 boys); mean age five years seven months (4 years 1 month to 8 years 2 months); 19 with unilateral and 18 bilateral involvement. At a mean four weeks post-injection, the GPS and ankle GVS were unchanged. However maximum ankle dorsiflexion increased for the whole group; median 7.7° (confidence interval (CI) 4° to 10.6°) to 11.5° (CI 7.7° to 12.9°), p = 0.02. Maximum midstance knee extension was unchanged for the whole group, but median knee flexion increased in children with bilateral involvement; 10.9° (CI 7.4° to 20.8°) to 16.5° (CI 8.4° to 19.7°), p = 0.58. Conclusion Injections of the gastrocsoleus for spastic equinus did not result in objective improvements in overall gait. Improvements in ankle dorsiflexion for children with bilateral involvement may be offset by deterioration at the knee

Identifiers for the 21st century: How to design, provision, and reuse persistent identifiers to maximize utility and impact of life science data.

In many disciplines, data are highly decentralized across thousands of online databases (repositories, registries, and knowledgebases). Wringing value from such databases depends on the discipline of data science and on the humble bricks and mortar that make integration possible; identifiers are a core component of this integration infrastructure. Drawing on our experience and on work by other groups, we outline 10 lessons we have learned about the identifier qualities and best practices that facilitate large-scale data integration. Specifically, we propose actions that identifier practitioners (database providers) should take in the design, provision and reuse of identifiers. We also outline the important considerations for those referencing identifiers in various circumstances, including by authors and data generators. While the importance and relevance of each lesson will vary by context, there is a need for increased awareness about how to avoid and manage common identifier problems, especially those related to persistence and web-accessibility/resolvability. We focus strongly on web-based identifiers in the life sciences; however, the principles are broadly relevant to other disciplines