Blumetti Francesco C, Belloti João Carlos, Tamaoki Marcel Js, Pinto José A
Department of Orthopaedics and Traumatology, Universidade Federal de São Paulo, Rua Borges Lagoa, 783 - 5º andar, São Paulo, São Paulo, Brazil, 04038-032.
Cochrane Database Syst Rev. 2019 Oct 8;10(10):CD001408. doi: 10.1002/14651858.CD001408.pub2.
Cerebral palsy (CP) is the most common cause of physical disabilities in children in high-income countries. Spasticity is the most common motor disturbance in CP. Botulinum toxin type A (BoNT-A) is considered the first-line treatment for focal spasticity in people with CP.
To evaluate the effectiveness and safety of BoNT-A compared to other treatments used in the management of lower limb spasticity in children with CP.
We searched CENTRAL, PubMed, four other databases, and two trial registers in October 2018. We also searched the reference lists of relevant studies and reviews and contacted experts in the field. We did not apply any date or language restrictions.
Randomised controlled trials of children with CP, aged between birth and 19 years, treated with BoNT-A injections in the lower limb muscles compared to other interventions. The primary outcomes were gait analysis and function. The secondary outcomes were joint range of motion, quality of life, satisfaction, spasticity, and adverse events.
Two review authors independently selected studies, extracted data, assessed risk of bias, and rated the quality of the evidence using GRADE. A third review author arbitrated in case of disagreements. We conducted meta-analyses of available data whenever possible, analysing dichotomous data with risk ratios (RR), and continuous data with mean differences (MD) or standardised mean differences (SMD), with 95% confidence intervals (CI). We considered a 5% significance level for all analyses.Whenever possible, we analysed outcomes at the time points at which they were assessed: short term (2 to 8 weeks); medium term (12 to 16 weeks); and long term (> 24 weeks).
We included 31 randomised controlled trials assessing 1508 participants. Most studies included ambulatory patients with more than one motor type of CP, and with a mean age of between three and seven years. There was a slight predominance of males.Studies compared BoNT-A in the lower limb muscles to usual care or physiotherapy (14 studies), placebo or sham (12 studies), serial casting (4 studies), or orthoses (1 study).We rated studies as at high or unclear risk of bias mainly due to random sequence generation, allocation concealment, blinding of participants and personnel, and blinding of outcome assessment.BoNT-A versus usual care or physiotherapyBoNT-A might improve overall gait scores at medium-term follow-up (MD 2.80, 95% CI 1.55 to 4.05; 1 study, 40 children; very low-quality evidence) and is moderately effective at improving function at short-term (SMD 0.59, 95% CI 0.23 to 0.95; 2 studies, 123 children) and medium-term (SMD 1.04, 95% CI 0.16 to 1.91; 4 studies, 191 children) follow-up (all very low-quality evidence).BoNT-A improves ankle range of motion, satisfaction, and ankle plantarflexors spasticity at one or more time points (very low-quality evidence).The proportion of adverse events in the BoNT-A group was 0.37 (95% CI 0.08 to 0.66; I = 95%; very low-quality evidence). No adverse events were reported in the control group.BoNT-A versus placebo or shamBoNT-A improves overall gait scores at short-term (RR 1.66, 95% CI 1.16 to 2.37, P = 0.006; 4 studies, 261 assessments) and medium-term (RR 1.90, 95% CI 1.32 to 2.74, P < 0.001; 3 studies, 248 assessments) follow-up, and may improve peak ankle dorsiflexion in stance (MD 15.90 degrees, 95% CI 4.87 to 26.93, P = 0.005; 1 study, 19 children) and in swing (MD 10.20 degrees, 95% CI 4.01 to 16.39, P = 0.001; 1 study, 19 children) at short-term follow-up (all moderate-quality evidence).BoNT-A is not more effective than placebo or sham at improving function at short-term (SMD 0.24, 95% CI -0.35 to 0.83, P = 0.42; 4 studies, 305 children) or long-term (SMD -0.07, 95% CI -0.48 to 0.35, P = 0.76; 2 studies, 91 children) follow-up, but has a small positive effect at medium-term follow-up (SMD 0.28, 95% CI 0.06 to 0.49, P = 0.01; 5 studies, 327 children) (all moderate-quality evidence).BoNT-A improves passive ankle range of motion, satisfaction, and ankle plantarflexors spasticity at one or more time points (moderate-quality evidence).There was no difference between groups in the rate of adverse events at short-term follow-up (RR 1.29, 95% CI 0.87 to 1.93, P = 0.21; 12 studies, 918 children; moderate-quality evidence).BoNT-A versus serial castingThere was no difference between groups for overall gait scores at short-term (MD 0.00, 95% CI -1.66 to 1.66); medium-term (MD 0.65, 95% CI -1.21 to 2.51); or long-term (MD 0.46, 95% CI -1.33 to 2.25) follow-up in one study with 18 children (moderate-quality evidence).BoNT-A improved instrumented gait analysis only in terms of ankle dorsiflexion at initial contact (MD 6.59 degrees, 95% CI 1.39 to 11.78, P = 0.01; 2 studies, 47 children). There was no difference between groups for peak ankle dorsiflexion in stance and swing, and gait speed at any time point (moderate- and low-quality evidence).BoNT-A is not more effective than serial casting at improving function, ankle range of motion, and spasticity at any time point (moderate- and low-quality evidence).BoNT-A is not associated with a higher risk of adverse events than serial casting (RR 0.59, 95% CI 0.03 to 11.03; 3 studies, 64 children; low-quality evidence).BoNT-A versus orthosesThere was no difference between groups for function at medium-term follow-up (MD 11.14, 95% CI -0.05 to 22.33; 1 study, 43 children), but BoNT-A is more effective than orthoses at improving hip range of motion and hip adductors spasticity (all very low-quality evidence).
AUTHORS' CONCLUSIONS: The quality of the evidence was low or very low for most of the outcomes analysed. We found limited evidence that BoNT-A is more effective than placebo or a non-placebo control at improving gait, joint range of motion, satisfaction, and lower limb spasticity in children with CP, whereas the results for function were contradictory. The rate of adverse events with BoNT-A is similar to placebo. BoNT-A is not more effective than ankle serial casting to treat ankle contractures for any of the assessed outcomes, but is more effective than orthotics at improving range of motion and spasticity.
在高收入国家，脑瘫（CP）是儿童身体残疾的最常见原因。痉挛是脑瘫最常见的运动障碍。A型肉毒毒素（BoNT - A）被认为是脑瘫患者局灶性痉挛的一线治疗方法。
评估BoNT - A与用于治疗脑瘫儿童下肢痉挛的其他治疗方法相比的有效性和安全性。
我们于2018年10月检索了Cochrane系统评价数据库（CENTRAL）、PubMed以及其他四个数据库和两个试验注册库。我们还检索了相关研究和综述的参考文献列表，并联系了该领域的专家。我们未应用任何日期或语言限制。
将出生至19岁的脑瘫儿童进行下肢肌肉BoNT - A注射治疗与其他干预措施进行比较的随机对照试验。主要结局为步态分析和功能。次要结局为关节活动范围、生活质量、满意度、痉挛和不良事件。
两位综述作者独立选择研究、提取数据、评估偏倚风险，并使用GRADE对证据质量进行评级。如有分歧，由第三位综述作者进行仲裁。只要有可能，我们就对可用数据进行荟萃分析，使用风险比（RR）分析二分数据，使用均值差（MD）或标准化均值差（SMD）分析连续数据，并给出95%置信区间（CI）。我们所有分析均采用5%的显著性水平。只要有可能，我们在评估的时间点分析结局：短期（2至8周）；中期（12至16周）；长期（>24周）。
我们纳入了31项评估1508名参与者 的随机对照试验。大多数研究纳入了多种运动类型的能行走的脑瘫患者，平均年龄在3至7岁之间。男性略占多数。研究将下肢肌肉注射BoNT - A与常规护理或物理治疗（14项研究）、安慰剂或假治疗（12项研究）、连续石膏固定（4项研究）或矫形器（1项研究）进行了比较。我们将研究评为高偏倚风险或不清楚偏倚风险，主要原因是随机序列生成、分配隐藏、参与者和人员的盲法以及结局评估的盲法。
BoNT - A与常规护理或物理治疗相比
BoNT - A在中期随访时可能改善总体步态评分（MD 2.80，95%CI 1.55至4.05；1项研究，40名儿童；极低质量证据），在短期（SMD 0.59，95%CI 0.23至0.95；2项研究，123名儿童）和中期（SMD 1.04，95%CI 0.16至1.91；4项研究，191名儿童）随访时对改善功能有中度效果（均为极低质量证据）。BoNT - A在一个或多个时间点改善踝关节活动范围、满意度和踝关节跖屈肌痉挛（极低质量证据）。BoNT - A组不良事件的比例为0.37（95%CI 0.08至0.66；I = 95%；极低质量证据）。对照组未报告不良事件。
BoNT - A与安慰剂或假治疗相比
BoNT - A在短期（RR 1.66，95%CI 1.16至2.37，P = 0.006；4项研究，261次评估）和中期（RR 1.90，95%CI 1.32至2.74，P < 未找到相关结果0.001；3项研究，248次评估）随访时改善总体步态评分，并且在短期随访时可能改善站立期踝关节背屈峰值（MD 15.90度，95%CI 4.87至26.93，P = 0.005；1项研究，19名儿童）和摆动期（MD 10.20度，95%CI 4.01至16.39，P = 0.001；1项研究，19名儿童）（均为中等质量证据）。BoNT - A在短期（SMD 0.24，95%CI -0.35至0.83，P = 0.42；4项研究，305名儿童）或长期（SMD -0.07，95%CI -0.48至0.35，P = 0.76；2项研究，91名儿童）随访时改善功能并不比安慰剂或假治疗更有效，但在中期随访时有小的积极效果（SMD 0.28，95%CI 0.06至0.49，P = 0.01；5项研究，327名儿童）（均为中等质量证据）。BoNT - A在一个或多个时间点改善被动踝关节活动范围、满意度和踝关节跖屈肌痉挛（中等质量证据）。短期随访时两组不良事件发生率无差异（RR = 1.29，95%CI 0.87至1.93，P = 0.21；12项研究，918名儿童；中等质量证据）。
BoNT - A与连续石膏固定相比
在一项有18名儿童参与的研究中，短期（MD 0.00，95%CI -1.66至1.66）、中期（MD 0.65，95%CI -1.21至2.51）或长期（MD 0.46，95%CI -1.33至2.25）随访时，两组总体步态评分无差异（中等质量证据）。BoNT - A仅在初始接触时的踝关节背屈方面改善了仪器化步态分析（MD 6.59度，95%CI 1.39至11.78，P = 0.01；2项研究，47名儿童）。在任何时间点，两组在站立期和摆动期的踝关节背屈峰值以及步态速度方面无差异（中等质量和低质量证据）。在改善功能、踝关节活动范围和痉挛方面，BoNT - A在任何时间点都不比连续石膏固定更有效（中等质量和低质量证据）。BoNT - A与连续石膏固定相比，不良事件风险不更高（RR 0.59，95%CI 0.03至11.03；3项研究，6名儿童；低质量证据）。BoNT - A与矫形器相比
中期随访时两组功能无差异（MD 11.14，95%CI -0.05至22.33；1项研究，43名儿童），但在改善髋关节活动范围和髋内收肌痉挛方面，BoNT - A比矫形器更有效（均为极低质量证据）。
对于大多数分析的结局，证据质量低或非常低。我们发现有限的证据表明，在改善脑瘫儿童的步态、关节活动范围、满意度和下肢痉挛方面，BoNT - A比安慰剂或非安慰剂对照更有效，而功能结果相互矛盾。BoNT - A的不良事件发生率与安慰剂相似。在治疗踝关节挛缩的任何评估结局方面，BoNT - A不比踝关节连续石膏固定更有效，但在改善活动范围和痉挛方面比矫形器更有效。
