Department of Pediatrics, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada.
Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
Headache. 2024 Nov-Dec;64(10):1200-1216. doi: 10.1111/head.14798. Epub 2024 Aug 11.
To qualitatively and quantitatively summarize the evidence for the use of onabotulinumtoxinA injections in children and adolescents with migraine.
There are limited evidence-based treatment options for youth with migraine, especially youth with chronic migraine (CM). OnabotulinumtoxinA injections are an established evidence-based treatment for adults with CM. While several studies have assessed their safety and efficacy among adolescents with CM, there are no published systematic reviews summarizing the pediatric evidence.
We carried out a systematic review, reported according to the Preferred Reporting Items for Systematic Review and Meta-Analysis, aiming to identify studies that included five or more children and adolescents aged ≤18 years with a diagnosis of migraine, who were treated with ≥50 units (U) of onabotulinumtoxinA and had outcomes assessed ≥4 weeks after one or more injection cycle. Both observational studies and randomized controlled trials (RCTs) were eligible for inclusion. Two investigators independently carried out the first (titles and abstracts) and second (full text) screening stages, as well as data extraction and quality appraisal. The American Academy of Neurology risk of bias grading scheme was used to assess study risk of bias. Studies with adequate data were pooled using random effects meta-analyses, and Hedge's g standardized mean differences with 95% confidence intervals (CIs) were generated to estimate the effect sizes of the continuous outcomes included. Studies lacking data required for meta-analysis were summarized qualitatively.
We screened 634 studies and included 14 studies comprising 491 participants, of whom 489 had CM. Two studies were RCTs, 12 were observational uncontrolled studies, and all but one study included only youth with CM. Five Class IV observational uncontrolled studies were amenable to pooling in meta-analyses. After a mean of 2-2.6 injection cycles, headache frequency was shown to decrease significantly after treatment with onabotulinumtoxinA (Hedge's g = 0.97, 95% CI 0.58-1.35; p < 0.0001), as did severity (Hedge's g = 1.24, 95% CI 0.55-1.94; p = 0.0005), with both estimates having a large effect size magnitude. A Class I parallel-group RCT of one injection series (155 U, 74 U, or placebo), powered to detect a change in 4 headache days per month, did not find outcome differences between the active and placebo treatment arms. A Class IV crossover RCT showed superiority of active (155 U) versus placebo injections. The remaining Class IV observational studies that were excluded from the meta-analyses all showed improved outcomes with onabotulinumtoxinA injections over time. No serious adverse events related to treatment occurred.
OnabotulinumtoxinA injections have established safety for use in children and adolescents with CM and are likely effective in reducing headache frequency and severity over time. However, in the absence of an adequately powered parallel-group RCT assessing the efficacy of multiple injection cycles, it remains unclear if this intervention is superior to placebo.
定性和定量总结肉毒毒素 A 注射剂在儿童和青少年偏头痛患者中的应用证据。
对于偏头痛青少年，尤其是慢性偏头痛（CM）青少年，治疗方法有限，缺乏循证医学依据。肉毒毒素 A 注射剂是 CM 成人的一种既定循证治疗方法。虽然已有几项研究评估了其在 CM 青少年中的安全性和有效性，但尚无发表的系统评价总结儿科证据。
我们进行了一项系统评价，根据系统评价和荟萃分析的首选报告项目进行了报告，旨在确定纳入了五项或更多患有偏头痛且年龄≤18 岁的儿童和青少年的研究，这些患者接受了≥50U 的肉毒毒素 A 治疗，并且在一次或多次注射周期后至少 4 周评估了结局。符合条件的研究包括观察性研究和随机对照试验（RCT）。两名研究人员独立进行了第一（标题和摘要）和第二（全文）筛选阶段，以及数据提取和质量评估。采用美国神经病学学会的偏倚风险分级方案评估研究的偏倚风险。对具有足够数据的研究进行了随机效应荟萃分析，并生成了 Hedge's g 标准化均数差值及其 95%置信区间（CI），以估计纳入的连续结局的效应大小。对于缺乏荟萃分析所需数据的研究，进行了定性总结。
我们筛选了 634 项研究，纳入了 14 项研究，共纳入 491 名参与者，其中 489 名患有 CM。两项研究为 RCT，12 项为观察性非对照研究，除一项研究外，所有研究均仅纳入 CM 青少年。五项 IV 级观察性非对照研究可进行荟萃分析。在平均接受 2-2.6 次注射周期后，肉毒毒素 A 治疗后头痛频率显著降低（Hedge's g=0.97，95%CI 0.58-1.35；p<0.0001），严重程度也显著降低（Hedge's g=1.24，95%CI 0.55-1.94；p=0.0005），两种评估均具有较大的效应大小。一项针对单次注射系列（155U、74U 或安慰剂）的 I 级平行组 RCT，旨在检测每月头痛天数的变化，未发现活性治疗组与安慰剂治疗组之间的结局差异。一项 IV 级交叉 RCT 显示活性（155U）优于安慰剂注射。其余四项被排除在荟萃分析之外的 IV 级观察性研究均显示肉毒毒素 A 注射随着时间的推移改善了结局。没有与治疗相关的严重不良事件。
肉毒毒素 A 注射在儿童和青少年 CM 患者中的使用具有明确的安全性，并且随着时间的推移，可能有效降低头痛频率和严重程度。然而，由于缺乏评估多次注射周期疗效的充分效力的平行组 RCT，尚不清楚该干预措施是否优于安慰剂。
