Alder Hey Children's NHS Foundation Trust, Liverpool, UK.
Motor Nerve Clinic, Academic Neurosciences Centre, King's College Hospital, London, UK.
Cochrane Database Syst Rev. 2022 May 20;5(5):CD006981. doi: 10.1002/14651858.CD006981.pub3.
Motor neuron disease (MND), also known as amyotrophic lateral sclerosis (ALS), is a progressive neurodegenerative condition that may cause dysphagia, as well as limb weakness, dysarthria, emotional lability, and respiratory failure. Since normal salivary production is 0.5 L to 1.5 L daily, loss of salivary clearance due to dysphagia leads to salivary pooling and sialorrhea, often resulting in distress and inconvenience to people with MND. This is an update of a review first published in 2011.
To assess the effects of treatments for sialorrhea in MND, including medications, radiotherapy and surgery.
On 27 August 2021, we searched the Cochrane Neuromuscular Specialised Register, CENTRAL, MEDLINE, Embase, AMED, CINAHL, ClinicalTrials.gov and the WHO ICTRP. We checked the bibliographies of the identified randomized trials and contacted trial authors as needed. We contacted known experts in the field to identify further published and unpublished papers.
We included randomized controlled trials (RCTs) and quasi-RCTs, including cross-over trials, on any intervention for sialorrhea and related symptoms, compared with each other, placebo or no intervention, in people with ALS/MND.
We used standard methodological procedures expected by Cochrane.
We identified four RCTs involving 110 participants with MND who were described as having intractable sialorrhea or bulbar dysfunction. A well-designed study of botulinum toxin B compared to placebo injected into the parotid and submandibular glands of 20 participants showed that botulinum toxin B may produce participant-reported improvement in sialorrhea, but the confidence interval (CI) was also consistent with no effect. Six of nine participants in the botulinum group and two of nine participants in the placebo group reported improvement (risk ratio (RR) 3.00, 95% CI 0.81 to 11.08; 1 RCT; 18 participants; low-certainty evidence). An objective measure indicated that botulinum toxin B probably reduced saliva production (in mL/5 min) at eight weeks compared to placebo (MD -0.50, 95% CI -1.07 to 0.07; 18 participants, moderate-certainty evidence). Botulinum toxin B may have little to no effect on quality of life, measured on the Schedule for Evaluation of Individual Quality of Life direct weighting scale (SEIQoL-DW; 0-100, higher values indicate better quality of life) (MD -2.50, 95% CI -17.34 to 12.34; 1 RCT; 17 participants; low-certainty evidence). The rate of adverse events may be similar with botulinum toxin B and placebo (20 participants; low-certainty evidence). Trialists did not consider any serious events to be related to treatment. A randomized pilot study of botulinum toxin A or radiotherapy in 20 participants, which was at high risk of bias, provided very low-certainty evidence on the primary outcome of the Drool Rating Scale (DRS; range 8 to 39 points, higher scores indicate worse drooling) at 12 weeks (effect size -4.8, 95% CI -10.59 to 0.92; P = 0.09; 1 RCT; 16 participants). Quality of life was not measured. Evidence for adverse events, measured immediately after treatment (RR 7.00, 95% CI 1.04 to 46.95; 20 participants), and after four weeks (when two people in each group had viscous saliva) was also very uncertain. A phase 2, randomized, placebo-controlled cross-over study of 20 mg dextromethorphan hydrobromide and 10 mg quinidine sulfate (DMQ) found that DMQ may produce a participant-reported improvement in sialorrhea, indicated by a slight improvement (decrease) in mean scores for the primary outcome, the Center for Neurologic Study Bulbar Function Scale (CNS-BFS). Mean total CNS-BFS (range 21 (no symptoms) to 112 (maximum symptoms)) was 53.45 (standard error (SE) 1.07) for the DMQ treatment period and 59.31 (SE 1.10) for the placebo period (mean difference) MD -5.85, 95% CI -8.77 to -2.93) with a slight decrease in the CNS-BFS sialorrhea subscale score (range 7 (no symptoms) to 35 (maximum symptoms)) compared to placebo (MD -1.52, 95% CI -2.52 to -0.52) (1 RCT; 60 participants; moderate-certainty evidence). The trial did not report an objective measure of saliva production or measure quality of life. The study was at an unclear risk of bias. Adverse events were similar to other trials of DMQ, and may occur at a similar rate as placebo (moderate-certainty evidence, 60 participants), with the most common side effects being constipation, diarrhea, nausea, and dizziness. Nausea and diarrhea on DMQ treatment resulted in one withdrawal. A randomized, double-blind, placebo-controlled cross-over study of scopolamine (hyoscine), administered using a skin patch, involved 10 randomized participants, of whom eight provided efficacy data. The participants were unrepresentative of clinic cohorts under routine clinical care as they had feeding tubes and tracheostomy ventilation, and the study was at high risk of bias. The trial provided very low-certainty evidence on sialorrhea in the short term (7 days' treatment, measured on the Amyotrophic Lateral Scelerosis Functional Rating Scale-Revised (ALSFRS-R) saliva item (P = 0.572)), and the amount of saliva production in the short term, as indicated by the weight of a cotton roll (P = 0.674), or daily oral suction volume (P = 0.69). Quality of life was not measured. Adverse events evidence was also very uncertain. One person treated with scopolamine had a dry mouth and one died of aspiration pneumonia considered unrelated to treatment.
AUTHORS' CONCLUSIONS: There is some low-certainty or moderate-certainty evidence for the use of botulinum toxin B injections to salivary glands and moderate-certainty evidence for the use of oral dextromethorphan with quinidine (DMQ) for the treatment of sialorrhea in MND. Evidence on radiotherapy versus botulinum toxin A injections, and scopolamine patches is too uncertain for any conclusions to be drawn. Further research is required on treatments for sialorrhea. Data are needed on the problem of sialorrhea in MND and its measurement, both by participant self-report measures and objective tests. These will allow the development of better RCTs.
运动神经元病（MND），又称为肌萎缩侧索硬化症（ALS），是一种可能导致吞咽困难、肢体无力、构音障碍、情绪不稳定和呼吸衰竭的进行性神经退行性疾病。由于正常唾液分泌量为 0.5 至 1.5 升/天，因此吞咽困难导致的唾液清除不足会导致唾液积聚和流涎，这通常会给 MND 患者带来困扰和不便。这是一篇 2011 年首次发表的综述的更新。
评估治疗 MND 流涎症的各种治疗方法的效果，包括药物、放疗和手术。
于 2021 年 8 月 27 日，我们检索了 Cochrane 神经肌肉疾病专库、CENTRAL、MEDLINE、Embase、AMED、CINAHL、ClinicalTrials.gov 和世界卫生组织国际临床试验注册平台。我们检查了随机试验的参考文献，并在需要时联系了试验作者。我们联系了该领域的知名专家，以确定已发表和未发表的论文。
我们纳入了针对 ALS/MND 患者的任何干预措施（包括相互之间、与安慰剂或无干预措施）治疗流涎症和相关症状的随机对照试验（RCT）和准随机对照试验，包括交叉试验。
我们使用了 Cochrane 预期的标准方法学程序。
我们共识别出四项 RCT，涉及 110 名 MND 患者，这些患者被描述为患有难治性流涎症或延髓功能障碍。一项关于肉毒杆菌毒素 B 与安慰剂的设计良好的研究，将肉毒杆菌毒素 B 注射到 20 名参与者的腮腺和下颌下腺中，结果表明肉毒杆菌毒素 B 可能会改善参与者报告的流涎症状，但置信区间（CI）也与无效应一致。肉毒杆菌毒素 B 组的 6 名参与者和安慰剂组的 2 名参与者报告有改善（RR 3.00，95%CI 0.81 至 11.08；1 项 RCT；18 名参与者；低质量证据）。一项客观测量指标表明，与安慰剂相比，肉毒杆菌毒素 B 可能会在 8 周时减少唾液分泌量（以 5 分钟内的毫升数表示）（MD -0.50，95%CI -1.07 至 0.07；18 名参与者，中等质量证据）。肉毒杆菌毒素 B 可能对生活质量几乎没有影响，使用“评估个人生活质量的时间表直接加权量表”（SEIQoL-DW；0-100，值越高表示生活质量越好）进行测量（MD -2.50，95%CI -17.34 至 12.34；1 项 RCT；17 名参与者；低质量证据）。肉毒杆菌毒素 B 组和安慰剂组的不良事件发生率可能相似（20 名参与者；低质量证据）。试验人员认为没有任何严重事件与治疗有关。一项针对 20 名参与者的肉毒杆菌毒素 A 或放疗的随机试验研究，由于偏倚风险高，仅提供了 12 周时 Drool Rating Scale（DRS；范围 8 至 39 分，得分越高表示流涎越严重）主要结局的极低质量证据（效应大小 -4.8，95%CI -10.59 至 0.92；P = 0.09；1 项 RCT；16 名参与者）。未测量生活质量。治疗后立即（RR 7.00，95%CI 1.04 至 46.95；20 名参与者）和 4 周后（当每组各有两人出现粘性唾液时）不良事件的证据也非常不确定。一项针对 20 毫克右美沙芬氢溴酸盐和 10 毫克奎尼丁硫酸盐（DMQ）的 20 名参与者的 2 期、随机、安慰剂对照交叉研究发现，DMQ 可能会改善流涎症状，表现为主要结局——神经病学研究中的延髓功能障碍量表（CNS-BFS）的评分略有下降。DMQ 治疗期的平均总 CNS-BFS（范围 21（无症状）至 112（最大症状））为 53.45（标准误（SE）为 1.07），安慰剂期为 59.31（SE 为 1.10）（平均差异）MD -5.85，95%CI -8.77 至 -2.93），与安慰剂相比，CNS-BFS 流涎子量表评分略有下降（范围 7（无症状）至 35（最大症状））（MD -1.52，95%CI -2.52 至 -0.52）（1 项 RCT；60 名参与者；中等质量证据）。该研究未报告唾液分泌的客观测量值或测量生活质量。该研究存在偏倚风险不确定。不良事件与其他 DMQ 试验相似，且与安慰剂的发生率可能相似（中等质量证据，60 名参与者），最常见的副作用包括便秘、腹泻、恶心和头晕。DMQ 治疗引起的恶心和腹泻导致 1 人退出。一项针对皮下贴剂形式的莨菪碱（氢溴酸东莨菪碱）的随机、双盲、安慰剂对照交叉研究纳入了 10 名随机参与者，其中 8 名提供了疗效数据。参与者代表了常规临床护理中接受喂养管和气管切开通气的诊所队列，该研究存在高偏倚风险。该试验在短期（7 天治疗，用肌萎缩侧索硬化症功能评定量表修订版（ALSFRS-R）的唾液项目进行测量，P = 0.572）和短期唾液产生量（以棉卷重量表示，P = 0.674）或每日口腔抽吸量（P = 0.69）方面提供了非常低质量或中等质量的证据。未测量生活质量。不良事件证据也非常不确定。接受莨菪碱治疗的 1 人出现口干，1 人因考虑与治疗无关的吸入性肺炎而死亡。
有一些低质量或中等质量的证据表明，肉毒杆菌毒素 B 注射到唾液腺和口服右美沙芬加奎尼丁（DMQ）治疗 MND 患者的流涎症可能有效。关于放疗与肉毒杆菌毒素 A 注射以及东莨菪碱贴片的证据还不够充分，无法得出任何结论。需要进一步研究治疗流涎症的方法。目前需要有关 MND 流涎症及其测量的问题的数据，包括参与者自我报告的措施和客观测试。这将有助于开发更好的 RCT。
