肉毒毒素临床应用进展及适应症审批的意义

肉毒毒素是肉毒梭菌增殖过程中产生的一种细菌外毒素,其可作用于周围神经末梢的神经肌肉接头处抑制突触前神经递质乙酰胆碱的释放,实现肌肉化学性去神经支配、镇痛、调节自主神经紊乱等效应。本文重点概述肉毒毒素的治疗效应,以及肉毒毒素临床应用进展和肉毒毒素适应症开发的临床价值。     

肉毒毒素治疗成人肢体肌痉挛中国指南(2010)

本文在参考和<肉毒毒素治疗痉挛英国全国指南>的基础上,尊重我国康复专家的共同意见形成的指南.肌痉挛是肌肉不自主的运动过度,通常发生于中枢神经系统(脑和脊髓)损伤以后.痉挛表现多种多样,具体取决于病灶的大小、部位和损伤时间.肌痉挛可导致各种有害的结果,如疼痛、畸形和功能受损.肌痉挛的处理比较复杂.局部肌肉注射肉毒毒素(botulinum toxin,BT)是治疗局灶性肌痉挛普遍接受方法,耐受性很好.有大量强有力的Ⅰ级证据说明了这种方法能降低痉挛患者的肌肉张力,继而改善患者功能.市场上有不同的肉毒毒素产品,不同肉毒毒素产品的生产工艺、配方、结构及均匀程度都不同,且采用不同的生物鉴定方法,故不同肉毒毒素产品剂量单位不可互换.不同肉毒毒素产品治疗肌痉挛都有效,但其耐受性和不良事件发生率不同.目前的临床证据显示:保妥适安全性良好,剂量增加不会导致副反应的增加;1997年以后的保妥适配方,纯度增加,抗体形成是很罕见的事件(1/191例成年人),不再是一个有临床意义的问题.该指南主要针对康复医学科,目的是给康复医生提供参考,以便他们能合理使用肉毒毒素治疗痉挛;但也可以作为其他学科应用的参考.肉毒毒素在各国的适应证不尽相同,大多数国家包括我国的专家均认为:有经验的临床医生可以超出说明书范畴而用于其他肌群的注射.只有在肌痉挛的评价和治疗方面有经验的临床医生才能注射肉毒毒素.肌痉挛的治疗主要目标是让肌肉伸展,恢复正常位置.因此,肉毒毒素不能单独使用,而是多学科综合疗法的组成部分.选择合适的患者以及制定明确、切实可行并且可测评的目标,对用肉毒毒素治疗肌痉挛取得成效至关紧要.采取各种干预措施的共同目标都是为了缓解疼痛、改善肢体的活动范围、减轻护理负担,某些情况下可以增强主动功能或为恢复主动功能提供机会.这些目标建议应记录于患者的病历中,每次注射肉毒毒素时,都应评价治疗效果.治疗效果的评价指标应与所记录的治疗目标相符.按照该指南使用肉毒毒素,有可能预防挛缩和畸形,从而减轻患者和医护人员的负担.     

肉毒毒素临床作用的影响因素及对策

目的：从国内外肉毒毒素对上运动神经元损伤后肢体痉挛的治疗及相关研究出发，探讨影响肉毒毒素临床作用的因素及对策。 资料来源：应用计算机检索Medline1998-01／2005-05与上运动神经元损伤后肉毒毒素治疗肢体痉挛相关的文献。检索词“botulinum toxin，spasticity／spastic”，并限定文献语种为英文。同时计算机检索万方数据库2003-01／2005-05与上运动神经元损伤后肉毒毒素治疗肢体痉挛相关的文献，检索词“肉毒毒素，痉挛”，并限定文献语种为中文。 资料选择：从资料中选取包括治疗组和对照组的文献，然后选择随机临床试验的研究。纳入标准：①上运动神经元损伤后肉毒毒素治疗肢体肌肉痉挛的随机对照临床试验。②临床试验研究包括平行对照组。③治疗组采用了含肉毒毒素的治疗。排除标准：非上运动神经元损伤后的肌张力异常，综述类文献，没有对照组的文献。 资料提炼：共收集98篇关于上运动神经元损伤后肉毒毒素治疗肢体肌肉痉挛的临床试验。49个试验纳入标准。排除的49篇中6篇是综述，43篇为无对照组。 资料综合：49个试验包括2679例患者，分别对肉毒毒素治疗上运动神经元损伤后肢体痉挛进行评价。在治疗过程中明确功能目标，采用个体化剂量，应用电刺激准确定位，确保A型肉毒毒素最大限度地与神经肌肉接头处的作用位点相结合，发挥其最大的生物学效应。而注射后采用电刺激、牵张等相应的康复治疗可以增强治疗效果。 结论：肉毒毒素对上运动神经元损伤后肢体肌肉痉挛的疗效是肯定的，但其应用方法需要进一步研究和规范。     

肉毒毒素在疼痛治疗中的应用

目的：A型肉毒毒素是肉毒梭菌产生的一种细菌外毒素，可与神经肌肉接头处胆碱能神经末梢结合，抑制乙酰胆碱的释出，使肌肉松弛，目前已广泛用于治疗肌肉活动过度性疾病，近年来许多研究发现，肉毒毒素还可用于疼痛的治疗。 资料来源：应用计算机检索Medline1988—01／2005—12的关于肉毒毒素的文章，检索词为“botulinum toxin type，headache，pain，nociceptor，mechanism”，并限定文章语言种类为English。 资料选择：对资料进行初审，选择与肉毒毒素的分子结构，作用机制，疼痛治疗中的应用相关的研究原著及个案报道。排除标准：重复性研究。 资料提炼：共收集到123篇关于肉毒毒素治疗疼痛的研究原著及个案报道，符合纳入标准60篇，排除63篇。详细分析31篇。 资料综合：肉毒毒素在疼痛治疗中的应用研究包括各种类型的头痛，急性和慢性颈部扭伤，慢性腰背痛，“网球肘”，肌筋膜痛综合征，足底筋膜炎，慢性骨盆痛，慢性前列腺痛，间质性膀胱炎，三叉神经痛等。局部注射A型肉毒毒素对由肌痉挛和非肌痉挛引起的疼痛均有效。 结论：肉毒毒素已广泛用于治疗肌肉活动过度性疾病，在疼痛中的应用首先用于治疗头痛的研究，此后在其他各种疼痛的研究也相继报道。肉毒毒素在疼痛中的应用是一种新的治疗方法，具有广泛的应用前景，值得进一步的研究。     

肉毒毒素临床作用的影响因素及对策

目的:从国内外肉毒毒素对上运动神经元损伤后肢体痉挛的治疗及相关研究出发,探讨影响肉毒毒素临床作用的因素及对策。资料来源:应用计算机检索Medline1998-01/2005-05与上运动神经元损伤后肉毒毒素治疗肢体痉挛相关的文献,检索词“botulinumtoxin,spasticity/spastic”,并限定文献语种为英文。同时计算机检索万方数据库2003-01/2005-05与上运动神经元损伤后肉毒毒素治疗肢体痉挛相关的文献,检索词“肉毒毒素,痉挛”,并限定文献语种为中文。资料选择:从资料中选取包括治疗组和对照组的文献,然后选择随机临床试验的研究。纳入标准:①上运动神经元损伤后肉毒毒素治疗肢体肌肉痉挛的随机对照临床试验。②临床试验研究包括平行对照组。③治疗组采用了含肉毒毒素的治疗。排除标准:非上运动神经元损伤后的肌张力异常,综述类文献,没有对照组的文献。资料提炼:共收集98篇关于上运动神经元损伤后肉毒毒素治疗肢体肌肉痉挛的临床试验。49个试验纳入标准。排除的49篇中6篇是综述,43篇为无对照组。资料综合:49个试验包括2679例患者,分别对肉毒毒素治疗上运动神经元损伤后肢体痉挛进行评价。在治疗过程中明确功能目标,采用个体化剂量,应用电刺激准确定位,确保A型肉毒毒素最大限度地与神经肌肉接头处的作用位点相结合,发挥其最大的生物学效应。而注射后采用电刺激、牵张等相应的康复治疗可以增强治疗效果。结论:肉毒毒素对上运动神经元损伤后肢体肌肉痉挛的疗效是肯定的,但其应用方法需要进一步研究和规范。     

肉毒毒素在疼痛治疗中的应用

目的:A型肉毒毒素是肉毒梭菌产生的一种细菌外毒素,可与神经肌肉接头处胆碱能神经末梢结合,抑制乙酰胆碱的释出,使肌肉松弛,目前已广泛用于治疗肌肉活动过度性疾病,近年来许多研究发现,肉毒毒素还可用于疼痛的治疗。资料来源:应用计算机检索Medline1988-01/2005-12的关于肉毒毒素的文章,检索词为“botulinumtoxintype,headache,pain,nociceptor,mechanism”,并限定文章语言种类为English。资料选择:对资料进行初审,选择与肉毒毒素的分子结构,作用机制,疼痛治疗中的应用相关的研究原著及个案报道。排除标准:重复性研究。资料提炼:共收集到123篇关于肉毒毒素治疗疼痛的研究原著及个案报道,符合纳入标准60篇,排除63篇。详细分析31篇。资料综合:肉毒毒素在疼痛治疗中的应用研究包括各种类型的头痛,急性和慢性颈部扭伤,慢性腰背痛,“网球肘”,肌筋膜痛综合征,足底筋膜炎,慢性骨盆痛,慢性前列腺痛,间质性膀胱炎,三叉神经痛等。局部注射A型肉毒毒素对由肌痉挛和非肌痉挛引起的疼痛均有效。结论:肉毒毒素已广泛用于治疗肌肉活动过度性疾病,在疼痛中的应用首先用于治疗头痛的研究,此后在其他各种疼痛的研究也相继报道。肉毒毒素在疼痛中的应用是一种新的治疗方法,具有广泛的应用前景,值得进一步的研究。     

A型肉毒毒素在治疗脑卒中后上肢痉挛中的应用

肉毒毒素（botulinum toxin, BTX）是治疗肌张力障碍和肌肉痉挛十分有效的药物.在我国,多应用于颜面部和颈部的肌肉痉挛.对于脑损伤后所致的肢体痉挛,我国应用这种方法治疗的情况并不多.本文就肉毒毒素治疗脑卒中后上肢痉挛的治疗应用进行综述.     

A型肉毒毒素治疗面肌痉挛的临床研究

目的 探讨A型肉毒毒素局部注射治疗面肌痉挛的临床疗效和安全性.方法 采用A型肉毒毒素局部多点注射面部痉挛肌肉,治疗前后进行疗效对照.结果 治疗面肌痉挛30例,有效率为100％,作用持续(20±4)周,不良反应轻微、可逆.结论 A型肉毒毒素治疗面肌痉挛安全、有效,可作为面肌痉挛的首选治疗.     

食用自制茄子酱致肉毒毒素中毒2例报告

肉毒毒素是肉毒杆菌产生的外毒素,最早在变质的火腿中被发现,少量食用即可致死,主要累及神经肌肉接头的突触前膜。近年来人们生活水平的提高,多食用新鲜食物,肉毒毒素中毒患者罕见。但是由于一些地区特殊的饮食习惯,喜食腌制食物,存在肉毒毒素中毒的潜在风险。本文报道的两例患者来自内蒙古,因食用肉沫茄子酱,造成中毒。由于诊断治疗及时,预后良好。     

肉毒杆菌食物中毒急诊救治一例

肉毒杆菌食物中毒是由肉毒杆菌释放的肉毒毒素引起严重的神经肌肉中毒症状。该病初期常因临床表现为急性胃肠道中毒症状引起误诊而耽误治疗,严重者导致患者死亡。及早明确诊断和临床对症治疗是成功救治该病的关键。该文总结分析1例肉毒杆菌食物中毒患者的急诊救治过程。经过详细询问该患者的发病史和进食史,进行全面的体格检查、常规检验、影像辅助检查和实验室血浆肉毒毒素检测分析并结合临床症状,该患者确诊为肉毒毒素中毒。在未明确肉毒毒素亚型情况下,对患者大剂量注射A、B型抗肉毒毒素,辅助抗感染和营养恢复神经功能的综合治疗取得较好的治疗效果。患者发病第7日症状好转,救治26 d后康复出院。     

Botulinum toxin A in the prophylactic treatment of migraine--a randomized, double-blind, placebo-controlled study

Botulinum toxin A has been suggested to be effective in the prophylactic treatment of migraine. However, only very few randomized, double-blind, placebo-controlled studies are available. We designed such a study with a specific focus on different injection sites. Sixty patients with a migraine according to the criteria of the International Headache Society were randomly assigned to receive either placebo in the frontal and neck muscles, or to receive 16 U botulinum toxin A in the frontal muscles and placebo in the neck muscles, or to receive in total 100 U botulinum toxin A in the frontal and neck muscles. The observation period was 3 months. In both treatment groups, 30% of patients showed a reduction of migraine frequency in month 3 by at least 50% compared with baseline, in the placebo group 25% of the patients showed such a reduction (P = 0.921). There were no significant differences between the three study groups with respect to reduction of migraine frequency, number of days with migraine, and the number of total single doses to treat a migraine attack. In the post hoc analysis, the reduction of all accompanying symptoms was significantly higher in the 16 U treatment group compared with the placebo group. In the 100 U treatment group significantly more adverse events occurred compared with the placebo group. All adverse events were mild and transient. Our study did not show any efficacy of botulinum toxin A in the prophylactic treatment of migraine. Only accompanying symptoms were significantly reduced in the 16 U but not in the 100 U treatment group. Future studies should focus on the efficacy of botulinum toxin A in specific subgroups of patients, on the efficacy of repetitive injections, and on other injection sites.     

书写痉挛责任肌群的认定及肉毒毒素治疗的疗效观察

目的　寻找引起患者书写痉挛 (writer scramp)并导致字迹抖动不清的主要责任肌群 ,并同时观察局部注射肉毒毒素 A (botulinumtoxin A ,BTX A)对书写痉挛病症的治疗效果及副反应发生情况。方法　通过对前臂肌群的选择性运动 ,判断各肌群对书写痉挛症状的影响 ,并初步认定责任肌群 ,然后用维库溴铵对初步确定的责任肌群进行选择性注射 ,以进一步确定引起书写痉挛的主要责任肌群 ,最后对已确定的主要责任肌群进行BTX A多点注射 ,观察其疗效及副反应发生情况。结果　本研究发现 ,当前臂旋转肌群运动时会加重书写痉挛症状 ,对该群肌肉注射维库溴铵后可消除痉挛症状。当对旋转肌群进行BTX A注射后 ,受试的 3例患者 (共 5侧患肢 )症状全部得到改善 ,无一例发生可察觉的握力减退及垂腕等副反应。结论　前臂旋转肌群是导致书写痉挛并致使字迹抖动不清的主要责任肌群 ,对其进行BTX A选择性多点注射可获得满意疗效 ,同时还可避免握力减退及垂腕等副反应的发生。     

Botulinum toxin treatment of axial and cervical dystonia

Axial truncal dystonia is characterized by an abnormal trunk posture often superimposed by myoclonic motor activities. Cervical dystonia is a motor syndrome characterized by abnormal head and neck posture due to tonic involuntary contractions in a certain set of muscles often superimposed by myoclonic or tremolous movements. Intramuscular injection of botulinum toxin is the first line treatment in cervical dystonia, in axial truncal dystonias botulinum toxin therapy is used only in mild forms. In this review the theoretical background, practical aspects and efficacy results especially in cervical dystonia are presented. Treatment of axial trunk dystonia is only briefly discussed at the beginning of this review.     

Serial injection of botulinum toxin for muscle imbalance due to regional spasticity in the upper limb

Background and purpose. Three-dimensional movement in the upper limb presents a challenge for functional management of regional spasticity. Potential toxicity of botulinum toxin limits the number of muscles which may be injected in any one session. Serial injection may offer a solution, but carries theoretical risk of development of resistance due to antibody formation. This article reviews a small case series, gathered in a post-acute neuro-rehabilitation setting, to evaluate the use of serial botulinum toxin injection in terms of goal achievement and clinical evidence for toxicity or resistance.

Methods. Nine patients with regional spasticity following acute stroke or brain injury had serial injection of botulinum toxin to muscle groups around the shoulder, elbow and/or wrist. Injection was followed by splinting/physiotherapy as appropriate. Goal attainment scaling was used to assess outcome.

Results. Functional goals achieved were reduction of pain (n = 6/7) associated reaction (n = 4/5) or care needs (n = 5/6), improved gait (n = 2/3) or independence in self-care (n = 2/5). Two ‘golden responder’ cases are presented in detail to demonstrate resolution of symptoms with up to four serial injections of botulinum toxin over a period of up to 6 months. No clinical evidence of toxicity or resistance was seen in any case.

Conclusion. These preliminary findings suggest that serial botulinum toxin injection followed by appropriate physiotherapy/splinting may provide effective treatment for regional spasticity. Resistance has not presented a problem in this post-acute situation, where treatment has not been required beyond a few months. Ongoing evaluation is underway.     

Effectiveness of botulinum toxin injection with and without needle electromyographic guidance for the treatment of spasticity in hemiplegic patients: a randomized controlled trial

Abstract

Purpose: To compare the effects of botulinum toxin injection with and without needle electromyographic guidance for the treatment of spasticity. Method: A randomized controlled study was conducted in a tertiary university hospital. Twenty-seven adult hemiplegic patients with spasticity due to brain or spinal cord damage were included. Spastic muscles were injected with botulinum toxin with or without EMG guidance. The modified Ashworth scale and modified Barthel index in each patient pre- and post-injection were documented. Results: In group A, which consisted of 15 patients (55.55%), the injection was administered with needle electromyographic guidance, while in 12 patients (44.44%) of group B without electromyographic guidance with the use of anatomic landmarks only. The follow-up period was 3 months. At 3 weeks post-injection, spasticity was decreased (p?<?0.05) in all patients and the mean (SD) reduction of spasticity was higher (p?<?0.05) in group A (1.67 (0.5)) than group B (1.25 (0.46)). Similarly, the mean (SD) functional modified Barthel index improved statistically significantly (p?<?0.001) post-injection (45.37 (8.43)) than pre-injection (54.07 (9.610), especially in group A (p?<?0.05). Conclusion: The effectiveness of intramuscular botulinum toxin injection for the treatment of spasticity in hemiplegic patients is superior when performed with needle electromyographic guidance than without electromyography.

• Implications for Rehabilitation

• It is recommended that botulinum toxin muscle injections of hemiplegic limbs be performed with EMG guidance

• More spasticity reduction and functional improvement at 3 months post-injection was observed in patients injected with botulinum toxin by the use of combined EMG guidance and anatomic landmarks

• EMG guidance might also save amount of botulinum toxin due to less spasticity observed during injection than when injection is performed with anatomic landmarks only

     

肉毒杆菌毒素在眼科的应用进展

肉毒杆菌毒素是由肉毒杆菌在繁殖过程中所产生的一种神经毒素蛋白,其作用机制是阻断乙酰胆碱在胆碱能神经的神经肌肉接头释放而阻断传导冲动。在眼科诊疗中,它已被常规用于眼睑痉挛、斜视、眼周除皱、上睑挛缩等眼部疾病的治疗,其疗效确切。本文综述了肉毒杆菌毒素在眼科的相关应用进展。     

Botulinum toxin injections for the treatment of frontal tension headache

Abstract We performed a randomized, double-blind, placebo-controlled trial to determine the efficacy of botulinum toxin type A (BOTOX; Allergan) in treating frontal tension-type headache (TTH). A total of 40 patients attending a headache treatment center were randomized to receive 50 U botulinum toxin type A or saline, injected at 10 sites of the forehead. Frequency and severity of headaches before and after injection were compared. The intensity of headaches in the botulinum toxin type A group, but not the placebo group, fell significantly from an average score of 5.19 to 4.65 (p<0.0001). Botulinum toxin type A patients and placebo patients experienced an average reduction in the number of headaches per month, but these reductions were not significantly different between groups. Botulinum toxin type A was well tolerated, with no significant adverse events. Botulinum toxin type A injections in the management of frontal TTH has been shown by this study to be both effective and well tolerated. It should be noted that the effect of botulinum toxin on intensity of headache, although statistically significant, was relatively small.     

A型肉毒毒素注射治疗卒中后肌张力障碍的临床观察

目的 观察A型肉毒毒素注射治疗卒中后肌张力障碍患者的肌张力、残疾水平和日常生活活动（ADL）能力的影响。 方法 选取卒中后肌张力障碍患者32例,按随机数字表法分为观察组（16例）和对照组（16例）,对照组失访1例,最终31例患者完成本研究。观察组患者给予靶肌肉注射A型肉毒毒素200～600 U,对照组给予盐酸苯海索片2 mg每日2次口服,逐渐加量至4 mg每日3次,共治疗12周。分别于治疗前及治疗2周后、治疗6周后和治疗12周后,采用改良版Ashworth量表（MAS）、残疾评估量表（DAS）、改良巴氏指数(MBI)量表分别评价2组患者的痉挛程度、残疾程度和ADL能力。 结果 治疗后,2组患者的MAS、DAS、MBI评分［观察组2周后MAS（1.50±0.53）分、DAS（2.10±0.83）分、MBI（58.50±8.86）分,6周后MAS（1.28±0.89）分、DAS（1.37±0.50）分、MBI（71.25±13.96）分,12周后MAS（2.03±0.59）分、DAS（1.50±0.63）分、MBI（73.1±12.35）分;对照组2周后MAS（3.00±0.46）分、DAS（2.58±0.64）分、MBI（54.66±7.18）分,6周后MAS（3.00±0.44）分、DAS（2.40±0.51）分、MBI（58.60±7.28）,12周后MAS（2.53±0.51）分、DAS（2.21±0.45）分、MBI（63.86±7.41）分］均优于组内治疗前评分［观察组MAS（3.46±0.51）分、DAS（2.60±0.50）分、MBI（53.56±6.03）分;对照组MAS（3.50±0.52）分、DAS（2.61±0.62）分、MBI（53.06±7.23）分］,差异有统计学意义(P<0.05)。观察组治疗后MAS、DAS、MBI评分明显优于对照组,且治疗后同时间点比较,组间差异有统计学意义(P<0.05)。 结论 A型肉毒毒素治疗可显著改善卒中后肌张力障碍患者的肌张力和残疾程度。