Botulinum toxin for the treatment of cervical dystonia

Cervical dystonia (CD) manifests clinically through involuntary spasms of neck muscles, producing abnormal head and neck movements and postures, which is often associated with pain. CD is the most common form of focal dystonia presenting to movement disorders clinics. Chemodenervation with botulinum toxin (BTX) has become the first-line treatment for CD, producing satisfactory relief of symptoms in > 80% of cases. Unresolved issues that may impact on the overall results include the method of selection for injection sites (clinical vs. electromyography), dosing, dilution and the role and relative efficacy of the different BTX serotypes. A guiding therapeutic principle of BTX injections is to achieve optimal results with the lowest possible dosage and frequency of administration. This strategy is critical in order to keep the risk of immunoresistance at a minimum. Development of antibodies that block the effects of BTX, usually associated with frequent injections of high doses, is the main reason for secondary unresponsiveness to this treatment. Although the mechanism of denervation at the neuromuscular junction by BTX is relatively well understood, the role of changes in muscle spindles and myopathic pain mechanisms, as well as secondary changes at the level of the basal ganglia, thalamus and cortex and their role in response to BTX, all need further exploration.     

Botulinum toxin A for the treatment of cervical dystonia

Idiopathic cervical dystonia (ICD) is the most common adult-onset focal dystonia. It is characterised by relatively sustained, involuntary contractions of neck muscles. Injections of botulinum toxin (BTX)-A are safe and effective for the treatment of ICD, and have substantially improved its treatment. BTX-A is manufactured by Allergan Pharmaceuticals in the US and Ireland, and is distributed as Botox^®. In Europe, BTX-A is manufactured and distributed by Ipsen Pharmaceuticals as Dysport^®. Success rates for BTX-A injections for ICD ranges 64 – 90%, with 76 – 93% of injected patients experiencing pain reduction. Side effects are generally mild and include dysphagia and neck weakness.     

The management of cervical dystonia

Cervical dystonia (CD), also known as ‘spasmodic torticollis’, is the most common form of adult-onset focal dystonia. It is a chronic disorder for which there is no curative treatment. Proposed interventions only have a symptomatic effect that is directed at controlling the intensity of the dystonic contractions and their associated symptoms. Both serotypes of botulinum toxin (BtA and BtB) have shown efficacy for the treatment of CD, and they constitute the first-line therapy for CD. BtB constitutes the best medical treatment for secondary failures to BtA. The efficacy of all other proposed medications, including anticholinergics, should be considered unknown due to the lack of good-quality trials. This lack of evidence applies also to all physical rehabilitation treatments. Although the authors have concluded that all surgical procedures for CD should still be considered investigational, the best data supporting benefit of surgery comes from case series of selective peripheral denervation and pallidal deep brain stimulation.     

A型肉毒毒素治疗肌张力障碍

A型肉毒毒素因用于高兴奋性肌肉疾病的有效性而倍受神经内科医生的关注,治疗的方法越来越多,治疗的病种不断扩展,被认为是近几年来神经内科领域重要进展之一.本文从A型肉毒毒素历史、药理、方法与剂量、适应证(偏侧面肌痉挛与单纯眼肌痉挛、痉挛性斜颈、Meige综合征、祛皱美容)、毒副作用、禁忌证等几个方面进行综述.     

The Role of Ultrasound for the Personalized Botulinum Toxin Treatment of Cervical Dystonia

The visualization of the human body has frequently been groundbreaking in medicine. In the last few years, the use of ultrasound (US) imaging has become a well-established procedure for botulinum toxin therapy in people with cervical dystonia (CD). It is now undisputed among experts that some of the most relevant muscles in this indication can be safely injected under visual US guidance. This review will explore the method from basic technical considerations, current evidence to conceptual developments of the phenomenology of cervical dystonia. We will review the implications of introducing US to our understanding of muscle function and anatomy of common cervical dystonic patterns. We suggest a flow chart for the use of US to achieve a personalized treatment of people with CD. Thus, we hope to contribute a resource that is useful in clinical practice and that stimulates the ongoing development of this valuable technique.     

A型肉毒毒素治疗偏头痛的临床研究

目的:观察A型肉毒毒素治疗预防偏头痛 发作的临床疗效和不良反应。方法:选取30例偏头 痛病人,应用A型肉毒毒素进行颅周肌内注射治 疗,问卷调查记录每例偏头痛病人治疗前3mo,治 疗后mo1,2,3偏头痛发作情况,比较偏头痛发作频 率、发作持续时间、发作严重程度及使用止痛药物情 况,观察不良反应。结果:A型肉毒毒素治疗后 mo1,偏头痛发作频率、发作持续时间、发作严重程 度均较治疗前明显下降(P<0.01),止痛药物的使 用较治疗前减少(P<0.01),疗效可至少维持3mo, 且不良反应轻微、短暂。结论:A型肉毒毒素颅周肌 内注射治疗预防偏头痛发作临床疗效显著,不良反 应轻微、短暂,值得临床研究。     

Effect of Botulinum Toxin on Non-Motor Symptoms in Cervical Dystonia

Patients with cervical dystonia (CD) may display non-motor symptoms, including psychiatric disturbances, pain, and sleep disorders. Intramuscular injection of botulinum toxin type A (BoNT-A) is the most efficacious treatment for motor symptoms in CD, but little is known about its effects on non-motor manifestations. The aim of the present study was to longitudinally assess BoNT-A’s effects on CD non-motor symptoms and to investigate the relationship between BoNT-A-induced motor and non-motor changes. Forty-five patients with CD participated in the study. Patients underwent a clinical assessment that included the administration of standardized clinical scales assessing dystonic symptoms, psychiatric disturbances, pain, sleep disturbances, and disability. Clinical assessment was performed before and one and three months after BoNT-A injection. BoNT-A induced a significant improvement in dystonic symptoms, as well as in psychiatric disturbances, pain, and disability. Conversely, sleep disorders were unaffected by BoNT-A treatment. Motor and non-motor BoNT-A-induced changes showed a similar time course, but motor improvement did not correlate with non-motor changes after BoNT-A. Non-motor symptom changes after BoNT-A treatment are a complex phenomenon and are at least partially independent from motor symptom improvement.     

A型肉毒毒素治疗肌张力过强

目的：探讨Ａ型肉毒毒素局部注射治疗面肌痉挛、各型头颈肌张力障碍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痉挛肌肉,治疗前后对照。结果：治疗面肌痉挛２５０例（１０２８轮次）,有效率１００％,作用持续１６ｗｋ±ｓ４ｗｋ;睑痉挛７８例（２６０轮次）,有效率９３．９％,作用持续１５ｗｋ±４ｗｋ;口颌肌痉挛５３例（１８１轮次）,有效率８５．１％,作用持续１４ｗｋ±４ｗｋ;痉挛性斜颈２８例（７９轮次）,有效率８１％,作用持续１４ｗｋ±４ｗｋ。副作用轻微、可逆。结论：该疗法安全、有效,可作为面肌痉挛及各型头颈部肌张力障碍的首选治疗。     

Botulinum toxin A for the Treatment of Overactive Bladder

The standard treatment for overactive bladder starts with patient education and behavior therapies, followed by antimuscarinic agents. For patients with urgency urinary incontinence refractory to antimuscarinic therapy, currently both American Urological Association (AUA) and European Association of Urology (EAU) guidelines suggested that intravesical injection of botulinum toxin A should be offered. The mechanism of botulinum toxin A includes inhibition of vesicular release of neurotransmitters and the axonal expression of capsaicin and purinergic receptors in the suburothelium, as well as attenuation of central sensitization. Multiple randomized, placebo-controlled trials demonstrated that botulinum toxin A to be an effective treatment for patients with refractory idiopathic or neurogenic detrusor overactivity. The urinary incontinence episodes, maximum cystometric capacity, and maximum detrusor pressure were improved greater by botulinum toxin A compared to placebo. The adverse effects of botulinum toxin A, such as urinary retention and urinary tract infection, were primarily localized to the lower urinary tract. Therefore, botulinum toxin A offers an effective treatment option for patients with refractory overactive bladder.     

Botulinum toxin therapy for pain and inflammatory disorders: mechanisms and therapeutic effects

Botulinum toxin (BTX) injections are a well-recognised therapeutic modality for the treatment of regional involuntary muscle disorders and recently BTX has been used for treatment of pain and inflammatory disorders. The primary purpose of this review is to discuss the mechanism of action of therapeutic BTX in light of both the traditional understanding of BTX pharmacological effects as well as new observations. The review will deal with clinical observations and relevant animal experimentation. The data and hypotheses presented are not only relevant to botulinum toxin technology but will certainly prove important in the basic mechanisms of some of the diseases where botulinum toxin has been successfully applied. BTX used clinically comprises botulinum neurotoxin (BoNT) complexed with non-toxic proteins. The non-toxic components of the BTX complexes stabilise the labile BoNT during purification and formulation as a therapeutic. The complex proteins may also have unrecognised clinical significance such as slowing diffusion in tissues or imparting stability. The mechanisms of BTX formulations acting on SNARE proteins are briefly reviewed providing a basis for BTX clinical applications. The potential for design of improved botulinum toxins and formulations is addressed.     

Botulinum toxin B: a review of its therapeutic potential in the management of cervical dystonia

Botulinum toxins are well known as the causative agents of human botulism food poisoning. However, in the past two decades they have become an important therapeutic mainstay in the treatment of dystonias including cervical dystonia, a neurological disorder characterised by involuntary contractions of the cervical and/or shoulder muscles. The toxins inhibit acetylcholine release from neuromuscular junctions, producing muscle weakness when injected into dystonic muscles. Data from three double-blind, randomised, placebo-controlled trials demonstrate that botulinum toxin B effectively reduces the severity, disability and pain of cervical dystonia. In two of the trials, mean Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS)-Total score at week 4 (primary efficacy measure) after botulinum toxin B 10 000U was reduced by 11.7 (25%) or 11 (21%) compared with baseline. These changes were significantly greater than those obtained with placebo [4.3 (10%) or 2 (4%)] and were generally similar in patients who were responsive or resistant to botulinum toxin A. Statistically significant benefits compared with placebo were also evident for a range of other efficacy parameters including TWSTRS-Severity, -Pain and -Disability subscales, patient- assessed pain and patient-/physician-assessed global improvement ratings. In another trial, the percentage of patients with botulinum toxin A-resistant or -responsive cervical dystonia who had a > or =20% improvement in the TWSTRS-Total score between baseline and week 4 was significantly higher with botulinum toxin B 2500 to 10 000U (58 to 77%) than with placebo (27%). Overall, botulinum toxin B was generally well tolerated. The most frequently reported treatment-related adverse events were dry mouth and dysphagia. Most adverse events in patients receiving botulinum toxin B were mild or moderate; no serious adverse events or laboratory abnormalities were associated with the use of botulinum toxin B and, where reported, no patients discontinued from any of the clinical trials as a result of adverse events. CONCLUSIONS: Botulinum toxin B has shown clinical efficacy in patients with cervical dystonia at doses up to 10 000U and is generally well tolerated. Its efficacy extends to patients who are resistant to botulinum toxin A. Although the potential for secondary resistance to botulinum toxin B remains unclear, it may occur less than with botulinum toxin A because methods for manufacturing commercially available botulinum toxin B do not include lyophilisation and the product does not require reconstitution before use. As injection with botulinum toxin is generally considered the treatment of choice for patients with cervical dystonia, botulinum toxin B should be considered a potential treatment option in this setting.     

Botulinum toxin A for palmar hyperhidrosis: assessment with sympathetic skin responses evoked by train of stimuli

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A型肉毒毒素重复治疗特发性睑痉挛剂量及长期疗效探讨

目的 :探讨反复局部注射A型肉毒毒素治疗特发性睑痉挛维持疗效是否需增加剂量及能否保持疗效持续时间。方法 :对 178例病人A型肉毒毒素重复治疗 ,随访时间 7a。将 6轮的剂量、疗效、作用持续时间及不良反应比较 ,痉挛程度按Cohen强度分级 ,统计采用SAS软件统计包。结果 :经 7a 6轮观察 ,各轮疗效为 89.9% ,97.1% ,96 .4 % ,95 % ,95 %及 98% ;平均作用持续时间均为 15～16wk、平均剂量均为 70U左右 ,除第 1轮有效率较第 2轮、第 3轮为低 (P <0 .0 5 ) ,其余各轮间疗效、平均剂量、作用持续时间均无显著差异 (P >0 .0 5 )。总体发生不良反应均为 30 %左右。结论 :A型肉毒毒素重复局部注射治疗特发性睑痉挛 ,维持相似疗效和作用持续时间 ,无需增加剂量     

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