The current use of botulinum toxin.

Botulinum toxin is the most potent neurotoxin known, and has been in clinical use since the late 1970s. The toxin inhibits the release of acetylcholine from nerve terminals by inhibiting transport of the synaptic vesicles, thus causing functional denervation lasting up to 6 months. Our understanding of the mechanism of action of the toxin and the spectrum of diseases treatable with this agent continues to increase. Efficacy has been demonstrated in hemifacial spasm, dystonia, spasticity, hyperhidrosis and other conditions. Alternative serotypes are used in some centres, generally after the development of immunoresistance to the standard toxin (serotype A), and are likely to be in routine use in the near future. This paper reviews the history, pharmacology and current uses of botulinum toxin.     

Expanding use of botulinum toxin

Botulinum toxin type A (BTX-A) is best known to neurologists as a treatment for neuromuscular conditions such as dystonias and spasticity and has recently been publicized for the management of facial wrinkles. The property that makes botulinum toxin type A useful for these various conditions is the inhibition of acetylcholine release at the neuromuscular junction. Although botulinum toxin types A and B (BTX-A and BTX-B) continue to find new uses in neuromuscular conditions involving the somatic nervous system, it has also been recognized that the effects of these medications are not confined to cholinergic neurons at the neuromuscular junction. Acceptors for BTX-A and BTX-B are also found on autonomic nerve terminals, where they inhibit acetylcholine release at glands and smooth muscle. This observation led to trials of botulinum neurotoxins in various conditions involving autonomic innervation. The article reviews the emerging use of botulinum neurotoxins in these and selected other conditions, including sialorrhea, primary focal hyperhidrosis, pathological pain and primary headache disorders that may be of interest to neurologists and related specialists.     

Clinical use of botulinum toxin

Over the past 20 years, botulinum toxin has proved the treatment of choice for a number of symptoms and disorders. Its successful therapeutic use in certain other diseases, however, has been limited by lack of approval. In many indications ? for example headaches ? its value has not yet been definitely established. Botulinum toxin is meanwhile offered by four manufacturers, and we may expect additional preparations in future.     

Sympathetic block with botulinum toxin to treat complex regional pain syndrome

Complex regional pain syndrome is a refractory pain condition with few tested therapies. We hypothesized that botulinum toxin A (BTA) would prolong analgesia after sympathetic blocks in patients with complex regional pain syndrome. We compared the duration of standard lumbar sympathetic block (LSB) with bupivacaine to LSB with bupivacaine and BTA in nine patients with refractory complex regional pain syndrome. Median time to analgesic failure was 71 (95% confidence interval, 12–253) days after LSB with BTA compared with fewer than 10 days (95% confidence interval, 0–12) after standard LSB (log‐rank, p < 0.02). BTA profoundly prolonged the analgesia from sympathetic block in this preliminary study. Ann Neurol 2009;65:348–351     

The use of botulinum toxin type-B in the treatment of patients who have become unresponsive to botulinum toxin type-A -- initial experiences.

The increasing use of botulinum toxin type-A, especially for focal dystonia and spasticity has highlighted the issue of secondary non-responsiveness. Within the last few years botulinum toxin type-B (Myobloc/Neurobloc) has become commercially available as an alternative to type-A. This paper discusses our initial experience of botulinum toxin type-B in a total of 63 individuals who attended our botulinum clinic. Thirty-six patients had cervical dystonia and a secondary non-response to type-A toxin. Thirteen of these patients (36%) had a reasonable clinical response to Neurobloc and continue to have injections. The other 23 patients either had no response, or a poor response, or had unacceptable side effects and ceased treatment. A small number of people with blepharospasm, hemifacial spasm and foot dystonia also had a disappointing response to injection. Twenty patients with spasticity were also type-A resistant. Seven of these show some continuing response to type-B, without unacceptable side effects. These findings demonstrate that botulinum toxin type-B has a place in the management of patients who have become non-responsive to type-A, but overall the responses to type-B toxin were disappointing.     

The use of botulinum toxins to treat hyperhidrosis and gustatory sweating syndrome

Hyperhidrosis is a chronic condition characterized by excessive sweating. Recent studies report that it affects approximately 2.8% of the population and typically begins during adolescence. Gustatory sweating usually occurs after parotid gland injury or surgery, and both disorders can be debilitating for those who are affected. Both diseases respond very well to botulinum toxin therapy and this article will review the use of botulinum toxins, including the serotypes used, dosing, and complications.     

Sustained benefit of painful legs moving toes syndrome with botulinum toxin type A

Painful legs moving toes (PLMT) is a rare disorder characterized by an often-severe painful sensation in the legs associated with involuntary movement of the toes. The treatment can be challenging given the poor response to pharmacotherapy. We present a patient with PLMT who obtained substantial benefit in both pain and severity of involuntary movement with botulinum toxin type A injections for more than 3 years.     

High doses of botulinum toxin effectively treat disabling up-going toe

Involuntary up-going toe can be a disabling consequence of dystonia or spasticity. In this study, we treated eight patients with botulinum toxin (BTx) in the extensor hallucis longus (EHL) and applied objective and subjective outcome measures to determine treatment efficacy. Using 100% higher doses than generally reported, patients noted 62+/-20% mean benefit and scores on a modified Fahn-Marsden Dystonia Scale decreased significantly by 1.8+/-0.6 (p=0.010). High doses (up to 160 BTx A units) into the EHL were safe and dosage correlated highly and significantly with treatment efficacy (rho=0.859, p=0.006).     

The use of botulinum toxin in the treatment of adductor spasmodic dysphonia.

Botulinum toxin injections have been used to treat 31 patients with adductor spasmodic dysphonia. Injections of 3.00-3.75 units of botulinum toxin were performed bilaterally into the thyroarytenoid muscle. This treatment significantly decreased the standard deviation of the fundamental frequency of the speech sample, indicating a reduction in the variability of pitch amongst patients. A total of 96% of patients' subjective diary reports showed an improvement with a median of 7 days to peak effect and a 5 week duration of peak effect.     

Clinical use of non-a botulinum toxins: botulinum toxin type B

Botulinum neurotoxin type B (BT, BT-B) has been used as NeuroBloc/MyoBloc since 1999 for treatment of cervical dystonia, hyperhidrosis, spastic conditions, cerebral palsy, hemifacial spasm, bladder dysfunction, spasmodic dysphonia, sialorrhoea, anal fissures, piriformis syndrome, various pain conditions and cosmetic applications. Generally, its therapeutic effects are comparable to BT type A (BT-A). The adverse effect profiles of BT-B and BT-A, however, differ considerably. BT-B has been found to produce more regional as well as systemic anticholinergic adverse effects, such as dryness of mouth, accommodation difficulties, conjunctival irritation, reduced sweating, dysphagia, heartburn, constipation, bladder voiding difficulties and dryness of nasal mucosa. In BT-B the relationship between autonomic and motor effects known from BT-A is substantially shifted towards autonomic effects. BT-B, therefore, should be used carefully in patients with autonomic disorders and in patients with concomitant anticholinergic therapy. If NeuroBloc/MyoBloc is used to treat cervical dystonia patients with antibody-induced failure of BT-A therapy, 86% of those will develop complete secondary therapy failure after five applications. If NeuroBloc/MyoBloc used to treat cervical dystonia patients without prior exposure to BT, 44% of those will develop complete secondary therapy failure after nine applications. NeuroBloc/MyoBloc, therefore, is associated with substantial antigenicity problems originating from a particular low specific biological potency. Systemic anticholinergic adverse effects and high antigenicity limits the clinical use of NeuroBloc/MyoBloc considerably.     

两种浓度A型肉毒毒素治疗偏侧面肌痉挛的疗效比较

目的　评估两种浓度A型肉毒毒素治疗偏侧面肌痉挛的疗效 ,并探讨减少其并发症的方法。方法　将 60例患者随机分为A、B两组 ,A组对上、下睑及面肌进行多点注射 ,A型肉毒毒素 (BTA)浓度为 5 0u/0 1ml,B组注射浓度为 2 2 5u/0 1ml。比较两组间疗效、副作用发生情况。结果　两组治疗疗效相似 ,总有效率为 10 0 % ,A组症状完全缓解 18例 (60 % ) ,明显缓解 6例(2 0 % ) ,部分缓解 6例 (2 0 % ) ,总显效率 80 % ;B组完全缓解 16例 (5 3 3 % ) ,明显缓解 6例 (2 0 % ) ,部分缓解 8例 (2 6 7% ) ,总显效率73 3 %。两组均无过敏和全身中毒反应 ,但A组出现上睑下垂、眼睑闭合不全、视物模糊等不良反应例数明显增多 ,差异显著 ,P <0 0 5。结论　BTA治疗面肌痉挛以小剂量为宜。A型肉毒毒素治疗偏侧面肌痉挛安全有效 ,简单易行 ,副作用少而轻微、短暂 ,为治疗面肌痉挛的首选方法     

Clinical use of non-a botulinum toxins: Botulinum toxin type C and botulinum toxin type F

Botulinum neurotoxin (BoNT) serotype A is commonly used in the treatment of focal dystonia, but some patients are primarily or become secondarily resistant to it. Consequently, other serotypes have to be used when immuno-resistance is proven. In the literature, patients with focal dystonia have been treated with BoNT serotype F with clinical benefit but with short lasting effects. Recently, BoNT serotype C has been used with positive clinical outcome. An update on the clinical use of BoNT serotype F and BoNT serotype C is provided.     

The use of botulinum toxin type A in spastic diplegia due to cerebral palsy

Spastic diplegia is a severely disabling condition and many current treatment options offer the patient no real therapeutic benefit. Intramuscular injection of botulinum toxin type A (BTX-A) has demonstrated the ability to decrease spasticity, improve mobility and delay the need for surgery in patients with spastic diplegia. The study described here was a pilot to a larger study and it aimed to identify the most suitable and sensitive outcome measures to detect the benefits of BTX-A injection. Five adolescents with hip spasticity due to cerebral palsy were injected with BTX-A into the psoas major muscle (for thigh adduction problems) or the soleus muscle (to correct 'toe clawing'). Assessments of gait and mobility were carried out every month for the 4-month study period. Following injection with BTX-A, improvement in patient mobility was most evident in subjects with thigh adduction problems. A reduction in 10-m walking time and an increase in stride length was also more pronounced in patients injected in the psoas. Three of the five patients treated demonstrated an improved Modified Ashworth Scale score at the end of the 4-month observation period. The results conclude that spastic diplegics with problems related to the hip, may benefit from BTX-A. Patients who experience 'toe clawing' present different problems and the measures used did not pick up on the benefits gained by the patients.     

Use of botulinum toxin to treat blepharospasm in a 16-year-old with a dystonic syndrome

A 16-year-old boy with generalized dystonia had continuous, severe blepharospasm and facial grimacing. Local intradermal injections of botulinum A toxin greatly reduced the spasms and improved function. No side effects were observed. Local botulinum A toxin injections may be useful in the treatment of eyelid and facial spasms in patients with generalized dystonias.     

Clinical correlates of response to botulinum toxin injections.

We studied 242 patients with cervical dystonia who had adequate follow-up after botulinum toxin injections to determine which clinical variables had a predictive value in the treatment outcome. Twenty-one patients (16%) categorized as nonresponders were compared with 113 patients (47%) considered to be definite responders. On average, the nonresponders had symptoms for 14 years longer than responders. Seventy-eight of 100 patients with complications were female compared with 54% of 190 patients without complications. In addition, patients with complications weighed less than those without complications. Both findings suggest that the occurrence of complications is related to smaller mean neck muscle mass. Botulinum toxin antibodies were detected in 35.7% of the nonresponders tested and in none of the responders. This comprehensive analysis of outcome variables leads us to conclude that patients with a long duration of dystonia before their first botulinum toxin injection respond less well than those with a short duration of symptoms, that some patients lose their responsiveness because of the development of blocking antibodies, and that women are more likely to develop complications, such as dysphagia and neck weakness, than are men.     

The use of botulinum toxin type A treatment in children with spasticity

The current modalities in managing spastic children have some limitations; thus, alternative therapeutic agents are in need. The purpose of this study is to investigate whether intramuscular botulinum toxin type A administration may be an alternative agent in the treatment of children with cerebral palsy. Eighteen children who were aged between 3 and 17 years and manifested cerebral palsy were administered intramuscular botulinum toxin type A with a total dose of 6 U/kg body weight. Outcome measurements were determined with four methods, including Ashworth Spasticity Scale, standardized videotape assessments, observational gait analysis, and walking velocity. Ashworth Spasticity Scale and videotape assessments were statistically significant before and after treatment in all muscles (P < 0.001). The best improvement in video gait analysis was evident at week 8. The botulinum toxin type A injections yielded an improved walking velocity at all visits. The observational gait analysis and walking velocity demonstrated an improvement after treatment in the gastrocnemius-injected group (P < 0.001). In conclusion, intramuscular botulinum toxin type A administration may be effective in children with cerebral palsy, especially at week 4 and when injected in gastrocnemius.