Botulinum toxin type A and other botulinum toxin serotypes: a comparative review of biochemical and pharmacological actions

Botulinum toxin type A is an important therapeutic agent for the treatment of movement and other disorders. As the clinical uses of botulinum toxin type A expand, it is increasingly important to understand the biochemical and pharmacological actions of this toxin, as well as those of other botulinum toxin serotypes (B-G). Botulinum neurotoxin serotypes exhibit differences in neurotoxin complex protein size, percentage of neurotoxin in the activated or nicked form, intracellular protein target, and potency. These properties differ even between preparations that contain the same botulinum toxin serotype due to variations in product formulations. As demonstrated in preclinical and clinical studies, these differences result in a unique combination of efficacy, duration of action, safety, and antigenic potential for each botulinum neurotoxin preparation.     

Pharmacology and immunology of botulinum toxin serotypes

Botulinum toxin preparations can provide patients with a therapeutic modality that may improve both their medical condition and quality of life. The mechanism of action of the various botulinum toxin preparations and serotypes is similar: they all block neurotransmitter release. The majority of clinical conditions treated are based upon the targeted temporary chemodenervation of the selected organ. The antinociceptive effects of botulinum toxin type A (BTX-A), based on preclinical studies and clinical experiences in treating movement disorders and other painful conditions, will also be reviewed to illustrate how this compound may act as it alleviates the discomfort associated with various conditions. Chronic therapies with preparations with the lowest amount of neurotoxin protein provide the best chance for long-term therapy by minimizing the potential of the patient to form neutralizing antibodies. Differences in formulations or serotypes impart unique efficacy and safety profiles and thus does not support a simple dose ratio conversion between products.     

Botulinum toxin in movement disorders

Botulinum toxin inhibits the vesicular release of acetylcholine in the neuromuscular junction, resulting in a transient, localized paralysis when small doses are injected. The successful use of serotypes A and B in conditions with muscle overactivity such as dystonia and spasticity has been well established. Apart from approved indications, treatment with botulinum toxin injections is attempted in a variety of new areas of neurology, including tremor, tics, and myoclonus. This article provides an update on the uses of botulinum toxin in the field of movement disorders and draws special attention to theoretical and practical treatment issues of primary and secondary dystonic disorders. Long-term experience with this agent suggests that it is an effective and safe treatment not only for approved indications but also for the increasing number of off-label indications. However, controlled studies for many conditions are lacking, and more clinical trials in many different areas are warranted.     

Pharmacology and immunology of botulinum toxin serotypes

Botulinum toxin preparations can provide patients with a therapeutic modality that may improve both their medical condition and quality of life. The mechanism of action of the various botulinum toxin preparations and serotypes is similar: they all block neurotransmitter release. The majority of clinical conditions treated are based upon the targeted temporary chemodenervation of the selected organ. The antinociceptive effects of botulinum toxin type A (BTX-A), based on preclinical studies and clinical experiences in treating movement disorders and other painful conditions, will also be reviewed to illustrate how this compound may act as it alleviates the discomfort associated with various conditions. Chronic therapies with preparations with the lowest amount of neurotoxin protein provide the best chance for long-term therapy by minimizing the potential of the patient to form neutralizing antibodies. Differences in formulations or serotypes impart unique efficacy and safety profiles and thus does not support a simple dose ratio conversion between products.

     

Pearls and pitfalls in the therapeutic use of botulinum toxin

Botulinum toxin is a potent toxin and powerful therapeutic tool. Botulinum toxin has therapeutic application in the treatment of a host of neurological, ophthalmologic, gastroenterological, urologic, and dermatologic conditions. Although there are issues specific to each disorder for which botulinum toxin therapy is employed, there are several common principles. This article reviews several of these general principles by addressing common questions that arise in the therapeutic use of botulinum toxin. Areas of focus include patient selection, drug preparation and delivery, use of electromyography to guide injections, drug resistance, and organization of a therapeutic botulinum toxin clinic.     

Botulinum toxins: pharmacology and its current therapeutic evidence for use

Botulinum toxins are, as a group, among the most potent neuromuscular toxins known, yet they are clinically useful in the management of conditions associated with muscular and glandular over-activity. Botulinum toxins act by preventing release of acetylcholine into the neuromuscular junction. While botulinum toxin type A is commonly available, different manufacturers produce specific products, which are not directly interchangeable and should not be considered as generically equivalent formulations. Type B is also available in the market. Each formulation of botulinum toxin is unique with distinct dosing, efficacy and safety profiles for each use to which it is applied. Botulinum toxin type A is the treatment of choice based on its depth of evidence in dystonias and most other conditions. Botulinum toxin type A is established as useful in the management of spasticity, tremors, headache prophylaxis and several other neurological conditions. Active research is underway to determine the parameters for which the type B toxin can be used in these conditions, as covered in this review. Botulinum toxin use has spread to several fields of medicine.     

Iatrogenic botulism in a child with spastic quadriparesis

Botulinum toxins are potent neurotoxins used in a variety of neurological disorders. Few pediatric reports have been published to date regarding the potential hazards of therapeutic use of botulinum toxins. We describe the case of a 10-year-old boy who developed systemic weakness following treatment of spasticity with botulinum toxin type B. The patient developed iatrogenic botulism with ptosis, facial diplegia, neck flexor and extensor weakness, and profound hypopharyngeal laxity with respiratory compromise from which he eventually recovered. Clinicians should be mindful of the risk for systemic botulism when using local injections of the neurotoxin.     

Comparison of analgesic effects of single versus repeated injection of botulinum toxin in orofacial formalin test in rats

Long-term effectiveness and repeated administration of botulinum toxin A are the basis for its use in both neuromuscular disorders and certain painful conditions. Botulinum toxin A has been recently approved for migraine treatment, and its off-label use extends to other craniofacial pain disorders. However, recently it was reported that, after repeated injection, botulinum toxin loses its antinociceptive efficacy in rats. In present study with a similar design, we compared the effects of single and repeated injections of botulinum toxin in formalin-induced orofacial pain. No statistically significant differences were found between single or repeatedly treated animal groups. Our results are in line with the clinical experience and suggest that botulinum toxin can be re-administered in orofacial pain treatment.     

Autonomic cardiovascular function and baroreflex sensitivity in patients with cervical dystonia receiving treatment with botulinum toxin type A

OBJECTIVE: To investigate possible changes in autonomic cardiovascular regulation and cardiopulmonary baroreflex sensitivity in patients with primary cervical dystonia receiving chronic treatment with botulinum toxin type A. METHODS: Short-term power spectral analysis of heart rate and systolic blood pressure variability, high-frequency and low-frequency oscillations of heart rate variability, low frequency/high frequency ratio and baroreflex sensitivity (alpha index) were measured in 12 patients with cervical dystonia before and 2-4 weeks after botulinum toxin type A injection and compared with normative data. RESULTS: Before treatment, at rest, patients had significantly lower high frequency power than healthy subjects (p < 0.01), whereas no differences were found in low frequency power. Botulinum toxin injection in patients induced no changes in either power frequency. In patients before treatment and healthy subjects the low frequency oscillatory components increased similarly from rest to tilt (p < 0.01), but tilt induced lower low frequency values in patients than in healthy subjects (p < 0.01). In patients before treatment, the high frequency variations from rest to tilt remained unchanged, whereas in healthy subjects they decreased significantly (p < 0.01). Botulinum toxin type A injection in patients induced no changes in low frequency or high frequency powers. In patients before treatment the low frequency/high frequency ratio increased slightly from rest to tilt, but in healthy subjects increased significantly (p < 0.01). Botulinum toxin type A left the pretreatment low frequency/high frequency ratio unchanged. The alpha-index measured at rest in patients before treatment was lower than in healthy subjects (p<0.05), whereas during tilt was similar in both groups. The alpha-index measured after botulinum toxin injection in patients remained unchanged at rest and during tilt. CONCLUSIONS: Patients with cervical dystonia receiving treatment with botulinum toxin type A have mild, subclinical abnormalities in autonomic cardiovascular regulation and cardiopulmonary baroreflex sensitivity. These changes do not worsen after acute botulinum toxin type A injection.     

Evidence for the effectiveness of botulinum toxin for sialorrhoea

Summary Sialorrhoea is a common symptom in many neurological disorders. Recently, botulinum toxin has been introduced as a treatment for sialorrhoea, and in this paper, we review the evidence for its effectiveness. The publications on the topic were searched and reviewed independently by two authors using the scale developed by the Therapeutics and Technology Assessment subcommittee for the American Academy of Neurology. All papers identified in our search fulfilled were evaluated, and classified into 1 of the 4 levels of evidence. According to this scheme, the effectiveness of botulinum toxin A in the treatment of sialorrhoea is considered established (level A). Botulinum toxin B is considered probably effective in the treatment of sialorrhoea (level B). Correspondence: Daniel D. Truong, The Parkinson’s and Movement Disorder Institute, 9940 Talbert Ave., Fountain Valley, CA 92708, USA     

Botulinum toxin injections reduce associative plasticity in patients with primary dystonia

Botulinum toxin injections ameliorate dystonic symptoms by blocking the neuromuscular junction and weakening dystonic contractions. We asked if botulinum toxin injections in dystonia patients might also affect the integrity of sensorimotor cortical plasticity, one of the key pathophysiological features of dystonia. We applied a paired associative stimulation protocol, known to induce long‐term potentiation–like changes in the primary motor cortex hand area to 12 patients with cervical dystonia before and 1 and 3 months after botulinum toxin injections to the neck muscles. Primary motor cortex excitability was probed by measuring transcranial magnetic stimulation‐evoked motor evoked potentials before and after paired associative stimulation. We also measured the input–output curve, short‐interval intracortical inhibition, intracortical facilitation, short afferent inhibition, and long afferent inhibition in hand muscles and the clinical severity of dystonia. Before botulinum toxin injections, paired associative stimulation significantly facilitated motor evoked potentials in hand muscles. One month after injections, this effect was abolished, with partial recovery after 3 months. There were significant positive correlations between the facilitation produced by paired associative stimulation and (1) the time elapsed since botulinum toxin injections and (2) the clinical dystonia score. One effect of botulinum toxin injection treatment is to modulate afferent input from the neck. We propose that subsequent reorganization of the motor cortex representation of hand muscles may explain the effect of botulinum toxin on motor cortical plasticity. © The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.     

Beneficial effects of botulinum toxin type a for patients with painful tic convulsif

Botulinum toxin is a well-known therapy for patients with diverse movement disorders. Its application has been extended to other disorders. Here, we document the case of a 70-year-old man with hemifacial spasm associated to trigeminal neuralgia secondary to an ectatic basilar artery. He was treated with botulinum toxin type A, 2.5 mouse units over five sites at the orbicularis oculi and one over the buccinator muscle. After botulinum toxin injections, relief was gained not only from twitching but also from pain. When the effects of the toxin vanished, spasms and pain recurred. Further infiltrations were given every 12 weeks following the same response pattern. This observation further validates the increasing role of botulinum toxin in pain management.     

Complete Remission of Neuroleptic-Induced Meige's Syndrome by Botulinum Toxin Treatment: A Case Report

Abstract: A botulinum A toxin injection has beneficial effects on patients suffering from facial and cervical spastic disorders. However, its effect almost completely disappears within three months. We have reported a case of a 23-year-old schizophrenic patient with severe neuroleptic-induced Meige's syndrome in whom botulinum toxin treatment exerted a marked effect which lasted more than 15 months after the final injection of botulinum toxin in spite of continuous neuroleptic medication. It is concluded that botulinum can be recommended as a treatment of choice in neuroleptic-induced Meige's syndrome.     

Botulinum toxin in therapy of craniocervical dystonia

Craniocervical dystonias are a major therapeutic problem, since in the majority of cases various drug regimens as well as surgical interventions either fail or are accompanied by serious side effects. Botulinum toxin, well known as a biological toxin which blocks the cholinergic neuromuscular synapse, proved to be a new and successful concept in the treatment of these disorders. In the present study, mechanisms of action, clinical indications and practical use of botulinum toxin are described.     

Botulinum toxin in the treatment of lingual movement disorders

Lingual movement disorders are a rare but serious manifestation of neurologic disease, which have the potential to cause significant morbidity. Traditionally, these disorders were treated with pharmacotherapy achieving only limited results. Several case series have demonstrated the effectiveness of Botulinum toxin injection for the management of focal lingual movement disorders; however, apprehension persists regarding intralingual injections due to the risk of dysphagia. Here, we report seven patients with lingual movement disorders treated with intralingual Botox? (Allergan product) injections via a novel superior approach into the genioglossus over a period of 3 to 72 months. All patients experienced a marked improvement in their abnormal tongue movements with no substantial bleeding or dysphagia. Lingual Botulinum toxin injection should be considered a safe and viable treatment option for a variety of disorders affecting the tongue. © 2009 Movement Disorder Society     

Botulinum neurotoxin serotype D is poorly effective in humans: An in vivo electrophysiological study

ObjectiveBotulinum neurotoxins act on nerve endings and block neurotransmitter release. Their potency is due to their enzymatic activity and high affinity binding to neurons. Botulinum toxin type A is used in the treatment of human diseases characterized by hyperactivity of peripheral cholinergic nerve terminals, but some patients are or become resistant to it. This can be overcome by using other botulinum toxins, and studies have been performed with different toxin serotypes. Botulinum neurotoxin type D has never been tested in humans in vivo, and, therefore, we investigated the action of this toxin in mouse and human muscles.MethodsBotulinum toxin type D potency was determined on mouse hemidiaphragm and on rat neuronal cultures. From these experiments, doses to be injected in human volunteers were decided. The compound muscle action potential of toxin-injected Extensor Digitorum Brevis muscle was measured at different times points after injection in human volunteers.ResultsBotulinum toxin type D is poorly effective in inducing human skeletal muscle paralysis.ConclusionsBotulinum toxin type D is very potent in mice and almost ineffective in humans in vivo.SignificanceThe results shed new light on the mechanism of toxin type D binding to the neuronal surface receptors.     

Botulinum toxin as treatment for focal dystonia: a systematic review of the pharmaco-therapeutic and pharmaco-economic value

Focal dystonia is a common, invalidating neurologic condition characterized by involuntary, sustained muscle contractions causing twisting movements and abnormal postures in one body part. Currently, botulinum toxin is the treatment of first choice. We performed a systematic review towards the pharmaco-therapeutic and pharmaco-economic value of botulinum toxin as treatment for focal dystonia, which yielded the following results. Botulinum toxin is the most effective treatment for reducing dystonic symptoms measured with dystonia-specific and general questionnaires, and pain in patients with focal dystonia. Seventy-one percent of patients with cervical dystonia had a reduction in neck pain compared to 12?% in placebo groups. Adverse events occur in 58?% of patients during treatment with botulinum toxin compared to 46?% treated with placebo. Especially dry mouth, neck weakness, dysphagia, and voice changes are common. Adverse events are usually mild and self-limiting. Health-related quality of life, measured with the SF-36 is 20?C50 points lower in patients with focal dystonia compared to controls and the effect of botulinum toxin on health-related quality of life is unclear. Botulinum toxin treatment is expensive because the drug itself is expensive. Yearly costs for treating a patient with focal dystonia with botulinum toxin range from EUR 347 to EUR 3,633 and the gain in QALYs with BTX treatment is small. Focal dystonia impairs the productivity and the ability to work. At start of botulinum toxin treatment only 47?C50?% was working. Botulinum toxin partly improves this. Overall, we conclude that botulinum toxin is an expensive drug with good effects. From a societal perspective, the costs may well weigh up to the regained quality of life. However, the available literature concerning costs, health-related quality of life and labor participation is very limited. An extensive cost-effectiveness study should be performed incorporating all these aspects.     

A randomized, double masked, controlled trial of botulinum toxin type A in essential hand tremor

OBJECTIVE: To evaluate the safety and efficacy of botulinum toxin type A injection in essential tremor of the hand. BACKGROUND: Botulinum toxin type A is an effective treatment for dystonia, spasticity, and other movement disorders and has been found to be useful in open-label studies and one double-masked study of essential hand tremor. METHODS: One hundred thirty-three patients with essential tremor were randomized to low-dose (50 U) or high-dose (100 U) botulinum toxin type A (Botox) or vehicle placebo treatment. Injections were made into the wrist flexors and extensors. Patients were followed for 16 weeks. The effect of treatment was assessed by clinical rating scales, measures of motor tasks and functional disability, and global assessment of treatment. Hand strength was evaluated by clinical rating and by a dynamometer. RESULTS: Both doses of botulinum toxin type A significantly reduced postural tremor on the clinical rating scales after 4 to 16 weeks. However, kinetic tremor was significantly reduced only at the 6-week examination. Measures of motor tasks and functional disability were not consistently improved with botulinum toxin type A treatment. Grip strength was reduced for the low- and high-dose botulinum toxin type A groups as compared with the placebo group. Adverse reactions consisted mainly of dose-dependent hand weakness. CONCLUSION: Botulinum toxin type A injections for essential tremor of the hands resulted in significant improvement of postural, but not kinetic, hand tremors and resulted in limited functional efficacy. Hand weakness is a dose-dependent significant side effect of treatment at the doses used in this study.     

A型肉毒杆菌毒素治疗头颈部肌张力不全的临床研究

局部注射Ａ型肉毒杆菌毒素治疗３８例头颈部肌张力不全患者取得满意疗效。其显效率和平均作用持续时间分别为：眼睑痉挛，９％和１３．８２周；颈肌弃挛，７６％和１２．４６周；口颌部肌痉挛，７３％和１２．７４周。绝大多数病例重复注射同样有效。无过敏和全身中毒反应。局部副作用轻微，可逆。结果表明；Ａ型肉毒杆菌毒素治疗方法简便，易行。可作为治疗头颈部肌张力不全的首选药物。     

Review of botulinum toxin type A for the prophylactic treatment of chronic daily headache

Botulinum toxin A is increasingly used in the treatment of idiopathic and symptomatic headache disorders. However, only few controlled trials are available and many trials can hardly be compared to each other because of different endpoints and different trial designs. In particular chronic daily headache, which is defined as an idiopathic headache occurring on more than 15 days per month for at least 3 months and a daily duration of at least 4 hours, is considered as a headache disorder with possible efficacy of botulinum toxin A. For the prophylactic treatment of chronic tension-type headache and chronic migraine, no sufficient positive evidence for a successful treatment can be obtained from randomized, double-blind, and placebo-controlled trials to date. For the treatment of chronic daily headache including medication overuse headache, there is some positive evidence for efficacy in a subgroup of patients. To date, the majority of double-blind and placebo-controlled studies do not suggest that botulinum toxin A is efficacious in the treatment of chronic idiopathic headache disorders. However, it is possible that some subgroups of patients with chronic daily headache will benefit from a long-term treatment with botulinum toxin A.