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.     

Botulinum toxins in neurological disease

Botulinum toxins are among the most potent neurotoxins known to humans. In the past 25 years, botulinum toxin has emerged as both a potential weapon of bioterrorism and as a powerful therapeutic agent, with growing applications in neurological and non-neurological disease. Botulinum toxin is unique in its ability to target peripheral cholinergic neurons, preventing the release of acetylcholine through the enzymatic cleavage of proteins involved in membrane fusion, without prominent central nervous system effects. There are seven serotypes of the toxin, each with a specific activity at the molecular level. Currently, serotypes A (in two preparations) and B are available for clinical use, and have been shown to be safe and effective for the treatment of dystonia, spasticity, and other disorders in which muscle overactivity gives rise to symptoms. This review focuses on the pharmacology, electrophysiology, immunology, and application of botulinum toxin in selected neurological disorders.     

Botulinum Toxin for the Treatment of Movement Disorders

After botulinum toxin was initially used to treat strabismus in the 1970s, others started using it to treat movement disorders including blepharospasm, hemifacial spasm, cervical dystonia, spasmodic dysphonia, and oromandibular dystonia. It was discovered that botulinum toxin can be an effective treatment for focal movement disorders with limited side effects. Over the past three decades, various formulations of botulinum toxin have been developed and the therapeutic use of these toxins has expanded in movement disorders and beyond. We review the history and mechanism of action of botulinum toxin, as well as describe different formulations available and their potential therapeutic uses in movement disorders.     

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.     

Botulism: update and review

Botulism is both an old and an emerging disease. Over 100 years ago, the classic food-borne type was found to be caused by ingesting contaminated food containing the toxin produced by a bacteria. In the first half of the 20th century a second form, wound botulism, was discovered. Three additional forms (infant, hidden, and inadvertent) were first described in the last quarter of the 20th century. Our understanding of how botulinum toxin blocks the release of acetylcholine at the neuromuscular junction has been clarified in the past 10 years. In the past 20 years, we have witnessed one of the strangest of all ironies in the history of medicine. The very lethal botulinum toxin is now being used as a treatment in an expanding list of disorders. Research is advancing in several directions. These new avenues include improved methods of preventing and treating botulism and additional novel uses of botulinum toxin as a therapeutic agent. In this article, the five clinical forms of botulism, the actions of botulinum toxins, electrodiagnostic methods, treatments, and possible future directions are discussed.     

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.     

Botulinum toxin B treatment in children with spastic movement disorders: a pilot study

The treatment of adult and pediatric patients suffering from movement disorders with elevated muscle tone includes the application of focally denervating botulinum toxins. Dystonic movement disorders in adult patients have been treated successfully using botulinum toxin type B (NeuroBloc). Thus far, there has been no systematic treatment of children with botulinum toxin type B. This study reports on the treatment of 29 children with spastic or dystonic movement disorders using botulinum toxin type B in an open-label pilot study. Sixty-two treatment sessions were performed. In 33 of these sessions, the therapy goal that had been defined before intervention was attained or surpassed. Seventeen nonresponders to botulinum toxin type A were also included in the treatment, 11 of whom attained the therapy goal. Side effects were observed in 24% of all treatments, dry mouth being the most frequent (10%), in some cases having a desirable clinical effect. With this preliminary data as a basis, we recommend a maximum dose for children of 400 U botulinum toxin type B per kg body weight, which should not exceed a total of 10,000 U botulinum toxin type B.     

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.     

Clinical value of botulinum toxin in neurological indications

Botulinum toxin type-A (BoNT-A) prevents the release of acetylcholine at cholinergic junctions, thereby causing temporary muscle weakness lasting 3–4 months. It is now widely used to treat a broad range of clinical disorders characterized by muscle hyperactivity. BoNT-A has proved effective in the management of several neurological conditions and, in particular, in the management of movement disorders (e.g. blepharospasm, cervical dystonia, laryngeal dystonia, limb dystonia, hemifacial spasm, focal tics, tremor and other hyperkinetic disorders). As a treatment of spasticity, BoNT-A can improve mobility and dexterity as well as preventing the development of distressing and costly secondary complications. In cerebral palsy, BoNT-A is of value, being able to delay or even avoid surgery until motion patterns have become established.     

Evidence based medicine on the use of botulinum toxin for headache disorders

Botulinum toxin blocks the release of acetylcholine from motor nerve terminals and other cholinergic synapses. In animal studies botulinum toxin also reduces the release of neuropeptides involved in pain perception. The implications of these observations are not clear. Based on the personal experiences of headache therapists, botulinum toxin injections have been studied in patients with primary headaches, namely tension-type headache (TTH), chronic migraine (CM) and chronic daily headache (CDH). So far, the results of randomized, double-blind, placebo controlled trials on botulinum toxin in a total of 1117 patients with CDH, 1495 patients with CM, and 533 patients with TTH have been published. Botulinum toxin and placebo injections have been equally effective in these studies. In some of the studies, the magnitude of this effect was similar to that of established oral pharmacotherapy. This finding may help to explain the enthusiasm that followed the first open-label use of botulinum toxin in patients with headache. However, research is continuing to determine the efficacy of botulinum toxin in certain subgroups of patients with CM or CDH.     

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.     

Botulinumtoxin A in der Kopfschmerztherapie

In recent years botulinum toxin type A has been used increasingly more in the treatment of specific headache disorders. Especially regarding chronic migraine with and without combined medication overuse, convincing randomized studies have proven the efficacy of this treatment option and have led to approval for this indication. Regarding other headache entities, such as episodic migraine, tension-type headache, trigeminal autonomic cephalalgia (TAC), neuralgic, neuropathic and myofascial pain, currently available scientific data on the efficacy of botulinum toxin type A are scarce and often ambiguous. The exact underlying mechanisms of the influence of botulinum toxin type A on the pathophysiology of headache are not completely clear but an influence on the release of calcitonin gene-related peptide (CGRP) seems to play a crucial role. This article summarizes the most important studies as well as experiences of treatment with botulinum toxin type A regarding different headache entities.     

The structure and mode of action of different botulinum toxins

The seven serotypes (A–G) of botulinum neurotoxin (BoNT) are proteins produced by Clostridium botulinum and have multifunctional abilities: (i) they target cholinergic nerve endings via binding to ecto-acceptors (ii) they undergo endocytosis/translocation and (iii) their light chains act intraneuronally to block acetylcholine release. The fundamental process of quantal transmitter release occurs by Ca²⁺-regulated exocytosis involving sensitive factor attachment protein-25 (SNAP-25), syntaxin and synaptobrevin. Proteolytic cleavage by BoNT-A of nine amino acids from the C-terminal of SNAP-25 disables its function, causing prolonged muscle weakness. This unique combination of activities underlies the effectiveness of BoNT-A haemagglutinin complex in treating human conditions resulting from hyperactivity at peripheral cholinergic nerve endings. In vivo imaging and immunomicroscopy of murine muscles injected with type A toxin revealed that the extended duration of action results from the longevity of its protease, persistence of the cleaved SNAP-25 and a protracted time course for the remodelling of treated nerve–muscle synapses. In addition, an application in pain management has been indicated by the ability of BoNT to inhibit neuropeptide release from nociceptors, thereby blocking central and peripheral pain sensitization processes. The widespread cellular distribution of SNAP-25 and the diversity of the toxin's neuronal acceptors are being exploited for other therapeutic applications.     

Updates on the antinociceptive mechanism hypothesis of botulinum toxin A

Botulinum toxin A has been traditionally viewed as a motor nerve specific treatment. However, clinical uses for botulinum toxin A have continued to expand, with increased use in conditions implicating sensory pain nerve dysfunction. Chronic pain is associated with excess pain fiber activity. When the site of this excess activity resides in the peripheral portion of the pain pathway, a condition of peripheral sensitization can establish. During this state, excess pain signaling reaches the central nervous system, which can then lead to a condition of central sensitization, manifesting as the symptoms associated with chronic pain (i.e. burning, electric pain, lowered pain threshold to normal stimuli, etc). Experimentally, botulinum toxin type A has been shown to reduce neuropeptides and neurotransmitter release from treated cells or nerve endings and to attenuate nociception in both neuropathic and non-neuropathic pain models. This review summarizes the literature to update the hypothesis for the mechanism by which botulinum toxin type A can modulate chronic pain.     

Acrylamide inhibits nerve sprouting induced by botulinum toxin type A

Botulinum toxin type A is a potent muscle relaxant that blocks the transmission and release of acetylcholine at the neuromuscular junction. Intramuscular injection of botulinum toxin type A has served as an effective and safe therapy for strabismus and focal dystonia. However, muscular weakness is temporary and after 3–4 months, muscle strength usually recovers because functional recovery is mediated by nerve sprouting and reconstruction of the neuromuscular junction. Acrylamide may produce neurotoxic substances that cause retrograde necrotizing neuropathy and inhibit nerve sprouting caused by botulinum toxin type A. This study investigated whether acrylamide inhibits nerve sprouting after intramuscular injection of botulinum toxin type A. A tibial nerve sprouting model was established through local injection of botulinum toxin type A into the right gastrocnemius muscle of Sprague-Dawley rats. Following intramuscular injection, rats were given intraperitoneal injection of 3% acrylamide every 3 days for 21 days. Nerve sprouting appeared 2 weeks after intramuscular injection of botulinum toxin type A and single-fiber electromyography revealed abnormal conduction at the neuromuscular junction 1 week after intramuscular injection of botulinum toxin type A. Following intraperitoneal injection of acrylamide, the peak muscle fiber density decreased. Electromyography jitter value were restored to normal levels 6 weeks after injection. This indicates that the maximal decrease in fiber density and the time at which functional conduction of neuromuscular junction was restored were delayed. Additionally, the increase in tibial nerve fibers was reduced. Acrylamide inhibits nerve sprouting caused by botulinum toxin type A and may be used to prolong the clinical dosage of botulinum toxin type A.     

Clostridium botulinum toxins: a general review of involvement in disease,structure, mode of action and preparation for clinical use

Summary The neurotoxins produced byClostridium botulinum are the most potent acute toxins known and are the causative agents of the neuroparalytic disease botulism. The toxins act primarily at peripheral cholinergic synapses by blocking the evoked release of the neurotransmitter acetylcholine. There are seven distinct serotypes of toxin. All are polypeptides ofM _r about 150 kDa that have similar structure and pharmacological action. In their most active forms the toxins exist as dichain molecules in which a heavy (H) chain is linked by disulphide bonding to a light (L) chain. The H chain is believed to be associated with the highly specific and avid binding of toxin to the motor nerve end plates and also with the process of internalisation of the toxin. The toxic activity appears to be associated with the L chain which blockades the calcium-mediated release of acetylcholine, probably by interfering at the molecular level with the mechanisms whereby neurotransmitter-containing vesicles merge with the plasmalemma. The type A toxin is now used therapeutically to treat a variety of conditions involving involuntary muscle spasm. The therapeutic toxin is a neurotoxin-haemagglutinin complex isolated from cultures ofC. botulinum. A controlled manufacturing process has been developed for the therapeutic toxin which is specially formulated to give a freeze-dried product having good stability.     

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.     

Chronic myokymia limited to the eyelid is a benign condition.

BACKGROUND: Eyelid myokymia, unlike myokymia of the other facial muscles, is assumed to be a benign, self-limited disorder. However, no systematic follow-up study has been performed on patients with chronic, isolated eyelid myokymia to verify its benign nature. METHODS: Retrospective single-institution chart review of 15 patients examined between 1983 and 2002 with a diagnosis of isolated eyelid myokymia who have had at least 12 months of follow-up. RESULTS: In all patients, symptoms began as unilateral, weekly or biweekly, intermittent eyelid spasms, and progressed to daily spasms over several months. The mean duration of symptoms at first examination was 91 months (range 2.5 months to 20 years). In no patient was the myokymia the first manifestation of a neurologic disease, although one patient progressed to ipsilateral hemifacial spasm. Thirteen patients (86.7%) underwent neuroimaging that gave negative results. The myokymia resolved spontaneously in four patients. Of the remaining 11 patients, eight were treated with botulinum toxin injection at regular intervals, with most reporting an improvement in symptoms. CONCLUSION: Chronic isolated eyelid myokymia is a benign condition. It tends not to progress to other facial movement disorders or to be associated with other neurologic disease. It responds well to treatment with botulinum toxin.     

Recent advances in infant botulism

Since infant botulism was first identified three decades ago, our understanding of botulinum toxins and the organisms that produce them has grown. A newer classification system now recognizes Clostridium baratii and Clostridium butyricum along with Clostridium botulinum as causative agents. Recently, increasing therapeutic use of botulinum toxins has sparked substantial new research into their mechanisms of action. This research, and some case reports from infants sickened by unusual botulinum toxins suggest that disease caused by different toxin types may result in varying clinical presentations. Perhaps most significantly for pediatricians and child neurologists, a specific treatment for infant botulism has just been approved. This article reviews the clinical presentation, diagnosis, and treatment of infant botulism, including human botulism immune globulin, and discusses the various organisms and toxins that cause this disease.     

Botulinum toxin in the treatment of tremors, dystonias, sialorrhea and other symptoms associated with Parkinson's disease

Botulinum toxins are an effective treatment modality for a growing number of neurologic conditions. Although there has been varied interest and success in their use, they have been studied for a variety of conditions associated with Parkinson's disease. Conditions reviewed in this paper include hand and jaw tremor, dystonia, blepharospasm and apraxia of eyelid opening, bruxism, camptocormia, freezing of gait, sialorrhea and constipation. We will make comments when applicable on our unique experience with botulinum toxin in these conditions. Other conditions associated with Parkinson's disease, which will not be reviewed here, but may benefit from botulinum toxin treatment include anterocollis (also known as dropped head syndrome), hyperhidrosis, seborrhea and overactive bladder.