Botulinum-Toxin A in der Therapie von Kopfschmerzerkrankungen und perikranialen Schmerzsyndromen

For 20 years botulinum toxin A has been used for the treatment of a variety of disorders characterised by pathologically increased muscle contraction. Recently, treatment of tension headache, migraine, cluster headache, and myofascial pain syndromes of neck, shoulder girdle, and back with botulinum toxin A has become a rapidly expanding new field of research. Several modes of action are discussed for these indications. The blockade of cholinergic innervation reduces muscular hyperactivity for 3 to 6 months. Degenerative changes in the musculoskeletal system of the head and neck are prevented. Nociceptive afferences and blood vessels of the pericranial muscles are decompressed and muscular trigger points and tender points are resolved. The normalisation of muscle spindle activity leads to a normalisation of muscle tone and central control mechanisms of muscle activity. Oromandibular dysfunction is eliminated and muscular stress removed. However, the effect of botulinum toxin A cannot be explained by muscular actions only. Its retrograde uptake into the central nervous system modulates the expression of substance P and enkephalins in the spinal cord and nucleus raphe. Recent findings suggest an inhibition of sterile inflammation which may lead to a blockade of the neurogenic inflammation believed to be the pathophysiological substrate of primary headache disorders. The efficacy of botulinum toxin A in the treatment of pain disorders is being investigated in several studies at the moment. The results and experiences obtained so far present new alternatives in the treatment of chronic pain disorders. The practical use of botulinum toxin A is demonstrated.     

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.     

A pilot study on the use of botulinum toxin in spasmodic torticollis

Dystonic torticollis has been treated with local injections of botulinum toxin in a single blind study of 12 patients. A significant decrease of abnormal movements was recorded, and pain improved. Further studies are desirable to define the optimum dosage and site for injections, and the long term effects of repeated injections.     

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.     

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.     

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.     

Placebo-controlled double-blind cross-over study of botulinum A toxin in hemifacial spasm

The evaluation of the efficacy of botulinum A toxin injection for hemifacial spasm has never previously been done in a double-blind study in spite of its use as a treatment. We thus conducted a double-blind cross-over study of botulinum A toxin use in hemifacial spasm in 55 patients at Siriraj Hospital, Mahidol University, Bangkok, Thailand. Thirteen patients decided to withdraw from the study due to a lack of efficacy, all of them were subsequently found to be in the saline injection group. The remaining 42 patients, in the botulinum A toxin injection (30 mouse units) group, reported the responses as: excellent (34 patients; 80.95%), moderate patients; 2.38%). In contrast, when given the saline injection they reported no excellent outcome, 1 patient (2.38%) with moderate improvement, 5 patients (11.90%) with mild improvement and, 36 patients (85.71%) with no response. Side effects of botulinum toxin injections were found in 14.29% of patients compared with 9.5% of the saline injection group. The side effects of botulinum toxin injection were mild transient facial weakness (7.14%), local pain (4.76%) and excessive lacrimation (2.38%).

We concluded that botulinum A toxin injection was a simple and effective out-patient treatment for the management of hemifacial spasm.     

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.     

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.     

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.     

The role of botulinus toxin type A in treatment--with special reference to children.

Although botulinum toxin A was first introduced to treat strabismus and blepherospasm it is now used in an increasing number of conditions, many in the field of pediatrics. Its action results from a prevention of the release of acetylcholine from nerve terminals. A number of studies recording the effects of the toxin in the treatment of spastic cerebral palsy are reviewed, and although these can be criticized, there seems to be no doubt that it can be of benefit. It is few side effects, but it may reveal an underlying weakness. Other disadvantages are its cost and the need for repeated injections. It can be used for the relief of rigidity, although the effects in the extrapyramidal form of cerebral palsy are not so dramatic. Also it can be beneficial in some forms of dystonia, rarely if this is generalized, but certainly if it is focal, and especially if there is accompanying pain. There are several conditions seen in children, such as strabismus, blepherospasm and tremors, in which this form of treatment will rarely be indicated; but they will be mentioned. An exception may be spasmodic torticollis during adolescence if it does not respond to other therapy, as it is so disabling. Botulinum toxin can be used to block the discharges from cholinergic sympathetic and parasympathetic terminals. Focal hyperhidrosis can be very distressing among older children, and the use of the toxin should sometimes be considered in this and other autonomic disorders.     

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 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.     

An Update on the Neurologic Applications of Botulinum Toxins

Initially used to treat strabismus in the 1970s, botulinum toxin now has more than a hundred possible medical applications. Its utility in neurologic conditions has largely involved treating movement disorders (particularly dystonia and conditions with muscle hyperactivity), although practically any hyperkinetic movement disorder may be relieved by botulinum toxin, including hemifacial spasm, tremor, tics, myoclonus, and spasticity. Although initially thought to inhibit acetylcholine release only at the neuromuscular junction, botulinum toxins are now recognized to inhibit acetylcholine release at autonomic cholinergic nerve terminals, as well as peripheral release of neurotransmitters involved in pain regulation. Thus, their use in neurology has been expanded to include headache and other pain syndromes, as well as hypersecretory disorders. This article highlights some of the common neurologic conditions currently improved by botulinum toxins and reviews the scientific evidence from research studies and clinical experience with these conditions.     

Efficacy and Safety of Long-term Botulinum Toxin Treatment in Craniocervical Dystonia: A Systematic Review

Botulinum neurotoxins have been shown to be a safe and effective therapeutic option for most forms of focal dystonia, and are now considered to provide the best symptomatic treatment in these disorders. However, only a few papers addressed the long-term efficacy and safety of repeated treatments with this drug. This article reviews the data from clinical trials that have assessed the long-term results of botulinum neurotoxin type A (BoNT-A) and type B in the treatment of the different forms of focal craniocervical dystonia, cervical dystonia (CD), blepharospasm, oromandibular, and laryngeal dystonia. Studies on the long-term effects of BoNT-A therapy have demonstrated that the majority of patients comply with this repeated treatment because they experience a positive and stable effect over time. It is still unclear whether in patients with focal dystonia the mean dose of BoNT-A changes over time. In spite of the wide spectrum of side effects reported to be associated with BoNT-A treatment, there is no evidence of specific side effects due exclusively to the long-term use of such drugs. The only exception to these positive long-term findings is the occurrence of a subgroup of patients with CD who fail to maintain a sustained response after the first or second effective treatment, partly owing to the development of neutralizing antibodies against the toxin. Longitudinal studies aimed at defining the risk factors for this abnormal pattern of response to botulinum toxin treatment are currently being conducted.     

A型肉毒毒素重复治疗偏头痛的临床疗效

目的 探讨A型肉毒毒素重复注射治疗偏头痛的疗效与安全性。方法 对30例偏头痛患者均进行2次A型内毒毒素注射治疗,两次均采用颅周固定位点注射,初次治疗间隔6个月以上后进行第2次治疗,2次治疗后分别于第1,2,3个月评定头痛发作天数、头痛发作次数、疼痛程度、偏头痛残疾程度及不良反应。结果 二次A型肉毒毒素注射治疗后偏头痛发作天数、发作次数、疼痛程度、残疾程度均较治疗前缓解（F分别为3．86,5．23,9．37,5．67;P〈0．05）,但两次治疗后各观察点评定指标比较差异无统计学意义（P〉0．05）。结论 A型肉毒毒素重复治疗偏头痛有效、安全,较初次治疗无差异．     

Use of botulinum toxin type A in pediatric patients with cerebral palsy: a three-center retrospective chart review

Over the last several years, botulinum toxin type A has gained widespread use for the management of focal spasticity in children with cerebral palsy. To assess the current patterns of botulinum toxin type A use in the clinical setting, the dose, muscles injected, age at injection, and interval between injections of botulinum toxin type A treatments were examined in a retrospective chart review of children with cerebral palsy (N = 270) over a 2-year period at three major treatment centers. The average dose of botulinum toxin type A across the three centers ranged from 7.7 to 10.8 U/kg body weight, and the average total amount of botulinum toxin type A injected at a single visit ranged from 154 to 205 U. The majority of botulinum toxin type A injections were to the muscles to the lower limbs. The average age at first injection was 6.2 years, and the average interval between injections ranged from 134 to 199 days.     

Hypercontractile esophageal motility disorder or functional esophageal symptoms and unrelated hypercontractility?

In this issue of the journal, Mion and coworkers describe 23 patients with dysphagia and/or thoracic pain and hypercontractile esophageal motility disorders who were either treated with botulinum toxin 100 U or underwent a sham procedure. The surprising outcome of the study was that both active botulinum toxin treatment and sham treatment resulted in a significant reduction in symptoms and manometric abnormalities after 3 months, with no difference between the two arms. One can interpret the lack of effect of botulinum toxin over placebo as indicative of the benign natural history of hypercontractile esophageal motility disorders or be convinced that many patients with hypercontractility on manometry actually have functional symptoms not related to the manometric findings, and thus, treatment of hypercontractility is not more effective than placebo. Either way, invasive, irreversible treatments with potential risks for complications seem difficult to justify in these patients.     

Botulinum toxin A relieved neuropathic pain in a case of post-herpetic neuralgia

Botulinum toxin type A (BTX-A) has been widely used in many clinical disorders including migraine, cervical dystonia, etc. The use of BTX-A in neuropathic pain, however, is uncommon, and the application of the anti-nociceptive effect of botulinum toxin is emerging. Here we report a case of an 80-year-old man who suffered from severe pain of post-herpetic neuralgia which was refractory to the usual therapies. However, this neuropathic pain was dramatically relieved by multiple BTX-A injection and the pain relief lasted 52 days.     

Langzeitbehandlung von Phantom- und Stumpfschmerzen mit Botulinumtoxin Typ A über 12 Monate

Recently we were able to describe the successful treatment of phantom pain and stump pain with botulinum toxin A in a first pilot study.This case report over a 1-year period now demonstrates that long-term treatment for this indication is possible. We injected 4 x 25 IU of botulinum toxin A (Botox) into trigger points of the stump muscles of a lower limb amputee who suffered from severe phantom and stump pain. With four injections performed every 3 months, the patient became almost completely pain-free, and his intrathecal morphine therapy could be reduced to 40% of the initial dose. Intrathecal clonidine was eliminated completely, as were the oral analgesics. A surgical treatment suggested for the stump pain was no longer necessary, and we suppose that botulinum toxin can also improve the tolerance of artificial limbs in cases of stump pain.