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.     

Posttraumatic focal dystonia of the shoulder

Posttraumatic movement disorders remain a controversial issue with focal dystonia being a prominent representative. Focal dystonia of the shoulder without concomittant cervical dystonia is a rare event. We describe 2 patients who, after minor trauma, developed focal dystonia of the shoulder with severe chronic pain. Response to local botulinum toxin A was favorable in 1 patient.     

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.     

A型肉毒毒素治疗口下颌肌张力障碍

目的观察A型肉毒毒素治疗口下颌肌张力障碍(OMD)患者的临床效果。方法对19例口下颌肌张力障碍患者进行临床分析,依据患者临床特点,将A型肉毒毒素注射到患者一侧或双侧咀嚼肌、颞肌及翼外肌,并根据肌肉收缩力量大小、肌肉体积及患者体重调整剂量。结果 68.4%的患者功能改善评分≥3分,疗效平均维持8～12周(有效范围2～28周)。4例患者注射后有轻度咀嚼无力,2～3周恢复。1例混合型患者注射后出现轻度鼻音,持续13天后症状消失。所有患者未出现其它严重副作用。结论 A型肉毒毒素对于口下颌肌张力障碍的治疗是有效、安全的。熟悉本病的临床特点及分型,选择正确的靶肌肉及注射适宜剂量的肉毒毒素是治疗本病的关键。     

Laryngeal dystonia in a case of severe motor and intellectual disabilities due to Japanese encephalitis sequelae

Laryngeal dystonia is characterized by stridor due to vocal cord dystonia and is observed in extrapyramidal disorders. Recently, botulinum toxin injection has been used as a primary therapy. Generally, severe motor and intellectual disabilities (SMID) are frequently complicated by various types of respiratory disorders. We report a SMID case with Japanese encephalitis sequelae showing repeated vocal cord abductor disturbance due to laryngeal dystonia, in addition to generalized dystonia, in whom MRI revealed basal ganglia lesions. Tracheostomy was effective for the case, and we believe that botulinum toxin injection may be inappropriate in SMID, both ethically and technically. Also, laryngeal dystonia should be considered as a cause of respiratory disorders in SMID.     

Treatment of hyperkinetic movement disorders

Parkinson's disease, the most common hypokinetic movement disorder, has received much attention from the clinical and scientific community, but there has been a relative paucity of comprehensive reviews of hyperkinetic disorders, even though they are equally or even more disabling. Hyperkinetic movement disorders include tremors, dystonia, chorea, tics, myoclonus, stereotypies, restless legs syndrome, and various other disorders with abnormal involuntary movements. Substantial progress has been made in the understanding of the role of the basal ganglia in the pathophysiology of these hyperkinesia disorders and in motor control, muscle tone, posture, and cognitive processes. Although therapies that target pathogenesis are still lacking, effective management of hyperkinetic movement disorders demands that physicians are knowledgeable about current and novel pharmacological and surgical approaches. In addition to tetrabenazine, a monoamine-depleting drug, new formulations of botulinum toxin are being increasingly used in the treatment of these movement disorders. Finally, success with surgical approaches, particularly deep brain stimulation in patients with Parkinson's disease who have levodopa-induced dyskinesias, has been extended to the treatment of many hyperkinetic movement disorders.     

Abnormal perception of vibration-induced illusion of movement in dystonia

OBJECTIVES: To examine the illusional sensation of movement evoked by vibration of an immobilized arm. METHODS: Patients with idiopathic focal dystonia were compared with those with idiopathic PD and with patients with dystonia secondary to PD. A 100-Hz transcutaneous vibratory stimulus was applied to the biceps brachii tendon to elicit an illusional sensation of arm extension. Blindfolded patients were instructed to copy any perceived movement of the vibrated arm with the opposite (tracking) arm. By recording movement of reflective markers on the tracking arm using infrared video cameras, the change in elbow angle was quantified over 45 seconds. The effect of treatment with botulinum toxin was examined by retesting previously untreated patients after commencing therapy. These results were also compared with patients with hemifacial spasm who had ongoing treatment with botulinum toxin. RESULTS: Vibration of the biceps in dystonic patients produced a smaller sensation of arm extension than in control subjects unaffected by botulinum toxin treatment. There were no differences between the types of idiopathic focal dystonia examined, including patients with dystonia in sites other than the arm. Those with idiopathic PD and hemifacial spasm did not differ from healthy control subjects. Patients with dystonia secondary to PD showed a unilateral abnormality on the side of dystonic symptoms. CONCLUSION: Bilateral abnormal perception of the illusion of vibration-induced movement is a feature of idiopathic focal dystonia but not idiopathic PD, and is independent of treatment with botulinum toxin. Unilateral, abnormal sensorimotor integration is implicated in dystonia secondary to PD. These results may reflect abnormal sensorimotor integration of Ia afferent activity.     

Use of botulinum toxin in the treatment of laryngeal dystonia (spasmodic dysphonia): preliminary study of twelve patients

Laryngeal dystonia (spasmodic dysphonia) is a movement disorder characterized by involuntary contractions of laryngeal muscles involved with vocalization. The introduction of botulinum toxin in the treatment of laryngeal dystonia had a major clinical impact due to the striking improvement of symptoms. We report the preliminary results of therapeutical use of botulinum toxin in the treatment of twelve patients with laryngeal dystonia. After an extensive clinical evaluation, the patients underwent a videostroboscopic exam for diagnostic confirmation. Botulinum toxin was injected in the cricothyreoid membrane, directed towards the thyreoaritenoid muscle, with the aid of eletromyography needles. Most of patients who underwent botulinum toxin injection had a significant improvement of their symptoms (83%), with effects lasting for four months in average and without important side effects.     

Change in the pattern of cervical dystonia might be the cause of benefit loss during botulinum toxin treatment

The muscular patterns of cervical dystonia were identified by polymyographic recordings in 76 patients before botulinum toxin treatment. The leading muscles were considered to be those which started dystonic movement and which showed constant and maximal activity during all dystonic movements. The dystonic muscles were repeatedly treated by local Injections of botulinum toxin. Sixteen patients showed (after repeated injections) loss of the benefit of local applications of botulinum toxin after various periods of time. Repeated polymyographic recordings were performed in these patients during the loss of the benefit of injected botulinum toxin. In four patients repeated polymyographic recordings showed an Identical pattern of cervical dystonia, but the activity of previously injected muscles was apparently decreased. In 12 patients only minimum or no activity was recorded in muscles which had previously been treated with botulinum toxin, but the pattern of cervical dystonia was changed. Different patterns of cervical dystonia with different leading muscles, but with identical directions of head deviation, were observed in six patients. In another six patients, the head deviation direction was to the opposite side and was accompanied by a change of the leading muscle and a change of the muscular pattern of dystonia. These results suggest either that dystonic activity from the cerebral generator changes to new effectors during the peripheral blockade of primary dystonic muscles, or that a change of generators at different levels of the CNS occurs. It may be neccessary to carry out repeated polymyographic recordings throughout the period of loss of benefit of previously successful local botulinum toxin injections.     

Delayed onset limb dystonia following electric injury

It has been recognized that head trauma can induce movement disorders including tremor, dystonia, parkinsonism and tics. Likewise, lesions involving the peripheral nervous system have been held responsible for such extrapyramidal manifestations, However, involuntary movements secondary to electric injury have seldom been described. Here we report a patient who developed limb dystonia 6 years after receiving an electric discharge in the ipsilateral limb. Although imaging and laboratory studies failed to ascribe the lesion either to the central or peripheral nervous system, initial symptoms such as local bruises, edema and pain would favor peripheral damage. Botulinum toxin injections markedly improved dystonia. Analysis of cases of dystonia following electric injury reported to date suggest that: (a) dystonia may be expected to develop immediately or even years after the electric insult; (b) dystonia usually develops in or adjacent to the area initially injured; (c) dystonia remains limited to a distinct body segment; (d) severity of dystonia as well as the interval between injury and the onset of the movement disorder fails to correlate with trauma severity; (e) no evidence supports the hypothesis that previous history of movement disorders or neuroleptic exposure are predisposing factors; and (f) botulinum toxic provides symptomatic relief.     

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.     

Lingual protrusion dystonia: Frequency,etiology and botulinum toxin therapy

The purpose of this study was to examine lingual protrusion dystonia (LPD); its frequency, etiology and response to botulinum toxin therapy. Previous literature suggests that LPD is more frequently the result of heredodegenerative disease and that the use of botulinum toxin therapy in LPD is associated with significant adverse effects. This is a retrospective database and record review from a movement disorder clinic. Of 421 dystonia patients, we identified 17 with LPD (4%). Of these cases, the diagnoses were: primary cranial dystonia (5), primary generalized dystonia (2), tardive dystonia (7), heredodegenerative disease (1), multifactorial (1) and post-infectious (1). All primary cases had concomitant oromandibular dystonia. In some secondary cases the LPD was the only cranial feature. Nine received botulinum toxin injections and 55.6% sustained moderate or marked improvement. Of 89 total botulinum toxin sessions, 66.3% had an excellent response, and 92.1% had some response. 97.8% of the sessions resulted in no significant adverse effects. On one occasion one patient developed severe dysphagia requiring placement of a percutaneous gastrostomy (PEG) tube. We conclude that LPD is rare, most commonly the result of tardive and primary dystonia. Botulinum toxin therapy may be very effective but needs to be utilized with care because of the possibility for the development of dysphagia.     

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.     

Other indications of botulinum toxin therapy

The therapeutic possibilities of botulinum toxin are manifold and certainly not yet fully exhausted. Apart from the classical indications – focal dystonia and focal spasticity – its use in the management of wrinkles has become well known. Moreover, the toxin is now being administered in many medical fields, including many other kinetic disorders like rare dystonias and tremor. The toxin is also used in a great number of autonomic disorders such as focal hyperhidrosis and even rhinitis. Substantial advances have been made in the field of urology after injections into the sphincter and detrusor muscle. Studies for approval are meanwhile under way concerning the treatment of detrusor hyperreflexia. Gastroenterology is another important field for application of botulinum toxin – be it to the esophagus (e.g. achalasia), stomach, gallbladder, or anorectum. Anal fissure is considered a particularly common indication. Controlled studies for many indications are frequently lacking because of the limited incidence of some of these disorders and symptoms.     

Case studies in movement disorders

Six cases representing the most commonly encountered movement disorders-restless legs syndrome with periodic limb movements, tics, myoclonus, chorea, essential tremor, and cervical dystonia-are presented. Discussion of each case focuses on a practical approach to recognizing the important clinical features of each movement disorder as well as the current therapeutic options. A detailed discussion of botulinum toxin follows the case on cervical dystonia, focusing on its mechanism of action, clinical indications, side effects, and dosing.     

Generalised muscular weakness after botulinum toxin injections for dystonia: a report of three cases

Three patients are reported on who developed transient generalised weakness after receiving therapeutic doses of botulinum toxin for cervical dystonia (one case) and symptomatic hemidystonia (two cases) respectively. Clinical and electrophysiological findings were in keeping with mild botulism. All patients had received previous botulinum toxin injections without side effects and one patient continued injections without recurrence of generalised weakness. The cause is most likely presynaptic inhibition due to systemic spread of the toxin. Patients with symptomatic dystonia may be more likely to have this side effect and botulinum toxin injections in these patients should be carried out cautiously.     

Treatment of tremor and dystonia

Treatment of movement disorders has expanded beyond traditional therapies with oral medications to include injection of drugs like botulinum toxin and the use of surgical interventions in cases that do not respond to medical therapy. This article provides an overview to the diagnosis and treatment of tremor and dystonia. The distinguishing features of rest, postural, and kinectic tremor are detailed with medical and surgical modalities for treatment. A discussion of idiopathic and secondary dystonia with focus on diagnosis and medical and surgical treatments encompasses the second part of the article.     

Dystonia and its disorders

Dystonia is a movement disorder characterized by sustained muscle contractions, frequently causing twisting and repetitive movements or abnormal postures. The term dystonia does not signify a single disease, but instead describes a symptom and sign that may be part of many disorders with a variety of causes. Dystonia may be classified by age of onset, distribution of symptoms, or by etiology. An increasing number of genetic forms of dystonia have been recognized and the findings have advanced knowledge of underlying neural mechanisms of pathogenesis. Options for treatment of dystonia include pharmacological therapy, botulinum toxin injection, or neurosurgical procedures.     

肌电图引导下A型肉毒毒素治疗不同类型痉挛性斜颈的临床研究

目的：探讨A型肉毒毒素（BTX-A）局部注射治疗不同类型原发性痉挛性斜颈的疗效。方法：在肌电图引导下,对24例痉挛性斜颈患者行BTX-A局部肌肉注射,按其临床类型分组比较疗效及不良反应。结果：全部患者治疗后Tsui量表评分均明显下降,混合型改善程度更明显。所有患者均未见严重不良反应。结论：肌电图引导下BTX-A治疗不同类型痉挛性斜颈均有效,且安全。