Ptosis as a remote effect of therapeutic botulinum toxin B injection

The authors report a patient with cervical dystonia, previously treated with botulinum toxin A (BTX-A), who developed bilateral ptosis and difficulty with accommodation only after botulinum toxin B (BTX-B). High-frequency repetitive nerve stimulation of the abductor digiti minimi demonstrated a 34% increment in compound muscle action potential. No increment in 20 people injected with BTX-A and no cases of ptosis in a chart review of 1,606 BTX-A injections for cervical dystonia were found. The authors conclude that systemic spread of BTX-B can cause symptomatic involvement of autonomic neurons.     

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.     

Autonomic function after botulinum toxin type A or B: a double-blind, randomized trial

To compare autonomic effects of botulinum toxin (BTX), we randomized patients with cervical dystonia to receive either BTX-A or BTX-B in a double-blind manner. Efficacy and physiologic questionnaire measures of autonomic function were assessed at baseline and 2 weeks after injection. Patients treated with BTX-B had less saliva production (p < 0.01) and greater severity of constipation (p = 0.037) than those treated with BTX-A, but did not differ in other tests of autonomic functions.     

The botulinum toxins in the treatment of cervical dystonia

The use of botulinum toxin to treat cervical dystonia (CD) has dramatically improved the quality of life of patients with this disabling, often painful disease. Two forms of toxins, botulinum toxin type A (BTX-A) and botulinum toxin type B (BTX-B), have each been studied in large multicenter trials in subjects with CD. A study of BTX-A demonstrated improvement of 5.15 to 10.65 degrees in head position using the Cervical Dystonia Severity Scale (CDSS) in those treated with BTX-A (trade name BOTOX) compared with placebo. A study in patients who continued to respond to BTX-A and a similarly designed study in patients who were resistant to BTX-A demonstrated statistical improvement in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) in those treated with BTX-B (evaluated as NeuroBloc) compared with placebo. The potential availability of both forms of toxin will allow physicians to offer further treatment options to patients with CD.     

Visual system side effects caused by parasympathetic dysfunction after botulinum toxin type B injections.

Botulinum toxin type B (BTX-B) has been approved by the Food and Drug Administration for the treatment of cervical dystonia. However, as with botulinum toxin type A (BTX-A) it has off-label uses, such as for hyperhidrosis, focal dystonias, spasticity, and facial wrinkles. BTX-B has also been shown to be a safe and effective alternative for patients who are resistant to BTX-A. The most commonly reported side effects include dry mouth and dysphagia. To date, there have been few reports of visual disturbances associated with BTX-B use. In this study, we report on three individual patients who received BTX-B and who subsequently developed parasympathetic dysfunction of the visual system after injections of BTX-B at remote sites.     

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.     

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 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.     

Subcutaneous botulinum toxin type A inhibits regional sweating: an individual observation

Botulinum toxin inhibits neuromuscular transmission by blocking the exocytosis of acetylcholine. It was tested for a similar effect on cholinergic postganglionic sympathetic neurones at the sudomotor junction. Subcutaneous injections of 0.1 and 1.0 units of type A botulinum toxin into the forearm of a healthy subject abolished local thermoregulatory sweating in cutaneous regions spanning 1.0 and 1.5 cm for nearly 1 year without producing weakness. Botulinum toxin, therefore appears to have potent anhidrotic activity.     

Disorders of neuromuscular transmission due to natural environmental toxins.

A variety of natural toxins of animal, plant, and bacterial origin are capable of causing disorders of neuromuscular transmission. Animal toxins include venomous snakes and arthropods, venoms of certain marine creatures, skin secretions of dart-poison frogs, and poisonous fish, shellfish, and crabs. There are plant poisons such as curare, and bacterial poisons such as botulinum toxin. These act at single or multiple sites of the neuromuscular apparatus interfering with voltage-gated ion channels, acetylcholine release, depolarization of the postsynaptic membrane, or generation and spread of the muscle action potential. The specific actions of these toxins are being widely exploited in the study of neuromuscular physiology and pathology. Some toxins have proved to be valuable pharmaceutical agents. Poisoning by natural neurotoxins is an important public health hazard in many parts of the world, particularly in the tropics. Poisoning may occur by a bite or a sting of a venomous animal, or by the ingestion of poisonous fish, shellfish or other marine delicacies. Contaminated food is a vehicle for poisons such as botulinum toxin. Clinically, a cardinal feature in the symptomatology is muscle paralysis with a distribution characteristic of myasthenia gravis, affecting muscles innervated by cranial nerves, neck flexors, proximal limb muscles, and respiratory muscles. Respiratory paralysis may end fatally. This paper reviews from the clinical and pathophysiologic viewpoints, naturally occurring environmental neurotoxins acting at the neuromuscular junction.     

Cholinergic dysautonomia and Eaton-Lambert syndrome.

Cholinergic autonomic function was abnormal in a 47-year-old woman with Eaton-Lambert syndrome (ELS), not associated with carcinoma. Pupillary constriction to light and accommodation, sweating, lacrimation, and salivation were all affected. There was no evidence of Sjogren syndrome or botulinum intoxication. The defect of acetylcholine release from presynaptic terminals in the Eaton-Lambert syndrome may not be restricted to the neuromuscular junction of skeletal muscle.     

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.     

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 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.     

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.

     

Regulation of acetylcholine release by muscarinic receptors at the mouse neuromuscular junction depends on the activity of acetylcholinesterase

Muscarinic acetylcholine receptors (mAChRs) play an important role in regulating the release of acetylcholine (ACh) in various tissues. We used subtype-specific antibodies and a fluorescent-labelled muscarinic toxin to demonstrate that mammalian neuromuscular junction expresses mAChR subtypes M1 to M4, and that localization of all subtypes is highly restricted to the innervated part of the muscle. To elucidate the roles of the mAChR subtypes regulating ACh release, we measured the mean quantal content of endplate potentials in isolated mouse phrenic--hemidiaphragm preparations in which release was reduced by a low Ca2+/high Mg2+ medium. Muscarine decreased evoked ACh release in normal junctions but, depending on the concentration, reduced or increased transmitter release in collagen Q-deficient junctions completely lacking acetylcholinesterase (AChE). Both effects were also seen in normal junctions when AChE was inhibited by various doses of fasciculin-2. Block of mAChRs by atropine had no effect on evoked release at normal junctions, but decreased release at junctions lacking AChE. The muscarine-elicited depression of ACh release in normal junctions was completely abolished by pertussis toxin or methoctramine pretreatment, but was not affected by muscarinic toxin MT-3, thus indicating the involvement of the M2 mAChR. The muscarine-induced increase of ACh release in AChE-deficient junctions was not affected by pertussis toxin, but was completely blocked by MT-7, a specific M1 mAChR antagonist. Our results show that the M1 and M2 mAChRs have opposite presynaptic functions in modulating quantal ACh release, and that regulation of release by the two receptor subtypes depends on the functional state of AChE at the neuromuscular junction.     

Characterization of neuronal nicotinic receptors by snake venom neurotoxins

Neuronal nicotinic ACh receptors differ pharmacologically from nicotinic receptors on skeletal muscle. The use of certain snake venom neurotoxins has now led to a more complete determination of the pharmacological properties of these neuronal receptors, as well as to their ultrastructural localization. This review highlights results found using one such neurotoxin, toxin F, (also called bungarotoxin 3.1 and κ-bungarotoxin. Toxin F blocks nicotinic receptors in several neuronal preparations while having little affinity for nicotinic receptors in skeletal muscle. Autoradiographic studies using [¹²⁵I] toxin F indicate that nicotinic receptors in autonomic ganglia are clustered at synaptic sites, though their density is 3–30 times lower than that of nicotinic receptors at the neuromuscular junction.     

Neurophysiological effects of botulinum toxin type a

Botulinum toxin type A (BoNT-A) acts peripherally by inhibiting acetylcholine release from the presynaptic neuromuscular terminals, thus weakening muscle contraction, and its clinical benefit depends primarily on the toxin's peripheral action. In addition to acting directly at the neuromuscular junction, the toxin alters sensory inputs to the central nervous system, thus indirectly inducing secondary central changes. Some of the long-term clinical benefits of BoNT-A treatment may also reflect plastic changes in motor output after the reorganization of synaptic density.     

Functional end-plate recovery in long-term botulinum toxin therapy of hemifacial spasm: a nerve conduction study

Botulinum toxin type-A is currently thought to be effective and safe for hemifacial spasm (HFS). The pre-synaptic block of acetylcholine release at the neuromuscular junction induces depression of orbicularis oculi muscle compound motor action potential (CMAP). The aim of our study was to evaluate at what extent end-plate functional recovery is possible even in botulinum toxin treatments lasting up to 15 years. We examined 81 outpatients with primary HFS (mean treatment duration = 7.2 ± 4.2 years) who underwent neurophysiologic study, once clinical effect of the previous treatment had vanished. The mean CMAP amplitude, mean rectified amplitude of response 1 (R1) of the blink reflex and area of response 2 (R2) of treated orbicularis oculi muscle were measured in comparison to the controlateral side. Mean amplitude of the above mentioned parameters was slightly lower (about 20%; p < 0.001) in the treated side at the end of the follow-up period (4.7 ± 1.7 months). The CMAP amplitude reduction weakly correlated with the interval from last treatment, while other neurophysiologic parameters did not change due to treatment duration or total toxin amount. Our study demonstrates that botulinum toxin affects compound motor action potential and blink-reflex responses for at least 4–5 months in HFS patients. The residual block is slight and does not increase with repeated injections after several years of treatment. Our study, beside confirming the long-term efficacy of botulinum toxin treatment for HFS, provides neurophysiologic evidence that therapeutic effect may be obtained without hindering the regenerative potential of the nerve-muscle complex.     

Secondary non-response due to antibody formation in a child after three injections of botulinum toxin B into the salivary glands

Botulinum toxin (BTX) offers a new treatment option to reduce drooling in adults and children. Antibody formation against BTX is known to be one reason for clinical secondary non-response to this treatment. This is a case report on the development of secondary non-response to BTX type B (BTX-B) in a 15-year-old male, with bilateral dyskinetic cerebral palsy (Gross Motor Function Classification System Level IV) with additional learning disability* and microcephaly, treated for the indication of drooling. After three successful treatment sessions, the fourth and fifth injections showed no clinical response. This was associated with the presence of antibodies against BTX-B as determined using the mouse diaphragm assay. Thus, formation of neutralizing antibodies against BTX-B appears to be an important issue, not only in patients treated for cervical dystonia but also in children treated for drooling. Subsequent injections with an adequate dose of BTX type A (BTX-A) did not show any clinical response either, although no antibodies to BTX-A were detected. Besides the unanswered questions of dosing and distribution, a second possible explanation could be that BTX-B gave rise to non-neutralizing antibodies that cross-react with BTX-A. The resulting immune complexes could be taken up by phagocytes and, thereby, impede clinical response.