How doctors think - and treat with botulinum toxin

The Journal of Physiology

• BoNT-A is known to block central synapses after muscular injection due to retrograde transport in animal models.

InTech eBooks, 2012

Dystonia-The Many Facets 84 2. BoNT: Peripheral blockade and beyond There are two kinds of BoNT (type A [BoNT-A: onabotulinumtoxinA or Botox ® , abobotulinumtoxinA or Dysport ® and incobotulinumtoxinA or Xeomin ® ], and type B [BoNT-B: rimabotulinumtoxinB or Neurobloc ® /Myobloc ® ]) t h a t h a v e b e e n p r o v e n t o b e s a f e a n d effective in treating various hyperfunctional cholinergic states. Their therapeutic applications range from various forms of muscle hyperactivity (e.g. dystonia, spasticity, spasms, tremors, and tics), autonomic hyperactivity (e.g. drooling, hyperhidrosis and bladder overactivity) and cosmesis (e.g. frown lines and "crow's feet). BoNT is more effective in blocking active neuromuscular junctions(9), and this effect can be enhanced by electric stimulation of the peripheral nerve(10). This toxin disrupts neurotransmission by cleavage of pre-synaptic vesicle fusion proteins; SNAP-25 for BoNT-A and synaptobrevin for BoNT-B, effectively blocking release of acetylcholine to the neuromuscular junctions and induce chemodenervation. The BoNT-A initially binds presynaptically (via the heavy chain attachment domain) and enters neurons by binding to the synaptic vesicle protein SV2(11). The toxin then undergoes internalization by vesicle endocytosis and translocation into the cytosol, to eventually exert its light chain proteolytic activity(12). After injection, the BoNT complex dissociates and diffuses into the target tissues. Toxin spread is a fast and active phenomenon that is driven by BoNT dose, dilution, needle size, and injection technique among others(13). Subclinical effects of BoNT on endplates far away from the injected sites can be demonstrated by increased jitter in single-fiber electromyography (SFEMG) in animals(3,14) and humans(15-16). Clinically not relevant for the moment and taken with a cautious stand because of the high animal doses applied, BoNT may undergo retrograde axonal transport, possibly transcytosed to afferent neurons, in which it cleaves its substrate SNAP-25. BoNT-truncated SNAP-25 appears not only at the injection site but also in distant regions that project to the infusion area. This retrograde spread was blocked by colchicine, pointing to a likely involvement of microtubule-dependent axonal transport(17). BoNTalso affects the cholinergically mediated intrafusal fibers of muscle spindles, parallel to that of extrafusal fibers , implying an important functional effect (see a review on the subject by Rosales and Dressler, 2010[4]). In healthy, dystonic or spastic adults, the effect on muscle spindles appear to be more prolonged than that in extrafusal fibers, and whether one applies studies using the tonic vibration reflex (TVR)(18-19); or the transcranial magnetic stimulation(20). Since the gamma-motor-neurons are unable to activate the intrafusal fibers with BoNT-A, the muscle spindle output via the afferent axons will be reduced, and because muscle activity is supported by afferent feedback, there may be reduced alpha-motorneuron drive(3). These events imply that there could be potential modulation of central motor programs following BoNT-A(21). In fact, recent BoNT-A studies in dystonia and spasticity have shown evidences of modifications in the cortical and subcortical levels(22-24); including plasticity changes(25). 3. BoNT for dystonia 3.1 Rationale Dystonia is a multi-level system disorder where involvement spans from the peripheral (muscular) to the segmental and suprasegmental levels (brainstem, basal ganglia and cortex)(4,26). Muscle hypertonus/spasms in dystonia are relieved by chemodenervation procedures that include muscle-based injections (i.e. muscle afferent block [MAB] and www.intechopen.com Dystonia, Spasticty and Botulinum Toxin Therapy

The Journal of Physiology, 2013

• BoNT-A is known to block central synapses after muscular injection due to retrograde transport in animal models.

Neuroscience Letters, 2013

Journal of Pre-Clinical and Clinical Research

Introduction and objective. Botulinum toxin (BoNT) has been used in medicine for many years. BoNT, prevents acetylcholine from being released into synapses, causing flaccid muscles paralysis. The article reviews the current knowledge of botulinum toxin application in the treatment of neurological diseases, focusing on therapeutic efficacy and side-effects. The aim of the review is to analyze the largest possible number of neurological conditions in which the application of botulinum toxin was considered. Materials and method. A literature review of the last 10 years was conducted using the key words: 'botulinum toxin neurology' in the PubMed database, with the search criteria: clinical trials, free full text in English, research on humans. 2,581 manuscripts were found. After initial analysis, 188 publications were selected for further elaboration. Finally, 61 compatible publications were identified and included in the review. Abbreviated description of the state of knowledge. In the treatment of Tourette's syndrome with BoNT, despite the reduction in tics frequency, patients did not report any benefits. There are promising reports on the reduction of the intensity of neuropathic pain and neuralgia in trigeminal neuralgia after the use of BoNT-A. Improvement in rest tremor has been seen in patients with Parkinson's disease. Administration of BoNT-A among patients with bruxism was associated with improved sleep quality and reduction of the symptoms intensity. Research confirms the effectiveness of using BoNT in the treatment of bothersome symptoms occurring in migraine, drooling, cervical dystonia and neurogenic bladder. Conclusions. Although the use of BoNT in neurological diseases is widely studied and used, the appropriate administration technique and safety of use are worth further research.

Journal of the Neurological Sciences, 2015

Toxins

Botulinum neurotoxins (BoNTs) produce local chemo-denervation by cleaving soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) proteins. Botulinum neurotoxins are therapeutically indicated in several neurological disorders and have been in use for three decades. The long-term efficacy, safety, and side effects of BoNTs have been well documented in the literature. However, the development of muscle atrophy following chronic exposure to BoNTs has not received sufficient attention. Muscle atrophy is not only cosmetically distressing, but also has an impact on future injections. An extensive literature search was conducted on atrophy and mechanisms of atrophy. Five hundred and four relevant articles in the English language were reviewed. This review revealed the surprising lack of documentation of atrophy within the literature. In addition, as demonstrated in this review, the mechanisms and the clinical factors that may lead to atrophy have also been poorly stud...

Clinical Neurophysiology, 2002

Objectives: Botulinum neurotoxin serotype A (BoNT/A) is a valid therapy for dystonia but repeated BoNT/A injections may induce a clinical immuno-resistance that could be overcome by using other BoNT serotypes. In vitro experiments and our preliminary investigations in vivo, indicate that botulinum neurotoxin serotype C (BoNT/C) could be an effective alternative to BoNT/A. Moreover, in cultured neurons 'in vitro' BoNT/C has been reported to be more toxic than BoNT/A. Methods: To verify this possibility, we compare the effect of BoNT/C and BoNT/A on the motor units count in humans by using the electrophysiological motor unit number estimation (MUNE) technique ('multiple point nerve stimulation'). Preliminarily, BoNT/C and BoNT/A dosage was calibrated in a mouse hemidiaphragm neuromuscular junction preparation. Subsequently, 8 volunteers were treated with 3 IU of BoNT/C in the extensor digitorum brevis muscle of one foot and 3 IU of BoNT/A in the contralateral one. Other 4 subjects were similarly injected at higher doses (10 IU of BoNT/C or BoNT/A) to detect a possible dose-toxic effect. Results: In both groups, no statistically significant variations in MUNE counting or single motor unit potential size were detected after 4 months from injections, when it was evident a recovery from the BoNTs blockade. Conclusions: We conclude that BoNT/C, similarly to BoNT/A, is safe and effective in humans and it could be proposed for a clinical use.

2013

Expert Opinion on Drug Metabolism & Toxicology, 2016