The Use of Botulinum Neurotoxin in Spasticity Using Ultrasound Guidance

Introduction: In recent years, there has been an increased interest in the use of botulinum neurotoxin (BoNT) to treat medical conditions refractory to conventional treatment. The following article provides an overview of the clinical use and efficacy of BoNT in the treatment of various urologic and sexual conditions.Areas covered: BoNT has been accepted and/or explored as novel treatment for various lower urinary tract and sexual dysfunctions such as overactive bladder/detrusor overactivity (DO), detrusor-sphincter dyssynergia (DSD), benign prostatic hyperplasia, interstitial cystitis/painful bladder syndrome, chronic pelvic pain and more recently premature ejaculation. The following terms ‘botulinum toxin’, ‘BoNT’, ‘botulinum toxin A’, ‘Botox’, ‘Dysport’, ‘Xeomin’, ‘botulinum toxin B’, ‘Myobloc’, ‘OnabotulinumA’, ‘RimabotulinumA’, ‘IncobotulinumA’ and ‘AbobotulinumA’ were used to search several databases including MEDLINE, Pubmed, EMBASE, CINAHL and clinicaltrials.gov for inclusion in this review article. Only English language articles were considered and all studies were limited to BoNT therapy in urological conditions in the adult population.Expert opinion: BoNT-A has received regulatory approval for use in neurogenic DO and overactive bladder, but its use remains unlicensed in other lower urinary tract conditions such as non-neurogenic lower urinary tract symptoms in men with benign prostatic hyperplasia, bladder pain syndrome and DSD. Published literature shows that BoNT can be effective in carefully selected patient groups, has minimal adverse event profile and is generally well tolerated by many patients. However, many questions remain unanswered and larger scale multi-institutional studies are required to determine the key factors in BoNT treatment success.

One important factor influencing the effectiveness of botulinum neurotoxin (BoNT) injection in the treatment of upper and lower limb spasticity is the accuracy of administration into the target muscle. Indeed, incorrect needle placement can result in complete failure of treatment. Neurotoxin diffusion outside of target muscles can cause weakness or paresis, particularly for small muscles of the hand and forearm. The use of various guidance techniques may improve both effectiveness and safety, decreasing the occurrence of side effects.

Botulinum neurotoxins, causative agents of botulism in humans, are produced by Clostridium botulinum, an anaerobic spore-former Gram-positive bacillus. Botulinum neurotoxin poses a major bioweapon threat because of its extreme potency and lethality; its ease of production, transport, and misuse; and the need for prolonged intensive care among affected persons. This paper aims at discussing botulinum neurotoxin, its structure, mechanism of action, pharmacology, its serotypes and the reasons for wide use of type A, the various indications and contraindications of the use of botulinum neurotoxin and finally the precautions taken when botulinum neurotoxin is used as a treatment approach. We have searched relevant articles on this subject in various medical databases including Google Scholar, PubMed Central, ScienceDirect, Wiley Online Library, Scopus, and Copernicus. The search resulted in more than 2669 articles, out of which a total of 187 were reviewed. However, the review has been further constricted into only 54 articles as has been presented in this manuscript keeping in mind the page limitation and the limitation to the number of references. A single gram of crystalline toxin, evenly dispersed and inhaled, can kill more than one million people. The basis of the phenomenal potency of botulinum toxin (BT) is enzymatic; the toxin is a zinc proteinase that cleaves neuronal vesicle-associated proteins responsible for acetylcholine release into the neuromuscular junction. A fascinating aspect of BT research in recent years has been the development of the most potent toxin into a molecule of significant therapeutic utility. It is the first biological toxin which is licensed for the treatment of human diseases. The present review focuses on both warfare potential as well as medical uses of botulinum neurotoxin.

Botulinum neurotoxin is one of the most versatile and widely used medical products in the world. The review's focus is the plastic and dermatologic uses of botulinum neurotoxin currently supported by published data. Relevant clinical articles regarding botulinum neurotoxin use in plastic surgery, dermatology, and general esthetic literature were searched and reviewed. The search yielded 258 studies. Two hundred articles were excluded following title and abstract review. Twenty-one studies were excluded following full-text screening. A total of 37 studies remained and were discussed in this review. Botulinum neurotoxin is widely used for numerous off-label indications from head to toe. Some uses are well documented, and their safety has been demonstrated in controlled trials, yet most remain poorly researched.

Objective: To describe the latest progress in the use of botulinum neurotoxin for post-stroke limb spasm. Methods: This paper looks up the relevant research literatures in recent years in PubMed, Web of Science, Springer, Ovid, CNKI, WanFang databases and summarizes them. Results: The latest progress in the use of botulinum neurotoxin for post-stroke limb spasm was studied from the following aspects: the action mechanism of botulinum neurotoxin; efficacy evaluation; injection dose; target muscle selection; guiding technology; combination therapy. Conclusion: Botulinum neurotoxin is the first-line treatment for post-stroke limb spasm. We need to make continuous improvement and progress from the treatment period, injection dose, target muscle selection, guiding technology and efficacy evaluation to improve the quality of life of the majority of post-stroke survivors in China.

To present the latest findings and future developments in the cosmetic use of botulinum neurotoxin. Review of recent literature and new scientific developments. Botulinum neurotoxin type A preparations onabotulinumtoxinA (BOTOX(®) Cosmetic/Vistabel(®), Allergan Inc.) and abobotulinumtoxinA (Dysport(®) /Azzalure(®) /Reloxin(®) , Ipsen Pharma,) have been used for many years and are effective and well tolerated for facial esthetic procedures. However, advances are continually made in the esthetics field. New formulations that may exhibit reduced antigenicity are becoming available, such as incobotulinumtoxinA (Xeomin(®) /Xeomeen(®) /Bocouture(®); formerly known as NT 201, Merz Pharma), which is a botulinum neurotoxin type A free from complexing proteins. In addition, lower facial procedures using botulinum toxin combined with fillers are becoming increasingly popular. Injection techniques and patterns are also evolving, with the aim of creating a more natural result and avoiding a "frozen" appearance. Moreover, the diversity of individuals requesting esthetic procedures is increasing, with growing interest from men and patients with a variety of skin types and colors. The uses of botulinum toxins for facial esthetics procedures continue to expand, with new techniques and formulations. The availability of products such as incobotulinumtoxinA may reduce the risk of neutralizing antibody development while maintaining the good efficacy and safety of existing formulations.

Parkinson’s disease is the most common age-related motoric neurodegenerative disease. In addition to the cardinal motor symptoms of tremor, rigidity, bradykinesia, and postural instability, there are numerous non-motor symptoms as well. Among the non-motor symptoms, autonomic nervous system dysfunction is common. Autonomic symptoms associated with Parkinson’s disease include sialorrhea, hyperhidrosis, gastrointestinal dysfunction, and urinary dysfunction. Botulinum neurotoxin has been shown to potentially improve these autonomic symptoms. In this review, the varied uses of botulinum neurotoxin for autonomic dysfunction in Parkinson’s disease are discussed. This review also includes discussion of some additional indications for the use of botulinum neurotoxin in Parkinson’s disease, including pain.

Recommendations on the Use of Botulinum Toxin in the Treatment of Lower Urinary Tract Disorders and Pelvic Floor Dysfunctions: A European Consensus Report

Botulinum Toxin Injections for Neurogenic and Idiopathic Detrusor Overactivity: A Critical Analysis of Results

The formation of neutralizing antibodies is a growing concern in the use of botulinum neurotoxin A (BoNT/A) as it may result in secondary treatment failure. Differences in the immunogenicity of BoNT/A formulations have been attributed to the presence of pharmacologically unnecessary bacterial components. Reportedly, the rate of antibody-mediated secondary non-response is lowest in complexing protein-free (CF) IncobotulinumtoxinA (INCO). Here, the published data and literature on the composition and properties of the three commercially available CF-BoNT/A formulations, namely, INCO, Coretox® (CORE), and DaxibotulinumtoxinA (DAXI), are reviewed to elucidate the implications for their potential immunogenicity. While all three BoNT/A formulations are free of complexing proteins and contain the core BoNT/A molecule as the active pharmaceutical ingredient, they differ in their production protocols and excipients, which may affect their immunogenicity. INCO contains only two immunologically inconspicuous excipients, namely, human serum albumin and sucrose, and has demonstrated low immunogenicity in daily practice and clinical studies for more than ten years. DAXI contains four excipients, namely, L-histidine, trehalosedihydrate, polysorbate 20, and the highly charged RTP004 peptide, of which the latter two may increase the immunogenicity of BoNT/A by introducing neo-epitopes. In early clinical studies with DAXI, antibodies against BoNT/A and RTP004 were found at low frequencies; however, the follow-up period was critically short, with a maximum of three injections. CORE contains four excipients: L-methionine, sucrose, NaCl, and polysorbate 20. Presently, no data are available on the immunogenicity of CORE in human beings. It remains to be seen whether all three CF BoNT/A formulations demonstrate the same low immunogenicity in patients over a long period of time.

Clinical differences between botulinum neurotoxin type A and B

The discrepancy between the widespread use of botulinum neurotoxin (BoNT) in managing headache and the supporting clinical evidence is unprecedented. No substance seems to have inspired more physicians and patients to undertake spirited treatment attempts. Tremendous treatment success in small, uncontrolled clinical trials has been repeatedly reported, but no substance that has been studied to an equal extent has so utterly failed to provide proof of effect in controlled clinical trials. Nevertheless, even though most randomized, controlled clinical trials have not met their defined primary outcome criterion, BoNT is still considered a promising treatment alternative for primary headache disorders. Experimental approaches to the pathophysiologic impact of BoNT on the perception of pain have been equally unsuccessful. Although most studies have been unable to find a direct antinociceptive effect in humans, some researchers continue to seek specific injection sites or injection techniques that may promise more successful results. Others look for a positive effect by narrowing the indications for BoNT to more homogenous symptoms or special patient subgroups. The results of randomized, controlled studies involving a total of 3552 patients indicate that BoNT injection is probably ineffective for patients with migraine and chronic tension-type headache regardless of injection site, dosage, or injection regimen, and there is insufficient evidence to draw a conclusion about its effectiveness for the treatment of chronic daily headache or subforms. The lack of direct experimental or clinical trial evidence that BoNT has a direct antinociceptive effect in humans must be addressed before more trials are conducted, involving even more patients. Additional pathophysiologically oriented research is also needed to unravel the mechanisms of action of BoNT in human pain perception or, alternatively, to bring it all down to the placebo effect.

More than fifty years following the discovery that botulinum neurotoxins inhibit neuromuscular transmission, these powerful poisons have become drugs with many indications. First used to treat strabismus, local injections of botulinum neurotoxin are now considered a safe and efficacious treatment for neurological and non-neurological conditions. One of the most recent achievements in the field is the observation that botulinum neurotoxin is a treatment for diseases of the gastrointestinal tract. Botulinum neurotoxin is not only potent in blocking skeletal neuromuscular transmission, but also block cholinergic nerve endings in the autonomic nervous system. The capability to inhibit contraction of smooth muscles of the gastrointestinal tract was first suggested based on in vitro observations and later demonstrated in vivo; it has also been shown that botulinum neurotoxin does not block non adrenergic non cholinergic responses mediated by nitric oxide. This has further promoted the interest to use botulinum neurotoxin as a treatment for overactive smooth muscles and sphincters, such as the lower esophageal sphincter to treat esophageal achalasia, or the internal anal sphincter to treat anal fissure. Information on the anatomical and functional organization of innervation of the gastrointestinal tract is a prerequisite to understand many features of botulinum neurotoxin action on the gut and the effects of injections placed into specific sphincters. This review presents current data on the use of botulinum neurotoxin to treat diseases of the gastrointestinal tract and summarizes recent knowledge on the pathogenesis of disorders of the gut due to a dysfunction of the enteric nervous system.

The growing use of botulinum neurotoxins (BoNTs) for medical and aesthetic purposes has led to the development and marketing of an increasing number of BoNT products. Given that BoNTs are biological medications, their characteristics are heavily influenced by their manufacturing methods, leading to unique products with distinct clinical characteristics. The manufacturing and formulation processes for each BoNT are proprietary, including the potency determination of reference standards and other features of the assays used to measure unit potency. As a result of these differences, units of BoNT products are not interchangeable or convertible using dose ratios. The intrinsic, product-level differences among BoNTs are compounded by differences in the injected tissues, which are innervated by different nerve fiber types (e.g., motor, sensory, and/or autonomic nerves) and require unique dosing and injection sites that are particularly evident when treating complex therapeutic and aesthetic conditions. It is also difficult to compare across studies due to inherent differences in patient populations and trial methods, necessitating attention to study details underlying each outcome reported. Ultimately, each BoNT possesses a unique clinical profile for which unit doses and injection paradigms must be determined individually for each indication. This practice will help minimize unexpected adverse events and maximize efficacy, duration, and patient satisfaction. With this approach, BoNT is poised to continue as a unique tool for achieving individual goals for an increasing number of medical and aesthetic indications.

For well over 30 years, the botulinum neurotoxin (BoNT) has been used for a large number of indications, some of which however have not been licensed. Admittedly, approval varies in many countries and this permits a large spectrum for evaluation. Thus, BoNT is used for patients with Parkinson’s disease (PD) and other Parkinson’s syndromes (PS) in varying degrees of frequency. We have to distinguish between (1) indications that are either approved or (2) those not approved, (3) indications that might be a result of PS and (4) finally those which appear independent of PS. The most important indication for BoNT in PS patients is probably sialorrhea, for which approval has been granted in the majority of countries. Cervical dystonia is a frequent symptom in PS, with anterocollis as a specific entity. A further indication is blepharospasm in the different forms, especially the inhibition of eyelid opening in atypical PS. The use of BoNT in cases of camptocormia, the Pisa syndrome and neck rigidity is still a matter of debate. In dystonia of the extremities BoNT can be recommended, especially in dystonia of the feet. One well-known indication, for which however sufficient data are still lacking, involves treating tremor with BoNT. As to autonomic symptoms: Focal hyperhidrosis and detrusor hyperactivity can be mentioned, in this last case BoNT has already been approved. A number of further but rare indications such as freezing-of-gait, dyskinesia, and dysphagia will be discussed and evaluated.