Aktories, Klaus; Barth, Holger
Clostridium botulinum C2 toxin is the prototype of actin-ADP-ribosylating toxins. The toxin consists of the enzyme component C2I and the separated binding/translocation component C2II. C2II is proteolytically activated to form heptamers, which bind the enzyme component. After endocytosis of the receptor-toxin complex, the enzyme component enters the cytosol from an acidic endosomal compartment to modify G-actin at arginine177. Recent data indicate that chaperons are involved in the translocation process of the toxin.
Prisilla, A; Prathiviraj, R; Chellapandi, P
Clostridium botulinum (group-III) is an anaerobic bacterium producing C2 toxin along with botulinum neurotoxins. C2 toxin is belonged to binary toxin A family in bacterial ADP-ribosylation superfamily. A structural and functional diversity of binary toxin A family was inferred from different evolutionary constraints to determine the avirulence state of C2 toxin. Evolutionary genetic analyses revealed evidence of C2 toxin cluster evolution through horizontal gene transfer from the phage or plasmid origins, site-specific insertion by gene divergence, and homologous recombination event. It has also described that residue in conserved NAD-binding core, family-specific domain structure, and functional motifs found to predetermine its virulence state. Any mutational changes in these residues destabilized its structure-function relationship. Avirulent mutants of C2 toxin were screened and selected from a crucial site required for catalytic function of C2I and pore-forming function of C2II. We found coevolved amino acid pairs contributing an essential role in stabilization of its local structural environment. Avirulent toxins selected in this study were evaluated by detecting evolutionary constraints in stability of protein backbone structure, folding and conformational dynamic space, and antigenic peptides. We found 4 avirulent mutants of C2I and 5 mutants of C2II showing more stability in their local structural environment and backbone structure with rapid fold rate, and low conformational flexibility at mutated sites. Since, evolutionary constraints-free mutants with lack of catalytic and pore-forming function suggested as potential immunogenic candidates for treating C. botulinum infected poultry and veterinary animals. Single amino acid substitution in C2 toxin thus provides a major importance to understand its structure-function link, not only of a molecule but also of the pathogenesis.
Nagahama, Masahiro; Takehara, Masaya; Takagishi, Teruhisa; Seike, Soshi; Miyamoto, Kazuaki; Kobayashi, Keiko
Clostridium botulinum C2 toxin consists of an enzyme component (C2I) and a binding component (C2II). Activated C2II (C2IIa) binds to a cell receptor, giving rise to lipid raft-dependent oligomerization, and it then assembles with C2I. The whole toxin complex is then endocytosed into the cytosol, resulting in the destruction of the actin cytoskeleton and cell rounding. Here, we showed that C2 toxin requires acid sphingomyelinase (ASMase) activity during internalization. In this study, inhibitors of ASMase and lysosomal exocytosis blocked C2 toxin-induced cell rounding. C2IIa induced Ca(2+) influx from the extracellular medium to cells. C2 toxin-induced cell rounding was enhanced in the presence of Ca(2+) ASMase was released extracellularly when cells were incubated with C2IIa in the presence of Ca(2+) Small interfering RNA (siRNA) knockdown of ASMase reduced C2 toxin-induced cell rounding. ASMase hydrolyzes sphingomyelin to ceramide on the outer leaflet of the membrane at acidic pH. Ceramide was detected in cytoplasmic vesicles containing C2IIa. These results indicated that ASMase activity is necessary for the efficient internalization of C2 toxin into cells. Inhibitors of ASMase may confer protection against infection. Copyright © 2017 American Society for Microbiology.
Pavlik, Benjamin J.; Hruska, Elizabeth J.; Van Cott, Kevin E.; Blum, Paul H.
Many biological toxins are known to attack specific cell types, delivering their enzymatic payloads to the cytosol. This process can be manipulated by molecular engineering of chimeric toxins. Using toxins with naturally unlinked components as a starting point is advantageous because it allows for the development of payloads separately from the binding/translocation components. Here the Clostridium botulinum C2 binding/translocation domain was retargeted to neural cell populations by deleting its non-specific binding domain and replacing it with a C. botulinum neurotoxin binding domain. This fusion protein was used to deliver fluorescently labeled payloads to Neuro-2a cells. Intracellular delivery was quantified by flow cytometry and found to be dependent on artificial enrichment of cells with the polysialoganglioside receptor GT1b. Visualization by confocal microscopy showed a dissociation of payloads from the early endosome indicating translocation of the chimeric toxin. The natural Clostridium botulinum C2 toxin was then delivered to human glioblastoma A172 and synchronized HeLa cells. In the presence of the fusion protein, native cytosolic enzymatic activity of the enzyme was observed and found to be GT1b-dependent. This retargeted toxin may enable delivery of therapeutics to peripheral neurons and be of use in addressing experimental questions about neural physiology. PMID:27025362
Pavlik, Benjamin J; Hruska, Elizabeth J; Van Cott, Kevin E; Blum, Paul H
Many biological toxins are known to attack specific cell types, delivering their enzymatic payloads to the cytosol. This process can be manipulated by molecular engineering of chimeric toxins. Using toxins with naturally unlinked components as a starting point is advantageous because it allows for the development of payloads separately from the binding/translocation components. Here the Clostridium botulinum C2 binding/translocation domain was retargeted to neural cell populations by deleting its non-specific binding domain and replacing it with a C. botulinum neurotoxin binding domain. This fusion protein was used to deliver fluorescently labeled payloads to Neuro-2a cells. Intracellular delivery was quantified by flow cytometry and found to be dependent on artificial enrichment of cells with the polysialoganglioside receptor GT1b. Visualization by confocal microscopy showed a dissociation of payloads from the early endosome indicating translocation of the chimeric toxin. The natural Clostridium botulinum C2 toxin was then delivered to human glioblastoma A172 and synchronized HeLa cells. In the presence of the fusion protein, native cytosolic enzymatic activity of the enzyme was observed and found to be GT1b-dependent. This retargeted toxin may enable delivery of therapeutics to peripheral neurons and be of use in addressing experimental questions about neural physiology.
Schnell, Leonie; Mittler, Ann-Katrin; Sadi, Mirko; Popoff, Michel R; Schwan, Carsten; Aktories, Klaus; Mattarei, Andrea; Azarnia Tehran, Domenico; Montecucco, Cesare; Barth, Holger
The pathogenic bacteria Clostridium difficile, Clostridium perfringens and Clostridium botulinum produce the binary actin ADP-ribosylating toxins CDT, iota and C2, respectively. These toxins are composed of a transport component (B) and a separate enzyme component (A). When both components assemble on the surface of mammalian target cells, the B components mediate the entry of the A components via endosomes into the cytosol. Here, the A components ADP-ribosylate G-actin, resulting in depolymerization of F-actin, cell-rounding and eventually death. In the present study, we demonstrate that 4-bromobenzaldehyde N-(2,6-dimethylphenyl)semicarbazone (EGA), a compound that protects cells from multiple toxins and viruses, also protects different mammalian epithelial cells from all three binary actin ADP-ribosylating toxins. In contrast, EGA did not inhibit the intoxication of cells with Clostridium difficile toxins A and B, indicating a possible different entry route for this toxin. EGA does not affect either the binding of the C2 toxin to the cells surface or the enzyme activity of the A components of CDT, iota and C2, suggesting that this compound interferes with cellular uptake of the toxins. Moreover, for C2 toxin, we demonstrated that EGA inhibits the pH-dependent transport of the A component across cell membranes. EGA is not cytotoxic, and therefore, we propose it as a lead compound for the development of novel pharmacological inhibitors against clostridial binary actin ADP-ribosylating toxins.
Schnell, Leonie; Mittler, Ann-Katrin; Sadi, Mirko; Popoff, Michel R.; Schwan, Carsten; Aktories, Klaus; Mattarei, Andrea; Tehran, Domenico Azarnia; Montecucco, Cesare; Barth, Holger
The pathogenic bacteria Clostridium difficile, Clostridium perfringens and Clostridium botulinum produce the binary actin ADP-ribosylating toxins CDT, iota and C2, respectively. These toxins are composed of a transport component (B) and a separate enzyme component (A). When both components assemble on the surface of mammalian target cells, the B components mediate the entry of the A components via endosomes into the cytosol. Here, the A components ADP-ribosylate G-actin, resulting in depolymerization of F-actin, cell-rounding and eventually death. In the present study, we demonstrate that 4-bromobenzaldehyde N-(2,6-dimethylphenyl)semicarbazone (EGA), a compound that protects cells from multiple toxins and viruses, also protects different mammalian epithelial cells from all three binary actin ADP-ribosylating toxins. In contrast, EGA did not inhibit the intoxication of cells with Clostridium difficile toxins A and B, indicating a possible different entry route for this toxin. EGA does not affect either the binding of the C2 toxin to the cells surface or the enzyme activity of the A components of CDT, iota and C2, suggesting that this compound interferes with cellular uptake of the toxins. Moreover, for C2 toxin, we demonstrated that EGA inhibits the pH-dependent transport of the A component across cell membranes. EGA is not cytotoxic, and therefore, we propose it as a lead compound for the development of novel pharmacological inhibitors against clostridial binary actin ADP-ribosylating toxins. PMID:27043629
Chellapandi, P; Prisilla, A
Clostridium botulinum group III strains are able to produce cytotoxins, C2 toxin and C3 exotoxin, along with botulinum neurotoxin types C and D. C2 toxin and C3 exotoxin produced from this organism are the most important members of bacterial ADP-ribosyltransferase superfamily. Both toxins have distinct pathophysiological functions in the avian and mammalian hosts. The members of this superfamily transfer an ADP-ribose moiety of NAD+ to specific eukaryotic target proteins. The present review describes the structure, function and evolution aspects of these toxins with a special emphasis to the development of veterinary vaccines. C2 toxin is a binary toxin that consists of a catalytic subunit (C2I) and a translocation subunit (C2II). C2I component is structurally and functionally similar to the VIP2 and iota A toxin whereas C2II component shows a significant homology with the protective antigen from anthrax toxin and iota B. Unlike C2 toxin, C3 toxin is devoid of translocation/binding subunit. Extensive studies on their sequence-structure-function link spawn additional efforts to understand the catalytic mechanisms and target recognition. Structural and functional relationships of them are often determined by using evolutionary constraints as valuable biological measures. Enzyme-deficient mutants derived from these toxins have been used as drug/protein delivery systems to eukaryotic cells. Thus, current knowledge on their molecular diversity is a well-known perspective to design immunotoxin or subunit vaccine for C. botulinum infection.
Stimulation of human neutrophils with the chemotactic N-formyl peptide causes production of oxygen radicals and conversion of monomeric actin (G-actin) to polymeric actin (F-actin). The effects of the binary botulinum C2 toxin on the amount of F-actin and on neutrophil cell responses were studied. Two different methods for analyzing the actin response were used in formyl peptide-stimulated cells: staining of F- actin with rhodamine-phalloidin and a transient right angle light scatter. Preincubation of neutrophils with 400 ng/ml component I and 1,600 ng/ml component II of botulinum C2 toxin for 30 min almost completely inhibited the formyl peptide-stimulated polymerization of G- actin and at the same time decreased the amount of F-actin in unstimulated neutrophils by an average of approximately 30%. Botulinum C2 toxin preincubation for 60 min destroyed approximately 75% of the F- actin in unstimulated neutrophils. Right angle light scatter analysis showed that control neutrophils exhibited the transient response characteristic of actin polymerization; however, after botulinum C2 toxin treatment, degranulation was detected. Single components of the binary botulinum C2 toxin were without effect on the actin polymerization response. Fluorescence flow cytometry and fluorospectrometric binding studies showed little alteration in N- formyl peptide binding or dissociation dynamics in the toxin-treated cells. However, endocytosis of the fluorescent N-formyl peptide ligand- receptor complex was slower but still possible in degranulating neutrophils treated with botulinum C2 toxin for 60 min. The half-time of endocytosis, estimated from initial rates, was 4 and 8 min in control and botulinum C2 toxin-treated neutrophils, respectively. PMID:2768337
Jensen, W.I.; Duncan, R.M.
Most strains of Clostridium botulinum type C, after having lost their capacity to produce their dominant toxin (C1) as a result of being "cured" of their prophages, continue to produce C2, a trypsin-activable toxin reported by other investigators. While of relatively low toxicity when administered perorally to the adult mallard duck (Anas platyrhynchos), it was highly toxic when given parenterally. By the intravenous route, for example, it was more than 1,000 times as toxic as C1 toxin by the same route, when compared on the basis of mouse intraperitoneal toxicity. The cause of death in every instance was massive pulmonary edema and hemorrhage rather than the respiratory paralysis that occurs in C1 intoxication.
Aktories, Klaus; Barth, Holger
Clostridium botulinum C2 toxin is a member of the family of binary actin-ADP-ribosylating toxins. It consists of the enzyme component C2I, and the separated binding/translocation component C2II. Proteolytically activated C2II forms heptamers and binds to a carbohydrate cell surface receptor. After attachment of C2I, the toxin complex is endocytosed to reach early endosomes. At low pH of endosomes, C2II-heptamers insert into the membrane, form pores and deliver C2I into the cytosol. Here, C2I ADP-ribosylates actin at Arg177 to block actin polymerization and to induce depolymerization of actin filaments. The mini-review describes main properties of C2 toxin and discusses new findings on the involvement of chaperones in the up-take process of the toxin.
Prisilla, A; Prathiviraj, R; Sasikala, R; Chellapandi, P
Clostridium botulinum (group-III) is an anaerobic bacterium producing C2 and C3 toxins in addition to botulinum neurotoxins in avian and mammalian cells. C2 and C3 toxins are members of bacterial ADP-ribosyltransferase superfamily, which modify the eukaryotic cell surface proteins by ADP-ribosylation reaction. Herein, the mutant proteins with lack of catalytic and pore forming function derived from C2 (C2I and C2II) and C3 toxins were computationally evaluated to understand their structure-function integrity. We have chosen many structural constraints including local structural environment, folding process, backbone conformation, conformational dynamic sub-space, NAD-binding specificity and antigenic determinants for screening of suitable avirulent toxins. A total of 20 avirulent mutants were identified out of 23 mutants, which were experimentally produced by site-directed mutagenesis. No changes in secondary structural elements in particular to α-helices and β-sheets and also in fold rate of all-β classes. Structural stability was maintained by reordered hydrophobic and hydrogen bonding patterns. Molecular dynamic studies suggested that coupled mutations may restrain the binding affinity to NAD(+) or protein substrate upon structural destabilization. Avirulent toxins of this study have stable energetic backbone conformation with a common blue print of folding process. Molecular docking studies revealed that avirulent mutants formed more favorable hydrogen bonding with the side-chain of amino acids near to conserved NAD-binding core, despite of restraining NAD-binding specificity. Thus, structural constraints in the avirulent toxins would determine their immunogenic nature for the prioritization of protein-based subunit vaccine/immunogens to avian and veterinary animals infected with C. botulinum. Copyright © 2016 Elsevier B.V. All rights reserved.
Kreidler, Anna-Maria; Benz, Roland; Barth, Holger
The pathogenic bacteria Clostridium botulinum and Bacillus anthracis produce the binary protein toxins C2 and lethal toxin (LT), respectively. These toxins consist of a binding/transport (B7) component that delivers the separate enzyme (A) component into the cytosol of target cells where it modifies its specific substrate and causes cell death. The B7 components of C2 toxin and LT, C2IIa and PA63, respectively, are ring-shaped heptamers that bind to their cellular receptors and form complexes with their A components C2I and lethal factor (LF), respectively. After receptor-mediated endocytosis of the toxin complexes, C2IIa and PA63 insert into the membranes of acidified endosomes and form trans-membrane pores through which C2I and LF translocate across endosomal membranes into the cytosol. C2IIa and PA63 also form channels in planar bilayer membranes, and we used this approach earlier to identify chloroquine as a potent blocker of C2IIa and PA63 pores. Here, a series of chloroquine derivatives was investigated to identify more efficient toxin inhibitors with less toxic side effects. Chloroquine, primaquine, quinacrine, and fluphenazine blocked C2IIa and PA63 pores in planar lipid bilayers and in membranes of living epithelial cells and macrophages, thereby preventing the pH-dependent membrane transport of the A components into the cytosol and protecting cells from intoxication with C2 toxin and LT. These potent inhibitors of toxin entry underline the central role of the translocation pores for cellular uptake of binary bacterial toxins and as relevant drug targets, and might be lead compounds for novel pharmacological strategies against severe enteric diseases and anthrax.
Heffron, Ann; Poxton, Ian R
The closely related Clostridium novyi and Clostridium botulinum types C and D are of current interest because of their association with serious infections in injecting drug users (C. novyi type A) and equine and feline dysautonomias (C. botulinum types C/D). The species are defined by the major toxins they produce: the alpha toxin of C. novyi, and the type C and D neurotoxins of C. botulinum (BoNT/C and BoNT/D). The other major toxin produced by this group, and previously thought to be restricted to the botulinum types, is the chromosomally encoded C2--a binary toxin consisting of two components, I and II. In the current study 44 of these clostridia from the authors' culture collection were investigated--most of which had been identified previously by conventional biochemical tests as 'C. novyi type A'. The aim was to check the distribution of toxin genes by PCR to see if the identities were consistent with the genes carried, and to ascertain if the C2 gene was only found in authentic C. botulinum strains. Several combinations of the species-defining genes and the two components of the C2 genes were detected. Only the authentic BoNT/C- and BoNT/D-positive C. botulinum strains and one of two non-neurotoxic variants of type C carried genes for both components of the C2 toxin. Of the remaining 40 C. novyi type A-like strains, the gene for the alpha toxin was found in 22, with 19 of these also possessing the gene for component I (16) or component II (3) but not both. In the alpha toxin-negative strains (22), both of the C2 genes were detected in 5 strains (3 C. botulinum), with component I in 11 strains and neither gene in 6 strains.
Botulinum toxin is an egzotoxin produced by Gram positive bacteria Clostridium botulinum. It is among the most potent toxins known. The 3 main clinical presentations of botulism are as follows: foodborne botulism, infant botulism and wound botulism. The main symptom of intoxication is flat muscles paralysis. The treatment is supportive care and administration of antitoxin. In prevention the correct preparing of canned food is most important. Botulinum toxin is accepted as a biological weapon.
Injection laryngoplasty; Botox - larynx: spasmodic dysphonia-BTX; Essential voice tremor (EVT)-btx; Glottic insufficiency; Percutaneous electromyography - guided botulinum toxin treatment; Percutaneous indirect laryngoscopy - ...
1980) and the other in gibbons (Hylobates lar) (Smith et aI., 1985). In addition to nonhuman primates , most other animal species that show some...nonhuman primate species are known to be susceptible to type Cl and D toxins both in nature and as experimental models. A large natural outbreak of... primates were previously reported, one in squirrel monkeys (Saimiri sciureus) and capuchin monkeys (Cebus capucinus and Cebus olivaceus) (Smart et al
Ozcan, Cengiz; Ismi, Onur
Rhinitis is a common clinical entity. Besides nasal obstruction, itching, and sneezing, one of the most important symptoms of rhinitis is nasal hypersecretion produced by nasal glands and exudate from the nasal vascular bed. Allergic rhinitis is an IgE-mediated inflammatory reaction of nasal mucosa after exposure to environmental allergens. Idiopathic rhinitis describes rhinitis symptoms that occur after non-allergic, noninfectious irritants. Specific allergen avoidance, topical nasal decongestants, nasal corticosteroids, immunotherapy, and sinonasal surgery are the main treatment options. Because the current treatment modalities are not enough for reducing rhinorrhea in some patients, novel treatment options are required to solve this problem. Botulinum toxin is an exotoxin generated by Clostridium botulinum. It disturbs the signal transmission at the neuromuscular and neuroglandular junction by inhibiting the acetylcholine release from the presynaptic nerve terminal. It has been widely used in neuromuscular, hypersecretory, and autonomic nerve system disorders. There have been a lot of published articles concerning the effect of this toxin on rhinitis symptoms. Based on the results of these reports, intranasal botulinum toxin A administration appears to be a safe and effective treatment method for decreasing rhinitis symptoms in rhinitis patients with a long-lasting effect. Botulinum toxin type A will be a good treatment option for the chronic rhinitis patients who are resistant to other treatment methods.
Brodsky, Matthew A.; Swope, David M.; Grimes, David
Background It is generally agreed that diffusion of botulinum toxin occurs, but the extent of the spread and its clinical importance are disputed. Many factors have been suggested to play a role but which have the most clinical relevance is a subject of much discussion. Methods This review discusses the variables affecting diffusion, including protein composition and molecular size as well as injection factors (e.g., volume, dose, injection method). It also discusses data on diffusion from comparative studies in animal models and human clinical trials that illustrate differences between the available botulinum toxin products (onabotulinumtoxinA, abobotulinumtoxinA, incobotulinumtoxinA, and rimabotulinumtoxinB). Results Neither molecular weight nor the presence of complexing proteins appears to affect diffusion; however, injection volume, concentration, and dose all play roles and are modifiable. Both animal and human studies show that botulinum toxin products are not interchangeable, and that some products are associated with greater diffusion and higher rates of diffusion-related adverse events than others. Discussion Each of the botulinum toxins is a unique pharmacologic entity. A working knowledge of the different serotypes is essential to avoid unwanted diffusion-related adverse events. In addition, clinicians should be aware that the factors influencing diffusion may range from properties intrinsic to the drug to accurate muscle selection as well as dilution, volume, and dose injected. PMID:23440162
Lim, Erle C H; Seet, Raymond C S
Botulinum toxin (BTX), derived from the exotoxin of Clostridium botulinum, cleaves Soluble N-ethylmaleimide-sensitive factor-Attachment protein REceptor (SNARE) proteins, causing chemodenervation of cholinergic neurons. BTX also inhibits exocytosis of vesicles containing norepinephrine, glutamate, substance P and calcitonin gene-related peptide (CGRP) and inhibits expression of the vanilloid receptor. Clinical applications of BTX, which include the treatment of overactive skeletal and smooth muscles, hypersecretory and painful disorders, have increased exponentially since it was first used clinically to treat strabismus more than two decades ago. In this editorial, we discuss reports of new therapeutic indications of BTX, and propose new areas for research.
Dhaked, Ram Kumar; Singh, Manglesh Kumar; Singh, Padma; Gupta, Pallavi
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. 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 is enzymatic; the toxin is a zinc proteinase that cleaves neuronal vesicle associated proteins responsible for acetylcholine release into the neuromuscular junction. As a military or terrorist weapon, botulinum toxin could be disseminated via aerosol or by contamination of water or food supplies, causing widespread casualties. A fascinating aspect of botulinum toxin research in recent years has been development of the most potent toxin into a molecule of significant therapeutic utility. It is the first biological toxin which is licensed for treatment of human diseases. In the late 1980s, Canada approved use of the toxin to treat strabismus, in 2001 in the removal of facial wrinkles and in 2002, the FDA in the United States followed suit. The present review focuses on both warfare potential and medical uses of botulinum neurotoxin. PMID:21149997
Dhaked, Ram Kumar; Singh, Manglesh Kumar; Singh, Padma; Gupta, Pallavi
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. 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 is enzymatic; the toxin is a zinc proteinase that cleaves neuronal vesicle associated proteins responsible for acetylcholine release into the neuromuscular junction. As a military or terrorist weapon, botulinum toxin could be disseminated via aerosol or by contamination of water or food supplies, causing widespread casualties. A fascinating aspect of botulinum toxin research in recent years has been development of the most potent toxin into a molecule of significant therapeutic utility . It is the first biological toxin which is licensed for treatment of human diseases. In the late 1980s, Canada approved use of the toxin to treat strabismus, in 2001 in the removal of facial wrinkles and in 2002, the FDA in the United States followed suit. The present review focuses on both warfare potential and medical uses of botulinum neurotoxin.
Castillo-Álvarez, Federico; Hernando de la Bárcena, Ignacio; Marzo-Sola, María Eugenia
Trigeminal neuralgia is one of the most disabling facial pain syndromes, with a significant impact on patients' quality of life. Pharmacotherapy is the first choice for treatment but cases of drug resistance often require new strategies, among which various interventional treatments have been used. In recent years a new therapeutic strategy consisting of botulinum toxin has emerged, with promising results. We reviewed clinical cases and case series, open-label studies and randomized clinical trials examining the use of botulinum toxin for drug-refractory trigeminal neuralgia published in the literature. The administration of botulinum toxin has proven to be a safe and effective therapeutic strategy in patients with drug-refractory idiopathic trigeminal neuralgia, but many questions remain unanswered as to the precise role of botulinum toxin in the treatment of this disease. Copyright © 2016 Elsevier España, S.L.U. All rights reserved.
Botulinum toxin, the most potent biological toxin, has become a powerful therapeutic tool for a growing number of clinical applications. This review draws attention to new findings about the mechanism of action of botulinum toxin and briefly reviews some of its most frequent uses, focusing on evidence based data. Double blind, placebo controlled studies, as well as open label clinical trials, provide evidence that, when appropriate targets and doses are selected, botulinum toxin temporarily ameliorates disorders associated with excessive muscle contraction or autonomic dysfunction. When injected not more often than every three months, the risk of blocking antibodies is slight. Long term experience with this agent suggests that it is an effective and safe treatment not only for approved indications but also for an increasing number of off-label indications. PMID:15201348
ILGAZ AYDINLAR, Elif; YALINAY DİKMEN, Pınar; SAĞDUYU KOCAMAN, Ayşe
Since botulinum toxin might have a therapeutic effect on pain, many studies investigating the efficiency of botulinum toxin in headache treatment have been done. The most satisfying results were achieved by botulinum toxin type A (BoNT/A) in the treatment of chronic migraine. In this paper, we reviewed the clinical effectiveness of BoNT/A in migraine and included our clinical experience. In our ongoing pilot study, where we have repeated BoNT/A injections every 12 weeks, The difference in the Migraine Disability Assessment (MIDAS) scores between the first and the second injections was 61.1%; and between the first and the 3rd injections was found to be 65.72%.
Abdallah, Enas Abdallah Ali
Botulinum neurotoxins are natural molecules produced by anaerobic spore-forming bacteria called Clostradium boltulinum. The toxin has a peculiar mechanism of action by preventing the release of acetylcholine from the presynaptic membrane. Consequently, it has been used in the treatment of various neurological conditions related to muscle hyperactivity and/or spasticity. Also, it has an impact on the autonomic nervous system by acting on smooth muscle, leading to its use in the management of pain syndromes. The use of botulinum toxin in children separate from adults has received very little attention in the literature. This review presents the current data on the use of botulinum neurotoxin to treat various neurological disorders in children. PMID:27335961
Shilpa, P. S.; Kaul, Rachna; Sultana, Nishat; Bhat, Suraksha
Botulinum Toxin (BT) is a natural molecule produced during growth and autolysis of bacterium called Clostridium botulinum. Use of BT for cosmetic purposes has gained popularity over past two decades, and recently, other therapeutic uses of BT has been extensively studied. BT is considered as a minimally invasive agent that can be used in the treatment of various orofacial disorders and improving the quality of life in such patients. The objective of this article is to review the nature, mechanism of action of BT, and its application in various head and neck diseases. PMID:24678189
... Health Resources Drugs, Procedures & Devices Procedures & Devices Botulinum Toxin Injections: A Treatment for Muscle Spasms Botulinum Toxin Injections: A Treatment for Muscle Spasms Share Print ...
Sherris, David A; Gassner, Holger G
Botulinum toxin injection has been used for a variety of indications in humans, including blepharospasm and hyperfunctional facial lines. This article describes a novel formulation of botulinum toxin, which supplies immediate feedback to the injecting physician. Additionally, recent findings are described that indicate the immediate injection of botulinum toxin into the muscles underlying a wound can improve the cosmetic outcome of the facial cutaneous scar. Future applications of these findings are discussed.
Al-Muharraqi, Mohammed A; Fedorowicz, Zbys; Al Bareeq, Jaffer; Al Bareeq, Reem; Nasser, Mona
Benign masseter muscle hypertrophy is an uncommon clinical phenomenon of uncertain aetiology which is characterised by a soft swelling near the angle of the mandible. The swelling may on occasion be associated with facial pain and can be prominent enough to be considered cosmetically disfiguring. Varying degrees of success have been reported for some of the treatment options for masseter hypertrophy, which range from simple pharmacotherapy to more invasive surgical reduction. Injection of botulinum toxin type A into the masseter muscle is generally considered a less invasive modality and has been advocated for cosmetic sculpting of the lower face. Botulinum toxin type A is a powerful neurotoxin which is produced by the anaerobic organism Clostridium botulinum and when injected into a muscle causes interference with the neurotransmitter mechanism producing selective paralysis and subsequent atrophy of the muscle. To assess the effects of botulinum toxin type A in the management of benign bilateral masseter hypertrophy. We searched the following databases in August 2008: the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2008, issue 3); MEDLINE (via PubMed) (1950 to August 2008); EMBASE (via embase.com) (1980 to August 2008); and LILACS via BIREME. We searched two bibliographic databases of regional journals which may be expected to contain relevant trials (IndMED and Iranmedex) using free text terms appropriate for this review. Randomised controlled clinical trials (RCTs) and controlled clinical trials (CCTs) comparing intra-masseteric injections of botulinum toxin versus placebo administered for cosmetic facial sculpting in individuals of any age with bilateral benign masseter hypertrophy, which had been self-evaluated and confirmed by clinical and radiological examination. We excluded participants with unilateral or compensatory contralateral masseter hypertrophy resulting from head and neck radiotherapy. Two review authors
Weiser, Kirsten; Kennedy, Abigail
The history of botulinum toxin is fascinating. First recognized as the cause of botulism nearly 200 years ago, it was originally feared as a deadly poison. Over the last 30 years, however, botulinum toxin has been transformed into a readily available medication used to treat a variety of medical disorders. Interest in the use of botulinum toxin has been particularly strong for patients with spastic smooth muscle disorders of the gastrointestinal tract. Patients with achalasia, diffuse esophageal spasm, gastroparesis, sphincter of Oddi dysfunction, and anal fissures have all been treated with botulinum toxin injections, often with impressive results. However, not all patients respond to botulinum toxin therapy, and large randomized controlled trials are lacking for many conditions commonly treated with botulinum toxin. This paper reviews the history, microbiology, and pharmacology of botulinum toxin, discusses its mechanism of action, and then presents recent evidence from the literature regarding the use of botulinum toxin for the treatment of a variety of gastrointestinal tract disorders. PMID:21960915
Botulinum toxin injection for treatment of facial wrinkles is the most frequently performed cosmetic procedure in the United States, and it is one of the most common entry procedures for clinicians seeking to incorporate aesthetic treatments into their practice. Treatment of frown lines and crow's feet, which are the cosmetic indications approved by the U.S. Food and Drug Administration, and horizontal forehead lines, offers predictable results, has few adverse effects, and is associated with high patient satisfaction. Wrinkles are formed by dermal atrophy and repetitive contraction of underlying facial musculature. Botulinum toxin is a potent neurotoxin that inhibits release of acetylcholine at the neuromuscular junction. Injection of small quantities of botulinum toxin into specific overactive muscles causes localized muscle relaxation that smooths the overlying skin and reduces wrinkles. Botulinum toxin effects take about two weeks to fully develop and last three to four months. Dynamic wrinkles, seen during muscle contraction, yield more dramatic results than static wrinkles, which are visible at rest. Botulinum toxin injection is contraindicated in persons with keloidal scarring, neuromuscular disorders (e.g., myasthenia gravis), allergies to constituents of botulinum toxin products, and body dysmorphic disorder. Minor bruising can occur with botulinum toxin injection. Temporary blepharoptosis and eyebrow ptosis are rare complications that are technique-dependent; incidence declines as injector skill improves.
Cordonnier, M; van Nechel, C; van den Ende, P; Zumaran, C; Benammar, L
Having used botulinum toxin for four years, we describe our experience in one hundred squinting patients and compare our results with the literature. We have good results in unilateral sixth nerve palsy and small deviations with binocular potential. Botulinum toxin can also be helpful in third and fourth nerve palsy, in Graves' ophthalmopathy, as an adjunct to transposition surgery and in cases of under- or overcorrections after surgery. In cases of muscle fibrosis and wide angle strabismus, the results are more disappointing. We describe an original method of conditioning the toxin in individual doses which eases the botulinum consultation processing.
The clinical application of botulinum toxin (BoNT) was first proposed by Justinus Kerner in 1822. BoNT was formally accepted as a therapeutic agent in the 1970s, and currently, it is used worldwide for treating diseases as well as for cosmetic conditions. In Japan, Botox® is the only type A formulation that has been officially approved for the treatment of blepharospasm, hemifacial spasm, cervical dystonia, pes equinus of cerebral palsy, adult spasticity of upper and lower limbs, and Botox Vista® is applied for glabellar frown lines. Its effect is symptomatic, but long-lasting remission is noted after treatment in more than 30% of cases with cervical dystonia. Ultrasound guidance is useful and may be even superior to electromyographic monitoring, especially when the obliquus capitis inferior muscle is targeted in rotatocollis, because the vertebral artery or upper cervical nerve root(s) may be injured when the needle penetrates the muscle. BoNT alleviates pain or glandular secretion besides causing a neuromuscular block. After being transported to the axons, BoNT is carried centrally and even to the adjacent neurons via synapses (toxin jump). A direct central action has also been postulated. BoNT is generally safe, but serious adverse reactions may occur very rarely. Individual differences in toxin sensitivity may be considerably greater than assumed, and even the routine clinical dose may be too high in some patients. The future strategy includes clinical application of other types of toxin or chimera toxins, or the use of the toxin as a cargo ("Trojan Horse") carrying some bioactive molecules into the cell. A non-injection procedure for mucosal application or cosmetic use is currently under clinical trials.
Tinastepe, Neslihan; Küçük, Burcu Bal; Oral, Koray
Botulinum toxin, the most potent biological toxin, has been shown to be effective for a variety of disorders in several medical conditions, when used both therapeutically and cosmetically. In recent years, there has been a rising trend in the use of this pharmacological agent to control bruxing activity, despite its reported adverse effects. The aim of this review was to provide a brief overview to clarify the underlying essential ideas for the use of botulinum toxin in bruxism based on available scientific papers. An electronic literature search was performed to identify publications related to botulinum toxin and its use for bruxism in PubMed. Hand searching of relevant articles was also made to identify additional studies. Of the eleven identified studies, only two were randomized controlled trials, compared with the effectiveness of botulinum toxins on the reduction in the frequency of bruxism events and myofascial pain after injection. The authors of these studies concluded that botulinum toxin could be used as an effective treatment for reducing nocturnal bruxism and myofascial pain in patients with bruxism. Evidence-based research was limited on this topic. More randomized controlled studies are needed to confirm that botulinum toxin is safe and reliable for routine clinical use in bruxism.
Tinastepe, Neslihan; Küçük, Burcu Bal; Oral, Koray
Aims: Botulinum toxin, the most potent biological toxin, has been shown to be effective for a variety of disorders in several medical conditions, when used both therapeutically and cosmetically. In recent years, there has been a rising trend in the use of this pharmacological agent to control bruxing activity, despite its reported adverse effects. The aim of this review was to provide a brief overview to clarify the underlying essential ideas for the use of botulinum toxin in bruxism based on available scientific papers. Methodology: An electronic literature search was performed to identify publications related to botulinum toxin and its use for bruxism in PubMed. Hand searching of relevant articles was also made to identify additional studies. Results: Of the eleven identified studies, only two were randomized controlled trials, compared with the effectiveness of botulinum toxins on the reduction in the frequency of bruxism events and myofascial pain after injection. The authors of these studies concluded that botulinum toxin could be used as an effective treatment for reducing nocturnal bruxism and myofascial pain in patients with bruxism. Conclusion: Evidence-based research was limited on this topic. More randomized controlled studies are needed to confirm that botulinum toxin is safe and reliable for routine clinical use in bruxism.
Aoki, K R; Francis, J; Jost, W H
Botulinum toxin has been used in pain therapy for several years. Its application in migraine and headaches is particularly interesting. Clinical results have not yet been definitely conclusive, and a uniform model of the mode of action has not been established either. Apart from a purely muscular effect, a direct antinociceptive effect of botulinum toxin has been found in patients, in the preclinical model, and in a clinical pain model. This is contradicted by negative observations in the clinical model of pain, which might be related to methodological deficits. Further basics need to be worked out before arriving at any final result. Clinical studies with patients and pain models should then follow. Studying botulinum toxin within the context of pain will also provide many new insights into pain therapy in general. In which pain model botulinum toxin may play a role in the future, has to be awaited.
Messikh, R; Atallah, L; Aubin, F; Humbert, P
Botulinum toxin could represent nowadays a new treatment modality especially for cutaneous conditions in course of which conventional treatments remain unsuccessful. Besides palmar and plantar hyperhidrosis, botulinum toxin has demonstrated efficacy in different conditions associated with hyperhidrosis, such as dyshidrosis, multiple eccrine hidrocystomas, hidradenitis suppurativa, Frey syndrome, but also in different conditions worsened by hyperhidrosis such as Hailey-Hailey disease, Darier disease, inversed psoriasis, aquagenic palmoplantar keratoderma, pachyonychia congenital. Moreover, different cutaneous conditions associated with sensitive disorders and/or neurological involvements could benefit from botulinum toxin, for example anal fissures, leg ulcers, lichen simplex, notalgia paresthetica, vestibulitis. Endly, a case of cutis laxa was described where the patient was improved by cutaneous injections of botulinum toxin.
Rowe, Fiona J; Noonan, Carmel P
The use of botulinum toxin as an investigative and treatment modality for strabismus is well reported in the medical literature. However, it is unclear how effective it is in comparison to other treatment options for strabismus. The primary objective was to examine the efficacy of botulinum toxin therapy in the treatment of strabismus compared with alternative conservative or surgical treatment options. This review sought to ascertain those types of strabismus that particularly benefit from the use of botulinum toxin as a treatment option (such as small angle strabismus or strabismus with binocular potential, i.e. the potential to use both eyes together as a pair). The secondary objectives were to investigate the dose effect and complication rates associated with botulinum toxin. We searched CENTRAL (which contains the Cochrane Eyes and Vision Trials Register) (2016, Issue 6), Ovid MEDLINE, Ovid MEDLINE In-Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to July 2016), Embase (January 1980 to July 2016), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to July 2016), the ISRCTN registry (www.isrctn.com/editAdvancedSearch), ClinicalTrials.gov (www.clinicaltrials.gov), and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 11 July 2016. We handsearched the British and Irish Orthoptic Journal, Australian Orthoptic Journal, proceedings of the European Strabismological Association (ESA), International Strabismological Association (ISA) and International Orthoptic Association (IOA) (www.liv.ac.uk/orthoptics/research/search.htm) and American Academy of Paediatric Ophthalmology and Strabismus meetings (AAPOS). We contacted researchers who are active in this field for information about further
Rossow, Heidi; Kinnunen, Paula M; Nikkari, Simo
Botulism is caused by botulinum neurotoxin produced by the bacterium Clostridium botulinum. It is a flaccid paralysis in which consciousness and nociception are preserved. Natural botulism typically results from ingestion of inadequately heated or unheated vacuum-packed foods. In addition, botulinum toxin is one of the most feared biological weapons. In the diagnosis and treatment of botulism early suspicion is essential. Several coinciding or local clusters without a typical connecting source, or an uncommon type of toxin may indicate an intentionally caused epidemic.
The aim of this article is to provide a review of the use of injections of botulinum toxin in the management of selected symptoms and signs of Parkinson's disease and other forms of parkinsonism. Sialorrhea is defined as inability to control oral secretions, resulting in excessive saliva in the oropharynx. There is a high level of evidence for the treatment of sialorrhea in parkinsonism with injections of different forms of botulinum toxin type A as well as botulinum toxin type B. Tremor can be improved by the use of botulinum toxin injections but improved tremor control often leads to concomitant motor weakness, limiting its use. Levodopa induced dyskinesias are difficult to treat with botulinum toxin injections because of their variable frequency and direction. Apraxia of eyelid opening, a sign more commonly seen in progressive supranuclear palsy and other tauopathies, often improves after botulinum toxin injections. Recent data suggest that regardless of the underlying mechanism, pain in parkinsonism can be alleviated by botulinum toxin injections. Finally, freezing of gait, camptocormia and Pisa syndrome in parkinsonism almost invariably fail to respond to botulinum toxin injections. Copyright © 2017 Elsevier Ltd. All rights reserved.
Ozcakir, Suheda; Sivrioglu, Koncuy
Poststroke hemiparesis, together with abnormal muscle tone, is a major cause of morbidity and disability. Although most hemiparetic patients are able to reach different ambulatory levels with rehabilitation efforts, upper and lower limb spasticity can impede activities of daily living, personal hygiene, ambulation and, in some cases, functional improvement. The goals of spasticity management include increasing mobility and range of motion, attaining better hygiene, improving splint wear and other functional activities. Conservative measures, such as positioning, stretching and exercise are essential in spasticity management, but alone often are inadequate to effectively control it. Oral antispastic medications often provide limited effects with short duration and frequent unwanted systemic side effects, such as weakness, sedation and dry mouth. Therefore, neuromuscular blockade by local injections have become the first choice for the treatment of focal spasticity, particularly in stroke patients. Botulinum toxin (BTX), being one of the most potent biological toxins, acts by blocking neuromuscular transmission via inhibiting acetylcholine release. Currently, focal spasticity is being treated successfully with BTX via injecting in the spastic muscles. Two antigenically distinct serotypes of BTX are available on the market as type A and B. Clinical studies of BTX used for spastic hemiplegic patients are reviewed in this article in two major categories, upper and lower limb applications. This review addresses efficacy in terms of outcome measures, such as muscle tone reduction and functional outcome, as well as safety issues. Application modifications of dose, dilutions, site of injections and combination therapies with BTX injections are also discussed. PMID:17607049
Botulinum toxin (BTX) administered as an adjunct to other interventions for spasticity can act as a useful and effective therapeutic tool for treating patients disabled by spasticity. Presence of other non-reflex motor disorders (muscle stiffness, shortness, and contracture) can complicate the clinical course and disturb rehabilitative process of patients with spasticity. Treatment of spasticity using BTX can improve paralysis by correcting muscular imbalance that follows these diseases. In patients with chronic severe spasticity, we also have to address unique and difficult-to-treat clinical conditions such as abnormal posture and movement disorders. The effectiveness of BTX in treating some of these conditions is discussed. Because patients with neurological disabilities can show complex dysfunctions, specific functional limitations, goals, and expected outcomes of treatment should be evaluated and discussed with the patient, family members, and caregivers, prior to initiating BTX therapy. BTX therapy might improve not only care, passive function, but also motor functions in these patients by supplementing intensive rehabilitation with repetitive transcranial magnetic stimulation, transcranial direct-current stimulation, peripheral electrical stimulation, muscle stretching, and other rehabilitation strategies.
Dressler, Dirk; Adib Saberi, Fereshte
Botulinum toxin (BT) has been perceived as a lethal threat for many centuries. In the early 1980s, this perception completely changed when BT's therapeutic potential suddenly became apparent. We wish to give an overview over BT's mechanisms of action relevant for understanding its therapeutic use. BT's molecular mode of action includes extracellular binding to glycoprotein structures on cholinergic nerve terminals and intracellular blockade of the acetylcholine secretion. BT affects the spinal stretch reflex by blockade of intrafusal muscle fibres with consecutive reduction of Ia/II afferent signals and muscle tone without affecting muscle strength (reflex inhibition). This mechanism allows for antidystonic effects not only caused by target muscle paresis. BT also blocks efferent autonomic fibres to smooth muscles and to exocrine glands. Direct central nervous system effects are not observed, since BT does not cross the blood-brain barrier and since it is inactivated during its retrograde axonal transport. Indirect central nervous system effects include reflex inhibition, normalisation of reciprocal inhibition, intracortical inhibition and somatosensory evoked potentials. Reduction of formalin-induced pain suggests direct analgesic BT effects possibly mediated by blockade of substance P, glutamate and calcitonin gene-related peptide.
Maurri, S; Brogelli, S; Alfieri, G; Barontini, F
Four patients with severe Meige's disease (blepharospasm-oromandibular dystonia) have been treated, after having given an informed consent, by local injections of purified botulinum toxin type "A". Previous systemic therapy with anticholinergics, dopamine antagonists and other drugs had been unsuccessful in all these subjects. Each patient was treated by saline solution injected with the same method as botulinum toxin, just once. The self-evaluation of patients and the clinical evaluation that some of us- unaware of the kind of therapy which had been performed- gave to the symptoms on the basis of videotapes, for each session of injection, showed that the injections of botulinum toxin are effective in the treatment of such disorder. The duration of the beneficial effect was slightly shorter in these patients than in patients with blepharospasm treated by the same method.
Hoque, Afreen; McAndrew, Maureen
A growing number of dentists are providing botulinum toxin to patients. The research presented here outlines potential uses of Botox related to oral health and facial problems as compared to traditional treatment methods. The administration of Botox (historically done by dermatologists and neurologists) may fall under dentists' jurisdiction, as their training and knowledge encompasses the entire head and neck. A review is made of the literature, based on Ovid and PubMed searches, selecting articles describing the injection of botulinum toxin A in areas related to the oral cavity and the face, excluding cosmetic purposes.
Hubálek, Z.; Halouzka, J.
A sterile suspension containing 950 mouse LD50 per ml of type C botulinum toxin was exposed for various periods to different temperatures. The time required for the 99% (hundred-fold) reduction of toxicity was more than 5 years at -70 degrees C or -20 degrees C, 6 months at +5 degrees C, 3 weeks at +20 degrees C, 2 weeks at +28 degrees C, 2 days at +37 degrees C, 9 h at +42 degrees C, less than 30 min at +56 degrees C, less than 20 min at +60 degrees C, and below 5 min at +80 degrees C. The results suggest that Clostridium botulinum type C toxin, if produced in an ecosystem of the mild climatic zone, might persist there over the winter season and cause the intoxication of vertebrates next early spring in the absence of further microbial toxigenesis. PMID:2972554
Patil, Shilpadevi; Willett, Olga; Thompkins, Terin; Hermann, Robert; Ramanathan, Sathish; Cornett, Elyse M; Fox, Charles J; Kaye, Alan David
Botulinum toxin, also known as Botox, is produced by Clostridium botulinum, a gram-positive anaerobic bacterium, and botulinum toxin injections are among the most commonly practiced cosmetic procedures in the USA. Although botulinum toxin is typically associated with cosmetic procedures, it can be used to treat a variety of other conditions, including pain. Botulinum toxin blocks the release of acetylcholine from nerve endings to paralyze muscles and to decrease the pain response. Botulinum toxin has a long duration of action, lasting up to 5 months after initial treatment which makes it an excellent treatment for chronic pain patients. This manuscript will outline in detail why botulinum toxin is used as a successful treatment for pain in multiple conditions as well as outline the risks associated with using botulinum toxin in certain individuals. As of today, the only FDA-approved chronic condition that botulinum toxin can be used to treat is migraines and this is related to its ability to decrease muscle tension and increase muscle relaxation. Contraindications to botulinum toxin treatments are limited to a hypersensitivity to the toxin or an infection at the site of injection, and there are no known drug interactions with botulinum toxin. Botulinum toxin is an advantageous and effective alternative pain treatment and a therapy to consider for those that do not respond to opioid treatment. In summary, botulinum toxin is a relatively safe and effective treatment for individuals with certain pain conditions, including migraines. More research is warranted to elucidate chronic and long-term implications of botulinum toxin treatment as well as effects in pregnant, elderly, and adolescent patients.
Jablonka, Eric M; Sherris, David A; Gassner, Holger G
Chemoimmobilization with botulinum toxin A is an ideal biochemical agent that allows near-total elimination of muscle pull on the healing facial wound. The goal of chemoimmobilization of facial cutaneous wounds is to eliminate dynamic tension on the healing tissues to improve wound healing and minimize scarring for optimal aesthetic results.
Stiles, Bradley G.; Wigelsworth, Darran J.; Popoff, Michel R.; Barth, Holger
There are many pathogenic Clostridium species with diverse virulence factors that include protein toxins. Some of these bacteria, such as C. botulinum, C. difficile, C. perfringens, and C. spiroforme, cause enteric problems in animals as well as humans. These often fatal diseases can partly be attributed to binary protein toxins that follow a classic AB paradigm. Within a targeted cell, all clostridial binary toxins destroy filamentous actin via mono-ADP-ribosylation of globular actin by the A component. However, much less is known about B component binding to cell-surface receptors. These toxins share sequence homology amongst themselves and with those produced by another Gram-positive, spore-forming bacterium also commonly associated with soil and disease: Bacillus anthracis. This review focuses upon the iota and C2 families of clostridial binary toxins and includes: (1) basics of the bacterial source; (2) toxin biochemistry; (3) sophisticated cellular uptake machinery; and (4) host–cell responses following toxin-mediated disruption of the cytoskeleton. In summary, these protein toxins aid diverse enteric species within the genus Clostridium. PMID:22919577
Woodson, Gayle; Hochstetler, Heidi; Murry, Thomas
Botulinum toxin has been widely accepted as an effective therapy for controlling the symptoms of adductor spasmodic dysphonia (ADSD). Reported experience with botulinum treatment for abductor spasmodic dysphonia (ABSD) has been less impressive. Factors that may impair outcomes for ABSD include differences in the pathophysiology of ADSD and ABSD and limitation of maximal dose from airway restriction with posterior cricoarytenoid muscle (PCA) weakness. We report our experience with botulinum injection of the PCA with an asymmetric dose escalation protocol, based on clinical observations that in ABSD, abductor spasms are often stronger on one side, usually the left. The nondominant side was injected with 1.25 units. Dominant side dose began at 5 units, with step-wise increments of 5 units per week until one of three endpoints was reached: Elimination of breathy voice breaks, complete abductor paralysis of the dominant side, or airway compromise. Fourteen of 17 patients achieved good or fair voice, with dominant-side doses ranging from 10 to 25 units. Exercise intolerance limited PCA dose in two patients. One patient had persisting breathiness that improved with medialization thyroplasty. Asymmetric botulinum toxin injection into PCA muscles can suppress abductor spasm in patients with ABSD, but breathiness may persist, because of inadequate glottal closure.
Olthoff, Arno; Grosheva, Maria; Reichel, Gerhard; Volk, Gerd Fabian; Laskawi, Rainer
The treatment of laryngeal dystonias with botulinum toxin is successful. Every patient suffering from a laryngeal dystonia should be assured of high quality therapeutic intervention. Therefore it is important to establish general standards by experts in this field. In this connection, we want to focus here on different relevant aspects of laryngeal dystonias. This includes new aspects in etiology, anatomical landmarks for the injection, standards in diagnostics and therapy and finally open issues needing discussion. Georg Thieme Verlag KG Stuttgart · New York.
Singh, Jasvinder A
Chronic musculoskeletal pain is a common cause of chronic pain, which is associated with a total cost of $635 billion per year in the U.S. Emerging evidence suggests an anti-nociceptive action of botulinum toxin, independent of its muscle paralyzing action. This review provides a summary of data from both non-randomized and randomized clinical studies of botulinum toxin in back pain and various osteoarticular conditions, including osteoarthritis, tennis elbow, low back pain and hand pain. Three randomized controlled trials (RCTs) of small sizes provide evidence of short-term efficacy of a single intra-articular injection of 100 units of botulinum toxin A (BoNT/A) for the relief of pain and the improvement of both function and quality of life in patients with chronic joint pain due to arthritis. Three RCTs studied intramuscular BoNT/A for tennis elbow with one showing a significant improvement in pain relief compared with placebo, another one showing no difference from placebo, and the third finding that pain and function improvement with BoNT/A injection were similar to those obtained with surgical release. One RCT of intramuscular BoNT/A for low back pain found improvement in pain and function compared to placebo. Single RCTs using local injections of BoNT in patients with either temporomandibular joint (TMJ) pain or plantar fasciitis found superior efficacy compared to placebo. One RCT of intramuscular BoNT/B in patients with hand pain and carpal tunnel syndrome found improvement in pain in both BoNT/B and placebo groups, but no significant difference between groups. Most evidence is based on small studies, but the use of BoNT is supported by a single, and sometimes up to three, RCTs for several chronic musculoskeletal pain conditions. This indicates that botulinum toxin may be a promising potential new treatment for chronic refractory musculoskeletal pain. Well-designed large clinical trials are needed. PMID:24715952
Mahan, Marielle; Engel, J Mark
The present review discusses recent advances in the use of botulinum toxin for the management of strabismus in children. Botulinum toxin injection produces similar results compared to surgery for certain subtypes of strabismus, especially acute onset esotropia. It may be more effective in many subtypes of esotropia where surgery has been less reliable, including partially accommodative esotropia, esotropia associated with cerebral palsy, and thyroid eye disease. Small retrospective studies have demonstrated the efficacy of botulinum toxin in the treatment of many types of pediatric strabismus, providing some guidance for clinicians to determine which patients would benefit most from this intervention. Although administration of botulinum toxin is generally accepted as a reasonable option in select cases, many strabismus surgeons have not fully embraced the treatment, in part because of perceived disadvantages compared to surgery and difficulty in identifying subsets with the highest potential for therapeutic success. A recent study compared the administration of botulinum toxin in children with acute-onset esotropia to surgical correction and found botulinum toxin had a statistically equal success rate, but with the advantage of significantly less time under general anesthesia. In addition, botulinum toxin has been recently tried in patients with partially accommodative esotropia, esotropia associated with cerebral palsy, cyclic esotropia, and in patients with thyroid eye disease. The present review will discuss current clinical recommendations based on recent studies on the use of botulinum toxin in children with strabismus.
Dhull, Pawan; Tewari, A K; Upreti, Vimal; Prakash, M S; Hari Kumar, K V S
Botulinum toxin has been used for a variety of neuropathic conditions in diabetes mellitus. Meralgia paresthetica is a mononeuropathy of femoral nerve seen in diabetes and obesity with an unclear etiopathogenesis. We studied the role of botulinum toxin in resistant cases of meralgia paresthetica in type 2 diabetes.
Therapeutic preparations of botulinum toxin (BT) consist of botulinum neurotoxin (BNT), complexing proteins, and excipients. Depending on the target tissue, BNT can block cholinergic neuromuscular innervation of intra- and extrafusal muscle fibres or cholinergic autonomic innervation of sweat, lacrimal, and salival glands and smooth muscles. Indirect CNS effects are numerous; direct ones have not been reported after intramuscular application. Botulinum toxin type A is distributed as Botox, Dysport, Xeomin, Hengli/CBTX-A, and Neuronox and BT type B as NeuroBloc/Myobloc. Differences in potency labelling of therapeutic BT preparations can be corrected by introduction of a conversion factor of 1:3 between Botox and Dysport, of 1:1 between Botox and Xeomin, and of 1:40 between Botox and NeuroBloc/Myobloc. Acute adverse effects of BT can be obligate, local or systemic. Adverse effect profiles of the different preparations are similar. However, BT type B frequently produces additional autonomic systemic adverse effects. Long-term application does not produce additional adverse effects. BNT can be partially or completely blocked by antibodies. Risk factors include the amount of BNT applied at each injection series, the interval between injection series, and the specific biological potency (SBP) of the BT preparation used. The SBP is 5 equivalent mouse units/ng BNT for NeuroBloc, 60 for Botox, 100 for Dysport, and 167 for Xeomin. Xeomin should therefore have a particularly low antigenicity. Clinical confirmation of this predicition, however, is lacking.
Durand, Paul D; Couto, Rafael A; Isakov, Raymond; Yoo, Donald B; Azizzadeh, Babak; Guyuron, Bahman; Zins, James E
While the facial rejuvenating effect of botulinum toxin type A is well known and widespread, its use in body and facial contouring is less common. We first describe its use for deliberate muscle volume reduction, and then document instances of unanticipated and undesirable muscle atrophy. Finally, we investigate the potential long-term adverse effects of botulinum toxin-induced muscle atrophy. Although the use of botulinum toxin type A in the cosmetic patient has been extensively studied, there are several questions yet to be addressed. Does prolonged botulinum toxin treatment increase its duration of action? What is the mechanism of muscle atrophy and what is the cause of its reversibility once treatment has stopped? We proceed to examine how prolonged chemodenervation with botulinum toxin can increase its duration of effect and potentially contribute to muscle atrophy. Instances of inadvertent botulinum toxin-induced atrophy are also described. These include the "hourglass deformity" secondary to botulinum toxin type A treatment for migraine headaches, and a patient with atrophy of multiple facial muscles from injections for hemifacial spasm. Numerous reports demonstrate that muscle atrophy after botulinum toxin type A treatment occurs and is both reversible and temporary, with current literature supporting the notion that repeated chemodenervation with botulinum toxin likely responsible for both therapeutic and incidental temporary muscle atrophy. Furthermore, duration of response may be increased with subsequent treatments, thus minimizing frequency of reinjection. Practitioners should be aware of the temporary and reversible effect of botulinum toxin-induced muscle atrophy and be prepared to reassure patients on this matter. © 2016 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: email@example.com.
Liu, W.; Montana, Vedrana; Chapman, Edwin R.; Mohideen, U.; Parpura, Vladimir
Botulinum neurotoxin (BoNT) types A, B, E, and F are toxic to humans; early and rapid detection is essential for adequate medical treatment. Presently available tests for detection of BoNTs, although sensitive, require hours to days. We report a BoNT-B sensor whose properties allow detection of BoNT-B within minutes. The technique relies on the detection of an agarose bead detachment from the tip of a micromachined cantilever resulting from BoNT-B action on its substratum, the synaptic protein synaptobrevin 2, attached to the beads. The mechanical resonance frequency of the cantilever is monitored for the detection. To suspend the bead off the cantilever we use synaptobrevin's molecular interaction with another synaptic protein, syntaxin 1A, that was deposited onto the cantilever tip. Additionally, this bead detachment technique is general and can be used in any displacement reaction, such as in receptor-ligand pairs, where the introduction of one chemical leads to the displacement of another. The technique is of broad interest and will find uses outside toxicology. PMID:14573702
Merino, Pilar S; Vera, Rebeca E; Mariñas, Laura G; Gómez de Liaño, Pilar S; Escribano, Jose V
To study the types of acquired restrictive strabismus treated in a tertiary hospital and the outcome of treatment with botulinum toxin. We performed a 10-year retrospective study of patients with restrictive strabismus aged ≥18 years who were treated with botulinum toxin. Treatment was considered successful if the final vertical deviation was ≤5 PD, horizontal deviation ≤10 PD, with no head turn or diplopia. We included 27 cases (mean age, 61.9 years). Horizontal strabismus was diagnosed in 11.1%, vertical in 51.9%, and mixed in 37%. Strabismus was secondary to cataract surgery in 6 cases, high myopia in 6, orbital fractures in 5, retinal surgery in 5, Graves ophthalmopathy in 4, and repair of conjunctival injury in 1 case. Diplopia was diagnosed in all patients, head turn in 33.3%. The initial deviation was 14 PD (range, 2-40), the mean number of injections per patient was 1.6 (range, 1-3), and the mean dose was 9.5 IU (range, 2.5-22.5). At the end of follow-up, diplopia was recorded in 59.3%, head turn in 18.5%, surgical treatment in 51.9%, and need for prism glasses in 14.8%. Outcome was successful in 37% of patients (4 high myopia, 3 orbital fractures, 2 post-surgical retinal detachment, and 1 post-cataract surgery). Mean follow-up was 3±1.8 years. Vertical deviation was observed in half of the sample. The most frequent deviation was secondary to cataract surgery and high myopia. Treatment with botulinum toxin was successful in one-third of the patients at the end of follow-up. Copyright © 2016 Spanish General Council of Optometry. Published by Elsevier España, S.L.U. All rights reserved.
Smith, Christopher P; Somogyi, George T; Chancellor, Michael B
Botulinum toxin has proven to be a safe and effective therapy for a variety of somatic and autonomic motor disorders. Urologists are now finding clinical success with urethral and bladder injection of this fascinating toxin for detrusor sphincter dyssynergia, conditions of pelvic floor spasticity, and overactive bladder. One cannot deny the ingenuity of man in transforming the lethal toxin of Clostridium botulinum into a modern day therapeutic medicine. PMID:16985657
Daniel, Fady; de Parades, Vincent; Siproudhis, Laurent; Atienza, Patrick
Lateral internal sphincterotomy is widely used in the treatment of chronic anal fissure. However, it is associated with a high rate of irreversible incontinence. For this reason the botulinum toxin has become a medical means of reversible sphincterotomy. Indeed, this neurotoxin induces relaxation of the smooth internal anal sphincter lasting one to three months after one injection. We reviewed the published studies about the use of this technique in the management of chronic anal fissure. Healing occurred in more than 70% of fissures without irreversible incontinence. Although further studies are needed to determine the best modalities of administration, especially due to the remaining significant recurrence rate, this toxin may be a valuable treatment for chronic anal fissure in the future.
Ramstad, Kjersti; Karstensen, Anne Bergsjø; Risberg, Knut; Bergsaker, David Kristian; Sommer, Finn Fredrik
Botulinum toxin injection is one of the newer options in the treatment of spasticity. Treatment with botulinum toxin is always combined with physiotherapy and often with casting. We show the extent to which botulinum toxin treatment has been taken into use in our department and discuss advantages and disadvantages of giving botulinum toxin injections at local hospitals. 88 children with cerebral palsy aged 14 months to 16 years were treated with botulinum toxin between March 2000 and Dec. 2004. Injections were given in an outpatient setting, usually with the patient sedated with midazolam. Clinical examination after injection included assessment of spasticity and range of movement of joints. Motor function was videotaped. Side effects were continuously supervised. We performed 278 treatments; during the last year (2004) 7 treatments a month on average. 59 children were injected in lower limbs only, 14 were injected in upper limbs only, and 15 were injected in both upper and lower limbs. No serious side effects were recorded, neither from the botulinum toxin itself nor related to the injection procedure. Assessment of indications for the use of botulinum toxin is now part of the medical follow up for children with spastic cerebral palsy. Treatment can safely be given at the paediatrics department in a local hospital. Injection in superficial muscles of the lower limbs is an easy task, while injection in small muscles and deep-seated muscles requires more special skills.
Brisinda, Giuseppe; Sivestrini, Nicola; Bianco, Giuseppe; Maria, Giorgio
Botulinum toxin A inhibits neuromuscular transmission. It has become a drug with many indications. The range of clinical applications has grown to encompass several neurological and non-neurological conditions. One of the most recent achievements in the field is the observation that botulinum toxin A provides benefit in diseases of the gastrointestinal tract. Although toxin blocks cholinergic nerve endings in the autonomic nervous system, it has also been shown that it does not block non-adrenergic non-cholinergic responses mediated by nitric oxide. This has promoted further interest in using botulinum toxin A as a treatment for overactive smooth muscles and sphincters. The introduction of this therapy has made the treatment of several clinical conditions easier, in the outpatient setting, at a lower cost and without permanent complications. This review presents current data on the use of botulinum toxin A in the treatment of pathological conditions of the gastrointestinal tract.
Brisinda, Giuseppe; Sivestrini, Nicola; Bianco, Giuseppe; Maria, Giorgio
Botulinum toxin A inhibits neuromuscular transmission. It has become a drug with many indications. The range of clinical applications has grown to encompass several neurological and non-neurological conditions. One of the most recent achievements in the field is the observation that botulinum toxin A provides benefit in diseases of the gastrointestinal tract. Although toxin blocks cholinergic nerve endings in the autonomic nervous system, it has also been shown that it does not block non-adrenergic non-cholinergic responses mediated by nitric oxide. This has promoted further interest in using botulinum toxin A as a treatment for overactive smooth muscles and sphincters. The introduction of this therapy has made the treatment of several clinical conditions easier, in the outpatient setting, at a lower cost and without permanent complications. This review presents current data on the use of botulinum toxin A in the treatment of pathological conditions of the gastrointestinal tract. PMID:26035487
Ruiz-Rodriguez, R; Martin-Gorgojo, A
Injection of botulinum toxin is currently the most common cosmetic procedure in the United States, and in recent years it has become-together with dermal fillers-the mainstay of therapy for the prevention and treatment of facial aging. However, in some cases the treatment may lead to a somewhat unnatural appearance, usually caused by loss of facial expression or other telltale signs. In the present article, we review the 10 mistakes that should be avoided when injecting botulinum toxin. We also reflect on how treatment with botulinum toxin influences us through our facial expressions, both in terms of how we feel and what others perceive.
Karp, Barbara Illowsky
The safety and efficacy of botulinum toxin for the treatment of focal hand and cranial dystonias are well-established. Studies of these adult-onset focal dystonias reveal both shared features, such as the dystonic phenotype of muscle hyperactivity and overflow muscle contraction and divergent features, such as task specificity in focal hand dystonia which is not a common feature of cranial dystonia. The physiologic effects of botulinum toxin in these 2 disorders also show both similarities and differences. This paper compares and contrasts the physiology of focal hand and cranial dystonias and of botulinum toxin in the management of these disorders.
Hines, Harry B.; Lebeda, Frank; Hale, Martha; Brueggemann, Ernst E.
Botulinum toxin analysis has renewed importance. This study included the use of nanochromatography-nanoelectrospray-mass spectrometry/mass spectrometry to characterize the protein composition of botulinum progenitor toxins and to assign botulinum progenitor toxins to their proper serotype and strain by using currently available sequence information. Clostridium botulinum progenitor toxins from strains Hall, Okra, Stockholm, MDPH, Alaska, and Langeland and 89 representing serotypes A through G, respectively, were reduced, alkylated, digested with trypsin, and identified by matching the processed product ion spectra of the tryptic peptides to proteins in accessible databases. All proteins known to be present in progenitor toxins from each serotype were identified. Additional proteins, including flagellins, ORF-X1, and neurotoxin binding protein, not previously reported to be associated with progenitor toxins, were present also in samples from several serotypes. Protein identification was used to assign toxins to a serotype and strain. Serotype assignments were accurate, and strain assignments were best when either sufficient nucleotide or amino acid sequence data were available. Minor difficulties were encountered using neurotoxin-associated protein identification for assigning serotype and strain. This study found that combined nanoscale chromatographic and mass spectrometric techniques can characterize C. botulinum progenitor toxin protein composition and that serotype/strain assignments based upon these proteins can provide accurate serotype and, in most instances, strain assignments using currently available information. Assignment accuracy will continue to improve as more nucleotide/amino acid sequence information becomes available for different botulinum strains. PMID:16085839
Hines, Harry B; Lebeda, Frank; Hale, Martha; Brueggemann, Ernst E
Botulinum toxin analysis has renewed importance. This study included the use of nanochromatography-nanoelectrospray-mass spectrometry/mass spectrometry to characterize the protein composition of botulinum progenitor toxins and to assign botulinum progenitor toxins to their proper serotype and strain by using currently available sequence information. Clostridium botulinum progenitor toxins from strains Hall, Okra, Stockholm, MDPH, Alaska, and Langeland and 89 representing serotypes A through G, respectively, were reduced, alkylated, digested with trypsin, and identified by matching the processed product ion spectra of the tryptic peptides to proteins in accessible databases. All proteins known to be present in progenitor toxins from each serotype were identified. Additional proteins, including flagellins, ORF-X1, and neurotoxin binding protein, not previously reported to be associated with progenitor toxins, were present also in samples from several serotypes. Protein identification was used to assign toxins to a serotype and strain. Serotype assignments were accurate, and strain assignments were best when either sufficient nucleotide or amino acid sequence data were available. Minor difficulties were encountered using neurotoxin-associated protein identification for assigning serotype and strain. This study found that combined nanoscale chromatographic and mass spectrometric techniques can characterize C. botulinum progenitor toxin protein composition and that serotype/strain assignments based upon these proteins can provide accurate serotype and, in most instances, strain assignments using currently available information. Assignment accuracy will continue to improve as more nucleotide/amino acid sequence information becomes available for different botulinum strains.
França, Katlein; Kumar, Anagha; Fioranelli, Massimo; Lotti, Torello; Tirant, Michael; Roccia, Maria Grazia
Botulinum toxin, also called the "miracle toxin," is a neurotoxin produced by the bacteria Clostridium botulinum. It is known to block nerve signals that contract muscles resulting in a temporary paralysis of the muscles. Toxins type A and B have been extensively studied and utilized in the realm of beauty and cosmetology. Initially, the toxin gained popularity as a disease-causing "poison". It was only later that it found its way to becoming a must have in modern aesthetic practice. Today, this wonder toxin has proven to be an apt and convenient option in the field of anti-aging medicine.
Woisard, Virginie; Liu, Xuelai; Bes, Marie Christine Arné; Simonetta-Moreau, Marion
Data, regarding the use of botulinum toxin (BT-A) in laryngeal dyspnea, are scarce, coming from some cases reports in the literature, including Vocal fold paralysis, laryngeal dystonia, vocal cord dysfunction also called paradoxical motion of the vocal fold (PMVF), and post-neuroleptic laryngeal dyskinesia. There is no consensus regarding the muscles and the doses to inject. The aim of this study is to present a retrospective review of patients treated in our ENT Department by BT-A injection in this indication. This study is a retrospective study describing patients who underwent an injection of botulinum toxin for laryngeal dyspnea in the ENT Department from 2005 to 2015 years. The inclusion criteria were a dyspnea associated with a laryngeal dysfunction, confirmed by flexible fiberoptic nasopharyngolaryngoscopy. Information concerning the causes of the dyspnea, the botulinum toxin BT-A injections procedure, post-injection follow-up, and respiratory outcome were collected for all patients included. In the group of 13 patients included, the main cause identified as principal factor linked with the short breath was: a bilateral VF paralysis (Patel et al., Otolaryngol Head Neck Surg 130:686-689, 7), laryngeal dystonia (Balkissoon and Kenn, Semin Respir Crit Care Med 33:595-605, 2), Anxiety syndrome associated with unilateral vocal fold paralysis or asthma (Marcinow et al., Laryngoscope 124:1425-1430, 3), and an isolated asthma (Zwirner et al., Eur Arch Otorhinolaryngol 254:242-245, 1). Nine out of the thirteen patients were improved by the injections. A BT-A-induced stable benefit for four patients led them to stop the injections in the follow-up. Good outcome was observed in five other patients (main cause: bilateral VP paralysis), allowing a progressive lengthening of the delay between BT-A injections. Four patients did not report a positive risk/benefit ratio after BT-A injections; two of them (with bilateral VF paralysis), because of respiratory side effects and
Hou, Saiyun; Ivanhoe, Cindy; Li, Sheng
Abstract Spastic scapular dyskinesia after stroke is rare, which causes impaired shoulder active range of motion (ROM). To date, there has been no report about botulinum toxin injection to spastic periscapular muscles. This study presents botulinum toxin A injection for management of spastic periscapular muscles after stroke in 2 cases. This is a retrospective study of 2 cases of spastic scapular dyskinesia after stroke. Spasticity of periscapular muscles including rhomboid and lower trapezius was diagnosed by physical examination and needle electromyographic study. Botulinum toxin was injected into the spastic periscapular muscles under ultrasound imaging guidance. During the 3-week follow-up visit after injection, both patients showed increased shoulder active ROM, without any sign of scapular destabilization. The results suggest that botulinum toxin injection to spastic periscapular muscles can increase shoulder active ROM without causing scapular destabilization in patients with poststroke spastic scapular dyskinesia. PMID:26266368
After the spastic foot in cerebral palsy, there are now wider indications for botulinum toxin injections in spasticity. Post stroke upper limb spasticity has been usefully treated by botulinum toxin in several studies, including double blind placebo-controlled studies. Two serotypes and one serotype B are marketed, with various properties. Botulinum toxin has been studied in multiple etiologies of spasticity. In multiple sclerosis, few studies revealed an efficacy in angulations and comfort. In spinal cord injuries, gait and sphincter disorders can be improved. In post stroke spasticity, lower limb angulations are improved, but gait remained difficult to evaluate. In upper limb spasticity, angulation, function and quality of life were improved in double blind, placebo controlled studies. Comparisons of costs and efficacy are made between botulinum toxin and the other antispastic methods.
Uyesugi, Betty; Lippincott, Benjamin; Dave, Shashank
Keloids are associated with small-fiber neuropathy and typically present with itching, pain, and allodynia. The following is a case presentation in which painful neuropathic symptoms from a keloid were treated successfully with botulinum toxin type A. To our knowledge, this is the first such case report in the literature. Further research in the use of botulinum toxin to treat keloidal pain is warranted.
food bacteria such as ’Clostridium botulinum. and closely related > organisms. Results from these studies show that C. botulinum types C and D cease...S to produce their dominant toxins when -they are cured o’ftheir prophages.’. These i nontoxigenic derivatives then become sensitive to bacteriophages...of other. culture C.) which induce the production of different toxins . One cured-strain of type C was shown to be sensitive to bacteriophages from C
Dressler, Dirk; Benecke, Reiner
Therapeutic preparations of botulinum toxin (BT) consist of botulinum neurotoxin (BNT), complexing proteins and excipients. Depending on the target tissue BT can block the cholinergic neuromuscular or the cholinergic autonomic innervation of exocrine glands and smooth muscles. Additional effects can be demonstrated on the muscle spindle organ. Indirect effects on the central nervous system are numerous, direct ones have not been recorded after intramuscular injections. BT type A is being distributed as Botox, Dysport and Xeomin, BT type B as NeuroBloc/Myobloc. Adverse effects can be obligate, local or systemic. The adverse effect profiles of the available BT preparations are similar. BT type B, however, has additional systemic autonomic adverse effects. Long-term treatment does not produce additive adverse effects. BNT can be partially or completely blocked by antibodies. The major risk factors for antibody-induced therapy failure are the amount of BNT applied at each injection series, the interval between injection series and the specific biological activity (SBA) of the BT preparation used. The SBA is 5 for NeuroBloc, 60 for Botox, 100 for Dysport and 167MU-E/ng BNT for Xeomin (MU-E: equivalence mouse units). Therapeutic BT preparations are a group of highly potent drugs with an intriguing mechanism of action. With the advent of new competitors comparative studies amongst different therapeutic BT preparations will become more and more interesting.
Today, botulinum toxin (Btx) belongs to the standard repertoire in the treatment of spasticity. It is usually used in combination with other measures, such as oral or intrathecal medicinal products or physiotherapy. Btx improves the ability to walk and stand of patients with spastic equinus deformity and hip and knee flexor spasticity. Btx treatment eases the care of patients with severe adductor spasticity and flexor spasticity of the extremities and hands and also the self-care and dressing of patients with arm spasticity. Through the local application of Btx, painful spasms have become treatable without having to also accept the generally negative effects of, for example, oral antispasticity drugs. For children with congenital or who acquired spasticity in early childhood, the long-term treatment with Btx can fundamentally contribute to the improvement of motor development.
Chronic anal fissure is a common proctological disease. Botulinum toxin (BTX) can be used for temporary chemical denervation. The administration is by intramuscular injections into either the external or the internal anal sphincter muscles. The mode of action, administration techniques and possible complications or adverse effects of BTX therapy are discussed. The healing rate is dependent on the BTX dosage. The short-term healing rate (< or = 6 months) is between 60 and 90 %. In long-term follow-up studies (> 1 year), about 50 % of patients show a complete response. Adverse effects are generally mild but relapses occur more often compared to surgery. Conservative therapies including BTX are currently considered mostly as the first-line treatment. Among the surgical procedures, lateral sphincterotomy is the most effective treatment but shows higher incontinence and general morbidity rates than BTX.
The global botulinum toxin (BT) market is currently undergoing rapid changes: this may be the time to review the history and the future of BT drug development. Since the early 1990s Botox(®) and Dysport(®) dominated the international BT market. Later, Myobloc(®)/NeuroBloc(®), a liquid BT type B drug, came out, but failed. Xeomin(®) is the latest major BT drug. It features removal of complexing proteins and improved neurotoxin purity. Several new BT drugs are coming out of Korea, China and Russia. Scientific challenges for BT drug development include modification of BT's duration of action, its transdermal transport and the design of BT hybrid drugs for specific target tissues. The increased competition will change the global BT market fundamentally and a re-organisation according to large indication groups, such as therapeutic and cosmetic applications, might occur.
Preventive measures are necessary against contraction of botulism through food intake or due to other factors because the botulinum neurotoxin (BoNT) is one of the strongest toxins. Despite this, given its therapeutic utility in the controll of neuromuscular transmission, BoNT has been utilized to treat diseases related to muscular hyperactivity, such as dystonia and spasticity. Furthermore, it has been recognized that BoNT is also useful in controlling the neurotransmitter release of sensory and autonomic nerve terminals as well. This paper reviews the recent progress in the therapeutic use of BoNT in pain management, for example, in condition such as migraine, myofascial pain syndrome, pelvic pain, and interstitial cystitis.
Cooper, Lilli; Lui, Michael; Nduka, Charles
Facial palsy may be complicated by ipsilateral synkinesis or contralateral hyperkinesis. Botulinum toxin is increasingly used in the management of facial palsy; however, the optimum dose, treatment interval, adjunct therapy and performance as compared with alternative treatments have not been well established. This study aimed to systematically review the evidence for the use of botulinum toxin in facial palsy. The Cochrane central register of controlled trials (CENTRAL), MEDLINE(R) (1946 to September 2015) and Embase Classic + Embase (1947 to September 2015) were searched for randomised studies using botulinum toxin in facial palsy. Forty-seven studies were identified, and three included. Their physical and patient-reported outcomes are described, and observations and cautions are discussed. Facial asymmetry has a strong correlation to subjective domains such as impairment in social interaction and perception of self-image and appearance. Botulinum toxin injections represent a minimally invasive technique that is helpful in restoring facial symmetry at rest and during movement in chronic, and potentially acute, facial palsy. Botulinum toxin in combination with physical therapy may be particularly helpful. Currently, there is a paucity of data; areas for further research are suggested. A strong body of evidence may allow botulinum toxin treatment to be nationally standardised and recommended in the management of facial palsy. Copyright © 2017 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.
Hsieh, Po-Fan; Chiu, Hung-Chieh; Chen, Kuan-Chieh; Chang, Chao-Hsiang; Chou, Eric Chieh-Lung
The standard treatment for overactive bladder starts with patient education and behavior therapies, followed by antimuscarinic agents. For patients with urgency urinary incontinence refractory to antimuscarinic therapy, currently both American Urological Association (AUA) and European Association of Urology (EAU) guidelines suggested that intravesical injection of botulinum toxin A should be offered. The mechanism of botulinum toxin A includes inhibition of vesicular release of neurotransmitters and the axonal expression of capsaicin and purinergic receptors in the suburothelium, as well as attenuation of central sensitization. Multiple randomized, placebo-controlled trials demonstrated that botulinum toxin A to be an effective treatment for patients with refractory idiopathic or neurogenic detrusor overactivity. The urinary incontinence episodes, maximum cystometric capacity, and maximum detrusor pressure were improved greater by botulinum toxin A compared to placebo. The adverse effects of botulinum toxin A, such as urinary retention and urinary tract infection, were primarily localized to the lower urinary tract. Therefore, botulinum toxin A offers an effective treatment option for patients with refractory overactive bladder.
Hsieh, Po-Fan; Chiu, Hung-Chieh; Chen, Kuan-Chieh; Chang, Chao-Hsiang; Chou, Eric Chieh-Lung
The standard treatment for overactive bladder starts with patient education and behavior therapies, followed by antimuscarinic agents. For patients with urgency urinary incontinence refractory to antimuscarinic therapy, currently both American Urological Association (AUA) and European Association of Urology (EAU) guidelines suggested that intravesical injection of botulinum toxin A should be offered. The mechanism of botulinum toxin A includes inhibition of vesicular release of neurotransmitters and the axonal expression of capsaicin and purinergic receptors in the suburothelium, as well as attenuation of central sensitization. Multiple randomized, placebo-controlled trials demonstrated that botulinum toxin A to be an effective treatment for patients with refractory idiopathic or neurogenic detrusor overactivity. The urinary incontinence episodes, maximum cystometric capacity, and maximum detrusor pressure were improved greater by botulinum toxin A compared to placebo. The adverse effects of botulinum toxin A, such as urinary retention and urinary tract infection, were primarily localized to the lower urinary tract. Therefore, botulinum toxin A offers an effective treatment option for patients with refractory overactive bladder. PMID:26938559
Moguel-Ancheita, Silvia; Valdés-Barrena, Adriana; Padilla-Sánchez, Fátima Guadalupe
The neurorehabilitation of the patient with cerebral damage implies the reestablishment of the visual functions. Botulinum toxin can be considerate as a less invasive alternative for treatment. to demonstrate the answer to the treatment using botulinum toxin of the visual motor alterations in patients with cerebral damage. Descriptive study of patients with visual alterations associated to cerebral damage. The visual treatment included three areas: sensorial, refracting and motor under quimiodenervation with botulinum toxin, of May 2009 to May 2010. 48 patients were studied, age 22,4 years ± 23. The strabismus were: esotropia 52%, exotropia 39,5%, vertical 8%, nystagmus 4%. 50% of the patients had psychomotor delay. Some of the most important causes of cerebral damage were: Down syndrome, epilepsy, tumor, hydrocephalus, neuroinfection, infantile cerebral paralysis, multiple sclerosis, metabolic syndrome, cranial trauma, congenital cardiopathy, ventricular hemorrhage, cerebrovascular stroke. The dose of botulinum toxin was 8,1 UI ± 3. We registered good results in 56.5%, regular 23,9% and bad 19,5%. The global percentage of rehabilitation was 69% of correction with a r of Pearson of 0,5. Patients with cerebral damage have diverse types of visuomotor alterations, strabismus and nystagmus.Use of botulinum toxin as a paralytic muscle agent is a good alternative in these cases. The botulinum toxin is an effective option for the visual rehabilitation in patients with cerebral damage and prevents the progression of more cerebral changes secondary to strabismus.
Young, David L; Halstead, Lucinda A
Botulinum toxin is used to treat a wide range of dystonias in the head and neck. Occasionally, patients receiving laryngeal botulinum toxin experience severe dysphagia, dyspnea, or even distant and autonomic symptoms. Rarely, these patients may require hospitalization with possible intubation and placement of nasogastric tubes. Botulinum antitoxin is not readily available and ineffective once symptoms have progressed, so patients must wait until the toxin wears off over weeks to months. Pyridostigmine prevents the breakdown of acetylcholine at the neuromuscular junction, thus making more neurotransmitter available for the muscles. A retrospective case study of patients receiving botulinum toxin for dystonia in the head and neck from 1998 to 2012 who experienced adverse effects that were successfully treated with pyridostigmine. Twenty cases were selected and reviewed to demonstrate how pyridostigmine was used to modulate severe dysphagia, breathiness, dyspnea, and some distant/autonomic symptoms. Pyridostigmine was well tolerated and resulted in significant symptom improvement. Only one significant adverse effect, bradycardia, occurred in a patient with severe cardiac disease. Given the safety and efficacy of this medication, pyridostigmine should be considered to modulate severe sequelae of botulinum toxin in select patients when conservative management is deemed insufficient. Also, physicians should be aware that patient complaints of symptoms at distant sites and temporally delayed from the injection may be a result of the botulinum toxin and relieved with pyridostigmine. Copyright © 2014 The Voice Foundation. Published by Elsevier Inc. All rights reserved.
Steinsapir, Kenneth D; Groth, Michael J; Boxrud, Cynthia A
Upper eyelid ptosis after cosmetic botulinum toxin is generally considered short-lived and responsive to apraclonidine ophthalmic drops. The authors present a series with persistent ptosis. To report a series of patients with persistent upper eyelid ptosis after cosmetic botulinum toxin. A retrospective case review series of 7 patients referred for management after developing visually significant upper eyelid ptosis after cosmetic botulinum toxin type A treatment. Patients in this series experienced persistent visually significant ptosis after cosmetic botulinum toxin lasting from 6 weeks to 13 months. Six of the 7 patients were treated with apraclonidine ophthalmic solution. Apraclonidine drops appeared to be clinically effective within 4 to 6 weeks of the resolution of ptosis. Upper eyelid ptosis after cosmetic botulinum toxin can persist for many months after treatment. Based on this series, the authors propose that apraclonidine drops can be used at the time of initial assessment to predict the relative longevity of ptosis after cosmetic botulinum toxin treatment (Level 4 evidence recommendation). After a 1-week trial, responders can be advised that ptosis is likely to resolve in 4 to 6 weeks. Nonresponders should be counseled that resolution may take longer than 6 weeks.
Archana, M S
Paracelsus contrasted poisons from nonpoisons, stating that "All things are poisons, and there is nothing that is harmless; the dose alone decides that something is a poison". Living organisms, such as plants, animals, and microorganisms, constitute a huge source of pharmaceutically useful medicines and toxins. Depending on their source, toxins can be categorized as phytotoxins, mycotoxins, or zootoxins, which include venoms and bacterial toxins. Any toxin can be harmful or beneficial. Within the last 100 years, the perception of botulinum neurotoxin (BTX) has evolved from that of a poison to a versatile clinical agent with various uses. BTX plays a key role in the management of many orofacial and dental disorders. Its indications are rapidly expanding, with ongoing trials for further applications. However, despite its clinical use, what BTX specifically does in each condition is still not clear. The main aim of this review is to describe some of the unclear aspects of this potentially useful agent, with a focus on the current research in dentistry.
Leigh, R. John; Tomsak, Robert L.; Grant, Michael P.; Remler, Bernd F.; Yaniglos, Stacy S.; Lystad, Lisa; Dell'Osso, Louis F.
We injected botulinum toxin into the horizontal rectus muscles of the right eyes of two patients who had acquired pendular nystagmus with horizontal, vertical, and torsional components. This treatment successfully abolished the horizontal component of the nystagmus in the injected eye in both patients for approximately 2 months. Both patients showed a small but measurable improvement of vision in the injected eye that may have been limited by coexistent disease of the visual pathways. The vertical and torsional components of the nystagmus persisted in both patients. In one patient, the horizontal component of nystagmus in the noninjected eye increased; we ascribe this finding to plastic-adaptive changes in response to paresis caused by the botulinum toxin. Such plastic-adaptive changes and direct side effects of the injections - such as diplopia and ptosis - may limit the effectiveness of botulinum toxin in the treatment of acquired nystagmus. Neither patient elected to repeat the botulinum treatment.
Leigh, R. John; Tomsak, Robert L.; Grant, Michael P.; Remler, Bernd F.; Yaniglos, Stacy S.; Lystad, Lisa; Dell'Osso, Louis F.
We injected botulinum toxin into the horizontal rectus muscles of the right eyes of two patients who had acquired pendular nystagmus with horizontal, vertical, and torsional components. This treatment successfully abolished the horizontal component of the nystagmus in the injected eye in both patients for approximately 2 months. Both patients showed a small but measurable improvement of vision in the injected eye that may have been limited by coexistent disease of the visual pathways. The vertical and torsional components of the nystagmus persisted in both patients. In one patient, the horizontal component of nystagmus in the noninjected eye increased; we ascribe this finding to plastic-adaptive changes in response to paresis caused by the botulinum toxin. Such plastic-adaptive changes and direct side effects of the injections - such as diplopia and ptosis - may limit the effectiveness of botulinum toxin in the treatment of acquired nystagmus. Neither patient elected to repeat the botulinum treatment.
Pero, Raffaela; Coretti, Lorena; Lembo, Francesca
Rapid growth of the overweight population and the number of obese individuals in recent decades suggests that current strategies based on diet, exercise, and pharmacological knowledge are not sufficient to address this epidemic. Obesity is the result of a high caloric intake and energy storage, not counterbalanced by an equally important energy expense. Botulinum toxin type A (BoNT-A) use is rapidly expanding to include treatment of a variety of ophthalmological, gastrointestinal, urological, orthopedic, dermatological, secretory, painful, and cosmetic disorders. Many studies evaluating the effect of BoNT-A in gastric antrum e/o fundus for the treatment of obesity have been published. This treatment modality was based on the observation that gastric injection of BoNT-A in laparatomized rats induced a significant reduction of food intake and body weight. These studies have been published yielding debated results. Differences in the selection of patients, the doses of BoNT-A, the method of administration of the toxin, and the instruments of evaluation of some parameters among these studies may be the cause. In this review, it will study the state-of-the-art use of BoNT-A in obesity basic science models and review the clinical evidence on the therapeutic applications of BoNT-A for obesity. PMID:27681739
... approves first Botulism Antitoxin for use in neutralizing all seven known botulinum nerve toxin serotypes Product to ... contains a mixture of antibody fragments that neutralize all of the seven botulinum nerve toxin serotypes known ...
Bruno, John G; Richarte, Alicia M; Carrillo, Maria P; Edge, Allison
Sixty candidate DNA aptamers were developed against botulinum neurotoxin (BoNT) type A light chain (LC) from ten rounds of selection, resulting in several identical sequences. Secondary structures of the identical aptamers were compared to structures of previously reported BoNT A DNA aptamers. A series of ten candidate loop structures were selected from this comparison as potential binding pockets and aptamer beacons. These candidate beacons were synthesized with 5'-TYE 665 and 3'-Iowa Black quencher labels for comparison of fluorescence levels as a function of BoNT A LC concentration. Only three of the ten candidates exhibited any fluorescence response to increasing levels of BoNT A LC. However, of the two most responsive candidates, one represented a subset loop of the larger more intensely fluorescent double-looped structure, designated Beacon 10. This beacon yielded a lower limit of detection of 1 ng/mL in buffer using a spectrofluorometer and a portable handheld fluorometer, but also responded substantially to BoNT A, B, E holotoxins and heavy or light chain components even in a dilute soil suspension, but not in 50% human serum. Beacon 10 did not respond strongly to a variety of other divergent peptides, suggesting that it is relatively specific to the level of botulinum toxins and is only useful for environmental testing. Beacon 10 also shared short sequence segments with other published BoNT aptamer DNA sequences, suggesting that these may be points of physical contact between the aptamers and BoNTs.
Kaplan, Seth E; Sherris, David A; Gassner, Holger G; Friedman, Oren
Botulinum toxin A is an effective and safe treatment for perioral rejuvenation. This article explores the application of this toxin for cosmetic use in the perioral region, facial asymmetry, and improved facial wound healing. This article also describes how the use of botulinum toxin A, which has traditionally been used on the upper one third of the face, has expanded to the lower two thirds with the advent of a new formulation that consists of botulinum toxin combined with an anesthetic agent and a vasoconstrictor. The new formula provides the injecting physician with immediate feedback on the eventual treatment effect and reduces local diffusion of the simultaneously injected agents, potentially limiting systemic absorption and diffusion to neighboring muscle groups and adding to an already remarkable safety profile.
Dutta, Shubha Ranjan; Passi, Deepak; Singh, Mahinder; Singh, Purnima; Sharma, Sarang; Sharma, Abhimanyu
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.
Dutta, Shubha Ranjan; Passi, Deepak; Singh, Mahinder; Singh, Purnima; Sharma, Sarang; Sharma, Abhimanyu
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. PMID:28163472
Clostridium botulinum is a ubiquitous microorganism which under certain anaerobic conditions can produce botulinum toxins. Due to concerns in regards to both food-borne illness and the potential use of botulinum toxin as a biological weapon, the capability to assess the amount of toxin in a food or...
Tincello, Douglas G; Rashid, Tina; Revicky, Vladimir
Overactive bladder (OAB) is a symptom syndrome including urgency, frequency, and nocturia - with or without incontinence. It is a common manifestation of detrusor overactivity (DO). DO is a urodynamic observation of spontaneous or provoked contractions of the detrusor muscle is seen during the filling phase of the micturition cycle. OAB is, therefore, both a motor and sensory disorder. Botulinum toxin is a purified form of the neurotoxin from Clostridium botulinum and has been used in medicine for many years. Over the last 10 years, it has been used for the treatment of DO and OAB when standard treatments, such as bladder training and oral anticholinergic medication, have failed to provide symptom relief. Botulinum toxin acts by irreversibly preventing neurotransmitter release from the neurons in the motor end plate and also at sensory synapses, although the clinical effect is not permanent due to the growth of new connections within treated tissues. It is known that botulinum toxin modulates vanillioid, purinergic, capsaicin, and muscarinic receptor expression within the lamina propria, returning them to levels seen in normal bladders. Clinically, the effect of botulinum toxin on symptoms of OAB and DO is profound, with large effects upon the symptom of urgency, and also large effects on frequency, nocturia, leakage episodes, and continence rates. These effects have been seen consistently within eight randomized trials and numerous case series. Botulinum toxin appears safe, with the only common side effect being that of voiding difficulty, occurring in up to 10% of treated patients. Dosing regimens are variable, depending on which preparation is used, but it is clear that dose recommendations have fallen over the last 5 years. There is limited evidence about the efficacy of repeat treatments. Botulinum toxin is an effective and safe second-line treatment for patients with OAB and DO.
Gooch, Judith L; Patton, Christopher P
To describe the specific techniques and adverse reactions of using concurrent, multiple injections of both botulinum toxin and phenol to manage spasticity in children with cerebral palsy (CP) and other neurologic conditions. A retrospective case series. A tertiary care children's hospital. Consecutive patients (N=68) with spasticity related to CP or other neurologic conditions. Ninety injection sessions combining botulinum toxin and phenol to manage spasticity. Documentation of adverse reactions. The mean phenol dosage was 9.5mL at a mean of 0.6mL/kg per injection dose. The mean botulinum toxin type A (Botox) dose injected was 193U (12U/kg), and the mean of botulinum toxin type B (Myobloc) dose injected was 7750U (530U/kg). The mean number of muscles injected was 14. Adverse reactions are described but were infrequent. Dysesthetic hand pain occurred in 2 patients. One patient developed a systemic reaction to Myobloc. Using botulinum toxin and phenol injections allowed many muscles to be injected to manage spasticity in children with CP and other neurologic conditions. Using this combination allowed an increased number of injections at the maximal recommended dose.
Cantarella, Giovanna; Berlusconi, Alessandra; Mele, Vincenzo; Cogiamanian, Filippo; Barbieri, Sergio
Frey's syndrome is a frequent sequela of parotidectomy, causing facial sweating and flushing because of gustatory stimuli. Although botulinum toxin type A has become first-line therapy for Frey's syndrome, some patients become resistant. In this study, we investigated whether another serotype, botulinum toxin type B, might be an effective alternative. Case series with planned data collection. Otolaryngology department in a university hospital. Seven patients aged 30 to 68 years, with severe Frey's syndrome, underwent the Minor test and had 80 U of botulinum toxin type B per cm(2) (mean total dose, 2354 U) injected intracutaneously in the mapped area of gustatory sweating. All patients were followed up for 12 months. One month after treatment, six of the seven patients reported that gustatory sweating and flushing had resolved, and, in the remaining patient, these symptoms had decreased. The Minor test confirmed a significant improvement. The subjective benefits remained stable for six months in four patients and for nine months in the remaining three patients; 12 months after treatment, all patients still reported some improvement. Botulinum toxin type B afforded symptomatic relief in a small sample of patients with Frey's syndrome and might be considered a potential alternative to botulinum toxin type A. Copyright (c) 2010 American Academy of Otolaryngology-Head and Neck Surgery Foundation. Published by Mosby, Inc. All rights reserved.
Sharma, Shashi K; Whiting, Richard C
Botulism is a deadly disease caused by ingestion of the preformed neurotoxin produced from the anaerobic spore-forming bacteria Clostridium botulinum. Botulinum neurotoxins are the most poisonous toxins known and have been a concern in the food industry for a long time. Therefore, rapid identification of botulinum neurotoxin using molecular and biochemical techniques is an essential component in the establishment of coordinated laboratory response systems and is the focus of current research and development. Because of the extreme toxicity of botulinum neurotoxin, some confirmatory testing with the mouse bioassay is still necessary, but rapid methods capable of screening large numbers of samples are also needed. This review is focused on the development of several detection methods for botulinum neurotoxins in foods.
Matak, Ivica; Lacković, Zdravko
Botulinum neurotoxin type A (BoNT/A) is one of the most potent toxins known and a potential biological threat. At the same time, it is among the most widely used therapeutic proteins used yearly by millions of people, especially for cosmetic purposes. Currently, its clinical use in certain types of pain is increasing, and its long-term duration of effects represents a special clinical value. Efficacy of BoNT/A in different types of pain has been found in numerous clinical trials and case reports, as well as in animal pain models. However, sites and mechanisms of BoNT/A actions involved in nociception are a matter of controversy. In analogy with well known neuroparalytic effects in peripheral cholinergic synapses, presently dominant opinion is that BoNT/A exerts pain reduction by inhibiting peripheral neurotransmitter/inflammatory mediator release from sensory nerves. On the other hand, growing number of behavioral and immunohistochemical studies demonstrated the requirement of axonal transport for BoNT/A's antinociceptive action. In addition, toxin's enzymatic activity in central sensory regions was clearly identified after its peripheral application. Apart from general pharmacology, this review summarizes the clinical and experimental evidence for BoNT/A antinociceptive activity and compares the data in favor of peripheral vs. central site and mechanism of action. Based on literature review and published results from our laboratory we propose that the hypothesis of peripheral site of BoNT/A action is not sufficient to explain the experimental data collected up to now.
Pikielny, R T; Micheli, F E; Fernández Pardal, M M; Casas Parera, I; Giannaula, R J; Gatto, M
Blepharospasm is a relatively frequent cranial dystonia which may be seen either alone or related to orofacial-mandibular dystonia (Meige's syndrome). In its maximum degree it can cause functional blindness.Twelve patients with blepharospasm (4 essential and 8 Meige's syndrome) who had been previously treated unsuccessfully with drugs (trihexyphenidyl, biperiden, carbamazepine, lithium, baclofen, lisuride, imipramine, clonazepam and butyrophenones) were treated for 12 months with periocular injections of botulinum toxin (BOTOX). A "low" dose of 12,5 U per eye was employed. With this dose, eleven out of twelve patients experienced significant improvement which lasted from five to fifteen weeks. The only nonresponder obtained complete relief upon duplicating the dose. The only side effect was uni or bilateral ptosis in six patients which improved completely in seven to twenty one days. One patient developed a peripheral facial palsy with complete remission in nineteen days. No systemic side effects were noted. There was only one desertion from this study due to depression enhanced by prolonged (21 days) ptosis. All patients (including the deserter) agreed that treatment with BOTOX provided more relief than any other previous therapeutic method. Our results confirm those obtained by others but a more prolonged study is needed to better evaluate long term effects.
The botulinum toxins (BTX), type A and type B by blocking vesicle acetylcholine release at neuro-muscular and neuro-secretory junctions can result efficacious therapeutic agents for the treatment of numerous disorders in patients requiring neuro-rehabilitative intervention. Its use for the reduction of focal spasticity following stroke, brain injury, and cerebral palsy is provided. Although the reduction of spasticity is widely demonstrated with BTX type A injection, its impact on the improvement of dexterity and functional outcome remains controversial. The use of BTX for the rehabilitation of children with obstetrical brachial plexus palsy and in treating sialorrhea which can complicate the course of some severe neurological diseases such as amyotrophic lateral sclerosis and Parkinson's disease is also addressed. Adverse events and neutralizing antibodies formation after repeated BTX injections can occur. Since impaired neurological persons can have complex disabling feature, BTX treatment should be viewed as adjunct measure to other rehabilitative strategies that are based on the individual's residual ability and competence and targeted to achieve the best functional recovery. BTX therapy has high cost and transient effect, but its benefits outweigh these disadvantages. Future studies must clarify if this agent alone or adjunctive to other rehabilitative procedures works best on functional outcome. PMID:21941544
Bertram, Kelly L; Stirpe, Paola; Colosimo, Carlo
Camptocormia is defined as an involuntary axial postural distortion of >45° flexion which occurs in the upright position, increases whilst walking and resolves when supine (Ashour and Jankovic, 2006). Unlike orthopaedic or age related kyphosis it is not a fixed structural deformity and produces kyphosis at predominantly lumbar and thoracic rather than cervical regions. Camptocormia has been reported due to a wide range of neurologic, psychiatric, muscular and orthopaedic conditions as well as rare reports of its emergence following the initiation of a number of medications (Finsterer and Strobl, 2010). Parkinson's disease (PD) includes prominent motor features of bradykinesia, rigidity and reduced postural balance responses in all those affected with this disease, but can also cause a range of other motor and non-motor features. Camptocormia is reported in a minority of patients with PD, and it is usually associated with longer disease duration and greater disease burden (Tiple et al., 2009). The aetiology of camptocormia in PD is debated, and responses to treatment have been generally poor and variable between studies. Recent studies have suggested the use of botulinum toxin may improve posture in some affected individuals.
Dressler, D; Saberi, F A
For most of its time, the history of botulinum toxin (BT) has been the history of botulism, i. e. of an intoxication with BT. By the end of the 1960's a paradigm shift took place which in this radicalness had never occurred before in the history of mankind. At that time BT was first used therapeutically to treat strabismus. From ophthalmology BT rapidly spread into numerous medical specialties. For most of its indications BT is the therapy of choice, for some it has revolutionized their treatment altogether. The widespread therapeutic use of BT allowed detailed clinical and technical investigations of BT's action upon the human body. Applying this knowledge we diagnosed for the first time chronic botulism in adults living on a farm with chronic bovine botulism. This constitutes another radical paradigm shift. The history of BT is the history of a dual paradigm shift each time induced by a complete reversal of the viewing perspective. Knowledge gain can be a linear process. It can, however, also be a circular one. Changes of the viewing perspective are crucial. Changing the viewing perspective may facilitate knowledge gain. This might be used to develop an instrument to facilitate knowledge gain.
Duarte, Gonçalo S; Castelão, Mafalda; Rodrigues, Filipe B; Marques, Raquel E; Ferreira, Joaquim; Sampaio, Cristina; Moore, Austen P; Costa, João
This is an update of a Cochrane review first published in 2003. Cervical dystonia is the most common form of focal dystonia and is a disabling disorder characterised by painful involuntary head posturing. There are two available formulations of botulinum toxin, with botulinum toxin type A (BtA) usually considered the first line therapy for this condition. Botulinum toxin type B (BtB) is an alternative option, with no compelling theoretical reason why it might not be as- or even more effective - than BtA. To compare the efficacy, safety and tolerability of botulinum toxin type A (BtA) versus botulinum toxin type B (BtB) in people with cervical dystonia. To identify studies for this review we searched the Cochrane Movement Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, reference lists of articles and conference proceedings. All elements of the search, with no language restrictions, were last run in October 2016. Double-blind, parallel, randomised, placebo-controlled trials (RCTs) comparing BtA versus BtB in adults with cervical dystonia. Two independent authors assessed records, selected included studies, extracted data using a paper pro forma, and evaluated the risk of bias. We resolved disagreements by consensus or by consulting a third author. We performed meta-analyses using the random-effects model, for the comparison BtA versus BtB to estimate pooled effects and corresponding 95% confidence intervals (95% CI). No prespecified subgroup analyses were carried out. The primary efficacy outcome was improvement on any validated symptomatic rating scale, and the primary safety outcome was the proportion of participants with adverse events. We included three RCTs, all new to this update, of very low to low methodological quality, with a total of 270 participants.Two studies exclusively enrolled participants with a known positive response to BtA treatment. This raises concerns of population enrichment
1), 400 LD50 of type B toxin (2) and 80 LD50 of type E toxin (3). These botulinum toxin ELISA are based on the " double sandwich" prin- ciple but...antibody for IgG of AT but not of AT 2 1, The double sandwich approach is possible because of multiple antigenic determinants of the toxin molecule... immunodiffusion tests against homologous type antitoxin obtained by injecting a rabbit with toxoid made of a relatively crude toxin sample. All neurotoxins
Reuter, Iris; Lorbach, Olaf; Mehnert, Sabine; Kaps, Manfred; Engelhardt, Martin
Generally, outcome after surgical repair of complete Achilles tendon rupture is good. However, some patients have ongoing problems with dorsiflexion of the ankle joint. We report on eight patients, who did not achieve heel contact because of reduced ankle dorsiflexion 5 months after surgical repair of complete Achilles tendon rupture. All patients received at least three cycles of injections with 200-300 units of Botulinum toxin A (BOTOX) into the gastrocnemius and soleus muscle. Weakening of the triceps surae by Botulinum toxin allowed patients to perform the required exercises and to tolerate casting at night. Thus, all patients were able to tolerate plantigrade foot position 9 months after beginning of Botulinum toxin treatment. At final follow-up after 2 years, pain had significantly improved, and a mean dorsiflexion of 21 degrees was reached. In conclusion, treatment of the calf muscles with BOTOX is a safe and effective method to improve restricted dorsiflexion in patients after Achilles tendon repair.
Pérez-Pérez, L; García-Gavín, J; Allegue, F; Caeiro, J L; Fabeiro, J M; Zulaica, A
Notalgia paresthetica is a sensory mononeuropathy that affects dorsal segments T2 to T6. It can have a significant effect on quality of life. Numerous treatments have been used with variable results. Five patients diagnosed with notalgia paresthetica were treated with intradermal botulinum toxin A. None had achieved relief of the pruritus with previous treatments. Variable results were observed after the administration of intradermal botulinum toxin. Complete resolution of the pruritus was not achieved in any of the patients. Botulinum toxin A appears to be a safe therapeutic option for patients with notalgia paresthetica. However, data currently available come from small patient series, making it difficult to draw definitive conclusions regarding the true efficacy and long-term effects of this treatment. Copyright © 2013 Elsevier España, S.L. and AEDV. All rights reserved.
Akbay, Ercan; Cevik, Cengiz; Damlar, Ibrahim; Altan, Ahmet
The aim of this case report is to discuss the effect on condylar reduction of botulinum toxin A treatment used in a child with displaced fracture at condylar neck of mandible. A 3-years old boy was admitted to our clinic for incomplete fracture of mandibular symphysis and displaced condylar fracture at the left side. An asymmetrical occlusal splint with intermaxillary fixation was used instead of open reduction and internal fixation because of incomplete fracture of symphysis and possible complications of condyle surgery. However, it was observed that condylar angulation persisted despite this procedure. Thus, botulinum toxin A was administered to masseter, temporalis and pterygoideus medialis muscles. At the end of first month, it was seen that mandibular condyle was almost completely recovered and that fusion was achieved. In conclusion, Botulinum A toxin injection aiming the suppression of masticatory muscle strength facilitates the reduction in the conservative management of displaced condyle in pediatric patients.
Lin, Kuan-Hsiang; Wang, Shuu-Jiun; Fuh, Jong-Ling; Chen, Shih-Pin
Erythromelalgia is characterized by intense burning pain, erythema, and heat in affected areas after precipitating factors such as warm temperature or stress. It is refractory to treatment in some situations. We describe a woman with adenosquamous cell carcinoma of the lung and medically refractory erythromelalgia. The symptoms of erythromelalgia presented as refractory to any medical treatment. Due to the unresponsive nature of her condition, botulinum toxin type A (onabotulinumtoxin A) was injected over both of her cheeks, periodically for six cycles. Her symptoms responded dramatically to subcutaneous and intradermal injection of botulinum toxin type A. Repetitive injection demonstrated consistent and reproducible responses, and the efficacy was maintained for approximately 1 month. No adverse effects or complications were noted. Botulinum toxin type A might be safe and effective as an alternative treatment for refractory erythromelalgia, but further large-scale studies are required. Copyright © 2013. Published by Elsevier B.V.
Hill, Karen K; Smith, Theresa J
Clostridium botulinum is a species of spore-forming anaerobic bacteria defined by the expression of any one or two of seven serologically distinct botulinum neurotoxins (BoNTs) designated BoNT/A-G. This Gram-positive bacterium was first identified in 1897 and since then the paralyzing and lethal effects of its toxin have resulted in the recognition of different forms of the intoxication known as food-borne, infant, or wound botulism. Early microbiological and biochemical characterization of C. botulinum isolates revealed that the bacteria within the species had different characteristics and expressed different toxin types. To organize the variable bacterial traits within the species, Group I-IV designations were created. Interestingly, it was observed that isolates within different Groups could express the same toxin type and conversely a single Group could express different toxin types. This discordant phylogeny between the toxin and the host bacteria indicated that horizontal gene transfer of the toxin was responsible for the variation observed within the species. The recent availability of multiple C. botulinum genomic sequences has offered the ability to bioinformatically analyze the locations of the bont genes, the composition of their toxin gene clusters, and the genes flanking these regions to understand their variation. Comparison of the genomic sequences representing multiple serotypes indicates that the bont genes are not in random locations. Instead the analyses revealed specific regions where the toxin genes occur within the genomes representing serotype A, B, C, E, and F C. botulinum strains and C. butyricum type E strains. The genomic analyses have provided evidence of horizontal gene transfer, site-specific insertion, and recombination events. These events have contributed to the variation observed among the neurotoxins, the toxin gene clusters and the bacteria that contain them, and has supported the historical microbiological, and biochemical
Connan, Chloé; Denève, Cécile; Mazuet, Christelle; Popoff, Michel R
Botulinum and tetanus neurotoxins are structurally and functionally related proteins that are potent inhibitors of neuroexocytosis. Botulinum neurotoxin (BoNT) associates with non-toxic proteins (ANTPs) to form complexes of various sizes, whereas tetanus toxin (TeNT) does not form any complex. The BoNT and ANTP genes are clustered in a DNA segment called the botulinum locus, which has different genomic localization (chromosome, plasmid, phage) in the various Clostridium botulinum types and subtypes. The botulinum locus genes are organized in two polycistronic operons (ntnh-bont and ha/orfX operons) transcribed in opposite orientations. A gene called botR lying between the two operons in C. botulinum type A encodes an alternative sigma factor which regulates positively the synthesis of BoNT and ANTPs at the late exponential growth phase and beginning of the stationary phase. In Clostridium tetani, the gene located immediately upstream of tent encodes a positive regulatory protein, TetR, which is related to BotR. C. botulinum and C. tetani genomes contain several two-component systems and predicted regulatory orphan genes. In C. botulinum type A, four two-component systems have been found that positively or negatively regulate the synthesis of BoNT and ANTPs independently of BotR/A. The synthesis of neurotoxin in Clostridia seems to be under the control of complex network of regulation. Copyright © 2013 Elsevier Ltd. All rights reserved.
Kulagina, Nadezhda V.; Anderson, George P.; Ligler, Frances S.; Shaffer, Kara M.; Taitt, Chris Rowe
Many organisms secrete antimicrobial peptides (AMPs) for protection against harmful microbes. The present study describes detection of botulinum neurotoxoids A, B and E using AMPs as recognition elements in an array biosensor. While AMP affinities were similar to those for anti-botulinum antibodies, differences in binding patterns were observed and can potentially be used for identification of toxoid serotype. Furthermore, some AMPs also demonstrated superior detection sensitivity compared to antibodies: toxoid A could be detected at 3.5 LD50 of the active toxin in a 75-min assay, whereas toxoids B and E were detected at 14 and 80 LD50 for their respective toxins.
Botulinum toxin type A, a protein long used in the successful treatment of various dystonias, has a complex mechanism of action that results in muscle relaxation. At the neuromuscular junction, the presynaptic nerve ending is packed with synaptic vesicles filled with acetylcholine, and clustered at the tip of the folds of the postsynaptic muscle membrane are the acetylcholine receptors. Synaptic vesicles fuse with the membrane in response to an elevation of intraneuronal calcium concentration and undergo release of their transmitter by exocytosis. Intracellular proteins that contribute to the fusion of the vesicles with the plasma membrane during exocytosis include synaptosomal protein with a molecular weight of 25 kDa (SNAP-25); vesicle-associated membrane protein (VAMP), also known as synaptobrevin; and syntaxin. Through their proteolytic action on these proteins, botulinum toxins prevent exocytosis, thereby inhibiting the release of acetylcholine. There are 7 serotypes of this toxin-A, B, C1, D, E, F, and G-and each cleaves a different intracellular protein or the same target at distinct bonds. The separate cleavage sites in SNAP-25 for botulinum toxin types A and E contribute to their dissimilar durations of muscle relaxation. This report describes the molecular basis for the inhibition by botulinum toxins of neuroexocytosis and subsequent functional recovery at the neuromuscular junction.
de Miguel, F; Chancellor, M B
We report one institution's six-year experience using botulinum toxin A (BONT-A) in the bladder and urethra in 110 patients for a variety of lower urinary tract dysfunction. 110 patients (age 19-82) were injected with BONT-A into the bladder (n=42) or urethra (n=68), 35 M, 75 F. Voiding dysfunction included: neurogenic detrusor overactivity and/or detrusor sphincter dyssynergia, overactive bladder (OAB), benign prostatic hyperplasia (BPH), bladder neck obstruction (BNO) and interstitial cystitis (IC). Currently, 27 patients have undergone further injections (up to 6) at intervals > 6 months. All the patients with bladder BONT-A injection had preoperative evidence of involuntary detrusor contractions during urodynamic testing. Analysis of the 110 patients indicates that 67.3% reported a decrease or absence of incontinence. Diaries indicate a decrease in both day and night voiding symptoms. Efficacy occurred within 7 days and lasted for at least 6 months. Condition specific QOL symptom scores also demonstrated improvement. There have been no long-term complications. Two MS women with mild baseline stress urinary incontinence reported increased leakage with stress after BONT-A external sphincter injection. One MS woman who had a bladder injection had an increased residual urine from 78 to 155 ml. She did not have to perform intermittent catheterization. BONT-A injection is a safe and promising treatment modality for a variety of lower urinary tract dysfunctions for both skeletal and smooth muscle dysfunction. In our series, BONT-A is equally effective in women as it is in men. Bladder injections with BONT-A are effective for not only neurogenic detrusor overactivity but also overactive bladder. BONT-A can even be considered for IC.
Prevous eoatos are cosoiee ,-,,j - -C,:.;S3,CATCI OF ;J T AG-’E Introduction The study of the mechanism of action of botulinum toxin ( botox ) would be...define a model system of study for botox . It has become apparent that different toxin molecules, such as diphtheria or bacteriocins, contain some...similar structure exists between these molecules from diverse sources. Recent reports on the ability of the botox molecule in supported planar bilayer
their mechanism of action most important. The history of the study of botulinum toxins ( botox ) reveals the difficulties brought about by i) the...dangers of working with such a poison, ii) the number of different serotypes of botox which can confuse the field of study, iii) the lack of precedence...from other systems of protein toxins to produce working models that can be tested and applied to experiments on botox , and iv) the deficiency of suitable
Sager, Cristian; Burek, Carol; Durán, Victor; Corbetta, Juan Pablo; Weller, Santiago; Juan, Bortagaray; López, Juan Carlos
When the neurogenic bladder is refractory to anticholinergics, botulinum toxin type A is used as an alternative. The neurotoxin type A reduces bladder pressure and increases its capacity and wall compliance. Additionally, it contributes to improving urinary continence and quality of life. This novel therapy is ambulatory with a low incidence of adverse effects. Due to its transitory effect, it is necessary to repeat the injections in order to sustain its therapeutic effect. In these review article we talk about Mechanism of Action, Indications, effects, administration and presentations of the Botulinum Neurotoxin Type A in pediatric patients. Also, we make references to controversial issues surrounding its use. A bibliographic search was done selecting articles and revisions from Pubmed. The key words used were botulinum toxin A, neurogenic bladder, and children. The search was limited to patients younger than 18 years of age and reports written in English in the past ten years. PMID:22720170
Botulinum neurotoxin – a global public health threat and category A bioterrorism agent - is the most toxic substance known and one of the most challenging toxins to detect due to its lethality at extremely low concentrations. Hence the live-mouse bioassay because of its superior sensitivity, remains...
Murthy, Ramesh; Kesarwani, Siddharth
Acquired disruption of motor fusion is a rare condition characterized by intractable diplopia. Management of these patients is extremely difficult. Prisms in any combination or even surgery may not help relieve their symptoms. We describe a longstanding case of acquired motor fusion disruption which was managed successfully with botulinum toxin injection. PMID:19861751
Fisher, Kimberly V.; And Others
A study investigated the long-term effects of a Botulinum Toxin Type A injection on the glottal competency of a man with adductor spasmodic dysphonia. Results suggest that change in degree of glottal adduction over time can be observed even when vocal instability is present within each recording session. (CR)
Fisher, Kimberly V.; And Others
A study investigated the long-term effects of a Botulinum Toxin Type A injection on the glottal competency of a man with adductor spasmodic dysphonia. Results suggest that change in degree of glottal adduction over time can be observed even when vocal instability is present within each recording session. (CR)
Pascual-Pascual, S I; Herrera-Galante, A; Póo, P; García-Aymerich, V; Aguilar-Barberà, M; Bori-Fortuny, I; García-Ruiz, P J; Garreta-Figuera, R; Lanzas-Melendo, G; de Miguel-León, I; Miquel-Rodríguez, F; Vivancos-Matellano, F
The introduction of botulinum toxin has been a significant step forward in the treatment of spasticity in children and is now considered to be the preferred treatment in focal spasticity. With the aim of optimising this therapeutic resource, a group of Spanish neurologists and specialists in rehabilitation have drawn up these therapeutic guidelines based on the currently available evidence on its use and indications, and on their own experience. Spasticity in childhood is mainly caused by infantile cerebral palsy. Its natural history is not favourable due to the negative effect of growth and it should be treated before permanent deformities in bones and joints appear. Treatment with botulinum toxin diminishes hyperactivity and muscle tone, and allows the muscle to grow longitudinally, which prevents permanent contractions. The advantages of botulinum toxin are obvious (ease of use and dosing, long-lasting effects, reversibility in case of adverse responses, and so forth) and outnumber by far the few drawbacks it offers. Before it can be used patients, treatment goals and the muscle areas to be treated must all be selected correctly and, at the same time, a tailored rehabilitation scheme must also be developed. The growing body of experience suggests that its early administration is effective in preventing or reducing the severe complications of spasticity. Botulinum toxin type A is very effective in the treatment of spasticity. These guidelines offer the well-documented experience gained from its use and our knowledge about its indications, effects and safety in clinical practice.
Background The frontiers of clinical medicine constantly expand as a result of the innovative efforts of visionary researchers and keen observations of seasoned clinicians. In medicine, rarely has a therapeutic agent been found efficacious in the management of so many symptoms and in such a relatively short time as botulinum toxin. One of the most notable contributions of botulinum toxin therapy in clinical medicine is in the field of movement disorders. Methods The English literature was searched using the Yale search engine including but not limited to PubMed and Ovid. The search includes articles from January 1 1980 to March 1 2016. Results A total of 2055 articles were identified. Of these, 132 met the criteria for this review. Discussion This historical review highlights early and seminal contributions that have introduced the application of botulinum toxins in the field of movement disorders and provides evidence-based contributions that have established botulinum toxin as an effective treatment for abnormal movements. PMID:27917308
Erbguth, F J
Botulinum toxin poisoning has afflicted mankind through the mists of time. However, the first incident of food-borne botulism was documented as late as the 18th century, when the consumption of meat and blood sausages gave rise to many deaths throughout the kingdom of Württemberg in South Western Germany. The district medical officer Justinus Kerner (1786--1862), who was also a well-known German poet, published the first accurate and complete descriptions of the symptoms of food-borne botulism between 1817 and 1822 and attributed the intoxication to a biological poison. Kerner also postulated that the toxin might be used for treatment purposes. In 1895, an outbreak of botulism in the small Belgian village of Ellezelles led to the discovery of the pathogen "Clostridium botulinum" by Emile Pierre van Ermengem. Modern botulinum toxin treatment was pioneered by Alan B. Scott and Edward J. Schantz in the early 1970s, when the type-A serotype was used in medicine to correct strabismus. Other preparations of the type-A toxin were developed and manufactured in the United Kingdom, Germany, and China, whereas a therapeutic type-B toxin was prepared in the United States. To date, the toxin has been used to treat a wide variety of conditions associated with muscular hyperactivity, glandular hypersecretions and pain.
van Esch, Babette F; Wegner, Inge; Stegeman, Inge; Grolman, Wilko
Objective The effect of botulinum toxin among patients with adductor spasmodic dysphonia (AdSD) is temporary. To optimize long-term treatment outcome, other therapy options should be evaluated. Alternative treatment options for AdSD comprise several surgical treatments, such as thyroarytenoid myotomy, thyroplasty, selective laryngeal adductor denervation-reinnervation, laryngeal nerve crush, and recurrent laryngeal nerve resection. Here, we present the first systematic review comparing the effect of botulinum toxin with surgical treatment among patients diagnosed with AdSD. Data Sources MEDLINE (PubMed), EMBASE, and the Cochrane Library. Methods Articles were reviewed by 2 independent authors, and data were compiled in tables for analysis of the objective outcome (voice expert evaluation after voice recording), the subjective outcome (patient self-assessment scores), and voice-related quality of life (Voice Health Index scores). Results No clinical trials comparing both treatment modalities were identified. Single-armed studies evaluated either the effect of botulinum toxin or surgical treatment. Thirteen studies reported outcomes after botulinum toxin treatment (n = 419), and 9 studies reported outcomes after surgical treatment (n = 585 patients). A positive effect of bilateral botulinum toxin injections was found for the objective voice outcome, subjective voice outcome, and quality of life. The duration of the beneficial effect ranged from 15 to 18 weeks. Surgical treatment had an overall positive effect on objective voice improvement, subjective voice improvement, and quality of live. Conclusion No preference for one treatment could be demonstrated. Prospective clinical trials comparing treatment modalities are recommended to delineate the optimal outcomes by direct comparison.
There is an emerging literature describing the absorption, distribution, metabolism and elimination of botulinum toxin. This work reveals that the toxin can be absorbed by both the oral and inhalation routes. The primary mechanism for absorption is binding and transport across epithelial cells. Toxin that enters the body undergoes a distribution phase, which is quite short, and an elimination phase, which is comparatively long. During the distribution phase, botulinum toxin migrates to the peri-neuronal microcompartment in the vicinity of vulnerable cells, such as cholinergic nerve endings. Only these cells have the ability to selectively accumulate the molecule. When the toxin moves from the cell membrane to the cell interior, it undergoes programmed death. This is coincident with release of the catalytically active light chain that paralyzes transmission. Intraneuronal metabolism of light chain is via the ubiquitination-proteasome pathway. Systemic metabolism and elimination is assumed to be via the liver. The analysis of absorption, distribution, metabolism and elimination of the toxin helps to create a life history of the molecule in the body. This has many benefits, including: a) clarifying the mechanisms that underlie the disease botulism, b) providing insights for development of medical countermeasures against the toxin, and c) helping to explain the meaning of a lethal dose of toxin. It is likely that work intended to enhance understanding of the fate of botulinum toxin in the body will intensify. These efforts will include new and powerful analytic tools, such as single molecule-single cell analyses in vitro and real time, 3-dimensional pharmacokinetic studies in vivo. Copyright © 2013 Elsevier Ltd. All rights reserved.
Injection of botulinum toxin A is a common procedure in Otorhinolaryngology, Ophtalmology and Neurolgy. Recently botulinum toxin treatment has been described to improve woundhealing after facial injuries. The lack of immediate predictibility of the ensuing paralytic effect is one of the daily challenges of botulinum toxin injections. In the present report we describe the simultaneous injection of botulinum toxin and lidocaine with the purpose to gain immediate feed back of the treatment effect. Furthermore we recommend the addition of adrenalin to reduce possible systemical toxin circulation.
Thomas, Anila M; Simpson, David M
We describe 2 patients who received botulinum toxin A (BoNT) for poststroke spasticity and developed contralateral limb weakness. Both patients received high doses of BoNT with large dilution volumes and injection in the proximal upper extremity muscles, and developed weakness of the contralateral upper limb. These patients then underwent electrodiagnostic testing of the affected limb. Repetitive nerve stimulation of the axillary and spinal accessory nerves revealed decrements of 23% and 16%, respectively. EMG revealed abnormal spontaneous activity and small polyphasic motor unit potentials with reduced recruitment. These findings indicated blockade of the neuromuscular junction. Both patients improved. Isolated weakness of the contralateral limb after BoNT injection for poststroke spasticity suggests diffusion of toxin through tissue planes from proximal upper extremity muscles, across the midline, to contralateral muscles. High doses of botulinum toxin, high dilution volumes, and injection of proximal upper extremity muscles appear to be risk factors for this adverse effect. Copyright © 2012 Wiley Periodicals, Inc.
Lotia, Mitesh; Jankovic, Joseph
The therapeutic applications of botulinum toxin (BoNT) have grown manifold since its initial approval in 1989 by the U.S. Food and Drug Administration for the treatment of strabismus, blepharospasm, and other facial spasms. Although it is the most potent biologic toxin known to man, long-term studies have established its safety in the treatment of a variety of neurologic and nonneurologic disorders. Despite a paucity of randomized controlled trials, BoNT has been found to be beneficial in treating a variety of tremors and tics when used by clinicians skilled in the administration of the drug for these hyperkinetic movement disorders. Botulinum toxin injections can provide meaningful improvement in patients with localized tremors and tics; in some cases, they may be an alternative to other treatments with more undesirable adverse effects.
Wheeler, Anthony; Smith, Howard S
Botulinum toxin (BoNT) is a potent neurotoxin that is produced by the gram-positive, spore-forming, anaerobic bacterium, Clostridum botulinum. There are 7 known immunologically distinct serotypes of BoNT: types A, B, C1, D, E, F, and G. Clostridum neurotoxins are produced as a single inactive polypeptide chain of 150kDa, which is cleaved by tissue proteinases into an active di-chain molecule: a heavy chain (H) of ∼100 kDa and a light chain (L) of ∼50 kDa held together by a single disulfide bond. Each serotype demonstrates its own varied mechanisms of action and duration of effect. The heavy chain of each BoNT serotype binds to its specific neuronal ecto-acceptor, whereby, membrane translocation and endocytosis by intracellular synaptic vesicles occurs. The light chain acts to cleave SNAP-25, which inhibits synaptic exocytosis, and therefore, disables neural transmission. The action of BoNT to block the release of acetylcholine botulinum toxin at the neuromuscular junction is best understood, however, most experts acknowledge that this effect alone appears inadequate to explain the entirety of the neurotoxin's apparent analgesic activity. Consequently, scientific and clinical evidence has emerged that suggests multiple antinociceptive mechanisms for botulinum toxins in a variety of painful disorders, including: chronic musculoskeletal, neurological, pelvic, perineal, osteoarticular, and some headache conditions.
Dystonia is an involuntary movement involving twisting and turning of agonist and antagonist muscles. Cervical dystonia is isolated to neck musculature. Botulinum toxin type A is a safe and effective treatment of this disabling and often painful syndrome. Three forms of botulinum toxin type A are available worldwide to treat patients with cervical dystonia. This is a review of the studies of botulinum toxin type A to treat cervical dystonia. PMID:19707390
Shah, Anil R
Review the safety profile and subjective efficacy of intradermal botulinum toxin type A in facial pore size and sebum production. Retrospective analysis of 20 patients. Twenty consecutive patients with a single application of intradermal botulinum toxin type A were examined: Patients (17/20) noted an improvement in sebum production and a decrease in pores size at 1 month after injection. No complications were observed, and 17/20 patients were satisfied with the procedure. Preliminary data suggests that intradermal botulinum toxin may play a role in decreasing sebum production. Further quantitive study may be necessary to determine effects of intradermal botulinum toxin on pore size.
Budak, F; Aydın, E; Koçkaya, A; Ilbay, G
Primary lingual dystonia is a rare condition, especially when it is only induced by speaking. Trihexyphenidyl failed to improve the symptoms. Several case series have demonstrated the effectiveness of botulinum toxin injection for the management of focal lingual movement disorders. Only 1 case of botulinum toxin injection for primary lingual dystonia induced by speaking has been reported, but this treatment has limited effectiveness. Our patient was treated with botulinum toxin using a superficial approach for injection into the tongue with continuing excellent results. Lingual botulinum toxin injection is a fairly simple, safe and viable treatment option for lingual dystonia induced by speaking.
Matic, Damir B; Lee, Ting Y; Wells, R Glenn; Gan, Bing S
Botulinum toxin type A is approved by the U.S. Food and Drug Administration for the treatment of facial rhytides. However, the complete spectrum of action of botulinum toxin A has not yet been completely defined. Little is known about the metabolism of muscle after botulinum toxin A injection. This information may give insight into the additional effects botulinum toxin A may have on muscle. The authors assessed the influence of botulinum toxin A on the metabolism of muscle using dynamic investigative techniques. Twenty New Zealand White rabbits were divided into control, paralysis, and sham groups. Masseter muscle paralysis was achieved with botulinum toxin A. Dynamic computed tomographic and positron emission tomographic scans were obtained. Masseter muscle blood flow, blood volume, permeability surface, and mean transit time and glucose uptake were measured. Eighteen animals completed the study. Masseter blood perfusion showed consistent results across all parameters. Blood flow, blood volume, and permeability surface were significantly increased at weeks 4 and 8 on the paralyzed side. Mean transit time at week 4 was decreased on the paralyzed side. Positron emission tomographic scans showed that injected muscles in the botulinum toxin A group tended to have increased glucose uptake compared with untreated muscles. Botulinum toxin A injection increases muscle blood perfusion parameters and glucose uptake for a transient period. This increase is similar in duration to the known interval of botulinum toxin A-induced paralysis. These changes have been identified in a dynamic fashion and may represent changes in calcitonin gene-related peptide release.
Merino, P; Rojas, P; Gómez de Liaño, P; Franco Iglesias, G
A 38-year old female with diplopia and esotropia, with limitation of ocular abduction in both eyes, with full abduction after doll's head rotation also being observed. She was diagnosed with spasm of the near reflex. Treatment with injections of botulinum toxin in both medial rectus has temporally resolved the convergence spasm. Near reflex spasm is characterized as miosis, pseudomyopia, and convergent strabismus that lead to diplopia, blurred vision, headache, and variable, progressive, and intermittent esotropia. As the spasm worsens there will be limited ocular versions and ductions simulating a sixth nerve palsy. Botulinum toxin may be effective in some cases. Copyright © 2013 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.
Flores-Reyes, E M; Castillo-López, M G; Toledo-Silva, R; Vargas-Ortega, J; Murillo-Correa, C E; Aguilar-Ruiz, A
To determine the effectiveness of a botulinum toxin type A injection in both medial rectus muscles in patients with partially accommodative esotropia. Residual deviation and stability of strabismus were evaluated at 18 months follow up. A prospective, analytical, quasi-experimental study was conducted on a cohort of 21 patients who underwent total cycloplegic refraction and with a residual deviation of at least 14 DP. A botulinum toxin type A dose of 5 IU was injected into each medial rectus muscle for a residual deviation greater than 18 DP, with a dose of 2.5 IU being used for a deviation between 14 and 18 DP. Multivariate logistic regression analyses were performed to relate residual deviation to variables recorded as potential predictors. A total of 21 patients were included, 33.3% (n=7) males and 66.6% (n=14) females. Mean visual acuity was -.28±.25 logMAR for right eye (range 0 to -1) and -.42±.31 logMAR for left eye (range 0 to -1.3). Mean angle of residual deviation before application of botulinum toxin was 40.95±8.6DP without spectacles correction, and 22.3±7.99 DP with full cycloplegic refraction. Adverse effects were ptosis in 14.2% (n=3), diplopia 23.8% (n=5), and vertical deviation in 33% (n=7). One patient had a poor outcome, therefore required surgical treatment. At one year follow up, 85.71% of patients showed good results with esotropia of 12 DP or less, dropping to 71.43% at 18 months of follow up. Botulinum toxin type A is an effective long-term treatment with a good response in 71.43% of patients. No predictors of good response were demonstrated. Copyright © 2015 Sociedad Española de Oftalmología. Published by Elsevier España, S.L.U. All rights reserved.
Sánchez-Hernández, América Rocío; Arroyo-Yllanes, María Estela; Pérez-Pérez, José Fernando; Murillo-Murillo, Leopoldo
Congenital esotropia is the most frequent type of strabismus. Botulinum toxin is a treatment option with variable results. We undertook this study to determine the frequency and associated factors with consecutive permanent esotropia in patients diagnosed with congenital esotropia treated with botulinum toxin. A retrospective review was achieved in patients with congenital esotropia treated with botulinum toxin and who remained in esotropia after a minimal follow-up of 6 months. Pre- and postnatal background, cycloplejia, magnitude of the pre-application deviation, injected dose and number of applications were analyzed. A total of 84 patients were included. Of all patients,12 (14.28%) remained in consecutive esotropia (six males and six females). Age range was from 5 months to 2 years (average: 10.75 months). Initial esotropia ranged from 20-50 prism diopters (PD) with an average of 37.9 ± 9.64 PD. One patient had variability in the magnitude of the deviation prior to treatment. During the maximum follow-up, the magnitude of the esotropia was from 10 to 40 (average, SD 18 ± 8.01 PD). In five subjects a variability was observed in the magnitude of the angle of deviation by a range of 10-40 PD, and in seven subjects the deviation was stable with an average of 20 PD. Eleven subjects had some degree of psychomotor delay (91.66%) and one subject had a non-significant history. In patients with consecutive permanent esotropia after application of botulinum toxin, the most prevalent characteristic is neurological.
strains Hall, Okra , Stockholm, MDPH, Alaska, and Langeland and 89 representing serotypes A through G, respectively, were reduced, alkylated, digested with...sequence information. Clostridium botulinum progenitor toxins from strains Hall, Okra , Stockholm, MDPH, Alaska, Langeland, and 89 representing...from sero- types A (strain 62A), B (strain Okra ), C (003-9), D (CB-16), E (no designation; equivalent to NCTC 11219 by analysis), and F (Langeland) that
Questions are raised concerning the testing of botulinum toxin in animals, and the British Government's answers to Parliamentary Questions on this issue are reviewed, with an emphasis on the potential for reducing, refining and replacing the animal tests, which can involve substantial severity, and on the responsibility of the Home Office so see that the Three Rs approach is fully applied in this specific case.
Mor, Niv; Tang, Christropher; Blitzer, Andrew
This article reviews the diagnoses and treatment of temporomandibular disorders (TMD) and outlines of the role of botulinum toxin (BoNT) in the treatment of myofacial TMD. This manuscript includes a brief history of the use of BoNT in the treatment of pain, the mechanism of action of BoNT, and the techniques for injections, adverse effects and contraindications when using BoNT to treat mayofacial pain caused by TMD. PMID:26213970
Di Martino, Siria; Dalise, Stefania; Lamola, Giuseppe; Venturi, Martina; Rossi, Bruno; Chisari, Carmelo
Treatment options for dystonia are not curative but symptomatic; the treatment of choice for focal dystonias is repeated botulinum toxin injections. Here, we present the case of a 46-year-old beautician with focal dystonia in her left hand that affected her ability to work. Pharmacological treatment with clonazepam and gabapentin failed to resolve her symptoms and was discontinued due to side effects (sleepiness, gastrointestinal disorders). Intramuscular injection of botulinum toxin (incobotulinumtoxinA, Xeomin) into the extensor digitorum communis (35 U), flexor carpi radialis (35 U), and flexor digitorum superficialis (30 U) muscles resulted in complete resolution of symptoms at clinical assessments at 1, 3, 6, and 10 months after the injections, confirmed by the results of surface electromyography 10 months after treatment. The patient was able to work again 1 month after treatment. No reinjection has been necessary at the last evaluation (12 months after treatment). In conclusion, botulinum toxin is an effective treatment for focal dystonia that can have long-lasting effects and can improve patients' ability to work and quality of life. PMID:25143844
Benrhouma, H; Yacoubi, J; Kraoua, I; Klaa, H; Ben Youssef-Turki, I; Gouider-Khouja, N
Spasticity is a motor disorder, which can be treated by botulinum toxin (BT). We found no studies describing BT management of spasticity in Tunisian children. The aim of our study was to determine the frequency of spastic children treated with BT in the Tunisian hospital population and to evaluate treatment efficacy. We conducted a prospective study over a 5-year period including all children diagnosed with spasticity treated with BT and attending the "Movement Disorders and Botulinum Toxin" outpatient clinic of the National Institute of Neurology of Tunis. Hundred and fifteen patients were included (31% of patients attending the "Movement Disorders and Botulinum Toxin" outpatient clinic). Mean age was 7.6years and M:F sex ratio 1.7. Main clinical features were: spastic quadriplegia (48%), equinus deformity (70.4%) and cerebral palsy (88%). All patients were evaluated with the modified Ashworth score and were treated with BT. Other treatments were associated with BT: baclofene, physiotherapy, ortheses, plaster, and sometimes surgical treatment. The average percentage of improvement after BT was>50%. The Ashworth score was significantly lower for the majority of injected muscles. Our study is the first to describe BT management of spasticity in Tunisian children. Treatments of spasticity are numerous and vary according to location and extent of spasticity. BT is the main treatment for focal spasticity. Associated with physical therapy, BT allows optimal management of spastic children. Copyright © 2014 Elsevier Masson SAS. All rights reserved.
Brown, E Alexandra; Schütz, Sonja G; Simpson, David M
In recent years, a large body of data has surfaced reporting the therapeutic benefit of botulinum toxin injection in multiple conditions. The aim of this review is: to summarize the highest quality literature pertaining to clinical application of botulinum toxin in neuropathic pain conditions including postherpetic neuralgia, trigeminal neuralgia, diabetic polyneuropathy, post-traumatic neuralgia, carpal tunnel syndrome, complex regional pain syndrome, phantom limb and stump pain, and occipital neuralgia; to provide an overview of the clinical trials using botulinum toxin in adult spasticity; and to assign levels of evidence according to the American Academy of Neurology guidelines. In summary, there is level A evidence for established efficacy in postherpetic neuralgia and adult spasticity; level B evidence for probable efficacy in trigeminal neuralgia and post-traumatic neuralgia; level B evidence for probable lack of efficacy in carpal tunnel syndrome; level C evidence for possible efficacy in diabetic polyneuropathy; and level U (insufficient) evidence in complex regional pain syndrome, phantom limb and stump pain, and occipital neuralgia.
Ohishi, Iwao; Sakaguchi, Genji
Clostridium botulinum type F progenitor toxin was purified to a homogeneous state as judged by gel filtration on Sephadex G-200, ultracentrifugation, and disc electrophoresis. The sedimentation constant, corrected to water at 20 C, of type F progenitor toxin was determined to be 10.3 and the molecular weight to be 235,000 by ultracentrifugation at pH 6.0. The purified toxin contained a toxicity of 1.2 × 108 50% lethal doses/mg of N. In agar gel double diffusion, it formed two precipitin lines at pH 6.0. The progenitor toxin of type F differs from that of type A in that it contains no hemagglutinin and from that of type E in that it is not activable. Images PMID:4615636
Aoki, K Roger
The neurotoxin, botulinum toxin type A, has been used successfully, in some patients, as an analgesic for myofascial pain syndromes, migraine, and other headache types. The toxin inhibits the release of the neurotransmitter, acetylcholine, at the neuromuscular junction thereby inhibiting striated muscle contractions. In the majority of pain syndromes where botulinum toxin type A is effective, inhibiting muscle spasms is an important component of its activity. Even so, the reduction of pain often occurs before the decrease in muscle contractions suggesting that botulinum toxin type A has a more complex mechanism of action than initially hypothesized. Current data points to an antinociceptive effect of botulinum toxin type A that is separate from its neuromuscular activity. The common biochemical mechanism, however, remains the same between botulinum toxin type A's effect on the motor nerve or the sensory nerve: enzymatic blockade of neurotransmitter release. The antinociceptive effect of the toxin was reported to block substance P release using in vitro culture systems. The current investigation evaluated the in vivo mechanism of action for the antinociceptive action of botulinum toxin type A. In these studies, botulinum toxin type A was found to block the release of glutamate. Furthermore, Fos, a product of the immediate early gene, c-fos, expressed with neuronal stimuli was prevented upon peripheral exposure to the toxin. These findings suggest that botulinum toxin type A blocks peripheral sensitization and, indirectly, reduces central sensitization. The recent hypothesis that migraine involves both peripheral and central sensitization may help explain how botulinum toxin type A inhibits migraine pain by acting on these two pathways. Further research is needed to determine whether the antinociceptive mechanism mediated by botulinum toxin type A affects the neuronal signaling pathways that are activated during migraine.
Kronhardt, Angelika; Beitzinger, Christoph; Barth, Holger; Benz, Roland
C2-toxin from Clostridium botulinum and Iota-toxin from Clostridium perfringens belong both to the binary A-B-type of toxins consisting of two separately secreted components, an enzymatic subunit A and a binding component B that facilitates the entry of the corresponding enzymatic subunit into the target cells. The enzymatic subunits are in both cases actin ADP-ribosyltransferases that modify R177 of globular actin finally leading to cell death. Following their binding to host cells’ receptors and internalization, the two binding components form heptameric channels in endosomal membranes which mediate the translocation of the enzymatic components Iota a and C2I from endosomes into the cytosol of the target cells. The binding components form ion-permeable channels in artificial and biological membranes. Chloroquine and related 4-aminoquinolines were able to block channel formation in vitro and intoxication of living cells. In this study, we extended our previous work to the use of different chloroquine analogs and demonstrate that positively charged aminoquinolinium salts are able to block channels formed in lipid bilayer membranes by the binding components of C2- and Iota-toxin. Similarly, these molecules protect cultured mammalian cells from intoxication with C2- and Iota-toxin. The aminoquinolinium salts did presumably not interfere with actin ADP-ribosylation or receptor binding but blocked the pores formed by C2IIa and Iota b in living cells and in vitro. The blocking efficiency of pores formed by Iota b and C2IIa by the chloroquine analogs showed interesting differences indicating structural variations between the types of protein-conducting nanochannels formed by Iota b and C2IIa. PMID:27517960
Yang, K. H.; Sugiyama, H.
Clostridium botulinum type F toxin of proteolytic Langeland strain was purified. Toxin in whole cultures was precipitated with (NH4)2SO4. Extract of the precipitate was successively chromatographed on diethylaminoethyl-cellulose at pH 6.0, O-(carboxymethyl) cellulose at pH 4.9, Sephadex G-200 at pH 8.1, quaternary aminoethyl-Sephadex at pH 4.9, and finally diethylaminoethyl-cellulose at pH 8.1. The procedure recovered 14% of the toxin assayed in the starting culture. The toxin was homogeneous by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, double gel diffusion serology, and isoelectric focusing. Purified toxin had a molecular weight of 150,000 by gel filtration and 155,000 by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. Specific toxicity was 9.6 × 106 mean lethal doses per absorbancy (278 nm) unit. Sub-units of 105,000 and 56,000 molecular weight are found when purified toxin is treated with a disulfide reducing agent and electrophoresed on sodium dodecyl sulfate-polyacrylamide gels. Reciprocal cross neutralizations were demonstrated when purified type F and E toxins were reacted with antitoxins which were obtained with immunizing toxoids prepared with purified toxins. Images PMID:807160
Peyronnet, Benoit; Castel-Lacanal, Evelyne; Manunta, Andréa; Roumiguié, Mathieu; Marque, Philippe; Rischmann, Pascal; Gamé, Xavier
To evaluate the efficacy of a second injection of the same toxin versus switching to a different botulinum toxin A after failure of a first detrusor injection in patients with neurogenic detrusor overactivity. The charts of all patients who underwent detrusor injections of botulinum toxin A (either abobotulinumtoxinA or onabotulinumtoxinA) for the management of neurogenic detrusor overactivity at a single institution were retrospectively reviewed. Patients in whom a first detrusor injection had failed were included in the present study. They were managed by a second injection of the same toxin at the same dosage or by a new detrusor injection using a different botulinum toxin A. Success was defined as a resolution of urgency, urinary incontinence and detrusor overactivity in a patient self-catheterizing seven times or less per 24 h. A total of 58 patients were included for analysis. A toxin switch was carried out in 29 patients, whereas the other 29 patients received a reinjection of the same toxin at the same dose. The success rate was higher in patients who received a toxin switch (51.7% vs. 24.1%, P = 0.03). Patients treated with a switch from abobotulinumtoxinA to onabotulinumtoxinA and those treated with a switch from onabotulinumtoxinA to abobotulinumtoxinA had similar success rates (52.9% vs. 50%, P = 0.88). After failure of a first detrusor injection of botulinum toxin for neurogenic detrusor overactivity, a switch to a different toxin seems to be more effective than a second injection of the same toxin. The replacement of onabotulinumtoxin by abobotulinumtoxin or the reverse provides similar results. © 2015 The Japanese Urological Association.
Tatlidede, Soner; Baslo, M Baris; Özkaya, Özay; Soydan, Tufan; Orhan, Elif Kocasoy; Yeşilada, Ayşin Karasoy
Botulinum toxin prevents acetylcholine release at motor nerve terminals. Group B vitamins (B-vit) are essential for proper nerve function. The present study addresses the question of whether B-vit accelerate recovery in rat skeletal muscle after botulinum toxin A (Btx-A) injection. Forty-four adult male Wistar albino rats were used in this experimental study. Rats were divided into three groups: group 1 rats were given Btx-A injection only, group 2 rats were given B-vit supplementation before Btx-A injection, and group 3 rats were given Btx-A and B-vit injections together. During the experiment, compound muscle action potential (CMAP) of the gastrocnemius muscle was recorded before Btx-A injection and sequentially ten times after toxin injection. The statistical significance of the CMAP amplitude change among the groups was analyzed. All groups showed similar amplitude change between consecutive measurement points. In conclusion, combining Btx-A injection with B-vit supplement does not decrease the efficacy of the toxin.
Koh, Chung -Yan; Schaff, Ulrich Y.; Sandstone Diagnostics, Livermore, CA; ...
In this study, we present an innovative centrifugal microfluidic immunoassay platform (SpinDx) to address the urgent biodefense and public health need for ultrasensitive point-of-care/incident detection of botulinum toxin. The simple, sample-to-answer centrifugal microfluidic immunoassay approach is based on binding of toxins to antibody-laden capture particles followed by sedimentation of the particles through a density-media in a microfluidic disk and quantification by laser-induced fluorescence. A blind, head-to-head comparison study of SpinDx versus the gold-standard mouse bioassay demonstrates 100-fold improvement in sensitivity (limit of detection = 0.09 pg/mL), while achieving total sample-to-answer time of <30 min with 2-μL required volume of themore » unprocessed sample. We further demonstrate quantification of botulinum toxin in both exogeneous (human blood and serum spiked with toxins) and endogeneous (serum from mice intoxicated via oral, intranasal, and intravenous routes) samples. SpinDx can analyze, without any sample preparation, multiple sample types including whole blood, serum, and food. It is readily expandable to additional analytes as the assay reagents (i.e., the capture beads and detection antibodies) are disconnected from the disk architecture and the reader, facilitating rapid development of new assays. SpinDx can also serve as a general-purpose immunoassay platform applicable to diagnosis of other conditions and diseases.« less
Koh, Chung-Yan; Schaff, Ulrich Y; Piccini, Matthew E; Stanker, Larry H; Cheng, Luisa W; Ravichandran, Easwaran; Singh, Bal-Ram; Sommer, Greg J; Singh, Anup K
We present an innovative centrifugal microfluidic immunoassay platform (SpinDx) to address the urgent biodefense and public health need for ultrasensitive point-of-care/incident detection of botulinum toxin. The simple, sample-to-answer centrifugal microfluidic immunoassay approach is based on binding of toxins to antibody-laden capture particles followed by sedimentation of the particles through a density-media in a microfluidic disk and quantification by laser-induced fluorescence. A blind, head-to-head comparison study of SpinDx versus the gold-standard mouse bioassay demonstrates 100-fold improvement in sensitivity (limit of detection = 0.09 pg/mL), while achieving total sample-to-answer time of <30 min with 2-μL required volume of the unprocessed sample. We further demonstrate quantification of botulinum toxin in both exogeneous (human blood and serum spiked with toxins) and endogeneous (serum from mice intoxicated via oral, intranasal, and intravenous routes) samples. SpinDx can analyze, without any sample preparation, multiple sample types including whole blood, serum, and food. It is readily expandable to additional analytes as the assay reagents (i.e., the capture beads and detection antibodies) are disconnected from the disk architecture and the reader, facilitating rapid development of new assays. SpinDx can also serve as a general-purpose immunoassay platform applicable to diagnosis of other conditions and diseases.
We present an innovative centrifugal microfluidic immunoassay platform (SpinDx) to address the urgent biodefense and public health need for ultrasensitive point-of-care/incident detection of botulinum toxin. The simple, sample-to-answer centrifugal microfluidic immunoassay approach is based on binding of toxins to antibody-laden capture particles followed by sedimentation of the particles through a density-media in a microfluidic disk and quantification by laser-induced fluorescence. A blind, head-to-head comparison study of SpinDx versus the gold-standard mouse bioassay demonstrates 100-fold improvement in sensitivity (limit of detection = 0.09 pg/mL), while achieving total sample-to-answer time of <30 min with 2-μL required volume of the unprocessed sample. We further demonstrate quantification of botulinum toxin in both exogeneous (human blood and serum spiked with toxins) and endogeneous (serum from mice intoxicated via oral, intranasal, and intravenous routes) samples. SpinDx can analyze, without any sample preparation, multiple sample types including whole blood, serum, and food. It is readily expandable to additional analytes as the assay reagents (i.e., the capture beads and detection antibodies) are disconnected from the disk architecture and the reader, facilitating rapid development of new assays. SpinDx can also serve as a general-purpose immunoassay platform applicable to diagnosis of other conditions and diseases. PMID:25521812
Koh, Chung -Yan; Schaff, Ulrich Y.; Piccini, Matthew E.; Stanker, Larry H.; Cheng, Luisa W.; Ravichandran, Easwaran; Singh, Bal -Ram; Sommer, Greg J.; Singh, Anup K.
In this study, we present an innovative centrifugal microfluidic immunoassay platform (SpinDx) to address the urgent biodefense and public health need for ultrasensitive point-of-care/incident detection of botulinum toxin. The simple, sample-to-answer centrifugal microfluidic immunoassay approach is based on binding of toxins to antibody-laden capture particles followed by sedimentation of the particles through a density-media in a microfluidic disk and quantification by laser-induced fluorescence. A blind, head-to-head comparison study of SpinDx versus the gold-standard mouse bioassay demonstrates 100-fold improvement in sensitivity (limit of detection = 0.09 pg/mL), while achieving total sample-to-answer time of <30 min with 2-μL required volume of the unprocessed sample. We further demonstrate quantification of botulinum toxin in both exogeneous (human blood and serum spiked with toxins) and endogeneous (serum from mice intoxicated via oral, intranasal, and intravenous routes) samples. SpinDx can analyze, without any sample preparation, multiple sample types including whole blood, serum, and food. It is readily expandable to additional analytes as the assay reagents (i.e., the capture beads and detection antibodies) are disconnected from the disk architecture and the reader, facilitating rapid development of new assays. SpinDx can also serve as a general-purpose immunoassay platform applicable to diagnosis of other conditions and diseases.
Murakami, Eiji; Iwata, Hisashi; Imaizumi, Matsuhisa; Takemura, Hirohumi
In coronary artery bypass surgery, arterial grafts result in improved patency rates. However, these grafts frequently fail due to spasm. Papaverine has been used to prevent graft spasm, but its effect is short-lived. Botulinum toxin inhibits muscle contraction for about three months. We investigated the usefulness of botulinum toxin in preventing arterial grafts spasm in vitro. Samples of abdominal aorta from male Wistar rats were cut into 2 mm rings and treated with various doses of botulinum toxin or papaverine for 30 min. All rings were stimulated with KCl and noradrenaline. Tension was recorded using myography. We compared constriction caused by noradrenaline or KCl in rings treated with botulinum toxin, or papaverine, or physiological salt solution (PSS) (control). In the presence of KCl and noradrenaline, almost all concentrations of botulinum toxin completely inhibited arterial contraction when compared with controls. Spasm prevention was lost after 60 min in rings with papaverine but persisted for 120 min in rings with botulinum toxin. In the histological examination, arterial wall structure was not destroyed by botulinum toxin. Botulinum toxin prevented arterial graft spasm in vitro and had a longer lasting effect than papaverine, with no toxic effect on the artery.
Clostridium botulinum is a ubiquitous microorganism which can produce botulinum toxins and the ability to assess toxin activity in a food sample is critical. As an alternative to the mouse assay incubating quail (Coturnix coturnix japonica) and chicken (Gallus gallus domestics) embryos were evaluat...
Huynh, William; Krishnan, Arun V; Lin, Cindy S-Y; Vucic, Steve; Katrak, Pesi; Hornberger, Michael; Kiernan, Matthew C
Maladaptive plasticity involving the unaffected hemisphere (UH) in stroke patients may contribute to post-stroke deficits, including spasticity. We investigated the central and peripheral effects of botulinum toxin in post-stroke spasticity to determine whether there is modulation of cortical processes in the UH. Transcranial magnetic stimulation and peripheral nerve excitability studies were undertaken in 5 stroke patients with upper limb spasticity before (T1) and 6 weeks after (T2) botulinum injection. Transcranial magnetic stimulation demonstrated inexcitable motor cortices of the affected hemisphere at T1 and T2, and short-interval intracortical inhibition (SICI) in the UH was significantly reduced at T1. At T2, SICI in the UH increased significantly compared with T1, normalizing to controls, and was found to be associated with clinical improvements in spasticity. Peripheral excitability parameters were unchanged after injection. Cortical excitability changes were demonstrated in UH, suggesting that the clinical benefits of botulinum toxin relate to modulation of abnormal central reorganization (maladaptive plasticity) in post-stroke spasticity. Copyright © 2012 Wiley Periodicals, Inc., a Wiley company.
Segner, W P; Schmidt, C F
In inoculated pack experiments on Clostridium botulinum type E, unirradiated and 0.1-Mrad irradiated haddock fillets often gave nonspecific toxicities by the mouse assay test for botulinum toxin. Samples given 0.2-Mrad radiation failed to produce nonspecific reactions. Nonspecific deaths sometimes occurred within 24 hr after injection, although deaths between 24 and 48 hr were more common. The symptoms and the pattern of these deaths suggested a septicemia. Heart-blood cultured from mice showing nonspecific symptoms indicated an infectious process. Among 23 isolates from the blood, eight were identified as Proteus vulgaris, two P. morganii, one P. rettgeri, one Providence subgroup B, two Aerobacter aerogenes, one Actinobacillus, three enterococci, one Alcaligenes marshalli, and four Erysipelothrix insidiosa. The E. insidiosa, Aerobacter, Providence group, and most of the Proteus isolates were infectious for mice when injected by the intraperitoneal route. But the enterococci, Alcaligenes, and Actinobacillus isolates were not infectious and probably represent secondary invaders. The cultural characteristics of the E. insidiosa isolates conform to those described in the literature, with the exception that the four strains grew in the temperature range 50 F (10 C) to 40 F (4.4 C). Nonspecific toxicities were avoided in assays for botulinum toxin by the protection of mice with chloramphenicol and oxytetracycline.
Marshall, R.; Quinn, L. Y.
Type A botulinum toxin was studied for its ability to inhibit the action of acetyl-cholinesterase. The chromogenic substrate, indophenyl acetate, was used for assay of enzyme activity. Inhibition of enzyme function was detected through use of both 6.6 × 10−6 mg (20 ld50) and 6.6 × 10−10 mg (2 × 10−3ld50) of type A botulinal toxin. Control assays were performed by use of both homologous antitoxin and heterologous antitoxins (types B and E). Enzyme inhibition was effectively prevented by use of homologous antitoxin only. The inhibition noted was specific and reproducible for given substrate, enzyme, and toxin concentrations. PMID:4860916
Lim, Erle C H; Seet, Raymond C S
The restless legs syndrome (RLS), affecting between 3% and 15% of the population, is characterised by an urge to move the legs during wakefulness, associated with a range of unpleasant sensory symptoms, especially when sitting or lying down at night. The symptoms can even be painful, and lead to sleep disturbances and depression. RLS is treated with dopaminergic agents, anticonvulsants, opioids, clonidine and benzodiazepines. In a small percentage of cases, RLS is refractory to treatment, requiring combination therapy. Botulinum toxin (BTX), derived from the exotoxin of Clostridium botulinum, cleaves soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, causing chemodenervation of cholinergic neurons. BTX has been demonstrated to ameliorate pain syndromes, possibly by reducing peripheral and central sensitization to pain. We postulate that BTX can be injected subcutaneously to the lower limbs to effect amelioration of the symptoms of RLS.
Wester, Tomas; Granström, Anna Löf
Obstructive symptoms are common after pull-through for Hirschsprung disease. Botulinum toxin injection treatment may improve the bowel function if internal sphincter achalasia is the cause of obstructive symptoms. The aim of this study was to review the outcome in patients treated with intrasphincteric botulinum toxin injections after pull-through for Hirschsprung disease. The operative records were used to identify children with Hirschsprung disease who were treated with botulinum toxin injections at Karolinska University Hospital, Stockholm, Sweden, from September 2007 to November 2014. Data on age, sex, associated syndromes, length of aganglionic segment, age at pull-through, type of pull-through, age at first botulinum toxin injection, indication for botulinum toxin injection, and effect of first botulinum toxin injection were retrieved from the case records. Bowel function at last follow-up visit or telephone contact was recorded. Nineteen patients were identified. All had biopsy-verified Hirschsprung disease. Eighteen (15 males and 3 females) children had undergone intrasphincteric botulinum toxin injection treatment for obstructive symptoms after pull-through, which was done at 127 (18-538) days of age. Four children had total colonic aganglionosis. The first botulinum toxin injection was given at 2.4 (0.53-6.9) years of age. Thirteen children (72 %) had a good response to the first injection treatment. The children underwent 3 (1-13) injection treatments. At follow-up four patients had improved and did not need treatment for obstruction, four were scheduled for further botulinum toxin injections, eight had persistent obstructive symptoms treated with laxatives or enemas, and two children had an ileostomy. Botulinum toxin injection treatment improves the obstructive symptoms in children after pull-through for Hirschsprung disease. The effect is reversible and a majority of patients need repeat injections. When injection treatment is not repeated, a large
Prutthipongsit, Anuwat; Aui-aree, Nipat
To compare hemifacial spasm treatment results between Botulinum toxin A split injection sites and Botulinum toxin A non-split injection sites. Thirty-one hemifacial spasm patients were randomly assigned into the non-split injection sites group (injecting Botulinum toxin A to the zygomaticus major and risorius each) or split injection sites group with the same amount of Botulinum toxin A as the first method (injection Botulinum toxin A to the zygomaticus major and minor and risorius two injections each) The main outcomes are onset of improvement and effective duration of treatment. Fifteen patients were assigned to non-split injection sites group and 16 patients were assigned to split injection sites group. The median onset of improvement in non-split injection sites group and split injection sites group was 4.0 and 4.5 days, respectively (p = 0.984). The effective duration of treatment in the non-split injection sites group was 60.0 days and in the split injection sites group was 54.5 days (p = 0.582). The splitting of injection sites did not signicantly improve the efficacy of Botulinum toxin A in the treatment of hemifacial spasm.
Hicks, Rickey P; Hartell, Mark G; Nichols, Daniel A; Bhattacharjee, Apurba K; van Hamont, John E; Skillman, Donald R
The potential use of weapons of mass destruction (nuclear, biological or chemical) by terrorist organizations represents a major threat to world peace and safety. Only a limited number of vaccines are available to protect the general population from the medical consequences of these weapons. In addition there are major health concerns associated with a pre-exposure mass vaccination of the general population. To reduce or eliminate the impact of these terrible threats, new drugs must be developed to safely treat individuals exposed to these agents. A review of all therapeutic agents under development for the treatment of the illnesses and injuries that result from exposure to nuclear, biological or chemical warfare agents is beyond the scope of any single article. The intent here is to provide a focused review for medicinal and organic chemists of three widely discussed and easily deployed biological warfare agents, botulinum neurotoxin and ricin toxins and the bacteria Bacillus anthracis. Anthrax will be addressed because of its similarity in both structure and mechanism of catalytic activity with botulinum toxin. The common feature of these three agents is that they exhibit their biological activity via toxin enzymatic hydrolysis of a specific bond in their respective substrate molecules. A brief introduction to the history of each of the biological warfare agents is presented followed by a discussion on the mechanisms of action of each at the molecular level, and a review of current potential inhibitors under investigation.
Norheim, Arne Johan; Mercer, James; Musial, Frauke; de Weerd, Louis
ABSTRACT Frostbite sequelae are a relevant occupational injury outcome for soldiers in arctic environments. A Caucasian male soldier suffered frostbite to both hands during a military winter exercise. He developed sensory-motor disturbances and cold hypersensitivity. Angiography and thermography revealed impaired blood flow while Quantitative Sensory Testing indicated impaired somato-sensory nerve function. Two years after the initial event, he received an off label treatment with Botulinum toxin distributed around the neurovascular bundles of each finger. After treatment, cold sensitivity was reduced while blood flow and somato-sensory nerve function improved. The successful treatment enabled the soldier to successfully pursue his career in the army.
Jones, Alistair; Jain, Saurabh
Cyclic esotropia is a rare entity in which an esotropia presents in a regular 48-96 hour cycle, typically described as a 24-hour period of orthotropia followed by a 24-hour period of esotropia. The underlying mechanism of this phenomenon is unknown. Treatment usually involves surgical correction of the manifest strabismus. We report the case of a 3-year-old girl whose cyclic esotropia was broken following injection of botulinum toxin to both medial rectus muscles. She has remained constantly esophoric for 1 year.
Saeb-Lima, Marcela; Solis-Arreola, Gerardo-Victor
We report a case of mycobacterial infection at the sites of previous injections of botulinum toxin A in a 45-year-old woman. She presented with erythematous, swollen, warm, and tender plaques and nodules at the points of injection from which a biopsy was taken, demonstrating a deep dermal and hypodermal abscessified epithelioid granulomatous inflammatory infiltrate in which some acid-fast bacilli were identified with Ziehl-Neelsen and Fite-Faraco stains. The lesion was first treated with clarithromycin plus azithromycin, to which rifampicin was later added. A good therapeutic response was obtained. PMID:26023629
Grate, Jay W.; Ozanich, Richard M.; Warner, Marvin G.; Bruckner-Lea, Cindy J.; Marks, James D.
Methods to detect botulinum toxin, the most poisonous substance known, are reviewed. Current assays are being developed with two main objectives in mind: 1) to obtain sufficiently low detection limits to replace the mouse bioassay with an in vitro assay, and 2) to develop rapid assays for screening purposes that are as sensitive as possible while requiring an hour or less to process the sample an obtain the result. This review emphasizes the diverse analytical approaches and devices that have been developed over the last decade, while also briefly reviewing representative older immunoassays to provide background and context.
Suzuki, Tomonori; Miyazaki, Satoru
Protein-protein interactions play many important roles in biological function. Knowledge of protein-protein complex structure is required for understanding the function. The determination of protein-protein complex structure by experimental studies remains difficult, therefore computational prediction of protein structures by structure modeling and docking studies is valuable method. In addition, MD simulation is also one of the most popular methods for protein structure modeling and characteristics. Here, we attempt to predict protein-protein complex structure and property using some of bioinformatic methods, and we focus botulinum toxin complex as target structure.
Böhnel, H; Wagner, C; Gessler, F
Since a case of a veterinarian was reported, who was likely to be infected/intoxicated by Clostridium botulinum during the handling of a diseased animal, tonsils in animals were tested for botulinum neurotoxin and bacterial forms of neurotoxic Clostridium botulinum during routine botulism laboratory examinations including standard samples (intestinal tract and liver) from 48 cattle, 11 horses, and 14 goats. Ten out of 60 samples from tonsils contained free botulinum toxin, and 12 out of 59 were positive for live toxin producing bacteria. In 32 out of 162 intestinal samples toxin was detected. Toxin producing bacteria were found in 37 samples. Eight of 56 liver samples contained free toxin, and 15 out of 43 toxigenic bacteria. Samples from 10 slaughter pigs were all negative, whereas from slaughter cattle tonsils had a high incidence of toxin (7 of 10) or toxigenic bacteria (2 of 8). The results are discussed in the context of effects on animal health and botulism as zoonosis.
Baş, Burcu; Ozan, Bora; Muğlali, Mehtap; Celebi, Nükhet
Masseter muscle hypertrophy is a rare condition of unknown cause which is important in the differential diagnosis of head and neck masses, located in the cheek. Several treatment options reported for masseter hypertrophy, which range from simple pharmacotherapy to more invasive surgical reduction. Botulinum toxin type A is a powerful neurotoxin which is produced by the anaerobic organism Clostridium botulinum and when injected into a muscle causes interference with the neurotransmitter mechanism producing selective paralysis and subsequent atrophy of the muscle. Injection of botulinum toxin type A into the masseter muscle is generally considered a less invasive modality and has been advocated for cosmetic sculpting of the lower face. Botulinum toxin type A injection is considered to be a beneficial treatment modality in masseter muscle hypertrophy patients. The aim of this article is to report two cases of masseteric muscle hypertrophy which were treated with botulinum toxin type A injection. Marked changes in facial feature were achieved 3 months after the procedure.
Erbguth, Frank J
Food-borne botulism probably has accompanied mankind since its beginning. However, we have only few historical sources and documents on food poisoning before the 19th century. Some ancient dietary laws and taboos may reflect some knowledge about the life-threatening consumption of poisoned food. One example of such a dietary taboo is the 10th century edict of Emperor Leo VI of Byzantium in which manufacturing of blood sausages was forbidden. Some ancient case reports on intoxications with Atropa belladonna probably described patients with food-borne botulism, because the combination of dilated pupils and fatal muscle paralysis cannot be attributed to an atropine intoxication. At the end of the 18th century, some well-documented outbreaks of "sausage poisoning" in Southern Germany, especially in Württemberg, prompted early systematic botulinum toxin research. The German poet and district medical officer Justinus Kerner (1786-1862) published the first accurate and complete descriptions of the symptoms of food-borne botulism between 1817 and 1822. Kerner did not succeed in defining the suspected "biological poison" which he called "sausage poison" or "fatty poison." However, he developed the idea of a possible therapeutic use of the toxin. Eighty years after Kerner's work, in 1895, a botulism outbreak after a funeral dinner with smoked ham in the small Belgian village of Ellezelles led to the discovery of the pathogen Clostridium botulinum by Emile Pierre van Ermengem, Professor of bacteriology at the University of Ghent. The bacterium was so called because of its pathological association with the sausages (Latin word for sausage = "botulus") and not-as it was suggested-because of its shape. Modern botulinum toxin treatment was pioneered by Alan B. Scott and Edward J. Schantz. Copyright 2004 Movement Disorder Society
Zhao, Li-Chun; Yang, Bo; Wang, Rengang; Lipton, Stuart A; Zhang, Dongxian
All botulinum toxins (BoNTs, types A-G) inhibit synaptic transmitter release from motoneurons, and thus result in respiratory arrest and death. Rapid treatment with anti-BoNT antibodies can prevent progression, but recovery still requires weeks on a ventilator. Even after recovery, there is a potential for persistent fatigue in some cases of botulism even years after the insult, possibly because of motoneuron dropout for previously unknown reasons. Unique among BoNTs, the C-type (BoNT/C) cleaves two proteins involved in neurotransmitter release, syntaxin and SNAP-25, and induces apoptotic cell death in cultured cerebellar neurons. It is not clear, however, whether BoNT/C also affects neurons that encounter toxin in vivo, namely motoneurons. Here, we provide experimental evidence that BoNT/C causes a slow degeneration of motoneurons both in vitro and in vivo. This novel form of BoNT/C-induced cell death may require new treatment strategies.
Teasell, Robert; Foley, Norine; Pereira, Shelialah; Sequeira, Keith; Miller, Thomas
Spasticity is a significant problem following stroke. Although there is extensive research examining the efficacy of botulinum toxin as a treatment, there are challenges in implementing its use. The results from previously published randomized controlled trials and systematic reviews examining the use of botulinum toxin as a treatment for poststroke spasticity of the upper and lower limb and the shoulder are summarized. Several barriers to implementation are discussed. There is strong evidence that denervation of muscles, in the lower extremity and upper extremity post stroke, with botulinum toxin reduces focal spasticity. There is also strong evidence that it is associated with a small but significant improvement in gait velocity based on a recent meta-analysis. However, evidence that botulinum toxin injections are associated with improved function and improved quality of life is not as compelling. There is evidence that botulinum toxin injected into the subscapularis muscle can reduce spastic shoulder pain and improve passive range of motion of the hemiplegic shoulder. There are a number of challenges with botulinum toxin, including uncertainty over its role in improving motor dysfunction following stroke, the determination of which subsets of patients may benefit, the cost of treatment, and the identification of meaningful outcome measures. Botulinum toxin has been shown to be an effective treatment in reducing tone and managing spasticity post stroke. However, its effectiveness in improving function has been more controversial.
Kojovic, Maja; Caronni, Antonio; Bologna, Matteo; Rothwell, John C.; Bhatia, Kailash P.; Edwards, Mark J.
Botulinum toxin injections ameliorate dystonic symptoms by blocking the neuromuscular junction and weakening dystonic contractions. We asked if botulinum toxin injections in dystonia patients might also affect the integrity of sensorimotor cortical plasticity, one of the key pathophysiological features of dystonia. We applied a paired associative stimulation protocol, known to induce long-term potentiation–like changes in the primary motor cortex hand area to 12 patients with cervical dystonia before and 1 and 3 months after botulinum toxin injections to the neck muscles. Primary motor cortex excitability was probed by measuring transcranial magnetic stimulation-evoked motor evoked potentials before and after paired associative stimulation. We also measured the input–output curve, short-interval intracortical inhibition, intracortical facilitation, short afferent inhibition, and long afferent inhibition in hand muscles and the clinical severity of dystonia. Before botulinum toxin injections, paired associative stimulation significantly facilitated motor evoked potentials in hand muscles. One month after injections, this effect was abolished, with partial recovery after 3 months. There were significant positive correlations between the facilitation produced by paired associative stimulation and (1) the time elapsed since botulinum toxin injections and (2) the clinical dystonia score. One effect of botulinum toxin injection treatment is to modulate afferent input from the neck. We propose that subsequent reorganization of the motor cortex representation of hand muscles may explain the effect of botulinum toxin on motor cortical plasticity. PMID:21469207
Long, Hu; Liao, Zhengyu; Wang, Yan; Liao, Lina; Lai, Wenli
The objective of this study was to assess the efficacy of botulinum toxins on bruxism. Electronic databases (PubMed, Embase and Science Citation Index), websites (Cochrane Central Register of Controlled Trials and ClinicalTrials.gov) and the literature database of SIGLE (System for Information on Grey Literature in Europe) were searched from January 1990 to April 2011 for randomised controlled trials or nonrandomised studies assessing the efficacy of botulinum toxins on bruxism. There was no language restriction. Through a predefined search strategy, we retrieved 28 studies from PubMed, 94 from Embase, 60 from the Science Citation Index, two ongoing clinical trials and two from the Cochrane Central Register of Controlled Trials. Of these, only four studies met our inclusion criteria and were finally included. Of the four included studies, two were randomised controlled trials and two were controlled before-and-after studies. These studies showed that botulinum toxin injections can reduce the frequency of bruxism events, decrease bruxism-induced pain levels and satisfy patients' self-assessment with regard to the effectiveness of botulinum toxins on bruxism. In comparison with oral splint, botulinum toxins are equally effective on bruxism. Furthermore, botulinum toxin injections at a dosage of <100 U are safe for otherwise healthy patients. Botulinum toxin injections are effective on bruxism and are safe to use. Therefore, they can be used clinically for otherwise healthy patients with bruxism.
Ahmed, Karman; Oas, Kimberly Hall; Mack, Kenneth J; Garza, Ivan
In adults, botulinum toxin type A has been studied as a potentially effective treatment for chronic daily headache. For pediatric chronic daily headache, the literature evaluating efficacy of botulinum toxin type A is sparse, with no studies assessing tolerability. The purpose of this retrospective case series study was to assess tolerability and efficacy of botulinum toxin type A in the treatment of pediatric chronic daily headache. The series comprises 10 patients (ages 11-17 years) who received a standard 100-unit dose of onabotulinumtoxinA (trade name, Botox) for refractory chronic daily headache. Attention was given to therapeutic history, efficacy, and tolerability. The patients had attempted an average of 8.0 ± 2.40 S.D. therapies prior to botulinum toxin type A. Most patients reported adverse events from at least one of these prior medications. With botulinum toxin type A, four patients (40%) reported subjective but clinically meaningful relief, consisting of a decrease in headache intensity, and two patients additionally noted a decrease in headache frequency. The four responders noted improvements in quality of life. Three patients experienced minor adverse events from botulinum toxin type A. This case series suggests that botulinum toxin type A can be well tolerated and may be a useful therapeutic in pediatric patients with highly medically intractable chronic daily headache. Copyright © 2010 Elsevier Inc. All rights reserved.
Dastoor, Sarosh F; Misch, Carl E; Wang, Hom-Lay
Dental implants have emerged as a predictable treatment option for partial edentulism. Their ability to preserve bone and soft tissue yields highly esthetic results in the long term. Increasingly, patients are demanding not only enhancements to their dental (micro) esthetics but also to their overall facial (macro) esthetics. Dynamic wrinkles (caused by hyperfunctional muscles) in the perioral, glabellar, and forehead regions can cause a patient's expressions to be misinterpreted as angry, anxious, fearful, or fatigued. An emerging treatment option to address these issues is the use of a paralyzing material such as botulinum toxin A (Botox) to decrease the appearance of the wrinkles, which yields a more esthetic and youthful facial appearance. Botox is a deadly poison that is produced by the bacterium Clostridium botulinum and causes muscle paralysis by inhibiting acetylcholine release at the neuromuscular junction. When used in areas of hyperfunctional muscles, a transient partial paralysis occurs that diminishes the appearances of wrinkles, Therefore, wrinkles not attributable to hyperfunctional muscles (e.g., wrinkles caused by aging, gravity, photodamage, trauma, and scarring) will not be amenable to treatment with the toxin. As a result, proper case selection is essential. A thorough understanding of the indications, techniques, dosages, and complications and their management is imperative to achieve a satisfactory result. This article will review the pathogenesis of facial wrinkles as well as the history, techniques, clinical controversies, and other important considerations for successful treatment of facial wrinkles with Botox.
Papavasiliou, Antigone S; Nikaina, Irene; Bouros, Panagiotis; Rizou, Ioanna; Filiopoulos, Constantine
This study assessed treatment consistency of botulinum toxin administration in spastic upper limbs under pragmatic conditions, as derived through stability of dosages and between injections intervals. Over a period of 8 years, 153 children (81 with bilateral spastic cerebral palsy, 72 with unilateral) were treated according to accepted, experience-based guidelines with Botox and Dysport. Treatment response was based on assessment of spasticity and attainment of pre-determined goals at 3, 6 and 12 months post each treatment. Mean age at treatment onset was 6y 4mo (SD: 4y 10mo), median F/U, 2.5 years (4 months-6 8/12 years). Number of injection sessions was 1-10; few had more than 6 sessions. In 106 (69.28%) children, more than one anatomic regions of the limb were injected. Most (56.2%), had at least two injection sessions; median time interval between the sessions was 9 months (IQR: 4-35 months, similar for unilateral and bilateral cerebral palsy, p = 0.874). Children >4 years old at the first treatment had longer intervals between sessions (25.8%) compared to younger ones (p = 0.010). The mixed effects models demonstrated that botulinum toxin dosage was stable over subsequent visits (p = 0.144) and that intermediate intervals for subsequent visits were similar to the first one (p = 0.279). Copyright © 2011 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Phadke, Chetan P; Balasubramanian, Chitra K; Holz, Alanna; Davidson, Caitlin; Ismail, Farooq; Boulias, Chris
The adverse events (AEs) with botulinum toxin type-A (BoNTA), used for indications other than spasticity, are widely reported in the literature. However, the site, dose, and frequency of injections are different for spasticity when compared to the treatment for other conditions and hence the AEs may be different as well. The objective of this study was to summarize the AEs reported in Canada and systematically review the AEs with intramuscular botulinum toxin injections to treat focal spasticity. Data were gathered from Health Canada (2009-2013) and major electronic databases. In a 4 year period, 285 AEs were reported. OnabotulinumtoxinA (n=272 events): 68% females, 53% serious, 18% hospitalization, and 8% fatalities. The type of AEs reported were - muscle weakness (19%), oropharyngeal (14%), respiratory (14%), eye related (8%), bowel/bladder related (8%), and infection (5%). IncobotulinumtoxinA (n=13): 38% females, 62% serious, and 54% hospitalization. The type of AEs reported were - muscle weakness (15%), oropharyngeal (15%), respiratory (38%), eye related (23%), bowel/bladder related (15%), and infection (15%). Commonly reported AEs in the literature were muscle weakness, pain, oropharyngeal, bowel/bladder, blood circulation, neurological, gait, and respiratory problems. While BoNTA is useful in managing spasticity, future studies need to investigate the factors that can minimize AEs. A better understanding of the underlying mechanisms of the AEs can also improve guidelines for BoNTA administration and enhance outcomes.
Bjornson, Kristie; Hays, Ross; Graubert, Cathy; Price, Robert; Won, Francine; McLaughlin, John F; Cohen, Morty
Spasticity is a prevalent disabling clinical symptom for children with cerebral palsy. Treatment of spasticity with botulinum toxin in children with cerebral palsy was first reported in 1993. Botulinum toxin provides a focal, controlled muscle weakness with reduction in spasticity. Interpretation of the literature is difficult because of the paucity of reliable measures of spasticity and challenges with measuring meaningful functional changes in children with disabilities. This study documents the effects of botulinum toxin A injections into the gastrocnemius muscles in children with spastic diplegia. Outcomes are evaluated across all 5 domains of the National Centers for Medical and Rehabilitation Research domains of medical rehabilitation. A randomized, double-masked, placebo-controlled design was applied to 33 children with spastic diplegia with a mean age of 5.5 and Gross Motor Function Classification System Levels of I through III. Participants received either 12 U/kg botulinum toxin A or placebo saline injections to bilateral gastrocnemius muscles. Outcomes were measured at baseline and 3, 8, 12, and 24 weeks after injection. Significant decreases in the electromyographic representation of spasticity were documented 3 weeks after botulinum toxin A treatment. A significant decrease in viscoelastic aspects of spasticity was present at 8 weeks, and subsequent increases in dorsiflexion range were documented at 12 weeks for the botulinum toxin A group. Improvement was found in performance goals at 12 weeks and in maximum voluntary torque and gross motor function at 24 weeks for the botulinum toxin A. There were no significant differences between groups in satisfaction with performance goals, energy expenditure, Ashworth scores, or frequency of adverse effects. The safety profile of 12 U/kg of botulinum toxin A is excellent. Although physiologic and mechanical effects of treatment with botulinum toxin A were documented with functional improvement at 6 months
Barash, Jason R; Arnon, Stephen S
A retrospective study of Clostridium botulinum strains isolated from patients from California with infant botulism identified the fourth known C. botulinum strain that produces both type B and type F botulinum toxins. This unique strain represented 0.12% of the California infant botulism case isolates from 1976 to 2003. The relative concentrations of type B and F toxins produced were temperature dependent.
Micheli, Federico; Scorticati, María Clara; Raina, Gabriela
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.
Santana-Rodríguez, Norberto; Clavo, Bernardino; Calatayud-Gastardi, Joaquín; García-Castellano, José Manuel; Ponce-González, Miguel A; Olmo-Quintana, Vicente; Llontop, Pedro; Alvarez-Prats, Alejandro; Yordi, Nagib Atallah; Ruíz-Caballero, José Antonio
Compensatory hyperhidrosis is an adverse effect of thoracic sympathectomy that can be debilitating, which is why an efficient treatment is demanded. Botulinum toxin is an emerging treatment, not well known yet. We report two cases of compensatory hyperhidrosis following thoracic sympathectomy which were both treated with low doses of botulinum toxin A. The patients, a male and a female, noted a high level of satisfaction with the abolishment of sweating that was maintained up to 10 months. We consider that low doses of botulinum toxin A is a well tolerated, safe and effective treatment for compensatory hyperhidrosis and should be offered as an alternative treatment.
Kroll, Paweł; Jankowski, Andrzej; Zachwieja, Jacek; Zaniew, Marcin; Mańkowski, Przemysław; Harasymczuk, Jerzy; Antczak, Andrzej; Murias, Marek
To present our experience with endoscopic intradetrusor injections of botulinum-A toxin. Endoscopic treatment was proposed for children in which no improvement or side effects were observed. Botulinum-A toxin was injected in 25 children 3 to 7 years old. All children were evaluated with voiding-charts, in all of them urodynamic investigations were also performed in the pre and post-procedure period. Increased bladder volume was found in 18 patients, in 5 children bladder volume decreased. No major side effects were noted post BTX injections. Botulinum-A toxin in useful in children with neurogenic bladder overactivity.
Botulism is a serious foodborne neuroparalyic disease caused by botulinum neurotoxin (BoNT) produced by the anaerobic bacterium Clostridium botulinum. Seven toxin serotypes (A-H) have been described. The majority of human cases of botulism are caused by serotypes A and B followed by E and F. We repo...
Oleszek, Joyce L; Chang, Nicki; Apkon, Susan D; Wilson, Pamela E
This is a retrospective case series describing the use of botulinum toxin type A in the treatment of children with congenital muscular torticollis who fail to progress with conservative management. A total of 27 children with congenital muscular torticollis, 6-18 mos of age, received 30 botulinum toxin type A injections into their sternocleidomastoid or upper trapezius muscle, or both, at a pediatric tertiary care center between 1995 and 2001. Three children received repeat injections. Twenty of 27 children (74%) had improved cervical rotation or head tilt after the injections, and 2 of 27 (7%) experienced transient adverse events, specifically, mild dysphagia and neck weakness. This series suggests that botulinum toxin type A may be a safe and effective treatment option for children with congenital muscular torticollis who are unresponsive to a traditional regimen of physical therapy and a home program. A prospective, randomized controlled trial is necessary to definitively assess the role of botulinum toxin type A in this population.
Chow, Tam-Lin; Chan, Sharon W W; Lam, Siu-Ho
The conventional treatment of ranula is surgical procedure. We report an innovative method for ranula by using botulinum toxin type A on 3 patients. All 3 cases of ranula resolved after this minimally invasive therapy. The treatment complication was minimal.
Cigna, Emanuele; Maruccia, Michele; Fanelli, Benedetta; Scuderi, Nicolò
Use of botulinum toxin is expanding as the clinical studies demonstrate new potential therapeutic applications. In rehabilitation, botulinum toxin is above all used as adjunct therapy for the treatment of spasticity, but it may prove useful for other atypical clinical situations. A 17-year-old man had a sub-arachnoid haemorrhage following the rupture of cerebral aneurism. The patient presented gluteus maximus and medius bilaterally spasticity that produced a chronic lesion in the intergluteal cleft, a flexed wrist and a flexed elbow. As treatment for this spasticity, a total of 100 U botulinum toxin type A were injected into the glutei muscles. This treatment allowed for application of topical medication and subsequently, chronic lesion healing. Botulinum toxin A may be an important therapeutic aid for clinicians faced with treating persistent pathological conditions caused by spasticity. © 2012 The Authors. International Wound Journal © 2012 Medicalhelplines.com Inc and John Wiley & Sons Ltd.
Hou, Saiyun; Ivanhoe, Cindy; Li, Sheng
Spastic scapular dyskinesia after stroke is rare, which causes impaired shoulder active range of motion (ROM). To date, there has been no report about botulinum toxin injection to spastic periscapular muscles. This study presents botulinum toxin A injection for management of spastic periscapular muscles after stroke in 2 cases.This is a retrospective study of 2 cases of spastic scapular dyskinesia after stroke. Spasticity of periscapular muscles including rhomboid and lower trapezius was diagnosed by physical examination and needle electromyographic study. Botulinum toxin was injected into the spastic periscapular muscles under ultrasound imaging guidance.During the 3-week follow-up visit after injection, both patients showed increased shoulder active ROM, without any sign of scapular destabilization.The results suggest that botulinum toxin injection to spastic periscapular muscles can increase shoulder active ROM without causing scapular destabilization in patients with poststroke spastic scapular dyskinesia.
Di Pietro, Antonino; Piraccini, Bianca Maria
Background Injections of botulinum toxin type A in the forehead have never been reported to cause hair side effects. Objective The aim of this paper is to report a new type of alopecia, which we have seen in women undergoing periodic injections of botulinum toxin type A for forehead wrinkles, and to differentiate it from other types of hair loss. Methods We conducted an observational study on 5 females recruited from a private and an institutional practice who complained of progressive recession of the hairline after periodic injections of botulinum toxin type A in the forehead. Results Alopecia of the frontal hairline was evident in all 5 patients, with absence of skin atrophy or scarring and progressive hair miniaturization at trichoscopy. Conclusion Dermatologists should be aware of the possible occurrence of frontal alopecia after repeated injections of botulinum toxin type A for forehead wrinkles. PMID:27843928
Galárraga, Iván Marcelo Cueva
OBJECTIVE: To determine if the use of botulinum toxin during cheiloplasty could help in the management of tension at the surgical wound level. INTERVENTIONS: Five children younger than six months of age, who were born with complete cleft lip and palate, were treated with a dose of 10 units of botulinum toxin injected into the upper lip during surgery. Before the surgery, an electromyographic study was carried out on the patients’ upper lips. A Millard-type cheiloplasty was performed and 10 days later, a second electromyographic study was performed on the upper lips of all the patients. RESULTS: There was a significant change (P<0.039) in the electromyographic tracing obtained after the application of botulinum toxin, especially during rest. CONCLUSION: As confirmed by electromyography, botulinum toxin effectively inhibits the action of the orbicularis oris muscle, especially when at rest; consequently, the tension is decreased at the level of the surgical wound. PMID:20808741
Böhnel, H; Gessler, F
Clostridium botulinum is an anaerobic spore-forming bacterium prevalent in the environment, and causes botulism in man and animals via toxins. Dairy cattle may be contaminated or infected by feed, water or other environmental factors. Milk may also carry the pathogen. Hence, milk and udder samples need to be tested. The number of clinical cases of bovine botulism in Germany has been increasing since the mid-1990s. Besides routine samples, additional 99 milk samples from 37 farms, and 51 udder samples from 51 farms from sick animals presumably affected by botulism were tested microbiologically by the mouse bioassay. Milk from three farms (8.1 per cent) contained botulinum toxin, and from two (5.4 per cent) bacterial states of C botulinum. Ten udder samples (19.6 per cent) contained toxin, and 7 (13.7 per cent) bacterial forms, including one case where both toxin and bacteria were found. The findings are discussed. Positive milk samples containing botulinum toxin or bacteria raise concern of food safety for the human consumer. Pathological udder samples may show either infection prior to, or contamination after death.
Smits, Martijn A C; Oerlemans, Dennis; Marcelissen, Tom A T; Van Kerrebroeck, Philip E V; De Wachter, Stefan G G
We evaluated whether patients with overactive bladder and incontinence who discontinued intravesical botulinum toxin therapy can be successfully treated with sacral neuromodulation. All patients who were referred to our center after discontinuation of botulinum toxin-A between 2005 and 2010 were included in this observational study. All patients underwent test stimulation with sacral neuromodulation and were evaluated with voiding diaries. Success was defined as more than 50% improvement in leakage episodes. Successful test stimulation was subsequently followed by a definitive implant. Patient satisfaction with sacral neuromodulation therapy was evaluated 1 year after the definitive implant. A total of 20 patients were included in the study. Of these patients 17 (85%) had discontinued botulinum toxin-A because of lack of efficacy and 3 had been treated successfully with botulinum toxin-A but requested a more permanent solution. The mean interval between the botulinum toxin-A and the sacral neuromodulation test stimulation was 23 months. In 14 patients (70%) the test stimulation was successful and they received a definitive implant. Of the 14 patients 5 even showed a decrease of greater than 90% in leakage episodes. One year after implantation 11 patients (79%) were satisfied with the sacral neuromodulation treatment. Despite the small sample size, this study indicates that patients who are dissatisfied with or in whom botulinum toxin-A treatment fails can respond successfully to sacral neuromodulation. The success rate of the test stimulation was comparable to that of patients who have never been treated with botulinum toxin-A. The 1-year satisfaction rate was comparable that of patients without a history of botulinum toxin-A treatment. Copyright © 2013 American Urological Association Education and Research, Inc. Published by Elsevier Inc. All rights reserved.
Conill Tobías, Noemi; de Paula Vernetta, Carlos; García Callejo, Francisco Javier; Marco Algarra, Jaime
Objective tinnitus can have many different etiologies, palatal myoclonus being one of the less frequent. This type of tinnitus is generated by involuntary rhythmic contraction of the soft palate, which generates an audible click for the patient and for the explorer. Botulinum toxin achieves temporary muscle paralysis through presynaptic inhibition of the acetylcholine level at the neuromuscular union. We present a patient with long-term objective tinnitus, along with this patient's response to botulinum toxin injection.
El Maaytah, Mohammed; Jerjes, Waseem; Upile, Tahwinder; Swinson, Brian; Hopper, Colin; Ayliffe, Peter
We report a successful treatment of bruxism in a patient with anoxic brain injury using botulinum toxin-A (BTX-A). On examination the mouth opening was 0 mm, no feeding was possible through the mouth. Botulinum toxin was injected into the masseter and temporalis; great improvement in trismus and bruxism was noted after 3 weeks. One further treatment improved the mouth opening on the following week and the patient was discharged from our care to be reviewed when required. PMID:17123443
Blood, Anne J.; Tuch, David S.; Makris, Nikos; Makhlouf, Miriam L.; Sudarsky, Lewis R.; Sharma, Nutan
The pathophysiology of dystonia is still poorly understood. We used diffusion tensor imaging to screen for white matter abnormalities in regions between the basal ganglia and the thalamus in cervical and hand dystonia patients. All patients exhibited an abnormal hemispheric asymmetry in a focal region between the pallidum and the thalamus. This asymmetry was absent 4 weeks after the same patients were treated with intramuscular botulinum toxin injections. These findings represent a new systems-level abnormality in dystonia, which may lead to new insights about the pathophysiology of movement disorders. More generally, these findings demonstrate central nervous system changes following peripheral reductions in muscle activity. This raises the possibility that we have observed activity-dependent white matter plasticity in the adult human brain. PMID:16951564
Blood, Anne J; Tuch, David S; Makris, Nikos; Makhlouf, Miriam L; Sudarsky, Lewis R; Sharma, Nutan
The pathophysiology of dystonia is still poorly understood. We used diffusion tensor imaging to screen for white matter abnormalities in regions between the basal ganglia and the thalamus in cervical and hand dystonia patients. All patients exhibited an abnormal hemispheric asymmetry in a focal region between the pallidum and the thalamus. This asymmetry was absent 4 weeks after the same patients were treated with intramuscular botulinum toxin injections. These findings represent a new systems-level abnormality in dystonia, which may lead to new insights about the pathophysiology of movement disorders. More generally, these findings demonstrate central nervous system changes following peripheral reductions in muscle activity. This raises the possibility that we have observed activity-dependent white matter plasticity in the adult human brain.
Mor, Niv; Tang, Christopher; Blitzer, Andrew
Chemodenervation with botulinum toxin (BoNT) has been effective and well tolerated for all types of dystonia for >30 years. We reviewed outcomes of our patients treated with BoNT serotype A (BoNT-A) for spasmodic dysphonia (SD) who became secondarily nonresponsive. We found that 8 of 1400 patients became nonresponsive to BoNT-A (0.57%), which is lower than the secondary nonresponse rate in other dystonias. After a cessation period, 4 of our patients resumed BoNT-A injections, and recurrence of immunoresistance was not seen in any of them. When compared with patients with other dystonias, patients with SD receive extremely low doses of BoNT. Small antigen challenge may explain the lower rate of immunoresistance and long-lasting efficacy after BoNT-A is restarted among secondary nonresponsive patients with SD.
Srivastava, Sanjeev; Kharbanda, Smriti; Pal, U. S.; Shah, Vinit
The horizons of treatment options in dentistry are broadening rapidly. In this scenario, applications of unconventional treatment options like use of botulinum toxin (BT) are gaining momentum. The use of BT has been popularly accepted in esthetic procedures like management of facial wrinkles; however, it has been documented to be successful in a variety of conditions. Of particular interest to this paper are applications of BT in the maxillofacial region, concerned to dentistry. BT offers a transient, reversible, relatively safe treatment option to many conditions of interest to a dental practitioner. Dental surgeons by their virtue of being extensively aware of the anatomy of faciomaxillary region are a potential pool of operators who can use BT in their armamentarium with minor skill enhancement and thus widen the perspective of alternative, minimally invasive options to refractory conditions or invasive protocols. PMID:27390488
Chaurand, Jorge; Pacheco-Ruíz, Laura; Orozco-Saldívar, Hector; López-Valdés, Julio
The present study aimed to assess the efficacy of using botulinum toxin (BTX) in temporomandibular joint disorders, particularly pertaining to myofascial pain from masseter and temporal muscles. The study included 11 patients who were diagnosed with masseter and temporalis myofascial pain. Visual analog scale for pain and pressure algometry were conducted initially, after 1 month of conservative therapy (control group), and after 1 month of BTX type A injections (study group). Data were statistically analyzed (analysis of variance and Wilcoxon's test) to determine intergroup differences. Both conservative therapy and BTX injections showed reduction in pain scores and increase in pain threshold compared with baseline, and statistically significant differences were noted between both groups. Thus, BTX injections appear to be effective in management of chronic myofascial pain targeting masseter and temporalis muscles.
Peng-Chen, Zhongxing; Thompson, Amanda; Rodriguez, Ramon L
Anterocollis is a type of cervical dystonia characterized by simultaneous and repetitive antagonist muscles contractions, resulting in abnormal neck flexion. It was described with a frequency of 6.8% from 399 patients with diagnosis of cervical dystonia and usually coexists with torticollis and/or laterocollis, as mixed cervical dystonia patterns. Botulinum toxin is usually a practical and effective treatment for cervical dystonia. The target muscles to inject in anterocollis are usually sternocleidomastoid and scalene muscles. There is also a case report suggesting longus collis involvement. Nevertheless, the dosage of the medication in anterocollis is limited by frequent side effects of dysphagia. We described 2 cases of refractory anterocollis. They did not benefit from conventional bilateral upper portion of sternocleidomastoid muscle injections with OnabotulinumtoxinA, but notably improved their symptoms and clinical global impression after switching to injections into bilateral lower portion of sternocleidomastoid muscles, without significant side effects.
Pavone, Vito; Testa, Gianluca; Restivo, Domenico A.; Cannavò, Luca; Condorelli, Giuseppe; Portinaro, Nicola M.; Sessa, Giuseppe
CP is the most common cause of chronic disability in childhood occurring in 2–2.5/1000 births. It is a severe disorder and a significant number of patients present cognitive delay and difficulty in walking. The use of botulinum toxin (BTX) has become a popular treatment for CP especially for spastic and dystonic muscles while avoiding deformity and pain. Moreover, the combination of physiotherapy, casting, orthotics and injection of BTX may delay or decrease the need for surgical intervention while reserving single-event, multi-level surgery for fixed musculotendinous contractures and bony deformities in older children. This report highlights the utility of BTX in the treatment of cerebral palsy in children. We include techniques for administration, side effects, and possible resistance as well as specific use in the upper and lower limbs muscles. PMID:26924985
Zychowska, Magdalena; Rojewska, Ewelina; Makuch, Wioletta; Luvisetto, Siro; Pavone, Flaminia; Marinelli, Sara; Przewlocka, Barbara; Mika, Joanna
Our data show that botulinum toxin A (BoNT/A) didn't influence motor functions in naïve and CCI-exposed rats, but diminished the neuropathic pain-related behavior. The results indicate that BoNT/A administration diminished the spinal Iba-1 positive cells activation and, in parallel, downregulated IL-1beta. Moreover, we observed that in DRG the protein level of pronociceptive factors (IL-1beta and IL-18) decreased and antinociceptive (IL-10 and IL-1RA) factors increased. Additionally, our behavioral analysis shows that chronic minocycline treatment together with a single BoNT/A injection in CCI-exposed rats has beneficial analgesic effects (M. Zychowska, E. Rojewska, W. Makuch, S. Luvisetto, F. Pavone, S. Marinelli, B. Przewlocka, J. Mika, 2016) .
Lacout, M; Guinet-Lacoste, A; Popoff, M; Verollet, D; Lebreton, F; Amarenco, G
Intradetrusor injection of botulinum toxin is one of the second-line therapy of neurologenic detrusor overactivity. In 26% to 66% of the cases, intradetrusor injection of botulinum toxin is inefficient in order to reduce overactive bladder symptoms and/or overactive detrusor. The objective of this study is to determine whether it exists a link between the efficacy of the first IDBT and the length of neurological detrusor overactivity symptoms. Retrospective study on 79 patients which have a first intradetrusor injection of botulinum toxin between January 2001 and December 2013. Inclusion criteria were patients older than 18 and having neurological detrusor overactivity. There is no significant difference of intradetrusor injection of botulinum toxin efficacy according to duration of urinary symptoms in the general neurologigal population (multiple sclerosis, spinal cord injury, spinal cord compression, ischemic pathology, infectious pathology) with the mean age being 46 years. On the contrary, the length of evolution of neurological detrusor overactivity symptoms before the intradetrusor botox injection therapy and the efficiency of the first intradetrusor injection of botulinum toxin seem to be correlated with negative results in patients with multiple sclerosis. The duration of urinary symptoms is a predictive factor of primary failure of intradetrusor injection of botulinum toxin in multiple sclerosis patients, in univariate analysis. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
Xie, Aiguo; Nie, Lanjun; Tan, Qian
The objective of this study was to investigate the efficacy of local injection of botulinum toxin A for treating axillary osmidrosis. One hundred and fifty patients with axillary osmidrosis were randomly divided to receive botulinum toxin A injection treatment (50 U of botulinum toxin A was injected intracutaneously into 6-20 different sites within each axilla, n = 74) or surgical excision of the apocrine glands (n = 76). The patients were followed up for 1-3 months to analyze the therapeutic effect and complications of the two methods. The curative effect in patients with mild and moderate axillary osmidrosis was not significantly different between the botulinum toxin A injection group and operation group. However, for patients with severe axillary osmidrosis, surgery treatment seemed to be superior to botulinum toxin A treatment (P = 0.005). There was also no significant difference in the modified Dermatology Life Quality Index between the two treatments. Two cases showed complications related to hemorrhage and incision infection in the operation group. In conclusion, local injection of botulinum toxin A is a safe, fast and effective treatment for mild and moderate axillary osmidrosis, but the long-term effect remains to be further investigated.
Stephan, Farid; Habre, Maya; Tomb, Roland
Botulinum toxin injections have become the most frequent noninvasive cosmetic procedure carried out worldwide. Botulinum toxin has also multiple other indications in different medical fields. However, with the repetition of injections, a new concern has emerged: clinical resistance and loss of effectiveness of the treatment. After reporting a case of primary nonresponsiveness to three types of botulinum toxin type A injections, we conducted a review about all factors leading to the primary or secondary nonresponsiveness, as well as the factors affecting the immunogenicity of this neurotoxin. Most of the reports and studies focused on secondary resistance to botulinum toxin (BT) and the neurotoxin immunogenicity; primary nonresponsiveness was rarely reported. Factors leading to primary or secondary resistance to BT injections were numerous. In the majority of the studies, development of neutralizing antibodies to botulinum toxin was considered responsible of the induced clinical resistance. Patients should be aware of this rising concern as well as clinicians who should learn how to minimize the risk of resistance development, sparing the patients more invasive treatment modalities. Further studies related to botulinum toxin resistance are needed.
Phadke, Chetan P; On, Arzu Y; Kirazli, Yesim; Ismail, Farooq; Boulias, Chris
Botulinum toxin, frequently used to manage focal limb spasticity, has been reported to affect both extrafusal and intrafusal fibers of the injected muscle. Since most studies have used spinal reflexes, it is difficult to isolate the intrafusal effects from extrafusal and central effects. In a paper by On et al. , both stretch and H-reflexes were used to examine the intrafusal effects of botulinum toxin injections. Revisiting the data from On et al.  presented a unique opportunity to describe a novel method of measuring the effect of botulinum toxin-A on muscle spindle activity in patients with spasticity. H-reflex, maximum M-wave, and Achilles tendon reflex were serially assessed in ten patients with stroke pre-, 2, 4, and 12 weeks post-botulinum. In order to assess the intrafusal effects, we subtracted the %change in H-reflex amplitude from baseline (representing extrafusal and central effects) from the %change in Achilles tendon reflex amplitude from baseline (representing intrafusal, extrafusal and central effects). Using this formula, our results suggest that botulinum induces significant chemodenervation of the intrafusal muscle fibers (33% decreases). Intrafusal effects were greatest at 2 weeks, but tapered off by 12 weeks post-botulinum (p<0.017). We found a significant positive correlation between the intrafusal effects of botulinum toxin and changes in modified Ashworth scale. Our method of assessing the effects of botulinum toxin shows significant effect on intrafusal fibers, which correlates with clinical manifestation of spasticity. Future studies need to investigate ways to maximize intrafusal effects and minimize extrafusal effects of botulinum therapy. Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Phadke, Chetan Purushottam; Ismail, Farooq; Boulias, Chris; Gage, William; Mochizuki, George
Although falls, balance impairment, and spasticity are common post-stroke, their interrelationship remains unclear. We review the literature for a) a relationship between spasticity and balance and b) the effect of botulinum toxin injections on balance. Electronic databases were searched based on two criteria: a) studies assessing balance in subjects with spasticity and b) studies examining the effect of botulinum toxin on balance. The primary findings were a) balance is impaired in subjects with spasticity, but only one study assessed relationship between spasticity and balance; and b) four studies reported that balance improves following botulinum treatment for limb spasticity. Persons with spasticity demonstrate impaired balance, but the correlation between spasticity and balance has not been adequately assessed in the literature. Evidence for balance changes following botulinum toxin is weak because of lack of randomization, control group comparison, objective balance assessment measures, and standard clinical scales.
Mills, Reversa R; Pagan, Fernando L
Cervical dystonia is the most common form of focal dystonia characterized by involuntary muscle contractions causing abnormal movements and posturing of the head and neck and is associated with significant pain. Botulinum toxin is considered first-line therapy in the treatment of pain and abnormal head posturing associated with cervical dystonia. There are currently three botulinum toxin type A neurotoxins and one botulinum type B neurotoxin commercially available and US Food and Drug Administration (FDA) labeled for the treatment of cervical dystonia. This review will focus on the efficacy, safety, and therapeutic use of botulinum type A neurotoxins in the treatment of cervical dystonia. We conclude with a discussion of factors influencing toxin selection including therapeutic effect, duration of effect, side effect profile, cost, and physician preference. PMID:26082621
Imamura, K.; Spriggs, D.; Ohno, T.; Kufe, D.
Botulinum toxins are potent neurotoxins which block the release of neurotransmitters. The effects of these toxins on hematopoietic cells, however, are unknown. Monocytes secrete a variety of polypeptide growth factors, including tumor necrosis factor (TNF). In the study reported here, the effects of botulinum toxin type D on the secretion of TNF from human monocytes were examined. The results demonstrate that biotulinum toxin type D inhibits the release of TNF from monocytes activated by lipopolysaccharide (LPS) but not by 12-O-tetradecanoylphorbol-13-acetate. Botulinum toxin type D had no detectable effect on intracellular TNF levels in LPS-treated monocytes, indicating that the effects of this toxin involve the secretory process. This inhibitory effect of botulinum toxin type D on TNF secretion from LPS-treated monocytes was partially reversed by treatment with 12-O-tetradecanoylphorbol-13-acetate or introduction of guanosine 5'-(/gamma/-thio)t-riphosphate into these cells. The results demonstrate that TNF secretion is regulated by at least two distinct guanine nucleotide-binding proteins, one responsible for the activation of phospholiphase C and another which acts as a substrate for botulinum toxin type D. ADP-ribosylation of monocyte membranes by botulinum toxin type D demonstrated the presence of three substrates with M/sub r/s of 45,000, 21,000, and 17,000. While the role of these substrates in exocytosis is unknown, the results suggest that the M/sub r/ 21,000 substrate is involved in a process other than TNF secretion.
Brashear, Allison; Gordon, Mark F; Elovic, Elie; Kassicieh, V Daniel; Marciniak, Christina; Do, Mai; Lee, Chia-Ho; Jenkins, Stephen; Turkel, Catherine
Spasticity is a disabling complication of stroke, and it is uncertain whether intramuscular injections of botulinum toxin type A reduce disability in persons with spasticity of the wrist and fingers after a stroke. We performed a randomized, double-blind, placebo-controlled, multicenter trial to assess the efficacy and safety of one-time injections of botulinum toxin A (200 to 240 units) in 126 subjects with increased flexor tone in the wrist and fingers after a stroke. The primary outcome measure was self-reported disability in four areas: personal hygiene, dressing, pain, and limb position (on a four-point scale ranging from no disability to severe disability) at six weeks; at base line, each subject selected one of these areas in which there was moderate-to-severe disability as the principal target of treatment. Subjects who received botulinum toxin A had greater improvement in flexor tone in the wrist and fingers at all follow-up visits through 12 weeks than did subjects who received placebo (P<0.001 for all comparisons). Subjects treated with botulinum toxin A had greater improvement in the principal target of treatment at weeks 4, 6, 8, and 12 (P<0.001, P<0.001, P=0.03, and P=0.02, respectively); at week 6, 40 of the 64 subjects in the botulinum-toxin group (62 percent), as compared with 17 of the 62 in the placebo group (27 percent), reported improvement of at least one point on the Disability Assessment Scale in the principal target of treatment (P<0.001). There were no major adverse events associated with injection of botulinum toxin A. Intramuscular injections of botulinum toxin A reduce spasticity of the wrist and finger muscles and associated disability in patients who have had a stroke. Copyright 2002 Massachusetts Medical Society
Dressler, Dirk; Bigalke, Hans
Most botulinum toxin (BT) drugs are stored as powders which need to be reconstituted with normal saline before clinical use. As botulinum neurotoxin (BNT), the therapeutically active ingredient, is a large double-stranded protein the process of reconstitution should be performed with special attention to mechanical stress applied. We wanted to test the mechanical stability of BNT during the reconstitution process. For this, 100 MU onabotulinumtoxinA (Botox(®), Irvine, CA, USA) was reconstituted with 2.0 ml of NaCl/H2O. Gentle reconstitution (GR) was performed with a 5 ml syringe, a 0.90 × 70 mm injection needle, one cycle of injection-aspiration-injection and two gentle shakes of the vial. Aggressive reconstitution (AR) was performed with a 5 ml syringe, a 0.40 × 40 mm injection needle, ten injection-aspiration-injection cycles and 30 s of continuous shaking of the vial. AR increased the time to paralysis in the mouse hemidiaphragm assay (HDA) from 72.0 ± 4.6 to 106.0 ± 16.0 min (*p = 0.002, two-tailed t test after Kolmogorov-Smirnova test with Lilliefors correction for normal distribution). Construction of a calibration curve revealed that the increase in the time to paralysis was correlated with a loss of potency of from 100 to 58 MU (-42 %). BT users should use large diameter injection needles for reconstitution, apply two or three injection-aspiration-injection cycles and, maybe, shake the vials a few times to rinse the entire glass wall. Aggressive reconstitution with small diameter needles, prolonged injection-aspiration-injection and violent shaking should be avoided.
Weingart, Oliver G.; Schreiber, Tanja; Mascher, Conny; Pauly, Diana; Dorner, Martin B.; Berger, Thomas F. H.; Egger, Charlotte; Gessler, Frank; Loessner, Martin J.; Avondet, Marc-Andre; Dorner, Brigitte G.
Botulinum neurotoxin (BoNT) is the most toxic substance known to man and the causative agent of botulism. Due to its high toxicity and the availability of the producing organism Clostridium botulinum, BoNT is regarded as a potential biological warfare agent. Because of the mild pasteurization process, as well as rapid product distribution and consumption, the milk supply chain has long been considered a potential target of a bioterrorist attack. Since, to our knowledge, no empirical data on the inactivation of BoNT in milk during pasteurization are available at this time, we investigated the activities of BoNT type A (BoNT/A) and BoNT/B, as well as their respective complexes, during a laboratory-scale pasteurization process. When we monitored milk alkaline phosphatase activity, which is an industry-accepted parameter of successfully completed pasteurization, our method proved comparable to the industrial process. After heating raw milk spiked with a set amount of BoNT/A or BoNT/B or one of their respective complexes, the structural integrity of the toxin was determined by enzyme-linked immunosorbent assay (ELISA) and its functional activity by mouse bioassay. We demonstrated that standard pasteurization at 72°C for 15 s inactivates at least 99.99% of BoNT/A and BoNT/B and at least 99.5% of their respective complexes. Our results suggest that if BoNTs or their complexes were deliberately released into the milk supply chain, standard pasteurization conditions would reduce their activity much more dramatically than originally anticipated and thus lower the threat level of the widely discussed “BoNT in milk” scenario. PMID:20363798
The quail embryo was evaluated for use as a bioassay to detect biologically active botulinum toxin serotype A (BoNT/A). Day 15 of incubation embryos were injected with decreasing dosages of BoNT/A from 250 to 0.5 ng of toxin. At 1 day post-injection, embryos receiving 20 ng of BoNT or higher had m...
Miller, Carol A.; Anderson, Arthur W.
An experimental system is described for the detection and quantitative estimation of type A botulinum toxin by electroimmunodiffusion. The method is shown to be rapid, specific, and quantitative. As little as 14 mouse LD50 per 0.1 ml of type A toxin was detected within 2 hr. When applied to experimentally contaminated foods such as canned tuna, pumpkin, spinach, green beans, and sausage, the technique detected botulinum toxin rapidly and identified it as to type and quantity. A specific rabbit type A antitoxin was produced for this in vitro system since the equine antitoxin (Center for Disease Control) tested in this experiment was found to be unsuitable. Images PMID:5005291
Andrew, Clifford G.; Drachman, Daniel B.; Pestronk, Alan; Narayan, Opendra
Coxsackie A viruses can infect denervated but not innervated mature skeletal muscles. The role of synaptic transmission in preventing susceptibility to Coxsackievirus infection was studied by surgically denervating leg muscles of mice or injecting the muscles with botulinum toxin to block quantal release of acetylcholine. Control muscles were injected with heat-inactivated toxin. Subsequent injection of Coxsackie A2 virus resulted in extensive virus replication and tissue destruction in the denervated and botulinum toxin-treated muscles, while the control muscles showed only minimal changes. This suggests that the susceptibility of skeletal muscle to Coxsackievirus infection is regulated by synaptic transmission.
It is common knowledge that recovery of motor function is limited at 6 months after the onset of stroke. But there are some reports that motor functions are improved with using botulinum toxin type A for limb spasticity in the maintenance stage of stroke. Though it has been thought that botulinum toxin type A works in the peripheral nerves so far, Caleo showed botulinum toxin can affect the central nervous system. We suspected botulinum toxin type A affected the spinal cord directly following retrograde transynaptic transport from our experiments and his reports. So, we deduce the abnormal stretch reflex is made a modification by affecting the spinal cord, not only the injected muscle is relaxed, but also motor function is improved. Botulinum toxin type A shows sustained activity up to only 3 months, so we think we should use sufficient dose of botulinum toxin which may cause weakness. Rehabilitation with injected muscles contractions is important soon after botulinum toxin treatment, because botulinum toxin has a specific affinity to cleave certain proteins involved in the mechanism of acetylcholine exocytosis. The new botuslinum toxins type A which decrease the risk of production of antibodies and diffusion of noninjected muscles are under development.
Koman, L Andrew; Paterson Smith, Beth; Balkrishnan, Rajesh
Botulinum A toxin produces selective and reversible chemodenervation that can be employed to balance muscle forces across joints in children with cerebral palsy (CP). Currently, there are two commercially available botulinum A toxin formulations (BOTOX) and Dysport). The amount of botulinum A toxin required depends upon the number of muscles that are targeted, and the size of the patient. In order to achieve adequate chemodenervation with botulinum A toxin, the following conditions must be met: (i) a sufficient number of units of toxin must be injected in order to neutralize neuromuscular junction (NMJ) activity; (ii) an appropriate drug volume is required in order to optimize the delivery of the toxin to the NMJs; and (iii) localization of the injecting needle through the fascia of the target muscle is necessary. Localization of the injection may be facilitated by active electromyography, ultrasonography, palpation of the muscle belly, and/or use of anatomic landmarks. Botulinum A toxin injections are indicated for use in pediatric patients with CP to: (i) improve motor function by balancing muscle forces across joints; (ii) improve health-related quality of life by decreasing spasticity and/or decreasing caregiver burden; (iii) decrease pain from spasticity; (iv) enhance self-esteem by diminishing inappropriate motor responses; and (v) provide a presurgical diagnostic tool. Following intramuscular injections of botulinum A toxin, short-term benefits of reduced spasticity are observed in approximately 70-82% of children. The intermediate term (1-2 years) efficacy rate is approximately 50%. The most common deformity treated with toxin injections in pediatric patients with CP is equinus foot deformity. However, efficacy of toxin injections for the management of crouched gait, pelvic flexion contracture, cervical spasticity, seating difficulties, and upper extremity deformity also has been documented. In addition, toxin injections have been shown to manage painful
Mabvuure, N T; Hallam, M-J; Venables, V; Nduka, C
Aims To validate a new photogrammetric technique for quantifying eye surface area and using this to quantify the degree of improvement in symmetry in patients with oral–ocular synkinesis following Botulinum toxin injection. Study design Feasibility study and retrospective outcomes analysis Methods Ten patients' photographs were chosen from a photographic database. Their eye surface areas were measured independently by two raters using a graphics tablet. One rater repeated the procedure after 15 days. Bland–Altman plots were computed, ascertaining inter-rater and intra-rater variability. The eye surface areas of 19 patients were then derived from photographs taken before and after Botulinum toxin injections. Paired t-tests were used to analyse the significance of the difference in pre- and post-treatment symmetry. Results Ninety per cent of eye surface areas derived from the two raters were within a coefficient of variation of 0.1 (95% CI: 0.05–0.15). Similarly, 90% of eye surface areas derived from one rater had a coefficient of variation of 0.08 (95% CI: 0.04–0.12). Botulinum toxin significantly reduced synkinesis resulting from lip puckering, Mona Lisa smiling and Hollywood smiling (P<0.05). Conclusions We have proposed a clinically valid tool for quantifying the effects of Botulinum toxin treatment for oral–ocular synkinesis. We recommend this method be used to monitor the response of such patients when receiving Botulinum toxin treatment. Level of evidence 2c. PMID:23680716
Mabvuure, N T; Hallam, M-J; Venables, V; Nduka, C
To validate a new photogrammetric technique for quantifying eye surface area and using this to quantify the degree of improvement in symmetry in patients with oral-ocular synkinesis following Botulinum toxin injection. Feasibility study and retrospective outcomes analysis Ten patients' photographs were chosen from a photographic database. Their eye surface areas were measured independently by two raters using a graphics tablet. One rater repeated the procedure after 15 days. Bland-Altman plots were computed, ascertaining inter-rater and intra-rater variability. The eye surface areas of 19 patients were then derived from photographs taken before and after Botulinum toxin injections. Paired t-tests were used to analyse the significance of the difference in pre- and post-treatment symmetry. Ninety per cent of eye surface areas derived from the two raters were within a coefficient of variation of 0.1 (95% CI: 0.05-0.15). Similarly, 90% of eye surface areas derived from one rater had a coefficient of variation of 0.08 (95% CI: 0.04-0.12). Botulinum toxin significantly reduced synkinesis resulting from lip puckering, Mona Lisa smiling and Hollywood smiling (P<0.05). We have proposed a clinically valid tool for quantifying the effects of Botulinum toxin treatment for oral-ocular synkinesis. We recommend this method be used to monitor the response of such patients when receiving Botulinum toxin treatment.
Chung, Myung Eun; Song, Dae Heon; Park, Joo Hyun
Units of available botulinum toxin preparations are not interchangeable, and the dose-conversion ratios between such preparations remain controversial. To compare the efficacy and safety of four botulinum toxin type A preparations. Murine gastrocnemius compound muscle action potentials (CMAPs) were recorded before and after injecting the four botulinum toxin preparations (onabotulinumtoxinA, abobotulinumtoxinA, new botulinum toxin, and incobotulinumtoxinA). In all preparations, CMAP amplitudes decreased until 4 days after receiving the injection and then gradually recovered. On postinjection day 84, the amplitudes returned to baseline in all groups except the high-dose groups. CMAP amplitude in the contralateral limb also decreased up to postinjection days 4 to 7 and then gradually returned to baseline by postinjection day 28. The dose-conversion ratio between onabotulinumtoxinA and abobotulinumtoxinA was determined to be 1:2.6; previous reports of 1:3 were considered too high. A dose-conversion ratio between onabotulinumtoxinA and new botulinum toxin of 1:1 was deemed appropriate. OnabotulinumtoxinA and incobotulinumtoxinA demonstrated a dose-conversion ratio of 1:1.07. The efficacy of incobotulinumtoxinA was slightly lower than that of onabotulinumtoxinA. These dose-conversion ratios are applicable solely from an efficacy standpoint and not for safety. This study was conducted in mice, so it may not translate perfectly to human applications. © 2012 by the American Society for Dermatologic Surgery, Inc. Published by Wiley Periodicals, Inc.
Khenioui, Hichem; Houvenagel, Eric; Catanzariti, Jean François; Guyot, Marc Alexandre; Agnani, Olivier; Donze, Cécile
Botulinum toxin is a proven and widely used treatment for numerous conditions characterized by excessive muscular contractions. Recent studies have assessed the analgesic effect of botulinum toxin in joint pain and started to unravel its mechanisms. We searched the international literature via the Medline database using the term "intraarticular botulinum toxin injection" combined with any of the following terms: "knee", "ankle", "shoulder", "osteoarthritis", "adhesive capsulitis of the shoulder". Of 16 selected articles about intraarticular botulinum toxin injections, 7 were randomized controlled trials done in patients with osteoarthritis, adhesive capsulitis of the shoulder, or chronic pain after joint replacement surgery. Proof of anti-nociceptive effects was obtained in some of these indications and the safety and tolerance profile was satisfactory. The studies are heterogeneous. The comparator was usually a glucocorticoid or a placebo; a single study used hyaluronic acid. Pain intensity was the primary outcome measure. The number of randomized trials and sample sizes are too small to provide a satisfactory level of scientific evidence or statistical power. Unanswered issues include the effective dosage and the optimal dilution and injection modalities of botulinum toxin. Copyright © 2015 Société française de rhumatologie. Published by Elsevier SAS. All rights reserved.
Gibson, Noula; Graham, H Kerr; Love, Sarah
Cerebral palsy comprises a heterogenous group of neurological disorders representing a continuum of pathologies and clinical phenotypes. Although cerebral palsy is not a focal disorder, it is appropriate to treat identified focal problems as long as the intervention is goal directed. This paper reviews principles of managing muscle imbalance in the growing, changing child using a range of complementary, carefully timed intervention options. Over the past two decades these options have increasingly included intramuscular injection of botulinum toxin-A to manage focal spasticity and dystonia. The predictable movement patterns and postures characteristic of spasticity enable a systematic clinical rationale to be developed to determine the role of botulinum toxin-A to manage the spasticity and subsequently improve function. The management of dystonia with botulinum toxin-A is more complex, particularly when spasticity and dystonia are present in combination. An active therapy programme remains central to the management of movement problems in the child with cerebral palsy, including task-specific motor training, maintenance of muscle lengths, and improved muscle strength, aiming to achieve carry over improvements that persist beyond the pharmacological effects of the botulinum toxin-A. A series of case examples are presented to highlight the role of botulinum toxin-A in the overall management of the child with focal muscle hyperactivity.
Oliveira, J B; Evêncio-Neto, J; Baratella-Evêncio, L
The treatment of sialorrhea is necessary for the constant risks posed by hypersalivation. A new therapeutic option comes up with the application of botulinum toxin in salivary glands. However, little is known about its mechanism of action in glandular tissue. Based on the above, this work had the objective to systematically review the literature about the action of botulinum toxin on submandibular and parotid salivary glands tissues. Electronic search was performed in databases of great relevance for this study (PubMed, SciELO, HighWire, Crossref, Scopus, Science Direct, MEDLINE, OLDMEDLINE, Serials Database, NLM Catalog, LILACS and IBECS). Inclusion and exclusion criteria for articles were established, and a total number of 14 articles were selected and used. There are few publications that clarify how the salivary gland acini behave with application of botulinum toxin. Although, the immunohistochemical findings were consistent among authors, showing weak immunoreactivity in glands treated with botulinum toxin. Histometric data are divergent, requiring more detailed studies to answer the questions about the efficacy and safety of botulinum toxin in salivary glands.
Deebaj, Richard; Emtestam, Lennart; Lundeberg, Lena; Brandin Samuelsson, Karin; Girnita, Ada
When debilitating, hyperhidrosis can be seen as a disease and not just as a symptom. It is most often a primary condition but can be secondary to other diseases. Aluminum chloride products are the initial treatment modality for palmar hyperhidrosis followed by anticholinergics, iontophoresis and botulinum toxin. The Dermatology Department of the Karolinska University Hospital in Stockholm, Sweden treated 151 patients at 289 visits with botulinum toxin for palmar hyperhidrosis during a two year period (2012-2013). It was found that botulinum toxin had good effect, which lasted between two and five months in 72% of cases. Muscle weakness (pincer grip) was reported at 41% of return visits and was present for less than one to four weeks in 62% of cases. At 56% of return visits, no side effects of botulinum toxin were reported. 90% of patients surveyed thought that botulinum toxin worked well or very well for their condition and 99% valued the treatment they received at the clinic as good to excellent.
Isner-Horobeti, Marie-Eve; Muff, Guillaume; Masat, Julien; Daussin, Jean-Luc; Dufour, Stephane P; Lecocq, Jehan
Functional popliteal artery entrapment syndrome is responsible for exercise-induced muscle leg pain. This syndrome is caused, in most of the cases, by the excessive size of the gastrocnemius muscles. Currently, its treatment is based only on surgery with variable results. We report the case of a young professional soldier in a combat unit with bilateral functional popliteal artery entrapment syndrome that was confirmed by dynamic arteriography, magnetic resonance angiography, and ultrasonography and did not improve after bilateral popliteal arteriolysis without resection of the gastrocnemius medial head. Treatment by injecting botulinum toxin in the proximal part of the gastrocnemius muscles was proposed and carried out. Regular follow-up (from 1 month to 3 yr after botulinum toxin treatment) showed the disappearance of exercise-induced pain and the improvement of the patient's physical and sports performance. Results of follow-up ultrasonography during dynamic maneuvers at 2.5 months and 2 yr after botulinum toxin injection were normal. Neither adverse effects nor motor deficit of the gastrocnemius muscles was reported. This case report suggests that botulinum toxin treatment could be an alternative to surgery for patients with functional popliteal artery entrapment syndrome. Botulinum toxin could reduce functional compression and, consequently, exercise-induced pain by decreasing the volume of the gastrocnemius muscle.
Mücke, Thomas; Löffel, Anja; Kanatas, Anastasios; Karnezi, Sandy; Rana, Majeed; Fichter, Andreas; Haarmann, Stephan; Wolff, Klaus-Dietrich; Loeffelbein, Denys John
The etiology of deep bite is multifactorial. One of the causes is increased muscular activity. This makes the treatment of deep bite malocclusions difficult and often results in relapse in many cases. In this work we compared patients with surgical orthognathic treatment only and surgical orthognathic treatment with additional injections of botulinum toxin after mandibular advancement for class II division 2 malocclusion. This is a prospective study. Adult patients were assessed pretreatment (T1), posttreatment (T2), and long-term after 1 year (T3). In total, 32 patients (mean age, 30.7 years; 23 women and 9 men) reached the study end point (T3); 24 patients were treated without botulinum toxin and 8 patients received preoperative injections of botulinum toxin. Significant differences between both groups were observed, with a more stable result for the experimental group treated with botulinum toxin. In a selective group of adult patients with a class II division II incisor relationship and with a class II skeletal base, botulinum toxin injections can effectively prevent relapse. This may present an alternative to a conventional myotomy. Copyright © 2016 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
Yamaguchi, Daisuke; Tsuruoka, Nanae; Sakata, Yasuhisa; Shimoda, Ryo; Fujimoto, Kazuma; Iwakiri, Ryuichi
Botulinum toxin injection is an accepted treatment modality for esophageal achalasia in western countries. This pilot study aimed to clarify the effectiveness of botulinum toxin injection for esophageal achalasia in Japanese patients. We enrolled 10 patients diagnosed with esophageal achalasia between 2008 and 2014. A total of 100 U botulinum toxin A was divided into eight aliquots and injected around the esophagogastric junction. We compared the lower esophageal sphincter pressure before and 1 week after treatment. Scores of subjective symptoms for esophageal achalasia were assessed using a visual analog scale (VAS) before and after 1 week of follow-up of treatment. Barium passage was improved in barium esophagography and passage of contrast agent was also improved. Mean Eckardt score was reduced from 5.5 to 1.6 after treatment (p<0.001). By esophageal manometric study, mean lower esophageal sphincter pressure was reduced from 46.9 to 29.1 mmHg after treatment (p = 0.002). One week after treatment, mean VAS score was reduced from 10 to 3.9 (p<0.001). There were no side effects in any cases. Botulinum toxin injection for esophageal achalasia was safe and effective with few complications. Therefore, botulinum toxin could be used as minimally invasive therapy for esophageal achalasia in Japan.
Kim, Sena; Ahn, Moonsang; Piao, Yibo; Ha, Yooseok; Choi, Dae-Kyoung; Yi, Min-Hee; Shin, Nara; Kim, Dong Woon; Oh, Sang-Ha
One of the most serious complications of breast surgery using implants is capsular contracture. Several preventive treatments have been introduced; however, the mechanism of capsule formation has not been resolved completely. The authors previously identified negative effects of botulinum toxin type A on capsule formation, expression of transforming growth factor (TGF)-β1, and differentiation of fibroblasts into myofibroblasts. Thus, the authors investigated how to prevent capsule formation by using botulinum toxin type A, particularly by means of TGF-β1 signaling, in human fibroblasts. In vitro, cultured human fibroblasts were treated with TGF-β1 and/or botulinum toxin type A. Expression of collagen, matrix metalloproteinase, and Smad was examined by Western blotting. The activation of matrix metalloproteinase was observed by gelatin zymography. In vivo, the effect of botulinum toxin type A on the phosphorylation of Smad2 in silicone-induced capsule formation was evaluated by immunocytochemistry. In vitro, the phosphorylation of Smad2 was inhibited by botulinum toxin type A treatment. The expression levels of collagen types 1 and 3 were inhibited by botulinum toxin type A treatment, whereas those of matrix metalloproteinase-2 and matrix metalloproteinase-9 were enhanced. Gelatin zymography experiments confirmed enhanced matrix metalloproteinase-2 activity in collagen degradation. In vivo, botulinum toxin type A treatment reduced capsule thickness and Smad2 phosphorylation in silicone-induced capsules. This study suggests that botulinum toxin type A plays an important role in the inhibition of capsule formation through the TGF-β/Smad signaling pathway. Therapeutic, V.
Williamson, J.L.; Rocke, T.E.; Aiken, Judd M.
A nested PCR was developed for detection of the Clostridium botulinum type C1 toxin gene in sediments collected from wetlands where avian botulism outbreaks had or had not occurred. The C1 toxin gene was detected in 16 of 18 sites, demonstrating both the ubiquitous distribution of C. botulinum type C in wetland sediments and the sensitivity of the detection assay.
Ghasemi, Majid; Norouzi, Rasul; Salari, Mehri; Asadi, Bahador
Local injection of botulinum toxin-A is an accepted treatment for hyperhidrosis. We report 2 cases of primary hyperhidrosis who developed iatrogenic botulism after the therapeutic dose of onabotulinumtoxinA (Botox). This case report highlights the necessity of clinicians having sufficient information of potentially adverse effects, optimal dose, and correct preparation and injection of botulinum toxin-A.
Williamson, Judy L.; Rocke, Tonie E.; Aiken, Judd M.
A nested PCR was developed for detection of the Clostridium botulinum type C1 toxin gene in sediments collected from wetlands where avian botulism outbreaks had or had not occurred. The C1 toxin gene was detected in 16 of 18 sites, demonstrating both the ubiquitous distribution of C. botulinum type C in wetland sediments and the sensitivity of the detection assay. PMID:10388729
Barash, Jason R.; Arnon, Stephen S.
A retrospective study of Clostridium botulinum strains isolated from patients from California with infant botulism identified the fourth known C. botulinum strain that produces both type B and type F botulinum toxins. This unique strain represented 0.12% of the California infant botulism case isolates from 1976 to 2003. The relative concentrations of type B and F toxins produced were temperature dependent. PMID:15071029
Dayan, Steven H; Lieberman, Elliot D; Thakkar, Nirav N; Larimer, Karen A; Anstead, Amy
BACKGROUND First impression is influenced by facial appearance and improved by cosmetic surgery. OBJECTIVE We wanted to determine if treatment with botulinum toxin A (BTxnA) would improve first impression. MATERIALS AND METHODS Women received BTxnA in the forehead. Photos were taken prior to, and 1 week after, final BTxnA injection in smiling and relaxed poses. Photos were divided into books with each subject represented only once. Evaluators completed a survey rating first impression on various measures of success for each photo. RESULTS No differences were seen for social skills, financial, or relationship success scales. A significant decrease in first impression scores between treatment photos was seen for academic performance and occupational success. However, analysis of between-subject effects found that "smile/relax" accounted for the decreased score in both scales. Significant increases in first impression scores were seen for dating success, attractiveness, and athletic success scales where smile/relax and BTxnA contributed significantly to the improved scores. CONCLUSIONS BTxnA improved first impression scores for dating success, attractiveness, and athletic success scales. Academic performance and occupational success scores were not affected by BTxnA when the smile/relax variable was included. The smile/relax variable was a more important predictor for academic performance and occupational success scores.
Camargo, Carlos Henrique Ferreira; Cattai, Lígia; Teive, Hélio Afonso Ghizoni
Dystonia is a neurological disorder characterized by intermittent or sustained muscle contractions that cause abnormal, usually repetitive, movements and postures. Dystonic movements can be tremulous and twisting and often follow a pattern. They are frequently associated with overflow muscle activation and may be triggered or worsened by voluntary action. Most voluntary muscles can be affected and, in the case of the neck muscles, the condition is referred to as cervical dystonia (CD), the most common form of dystonia. The high incidence of pain distinguishes CD from other focal dystonias and contributes significantly to patient disability and low quality of life. Different degrees of pain in the cervical region are reported by more than 60% of patients, and pain intensity is directly related to disease severity. Botulinum toxin (BoNT) is currently considered the treatment of choice for CD and can lead to an improvement in pain and dystonic symptoms in up to 90% of patients. The results for BoNT/A and BoNT/B are similar. The complex relationship between pain and dystonia has resulted in a large number of studies and more comprehensive assessments of dystonic patients. When planning the application of BoNT, pain should be a key factor in the choice of muscles and doses. In conclusion, BoNT is highly effective in controlling pain, and its analgesic effect is sustained for a long time in most CD patients. PMID:26110508
Bayrak, Ömer; Sadioğlu, Erkan; Onur, Rahmi
Neurogenic detrusor overactivity (NDO) is a disorder that can cause high intravesical pressure, decreased capacity, decreased bladder compliance, and upper urinary system damage. The current treatment options for NDO are established on the basis of agents that block parasympathetic innervation of the detrusor and inhibit involuntary bladder contractions. Several side effects, such as dryness of mouth, constipation, dyspepsia, changes in visual accommodation, somnolence, and being unable to obtain consistently favorable results, caused by anticholinergic agents, which are frequently used for this purpose, decrease the patient’s compliance to treatment. Procedures such as neuromodulation, auto-augmentation, and enterocystoplasty are surgical options, and they could be used as the last alternative. Thus, botulinum toxin (BTX) injections to the detrusor have been commonly performed in recent years and lead to satisfactory results. The mechanism of action of BTX in NDO is based on the principal of smooth muscle relaxation in the bladder by the transient inhibition of neuromuscular nerve signals. The aim is to decrease acetylcholine secretion by blocking presynaptic vesicles in the neuromuscular junction. When studies were evaluated, it was observed that BTX injections to the detrusor muscle are a necessary and effective option in patients with incontinence caused by NDO. This treatment option could be indicated in situations where anticholinergic agents are not effective or could not be tolerated, and it could be a valuable alternative to major surgical treatments. In this review, we evaluated the effectiveness and reliability of BTX in patients with NDO. PMID:26623152
Park, JungHyun; Park, Hue Jung
Botulinum toxin (BoNT) has been used as a treatment for excessive muscle stiffness, spasticity, and dystonia. BoNT for approximately 40 years, and has recently been used to treat various types of neuropathic pain. The mechanism by which BoNT acts on neuropathic pain involves inhibiting the release of inflammatory mediators and peripheral neurotransmitters from sensory nerves. Recent journals have demonstrated that BoNT is effective for neuropathic pain, such as postherpetic neuralgia, trigeminal neuralgia, and peripheral neuralgia. The purpose of this review is to summarize the experimental and clinical evidence of the mechanism by which BoNT acts on various types of neuropathic pain and describe why BoNT can be applied as treatment. The PubMed database was searched from 1988 to May 2017. Recent studies have demonstrated that BoNT injections are effective treatments for post-herpetic neuralgia, diabetic neuropathy, trigeminal neuralgia, and intractable neuropathic pain, such as poststroke pain and spinal cord injury.
In rehabilitation medicine, botulinum toxin (BTX) as adjunct to other interventions for spasticity can result in a useful and effective therapeutic tool treating disabled stroke patients with spasticity. Other than spasticity, non-reflex motor disorders (muscle stiffness, shortness and contracture) can complicate clinical course and hamper rehabilitative process of stroke patients. After treating spasticity by BTX, the paralysis might be improved by changing muscular imbalance following stroke. We also have to face unique and difficult to treat clinical conditions abnormal posture and movement disorders due to chronic severe stroke patients. The effectiveness of BTX in treating some of these conditions is also provided. Since, neurologically disabled stroke patients can show complex dysfunction, prior to initiating BTX therapy, specific functional limitations, goals and expected outcomes of treatment should be evaluated and discussed with family and caregivers. BTX also might improve not only care, passive function, but also improve active function in stroke patients with intensive rehabilitation with rTMS, tDC, electrical stimulation, stretching and other rehabilitation strategy. Therefore BTX might change rehabilitation medicine.
Iversen, Helle K.; Frederiksen, Inge M.S.; Vilhelmsen, Jeanet R.; Biering-Sørensen, Fin
The aim of this study is to develop a treatment diary for patients receiving spasticity treatment including botulinum toxin injection and physiotherapy and/or occupational therapy. The diary focuses on problems triggered by skeletal muscle overactivity; agreed goals for treatment and the patient’s self-evaluation of achievement on the Goal Attainment Scale; which skeletal muscles were injected; physiotherapists’ and occupational therapists’ evaluation of the patients’ achievement of objectives on the Goal Attainment Scale; and proposals for optimization of treatment and changing goals. The evaluation included a satisfaction questionnaire and the WHO-QoL BREF and WHO-5 well-being score. Overall, 10 patients were enrolled in the pilot study. The patients were generally satisfied with the diary, found that it involved them more in their treatment and made it easier to set personal goals, and found it worth the time spent using it. However, no clear advantage in relation to their quality of life (WHO-QoL BREF and WHO-5 well-being score) was reported. PMID:28225535
Pirali, Caterina; Santus, Gianna; Faletti, Sofia; De Grandis, Domenico
Slipping rib syndrome (SRS) is a musculoskeletal cause of severe and recurrent thoracic or abdominal pain. The etiology of SRS is unknown, it seems to arise from costal hypermobility with a tendency of one of the ribs (usually from 8th to 10th but also 11th and 12th have been described) to slip under the superior adjacent rib. Its prevalence is underestimated because SRS is mainly a clinical diagnosis, frequently missed. The critical aspect of the diagnosis is knowledge of the condition itself, which, when lacking, often results in the patient being referred to many different specialists and exposed to unnecessary and costly investigations. The management of the condition includes conservative techniques such as manipulation, localized anesthetic, and steroid or anesthetic nerve block. However, where conservative therapy fails, surgical treatment, with excision of the rib, may be performed. In this paper we describe the case of a patient with persistent and debilitating flank pain who, after many investigations, was diagnosed with SRS. The usual conservative treatment failed, after which we treated the patient with injections of incobotulinumtoxin A into muscles inserting on the inferior side of the rib cage (quadratus lumborum muscle, muscle transversus abdomini, abdominal external oblique muscle, and recto abdomini) achieving a complete relief from pain. To our knowledge botulinum toxin has never been proposed before for the treatment of SRS. We believe that it should be considered as a therapeutic option, especially where other medical treatments have failed or as an intermediate step before surgical intervention.
Cantarella, Giovanna; Berlusconi, Alessandra; Maraschi, Barbara; Ghio, Alain; Barbieri, Sergio
The aim of this study was to analyze the effects of botulinum toxin (BT) injection on airflow stability, by measuring mean phonatory oral airflow and its coefficient of variation (CV), in subjects with adductor spasmodic dysphonia (SD). Twenty-four subjects with SD (aged 31-78 years) and 23 controls (aged 29-63 years) were evaluated for mean airflow and its CV during sustained phonation. Fifteen of the subjects with SD were also evaluated within 3 weeks after BT injection. BT increased airflow in subjects (P = 0.0130) but neither the preinjection nor postinjection values differed significantly from those of controls. Conversely, airflow CV was invariably higher in subjects than in controls (P < 0.0001). In 13 subjects in whom phonation perceptually improved, including 3 in whom airflow did not increase, airflow CV decreased significantly after BT treatment (P = 0.0232). Subjects with SD have highly unstable phonatory airflow; its CV is a valid measure for assessing the outcome of a BT injection. A reduced airflow CV probably does not depend solely on increased airflow due to thyroarytenoid muscle paresis, and may indicate a change in laryngeal motoneuronal activity. B-3b.
Shan, Xiao-Feng; Xu, Hui; Cai, Zhi-Gang; Wu, Li-Ling; Yu, Guang-Yan
Botulinum toxin A (BTXA) has been used in several clinical trials to treat excessive glandular secretion; however, the precise mechanism of its action on the secretory function of salivary gland has not been fully elucidated. In this study, we aimed to investigate the effect of BTXA on secretion of submandibular gland in rabbits and to identify its mechanism of action on the secretory function of salivary gland. At 12 weeks after injection with 5 units of BTXA, we found a significant decrease in the saliva flow from submandibular glands, while the salivary amylase concentration increased. Morphological analysis revealed reduction in the size of acinar cells with intracellular accumulation of secretory granules that coalesced to form a large ovoid structure. Expression of M3-muscarinic acetylcholine receptor (M3 receptor) and aquaporin-5 (AQP5) mRNA decreased after BTXA treatment, and distribution of AQP5 in the apical membrane was reduced at 1, 2 and 4 weeks after BTXA injection. Furthermore, BTXA injection was found to induce apoptosis of acini. These results indicate that BTXA decreases the fluid secretion of submandibular glands and increases the concentration of amylase in saliva. Decreased expression of M3 receptor and AQP5, inhibition of AQP5 translocation, and cell apoptosis might involve in BTXA-reduced fluid secretion of submandibular glands. PMID:24158141
Chronic anal fissure is a common proctologic disease. Botulinum toxin (BTX) can be used for temporary chemical denervation to treat this painful disorder. Its application is by intramuscular injections into either the external or internal anal sphincter muscle. The mode of action, application techniques, and possible complications or adverse effects of BTX therapy are discussed in this report. The healing rate is dependent on the BTX dosage. The short-term healing rate (≤ 6 months) is 60–90%, whereas about 50% of the patients show a complete response in long-term follow-up studies (> 1 year). Adverse effects are generally mild, but relapses occur more often than with surgery. Conservative therapy is currently considered as a first-line treatment. With increasing evidence for its efficacy, BTX can now be considered among the first-line nonsurgical treatements. Although, surgical management by lateral sphincterotomy is the most effective treatment, it shows a higher incidence of incontinence and greater general morbidity rate than BTX. BTX is a useful alternative to surgery and in many cases, surgery can be avoided with the use of BTX. PMID:20300345
Chronic anal fissure is a common proctologic disease. Botulinum toxin (BTX) can be used for temporary chemical denervation to treat this painful disorder. Its application is by intramuscular injections into either the external or internal anal sphincter muscle. The mode of action, application techniques, and possible complications or adverse effects of BTX therapy are discussed in this report. The healing rate is dependent on the BTX dosage. The short-term healing rate (= 6 months) is 60-90%, whereas about 50% of the patients show a complete response in long-term follow-up studies (> 1 year). Adverse effects are generally mild, but relapses occur more often than with surgery. Conservative therapy is currently considered as a first-line treatment. With increasing evidence for its efficacy, BTX can now be considered among the first-line nonsurgical treatements. Although, surgical management by lateral sphincterotomy is the most effective treatment, it shows a higher incidence of incontinence and greater general morbidity rate than BTX. BTX is a useful alternative to surgery and in many cases, surgery can be avoided with the use of BTX.
Wollina, U; Konrad, H
Anal fissures are common and painful. Botulinum toxin A (BTXA) is considered to be the most potent non-surgical treatment; however, no attention has been paid to associated hyperhidrosis. To compare traditional BTXA treatment of muscular spasticity in anal fissures with combined treatment of spasticity and focal hyperhidrosis of the anal fold and perianal skin. Outpatient department of a dermatological hospital. Ten patients with chronic anal fissures (of more than 6 months duration who failed to respond to conservative treatment and who had refused surgery) associated with focal hyperhidrosis as assessed by Minor's sweat test were investigated in an open, two-armed trial. Intramuscular injections of 20-25 U BTXA (Botox) were performed in group A (n = 5). In group B (n = 5) those injections were combined with intracutaneous injection of 30-50 U BTXA to treat focal hyperhidrosis. Mean follow-up was 5 months. Five of five patients in group B but only two of five patients in group A experienced a complete remission despite the fact that relief of pain was evident in eight of 10 patients within 2 weeks. Patient satisfaction with treatment was high but slightly better in group B. This open trial suggests that combined therapy of both muscular spasticity and focal hyperhidrosis may provide better results than intramuscular injections alone in anal fissure therapy with BTXA.
Xia, Jian-Hua; He, Cai-Hong; Zhang, Hai-Feng; Lian, Ya-Jun; Chen, Yuan; Wu, Chuan-Jie; Ma, Yun-Qing
The aims of this study were to investigate the clinical effects and safety of botulinum toxin A (BTX-A) in treating trigeminal neuralgia and its influences on accompanied depression, anxiety, sleep disorders, and quality of life. Eighty-seven patients with one-branch classical trigeminal neuralgia were injected with BTX-A in the pain area. The visual analogic scale score, sleep interference score, Hamilton Anxiety Scale score, Hamilton Depression Scale score, and side effects were assessed at 1 week prior to and 8 weeks after treatment, respectively. The effective rates after 1, 2, 4, and 8 weeks of treatment were 48.28%, 66.67%, 78.16%, and 80.46%, respectively. The effective rates of anxiety and depression were 90.32% and 96.77%, respectively. When compared to that before treatment, the quality of life was significantly better in terms of role-physical, bodily pain, general health, vitality, social functioning, role-emotional, and mental health (all P < 0.01), while physical function was not significantly improved (P = 0.317). BTX-A treatment can significantly relieve the pain in trigeminal neuralgia patients; improve anxiety, depression, and sleep; and increase the quality of life. BTX-A treatment is a safe and effective method to treat classical trigeminal neuralgia.
Cabin, Jonathan A; Massry, Guy G; Azizzadeh, Babak
Complete flaccid facial paralysis, as well as the synkinetic and hyperkinetic sequelae of partial recovery, has significant impact on quality of life. Patients suffer from functional deficiencies, cosmetic deformity, discomfort and social consequences leading to emotional distress. Despite an extensive and sophisticated array of available interventions for facial reanimation, most patients have persistent issues that require consistent follow-up. In long-term management, botulinum toxin (BT) injection remains a critical tool in the treatment of the facial paralysis patient, particularly in the case of synkinesis, hyperkinesis and imbalance. We review the recent scientific literature and highlight key principles and developments in the use of BT in the management of facial paralysis, including less common applications for acute facial paralysis, hyperlacrimation and pseudoptosis. We reviewed the literature for the latest advances in the use of BT in facial paralysis, including applications and technique, as well as measurement tools and adjunct exercises. We also share our experience in treating our own patient population. BT continues to be a well tolerated and effective tool in the long-term management of facial paralysis, specifically in treating synkinesis, imbalance and hyperkinesis, as well as hyperlacrimation and pseudoptosis. Consistent measurement tools and adjunct neuromuscular retraining are crucial in the successful deployment of BT. Controversy exists as to whether BT should be used to manage facial paralysis during the acute phase, and whether BT application to the nonparalyzed face can improve long-term recovery in the paralyzed side.
Trosch, R M; Pullman, S L
We conducted an open-label study to determine the utility of treating severe hand tremors with intramuscular injections of botulinum toxin (BTX) in forearm and arm muscles in 26 patients, 12 with Parkinson's disease (PD) and 14 with essential tremor (ET). The effect after 6 weeks for each patient was evaluated using two clinical rating scales, subjective evaluations of functional improvement and global disability, measures of weakness, and computer-assisted quantitative assessments of tremor. Although none of the clinical scores averaged > 3/4 point change, statistical significance was found on comparison of pre- and postinjection scores in the Webster Tremor and Global Disability Scales in the ET patients. Similarly, although average tremor amplitudes decreased by no more than 25% by quantitative analysis, amplitude decrease significantly correlated with patient subjective assessment in ET. In only two of 12 PD (17%) and three of 14 ET patients (21%) were major quantitative changes in tremor amplitude (> 50% reduction) found after BTX injections. Nevertheless, 10 patients (38%; five PD and five ET) reported moderate to marked subjective improvement in functional benefit after BTX. These findings suggest that although there were no major changes in clinical ratings or objective measurements, BTX injections may subjectively improve tremor in some patients, particularly those with ET.
Miyata, Keita; Suzuki, Tomonori; Hayashi, Shintaro; Miyashita, Shin-Ichiro; Ohyama, Tohru; Niwa, Koichi; Watanabe, Toshihiro; Sagane, Yoshimasa
Clostridium botulinum strains produce a large-sized toxin complex (TC) that is composed of botulinum neurotoxin (BoNT), non-toxic non-hemagglutinin and three different hemagglutinins (HA-70, HA-33 and HA-17). HA components enhance toxin delivery across the intestinal cell wall in a sugar chain-dependent manner. Here we characterized the sugar recognition of serotype D strain 1873 (D-1873) botulinum L-TC. Most L-TCs produced by serotype C and D strains bind to cells via interactions between HA-33 and cell surface sialo-oligosaccharides. However, like the previously reported L-TC produced by serotype C strain Yoichi (C-Yoichi), D-1873 L-TC binds only to cells that have been treated with neuraminidase, indicating that they recognize asialo-oligosaccharides. The D-1873 HA-33 amino acid sequence is similar to that of C-Yoichi, but had lower similarity to the majority of serotype C and D HA-33s. A comparison of TC component primary structures for 12 serotype C and D strains suggested that at least three types of HA-33 genes exist, and these are shuffled among the serotype C and D strains independently of BoNT serotype. This shuffling produces the distinct sugar recognition of serotype C and D botulinum TCs. © FEMS 2015. All rights reserved. For permissions, please e-mail: firstname.lastname@example.org.
Oguma, Keiji; Yamamoto, Yumiko; Suzuki, Tomonori; Fatmawati, Ni Nengah Dwi; Fujita, Kumiko
Clostridium botulinum produces seven immunological distinct poisonous neurotoxins, A to G, with molecular masses of approximately 150kDa. In acidic foods and culture fluid, the neurotoxins associate with non-toxic components, and form large complexes designated progenitor toxins. The progenitor toxins are found in three forms named LL, L, and M. These neurotoxins and progenitor toxins were purified, and whole nucleotide sequences of their structure genes were determined. In this manuscript, the structure and function of these toxins, and the application of these toxins to clinical usage have been described.
Lee, Jae-Bong; Kim, Byung-Soo; Kim, Moon-Bum; Oh, Chang-Keun; Jang, Ho-Sun; Kwon, Kyung-Sool
Genital odor is an uncommon condition characterized by an offensive and malodorous smell in the genital area. Although the etiology of foul genital odor is multifactorial, an important cause is sweat secretion and decomposition of sweat components by bacteria. Different methods are effective in reducing body odor secondary to bromhidrosis. Conservative methods only act for a short period of time, and more invasive surgical methods carry risk of complications or are inapplicable for the genital region. A patient with localized foul odor in the genital hair bearing area was treated with botulinum toxin A. Botulinum toxin A was effective in creating an odorless and anhydrous response in the genital region, and no major adverse effects were noted during a follow-up of 9 months after injection. Local injection of botulinum toxin A appears to be a useful treatment for foul genital odor related to sweat glands activity.
Trzciński, Radzisław; Dziki, Adam; Tchórzewski, Marcin
To find out how injections of botulinum A toxin influence the healing of anal fissures. Retrospective study. Medical University of Lodz, Poland. 13 patients (6 women, 7 men), mean age 49 (range 31-78), treated with injections of botulinum A toxin 50 units on either side of the anal fissure into the internal anal sphincter from May to December 1999. Complications and relapse. Seven fissures had healed by one month and four by two months. Two remained unhealed but asymptomatic. There was no incontinence of flatus or faeces after three months of treatment. Resting anal pressure was significantly lower in 10 of 13 patients compared with before treatment (p < 0.05). One fissure relapsed after 4 months and this patient had a successful anal stretch. Injection of botulinum A toxin gives good results in the treatment of anal fissures.
Junghans, Katharina; Rohrbach, Saskia; Ellies, Maik; Laskawi, Rainer
Background Facial pain syndromes can be very heterogeneous and need individual diagnosis and treatment. This report describes an interesting case of facial pain associated with eczema and an isolated dyskinesia of the lower facial muscles following dental surgery. Different aspects of the pain, spasms and the eczema will be discussed. Case presentation In this patient, persistent intense pain arose in the lower part of her face following a dental operation. The patient also exhibited dyskinesia of her caudal mimic musculature that was triggered by specific movements. Several attempts at therapy had been unsuccessful. We performed local injections of botulinum toxin type A (BTX-A) into the affected region of the patient's face. Pain relief was immediate following each set of botulinum toxin injections. The follow up time amounts 62 weeks. Conclusion Botulinum toxin type A (BTX-A) can be a safe and effective therapy for certain forms of facial pain syndromes. PMID:17714591
Simpson, Lance L.; Morimoto, Hiromi
An attempt has been made to replicate an earlier finding that type A botulinum toxin can inhibit the in vitro activity of acetylcholinesterase. Two methods of enzyme assay were employed, but with neither technique were we able to reproduce the finding of in vitro enzyme inhibition. In fact, an examination of the data from the previous report leads us to question the possibility of the observations that were given. Furthermore, an investigation was carried out to determine if botulinum toxin can exert an inhibiting effect on acetylcholinesterase that is situated in the biological tissue. The answer again is negative. The experimental observations, coupled with several mathematical computations, do not support the notion that botulinum toxin is an acetylcholinesterase inhibitor. PMID:5773011
Zoons, E; Dijkgraaf, M G W; Dijk, J M; van Schaik, I N; Tijssen, M A
Focal dystonia is a common, invalidating neurologic condition characterized by involuntary, sustained muscle contractions causing twisting movements and abnormal postures in one body part. Currently, botulinum toxin is the treatment of first choice. We performed a systematic review towards the pharmaco-therapeutic and pharmaco-economic value of botulinum toxin as treatment for focal dystonia, which yielded the following results. Botulinum toxin is the most effective treatment for reducing dystonic symptoms measured with dystonia-specific and general questionnaires, and pain in patients with focal dystonia. Seventy-one percent of patients with cervical dystonia had a reduction in neck pain compared to 12 % in placebo groups. Adverse events occur in 58 % of patients during treatment with botulinum toxin compared to 46 % treated with placebo. Especially dry mouth, neck weakness, dysphagia, and voice changes are common. Adverse events are usually mild and self-limiting. Health-related quality of life, measured with the SF-36 is 20-50 points lower in patients with focal dystonia compared to controls and the effect of botulinum toxin on health-related quality of life is unclear. Botulinum toxin treatment is expensive because the drug itself is expensive. Yearly costs for treating a patient with focal dystonia with botulinum toxin range from EUR 347 to EUR 3,633 and the gain in QALYs with BTX treatment is small. Focal dystonia impairs the productivity and the ability to work. At start of botulinum toxin treatment only 47-50 % was working. Botulinum toxin partly improves this. Overall, we conclude that botulinum toxin is an expensive drug with good effects. From a societal perspective, the costs may well weigh up to the regained quality of life. However, the available literature concerning costs, health-related quality of life and labor participation is very limited. An extensive cost-effectiveness study should be performed incorporating all these aspects.
Waseem, Zeeshan; Boulias, Chris; Gordon, Allan; Ismail, Farooq; Sheean, Geoffrey; Furlan, Andrea D
Adequate relief from low-back pain (LBP) is not always possible. Emerging evidence suggests a role for botulinum neurotoxin (BoNT) injections in treating pain disorders. Proponents of BoNT suggest its properties can decrease muscle spasms, ischemia and inflammatory markers, thereby reducing pain. To determine the effects of botulinum toxin injections in adults with LBP. We searched CENTRAL (The Cochrane Library 2009, issue 3) and MEDLINE, EMBASE, and CINAHL to August 2009; screened references from included studies; consulted with content experts and Allergan. We included published and unpublished randomised controlled trials without language restrictions We included randomised trials that evaluated BoNT serotypes versus other treatments in patients with non-specific LBP of any duration. Two review authors selected the studies, assessed the risk of bias using the Cochrane Back Review Group criteria, and extracted the data using standardized forms. We performed a qualitative analysis due to lack of data. We excluded evidence from nineteen studies due to non-randomisation, incomplete or unpublished data. We included three randomised trials (N =123 patients). Only one study included patients with chronic non-specific LBP; the other two examined unique subpopulations. Only one of the three trials had a low risk of bias and demonstrated that BoNT injections reduced pain at three and eight weeks and improved function at eight weeks better than saline injections. The second trial showed that BoNT injections were better than injections of corticosteroid plus lidocaine or placebo in patients with sciatica attributed to piriformis syndrome. The third trial concluded that BoNT injections were better than traditional acupuncture in patients with third lumbar transverse process syndrome. Both studies with high risk of bias had several key limitations. Heterogeneity of the studies prevented meta-analysis. There is low quality evidence that BoNT injections improved pain, function
Dover, Nir; Barash, Jason R.; Burke, Julianne N.; Hill, Karen K.; Detter, John C.; Arnon, Stephen S.
Botulinum neurotoxin (BoNT) is the most poisonous substances known and its eight toxin types (A to H) are distinguished by the inability of polyclonal antibodies that neutralize one toxin type to neutralize any of the other seven toxin types. Infant botulism, an intestinal toxemia orphan disease, is the most common form of human botulism in the United States. It results from swallowed spores of Clostridium botulinum (or rarely, neurotoxigenic Clostridium butyricum or Clostridium baratii) that germinate and temporarily colonize the lumen of the large intestine, where, as vegetative cells, they produce botulinum toxin. Botulinum neurotoxin is encoded by the bont gene that is part of a toxin gene cluster that includes several accessory genes. In this paper, we sequenced for the first time the complete botulinum neurotoxin gene cluster of nonproteolytic C. baratii type F7. Like the type E and the nonproteolytic type F6 botulinum toxin gene clusters, the C. baratii type F7 had an orfX toxin gene cluster that lacked the regulatory botR gene which is found in proteolytic C. botulinum strains and codes for an alternative σ factor. In the absence of botR, we identified a putative alternative regulatory gene located upstream of the C. baratii type F7 toxin gene cluster. This putative regulatory gene codes for a predicted σ factor that contains DNA-binding-domain homologues to the DNA-binding domains both of BotR and of other members of the TcdR-related group 5 of the σ70 family that are involved in the regulation of toxin gene expression in clostridia. We showed that this TcdR-related protein in association with RNA polymerase core enzyme specifically binds to the C. baratii type F7 botulinum toxin gene cluster promoters. Finally, this TcdR-related protein may therefore be involved in regulating the expression of the genes of the botulinum toxin gene cluster in neurotoxigenic C. baratii.
Dover, Nir; Barash, Jason R.; Burke, Julianne N.; Hill, Karen K.; Detter, John C.; Arnon, Stephen S.
Botulinum neurotoxin (BoNT) is the most poisonous substances known and its eight toxin types (A to H) are distinguished by the inability of polyclonal antibodies that neutralize one toxin type to neutralize any of the other seven toxin types. Infant botulism, an intestinal toxemia orphan disease, is the most common form of human botulism in the United States. It results from swallowed spores of Clostridium botulinum (or rarely, neurotoxigenic Clostridium butyricum or Clostridium baratii) that germinate and temporarily colonize the lumen of the large intestine, where, as vegetative cells, they produce botulinum toxin. Botulinum neurotoxin is encoded by the bont gene that is part of a toxin gene cluster that includes several accessory genes. We sequenced for the first time the complete botulinum neurotoxin gene cluster of nonproteolytic C. baratii type F7. Like the type E and the nonproteolytic type F6 botulinum toxin gene clusters, the C. baratii type F7 had an orfX toxin gene cluster that lacked the regulatory botR gene which is found in proteolytic C. botulinum strains and codes for an alternative σ factor. In the absence of botR, we identified a putative alternative regulatory gene located upstream of the C. baratii type F7 toxin gene cluster. This putative regulatory gene codes for a predicted σ factor that contains DNA-binding-domain homologues to the DNA-binding domains both of BotR and of other members of the TcdR-related group 5 of the σ70 family that are involved in the regulation of toxin gene expression in clostridia. We showed that this TcdR-related protein in association with RNA polymerase core enzyme specifically binds to the C. baratii type F7 botulinum toxin gene cluster promoters. This TcdR-related protein may therefore be involved in regulating the expression of the genes of the botulinum toxin gene cluster in neurotoxigenic C. baratii. PMID:24853378
Dover, Nir; Barash, Jason R; Burke, Julianne N; Hill, Karen K; Detter, John C; Arnon, Stephen S
Botulinum neurotoxin (BoNT) is the most poisonous substances known and its eight toxin types (A to H) are distinguished by the inability of polyclonal antibodies that neutralize one toxin type to neutralize any of the other seven toxin types. Infant botulism, an intestinal toxemia orphan disease, is the most common form of human botulism in the United States. It results from swallowed spores of Clostridium botulinum (or rarely, neurotoxigenic Clostridium butyricum or Clostridium baratii) that germinate and temporarily colonize the lumen of the large intestine, where, as vegetative cells, they produce botulinum toxin. Botulinum neurotoxin is encoded by the bont gene that is part of a toxin gene cluster that includes several accessory genes. We sequenced for the first time the complete botulinum neurotoxin gene cluster of nonproteolytic C. baratii type F7. Like the type E and the nonproteolytic type F6 botulinum toxin gene clusters, the C. baratii type F7 had an orfX toxin gene cluster that lacked the regulatory botR gene which is found in proteolytic C. botulinum strains and codes for an alternative σ factor. In the absence of botR, we identified a putative alternative regulatory gene located upstream of the C. baratii type F7 toxin gene cluster. This putative regulatory gene codes for a predicted σ factor that contains DNA-binding-domain homologues to the DNA-binding domains both of BotR and of other members of the TcdR-related group 5 of the σ70 family that are involved in the regulation of toxin gene expression in clostridia. We showed that this TcdR-related protein in association with RNA polymerase core enzyme specifically binds to the C. baratii type F7 botulinum toxin gene cluster promoters. This TcdR-related protein may therefore be involved in regulating the expression of the genes of the botulinum toxin gene cluster in neurotoxigenic C. baratii.
Smith, Eric B; Shafi, Karim A; Greis, Ari C; Maltenfort, Mitchell G; Chen, Antonia F
Flexion contracture after total knee arthroplasty (TKA) can cause significant dissatisfaction. Botulinum toxin A has shown improved extension in patients with spastic flexion contractures after TKA. The purpose of this study was to evaluate whether Botulinum toxin A improves knee extension for any patient with flexion contractures following TKA. A prospective, double-blinded, randomized controlled trial was conducted. Fourteen patients (15 knees), with a flexion contracture (≥10°) one month postoperatively, were randomized to receive either Botulinum toxin A or saline placebo to the affected hamstrings. The subject, surgeon, and administering physiatrist were blinded to the treatment group throughout the study. Subject range of motion (ROM) was evaluated at 1, 6, and 12 months following injection. Differences were tested using mixed-effects regression to control for multiple measurements. The initial post-operative flexion contracture averaged 19° ± 6° in the Botulinum toxin A group and 13° ± 3° in the saline group. Injections were performed 53 and 57 days after TKA in the Botulinum toxin A and saline groups, respectively. Post-injection extension improved to an average of 8, 5, and 1 degrees for BTX and 4, 2, and 1 degrees for SAL, at 1, 6, and 12 months, respectively, compared to pre-injection extension (p < 0.0001). Improvement in knee extension at 1 year improved 18° ± 7.5° for Botulinum toxin A and 12° ± 2° for saline (p = 0.04). No complications resulted from either injection. Patients who received Botulinum toxin A or placebo were able to achieve near full extension one year after surgery. There was a statistically significant improvement in the amount of extension achieved at 1 year with Botulinum toxin A, but this may be of little clinical significance. Since achieving full extension is important for patient function and satisfaction, novel techniques to address this issue deserve special attention. I.
Naik, Haley B; Steinberg, Seth M; Middelton, Lindsay A; Hewitt, Stephen M; Zuo, Rena C; Linehan, W Marston; Kong, Heidi H; Cowen, Edward W
Cutaneous leiomyomas can be associated with severe paroxysmal pain in which nerve conduction may have a key role. Medical management of painful cutaneous leiomyomas is generally unsatisfactory. To assess the efficacy of intralesional botulinum toxin A in the management of pain associated with cutaneous leiomyomas. Randomized, double-blind, placebo-controlled pilot study conducted from January 5, 2009, to March 27, 2014. The setting was a single-center study at the National Institutes of Health among participants 18 years or older with cutaneous leiomyomas characterized by pain at least once weekly and pain of at least 4 on a pain scale ranging from 0 to 10. Eighteen participants were randomized to receive intralesional botulinum toxin A (5 U per 1 cm2) or equivalent volumes of intralesional saline placebo. The primary outcomes were the differences in average lesional pain assessed by the Brief Pain Inventory and visual analog scale before and after ice provocation over a 4-week period. No significant difference in average lesional pain was observed between the study arms. Decreased pain was reported in the botulinum toxin vs placebo arms by visual analog scale scores before ice provocation (median, 0.00; range, -3.30 to 0.70 for botulinum toxin and median, 0.40; range, -1.30 to 1.50 for placebo; P = .06); however, this finding was nonsignificant. No significant difference was observed in change in pain after ice provocation. A significant difference was seen between the arms in skin-related quality of life by total Dermatology Life Quality Index (median, -4.00; range, -8.00 to 2.00 for botulinum toxin and median, 0.00; range, -1.00 to 4.00 for placebo; P = .007) and with the specific skin pain-related question on the Dermatology Life Quality Index (median, -1.00; range, -2.00 to 1.00 for botulinum toxin and median, 0.00; range, -1.00 to 0.00 for placebo; P = .048). No significant difference was found in pain as ascertained by Patient Global Impression
Hackert, Thilo; Klaiber, Ulla; Hinz, Ulf; Kehayova, Tzveta; Probst, Pascal; Knebel, Phillip; Diener, Markus K; Schneider, Lutz; Strobel, Oliver; Michalski, Christoph W; Ulrich, Alexis; Sauer, Peter; Büchler, Markus W
Postoperative pancreatic fistula represents the most important complication after distal pancreatectomy. The aim of this study was to evaluate the use of a preoperative endoscopic injection of botulinum toxin into the sphincter of Oddi to prevent postoperative pancreatic fistula (German Clinical Trials Register number: DRKS00007885). This was an investigator-initiated, prospective clinical phase I/II trial with an exploratory study design. We included patients who underwent preoperative endoscopic sphincter botulinum toxin injection (100 units of Botox). End points were the feasibility, safety, and postoperative outcomes, including postoperative pancreatic fistula within 30 days after distal pancreatectomy. Botulinum toxin patients were compared with a control collective of patients undergoing distal pancreatectomy without botulinum toxin injection by case-control matching in a 1:1 ratio. Between February 2015 and February 2016, 29 patients were included. All patients underwent successful sphincter of Oddi botulinum toxin injection within a median of 6 (range 0-10) days before operation. One patient had an asymptomatic, self-limiting (48 hours) increase in serum amylase and lipase after injection. Distal pancreatectomy was performed in 24/29 patients; 5 patients were not resectable. Of the patients receiving botulinum toxin, 7 (29%) had increased amylase levels in drainage fluid on postoperative day 3 (the International Study Group of Pancreatic Surgery definition of postoperative pancreatic fistula grade A) without symptoms or need for reintervention. Importantly, no clinically relevant fistulas (International Study Group of Pancreatic Surgery grades B/C) were observed in botulinum toxin patients compared to 33% postoperative pancreatic fistula grade B/C in case-control patients (P < .004). Preoperative sphincter of Oddi botulinum toxin injection is a novel and safe approach to decrease the incidence of clinically relevant postoperative pancreatic fistula
Baron, Maximilien; Grise, Philippe; Cornu, Jean-Nicolas
Intradetrusor injections of botulinum toxin are the cornerstone of medical treatment of neurogenic detrusor overactivity. The primary aim of this treatment is to ensure a low pressure regimen in the urinary bladder, but the mechanisms leading to long-term protection of the urinary tract remain poorly understood. In this paper, we highlight the potential benefits of intradetrusor injections of botulinum toxin regarding local effects on the bladder structures, urinary tract infections, stone disease, vesico ureteral reflux, hydronephrosis, renal function based on a comprehensive literature review. PMID:26981445
Whurr, R; Lorch, M; Fontana, H; Brookes, G; Lees, A; Marsden, C D
Botulinum toxin injections have been used to treat 31 patients with adductor spasmodic dysphonia. Injections of 3.00-3.75 units of botulinum toxin were performed bilaterally into the thyroarytenoid muscle. This treatment significantly decreased the standard deviation of the fundamental frequency of the speech sample, indicating a reduction in the variability of pitch amongst patients. A total of 96% of patients' subjective diary reports showed an improvement with a median of 7 days to peak effect and a 5 week duration of peak effect. Images PMID:8505645
Bertram, Kelly; Sirisena, Dharshana; Cowey, Max; Hill, Aron; Williams, David R
Primary orthostatic tremor (POT) is a rapid 13-18 Hertz tremor that produces a subjective feeling of unsteadiness when standing, and is absent when seated or supine. It predominantly affects the legs during isometric contraction though a similar tremor can be seen in the arms and jaw. When present in the jaw this rapid tremor has been successfully treated with botulinum toxin. We sought to test whether symptoms of POT improved following injection of abobotulinumtoxinA to muscles in the legs. This randomised, double blind, placebo controlled cross-over design study enrolled eight patients with electrophysiologically confirmed POT. Each patient received injections of either 200 mU abobotulinumtoxinA or 0.9% saline in the tibialis anterior bilaterally, with cross-over after 20 weeks. Electrophysiological and clinical assessments were performed before and 6 weeks after each injection. Seven patients completed the study. No significant differences were seen in the primary outcome measures of time from standing to unsteadiness or symptom diary scores. Electrophysiological characteristics of POT remained remarkably constant throughout the study in all patients with variability of less than 1 Hertz in the frequency recorded. Falls were common, with one patient experiencing a fall with upper limb fracture whilst on the placebo. The frequency of falls correlated with both the severity of the self-rated symptoms and a shorter time to feeling unsteady with eyes closed. In conclusion, treatment with 200 mU of abobotulinumtoxinA in the tibialis anterior does not alter subjective experience of unsteadiness in POT. Postural instability and falls are common.
Ramachandran, Roshni; Yaksh, Tony L
Migraine pain represents sensations arising from the activation of trigeminal afferents, which innervate the meningeal vasculature and project to the trigeminal nucleus caudalis (TNC). Pain secondary to meningeal input is referred to extracranial regions innervated by somatic afferents that project to homologous regions in the TNC. Such viscerosomatic convergence accounts for referral of migraine pain arising from meningeal afferents to particular extracranial dermatomes. Botulinum toxins (BoNTs) delivered into extracranial dermatomes are effective in and approved for treating chronic migraine pain. Aside from their well-described effect upon motor endplates, BoNTs are also taken up in local afferent nerve terminals where they cleave soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins, and prevent local terminal release. However, a local extracranial effect of BoNT cannot account for allthe effects of BoNT upon migraine. We now know that peripherally delivered BoNTs are taken up in sensory afferents and transported to cleave SNARE proteins in the ganglion and TNC, prevent evoked afferent release and downstream activation. Such effects upon somatic input (as from the face) likewise would not alone account for block of input from converging meningeal afferents. This current work suggests that BoNTs may undergo transcytosis to cleave SNAREs in second-order neurons or in adjacent afferent terminals. Finally, while SNAREs mediate exocytotic release, they are also involved in transport of channels and receptors involved in facilitated pain states. The role of such post-synaptic effects of BoNT action in migraine remains to be determined. PMID:24819339
Pacchetti, C; Albani, G; Martignoni, E; Godi, L; Alfonsi, E; Nappi, G
The "off" painful dystonia (OPD), usually concerning the feet, is a type of abnormal involuntary movement, induced by the chronic use of levodopa. It is mostly observed in the advanced stage of Parkinson's disease (PD), particularly in the early morning, in the evening, and late at night. Indeed, some patients have experienced OPD also during "on" periods when dystonic posture of the foot alternates with dyskinesia. The pain probably is due to sustained muscle contraction, which causes prolonged muscle spasm, as in primary dystonia or torticollis. Dopaminergic drugs like bromocriptine, pergolide, and especially apomorphine (s.c. infusions, or bolus), can dramatically improve the OPD. Anticholinergics baclofen and lithium are alos used in the management of OPD with some benefit. On the other hand, clinical experience shows that in many cases, these therapeutic procedures are not always enough to produce the expected results. Thirty PD patients (22 men and eight women) with OPD of the foot were treated with botulinum toxin (Botox, Btx) using electromyograms to guide injections. Dystonia was evaluated using a quantitative rating scale. The selection of the muscles for Btx treatment was carried out on the basis of foot posture. We injected Btx into tibialis posterior, tibialis anterior, gastrocnemius, flexor digitorum longus, and extensores hallucis longus with a median dose 40 IU for each muscle, distributed in two sites. In all patients, the pain improved within 10 days, whereas in 21 patients, the pain disappeared completely for 4 months (range, 3-7 months); a concomitant improvement in intensity of the dystonic spasm was also observed. No side effects were reported. Seven patients with associated "on" foot dystonia described an improvement of foot posture on walking. In conclusion, in this uncontrolled study, the use of Btx in OPD seemed a promising tool to improve pain linked to foot dystonia; however, because of the well-known underlying dopaminergic defect in
ADELOWO, Amos; HACKER, Michele R.; SHAPIRO, Alex; Modest, Anna Merport; ELKADRY, Eman
Objective To assess intralevator Botulinum toxin type A (Botox) injections for refractory myofascial pelvic pain with short tight pelvic floor. Methods Retrospective cohort study of all women with intralevator Botox injection (100-300 Units) from 2005 through 2010 for refractory myofascial pelvic pain. Primary outcomes were self-reported pain on palpation and symptom improvement. Secondary outcomes included post-injection complications and repeat injection. Pain was assessed during digital palpation of the pelvic floor muscles using a scale of 0-10, with 10 being the worst possible pain. Follow-up occurred at <6 weeks post-injection and again at ≥ 6 weeks. Data are presented as median (interquartile range) or proportion. Results Thirty-one patients met eligibility criteria; 2 were lost to follow up and excluded. Median age was 55.0 years (38.0-62.0). Before Botox injection, median pain score was 9.5 (8.0-10.0). Twenty-nine patients (93.5%) returned for the first follow-up visit; 79.3% reported improvement in pain, while 20.7% reported no improvement. Median pain with levator palpation was significantly lower than before injection (P<0.0001). Eighteen women (58.0%) had a second follow-up visit with a median pain score that remained lower than before injection (P<0.0001). Fifteen (51.7%) women elected to have repeat Botox injection; the median time to repeat injection was 4.0 (3.0-7.0) months. Three (10.3%) women developed de-novo urinary retention, 2 (6.9%) reported fecal incontinence and 3 (10.3%) reported constipation and/or rectal pain; all side effects resolved spontaneously. Conclusions Intralevator injection of Botox demonstrates effectiveness in women with refractory myofascial pelvic pain with few, self-limiting adverse effects. PMID:23982578
Moeller, R.B.; Puschner, B.; Walker, R.L.; Rocke, T.E.; Smith, S.R.; Cullor, J.S.; Ardans, A.A.
Three adult lactating Holstein cows were injected in the subcutaneous abdominal vein with 175 ng/kg of body weight of Clostridium botulinum type C toxin (451 cow median toxic doses) to determine if this botulinum toxin crosses the blood-milk barrier. Whole blood (in sodium heparin) and clotted blood serum samples were taken at 0 min, 10 min, and 3, 6, 9, and 12 h postinoculation. Milk samples were taken at 0 min and at 3, 6, 9 and 12 h postinoculation. All samples were tested for the presence of the toxin using the mouse bioassay and immunostick ELISA test. The immunostick ELISA identified the toxin in whole blood and the mouse bioassay identified the toxin in serum at all times examined in all 3 animals. Toxin was not identified by either detection method in milk samples collected from the 3 animals. From these results, it appears that Clostridium botulinum type C toxin does not cross from the blood to the milk in detectable concentrations. ?? American Dairy Science Association, 2009.
Moeller, R B; Puschner, B; Walker, R L; Rocke, T E; Smith, S R; Cullor, J S; Ardans, A A
Three adult lactating Holstein cows were injected in the subcutaneous abdominal vein with 175 ng/kg of body weight of Clostridium botulinum type C toxin (451 cow median toxic doses) to determine if this botulinum toxin crosses the blood-milk barrier. Whole blood (in sodium heparin) and clotted blood serum samples were taken at 0 min, 10 min, and 3, 6, 9, and 12 h postinoculation. Milk samples were taken at 0 min and at 3, 6, 9 and 12 h postinoculation. All samples were tested for the presence of the toxin using the mouse bioassay and immunostick ELISA test. The immunostick ELISA identified the toxin in whole blood and the mouse bioassay identified the toxin in serum at all times examined in all 3 animals. Toxin was not identified by either detection method in milk samples collected from the 3 animals. From these results, it appears that Clostridium botulinum type C toxin does not cross from the blood to the milk in detectable concentrations.
Tetanus toxin, the product of Clostridium tetani, is the cause of tetanus symptoms. Tetanus toxin is taken up into terminals of lower motor neurons and transported axonally to the spinal cord and/or brainstem. Here the toxin moves trans-synaptically into inhibitory nerve terminals, where vesicular release of inhibitory neurotransmitters becomes blocked, leading to disinhibition of lower motor neurons. Muscle rigidity and spasms ensue, often manifesting as trismus/lockjaw, dysphagia, opistotonus, or rigidity and spasms of respiratory, laryngeal, and abdominal muscles, which may cause respiratory failure. Botulinum toxin, in contrast, largely remains in lower motor neuron terminals, inhibiting acetylcholine release and muscle activity. Therefore, botulinum toxin may reduce tetanus symptoms. Trismus may be treated with botulinum toxin injections into the masseter and temporalis muscles. This should probably be done early in the course of tetanus to reduce the risk of pulmonary aspiration, involuntary tongue biting, anorexia and dental caries. Other muscle groups are also amenable to botulinum toxin treatment. Six tetanus patients have been successfully treated with botulinum toxin A. This review discusses the use of botulinum toxin for tetanus in the context of the pathophysiology, symptomatology, and medical treatment of Clostridium tetani infection. PMID:23299659
Brisinda, Giuseppe; Maria, Giorgio; Sganga, Gabriele; Bentivoglio, Anna Rita; Albanese, Alberto; Castagneto, Marco
Botulinum toxin induces healing in patients with idiopathic anal fissures. One hundred-fifty patients with posterior anal fissures were treated with botulinum toxin injected in the internal anal sphincter on each side of the anterior midline. Subjects were randomized into 2 treatment groups based on the number of units of botulinum toxin injected. Patients in group I were treated with 20 units of botulinum toxin and, if the fissure persisted, were retreated with 30 units. Patients in group II were treated with 30 units and retreated with 50 units, if the fissure persisted. The 2 groups were comparable in age, gender distribution, duration of symptoms, resting pressure, and maximum voluntary pressure at anorectal manometry. One month after the injection, examinations revealed complete healing in 55 patients (73%) from group I and 65 patients (87%) from group II (P =.04). Five patients from group II reported a mild incontinence of flatus that lasted 2 weeks after the treatment and disappeared spontaneously. The values of the resting anal pressure (P=.3) and the maximum voluntary pressure (P =.2) did not differ between the 2 groups. At 2 months' evaluation, a healing scar was found in 67 patients (89%) from group I and 72 patients (96%) from group II. A relapse of the fissure was observed in 6 patients (8%) from group I who had a healing scar at 1 month, and 2 other patients never healed. A persistent fissure was present in 3 patients from group II who had no other symptoms. Botulinum toxin injected into the internal anal sphincter is effective in managing anal fissures and avoiding permanent complications. All patients were treated with the active drug and healed after 1 or 2 successive treatments. The results also confirm that higher doses account for a higher success rate, with little increase in complications or side effects, which is probably related to the diffusion of the toxin to the external sphincter.
Dressler, Dirk; Adib Saberi, Fereshte
AbobotulinumtoxinA (Dysport®) was distributed for many years in vials containing 500MU (D500). Recently a new 300MU vial (D300) was additionally introduced (introduction). We wanted to explore whether more differentiated package sizes allow for more economic use of Dysport® in a large neurological botulinum toxin (BT) outpatient clinic. The study followed a retrospective chart review design based on our digital BT therapy data bank. All patients receiving Dysport® exclusively in a constant dose during the observation period (introduction ± 7 months) were included. Economic calculations are based on Dysport® prices as officially advertised in Germany. Sharing of vials between patients was not allowed. Altogether 83 patients (51 with dystonia, 25 with spasticity, 3 with hemifacial spasm, 4 with other diagnoses) were included in this study. The total amount of BT used before and after introduction was 102525MU, the amount prescribed 138000MU and 116300MU (-21700MU, -15.7%), the costs €146103 and €125250 (-€ 20853, -14.3%). The price for D500 before and after introduction was €529.36, for D300 €339.71. The D500 price for 1MU before and after introduction is €1.0587, the D300 price for 1MU €1.1324 (+ €0.073, +7.0% against D500). More flexible packaging reduces drug costs for BT therapy considerably. Introducing smaller packaging sizes is technically possible and should be encouraged. Extra costs for registration and logistics are moderate. Further cost reductions may be possible by introduction of even smaller packaging sizes. They can be calculated based on our model.
Barbeiro, Sandra; Atalaia-Martins, Catarina; Marcos, Pedro; Gonçalves, Cláudia; Canhoto, Manuela; Arroja, Bruno; Silva, Filipe; Cotrim, Isabel; Eliseu, Liliana; Santos, Antonieta; Vasconcelos, Helena
Chronic anal fissure is a frequent and disabling disease, often affecting young adults. Botulinum toxin and lateral internal sphincterotomy are the main therapeutic options for refractory cases. Botulinum toxin is minimally invasive and safer compared with surgery, which carries a difficult post-operative recovery and fecal incontinence risk. The long-term efficacy of Botulinum toxin is not well known. The aim of this study was to evaluate the long-term efficacy and safety of Botulinum toxin in the treatment of chronic anal fissure. This was a retrospective study at a single center, including patients treated with Botulinum toxin from 2005 to 2010, followed over at least a period of 5 years. All patients were treated with injection of 25U of Botulinum toxin in the intersphincteric groove. The response was registered as complete, partial, refractory and relapse. Botulinum toxin was administered to 126 patients, 69.8% (n = 88) were followed over a period of 5 years. After 3 months, 46.6% (n = 41) had complete response, 23.9% (n = 21) had partial response and 29.5% (n = 26) were refractory. Relapse was observed in 1.2% (n = 1) at 6 months, 11.4% (n = 10) at 1 year, 2.3% (n = 2) at 3 years; no relapse at 5 years. The overall success rate was 64.8% at 5 years of follow-up. Botulinum toxin was well tolerated by all patients and there were no complications. The use of Botulinum toxin to treat patients with chronic anal fissure was safe and effective in long-term follow-up.
Grecz, Nicholas; Wagenaar, R. O.; Dack, G. M.
Growth initiated from detoxified spores of Clostridium botulinum 62A resulted in toxin production of 50 to 10,000 mouse lethal doses (MLD) per gram of processed soft surface-ripened cheese. Regular assays during subsequent storage of toxic samples at 2 to 4 C revealed a characteristic two- to fivefold increase in toxin titer during the initial 1 week to 12 months of storage. Thereafter, the toxin titer remained constant for 2 to 4 years, after which the toxicity declined rapidly. At the end of 6 years of storage at 2 to 4 C, the samples still contained 20 to 5,000 MLD of toxin per gram, with the usual toxin level at 200 to 500 MLD. Toxic culture filtrates of C. botulinum incorporated into cheese and stored at 30 C for 60 days showed no decline in toxin in processed type I cheese, but toxin decreased slightly in processed type II and type III cheese. The surface flora of these cheeses did not attack but, on the contrary, protected C. botulinum toxin during storage at 30 C. Initial difficulties in recovering C. botulinum organisms from type I cheese were traced to growth inhibitory activity which could be removed by washing with distilled water in a centrifuge. Viable spores or vegetative cells could be recovered from all samples after 4 to 5 years of storage at 2 to 4 C. After 6 years, organisms were recovered from all except three samples of type I cheese. Two other samples showed a large decrease in viable organisms. In type III cheese, spores remained remarkably stable for 6 years at the level of the initial inoculum, i.e., approximately 105 spores per gram. PMID:5325415
Malgorzata, Pihut; Piotr, Ceranowicz; Edward, Kijak
In the course of temporomandibular joint, dysfunctions very often occur to the excessive increase in tension of masticatory muscles, so the main aim of the treatment is reduction of this hypertension of muscles. For this reason, we use botulinum toxin type A, which is produced by Grampositive Clostridium bacteria. There are six serotypes of the toxin: A, B, C, D, E, F, and G. The botulinum toxin type A was first isolated in 1920s. Today, botulinum toxin type A is used increasingly more often as an efficient and patient-friendly therapy in neurology, ophthalmology, neurology, urology and laryngology. The aim of the article was to review the literature and description of the current knowledge concerned with mechanism of action of botulinum toxin type A, clinical applications and metabolic determinants of muscle contraction and the beneficial effect of this drug on the state of muscle tension. Copyright© Bentham Science Publishers; For any queries, please email at email@example.com.
Lúquez, Carolina; Bianco, María I.; de Jong, Laura I. T.; Sagua, María D.; Arenas, Graciela N.; Ciccarelli, Alberto S.; Fernández, Rafael A.
We studied the presence of botulinum toxin-producing clostridia in 2,009 soil samples from five geographical regions of Argentina. The prevalence was 23.5%, and the distribution was not homogeneous among the regions. We observed a great multiplicity of serological types and a higher prevalence in nonvirgin soils than in virgin soils. PMID:16000834
Lúquez, Carolina; Bianco, María I; de Jong, Laura I T; Sagua, María D; Arenas, Graciela N; Ciccarelli, Alberto S; Fernández, Rafael A
We studied the presence of botulinum toxin-producing clostridia in 2,009 soil samples from five geographical regions of Argentina. The prevalence was 23.5%, and the distribution was not homogeneous among the regions. We observed a great multiplicity of serological types and a higher prevalence in nonvirgin soils than in virgin soils.
Goldman, Alberto; Wollina, Uwe
Indications for botulinum toxin type A have been constantly evolving, and it can currently be used in virtually any area of the face and neck. The authors present their experience with this neurotoxin in treating the platysmal bands and depressor anguli oris muscle with the purpose of cosmetically improving the anterior neck and lifting the oral commissure. PMID:21430826
Erasmus, Corrie E.; van Hulst, Karen; van den Hoogen, Frank J. A.; van Limbeek, Jacques; Roeleveld, Nel; Veerman, Enno C. I.; Rotteveel, Jan J.; Jongerius, Peter H.
Aim: The aim of this study was to evaluate the rheological properties of saliva after submandibular botulinum toxin type A (BoNT-A) injections. Method: We enrolled 15 children (11 males and six females; age range 3-17y, mean age 9y 10mo) diagnosed with spastic (n=9) or dyskinetic (n=6) quadriplegic cerebral palsy (CP); Gross Motor Function…
Alam, Marianne; Zgheib, Joseph; El Khoury, Fouad
Secondary to failure of optimal medical therapy and the high morbidity that accompanies surgical techniques in high risk patients, the use of de novo treatments including botulinum toxin A is emerging in the treatment of benign prostatic hyperplasia (BPH). However, the treatment of urinary retention secondary to BPH via injecting botulinum toxin into the bladder neck is not well established in the literature. This case report describes the case of a 75-year-old male patient with a chronic history of obstructive lower urinary tract symptoms (LUTS) and multiple comorbidities who was admitted to the hospital for management of recurrent urinary retention. The patient was not a surgical candidate for transurethral incision of the prostate (TUIP) or transurethral resection of the prostate (TURP). Botulinum toxin injection into the bladder neck was performed with very satisfying results. Botulinum toxin injection in the bladder neck presents a promising minimally invasive, tolerated, and cost-effective approach for the treatment of urinary retention in patients with benign prostatic obstruction who are not candidates for surgery or in whom medical treatment has failed. More research is needed to identify the efficacy of this novel approach. PMID:27088032
Santamato, Andrea; Micello, Maria Francesca; Ranieri, Maurizio; Valeno, Giovanni; Albano, Antonio; Baricich, Alessio; Cisari, Carlo; Intiso, Domenico; Pilotto, Alberto; Logroscino, Giancarlo; Panza, Francesco
Spasticity is a common disabling symptom for several neurological conditions. Botulinum toxin type A injection represents the gold standard treatment for focal spasticity with efficacy, reversibility, and low prevalence of complications. Current guidelines suggest a dose up to 600 units (U) of onabotulinumtoxinA/incobotulinumtoxinA or up to 1,500 U of abobotulinumtoxinA to treat post-stroke spasticity to avoid important adverse effects. However, recently, higher doses of botulinum toxin type A were employed, especially in case of upper and lower limb severe spasticity. With searches of US National Library of Medicine databases, we identified all studies published from December 1989 to July 2014 concerning the use of higher doses of this neurotoxin for spasticity treatment with at least a dose of 600 U of onabotulinumtoxinA and incobotulinumtoxinA or 1,800 U of abobotulinumtoxinA. The cumulative body of evidence coming from the eight studies selected suggested that higher doses of botulinum toxin type A appeared to be efficacious in reducing spasticity of the upper and lower limbs after stroke, with adverse effects generally mild. However, further investigations are needed to determine the safety and reproducibility in larger case series or randomized clinical trials of higher doses of botulinum toxin type A also after repeated injections. Copyright © 2015 Elsevier B.V. All rights reserved.
Rousseaux, M; Daveluy, W
To bring general elements of reflection on the use of the high doses of botulinum toxin in spastic children and adults. Review of the literature on the high doses and the benefit-risk associated with botulinum toxin injections. The medical literature exclusively relates to the use of the high doses in children and adolescents. Comparative work with conventional doses suggests a relative interest, but with a risk of increased side effects. Several articles report on treatments with high and even very high doses in series of patient, with a documented effectiveness. But their justification remains partial and the study of the possible side effects is limited. Reflections are brought to contribute to the debate on the use of high doses, taking into account the local physiological effect of botulinum toxin, the risk of regional and general diffusion, the need for a progressive strategy, the variability of effects, the cost of the treatment and the need for obtaining an informed consent of the patient and of significant others. The use of high doses of botulinum toxin increases progressively, but must remain very careful.
Sarioglu, Berrak; Serdaroglu, Gul; Tutuncuoglu, Sarenur; Ozer, Esra A
The current modalities in managing spastic children have some limitations; thus, alternative therapeutic agents are in need. The purpose of this study is to investigate whether intramuscular botulinum toxin type A administration may be an alternative agent in the treatment of children with cerebral palsy. Eighteen children who were aged between 3 and 17 years and manifested cerebral palsy were administered intramuscular botulinum toxin type A with a total dose of 6 U/kg body weight. Outcome measurements were determined with four methods, including Ashworth Spasticity Scale, standardized videotape assessments, observational gait analysis, and walking velocity. Ashworth Spasticity Scale and videotape assessments were statistically significant before and after treatment in all muscles (P < 0.001). The best improvement in video gait analysis was evident at week 8. The botulinum toxin type A injections yielded an improved walking velocity at all visits. The observational gait analysis and walking velocity demonstrated an improvement after treatment in the gastrocnemius-injected group (P < 0.001). In conclusion, intramuscular botulinum toxin type A administration may be effective in children with cerebral palsy, especially at week 4 and when injected in gastrocnemius.
Rinaldi, Max L.; Fransson, Boel A.; Barry, Sabrina L.
A toy Australian shepherd dog was referred for bile peritonitis following excision of a biliary mucocele. Subsequent delayed gastric emptying was refractory to prokinetic therapy but responded to injection of botulinum toxin A into the muscularis layer of the pylorus; a novel therapy for delayed gastric emptying in dogs. PMID:24982520
Bingol, Ugur Anil; Cinar, Can
Pachydermoperiostosis is a rare syndrome that hinders patients' quality of life thru its aesthetics manifestations and functional obstacles. Many techniques for addressing and correcting aesthetic defects associated with pachydermoperiostosis have been introduced, including facelift surgery. This case presentation includes treatment of facial pachydermoperiostosis and restoration of facial aesthetics via treatment with facelift, skin muscle excision, and botulinum toxin A.
Erasmus, Corrie E.; van Hulst, Karen; van den Hoogen, Frank J. A.; van Limbeek, Jacques; Roeleveld, Nel; Veerman, Enno C. I.; Rotteveel, Jan J.; Jongerius, Peter H.
Aim: The aim of this study was to evaluate the rheological properties of saliva after submandibular botulinum toxin type A (BoNT-A) injections. Method: We enrolled 15 children (11 males and six females; age range 3-17y, mean age 9y 10mo) diagnosed with spastic (n=9) or dyskinetic (n=6) quadriplegic cerebral palsy (CP); Gross Motor Function…
Puszczewicz, Mariusz J.
Introduction The management of Raynaud's phenomenon in its most severe form is challenging, and current medical and surgical treatment methods frequently do not lead to optimal symptom control and prevention of ischemic complications. The aim of the study was to critically evaluate all existing evidence on the use of botulinum toxin A in the management of Raynaud's phenomenon. Material and methods We adopted the PRISMA methodology and searched Cochrane Library, MEDLINE, SCOPUS, EULAR and ACR congresses abstract archives for Raynaud* AND botulinum toxin OR onabotulinum. All studies that contained reports of botulinum toxin A use and its outcome in Raynaud's phenomenon were included in the review. Results Eleven studies met our inclusion criteria and involved a total of 125 patients. Two reviewers extracted data from the studies under review and achieved a consensus in their selection. The main outcomes measured were pain reduction and healing of digital ulcers. The level of evidence across studies was very low to moderate. Conclusions There is insufficient evidence to assess the efficacy of botulinum toxin A in Raynaud's phenomenon. Despite many promising reports, further research in the form of randomized controlled trials is warranted in order to investigate this new treatment method for Raynaud's phenomenon. PMID:27478469
Objective To evaluate the beneficial effect of botulinum toxin A (Botox) injection into the subscapularis muscle on intractable hemiplegic shoulder pain. Methods Six stroke patients with intractable hemiplegic shoulder pain were included. Botulinum toxin A was injected into the subscapularis muscle. Intractable hemiplegic shoulder pain was evaluated using an 11-point numerical rating scale. Pain-free range of motion was assessed for shoulder abduction and external rotation. The spasticity of the shoulder internal rotator was measured using the modified Ashworth scale. Assessments were carried out at baseline and at 1, 2, 4, and, if possible, 8 weeks. Results Intractable hemiplegic shoulder pain was improved (p=0.004) after botulinum toxin injection into the subscapularis muscle. Restricted shoulder abduction (p=0.003), external rotation (p=0.005), and spasticity of the shoulder internal rotator (p=0.005) were also improved. Improved hemiplegic shoulder pain was correlated with improved shoulder abduction (r=–1.0, p<0.001), external rotation (r=–1.0, p<0.001), and spasticity of the internal rotator (r=1.0, p<0.001). Conclusion Botulinum toxin A injection into the subscapularis muscle appears to be valuable in the management of intractable hemiplegic shoulder pain. PMID:27606265
We recently demonstrated an effective new model for the detection of botulinum toxin type A using quail embryos in place of the mouse model. These experiments demonstrated that the Japanese quail embryo at 15 days of incubation was an effective vertebrate animal model to detect the activity of botu...
Rinaldi, Max L; Fransson, Boel A; Barry, Sabrina L
A toy Australian shepherd dog was referred for bile peritonitis following excision of a biliary mucocele. Subsequent delayed gastric emptying was refractory to prokinetic therapy but responded to injection of botulinum toxin A into the muscularis layer of the pylorus; a novel therapy for delayed gastric emptying in dogs.
Wierzbicka, Małgorzata; Szyfter, Witold
Introduction Stensen's duct injuries are uncommon but troublesome sequelae of facial surgery or other external traumas. Aim To investigate the feasibility of sialendoscopic control of Stensen's duct in iatrogenic injuries and the efficiency of botulinum toxin adjuvant therapy. Material and methods In 2008 and 2010, 5 patients with parotid sialoceles or fistulas, infrequent complications after plastic surgery or trauma, were treated in a single institution, Poznan University of Medical Sciences ENT Department. The group consisted of 5 patients with diagnosed Stensen's duct injuries, which were post-surgery and post-traumatic sequelae. All were treated by means of open surgery. Botulinum toxin injection was administered during the procedure to decrease the saliva secretion and to improve the healing process. A sialendoscopy was performed to control the lumen of the junction after the duct injury was repaired. Results Complete healing of the fistulas and sialoceles after the reparative surgery followed by a single botulinum toxin application was observed in all patients within 10-14 days. No side effects were noticed. Conclusions Our findings suggest that sialendoscopy is a valuable tool and an important step of control in the surgery of parotid duct injuries and the injection of botulinum toxin is an effective and safe second-line treatment. PMID:23837095
Huhtanen, C N; Naghski, J; Custer, C S; Russell, R W
Tomato juice inoculated with Cladosporium sp. or Penicillium sp. developed pH gradients with the upper portions near the mold mats having pH values near neutrality and the lower portions remaining more acid. Clostridium botulinum spores in these moldy tomato juices germinated, grew out, and produced toxin.
Huhtanen, C N; Naghski, J; Custer, C S; Russell, R W
Tomato juice inoculated with Cladosporium sp. or Penicillium sp. developed pH gradients with the upper portions near the mold mats having pH values near neutrality and the lower portions remaining more acid. Clostridium botulinum spores in these moldy tomato juices germinated, grew out, and produced toxin. PMID:10844
Cannito, Michael P; Kahane, Joel C; Chorna, Lesya
Aging of the larynx is characterized by involutional changes which alter its biomechanical and neural properties and create a biological environment that is different from younger counterparts. Illustrative anatomical examples are presented. This natural, non-disease process appears to set conditions which may influence the effectiveness of botulinum toxin injection and our expectations for its success. Adductor spasmodic dysphonia, a type of laryngeal dystonia, is typically treated using botulinum toxin injections of the vocal folds in order to suppress adductory muscle spasms which are disruptive to production of speech and voice. A few studies have suggested diminished response to treatment in older patients with adductor spasmodic dysphonia. This retrospective study provides a reanalysis of existing pre-to-post treatment data as function of age. Perceptual judgments of speech produced by 42 patients with ADSD were made by two panels of professional listeners with expertise in voice or fluency of speech. Results demonstrate a markedly reduced positive response to botulinum toxin treatment in the older patients. Perceptual findings are further elucidated by means of acoustic spectrography. Literature on vocal aging is reviewed to provide a specific set of biological mechanisms that best account for the observed interaction of botulinum toxin treatment with advancing age. PMID:18488884
Mall, V; Heinen, F; Linder, M; Philipsen, A; Korinthenberg, R
Three patients with cerebral palsy are described suffering, respectively, of pes equinus, spasm of the m. teres major and flexion spasm of the hand, who were treated with botulinum toxin A. These patients demonstrate not only the local reduction of the muscular hyperactivity following treatment with botulinum toxin A but also the potential functional benefit resulting from such a treatment. Thus, local intramuscular injection of botulinum toxin A in children with cerebral palsy should be considered as part of a multidisciplinary treatment concept, since reduction of the disability and the functional improvements could have high impact on daily living activities.
Chuang, Yao-Chi; Huang, Tung-Liang; Tyagi, Pradeep; Huang, Chao-Cheng
We investigated the feasibility of using low energy shock waves for intravesical botulinum toxin A delivery. We also evaluated its efficacy for acetic acid induced bladder hyperactivity in rats. In study 1 magnetic resonance imaging with intravesical administration of Gd-DTPA (Gd-diethylenetriamine pentaacetic acid) contrast medium was performed to visualize increased bladder urothelial permeability after low energy shock waves. In study 2 saline (1 ml) or botulinum toxin A (20 U/1 ml saline) was administered in the bladder with or without low energy shock waves (300 pulses at 0.12 mJ/mm(2)) and retained for 1 hour on day 1. Continuous cystometrograms were performed on day 8 by filling the bladder with saline followed by 0.3% acetic acid. The bladder was harvested for histology, and SNAP-25, SNAP-23 and COX-2 expression by Western blot or immunostaining. Magnetic resonance imaging established bladder urothelial leakage of Gd-DTPA after low energy shock waves, which was not seen in controls. The intercontraction interval was decreased 71.9%, 72.6% and 70.6% after intravesical instillation of acetic acid in saline, saline plus low energy shock wave and botulinum toxin A pretreated rats, respectively. However, rats that received botulinum toxin A plus low energy shock waves showed a significantly reduced response (48.6% decreased intercontraction interval) to acetic acid instillation without compromising voiding function. Rats pretreated with botulinum toxin A plus low energy shock waves showed a decreased inflammatory reaction (p <0.05), and decreased expression of SNAP-23 (p <0.05), SNAP-25 (p = 0.061) and COX-2 (p <0.05) compared with the control group. Low energy shock waves increased urothelial permeability, facilitated intravesical botulinum toxin A delivery and blocked acetic acid induced hyperactive bladder. These results support low energy shock waves as a promising method to deliver botulinum toxin A without the need for injection. Copyright © 2016
Schantz, E J; Johnson, E A
Crystalline botulinum toxin type A was licensed in December 1989 by the Food and Drug Administration for treatment of certain spasmodic muscle disorders following 10 or more years of experimental treatment on human volunteers. Botulinum toxin exerts its action on a muscle indirectly by blocking the release of the neurotransmitter acetylcholine at the nerve ending, resulting in reduced muscle activity or paralysis. The injection of only nanogram quantities (1 ng = 30 mouse 50% lethal doses [U]) of the toxin into a spastic muscle is required to bring about the desired muscle control. The type A toxin produced in anaerobic culture and purified in crystalline form has a specific toxicity in mice of 3 x 10(7) U/mg. The crystalline toxin is a high-molecular-weight protein of 900,000 Mr and is composed of two molecules of neurotoxin (ca. 150,000 Mr) noncovalently bound to nontoxic proteins that play an important role in the stability of the toxic unit and its effective toxicity. Because the toxin is administered by injection directly into neuromuscular tissue, the methods of culturing and purification are vital. Its chemical, physical, and biological properties as applied to its use in medicine are described. Dilution and drying of the toxin for dispensing causes some detoxification, and the mouse assay is the only means of evaluation for human treatment. Other microbial neurotoxins may have uses in medicine; these include serotypes of botulinum toxins and tetanus toxin. Certain neurotoxins produced by dinoflagellates, including saxitoxin and tetrodotoxin, cause muscle paralysis through their effect on the action potential at the voltage-gated sodium channel. Saxitoxin used with anaesthetics lengthens the effect of the anaesthetic and may enhance the effectiveness of other medical drugs. Combining toxins with drugs could increase their effectiveness in treatment of human disease. PMID:1579114
Hoch, David H.; Romero-Mira, Miryam; Ehrlich, Barbara E.; Finkelstein, Alan; Dasgupta, Bibhuti R.; Simpson, Lance L.
The heavy chains of both botulinum neurotoxin type B and tetanus toxin form channels in planar bilayer membranes. These channels have pH-dependent and voltage-dependent properties that are remarkably similar to those previously described for diphtheria toxin. Selectivity experiments with anions and cations show that the channels formed by the heavy chains of all three toxins are large; thus, these channels could serve as ``tunnel proteins'' for translocation of active peptide fragments. These findings support the hypothesis that the active fragments of botulinum neurotoxin and tetanus toxin, like that of diphtheria toxin, are translocated across the membranes of acidic vesicles.
Fredrick, Chase M; Lin, Guangyun; Johnson, Eric A
Botulinum neurotoxin (BoNT), produced by neurotoxigenic clostridia, is the most potent biological toxin known and the causative agent of the paralytic disease botulism. The nutritional, environmental, and genetic regulation of BoNT synthesis, activation, stability, and toxin complex (TC) formation is not well studied. Previous studies indicated that growth and BoNT formation were affected by arginine and glucose in Clostridium botulinum types A and B. In the present study, C. botulinum ATCC 3502 was grown in toxin production medium (TPM) with different levels of arginine and glucose and of three products of arginine metabolism, citrulline, proline, and ornithine. Cultures were analyzed for growth (optical density at 600 nm [OD600]), spore formation, and BoNT and TC formation by Western blotting and immunoprecipitation and for BoNT activity by mouse bioassay. A high level of arginine (20 g/liter) repressed BoNT production approximately 1,000-fold, enhanced growth, slowed lysis, and reduced endospore production by greater than 1,000-fold. Similar effects on toxin production were seen with equivalent levels of citrulline but not ornithine or proline. In TPM lacking glucose, levels of formation of BoNT/A1 and TC were significantly decreased, and extracellular BoNT and TC proteins were partially inactivated after the first day of culture. An understanding of the regulation of C. botulinum growth and BoNT and TC formation should be valuable in defining requirements for BoNT formation in foods and clinical samples, improving the quality of BoNT for pharmaceutical preparations, and elucidating the biological functions of BoNTs for the bacterium.IMPORTANCE Botulinum neurotoxin (BoNT) is a major food safety and bioterrorism concern and is also an important pharmaceutical, and yet the regulation of its synthesis, activation, and stability in culture media, foods, and clinical samples is not well understood. This paper provides insights into the effects of critical nutrients
Elwischger, K; Kasprian, G; Weber, M; Meyerspeer, M; Linder, C; Auff, E; Prayer, D; Sycha, T; Kranz, G
A precise knowledge of the spread of botulinum toxin (BoNT) in muscle tissue is required to efficiently access endplate zones and increase BoNT's therapeutic efficacy. Here, we aimed to understand the spatiotemporal dynamics of BoNT distribution in skeletal muscle and its modulating factors, such as injected volume and exercise after injection. To visualize distribution in muscle tissue, sagittal, dynamic, balanced fast field echo (BFFE) MRI imaging was performed during injection of 1 ml BoNT/NaCl bolus in spastic biceps brachii muscles (SBB, n=4), and 1 ml NaCl in the right and 2 ml NaCl in the left healthy biceps brachii (HBB, n=6), with or without successive muscle exercise. The pattern of extracellular fluid distribution was evaluated by T2-weighted and diffusion tensor imaging (DTI) sequences. BFFE indicated an immediate increase in hyperintensity, parallel to the muscle fibers, in the shape of a long (5.3±1.7 cm) and thin (0.52±1.3 cm) layer in HBB. The layer in SBB was shorter (3.25±0.6 cm, p=0.01) and tended to be thicker (0.74±2.9 cm, p=0.27). In HBB, an increase in volume (2 ml) resulted in an increase in thickness (0.95±0.2 cm, p=0.015), but a consistent length (5.67±1.3 cm, p=0.54). DTI visualized a change of diffusion, which exceeded the bolus region by approximately 0.5 cm. Redistribution occurred 10 min after injection and was more prominent in HBB, compared to SBB. Additional muscle activity did not alter the diffusion pattern or bolus distribution. Injecting BoNT at different depths perpendicular to the direction of the muscle fiber might optimize the efficacy of BoNT treatment. Additional sites along muscle fibers should be considered in SBB. Copyright © 2014 Elsevier B.V. All rights reserved.
Shayesteh, Alexander; Boman, Jens; Janlert, Urban; Brulin, Christine; Nylander, Elisabet
Primary hyperhidrosis affects approximately 3% of the population and reduces quality of life in affected persons. Few studies have investigated the symptoms of anxiety, depression and hazardous alcohol consumption among those with hyperhidrosis and the effect of treatment with botulinum toxin. The first aim of this study was to investigate the effect of primary hyperhidrosis on mental and physical health, and alcohol consumption. Our second aim was to study whether and how treatment with botulinum toxin changed these effects. One hundred and fourteen patients answered questionnaires regarding hyperhidrosis and symptoms, including hyperhidrosis disease severity scale (HDSS), visual analog scale (VAS) 10-point scale for hyperhidrosis symptoms, hospital anxiety and depression scale (HADS), alcohol use disorder identification test (AUDIT) and short-form health survey (SF-36) before treatment with botulinum toxin and 2 weeks after. The age of onset of hyperhidrosis was on average 13.4 years and 48% described heredity for hyperhidrosis. Significant improvements were noted in patients with axillary and palmar hyperhidrosis regarding mean HDSS, VAS 10-point scale, HADS, SF-36 and sweat-related health problems 2 weeks after treatment with botulinum toxin. Changes in mean AUDIT for all participants were not significant. Primary hyperhidrosis mainly impairs mental rather than physical aspects of life and also interferes with specific daily activities of the affected individuals. Despite this, our patients did not show signs of anxiety, depression or hazardous alcohol consumption. Treatment with botulinum toxin reduced sweat-related problems and led to significant improvements in HDSS, VAS, HADS and SF-36 in our patients. © 2016 Japanese Dermatological Association.
Shariat-Madar, Bahbak; Chun, Robert H; Sulman, Cecille G; Conley, Stephen F
To evaluate incidence of complications and hospital readmission as a result of ultrasound-guided botulinum toxin injections to manage sialorrhea. Case series with chart review. Children's Hospital of Wisconsin. A case series with chart review was performed of all cases of ultrasound-guided injection of botulinum toxin by pediatric otolaryngologists from March 5, 2010, to September 26, 2014,. Primary outcomes included complications such as dysphagia, aspiration pneumonia, and motor paralysis. Secondary outcomes included hospitalization, intubation, and nasogastric tube placement. There were 48 patients, 111 interventions, and 306 intraglandular injections identified. Botulinum toxin type A and type B were utilized in 4 and 107 operative interventions, respectively. Type A was injected into 4 parotid and 4 submandibular glands, utilizing doses of 20 U per parotid and 30 U per submandibular gland. Type B was injected into 98 parotid and 200 submandibular glands, with average dosing of 923 U per parotid and 1170 U per submandibular gland, respectively. There were 2 instances of subjectively worsening of baseline dysphagia that self-resolved. No cases were complicated by aspiration pneumonia or motor paralysis. No patients required hospital readmission, intubation, or nasogastric tube placement. Prior published data indicated 16% complication incidence with ultrasound-guided injection of botulinum toxin. Our study found a low complication rate (0.6%) with ultrasound-guided injections of botulinum toxin to manage sialorrhea, without cases of aspiration pneumonia or motor paralysis. Of 306 intraglandular injections, there were 2 cases of worsening baseline subjective dysphagia that self-resolved. © American Academy of Otolaryngology—Head and Neck Surgery Foundation 2016.
Lee, Michelle; Monson, Mikhal A; Liu, Mengyuan T; Reed, Deborah; Guyuron, Bahman
The objective of the study was to determine whether botulinum toxin type A injections can serve as a prognosticator for migraine surgery success. Patients who underwent migraine surgery from 2000 to 2010 by the senior author (B.G.) were reviewed. Patients were included if they had botulinum toxin type A injection before surgery; had completed postinjection, postsurgery Migraine Headache Questionnaires; and had at least 1-year follow-up. Outcome variables include patient demographics and Migraine Headache Index. Treatment success was defined as at least a 50 percent reduction in Migraine Headache Index. One hundred eighty-eight patients were included; 144 reported successful migraine headache reduction after injection (success group) and 44 did not (failure group). The groups were well matched for age, migraine headache characteristics, and number of surgical sites (p > 0.05). The surgery success rate was significantly higher in the success group overall (90.3 percent versus 72.3, p = 0.003), and in patients who reported botulinum toxin type A success and subsequent same-site surgery (97.9 percent versus 71.4 percent, p < 0.0001). Botulinum toxin type A success was prognostic for surgery success at the frontal trigger site (trigger site I) (92.5 percent versus 69.2 percent, p = 0.012), the temporal trigger site (trigger site II) (95.5 percent versus 73.3 percent, p = 0.005), and the occipital trigger site (trigger site IV) (95.9 percent versus 62.5 percent, p = 0.0003). Six patients had exclusively septum or turbinate (site III) surgery, and all failed injections. Positive botulinum toxin type A response is a significant predictor of migraine surgery success. When injections fail, nonmuscular abnormalities should be considered.
Prodromidou, Anastasia; Frountzas, Maximos; Vlachos, Dimitrios-Efthymios G; Vlachos, Georgios D; Bakoyiannis, Ioannis; Perrea, Despina; Pergialiotis, Vasilios
BACKGROUND: Botulinum toxin injections have been investigated for the treatment or prevention of hypertrophic scars in several clinical studies. However, its clinical effectiveness has not yet been established. OBJECTIVE: To examine all available evidence that support the use of botulinum toxin injections for the treatment or prevention of hypertrophic scars in current clinical practice. METHODS: A systematic review searching the MEDLINE (1966 to 2014), Scopus (2004 to 2014), Popline (1974 to 2014), ClinicalTrials.gov (2008 to 2014) and Cochrane Central Register of Controlled Trials (CENTRAL) (1999 to 2014) databases together with reference lists from included studies was conducted. RESULTS: Ten studies (255 patients) were included. Of these, 123 patients were injected with botulinum toxin type A, nine patients were offered botulinum toxin type B and the remaining 123 patients represented the control groups. Significantly improved cosmetic outcomes were observed among certain studies using the visual analogue scale (experimental group: median score 8.25 [range 6 to 10]) versus control group: median score 6.38 [range 2 to 9]; P<0.001) and the Stony Brook Scar Evaluation Scale (experimental group score: 6.7 versus control group score: 4.17; P<0.001) assessments. However, the methodological heterogeneity of the included studies, the lack of control group in the majority of them, the use of subjective scales of measurement and the frequent use of patient self-assessment precluded unbiased results. CONCLUSIONS: Current evidence does not support the usage of botulinum toxin. Future randomized controlled trials are needed in the field to reach firm conclusions regarding its place in current clinical practice. PMID:26665143
Liu, Mengyuan T; Armijo, Bryan S; Guyuron, Bahman
This study was designed to assess whether preoperative trigger-site confirmation using botulinum toxin type A injections significantly improved migraine surgery outcomes. The medical charts of 335 migraine surgery patients were reviewed. Patients who received stepwise diagnostic botulinum toxin type A injections were placed in the botulinum toxin type A group (n = 245). Patients who did not receive botulinum toxin type A or received only therapeutic botulinum toxin type A were placed in the control group (n = 90). The preoperative and 12-month postoperative migraine headache frequency, duration, and intensity were compared to determine the success of the operations. Seventy-two of 90 control patients (80 percent) experienced a significant improvement (a decrease of at least 50 percent in migraine headache frequency, duration, or intensity) at 12 months after surgery, with 29 (32 percent) reporting complete elimination. Of the 245 botulinum toxin type A patients, 207 (84 percent) experienced a significant improvement, with 89 (36 percent) experiencing complete elimination. The surgical success rate of the botulinum toxin type A group was not significantly higher than that of the control group (p = 0.33). Confirmation of trigger sites using botulinum toxin type A does not significantly improve the outcome of migraine surgery. Although botulinum toxin type A can be a useful diagnostic tool, this study demonstrates that there is no statistically significant difference between the injection of botulinum toxin type A and the use of a constellation of symptoms to identify trigger sites. Therapeutic, III.
Serefoglu, Ege C; Hawley, Wayne R; Lasker, George F; Grissom, Elin M; Mandava, Sree H; Sikka, Suresh C; Dohanich, Gary P; Hellstrom, Wayne J G
Premature ejaculation (PE) is the most common male sexual dysfunction. A variety of pharmacotherapeutic strategies have been employed to treat men suffering with lifelong PE. However, there are currently no pharmaceuticals approved by the U.S. Food and Drug Administration specifically designed for PE treatment. Given that the bulbospongiosus muscle is involved in the ejaculatory reflex in both humans and rodents and that local administration of botulinum-A can abolish muscle contractions, the current study examined the effect of injection of botulinum-A toxin into the bulbospongiosus muscle on the ejaculatory latency of male rats. After screening for normal sexual activity with sexually receptive female rats, 33 sexually experienced male Long-Evans rats (Harlan Laboratories, Indianapolis, IN, USA) underwent an additional four pretreatment sexual exposures over the course of the following week, during which all components of sexual behavior were video recorded by trained observers. On the day after their fourth experience, rats were anesthetized and received a single injection of either 0.5 unit (n = 11) or 1 unit (n = 11) of botulinum-A toxin or saline vehicle (n = 11). Botulinum-A toxin was dissolved in 0.1 mL of saline vehicle and injected bilaterally into the bulbospongiosus muscle by the percutaneous route. Beginning 2 days after treatment, sexual behaviors were reexamined over the course of the following week on four separate occasions. The latency to achieve ejaculation, and the frequencies and latencies of mounts and intromissions were video recorded by trained observers in a blinded fashion. Relative to pretreatment measurements, bilateral injection of saline vehicle into the bulbospongiosus muscle did not affect ejaculation latencies. However, rats treated with either 0.5 or 1 unit of botulinum-A toxin exhibited significantly longer latencies to achieve ejaculation relative to pretreatment performance. Of note, botulinum-A toxin did not
Miyashita, Shin-Ichiro; Sagane, Yoshimasa; Suzuki, Tomonori; Matsumoto, Takashi; Niwa, Koichi; Watanabe, Toshihiro
The botulinum neurotoxin (BoNT) causes muscle paralysis and is the most potent toxin in nature. BoNT is associated with a complex of auxiliary “Non-Toxic” proteins, which constitute a large-sized toxin complex (L-TC). However, here we report that the “Non-Toxic” complex of serotype D botulinum L-TC, when administered to rats, exerts in-vivo toxicity on small-intestinal villi. Moreover, Serotype C and D of the “Non-Toxic” complex, but not BoNT, induced vacuole-formation in a rat intestinal epithelial cell line (IEC-6), resulting in cell death. Our results suggest that the vacuole was formed in a manner distinct from the mechanism by which Helicobacter pylori vacuolating toxin (VacA) and Vibrio cholerae haemolysin induce vacuolation. We therefore hypothesise that the serotype C and D botulinum toxin complex is a functional hybrid of the neurotoxin and vacuolating toxin (VT) which arose from horizontal gene transfer from an ancestral BoNT-producing bacterium to a hypothetical VT-producing bacterium. PMID:27507612
Christiansen, L. N.; Tompkin, R. B.; Shaparis, A. B.; Kueper, T. V.; Johnston, R. W.; Kautter, D. A.; Kolari, O. J.
Pork bellies were formulated to 0, 30, 60, 120, 170, or 340 μg of nitrite per g of meat and inoculated with Clostridium botulinum via pickle or after processing and slicing. Processed bacon was stored at 7 or 27 C and assayed for nitrite, nitrate, and botulinal toxin at different intervals. Nitrite levels declined during processing and storage. The rate of decrease was more rapid at 27 than at 7 C. Although not added to the system, nitrate was detected in samples during processing and storage at 7 and 27 C. The amount of nitrate found was related to formulated nitrite levels. No toxin was found in samples incubated at 7 C throughout the 84-day test period. At 27 C, via pickle, inoculated samples with low inoculum (210 C. botulinum per g before processing and 52 per g after processing) became toxic if formulated with 120 μg of nitrite per g of meat or less. Toxin was not detected in bacon formulated with 170 or 340 μg of nitrite per g of meat under these same conditions. Toxin was detected at all formulated nitrite levels in bacon inoculated via the pickle with 19,000 C. botulinum per g (4,300 per g after processing) and in samples inoculated after slicing. However, increased levels of formulated nitrite decreased the probability of botulinal toxin formation in bacon inoculated by both methods. PMID:4596753
Lebeda, Frank J.; Dembek, Zygmunt F.; Adler, Michael
A relatively new approach in the treatment of specific wounds in animal models and in patients with type A botulinum toxin is the focus of this paper. The indications or conditions include traumatic wounds (experimental and clinical), surgical (incision) wounds, and wounds such as fissures and ulcers that are signs/symptoms of disease or other processes. An objective was to conduct systematic literature searches and take note of the reactions involved in the healing process and identify corresponding pharmacokinetic data. From several case reports, we developed a qualitative model of how botulinum toxin disrupts the vicious cycle of muscle spasm, pain, inflammation, decreased blood flow, and ischemia. We transformed this model into a minimal kinetic scheme for healing chronic wounds. The model helped us to estimate the rate of decline of this toxin's therapeutic effect by calculating the rate of recurrence of clinical symptoms after a wound-healing treatment with this neurotoxin. PMID:22174710
Wang, Yu-Lin; Chu, B. H.; Chen, K. H.; Chang, C. Y.; Lele, T. P.; Tseng, Y.; Pearton, S. J.; Ramage, J.; Hooten, D.; Dabiran, A.; Chow, P. P.; Ren, F.
Antibody-functionalized, Au-gated AlGaN /GaN high electron mobility transistors (HEMTs) were used to detect botulinum toxin. The antibody was anchored to the gate area through immobilized thioglycolic acid. The AlGaN /GaN HEMT drain-source current showed a rapid response of less than 5s when the target toxin in a buffer was added to the antibody-immobilized surface. We could detect a range of concentrations from 1to10ng/ml. These results clearly demonstrate the promise of field-deployable electronic biological sensors based on AlGaN /GaN HEMTs for botulinum toxin detection.
Gerwing, Julia; Dolman, Claude E.; Reichmann, M. E.; Bains, Hardial S.
Gerwing, Julia (The University of British Columbia, Vancouver, British Columbia, Canada), Claude E. Dolman, M. E. Reichmann, and Hardial S. Bains. Purification and molecular weight determination of Clostridium botulinum type E toxin. J. Bacteriol. 88:216–219. 1964.—A method was developed whereby type E botulinus toxin can be obtained in a highly purified state by elution through acidified diethylaminoethyl-cellulose columns. The material thus isolated appears to be electrophoretically and ultracentrifugally homogeneous. A molecular weight of 18,600 was calculated for the toxin. Images PMID:14197891
Wong, Shiu Man; Hui, Andrew C F; Tong, Po-Yee; Poon, Dawn W F; Yu, Evelyn; Wong, Lawrence K S
Lateral epicondylitis is a common condition for which botulinum toxin has been reported to have a therapeutic role in uncontrolled studies. To determine if an injection of botulinum toxin is more effective than placebo for reducing pain in adults with lateral epicondylitis. Randomized, double-blind, placebo-controlled trial conducted from September 2002 to December 2004. Outpatient clinics at a university hospital and a district hospital in Hong Kong. 60 patients with lateral epicondylitis. The primary outcome was change in subjective pain as measured by a 100-mm visual analogue scale (VAS) ranging from 0 (no pain) to 10 (worst pain ever) at 4 weeks and 12 weeks. All patients completed post-treatment follow-up. A single injection of 60 units of botulinum toxin type A or normal saline placebo. Mean VAS scores for the botulinum group at baseline and at 4 weeks were 65.5 mm and 25.3 mm, respectively; respective scores for the placebo group were 66.2 mm and 50.5 mm (between-group difference of changes, 24.4 mm [95% CI, 13.0 to 35.8 mm]; P < 0.001). At week 12, mean VAS scores were 23.5 mm for the botulinum group and 43.5 mm for the placebo group (between-group difference of changes, 19.3 mm [CI, 5.6 to 32.9 mm]; P = 0.006). Grip strength was not statistically significantly different between groups at any time. Mild paresis of the fingers occurred in 4 patients in the botulinum group at 4 weeks. One patient's symptoms persisted until week 12, whereas none of the patients receiving placebo had the same complaint. At 4 weeks, 10 patients in the botulinum group and 6 patients in the placebo group experienced weak finger extension on the same side as the injection site. The trial was small, and most participants were women. The blinding protocol may have been ineffective because the 4 participants who experienced paresis of the fingers could have correctly assumed that they received an active treatment. Botulinum toxin injection may improve pain over a 3-month period in
Hexsel, Camile; Hexsel, Doris; Porto, Manoela Donida; Schilling, Juliana; Siega, Carolina
Botulinum neurotoxin type A injection to correct and/or reverse the physical effects of aging process has become one of the most frequently requested cosmetic procedures at an outpatient setting. Careful clinical evaluation together with proper use of the techniques, including pre- and post-procedures recommendations, reconstitution of the products, techniques, and doses, are described in this article. This article also covers the main indications of botulinum neurotoxin type A for aging face and other aesthetic uses, as well as some possible adverse reactions and their management. © 2011 Wiley Periodicals, Inc.
Ramini, Mattia; Parolari, Giovanni; Barbuti, Silvana; Frustoli, Maria Angela; Taddei, Roberta; Pongolini, Stefano; Ardigò, Paolo; Cozzolino, Paolo
The objective of this study was to investigate Clostridium botulinum growth and toxin production in the industrially manufactured Italian Parma ham. The study focuses on the Parma ham production phase identified as maximum risk to C. botulinum proliferation, i.e. the transition from cold phase (salting and resting) to a phase carried out at temperature between 15 and 23°C (drying). A preliminary in vitro test was carried out in order to verify the capability of 6 C. botulinum strains (1 type A, 4 type B, and 1 type E strains) to grow in conditions of temperature, pH and NaCl concentration comparable to those of the beginning stage of ham drying. Five C. botulinum strains grew at 20°C and pH 6, four strains produced toxin when inoculated at a concentration equal to 103 cfu/mL at NaCl concentration of 4%, while when the inoculum concentration was 10 cfu/mL, NaCl concentration of 3% resulted the toxin-genesis limiting factor. An experimental contamination with a mixture of the 5 C. botulinum strains selected by the preliminary in vitro test was performed on 9 thighs inoculated at the end of the resting phase. The study was designed to evaluate the potential growth and toxin production in extremely favourable conditions for the bacterium. Type B proteolytic C. botulinum toxin was produced after 14 days of incubation at 20°C in 2 thighs characterised by high weight, low number of days of resting and anomalous physiochemical characteristics [one for very low NaCl concentration (1.59%), the other for elevated pH (6.27) and both for high water activity values (>0.970)]. The results of this research confirm that the cold resting step is a critical phase in the production process of Parma ham for the investigated hazard. Based on the present study, the long resting phase adopted in the manufacturing of Parma ham is proven effective to prevent the growth of C. botulinum, an event which could not otherwise be excluded if the hams were processed under less stringent
Kerzoncuf, Marjorie; Bensoussan, Laurent; Delarque, Alain; Durand, Jacques; Viton, Jean-Michel; Rossi-Durand, Christiane
The therapeutic effects of intramuscular injections of botulinum toxin-type A on spasticity can largely be explained by its blocking action at the neuromuscular junction. Botulinum toxin-type A is also thought to have a central action on the functional organization of the central nervous system. This study assessed the action of botulinum toxin-type A on spinal motor networks by investigating post-activation depression of the soleus H-reflex in post-stroke patients. Post-activation depression, a presynaptic mechanism controlling the synaptic efficacy of Ia-motoneuron transmission, is involved in the pathophysiology of spasticity. Eight patients with chronic hemiplegia post-stroke presenting with lower limb spasticity and requiring botulinum toxin-type A injection in the ankle extensor muscle. Post-activation depression of soleus H-reflex assessed as frequency-related depression of H-reflex was investigated before and 3, 6 and 12 weeks after botulinum toxin-type A injections in the triceps surae. Post-activation depression was quantified as the ratio between H-reflex amplitude at 0.5 and 0.1 Hz. Post-activation depression of soleus H-reflex, which is reduced on the paretic leg, was affected 3 weeks after botulinum toxin-type A injection. Depending on the residual motor capacity of the post-stroke patients, post-activation depression was either restored in patients with preserved voluntary motor control or further reduced in patients with no residual voluntary control. Botulinum toxin treatment induces synaptic plasticity at the Ia-motoneuron synapse in post-stroke paretic patients, which suggests that the effectiveness of botulinum toxin-type A in post-stroke rehabilitation might be partly due to its central effects.
Sung, Ki Hyuk; Chung, Chin Youb; Lee, Kyoung Min; Lee, Young-Kyun; Lee, Seung Yeol; Lee, Jaebong; Choi, In Ho; Cho, Tae-Joon; Yoo, Won Joon; Park, Moon Seok
The efficacy of using botulinum toxin A injections in cerebral palsy (CP) is controversial. The financial conflict of interest related to medical research can affect the conclusion of an evidence-based review. This study was performed to determine as to what proportion of studies on botulinum toxin A injections in patients with CP was sponsored by the industry and whether the assessments of botulinum toxin injection in CP were associated with industry support. Studies were identified with a search of the PubMed database (January 1991 to November 2011). All prospective, comparative, English language studies on the use of botulinum toxin A injections in patients with CP were included. A total of 374 articles were screened, 128 potentially eligible full articles were retrieved, and 66 studies met our inclusion criteria. The funding sources of the articles were reviewed, and qualitative conclusions regarding the effect of botulinum toxin A injection were classified as being either favorable, neutral, or unfavorable. Of 66 eligible articles, 28 were funded by the industry, and 25 were not. The other 13 studies did not include information on the funding source. A significant association was observed between the funding source and qualitative conclusions (P=0.042). Fifteen (53.6%) of the 28 industry-sponsored studies had favorable conclusions, whereas only 5 (20%) of the 25 non-industry-sponsored studies had favorable conclusions. About half of studies on the effect of botulinum toxin A in CP were sponsored by the industry. This systematic review revealed that the qualitative conclusions in those studies are more favorable to the use of the botulinum toxin A than the non-industry-sponsored studies. Clinicians should be aware of an industry-related conflict of interest regarding reports on the efficacy of botulinum toxin A injections in patients with CP. Level II-therapeutic study.
Marjoux, S; Brochard, C; Roman, S; Gincul, R; Pagenault, M; Ponchon, T; Ropert, A; Mion, F
Endoscopic injections of botulinum toxin in the cardia or distal esophagus have been advocated to treat achalasia and spastic esophageal motility disorders. We conducted a retrospective study to evaluate whether manometric diagnosis using the Chicago classification in high-resolution manometry (HRM) would be predictive of the clinical response. Charts of patients with spastic and hypertensive motility disorders diagnosed with HRM and treated with botulinum toxin were retrospectively reviewed at two centers. HRM recordings were systematically reanalyzed, and a patient's phone survey was conducted. Forty-five patients treated between 2008 and 2013 were included. Most patients had achalasia type 3 (22 cases). Other diagnoses were jackhammer esophagus (8 cases), distal esophageal spasm (7 cases), esophagogastric junction outflow obstruction (5 cases), nutcracker esophagus (1 case), and 2 unclassified cases. Botulinum toxin injections were performed into the cardia only in 9 cases, into the wall of the distal esophagus in 19 cases, and in both locations (cardia and distal esophagus) in 17 cases. No complication occurred in 31 cases. Chest pain was noticed for less than 7 days in 13 cases. One death related to mediastinitis occurred 3 weeks after botulinum toxin injection. Efficacy was assessed in 42 patients: 71% were significantly improved 2 months after botulinum toxin, and 57% remained satisfied for more than 6 months. No clear difference was observed in terms of response according to manometric diagnosis; however, type 3 achalasia previously dilated and with normal integrated relaxation pressure (4s-integrated relaxation pressure < 15 mmHg) had the worst outcome: none of these patients responded to the endoscopic injection of botulinum toxin. Endoscopic injections of botulinum toxin may be effective in some patients with spastic or hypercontractile esophageal motility disorders. The manometric Chicago classification diagnosis does not seem to predict the results
Golden, Max C; Wanless, Brandon J; David, Jairus R D; Kottapalli, Bala; Lineback, D Scott; Talley, Ryan J; Glass, Kathleen A
Clostridium botulinum may be of concern in prepared refrigerated meals, for which strict cold chain management cannot be guaranteed. This study evaluated the effect of temperature, product composition, and cultured celery juice powder (CCJP) as a source of nitrite on the inhibition of botulinum toxin formation in two experimental (meat- and vegetable-based) prepared meals. Data obtained from the challenge study were compared with a published mathematical model to determine whether the model is fail-safe with regard to the tested meals. Treatments were inoculated with proteolytic C. botulinum, vacuum packaged, cooked at 90°C for 10 min, and assayed for botulinum toxin at appropriate intervals in samples stored at 10, 15, or 20°C for up to 8 weeks. None of the treatments stored at 10°C for 8 weeks supported toxin production by proteolytic C. botulinum. The addition of CCJP delayed toxin production by 1 and 3 weeks in cauliflower potatoes and in Dijon pork, respectively, stored at 15°C. Toxin production was delayed by 1 week at 20°C when CCJP was added to the cauliflower potatoes. This study found that the predictive model was fail-safe but was overly conservative for the experimental meals described. Finally, this study confirms that product composition, the addition of nitrite via CCJP, storage time, and temperature play important roles in the inhibition of toxin formation by proteolytic C. botulinum.
Muller, François; Cugy, Emmanuelle; Ducerf, Camille; Delleci, Claire; Guehl, Dominique; Joseph, Pierre-Alain; Burbaud, Pierre; Dehail, Patrick
To determine the safety and the self-reported efficacy of botulinum toxin injections for adult spasticity in current clinical practice. A prospective observational study. A total of 406 adult patients with focal spasticity received of 1136 series botulinum toxin injections at Bordeaux University Hospital from January 2007 to December 2009. Adverse events following botulinum toxin injections were reported. Their severity and the therapeutic efficacy of botulinum toxin injections were estimated with a four-point self-reporting scale (0 to 3). Latency and duration of adverse events and subjective improvement were also noted. The data of 640 series of injections were analyzed. Forty-six (7.2%) adverse events were reported, of which 36 (78%) were local. There were 18 (39%) cases of local muscular weakness with an average duration of 30.0 (SD 38.2) days, and an average severity score of 1.0 (SD 0.97). Among systemic adverse events, there were 8 (17%) cases of excessive fatigue without global muscular weakness and 2 (4%) cases of transitory generalized muscular weakness. The average subjective improvement score was 1.89 (SD 0.97) and was higher for upper, than for lower, limbs (P=0.007). Self-reported adverse events following botulinum toxin injections in spasticity are rare, often benign and of short duration in current clinical practice. Botulinum toxin is considered effective by patients in treating spasticity of the upper and lower limbs.
Basaran, Aynur; Emre, Ufuk; Karadavut, Kiymet Ikbal; Bulmus, Nercivan
To determine the effect of botulinum toxin A on spasticity and somatosensory evoked potentials of hand muscles in patients who have undergone cerebrovascular accident. Preliminary, prospective, before-after study design. Six subjects prospectively followed after application of botulinum toxin A in the rehabilitation department of a university hospital. All patients underwent botulinum toxin A injection to the upper extremity muscles in varying combinations and carried out a home-based exercise programme. Primary outcome measure was median somatosensory evoked potential of hand muscles (N20). Secondary outcome measures were: spasticity assessed clinically by Modified Ashworth Scales (MAS); functional ability analysis assessed by Physician's Rating Scale (PRS); and functional difficulties reported by patients or their care-givers by patient disability and care-giver burden rating scale (PD & CBRS). MAS, PRS and PD & CBRS improved with botulinum toxin A treatment. In the affected limb, N20 potentials were impaired compared with those in the unaffected side. With botulinum toxin A treatment, although improvement in overall N20-P25 amplitudes was significant, as a result of limited sample size, post hoc pair-wise comparisons with Bonferroni correction failed to yield any significant pairs. The improvement in the median somatosensory evoked potentials following botulinum toxin A treatment suggests that central somatosensory patterns in hemiplegia can be modified by peripheral inputs.
Lorenzano, C; Bagnato, S; Gilio, F; Fabbrini, G; Berardelli, A
Botulinum toxin injected into a muscle may diffuse to nearby muscles thus producing unwanted effects. In patients with hemifacial spasm, we evaluated clinically and neurophysiologically, whether botulinum toxin type A (BoNT-A) diffuses from the injection site (orbicularis oculi) to untreated muscles (orbicularis oris from the affected side and orbicularis oculi and oris from the unaffected side). We studied 38 patients with idiopathic hemifacial spasm. Botulinum toxin was injected into the affected orbicularis oculi muscle alone (at 3 standardized sites) at a clinically effective dose. Patients were studied before (T0) and 3-4 weeks after treatment (T1). We evaluated the clinical effects of botulinum toxin and muscle strength in the affected and unaffected muscles. We also assessed the peak-to-peak amplitude compound muscle action potential (CMAP) recorded from the orbicularis oculi and orbicularis oris muscles on both sides after supramaximal electrical stimulation of the facial nerve at the stylomastoid foramen. In all patients, botulinum toxin treatment reduced muscle spasms in the injected orbicularis oculi muscle and induced no muscle weakness in the other facial muscles. The CMAP amplitude significantly decreased in the injected orbicularis oculi muscle, but remained unchanged in the other facial muscles (orbicularis oris muscle on the affected side and contra-lateral unaffected muscles). In conclusion, in patients with hemifacial spasm, botulinum toxin, at a clinically effective dose, induces no clinical signs of diffusion and does not reduce the CMAP size in the nearby untreated orbicularis oris or contralateral facial muscles.
Jhang, Jia-Fong; Jiang, Yuan-Hong; Kuo, Hann-Chorng
Bladder pain syndrome/interstitial cystitis is characterized by bladder pain associated with urgency, frequency, nocturia, dysuria and sterile urine. Recent studies have shown that these bladder dysfunctions could originate from chronic inflammation or urothelial insult and proceed to a cascade of tissue reactions, which finally ascends to the central nervous system. Pilot studies of intravesical injection of botulinum toxin type A for bladder pain syndrome/interstitial cystitis had been introduced since 2005 with a promising result. Recent evidence suggests that botulinum toxin type A could significantly improve symptoms such as daytime frequency, nocturia, pain, quality of life and bladder capacity in bladder pain syndrome/interstitial cystitis patients. Single injection of botulinum toxin could not achieve long-term successful therapeutic result, and repeat injections could provide a better long-term success rate. However, patients with ulcer type bladder pain syndrome/interstitial cystitis might not gain a benefit from botulinum toxin type A injection. Laboratory evidence showed that botulinum toxin type A for bladder pain syndrome/interstitial cystitis injection could induce peripheral desensitization, reduces bladder chronic inflammation and decreases apoptotic signal molecules in the urothelium. The present article reviewed the recent advances of botulinum toxin type A on bladder pain syndrome/interstitial cystitis.
Weickert, M J; Chambliss, G H; Sugiyama, H
Twelve strains of Clostridium botulinum type A and seven strains of Clostridium sporogenes were screened for plasmids by agarose gel electrophoresis of cleared lysates of cells from 5 ml of mid-log-phase culture. Nine type A strains had one or more plasmids of 4.3, 6.8, or 36 megadaltons (MDa); several strains showed a large plasmid of 61 MDa, but it was not consistently recovered. Four C. sporogenes strains had one or more plasmids of 4.3, 5.6 or 36 MDa. Isolates obtained from cultures of plasmid-containing C. botulinum type A strains grown in ionic detergent broth and from spontaneously arising variants were screened both for toxin production and for plasmid content. Toxigenicity of C. botulinum could not be correlated with the presence of any one plasmid. Images PMID:3082278
Wein, Lawrence M; Liu, Yifan
We developed a mathematical model of a cows-to-consumers supply chain associated with a single milk-processing facility that is the victim of a deliberate release of botulinum toxin. Because centralized storage and processing lead to substantial dilution of the toxin, a minimum amount of toxin is required for the release to do damage. Irreducible uncertainties regarding the dose-response curve prevent us from quantifying the minimum effective release. However, if terrorists can obtain enough toxin, and this may well be possible, then rapid distribution and consumption result in several hundred thousand poisoned individuals if detection from early symptomatics is not timely. Timely and specific in-process testing has the potential to eliminate the threat of this scenario at a cost of <1 cent per gallon and should be pursued aggressively. Investigation of improving the toxin inactivation rate of heat pasteurization without sacrificing taste or nutrition is warranted.
Giral, Adnan; Memişoğlu, Kemal; Gültekin, Yücel; İmeryüz, Neşe; Kalaycı, Cem; Ulusoy, Nefise B; Tözün, Nurdan
Background Although lateral internal sphincterotomy is the gold-standard treatment for chronic anal fissure, intrasphincteric injection of botulinum toxin seems to be a reliable new option. The aim of this non-randomized study is to compare the effect of lateral internal sphincterotomy and botulinum toxin injection treatments on the outcome and reduction of anal sphincter pressures in patients with chronic anal fissure. Methods Patients with chronic anal fissure were treated with either botulinum toxin injection or lateral internal sphincterotomy by their own choice. Maximal resting pressure and maximal squeeze pressure measurements were performed before and 2 weeks after treatments by anal manometry. Patients were followed for fissure relapse during 14 months. Results Twenty-one consecutive outpatients with posterior chronic anal fissure were enrolled. Eleven patients underwent surgery and ten patients received botulinum toxin injection treatment. Before the treatment, anal pressures were found to be similar in both groups. After the treatment, the maximal resting pressures were reduced from 104 ± 22 mmHg to 86 ± 15 mmHg in the surgery group (p < 0.05) and from 101 ± 23 mmHg to 83 ± 24 mmHg in the botulinum toxin group (p < 0.05). The mean maximal squeeze pressures were reduced from 70 ± 27 mmHg to 61 ± 32 mmHg (p > 0.05) in the surgery group, and from 117 ± 62 mmHg to 76 ± 34 (p < 0.01) in the botulinum toxin group. The fissures were healed in 70 percent of patients in the botulinum group and 82 percent in the surgery group (p > 0.05). There were no relapses during the 14 months of follow up. Conclusion Lateral internal sphincterotomy and botulinum toxin injection treatments both seem to be equally effective in the treatment of chronic anal fissure. PMID:15035674
Stanker, Larry H.; Scotcher, Miles C.; Cheng, Luisa; Ching, Kathryn; McGarvey, Jeffery; Hodge, David; Hnasko, Robert
Botulism is a serious foodborne neuroparalytic disease, caused by botulinum neurotoxin (BoNT), produced by the anaerobic bacterium Clostridium botulinum. Seven toxin serotypes (A – H) have been described. The majority of human cases of botulism are caused by serotypes A and B followed by E and F. We report here a group of serotype B specific monoclonal antibodies (mAbs) capable of binding toxin under physiological conditions. Thus, they serve as capture antibodies for a sandwich (capture) ELISA. The antibodies were generated using recombinant peptide fragments corresponding to the receptor-binding domain of the toxin heavy chain as immunogen. Their binding properties suggest that they bind a complex epitope with dissociation constants (KD’s) for individual antibodies ranging from 10 to 48 × 10−11 M. Assay performance for all possible combinations of capture-detector antibody pairs was evaluated and the antibody pair resulting in the lowest level of detection (L.O.D.), ~20 pg/mL was determined. Toxin was detected in spiked dairy samples with good recoveries at concentrations as low as 0.5 pg/mL and in ground beef samples at levels as low as 2 ng/g. Thus, the sandwich ELISA described here uses mAb for both the capture and detector antibodies (binding different epitopes on the toxin molecule) and readily detects toxin in those food samples tested. PMID:24253240
Smania, Nicola; Colosimo, Carlo; Bentivoglio, Anna Rita; Sandrini, Giorgio; Picelli, Alessandro
Summary The aim of this survey was to provide an overview of important issues relating to therapeutic strategies based on botulinum toxin type A injection for the treatment of patients with neurological disorders. Two hundred and ten physicians from neurology and neurorehabilitation units in Italian hospitals answered a questionnaire exploring some clinical aspects of the use of botulinum toxin type A in patients with spasticity/dystonia. 66% of the physicians treated patients with dystonia, 80% treated adults with spasticity, and 35% treated children with cerebral palsy. Palpation with no instrumental guidance was the injection technique most commonly used for treating patients with dystonia, spasticity and cerebral palsy; 57% of the physicians evaluated patients instrumentally before toxin injection, while 45% assessed post-injection improvements by instrumental means; 78% of the physicians prescribed (when appropriate) rehabilitation procedures after toxin injection. Our results seem to show that the routine use of botulinum toxin in clinics is far from standardized. PMID:24598392
Dai, Alper I; Demiryürek, Abdullah T
The purpose of this study was to examine whether combination therapy of serial casting and botulinum toxin type A injection can further enhance the effects of botulinum toxin type A in children with cerebral palsy with scissoring of both legs. This study was a prospective and randomized trial. The children were divided into 2 groups, one of which received serial casting after botulinum toxin type A (n = 40), and the other which only received botulinum toxin type A (n = 40). Serial casting started 3 weeks after the botulinum toxin type A. Both groups received physiotherapy. Groups were assessed at baseline then compared at 6 and 12 weeks following the intervention. Significant improvements in Gross Motor Function Measure-66 and Caregiver Health Questionnaire were recorded in both groups ( P < .001). The modified Ashworth scale improved significantly following botulinum toxin type A in the serial casting group ( P < .05), but not in botulinum toxin type A only group. These results suggest that serial casting after botulinum toxin type A can enhance the benefits of botulinum toxin type A in children with cerebral palsy.
Arbizu, Ricardo A; Rodriguez, Leonel
More than a century has elapsed since the identification of Clostridia neurotoxins as the cause of paralytic diseases. Clostridium botulinum is a heterogeneous group of Gram-positive, rod-shaped, spore-forming, obligate anaerobic bacteria that produce a potent neurotoxin. Eight different Clostridium botulinum neurotoxins have been described (A-H) and 5 of those cause disease in humans. These toxins cause paralysis by blocking the presynaptic release of acetylcholine at the neuromuscular junction. Advantage can be taken of this blockade to alleviate muscle spams due to excessive neural activity of central origin or to weaken a muscle for treatment purposes. In therapeutic applications, minute quantities of botulinum neurotoxin type A are injected directly into selected muscles. The Food and Drug Administration first approved botulinum toxin (BT) type A in 1989 for the treatment of strabismus and blepharospasm associated with dystonia in patients 12 years of age or older. Ever since, therapeutic applications of BT have expanded to other systems, including the gastrointestinal tract. Although only a single fatality has been reported to our knowledge with use of BT for gastroenterological conditions, there are significant complications ranging from minor pain, rash and allergic reactions to pneumothorax, bowel perforation and significant paralysis of tissues surrounding the injection (including vocal cord paralysis and dysphagia). This editorial describes the clinical experience and evidence for the use BT in gastrointestinal motility disorders in children. PMID:25992183
Kojima, Shoudou; Eguchi, Hironobu; Ookawara, Tomomi; Fujiwara, Noriko; Yasuda, Jun; Nakagawa, Kazuhiko; Yamamura, Takehira; Suzuki, Keiichiro
Botulism is a highly fatal disease caused by the botulinum progenitor toxin. In this study, the role of oligosaccharides for the binding of botulinum type A progenitor toxin (type A PTX) to human intestinal cells was investigated. The binding of type A PTX to Intestine-407 cells was inhibited by the addition of N-acetyllactosamine, lactose, and galactose. Treatment of Intestine-407 cells with neuraminidase led to a significant increase in the binding of type A PTX, while further digestion of cell surface oligosaccharides by beta-galactosidase and beta-N-acetylhexosaminidase decreased the binding. These results indicate that the N-acetyllactosamine moiety is responsible for the binding of type A PTX. These findings were further confirmed by a binding assay using synthesized oligosaccharides. Interestingly, sialylation or fucosylation of oligosaccharides inhibited the binding of type A PTX. These data suggest that the type A PTX binds to intestinal cells via cell surface N-acetyllactosamine moiety.
Lee, Sang Ju; Jeong, Se Yeong; No, Yeon A; Kim, Beom Joo
Traumatic scars on skin covering areas of high movement, especially areas on the face, can be stressful for patients. We report two cases of traumatic scars that occurred on the chin, and that were successfully treated with a combined therapy of 595-nm pulsed dye laser (PDL) and intramuscular injection of botulinum toxin. After the treatment, good cosmetic results were achieved in both patients. The only adverse effect during and after the treatments was mild pain, which resolved within several days without any additional treatment. In conclusion, the combination of 595-nm PDL and intramuscular botulinum toxin injection was shown to be a safe and effective treatment for traumatic scars on the mobile chin area in Korean patients. PMID:26719648
Lee, Sang Ju; Jeong, Se Yeong; No, Yeon A; Park, Kui Young; Kim, Beom Joo
Traumatic scars on skin covering areas of high movement, especially areas on the face, can be stressful for patients. We report two cases of traumatic scars that occurred on the chin, and that were successfully treated with a combined therapy of 595-nm pulsed dye laser (PDL) and intramuscular injection of botulinum toxin. After the treatment, good cosmetic results were achieved in both patients. The only adverse effect during and after the treatments was mild pain, which resolved within several days without any additional treatment. In conclusion, the combination of 595-nm PDL and intramuscular botulinum toxin injection was shown to be a safe and effective treatment for traumatic scars on the mobile chin area in Korean patients.
Fridman, Esteban A.; Crespo, Marcos; Argüello, Santiago Gomez; Degue, Lorena; Villarreal, Mirta; Bohlhalter, Stephan; Wheaton, Lewis; Hallett, Mark
Background and Purpose Focal spasticity is a significant motor disorder following stroke. Botulinum Toxin Type-A (BoNT-A) is a useful treatment for it. We evaluated kinematic modifications induced by spasticity, and whether or not there is an improvement following injection of BoNT-A. Methods Eight stroke patients with upper limb spasticity, showing a flexor pattern, were evaluated using kinematics before and after focal treatment with BoNT-A. A group of sex and age-matched normal volunteers acted as a control group. Results Repeated-measure ANOVA showed that stroke patients performed slower in comparison to the control group. Following treatment with BoNT-A there was a significant improvement in kinematics in stroke patients while in the control group performance remained unchanged. Conclusions Focal treatment of spasticity with Botulinum Toxin Type-A leads to an adaptive change in the upper limb of spastic stroke patients. PMID:19965856
Dinker, Sudeeptha; Anitha, A; Sorake, Abhinay; Kumar, Kishore
A 23 year old female patient presented with the chief complaint of gummy smile after previously undergoing Orthodontic treatment. Patient had a straight profile with competent lips and during posed and unposed smile the patient exhibited excessive gingival display. Since the patient was unwilling to undergo Orthodontic treatment and apprehensive about surgical procedures, this problem was addressed by injecting Botulinum toxin type-A as an alternative treatment approach. Two weeks post treatment; on follow up examination, improved results were seen without any side effects. As a result, an attractive and confident smile was perceived by the patient. How to cite the article: Dinker S, Anitha A, Sorake A, Kumar K. Management of gummy smile with Botulinum Toxin Type-A: A case report. J Int Oral Health 2014;6(1):111-5. PMID:24653614
Logan, Lynne Romeiser; Klamar, Karl; Leon, Jerry; Fedoriw, Wladislaw
An originally ambulatory 18-yr-old woman with spastic left hemiplegic cerebral palsy developed left plantar fasciitis with a gradual loss of function requiring use of a wheelchair. Her symptoms were resistant to physical therapy. Two hundred units of botulinum toxin A was diluted in 4 mL of saline and injected into the gastrocnemius. Three milliliters of autologous blood was injected into the plantar fascia. She reported decreased pain at 3 days postinjection. At 10 days, she had no pain on walking. Dorsiflexion increased and Ashworth and Tardieu improved. A stretching program was taught and a better-fitting night splint was obtained. At 21 days, she exhibited no pain and increased dorsiflexion. Autologous blood injection combined with botulinum toxin A may be an alternative treatment for resistant plantar fasciitis accompanied by spasticity. Our hypothesis is that chronic plantar fasciitis is a degenerative condition and thus is relieved when a mild inflammatory process is created that leads to healing.
de Oliveira, Ademar Francisco; Silva, Gêssyca Adryene de Menezes; Almeida, Débora Milenna Xavier
ABSTRACT Amyotrophic lateral sclerosis is a progressive and fatal neurodegenerative disease characterized by the degeneration of motor neurons, which are the central nervous system cells that control voluntary muscle movements. The excessive salivation (sialorrhea) is present in approximately 50% of amyotrophic lateral sclerosis cases. Thus, some alternative therapeutic methods are sought, such as anticholinergic drugs and surgery. Recently the use of botulinum toxin applied at a midpoint of the salivary glands, often guided by ultrasound, have demonstrated positive results. The objective was to review the literature to demonstrate an alternative method to treatments of sialorrhea in patients with amyotrophic lateral sclerosis. In recent studies, the efficacy of botulinum toxin is confirmed, although new applications are required. Since the side effects are negligible, this is an alternative to treat amyotrophic lateral sclerosis, and other patients with diseases that present sialorrhea. PMID:27759834
Roche, Nicolas; Zory, Raphaël; Sauthier, Antoine; Bonnyaud, Celine; Pradon, Didier; Bensmail, Djamel
Botulinum toxin injections are used to treat spasticity in stroke. Although this treatment is effective on muscle tone, its effect on functional gait-related activities remains uncertain. The aim of this randomized controlled trial was to determine the effect of a self-rehabilitation programme as an adjunct to botulinum toxin injections on gait-related activities in patients with chronic hemiparesis. Thirty-five outpatients were included. Each patient was randomized to 1 of 2 groups: botulinum toxin + standardized self-rehabilitation programme (R group, n = 19) or botulinum toxin alone (C group, n = 16). Each patient was evaluated with the following tests before botulinum toxin injections and one month afterwards: 10-m timed walk, Timed Up and Go, distance covered in 6 min over an ecological circuit, and the stair test. There were significant improvements in the R group compared with the C group: maximal gait speed improved by 8% (p = 0.003); distance covered in 6 min over an ecological circuit increased by 7.1% (p = 0.01); and time to ascend and to descend a flight of stairs decreased by 9.8% (p = 0.003) and 6.6% (p = 0.009), respectively. The self-rehabilitation programme was well tolerated and safe. These results strongly suggest that a standardized self-rehabilitation programme constitutes a useful adjunct to botulinum toxin injections in order to improve gait-related activities.
Shone, C; Wilton-Smith, P; Appleton, N; Hambleton, P; Modi, N; Gatley, S; Melling, J
A monoclonal antibody (BA11) has been produced against Clostridium botulinum type A neurotoxin by the fusion of myeloma cells (P3 NS1/1-Ag4-1) with spleen cells from BALB/c mice immunized with botulinum type A neurotoxoid. The antibody bound specifically to botulinum type A neurotoxin, showing no cross-reactivity with types B and E botulinum toxins or with any of several other bacterial toxins tested. The monoclonal antibody did not bind to botulinum type A neurotoxin which had been denatured with sodium dodecyl sulfate and bound only weakly to each of the separated heavy and light subunits of the neurotoxin, suggesting a conformational requirement for the antigenic determinant of the antibody. A sensitive immunoassay for C. botulinum type A toxin with monoclonal antibody BA11 in conjunction with an enzyme amplication system has been developed which allows detection of 5 to 10 mouse 50% lethal doses ml-1 of purified neurotoxin. The assay was equally sensitive when applied to the detection of crude toxin in food stuffs; the average value for the minimum level of detectable toxin in extracts of tinned salmon or corned beef was 9 +/- 3.1 mouse 50% lethal doses ml-1. PMID:3927840
Al-Saleem, Fetweh H; Ancharski, Denise M; Joshi, Suresh G; Elias, M; Singh, Ajay; Nasser, Zidoon; Simpson, Lance L
Botulinum toxin is a highly potent oral and inhalation poison, which means that the toxin must have an efficient mechanism for penetration of epithelial barriers. To date, three models for toxin passage across epithelial barriers have been proposed: (i) the toxin itself undergoes binding and transcytosis; (ii) an auxiliary protein, HA35, transports toxin from the apical to the basal side of epithelial cells; and (iii) an auxiliary protein, HA35, acts on the basal side of epithelial cells to disrupt tight junctions, and this permits paracellular flux of toxin. These models were evaluated by studying toxin absorption following inhalation exposure in mice. Three types of experiments were conducted. In the first, the potency of pure neurotoxin was compared with that of progenitor toxin complex, which contains HA35. The results showed that the rate and extent of toxin absorption, as well as the potency of absorbed toxin, did not depend upon, nor were they enhanced by, the presence of HA35. In the second type of experiment, the potencies of pure neurotoxin and progenitor toxin complex were compared in the absence or presence of antibodies on the apical side of epithelial cells. Antibodies directed against the neurotoxin protected against challenge, but antibodies against HA35 did not. In the final type of experiment, the potency of pure neurotoxin and toxin complex was compared in animals pretreated to deliver antibodies to the basal side of epithelial cells. Once again, antibodies directed against the neurotoxin provided resistance to challenge, but antibodies directed against HA35 did not. Taken collectively, the data indicate that the toxin by itself is capable of crossing epithelial barriers. The data do not support any hypothesis in which HA35 is essential for toxin penetration of epithelial barriers.
Dover, Nir; Barash, Jason R.; Burke, Julianne N.; ...
Botulinum neurotoxin (BoNT) is the most poisonous substances known and its eight toxin types (A to H) are distinguished by the inability of polyclonal antibodies that neutralize one toxin type to neutralize any of the other seven toxin types. Infant botulism, an intestinal toxemia orphan disease, is the most common form of human botulism in the United States. It results from swallowed spores of Clostridium botulinum (or rarely, neurotoxigenic Clostridium butyricum or Clostridium baratii) that germinate and temporarily colonize the lumen of the large intestine, where, as vegetative cells, they produce botulinum toxin. Botulinum neurotoxin is encoded by the bontmore » gene that is part of a toxin gene cluster that includes several accessory genes. In this paper, we sequenced for the first time the complete botulinum neurotoxin gene cluster of nonproteolytic C. baratii type F7. Like the type E and the nonproteolytic type F6 botulinum toxin gene clusters, the C. baratii type F7 had an orfX toxin gene cluster that lacked the regulatory botR gene which is found in proteolytic C. botulinum strains and codes for an alternative σ factor. In the absence of botR, we identified a putative alternative regulatory gene located upstream of the C. baratii type F7 toxin gene cluster. This putative regulatory gene codes for a predicted σ factor that contains DNA-binding-domain homologues to the DNA-binding domains both of BotR and of other members of the TcdR-related group 5 of the σ70 family that are involved in the regulation of toxin gene expression in clostridia. We showed that this TcdR-related protein in association with RNA polymerase core enzyme specifically binds to the C. baratii type F7 botulinum toxin gene cluster promoters. Finally, this TcdR-related protein may therefore be involved in regulating the expression of the genes of the botulinum toxin gene cluster in neurotoxigenic C. baratii.« less
Hosp, Christine; Naumann, Markus K; Hamm, Henning
Primary focal hyperhidrosis is a common autonomic disorder that significantly impacts quality of life. It is characterized by excessive sweating confined to circumscribed areas, such as the axillae, palms, soles, and face. Less frequent types of focal hyperhidrosis secondary to underlying causes include gustatory sweating in Frey's syndrome and compensatory sweating in Ross' syndrome and after sympathectomy. Approval of onabotulinumtoxinA for severe primary axillary hyperhidrosis in 2004 has revolutionized the treatment of this indication. Meanwhile further type A botulinum neurotoxins like abobotulinumtoxinA and incobotulinumtoxinA, as well as the type B botulinum neurotoxin rimabotulinumtoxinB are successfully used off-label for axillary and various other types of focal hyperhidrosis. For unexplained reasons, the duration of effect differs considerably at different sites. Beside hyperhidrosis, botulinum neurotoxin is also highly valued for the treatment of sialorrhea affecting patients with Parkinson's disease, cerebral palsy, amyotrophic lateral sclerosis, motor neuron disease, and other neurologic conditions. With correct dosing and application, side effects are manageable and transient.
Jang, Dae-Hyun; Sung, In Young
To identify factors associated with the efficacy of botulinum toxin-A (BoNT-A) injections. Thirty-eight children with spastic cerebral palsy (CP) received BoNT-A injections into the gastrocnemius. The baseline anti-botulinum antibodies were checked. The Static dorsiflexion range of motion (ROM), Modified Tardieu Scale (MTS) and Physician Rating Scale (PRS) were assessed at pre-injection as well as 4- and 12-week post-injection. No samples contained anti-botulinum antibodies. Greater baseline MTS dynamic range was associated with greater changes in MTS dynamic ranges at 4-week post-injection. More frequent physical therapy was associated with greater changes in static dorsiflexion ROM at 4-week post-injection and greater changes in PRS at 4- and 12-week post-injection. The improvement in PRS at 12-week post-injection was associated with the frequency of physical therapy. Therefore, intensive physical therapy programs may be necessary to maintain the beneficial effects of BoNT-A injections in children with CP.
Mathevon, L; Michel, F; Decavel, P; Fernandez, B; Parratte, B; Calmels, P
Botulinum toxin type A manages spasticity disorders in neurological central diseases. Some studies have reported that it might induce muscle changes. We present a literature review abiding by the PRISMA statement guidelines. The purpose was to explore the structural and passive biomechanical muscle properties after botulinum toxin type A injections in healthy and spastic limb muscles, on animals and humans, as well as methods for evaluating these properties. We searched the PubMed and Cochrane Library databases using the following keywords: "Botulinum toxin" AND ("muscle structure" OR "muscle atrophy") and, "Botulinum toxin" AND "muscle elasticity". From the 228 initially identified articles, 21 articles were included. Histological analyses were performed, especially on animals. A neurogenic atrophy systematically occurred. In humans, one year after a single injection, the histological recovery remained incomplete. Furthermore, 2D ultrasound analyses showed a reduction of the gastrocnemius thickness and pennation angle. MRI volumetric analysis evidenced muscular atrophy six months or one year after a single injection. Passive muscle stiffness depends on these structural changes. On the short term, the biomechanical analysis showed an elastic modulus increase in animals whereas no change was recorded in humans. On the short term, ultrasound elastography imaging showed a decreased elastic modulus. To date, few data are available, but all show a structural and mechanical muscle impact post injections, specifically muscle atrophy which can linger over time. Further studies are necessary to validate this element, and the possibility of change must be taken into account particularly with repeated injections. Thus, in clinical practice, 2D ultrasound and ultrasound elastography are two non-invasive techniques that will help physicians to develop an efficient long term monitoring. Copyright © 2015 Elsevier Masson SAS. All rights reserved.
Botulinum toxin (BTX) has gained a great interest in cosmetic dermatology for its effects on hyperkinetic facial lines. Understanding the basic research and analysis of effects of this potent drug can lead to other possible indications of interest for dermatologists. The use of BTX in focal hyperhidrosis is well established, but BTX has also effects on pain perception, itch and inflammation as discussed in this review. PMID:20300330
Karp, Barbara Illowsky; Alter, Katharine
Blepharospasm is a focal dystonia characterized by involuntary, repetitive eye closure. Orofacial and oromandibular dystonia describe involuntary dystonic movements of orofacial and oromandibular musculature. Hemifacial spasm is characterized by repetitive synchronous contraction of facial nerve innervated muscles on one side of the face. In this article, the clinical presentation, epidemiology, and approaches to treatment are reviewed. Technical aspects of using botulinum toxin for treatment and reported outcomes are discussed.
Zhao, HongMei; Lian, YaJun
Raynaud's phenomenon is often accompanied by pain, digital ulceration and compromised daily activities. Pharmacological therapy or sympathectomies have been administered to diminish these symptoms but existing treatments are not invariably efficacious. A recent case series has described the use of botulinum toxin type A in the treatment of Raynaud's phenomenon. We report two patients with severe or mild Raynaud's phenomenon who were injected with BTX-A; both of whom experienced clinical and image improvement after treatment.
Sundaram, Hema; Huang, Po-Han; Hsu, Nai-Jen; Huh, Chang Hun; Wu, Woffles T.L.; Wu, Yan; Cassuto, Daniel; Kerscher, Martina J.
Background: Botulinum toxin type A remains the most popular nonsurgical aesthetic treatment worldwide. Previous consensus statements have focused on Caucasians and on Koreans as generally representative of Asians. However, indications and dosages vary among different ethnic groups. This publication reports the results of a multidisciplinary, pan-Asian consensus focusing on incobotulinumtoxinA. Methods: A consensus group of plastic surgeons and dermatologists from Asia, Europe, and the United States convened for a live meeting in Asia, followed by a questionnaire-based Delphi procedure. Treatment of Asians in both their native countries and countries of migration was discussed. Results: For most items, the group achieved a majority consensus. A number of treatment indications, strategies, and dosages were identified in Asians, which are distinct to those previously described for Caucasians due to differences in facial morphotypes, anatomy, and cultural expectations. The group also formulated position statements for intradermal botulinum toxin type A (“mesotoxin”), body shaping with the calves as a paradigm, and reduction of parotid glands. While Asians have previously been considered a homogeneous group for the purposes of aesthetic treatment, this publication considers regional variations. A new classification of Asian facial morphotypes is proposed to aid treatment planning and implementation. Conclusions: This is the first pan-Asian consensus for aesthetic use of botulinum toxin type A. Its unique objective is to optimize treatment safety and efficacy for patients of complete or part-Asian ancestry in all regions. The recommendations for incobotulinumtoxinA may be extended with care to other botulinum toxin formulations. PMID:28293488
Durkee, Charles; Groth, Travis
Introduction. We present a novel case of persistent autonomic dysreflexia in a pediatric spinal cord injury patient treated successfully with intravesical botulinum toxin. Study Design. A retrospective chart review of one patient seen at the Children's Hospital of Wisconsin from 2006 to 2012 was performed. Results. A pediatric spinal cord injury patient with known neurogenic bladder presented with severe hypertension consistent with autonomic dysreflexia. His symptoms and hypertension did not improve with conservative measures, and he necessitated ICU admission and antihypertensive drips. He was taken to the operating room for intravesical botulinum toxin for refractory bladder spasms. Following this, his symptoms abated, and he was weaned off IV antihypertensives and returned to his baseline state. His symptoms were improved for greater than six months. Conclusions. There are few treatment options for the management of refractory autonomic dysreflexia. Intravesical botulinum toxin has never been reported for this use. Dedicated research is warranted to assess its efficacy, as it was used successfully to abort autonomic dysreflexia in this patient. PMID:27006855
Singer, Barbara J.; Silbert, Benjamin I.; Silbert, Peter L.; Singer, Kevin P.
Anterior knee pain is a highly prevalent condition affecting largely young to middle aged adults. Symptoms can recur in more than two thirds of cases, often resulting in activity limitation and reduced participation in employment and recreational pursuits. Persistent anterior knee pain is difficult to treat and many individuals eventually consider a surgical intervention. Evidence for long term benefit of most conservative treatments or surgical approaches is currently lacking. Injection of Botulinum toxin type A to the distal region of vastus lateralis muscle causes a short term functional “denervation” which moderates the influence of vastus lateralis muscle on the knee extensor mechanism and increases the relative contribution of the vastus medialis muscle. Initial data suggest that, compared with other interventions for anterior knee pain, Botulinum toxin type A injection, in combination with an active exercise programme, can lead to sustained relief of symptoms, reduced health care utilisation and increased activity participation. The procedure is less invasive than surgical intervention, relatively easy to perform, and is time- and cost-effective. Further studies, including larger randomized placebo-controlled trials, are required to confirm the effectiveness of Botulinum toxin type A injection for anterior knee pain and to elaborate the possible mechanisms underpinning pain and symptom relief. PMID:26308056
Arroyo-Yllanes, María Estela; Pérez-Pérez, José Fernando; Murillo-Murillo, Leopoldo
We undertook this study to evaluate the results of the treatment with botulinum toxin in patients with esotropia and psychomotor delay. Patients with esotropia and delayed psychomotor development, in rehabilitation therapy and without previous surgery were included. A complete ophthalmological and strabismological exploration was performed including cycloplegic refraction with atropine 1%. Botulinum toxin was applied under sedation in both internal recti. Results were evaluated 1 week, 1 month, 3 and 6 months and after 1 year of application. The reinjection was decided if a 25 DP esotropia or greater was obtained before 3 months of the first application. A good result was considered in patients who had 10 DP of deviation and variability <10 DP. Thirty two patients were included. There were 14 were women and 18 men with an age range from 5 months to 5 years (average 16.8 months). Eighteen patients had variability in the angle of deviation from 20 to 45 DP of esotropia and 14 without variability with an average of 39.12 DP. Thirteen patients were reinjected. A good result was obtained in 10 patients, fair in 17 patients and poor in 5 patients due to persistence of variability in four cases and 15 DP hypertropia in one. Application of botulinum toxin is a therapeutic alternative in patients with esotropia and psychomotor delay.
Singer, Barbara J; Silbert, Benjamin I; Silbert, Peter L; Singer, Kevin P
Anterior knee pain is a highly prevalent condition affecting largely young to middle aged adults. Symptoms can recur in more than two thirds of cases, often resulting in activity limitation and reduced participation in employment and recreational pursuits. Persistent anterior knee pain is difficult to treat and many individuals eventually consider a surgical intervention. Evidence for long term benefit of most conservative treatments or surgical approaches is currently lacking. Injection of Botulinum toxin type A to the distal region of vastus lateralis muscle causes a short term functional "denervation" which moderates the influence of vastus lateralis muscle on the knee extensor mechanism and increases the relative contribution of the vastus medialis muscle. Initial data suggest that, compared with other interventions for anterior knee pain, Botulinum toxin type A injection, in combination with an active exercise programme, can lead to sustained relief of symptoms, reduced health care utilisation and increased activity participation. The procedure is less invasive than surgical intervention, relatively easy to perform, and is time- and cost-effective. Further studies, including larger randomized placebo-controlled trials, are required to confirm the effectiveness of Botulinum toxin type A injection for anterior knee pain and to elaborate the possible mechanisms underpinning pain and symptom relief.
Singh, Swati; Ali, Mohammad Javed; Paulsen, Friedrich
To review the published literature on botulinum toxin (BTX) for epiphora secondary to refractory lacrimal drainage disorders. The authors performed a Pub Med search of all articles published in English on BTX injection into lacrimal gland for epiphora secondary to lacrimal drainage disorders. Relevant cross-references were obtained from the resultant studies. Data reviewed included demographics, indications, dose of BTX, number of injections, transconjunctival or transcutaneous route, outcomes and complications. Animal experiments of BTX into lacrimal gland were included and analyzed separately. Botulinum toxin injection into lacrimal gland, in animal studies, has shown to reduce the tear volume significantly lasting for approximately a month without any histological changes. The major indications have been refractory canalicular obstructions and functional epiphora. The commonly used dose was 2.5 U. Outcomes in the few studies published are encouraging with transient ptosis being the most common complication. Botulinum toxin into the lacrimal gland is a minimally invasive alternative in cases of refractory epiphora secondary to lacrimal drainage disorders. In these subsets of patients, the reported concentrations, dosage and outcome measures are variable and need larger studies for standardization.
Cullen, D M; Boyle, J J W; Silbert, P L; Singer, B J; Singer, K P
Intramuscular injection of Botulinum toxin to produce reduction of focal muscle overactivity, and localized muscle spasm, has been utilized therapeutically for almost two decades. Muscle overactivity in neurologically normal muscle, where an imbalance exists between a relatively overactive muscle and its less active synergist or antagonist, can inhibit control of the antagonist producing a functional muscle imbalance. This brief review provides an overview of the role of muscle imbalance in sports-related pain and dysfunction, and outlines the potential for intramuscular injection of Botulinum toxin to be used as an adjunct to specific muscle re-education and functional rehabilitation in this patient group. A comprehensive understanding of normal movement and the requirements of the sporting activity are essential to allow accurate diagnosis of abnormal motor patterns and to re-educate more appropriate movement strategies. Therapeutic management of co-impairments may include stretching of tight soft tissues, specific re-education aimed at isolation of the non-dominant weak muscles and improvement in their activation, 'unlearning' of faulty motor patterns, and eventual progression onto functional exercises to anticipate gradual return to sporting activity. Intramuscular injection of Botulinum toxin, in carefully selected cases, provides short term reduction of focal muscle overactivity, and may facilitate activation of relatively 'inhibited' muscles and assist the restoration of more appropriate motor patterns.
Kesikburun, Serdar; Alaca, Rıdvan; Aras, Berke; Tuğcu, Ilknur; Tan, Arif Kenan
Bruxism is involuntary grinding of the teeth and can occur as a complication of brain injury. If untreated, bruxism can lead to severe occlusal trauma. Herein, we present a patient with traumatic brain injury and nocturnal bruxism that was treated with botulinum toxin injection. A 21 yr old male patient with traumatic brain injury from a car accident was admitted to our inpatient rehabilitation unit. He had a history of coma for 2 wk in the intensive care unit. The initial cranial computed tomography scan indicated a superior thalamic hemorrhage. On admission to our department 3 mo postinjury, his mental status was good and he was able to walk without assistance, but he had mild ataxia. He complained about severe teeth grinding at night, which began 2 mo postinjury. Botulinum toxin-A was injected into the masseter muscles (20 U in each muscle) and temporalis muscles (15 U in each muscle) bilaterally. A decrease in bruxism was reported within 3 d. Clinical improvement persisted at assessment 4 mo posttreatment. Botulinum toxin injection can be used as an effective treatment for bruxism associated with brain injury.
Kirma, Nameer; Ferreira, Joseph L; Baumstark, Barbara R
Six Clostridium botulinum isolates exhibiting type A toxicity as measured by the mouse bioassay were found to contain both type A and type B neurotoxin DNA sequences. The six strains were divided into three groups based on the DNA sequence of the type B neurotoxin gene. Members of each group exhibited 100% sequence identity over the 3876 bp type B toxin open reading frame. The type B toxin sequence of all groups differed at more than 60 positions when compared to the BGB control strain.
Buonocore, Michelangelo; Demartini, Laura; Mandrini, Silvia; Dall'Angelo, Anna; Dalla Toffola, Elena
This case presentation describes a 47-year-old woman who developed complex regional pain syndrome type II with severe neuropathic pain following iatrogenic transection of the tibial nerve at the ankle. The pain and disability progressively worsened over time, markedly impaired ambulation, and were not relieved despite various analgesic treatments. After injection of botulinum toxin (abobotulinumtoxinA, BoNT-A) in the leg muscles the tendons of which pass through the tarsal tunnel (together with the tibial nerve), her pain decreased and her walking capacity improved. This case suggests a new therapeutic role for botulin toxin in treating peripheral neuropathic pain caused by movement-evoked ectopic potentials.
Chun, Chan Lan; Ochsner, Urs; Byappanahalli, Muruleedhara N.; Whitman, Richard L.; Tepp, William H.; Lin, Guangyun; Johnson, Eric A.; Peller, Julie; Sadowsky, Michael J.
Avian botulism, a paralytic disease of birds, often occurs on a yearly cycle and is increasingly becoming more common in the Great Lakes. Outbreaks are caused by bird ingestion of neurotoxins produced by Clostridium botulinum, a spore-forming, gram-positive, anaerobe. The nuisance, macrophytic, green alga Cladophora (Chlorophyta; mostly Cladophora glomerata L.) is a potential habitat for the growth of C. botulinum. A high incidence of botulism in shoreline birds at Sleeping Bear Dunes National Lakeshore (SLBE) in Lake Michigan coincides with increasingly massive accumulations of Cladophora in nearshore waters. In this study, free-floating algal mats were collected from SLBE and other shorelines of the Great Lakes between June and October 2011. The abundance of C. botulinum in algal mats was quantified and the type of botulism neurotoxin (bont) genes associated with this organism were determined by using most-probable-number PCR (MPN-PCR) and five distinct bont gene-specific primers (A, B, C, E, and F). The MPN-PCR results showed that 16 of 22 (73%) algal mats from the SLBE and 23 of 31(74%) algal mats from other shorelines of the Great Lakes contained the bont type E (bont/E) gene. C. botulinum was present up to 15 000 MPN per gram dried algae based on gene copies of bont/E. In addition, genes for bont/A and bont/B, which are commonly associated with human diseases, were detected in a few algal samples. Moreover, C. botulinum was present as vegetative cells rather than as dormant spores in Cladophora mats. Mouse toxin assays done using supernatants from enrichment of Cladophora containing high densities of C. botulinum (>1000 MPN/g dried algae) showed that Cladophora-borne C. botulinum were toxin-producing species (BoNT/E). Our results indicate that Cladophora provides a habitat for C. botulinum, warranting additional studies to better understand the relationship between this bacterium and the alga, and how this interaction potentially contributes to botulism
Chun, Chan Lan; Ochsner, Urs; Byappanahalli, Muruleedhara N; Whitman, Richard L; Tepp, William H; Lin, Guangyun; Johnson, Eric A; Peller, Julie; Sadowsky, Michael J
Avian botulism, a paralytic disease of birds, often occurs on a yearly cycle and is increasingly becoming more common in the Great Lakes. Outbreaks are caused by bird ingestion of neurotoxins produced by Clostridium botulinum, a spore-forming, gram-positive, anaerobe. The nuisance, macrophytic, green alga Cladophora (Chlorophyta; mostly Cladophora glomerata L.) is a potential habitat for the growth of C. botulinum. A high incidence of botulism in shoreline birds at Sleeping Bear Dunes National Lakeshore (SLBE) in Lake Michigan coincides with increasingly massive accumulations of Cladophora in nearshore waters. In this study, free-floating algal mats were collected from SLBE and other shorelines of the Great Lakes between June and October 2011. The abundance of C. botulinum in algal mats was quantified and the type of botulism neurotoxin (bont) genes associated with this organism were determined by using most-probable-number PCR (MPN-PCR) and five distinct bont gene-specific primers (A, B, C, E, and F). The MPN-PCR results showed that 16 of 22 (73%) algal mats from the SLBE and 23 of 31(74%) algal mats from other shorelines of the Great Lakes contained the bont type E (bont/E) gene. C. botulinum was present up to 15000 MPN per gram dried algae based on gene copies of bont/E. In addition, genes for bont/A and bont/B, which are commonly associated with human diseases, were detected in a few algal samples. Moreover, C. botulinum was present as vegetative cells rather than as dormant spores in Cladophora mats. Mouse toxin assays done using supernatants from enrichment of Cladophora containing high densities of C. botulinum (>1000 MPN/g dried algae) showed that Cladophora-borne C. botulinum were toxin-producing species (BoNT/E). Our results indicate that Cladophora provides a habitat for C. botulinum, warranting additional studies to better understand the relationship between this bacterium and the alga, and how this interaction potentially contributes to botulism
Namazi, Hamid; Torabi, Simin
This study aimed to investigate the effects of intra-articular botulinum toxin in preventing arthrofibrosis. Arthrofibrosis was induced in both stifle joints of 20 rabbits by transecting the anterior cruciate ligament under intramuscular anesthesia with ketamine and xylazine. Intra-articular toxin at a dose of 0.6 ml (50 unit) and physiologic saline solution (0.6 ml) were injected into the right and left stifle joints, respectively, 3 times with a 1-week interval between each injection. The rabbits were euthanized in the 12th week via high dose anesthesia to remove the stifle joint. The severity of adhesions was assessed, applying a universal scoring system. Also the stifle joints were histologically evaluated for fibrosis. With regards to severity of adhesion a significant reduction in the adhesion score was observed in the toxin-treated group in comparison to untreated controls with mean +/- SE values of 0.2 +/- 0.1 and 2.4 +/- 0.2, respectively (p < 0.01). The histological evaluation showed no significant fibroblast in the toxin-treated group versus dense fibers with mature fibroblasts in the control group. Our results suggest that botulinum toxin demonstrated efficacy in preventing adhesion after knee surgery and all the parameters monitored showed consistent statistically significant improvement.
Boroff, Daniel A.; Nyberg, Sverker; Höglund, Stefan
Electron micrographs of the toxin and the hemagglutinin of type A Clostridium botulinum showed the toxin to be either round or disclike particles of 4 to 4.5 nm. These particles could also be seen as arranged in long strands or tubules of 9 nm in width. The hemagglutinin appeared as a crystalloid monolayer of stacked particles of 9 nm forming regularly arranged structures of 20 nm. Seen in cross section, these structures appeared as tubules with a lumen of 9 nm. The regularity of the angle of 83° to the long axis of the structure in which the individual particles were arranged suggested that the hemagglutinins formed a helix with sufficient space within its coil to admit the strands of the toxins. A model of the possible arrangement of the toxin and the hemagglutinin in the native state is proposed. Images PMID:4565051
Lin, Jin Xin; Krishna, Sanjeev; Su'a, Bruce; Hill, Andrew G
Chronic anal fissures are associated with significant morbidity and reduced quality of life. Studies have investigated the efficacy of botulinum toxin with variable results; thus, there is currently no consensus on botulinum toxin dose or injection sites. This study aimed to systematically analyze trials studying the efficacy of botulinum toxin for treatment of chronic anal fissure to identify an optimum dosage and injection regimen. A comprehensive review of the literature was conducted according to PRISMA guidelines. PubMed/Medline, Embase, Scopus, and the Cochrane Library were searched from inception to June 2015. All clinical trials that investigated the efficacy of botulinum toxin for chronic anal fissure were selected according to specific criteria. The interventions used were various doses of botulinum toxin. Clinical outcomes, dosage, and injection site data were evaluated with weighted pooled results for each dosage and 95% confidence intervals. There were 1158 patients, with 661 in botulinum toxin treatment arms, from 18 clinical trials included in this review. The outcomes of interest were 3-month healing, incontinence, and recurrence rates. Meta-regression analysis demonstrated a small decrease in healing rate (0.34%; 95% CI, 0-0.68; p = 0.048) with each increase in dosage, a small increase in incontinence rate (1.02 times; 95% CI, 1.0002-1.049; p = 0.048) with each increase in dosage and a small increase in recurrence rate (1.037 times; 95% CI, 1.018-1.057; p = 0.0002) with each increase in dosage. The optimum injection site could not be determined. This study was limited by weaknesses in the underlying evidence, such as variable quality, short follow-up, and a limited range of doses represented. Fissure healing with lower doses of botulinum toxin is as effective as with high doses. Lower doses also reduce the risk of incontinence and recurrence in the long term.
Haykal, Siba; Arad, Ehud; Bagher, Shaghayegh; Lai, Carolyn; Hohman, Marc; Hadlock, Tessa; Zuker, Ronald M; Borschel, Gregory H
Botulinum toxin A has been described as an effective adjunct treatment for achieving symmetry in adults with facial paralysis. Few investigators have described the use of botulinum toxin A in pediatric patients with facial paralysis. To present our preliminary experience with botulinum toxin A in pediatric patients presenting with asymmetry of the lower lip. We performed a retrospective medical record review of all pediatric patients (age range, 4-17 years; mean [SD] age, 11.2 [4.7] years) with facial paralysis who were treated with botulinum toxin A injections from January 1, 2004, through December 31, 2012. Patients presented for treatment at The Hospital for Sick Children, Toronto, Ontario, Canada, or the Massachusetts Eye and Ear Infirmary, Boston. Using facial analysis software, we measured lower lip asymmetry in the patients' photographs before and after treatment, at rest, and in a dynamic state. We performed analysis of variance to assess for improvement in symmetry. We identified 18 patients with the following 3 primary indications for treatment: focal lip asymmetry (n = 11), extensive hemifacial asymmetry (n = 5), and focal synkinesis (n = 2). We found no complications related to botulinum toxin A treatment. The mean (SD) dynamic deviation before the injection was 3.5 (1.7) mm, whereas the mean dynamic deviation after the injection was 1.5 (0.8) mm. The mean (SD) deviation correction was evaluated at 61% (6%) and was statistically significant (P = .04). Botulinum toxin A injection is a safe procedure for improving localized asymmetry in pediatric patients with facial paralysis. Preliminary results indicate that botulinum toxin A may be an effective treatment for lower lip asymmetry in children and adolescents. 4.
Suzuki, Tomonori; Nagano, Thomas; Niwa, Koichi; Uchino, Masataka; Tomizawa, Motohiro; Sagane, Yoshimasa; Watanabe, Toshihiro
A non-toxigenic mutant of the toxigenic serotype C Clostridium botulinum strain Stockholm (C-St), C-N71, does not produce the botulinum neurotoxin (BoNT). However, the original strain C-St produces botulinum toxin complex, in which BoNT is associated with non-toxic non-hemagglutinin (NTNHA) and three hemagglutinin proteins (HA-70, HA-33, and HA-17). Therefore, in this study, we aimed to elucidate the effects of bont gene knockout on the formation of the "toxin complex." Nucleotide sequence analysis revealed that a premature stop codon was introduced in the bont gene, whereas other genes were not affected by this mutation. Moreover, we successfully purified the "toxin complex" produced by C-N71. The "toxin complex" was identified as a mixture of NTNHA/HA-70/HA-17/HA-33 complexes with intact NTNHA or C-terminally truncated NTNHA, without BoNT. These results indicated that knockout of the bont gene does not affect the formation of the "toxin complex." Since the botulinum toxin complex has been shown to play an important role in oral toxin transport in the human and animal body, a non-neurotoxic "toxin complex" of C-N71 may be valuable for the development of an oral drug delivery system.
Čapek, Petr; Dickerson, Tobin J.
Sensitive and rapid detection of botulinum neurotoxins (BoNTs), the most poisonous substances known to date, is essential for studies of medical applications of BoNTs and detection of poisoned food, as well as for response to potential bioterrorist threats. Currently, the most common method of BoNT detection is the mouse bioassay. While this assay is sensitive, it is slow, quite expensive, has limited throughput and requires sacrificing animals. Herein, we discuss and compare recently developed alternative in vitro detection methods and assess their ability to supplement or replace the mouse bioassay in the analysis of complex matrix samples. PMID:22069545
Capek, Petr; Dickerson, Tobin J
Sensitive and rapid detection of botulinum neurotoxins (BoNTs), the most poisonous substances known to date, is essential for studies of medical applications of BoNTs and detection of poisoned food, as well as for response to potential bioterrorist threats. Currently, the most common method of BoNT detection is the mouse bioassay. While this assay is sensitive, it is slow, quite expensive, has limited throughput and requires sacrificing animals. Herein, we discuss and compare recently developed alternative in vitro detection methods and assess their ability to supplement or replace the mouse bioassay in the analysis of complex matrix samples.
Song, J-H; Zhang, G-B; Ding, X-D; Huang, L; Hong, Y; Chen, H-X
To investigate the clinical value of the combination of ultrasound-and-hyponome-guided type A botulinum toxin injection and infrared polarized light on treating chronic migraine. Ninety-one patients with chronic migraine were randomly divided into four groups: in the control group (group A, 22 cases in total), nimodipine was used in the treatment of chronic migraine for two months; in the infrared polarized light therapy group (group B, 22 cases in total), infrared polarized light was adopted in the treatment of chronic migraine for 50-60d; in the botulinum toxin treatment group (group C, 24 cases in total), ultrasound-and-hyponome-guided type A botulinum toxin was injected into frontal, temporal, and occipital muscles in treating chronic migraine; in the joint treatment group (group D, 23 cases in total), ultrasound-and-hyponome-guided type A botulinum toxin injection in group C and infrared polarized light in group B were both used here in the treatment of chronic migraine. Infrared polarized light therapy lasted 50-60d and the time of study lasted six months. The survey would include the conditions of patients with chronic migraine three months before treatment and at one, three and six months after treatment. Patients were asked to fill the MIDAS (migraine disability assessment questionnaire) and were graded on the evaluation scale of life quality, so that the researchers would be able to compare attack frequency, duration of attack, attack severity, the use of painkillers and their recovery from chronic migraine, and then observe their adverse reactions. Eleven cases dropped out during the treatment, three cases in A group, two cases in group B, four cases in group C and two cases in group D. One, three and six months after treatment, the MIDAS scores in group A, B, C and D were significantly lower than before the treatment. Hence, the differences were statistically significant (p < 0.01). The scores in quality of life rating scale were significantly higher
Casse, Guillaume; Adenis, Jean-Paul; Sauvage, Jean-Pierre; Robert, Pierre-Yves
The aim of this paper was to study blinking parameters using a videonystagmography device, in order to objectively determine disability, and to assess the efficiency of botulinum toxin injection in patients with essential blepharospasm. Blinking was studied using the features of pupillary occlusion (PO) as recorded on a videonystagmography device. In 23 patients presenting with essential blepharospasm, we studied the frequency, the percentage, the mean duration of PO, and the longest PO in a 5-minute test period. Patients were tested prior to botulinum toxin injection, and 1 month and 3 months after injection, respectively. PO levels lower than 0.3 s and higher than 0.3 s were studied separately. At 1 month after injection, botulinum toxin significantly influenced PO higher than 0.3 s, both in frequency (9.6/min +/- 8.2 on Day 0 and 4.7/min +/- 7.2 at Month 1; p = 0.004), and in mean duration (0.95 s +/- 0.84 on Day 0 and 0.58 s +/- 0.34 at Month 1; p = 0.03). On the other hand, we found no significant effect on PO lower than 0.3 s, both in frequency (32.4/min +/- 28.4 on Day 0 and 31.3/min +/- 29.0 at Month 1; p = 0.7) and in mean duration (0.16 s +/- 0.04 on Day 0 and 0.15 s +/- 0.03 at Month 1; p = 0.04). Botulinum toxin also significantly influenced the mean duration of the longest PO (6.44 s +/- 9.4 on Day 0 and 1.55 s +/- 1.9 at Month 1; p = 0.004) as well as the percentage of PO (29.95% +/- 24.6 on Day 0 and 13.44% +/- 11.1 at Month 1; p = 0.003). PO can be used as the indirect sign of blinking. Videonystagmography provides a real-time result, and could be used to objectively evaluate the effect of botulinum toxin treatment in essential blepharospasm patients.
Shackley, Phil; Shaw, Lisa; Price, Christopher; van Wijck, Frederike; Barnes, Michael; Graham, Laura; Ford, Gary A; Steen, Nick; Rodgers, Helen
Stroke imposes significant burdens on health services and society, and as such there is a growing need to assess the cost-effectiveness of stroke treatment to ensure maximum benefit is derived from limited resources. This study compared the cost-effectiveness of treating post-stroke upper limb spasticity with botulinum toxin type A plus an upper limb therapy programme against the therapy programme alone. Data on resource use and health outcomes were prospectively collected for 333 patients with post-stroke upper limb spasticity taking part in a randomized trial and combined to estimate the incremental cost per quality adjusted life year (QALY) gained of botulinum toxin type A plus therapy relative to therapy alone. The base case incremental cost-effectiveness ratio (ICER) of botulinum toxin type A plus therapy was £93,500 per QALY gained. The probability of botulinum toxin type A plus therapy being cost-effective at the England and Wales cost-effectiveness threshold value of £20,000 per QALY was 0.36. The point estimates of the ICER remained above £20,000 per QALY for a range of sensitivity analyses, and the probability of botulinum toxin type A plus therapy being cost-effective at the threshold value did not exceed 0.39, regardless of the assumptions made.
Shackley, Phil; Shaw, Lisa; Price, Christopher; van Wijck, Frederike; Barnes, Michael; Graham, Laura; Ford, Gary A.; Steen, Nick; Rodgers, Helen
Stroke imposes significant burdens on health services and society, and as such there is a growing need to assess the cost-effectiveness of stroke treatment to ensure maximum benefit is derived from limited resources. This study compared the cost-effectiveness of treating post-stroke upper limb spasticity with botulinum toxin type A plus an upper limb therapy programme against the therapy programme alone. Data on resource use and health outcomes were prospectively collected for 333 patients with post-stroke upper limb spasticity taking part in a randomized trial and combined to estimate the incremental cost per quality adjusted life year (QALY) gained of botulinum toxin type A plus therapy relative to therapy alone. The base case incremental cost-effectiveness ratio (ICER) of botulinum toxin type A plus therapy was £93,500 per QALY gained. The probability of botulinum toxin type A plus therapy being cost-effective at the England and Wales cost-effectiveness threshold value of £20,000 per QALY was 0.36. The point estimates of the ICER remained above £20,000 per QALY for a range of sensitivity analyses, and the probability of botulinum toxin type A plus therapy being cost-effective at the threshold value did not exceed 0.39, regardless of the assumptions made. PMID:23342679
Linsenmeyer, Todd A.
Background Botulinum neurotoxin (BoNT) injection into the bladder wall has been shown to be an effective alternative to anticholinergic (antimuscarinic) medications and more invasive surgery in those with multiple sclerosis and spinal cord injury with neurogenic detrusor overactivity (NDO) and urinary incontinence who are not tolerating anticholinergic medications. In August 2011, Botox® (onabotulinumtoxinA) received Food and Drug Administration (FDA) approval for this use. Clinically, intradetrusor injection of BoNT has been found to decrease urinary incontinence and improve quality of life. Its impact on urodynamic parameters is an increase in the maximum cystometric (bladder) capacity and decrease in the maximum detrusor pressures. The most common side effects are urinary tract infections and urinary retention. There have been rare reports and a black box warning of distant spread of BoNT. BoNT has gained popularity because of its effectiveness and long duration of action, relative ease of administration, easy learning curve, reproducibility of results on repeated administration, and low incidence of complications. Objective To discuss the structure and function, mechanisms of action, clinical and urodynamic studies, injection technique, potential beneficial and adverse effects, and potential areas of research of BoNT. Methods Literature search focused on botulinum toxin in MEDLINE/PubMed. Search terms included botulinum toxin, neurogenic bladder, NDO, botox bladder, botox spinal cord injury, botox, FDA, botox side effects. All papers identified were English language, full-text papers. In addition, English abstracts of non-English papers were noted. The reference list of identified articles was also searched for further papers. Conclusion Botulinum toxin is an alternative treatment for individuals with NDO who fail to tolerate anticholinergic medications. Its popularity has increased because of the literature, which has supported its effectiveness, safety, easy
Chiu, Bin; Tai, Huai-Ching; Chung, Shiu-Dong; Birder, Lori A.
Botulinum neurotoxin A (BoNT-A), derived from Clostridium botulinum, has been used clinically for several diseases or syndrome including chronic migraine, spasticity, focal dystonia and other neuropathic pain. Chronic pelvic or bladder pain is the one of the core symptoms of bladder pain syndrome/interstitial cystitis (BPS/IC). However, in the field of urology, chronic bladder or pelvic pain is often difficult to eradicate by oral medications or bladder instillation therapy. We are looking for new treatment modality to improve bladder pain or associated urinary symptoms such as frequency and urgency for patients with BPS/IC. Recent studies investigating the mechanism of the antinociceptive effects of BoNT A suggest that it can inhibit the release of peripheral neurotransmitters and inflammatory mediators from sensory nerves. In this review, we will examine the evidence supporting the use of BoNTs in bladder pain from basic science models and review the clinical studies on therapeutic applications of BoNT for BPS/IC. PMID:27376330
Oh, Hyun-Mi; Chung, Myung Eun
Botulinum neurotoxin (BoNT), derived from Clostridium botulinum, has been used therapeutically for focal dystonia, spasticity, and chronic migraine. Its spectrum as a potential treatment for neuropathic pain has grown. Recent opinions on the mechanism behind the antinociceptive effects of BoNT suggest that it inhibits the release of peripheral neurotransmitters and inflammatory mediators from sensory nerves. There is some evidence showing the axonal transport of BoNT, but it remains controversial. The aim of this review is to summarize the experimental and clinical evidence of the antinociceptive effects, mechanisms, and therapeutic applications of BoNT for neuropathic pain conditions, including postherpetic neuralgia, complex regional pain syndrome, and trigeminal neuralgia. The PubMed and OvidSP databases were searched from 1966 to May 2015. We assessed levels of evidence according to the American Academy of Neurology guidelines. Recent studies have suggested that BoNT injection is an effective treatment for postherpetic neuralgia and is likely efficient for trigeminal neuralgia and post-traumatic neuralgia. BoNT could also be effective as a treatment for diabetic neuropathy. It has not been proven to be an effective treatment for occipital neuralgia or complex regional pain syndrome. PMID:26287242
Nishikawa, Atsushi; Uotsu, Nobuo; Arimitsu, Hideyuki; Lee, Jae-Chul; Miura, Yutaka; Fujinaga, Yukako; Nakada, Hiroshi; Watanabe, Toshihiro; Ohyama, Tohru; Sakano, Yoshiyuki; Oguma, Keiji
Orally ingested botulinum toxin enters the circulatory system and eventually reaches the peripheral nerves, where it elicits a response of neurological dysfunction. In this study, we report the important findings concerning the mechanism of Clostridium botulinum type C progenitor toxin (C16S) endocytic mechanism. C16S toxin bound to high molecular weight proteins on the surface of human colon carcinoma HT-29 cells and was internalized, but not if the cells were pretreated with neuraminidase. Benzyl-GalNAc which inhibited O-glycosylation of glycoproteins also interfered in the toxin's ability to bind the cell surface. On the other hand, the toxin was internalized in spite of pretreatment of the cells with PPMP, an inhibitor of ganglioside synthesis. These results suggest that the glycoproteins, like mucin, fulfill the important roles of receptor and transporter of C16S toxin.
Witte, M E; Klaase, J M; Koop, R
Chemical sphincterotomy, the use of pharmacological agents to reduce anal sphincter resting pressure, has become more and more popular in the treatment of chronic anal fissures (CAFs). It offers the possibility to avoid a lateral internal sphincterotomy and its associated risk of incontinence. In our hospital, patient with a chronic anal fissure are consecutively treated with isosorbide dinitrate 1% ointment, applied 6 times a day for 8 weeks, followed by diltiazem 2% ointment, applied 2 times a day for 8 weeks and Botulin Toxin A injections (Dysport; Ipsen, Hoofddorp, the Netherlands) in the internal anal sphincter. In a previous study (1), we describe high healing rates with this regime. Objective The objective of this study is to evaluate the effect of the combination of fissurectomy and Botulin Toxin A in the treatment of CAFs. Twenty-one patients (10 male patients, median age 48 years) with persistent symptoms of chronic anal fissures after following the above mentioned treatment, were enrolled in this study. Fissurectomy was combined with Botulinum Toxin A (80 U of Dysport) under regional anaesthesia in day care. Results After 12 weeks 19/21 CAFs (90%) had healed. Median follow-up was 16 (9-30) months. No recurrences were seen. Fissurectomy in combination with Botulinum Toxin A injection in the internal anal sphincter is an effective treatment for medically resistant CAFs.
Porte, Mélanie; Chaléat-Valayer, Emmanuelle; Patte, Karine; D'Anjou, Marie-Charlotte; Boulay, Christophe; Laffont, Isabelle
After the age of 4 years, drooling becomes pathological and impacts the quality of life of children with cerebral palsy. Intraglandular injection of Botulinum toxin is one of the treatments available to limit this phenomenon. The objectives of this review were to validate the efficacy of Botulinum toxin injections for drooling in children with cerebral palsy, determine recommendations and identify potential side effects. We conducted a literature review from 2001 in the following databases: Embase, Pubmed and Cochrane using the keywords: sialorrhea, drooling, hypersalivation, Botulinum toxin, cerebral palsy and children. Only the articles evaluating the efficacy of Botulinum toxin in children with cerebral palsy over the age of 4 were researched. Eight studies were found: 2 case studies, 3 open and non-controlled studies and 3 randomized controlled trials. Efficacy results in this indication are quite encouraging and the use of BTX injections is safe but the overall level of evidence of these studies was quite low. However, intraglandular injection of Botulinum toxin has a place among the therapeutic array available for the management of sialorrhea in this population even if no standardized protocol is available yet. Copyright © 2014 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Background To evaluate the role of botulinum toxin type A (BTX-A) in the treatment of pain associated with nocturnal bruxism. Material and Methods Fifty subjects reporting nocturnal bruxism were recruited for a randomized clinical trial. Twenty five bruxers were injected with botulinum toxin in both masseters, and twenty five were treated with traditional methods of treating bruxism. Patients were evaluated at 3rd week, 2nd and 6th month and one year after injection and then used to calculate bruxism events. Bruxism symptoms were investigated using questionnaires. Results Mean pain score due to Bruxism events in the masseter muscle decreased significantly in the botulinum toxin injection group A (P =0.000, highly significant). However, in the conventional treatment group, mean pain score does not show improvement with time (p>0.05). Conclusions Our results suggest that botulinum toxin injection reduced the mean pain score and number of bruxism events, most likely by decreasing the muscle activity of masseter rather than affecting the central nervous system. Key words:Temporomandibular pain, nocturnal bruxism, botulinum toxin. PMID:28149474
Climent, José M.; Fenollosa, Pedro; Martin-del-Rosario, Francisco
Introduction. Botulinum toxin inhibits acetylcholine (ACh) release and probably blocks some nociceptive neurotransmitters. It has been suggested that the development of myofascial trigger points (MTrP) is related to an excess release of ACh to increase the number of sensitized nociceptors. Although the use of botulinum toxin to treat myofascial pain syndrome (MPS) has been investigated in many clinical trials, the results are contradictory. The objective of this paper is to identify sources of variability that could explain these differences in the results. Material and Methods. We performed a content analysis of the clinical trials and systematic reviews of MPS. Results and Discussion. Sources of differences in studies were found in the diagnostic and selection criteria, the muscles injected, the injection technique, the number of trigger points injected, the dosage of botulinum toxin used, treatments for control group, outcome measures, and duration of followup. The contradictory results regarding the efficacy of botulinum toxin A in MPS associated with neck and back pain do not allow this treatment to be recommended or rejected. There is evidence that botulinum toxin could be useful in specific myofascial regions such as piriformis syndrome. It could also be useful in patients with refractory MPS that has not responded to other myofascial injection therapies. PMID:23533477
Vazquez-Delgado, Eduardo; Okeson, Jeffrey P
The following case report depicts the management of a patient suffering with a jaw opening oromandibular dystonia using a combination of botulinum toxin injections, zolpidem, and relaxation procedures. Eventually the botulinum toxin injections were eliminated, and the patient was maintained with only zolpidem and relaxation procedures.
Contarino, Maria Fiorella; Van Den Dool, Joost; Balash, Yacov; Bhatia, Kailash; Giladi, Nir; Koelman, Johannes H; Lokkegaard, Annemette; Marti, Maria J; Postma, Miranda; Relja, Maja; Skorvanek, Matej; Speelman, Johannes D; Zoons, Evelien; Ferreira, Joaquim J; Vidailhet, Marie; Albanese, Alberto; Tijssen, Marina A J
Cervical dystonia (CD) is the most frequent form of focal dystonia. Symptoms often result in pain and functional disability. Local injections of botulinum neurotoxin are currently the treatment of choice for CD. Although this treatment has proven effective and is widely applied worldwide, many issues still remain open in the clinical practice. We performed a systematic review of the literature on botulinum toxin treatment for CD based on a question-oriented approach, with the aim to provide practical recommendations for the treating clinicians. Key questions from the clinical practice were explored. Results suggest that while the beneficial effect of botulinum toxin treatment on different aspects of CD is well established, robust evidence is still missing concerning some practical aspects, such as dose equivalence between different formulations, optimal treatment intervals, treatment approaches, and the use of supportive techniques including electromyography or ultrasounds. Established strategies to prevent or manage common side effects (including excessive muscle weakness, pain at injection site, dysphagia) and potential contraindications to this treatment (pregnancy and lactation, use of anticoagulants, neurological comorbidities) should also be further explored.
Contarino, Maria Fiorella; Van Den Dool, Joost; Balash, Yacov; Bhatia, Kailash; Giladi, Nir; Koelman, Johannes H.; Lokkegaard, Annemette; Marti, Maria J.; Postma, Miranda; Relja, Maja; Skorvanek, Matej; Speelman, Johannes D.; Zoons, Evelien; Ferreira, Joaquim J.; Vidailhet, Marie; Albanese, Alberto; Tijssen, Marina A. J.
Cervical dystonia (CD) is the most frequent form of focal dystonia. Symptoms often result in pain and functional disability. Local injections of botulinum neurotoxin are currently the treatment of choice for CD. Although this treatment has proven effective and is widely applied worldwide, many issues still remain open in the clinical practice. We performed a systematic review of the literature on botulinum toxin treatment for CD based on a question-oriented approach, with the aim to provide practical recommendations for the treating clinicians. Key questions from the clinical practice were explored. Results suggest that while the beneficial effect of botulinum toxin treatment on different aspects of CD is well established, robust evidence is still missing concerning some practical aspects, such as dose equivalence between different formulations, optimal treatment intervals, treatment approaches, and the use of supportive techniques including electromyography or ultrasounds. Established strategies to prevent or manage common side effects (including excessive muscle weakness, pain at injection site, dysphagia) and potential contraindications to this treatment (pregnancy and lactation, use of anticoagulants, neurological comorbidities) should also be further explored. PMID:28286494
Matthys, Tori; Ho Dang, Hong An; Rafferty, Katherine L.; Herring, Susan W.
Introduction Temporary paralysis of the masseter muscle using botulinum toxin is a common treatment for temporomandibular disorders, bruxism, and muscle hypertrophy. Loss of masseter force is associated with decreased mandibular mineral density. Our objectives were (1) to establish whether bone loss at the mandibular condyle is regionally specific, and (2) to ascertain whether the treatment affects the condylar cartilage. Methods Young adult female rabbits received a unilateral masseter injection of botulinum neurotoxin serotype A (BoNT/A, n=31), saline (n=19) or no injection (n=3) and were also injected with bromodeoxyuridine (BrdU), a replication marker. Termination occurred 4 or 12 weeks following treatment. Condyles were processed by paraffin histology. Cortical thickness, cartilage thickness and trabecular bone areal density were measured, and replicating cells were counted after BrdU reaction. Results BoNT/A rabbits exhibited a high frequency of defects in the condylar bone surface, occurring equally on injected and uninjected sides. Bone loss was seen only on the side of the BoNT/A injection. Cortical as well as trabecular bone was severely affected. The midcondylar region lost the most bone. Recovery at 12 weeks was insignificant. Condylar cartilage thickness showed no treatment effect but did increase with time. Numbers of proliferating cells were similar in treatment groups, but BoNT/A animals showed more side asymmetry in association with the condylar defects. Conclusion Bone loss may be a risk factor for the use of botulinum toxin in jaw muscles. PMID:26672706
Moeini-Naghani, Iman; Hashemi-Zonouz, Taraneh; Jabbari, Bahman
Spasticity is a frequent symptom in stroke, multiple sclerosis, cerebral or spinal trauma, and cerebral palsy that affects and disables a large number of adults and children. In this review, we discuss the pathophysiology and nonpharmacologic and pharmacologic treatments of spasticity with emphasis on the role of botulinum neurotoxins (BoNTs). The world literature is reviewed on double-blind and placebo-controlled clinical trials reporting safety and efficacy of BoNT treatment in adult spasticity and spasticity of children with cerebral palsy. The evidence for efficacy is presented from recommendations of the Assessment and Therapeutics subcommittee of the American Academy of Neurology. A technical section describes the techniques and recommended doses of BoNTs in spasticity. Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.
Otofuji, T.; Tokiwa, H.; Takahashi, K.
Food poisoning caused by Clostridium botulinum toxin A occurred in Japan. Eleven (31%) of 36 patients from 14 different areas died of botulism. Most of the patients had eaten commercial fried lotus-rhizome solid mustard without heating. The food, which implicated one of the special local products used for gifts in Kumamoto, was found to have been produced by a manufacturer in Kumamoto prefecture. In Fukuoka prefecture, two of three patients died on days 4 and 8 after eating the food; they had typical symptoms of botulism. A total of 42 packages of the food bought as gifts was collected from different districts in Fukuoka prefecture for examination for both organism and toxin. Thirteen of these (31%) were contaminated with the organism, and in 11 (26%) a small amount of toxin A had been produced. PMID:3301378
Siegel, L S; Metzger, J F
To obtain high yields of toxin for the preparation of purified neurotoxoids, we examined the time of appearance and the quantity of toxin produced by the Bean strain of Clostridium botulinum type B under various conditions by using a fermentor system. The medium employed consisted of 2.0% casein hydrolylsate and 1.5% yeast extract plus an appropriate concentration of glucose. The maximum toxin concentration (4 x 10(5) to 5 x 10(5) mouse median lethal doses per ml) was attained within 48 h under the following fermentation conditions: an initial glucose concentration of 0.5 or 1.0%, a temperature of 35 degrees C, a nitrogen overlay at a rate of 5 liters/min, and an agitation rate of 50 rpm.
Park, Kyung-Soo; Lee, Chi-Heun
Botulinum toxin (BT) was the first toxin to be used in the history of human medicine. Among the eight known serotypes of this toxin, those currently used in medicine are types A and B. This review article mainly discusses BT type A (BTA) because it is usually used in dentistry including dental anesthesiology and oral and maxillofacial surgery. BTA has been used mainly in the treatment of temporomandibular joint disorder (TMD) and hypertrophy and hyperactivity of the masticatory muscles, along with being a therapeutic option to relieve pain and help in functional recovery from dental and oral and maxillofacial surgery. However, it is currently used broadly for cosmetic purposes such as reducing facial wrinkles and asymmetry. Although the therapeutic effect of BTA is temporary and relatively safe, it is essential to have knowledge about related anatomy, as well as the systemic and local adverse effects of medications that are applied to the face. PMID:28884147
Park, Kyung-Soo; Lee, Chi-Heun; Lee, Jung-Woo
Botulinum toxin (BT) was the first toxin to be used in the history of human medicine. Among the eight known serotypes of this toxin, those currently used in medicine are types A and B. This review article mainly discusses BT type A (BTA) because it is usually used in dentistry including dental anesthesiology and oral and maxillofacial surgery. BTA has been used mainly in the treatment of temporomandibular joint disorder (TMD) and hypertrophy and hyperactivity of the masticatory muscles, along with being a therapeutic option to relieve pain and help in functional recovery from dental and oral and maxillofacial surgery. However, it is currently used broadly for cosmetic purposes such as reducing facial wrinkles and asymmetry. Although the therapeutic effect of BTA is temporary and relatively safe, it is essential to have knowledge about related anatomy, as well as the systemic and local adverse effects of medications that are applied to the face.
Walshaw, John; Peck, Michael W.; Barker, Gary C.
Clostridium botulinum produces botulinum neurotoxins (BoNTs), highly potent substances responsible for botulism. Currently, mathematical models of C. botulinum growth and toxigenesis are largely aimed at risk assessment and do not include explicit genetic information beyond group level but integrate many component processes, such as signalling, membrane permeability and metabolic activity. In this paper we present a scheme for modelling neurotoxin production in C. botulinum Group I type A1, based on the integration of diverse information coming from experimental results available in the literature. Experiments show that production of BoNTs depends on the growth-phase and is under the control of positive and negative regulatory elements at the intracellular level. Toxins are released as large protein complexes and are associated with non-toxic components. Here, we systematically review and integrate those regulatory elements previously described in the literature for C. botulinum Group I type A1 into a population dynamics model, to build the very first computational model of toxin production at the molecular level. We conduct a validation of our model against several items of published experimental data for different wild type and mutant strains of C. botulinum Group I type A1. The result of this process underscores the potential of mathematical modelling at the cellular level, as a means of creating opportunities in developing new strategies that could be used to prevent botulism; and potentially contribute to improved methods for the production of toxin that is used for therapeutics. PMID:27855161
Ihekwaba, Adaoha E C; Mura, Ivan; Walshaw, John; Peck, Michael W; Barker, Gary C
Clostridium botulinum produces botulinum neurotoxins (BoNTs), highly potent substances responsible for botulism. Currently, mathematical models of C. botulinum growth and toxigenesis are largely aimed at risk assessment and do not include explicit genetic information beyond group level but integrate many component processes, such as signalling, membrane permeability and metabolic activity. In this paper we present a scheme for modelling neurotoxin production in C. botulinum Group I type A1, based on the integration of diverse information coming from experimental results available in the literature. Experiments show that production of BoNTs depends on the growth-phase and is under the control of positive and negative regulatory elements at the intracellular level. Toxins are released as large protein complexes and are associated with non-toxic components. Here, we systematically review and integrate those regulatory elements previously described in the literature for C. botulinum Group I type A1 into a population dynamics model, to build the very first computational model of toxin production at the molecular level. We conduct a validation of our model against several items of published experimental data for different wild type and mutant strains of C. botulinum Group I type A1. The result of this process underscores the potential of mathematical modelling at the cellular level, as a means of creating opportunities in developing new strategies that could be used to prevent botulism; and potentially contribute to improved methods for the production of toxin that is used for therapeutics.
Clark, Glenn T
Although much work is yet to be done in this area, nine general conclusions can be derived: 1. Local site-of-injection side effects from botulinum toxin injections are rare, assuming proper technique is used. 2. The two most common medication-related side effects from botulinum toxin orofacial injections are alterations in salivary consistency and inadvertent weakness of the swallowing, speech, and facial muscles. These complications are injection site-specific (eg, more common with lateral pterygoid injections and palatal and tongue muscle injections) and dose-dependent problems. These problems are bothersome but are not contraindications for the therapy if it is needed. 3. The data presented in this article are mostly case series-based and open trial-based information that is promising, but randomized, blinded, controlled trials are needed to establish the true efficacy of this method for the orofacial motor and pain disorders. 4. The novice should begin with injection of muscles he or she can inject with low risk of incorrect placement. The hard-to-find muscles should be avoided when starting out. The novice clinician should inject and dissect a few cadavers to improve injection technique. 5. The general latency for botulinum toxin type A is 1 week, its duration is 2 to 3 months, and it is recommended that injection be done no more than once every 12 weeks to avoid development of antibodies against the toxin. 6. Depending on the target muscle, injection dose is 10 to 50 U of Botox type A per site with a total dose of 200 U in the masticatory system. More than this can be used (400 U maximum) if other sites in the head and neck are included in the injection protocol. 7. Regarding injecting painful muscles that do not exhibit palpable muscle hardness or EMG-determined spasticity or observable involuntary movements but have chronic myofascial trigger points or the patient localizes them as the site of their chronic daily headache pain, botulinum toxin injections
Schulte-Mattler, Wilhelm J; Opatz, Oliver; Blersch, Wendelin; May, Arne; Bigalke, Hans; Wohlfahrt, Kai
A genuine peripheral antinociceptive and anti-inflammatory effect of Botulinum neurotoxin type A (BoNT/A) has been proposed but could not be demonstrated in humans so far. Therefore, 100 mouse units of Botulinum toxin A (Dysport) and placebo were injected in a double blind paradigm in defined skin areas of 50 subjects. At baseline and after 4 and 8 weeks allodynia was induced in the skin areas with capsaicin ointment. Heat and cold pain threshold temperatures were measured with quantitative sensory testing, and threshold intensities upon electrical stimulation with a pain specific surface electrode were determined. No BoNT/A related differences in pain perception were found at any quality. There is neither a direct peripheral antinociceptive effect nor a significant effect against neurogenic inflammation of BoNT/A in humans.
Jathoul, Amit P; Holley, Jane L; Garmory, Helen S
DNA vaccines which expressed the Hc fragment of the Clostridium botulinum type F neurotoxin (BoNT/F Hc) fused to a signal peptide downstream of four different eukaryotic promoters were prepared. Subsequently, the immunogenicity of the DNA vaccines and protection afforded in mice against challenge with 10(4) MLD of type F botulinum toxin was evaluated. The DNA vaccine containing the human ubiquitin gene (UbC) promoter induced the highest BoNT/F Hc-specific antibody concentration following two intramuscular immunisations and afforded 90% protection against challenge. The results from this study indicate that the selection of promoter used in DNA vaccination studies may be of importance in designing optimised vaccines.
Jasiński, Miłosz; Drewa, Tomasz; Tyloch, Janusz; Wolski, Zbigniew
Botulinum toxin type A is used in treatment of bladder hyperactivity and sphincter dyssynergia and was reported to alleviate lower urinary tract symptoms in patients with BPH. Some authors, however, failed to observe in their study apoptosis after BoNTA administration. We conducted an open-label study of BoNTA in men with BPH-related LUTS who were unsuitable for surgery as well as investigation of the effect of the toxin on in vitro growth of fibroblasts. In the clinical part, 5 patients aged from 75 to 88, suffering from BPH and UR were treated. Patients were previously disqualified from surgery and had not passed trials without catheters (TWOC). Prostate volume ranged from 38 to 104 mL. Botulinum toxin injection were performed. Each lobe of adenoma was injected with 100 U Botox under sonographic guidance. Prostate volume and TWOC were performed after 6 months. In the in vitro part, 3T3 mouse fibroblasts and fibroblasts isolated from human prostate were cultured in the presence of Botox (10, 5 and 1 U/mL) for 24 and 72 h. Cells were detached and counted in Neubauer chamber using trypan blue assay. Cells cultured in medium without botulinum toxin were the control group. Results are presented as the means with standard deviations. The means were compared, p <0.05 was considered statistically significant.No early complications were observed. Prostate volume remained unchanged after six months and patients were unable to void. Number of 3T3 cells after 24 h incubation was 7.12 +/- 1.88, 7.12 +/- 0.64, 6.75 +/- 1.28 and 6.88 +/- 0.83 x 10(4), after 24 h, 24.00 +/- 3.46, 22.75 +/- 3.73, 23.12 +/- 3.46 and 23.88 +/- 2.42 x 10(4) after 72 h, for 0, 1, 5 and 10 U/mL botulinum toxin type A concentrations, respectively. Similarly, number of prostate fibroblasts was 7.50 +/- 1.20, 7.12 +/- 1.73, 6.50 +/-1.93, and 6.25 +/- 1.58 x 10(4) after 24 h and 9.62 +/- 2.00, 9.12 +/- 1.55, 9.12 +/- 1.73 and 9.75 +/- 2.82 x 10(4) after 72 h. In conclusion, Botox had no statistically
Guo, Yao-Hong; Kuan, Ta-Shen; Chen, Kuan-Lin; Lien, Wei-Chih; Hsieh, Pei-Chun; Hsieh, I-Chieh; Chiu, Szu-Hao; Lin, Yu-Ching
To compare the effects of 2 different injection sites of low doses of botulinum toxin type A with steroid in treating lateral epicondylalgia. Double-blind, randomized, active drug-controlled trial. Tertiary medical center. Patients with lateral epicondylalgia for >6 months were recruited from a hospital-based outpatient population (N=26). A total of 66 patients were approached, and 40 were excluded. No participant withdrew because of adverse effects. Patients were randomly assigned into 3 groups: (1) botulinum toxin epic group (n=8), who received 20U of botulinum toxin injection into the lateral epicondyle; (2) botulinum toxin tend group (n=7), who received 20U of botulinum toxin injected into tender points of muscles; and (3) steroid group (n=11), who received 40mg of triamcinolone acetonide injected into the lateral epicondyle. A visual analog scale, a dynamometer, and the Patient-Rated Tennis Elbow Evaluation were used to evaluate the perception of pain, maximal grip strength, and functional status, respectively. Outcome measures were assessed before intervention and at 4, 8, 12, and 16 weeks after treatment. The primary outcome measure was a visual analog scale. At 4 weeks after injection, the steroid group was superior to the botulinum toxin tend group in improvement on the visual analog scale (P=.006), grip strength (P=.03), and Patient-Rated Tennis Elbow Evaluation (P=.02). However, these differences were not observed at the 8-, 12-, and 16-week follow-up assessments. There was no significant difference between the steroid and botulinum toxin epic groups. Injections with botulinum toxin and steroid effectively reduced pain and improved upper limb function in patients with lateral epicondylalgia for at least 16 weeks. The onset of effect was earlier in the steroid and botulinum toxin epic groups than in the botulinum toxin tend group. Copyright © 2016 American Congress of Rehabilitation Medicine. Published by Elsevier Inc. All rights reserved.
Hompes, R; Harmston, C; Wijffels, N; Jones, O M; Cunningham, C; Lindsey, I
Anismus causes obstructed defecation as a result of inappropriate contraction of the puborectalis/external sphincter. Proctographic failure to empty after 30 s is used as a simple surrogate for simultaneous electromyography/proctography. Botulinum toxin is theoretically attractive but efficacy is variable. We aimed to evaluate the efficacy of botulinum toxin to treat obstructed defecation caused by anismus. Botulinum toxin was administered, under local anaesthetic, into the puborectalis/external sphincter of patients with proctographic anismus. Responders (resolution followed by recurrence of obstructed defecation over a 1- to 2-month period) underwent repeat injection. Nonresponders underwent rectal examination under anaesthetic (EUA). EUA-diagnosed rectal prolapse was graded using the Oxford Prolapse Grade 1-5. Fifty-six patients were treated with botulinum toxin. Twenty-two (39%) responded initially and 21/22 (95%) underwent repeat treatment. At a median follow up of 19.2 (range, 7.0-30.4) months, 20/21 (95%) had a sustained response and required no further treatment. Isolated obstructed defecation symptoms (OR = 7.8, P = 0.008), but not proctographic or physiological factors, predicted response on logistic regression analysis. In 33 (97%) of 34 nonresponders, significant abnormalities were demonstrated at EUA: 31 (94%) had a grade 3-5 rectal prolapse, one had internal anal sphincter myopathy and one had a fissure. Exclusion of these alternative diagnoses revised the initial response rate to 96%. Simple proctographic criteria overdiagnose anismus and underdiagnose rectal prolapse. This explains the published variable response to botulinum toxin. Failure to respond should prompt EUA seeking undiagnosed rectal prolapse. A response to an initial dose of botulinum toxin might be considered a more reliable diagnosis of anismus than proctography. © 2011 The Authors. Colorectal Disease © 2011 The Association of Coloproctology of Great Britain and Ireland.
Pingel, Jessica; Wienecke, Jacob; Lorentzen, Jakob; Nielsen, Jens Bo
Botulinum toxin is used with the intention of diminishing spasticity and reducing the risk of development of contractures. Here, we investigated changes in muscle stiffness caused by reflex activity or elastic muscle properties following botulinum toxin injection in the triceps surae muscle in rats. Forty-four rats received injection of botulinum toxin in the left triceps surae muscle. Control measurements were performed on the noninjected contralateral side in all rats. Acute experiments were performed, 1, 2, 4, and 8 wk following injection. The triceps surae muscle was dissected free, and the Achilles tendon was cut and attached to a muscle puller. The resistance of the muscle to stretches of different amplitudes and velocities was systematically investigated. Reflex-mediated torque was normalized to the maximal muscle force evoked by supramaximal stimulation of the tibial nerve. Botulinum toxin injection caused severe atrophy of the triceps surae muscle at all time points. The force generated by stretch reflex activity was also strongly diminished but not to the same extent as the maximal muscle force at 2 and 4 wk, signifying a relative reflex hyperexcitability. Passive muscle stiffness was unaltered at 1 wk but increased at 2, 4, and 8 wk (P < 0.01). These data demonstrate that botulinum toxin causes a relative increase in reflex stiffness, which is likely caused by compensatory neuroplastic changes. The stiffness of elastic elements in the muscles also increased. The data are not consistent with the ideas that botulinum toxin is an efficient antispastic medication or that it may prevent development of contractures.
Kozaki, S; Miyazaki, S; Sakaguchi, G
Two fragments with molecular weights of 111,000 (fragment I) and 59,000 (fragment II) were separated from each other by gel filtration of dithiothreitol and urea-treated, trypsinized derivative toxin (molecular weight, 170,000) of the proteolytic Okra strain of Clostridium botulinum type B on a column of Sephadex G-200 (superfine) with a buffer containing dithiothreitol and urea. Upon removal of dithiothreitol and urea by dialysis, the two fragments reassembled to reconstruct the derivative toxin molecule. Both fragments were immunogenic, and both anti-fragments neutralized type B toxin. The neutralizing activities of both anti-fragment I and anti-fragment II were, however, lower than that of the anti-derivative toxin, suggesting that the molecular integrity of derivative toxin is essential for sufficient production of the neutralizing antibody. The immunological difference found between type B toxin from a proteolytic strain and that from a nonproteolytic strain was ascribed to the antigenic difference of fragment I. Images PMID:412790
Kozaki, S; Miyazaki, S; Sakaguchi, G
Two fragments with molecular weights of 111,000 (fragment I) and 59,000 (fragment II) were separated from each other by gel filtration of dithiothreitol and urea-treated, trypsinized derivative toxin (molecular weight, 170,000) of the proteolytic Okra strain of Clostridium botulinum type B on a column of Sephadex G-200 (superfine) with a buffer containing dithiothreitol and urea. Upon removal of dithiothreitol and urea by dialysis, the two fragments reassembled to reconstruct the derivative toxin molecule. Both fragments were immunogenic, and both anti-fragments neutralized type B toxin. The neutralizing activities of both anti-fragment I and anti-fragment II were, however, lower than that of the anti-derivative toxin, suggesting that the molecular integrity of derivative toxin is essential for sufficient production of the neutralizing antibody. The immunological difference found between type B toxin from a proteolytic strain and that from a nonproteolytic strain was ascribed to the antigenic difference of fragment I.
6. PERFORMING ORG. REPORT NUMBER AUTHOR(&) 8. CONTRACT OR GRANT NUMBER(&) SELLIN,/Lawrence C,’c ISM PERFORMING ORGANIZATION NAME AND ADDRESS 10...one quantum. however, end-plate potentials remained subthreshold and did not produce a muscle contraction upon nerve stimulation. Low frequency (0.5 Hz...muscle fibers -"_re not significantly affected by the toxin. It is interesting to note that, although fast- twitch and slow-twitch mucles were
Chancellor, Michael B; Fowler, Clare J; Apostolidis, Apostolos; de Groat, William C; Smith, Christopher P; Somogyi, George T; Aoki, K Roger
Botulinum toxins can effectively and selectively disrupt and modulate neurotransmission in striated muscle. Recently, urologists have become interested in the use of these toxins in patients with detrusor overactivity and other urological disorders. In both striated and smooth muscle, botulinum toxin A (BTX-A) is internalized by presynaptic neurons after binding to an extracellular receptor (ganglioside and presumably synaptic vesicle protein 2C). In the neuronal cytosol, BTX-A disrupts fusion of the acetylcholine-containing vesicle with the neuronal wall by cleaving the SNAP-25 protein in the synaptic fusion complex. The net effect is selective paralysis of the low-grade contractions of the unstable detrusor, while still allowing high-grade contraction that initiates micturition. Additionally, BTX-A seems to have effects on afferent nerve activity by modulating the release of ATP in the urothelium, blocking the release of substance P, calcitonin gene-related peptide and glutamate from afferent nerves, and reducing levels of nerve growth factor. These effects on sensory feedback loops might not only help to explain the mechanism of BTX-A in relieving symptoms of overactive bladder, but also suggest a potential role for BTX-A in the relief of hyperalgesia associated with lower urinary tract disorders.
Ivanhoe, C B; Lai, J M; Francisco, G E
Bruxism, the rhythmic grinding of teeth--usually during sleep--is not an infrequent complication of traumatic brain injury. Its prevalence in the general population is 21%, but its incidence after brain injury is unknown. Untreated, bruxism causes masseter hypertrophy, headache, temporomandibular joint destruction, and total dental wear. We report a case of complete resolution of postanoxic bruxism after treatment with botulinum toxin-A (BTX-A). The patient was a 28-year-old man with no history of bruxism who sustained an anoxic brain injury secondary to cardiac arrest of unknown etiology. On admission to our rehabilitation unit 2 months after the injury, the patient presented with severe bruxism and heavy dental wear. The patient was injected with a total of 200 units of BTX-A to each masseter and temporalis. There was total resolution of bruxism 2 days after injection, with no complications. On follow-up 3 months after injection, the patient remained free of bruxism. We propose that botulinum toxin be considered as a treatment for bruxism secondary to anoxic brain injury. Further studies regarding muscle selection and medication dosage are warranted to elucidate the toxin's efficacy in this condition.
Campos, José H; Oliveira, Lise B; Queiroz, Taise O; Santos, Kleber P; Freitas, Francesca M
Botulinum toxin type A (BTX-A) must be injected in the intramuscular area to exert its paralytic effect. The durability of the BTX-A effect varies in different patients, and this fact can result from different locations of the drug injection, for example, the muscle peripheral area (perimuscular). This study aimed to evaluate whether a difference exists in the effect duration of the muscle paralysis between intramuscular and perimuscular injections of BTX-A. This study used 18 male New Zealand rabbits divided into two groups (A and B) based on the location of the BTX-A injection. The group A animals received 10 units of BTX-A diluted with 0.1 ml of normal saline injected perimuscularly. The group B animals received the same dosage injected in the intramuscular area of the left masseter muscle. An electroneurophysiologic study was performed 1 week before the experiment for all the animals, then repeated 1, 4, and 8 weeks after the toxin injection. The amplitude values recorded in the masseter muscle were significantly lower in both groups throughout the study than the physiologic amplitude. The comparison between groups A and B did not show any statistically significant amplitude variations throughout the 8 weeks. No significant difference in the neuromuscular blockade induced by botulinum toxin type A was observed between injections into the muscle peripheral area and intramuscular injections.
Smith, Christopher P
Botulinum neurotoxins (BoNTs) are well known for their ability to potently and selectively disrupt and modulate neurotransmission. BoNT is currently undergoing regulatory evaluation for urological disorders in the United States and the European Union and is not FDA approved for urologic use. Overactive bladder (OAB) and benign prostatic hyperplasia (BPH) are common urologic conditions characterized by urinary frequency, urgency, nocturia, urge incontinence and, in the case of BPH, decreased urine flow that are currently being evaluated in clinical trials with BoNT-A. Interstitial cystitis (IC) is a chronic condition in which patients describe urinary frequency, urgency and associated bladder/pelvic pain. In the two former conditions, BoNT-A is currently being evaluated in Phase II or Phase III clinical trials as a therapeutic agent. Evidence for BoNT in the treatment of IC is limited to small case series. The purpose of this article is to provide up to date clinical evidence regarding the use of BoNT to treat these three urologic problems. For the sake of clarity, BoNT-A describes the use of Botox unless otherwise specified. In addition, when describing OAB, two sub-populations exist: those with OAB of neurogenic origin (NDO) and those with OAB of unknown (idiopathic) origin (IDO).
Walker, Heather W; Lee, Michael Y; Bahroo, Laxman B; Hedera, Peter; Charles, David
Spasticity is often experienced by individuals with injury or illness of the central nervous system from etiologies such as stroke, spinal cord injury, brain injury, multiple sclerosis, or other neurologic conditions. Although spasticity may provide benefits in some patients, it more often leads to complications negatively impacting the patient. Nonpharmacologic treatment options often do not provide long-term reduction of spasticity, and systemic interventions, such as oral medications, can have intolerable side effects. The use of botulinum neurotoxin injections is one option for management of focal spasticity. Several localization techniques are available to physicians that allow for identification of the selected target muscles. These methods include anatomic localization in isolation or in conjunction with electromyography guidance, electrical stimulation guidance, or ultrasound guidance. This article will focus on further description of each of these techniques in relation to the treatment of adult spasticity and will discuss the advantages and disadvantages of each technique, as well as review the literature comparing the techniques. Copyright © 2015 American Academy of Physical Medicine and Rehabilitation. Published by Elsevier Inc. All rights reserved.
Schwabe, Aloysia L.
Botulinum neurotoxin (BoNT) is one of the mainstays in the treatment of pediatric spasticity and dystonia. When considering initiation of BoNT treatment for spasticity, treatment goals and responses to prior conservative measures such as passive range of motion exercises, splinting, and other medication trials should be reviewed. As a general rule, children should be engaged in therapy services around the time of the injections and have a robust home program in place. When managing spasticity in children with BoNT injections, the practitioner should be well versed in functional anatomy with specialized training in injection techniques. Localization techniques in addition to anatomical landmarks are recommended for improved efficacy and include limited electromyography, electrical stimulation, and/or ultrasound guidance. A follow-up visit for the purpose of reassessment during the peak effect of the drug is advised. It is known that BoNT is effective at reducing spasticity and improving range of motion, but it remains to be determined to what degree this translates into improved function, activity, and participation. PMID:26869860
Erickson, Marilyn C; Ma, Li M; Doyle, Michael P
Shelf life of fish packaged under modified atmosphere (MA) is extended, but within the United States, commercial application of MA with impermeable packaging films is restricted due to concerns that botulinum toxin production would precede spoilage when contaminated fish are held at abusive storage temperatures. Use of semipermeable packaging films has been advocated; however, previous studies are inconclusive in determining the oxygen transmission rate (OTR) of a film that is needed to achieve an acceptable margin of safety (i.e., toxin production occurs only after spoilage). This study was conducted to determine the influence of OTR (target OTRs of 3 to 15,000) on the development of spoilage volatiles and toxin in salmon inoculated with type E Clostridium botulinum and subjected to air, vacuum, or 75:25 CO2:N2 MA and storage temperatures of 4, 8, 12, or 16°C. The most dominant headspace volatile peak that was produced during spoilage of samples at 4, 8 or 12°C was a peak, having a Kovats retention index (KI) of 753, and at which external standards of 2- or 3-methyl 1-butanol also eluted. Under anaerobic conditions, both the aerobic microbial populations and the size of the KI 753 spoilage peak were less in inoculated samples compared with uninoculated samples. C. botulinum-inoculated samples that were stored at 12 or 16°C under conditions favorable for anaerobic growth were also characterized by a KI 688 peak. Using a previously developed model that related the percentage of elderly consumers who would prepare a sample having the KI 753 spoilage peak of a specific size, it was determined that for salmon packaged with 3 or 3,000 OTR films under any atmosphere and stored at 12 or 16°C, 2 to 61% of the consumers could potentially prepare toxin-contaminated samples. Hence, when abusive storage conditions are suspected, the fish should not be consumed.
Bensmail, Djamel; Hanschmann, Angelika; Wissel, Jörg
To characterize patient and physician satisfaction with current standard-of-care botulinum toxin treatment regimens for symptom control in patients with post-stroke spasticity using structured interviews with patients and physicians. Two cross-sectional surveys were conducted in Canada, France, Germany, and the US. The patient survey included patients with post-stroke spasticity who had undergone at least two botulinum toxin A injection cycles. Information on patients' current and prior botulinum toxin treatment cycles and quality of life was collected. The physician survey included physicians treating post-stroke spasticity with botulinum toxins and collected information regarding physician satisfaction with botulinum toxin treatment for post-stroke spasticity. Of 79 participating patients with post-stroke spasticity, 61 (77%) received treatment with onabotulinumtoxinA, 15 (19%) with abobotulinumtoxinA, and three (4%) with incobotulinumtoxinA. Overall, 40.5% of patients were very satisfied, 48.1% were somewhat satisfied, and 11.4% were not at all satisfied with botulinum toxin treatment. Patient satisfaction was lowest just before injection and highest at the time of peak effect. The mean injection interval was 13.7 (SD = 3.5) weeks; however, 43.4% of patients expressed a preference for intervals of ≤ 10 weeks. Most of the 105 participating physicians' were moderately (57.7%) or very (36.5%) satisfied with botulinum toxin treatment. However, physicians estimated that 16.2% of their patients with post-stroke spasticity could benefit from shorter injection intervals, and that 24.6% of patients could benefit from higher doses than those permitted by current country directives. Patients' responses were based on subjective recollections and physicians' responses were based on general impressions. These surveys indicate that patients' and physicians' satisfaction with botulinum toxin therapy for post-stroke spasticity is overall very good. However, patients
Frascarelli, Flaminia; Di Rosa, Giuseppe; Bisozzi, Eleonora; Castelli, Enrico; Santilli, Valter
In the last few years botulinum toxin type A (BTX-A) has been widely used in the management of spasticity in children with cerebral palsy in order to reduce hypertonicity and improve functional outcomes enhancing motor skill development. The botulinum toxin injection seems to interact with intrafusal and extrafusal fibers producing a reduction of hypertone both through synaptic blockade and inhibition of stretch reflex loop and these changes may influence not only the spinal cord but also the central nervous system (CNS). The purpose of our study was to determine the neurophysiological changes induced by the BTX-A through an evaluation of cortical somatosensory Evoked Potential (SEP) and Soleus H wave, that is the index of excitability of stretch reflex loop. Eighteen children with Cerebral Palsy (CP), aged between 5 and 12, were recruited at Children's Hospital "Bambino Gesù" of Rome. All children were evaluated with appropriate clinical scales before and 1 month after the BTX-A injection. Neurophysiological measurements were performed before, and 1 month after botulinum toxin injection through lower limb SEPs, M-wave and Soleus H wave recording. After the injection the results showed a statistically significant improvement both of clinical scales and the neurophysiological variables. These findings suggest that spasticity itself can be considered as a factor affecting the cortical SEPs. And even though it seems that BTX-A does not have any direct central effect on sensory pathways we suppose an indirect mechanism on modulation of afferent fibers Ia due to the modification induced by BTX-A to central loop reflex. © 2010 European Paediatric Neurology Society. Published by Elsevier Ltd. All rights reserved.
Druschel, Claudia; Althuizes, Henriette C; Funk, Julia F; Placzek, Richard
The treatment of children with cerebral palsy with Botulinum Toxin is considered safe and effective, but is only approved for children older than two years of age. The effect of BoNT-A injection on juvenile skeletal muscle especially on neuromuscular junction density, distribution and morphology is poorly delineated and concerns of irreversible damage to the motor endplates especially in young children exist. In contrast, earlier treatment could be appropriate to improve the attainment of motor milestones and general motor development. This review systematically analyzes the evidence regarding this hypothesis. A database search, including PubMed and Medline databases, was performed and all randomized controlled trials (RCTs) comparing the efficacy of Botulinum Toxin in children younger than two years were identified. Two authors independently extracted the data and the methods of all identified trials were assessed. Three RCTs met the inclusion criteria. The results of the analysis revealed an improvement in spasticity of the upper and lower extremities as well as in the range of motion in the joints of the lower limbs. However, evidence of an improvement of general motor development could not be found, as the assessment of this area was not completely specified for this patient group. Based on available evidence it can not be concluded that Botulinum Toxin treatment in children younger than two years improves the achievement of motor milestones. However, there is evidence for the reduction of spasticity, avoiding contractures and delaying surgery. Due to some limitations, the results of this review should be cautiously interpreted. More studies, long-term follow up independent high-quality RCTs with effectiveness analyses are needed.
Bjornson, Kristie; Hays, Ross; Graubert, Cathy; Price, Robert; Won, Francine; McLaughlin, John F.; Cohen, Morty
BACKGROUND Spasticity is a prevalent disabling clinical symptom for children with cerebral palsy. Treatment of spasticity with botulinum toxin in children with cerebral palsy was first reported in 1993. Botulinum toxin provides a focal, controlled muscle weakness with reduction in spasticity. Interpretation of the literature is difficult due to the paucity of reliable measures of spasticity and challenges with measuring meaningful functional changes in children with disabilities. OBJECTIVE This study documents the effects of botulinum toxin-A (BTX-A) injections into the gastrocnemius muscles in children with spastic diplegia. Outcomes are evaluated across all five domains of the National Centers for Medical and Rehabilitation Research domains of medical rehabilitation. METHODS A randomized double masked placebo controlled design was applied to 33 children, with spastic diplegia with a mean age of 5.5 and Gross Motor Function Classification System Levels of I–III. Participants received either 12 units/kg BTX-A or placebo saline injections to bilateral gastrocnemius muscles. Outcomes were measured at baseline, 3, 8, 12, and 24 weeks after injection. RESULTS Significant decreases in the EMG representation of spasticity were documented at 3 weeks after BTX-A treatment. A significant decrease in viscoelastic aspects of spasticity was present at 8 weeks and subsequent increases in dorsiflexion range were documented at 12 weeks for the BTX-A group. Improvement was found in performance goals at 12 weeks and in maximum voluntary torque and gross motor function at 24 weeks for the BTX-A group. There were no significant differences between groups in satisfaction with performance goals, energy expenditure, Ashworth scores, or frequency of adverse effects. CONCLUSIONS The safety profile of 12 units/kg of BTX-A is excellent. Although physiologic and mechanical effects of treatment with BTX-A were documented with functional improvement at 6 months, family satisfaction with
El, Ozlem; Peker, Ozlen; Kosay, Can; Iyilikci, Leyla; Bozan, Ozgur; Berk, Haluk
Botulinum toxin type A can be both safe and effective in relieving spasticity in pediatric patients with cerebral palsy. In our prospective study, we evaluated the functional effect of botulinum toxin A in spastic diplegic-type cerebral palsy. Patients were examined on enrollment and at 1, 3, and 6 months after injection. Passive dorsiflexion of the ankle joint was measured using a goniometer as an angle of possible maximal dorsiflexion with the knee extended and flexed. Spasticity was graded using the Modified Ashworth Scale. Selective motor control at the ankle was assessed, and observational gait analysis was done. The functional status of the patients was determined by using the gross motor classification system. Botulinum toxin A was injected into the gastrocnemius muscle in all patients, and in four patients with concomitant jump knee gait, a hamstring muscle injection was added. Fourteen patients were included in the study. The mean age was 58.81 +/- 15.34 months. Following injection, spasticity was clinically decreased and statistically significant improvement was noticed in all clinical parameters after 1, 3, and 6 months of injection. The improvement in the clinical parameters decreased after 6 months but not to the baseline. One patient was Level II, four patients were Level III, and six patients were Level IV according to the Gross Motor Function Classification System at baseline. Improvement in the gross motor classification system is continued after 6 months in 12 children. The main goal of spasticity treatment in cerebral palsy is functional improvement. In our study, most of our patients had functional improvement according to the gross motor function classification system and did not change at 6 months.
Brunt, Denis; Woo, Raymund; Kim, Hyeong Dong; Ko, Man Soo; Senesac, Claudia; Li, Shuman
The purpose of this study was to determine the effects of botulinum toxin type A treatment on ankle muscle activity during gait of children who are idiopathic toe-walkers. Five children who were idiopathic toe-walkers with a mean age was 4.34 years participated. Gait of the subjects was evaluated prior to, 20 days following, and 12 months following bilateral botulinum toxin type A injection of the gastrocnemius and soleus muscles. Subjects received physical therapy following the 20-day evaluation. Dependent variables were type of foot contact pattern and duration of swing-phase tibialis anterior activity and onset of stance-phase gastrocnemius relative to ground contact. Prior to treatment 51% of foot contacts were with the toe (heel just off the ground) or were digitigrade, while the remaining contacts were flat foot or heel strike. At approximately 20 days following treatment, only 8% of foot contacts were toe contact or digitigrade. Prior to treatment, mean gastrocnemius onset was 30 ms prior to foot contact and the duration of swing-phase tibialis anterior was only 345 ms. Following treatment (and a more normal foot contact pattern), mean gastrocnemius onset followed ground contact by 36 ms and tibialis anterior duration increased through terminal swing and into the loading response. The posttreatment improvement was maintained at 12-month follow-up. It appears that botulinum toxin type A treatment normalizes the ankle EMG pattern during gait and a more normal foot-strike pattern is obtained. These data are discussed in terms of a neuromotor rationale for the rehabilitation of children who are idiopathic toe-walkers to maintain posttreatment improvements.
Richardson, D.; Sheean, G.; Werring, D.; Desai, M.; Edwards, S.; Greenwood, R.; Thompson, A.
OBJECTIVES—To investigate the effects of EMG guided botulinum toxin (BTX-A) on impairment and focal disability in adults presenting with focal hypertonia. METHODS—A prospective, randomised, double blind, placebo controlled, parallel group trial was carried out with standardised assessment before and at 3 week intervals until 12 weeks after injection, in patients with focal hypertonia affecting upper or lower limbs. Botulinum toxin or placebo was injected with EMG guidance after multidisciplinary assessment. The modified Ashworth scale of spasticity, percentage passive range of joint motion, subjective rating of problem severity, the Rivermead motor assessment scale, a timed 10 metre walk (lower limb patients), nine hole peg test (upper limb patients), and a modified goal attainment scale were used as outcome measures. The patients were 52 adults; 34 male, 18female; mean age 40.31, range 16-79 years; mean duration of symptoms 35 months (range 3 months to 22 years). Diagnoses included cerebrovascular accidents (23), head injury (12), incomplete spinal cord injury (six), tumour (five), cerebral palsy (three), and anoxic episodes (three). RESULTS—For each variable an overall score for the treatment period was computed by summing the scores from the 3, 6, 9, and 12 week assessments. These overall scores were significantly better in the treated group for the Ashworth scale, percentage passive range of movement, Rivermead lower limb, and subjective rating of problem severity. The significant treatment effect on the Ashworth scale was seen on analysis of variance (ANOVA) at 3 weeks and the subjective rating of problem severity at 3 and 6 weeks. The goal attainment scale score in both groups was similar at 12weeks. CONCLUSION—Selective use of botulinum toxin to weaken muscles can lead to a reduction in resistance to passive movement about a distal limb joint. This allows for improvements in passive range of movement and focal disability, particularly in
Mazzuco, Rosemarie; Hexsel, Dóris
Gummy smile (GS) is an aesthetic disorder for some patients, which can be corrected by injection of botulinum toxin. We sought to classify GS according to the area of gingival exposure and the respective muscles involved in order to perfect the botulinum toxin injection technique for each patient. Sixteen patients with GS were evaluated before receiving botulinum toxin injections. Based on the area of excessive gum displayed and identification of the muscles involved, 4 different types of GS were identified: anterior, posterior, mixed, and asymmetric. AbobotulinumtoxinA (Dysport, Ipsen Biopharm Limited, Wrexham, UK) was injected using a different injection technique for each type of GS, based on the main muscles involved. With the aid of two computer programs, the area of gum exposed was measured before and after the application of abobotulinumtoxinA, to evaluate the level of improvement. There was a decrease in the degree of gum display in all patients. The general average improvement achieved was 75.09%. Two patients showed slight adverse effects that were easily corrected with additional doses of abobotulinumtoxinA. For this study, there was no sample size calculation and no statistical analysis of the cases. The authors conclude that it is important to identify the type of GS and therefore the main muscles involved, so that the correct injection technique can be used. AbobotulinumtoxinA was shown to be effective and safe for use in all types of GS in the present sample. Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.
Bakhshipour, Alireza; Rabbani, Romina; Shirani, Shapoor; Soleimani, Hosein A S L; Mikaeli, Javad
Among the therapeutic options for achalasia are pneumatic dilatation (PD), an appropriate long-term therapy, and botulinum toxin injection (BT) that is a relatively short-term therapy. This study aimed to compare therapeutic effect of repetitive pneumatic dilation with a combined method (botulinum toxin injection and pneumatic dilation) in a group of achalasia patients who are low responder to two initial pneumatic dilations. Thirty-four patients with documented primary achalasia that had low response to two times PD (<50% decrease in symptom score and barium height at 5 minute in timed esophagogram after 3 month of late PD) were randomized to receive pneumatic dilation (n=18) or botulinum toxin injection and pneumatic dilation by four weeks interval (n=16), PD and BT+PD groups respectively. Symptom scores were evaluated before and at 1, 6 and 12 months after treatment. Clinical remission was defined as a decrease in symptom score > or = 50% of baseline. There were no significant differences between the two groups in gender, age and achalasia type. Remission rate of patients in BT-PD group in comparison with PD group were 87.5% vs. 67.1% (P = 0.7), 87.5% vs. 61.1% (P = 0.59) and 87.5% vs. 55.5% (P = 0.53) at 1, 6 and 12 months respectively .There were no major complications in either group. The mean symptom score decreased by 62.71% in the BT-PD group (P < 0.002) and 50.77% in the PD group (P < 0.01) at the end of the first year. Despite a better response rate in BT+PD group, a difference was not statistically significant. A difference may be meaningful if a large numbers of patients are included in the study.
Kim, Jung Wan; Baek, Sehyun
The purpose of this study was to evaluate changes in tear volume, epidermal growth factor (EGF), and histology of the rabbit lacrimal gland after intraglandular application of botulinum toxin. Ten New Zealand rabbits were separated into 3 groups. Eight rabbits received botulinum toxin injection (2.5 U per 0.1 mL) into the right lacrimal gland and saline injection (0.1 mL) into the left lacrimal gland as a sham control. Two rabbits were untreated to serve as normal controls. Tear volume was measured using cotton thread every 2 weeks, and 4 rabbits were killed after 2 and 4 weeks. The lacrimal glands were surgically excised and sectioned or lysed for gene expression analysis. Epidermal growth factor expression and concentration were evaluated by real-time polymerase chain reaction and enzyme-linked immunosorbent assay; morphometric and histologic analyses were performed. The rabbits that were killed 2 weeks after the injection showed decreased tear volume and increased EGF expression and concentration, but differences were not statistically significant. The rabbits that were killed 4 weeks after the injection exhibited similar results. When all 8 rabbits were considered, we detected a significant decrease in tear volume and increased EGF expression and concentration (P = 0.012, P = 0.011, and P = 0.012, respectively). The EGF level was not significantly correlated with the tear volume. There were no prominent histologic changes between the glands, and the lumen versus fibrosis ratio in the interlobular ducts showed no statistically significant difference. The use of botulinum toxin in patients with epiphora is effective, safe, and repeatable because it reduces tear volume and increases the EGF level to prevent corneal damage while causing no histologic changes.
Kanellopoulos, A D; Mavrogenis, A F; Mitsiokapa, E A; Panagopoulos, D; Skouteli, H; Vrettos, S G; Tzanos, G; Papagelopoulos, P J
Botulinum toxin A injections and orthotics have been used to manage upper extremity spasticity in hemiplegic children. The authors performed a study to evaluate the necessity and effectiveness of a static night splint following outpatient botulinum toxin A treatment in children with upper limb spastic cerebral palsy. Twenty children with upper limb spastic cerebral palsy were treated with botulinum toxin A injections. A static night splint was applied in half of them. Objective assessment of upper limb function was performed at baseline, at 2 and 6 months after botulinum toxin A injection using the Quality of Upper Extremity Skills Test. After botulinum toxin A treatment, both groups showed an improvement on their previous functional level of the injected upper extremity. At 2 months, children in group A showed a 15.4% improvement, whereas children in group B improved by 12.2% from baseline; these were not statistically significant (P=0.326). At 6 months, group A still maintained a 15.9% improvement in function compared to group B which differed only by 4.2% from prebotulinum toxin A baseline; these differences were statistically significant (P=0.000). Complications related to the botulinum toxin A injection were not observed. The static Static night splinting following botulinum toxin A injections has shown a definite treatment effect in reducing spasticity and improving function in children with upper limb spastic cerebral palsy.
Bouchard, Manon; Chouinard, Sylvain; Suchowersky, Oksana
Congenital muscular torticollis (CMT) is the most common cause of torticollis in childhood. This condition is usually recognized and successfully treated in infancy, but may persist in adulthood, particularly if not treated. In adult patients, CMT can be differentiated from idiopathic cervical dystonia by the frequent association with facial asymmetry, presence of a cord-like sternocleiodmastoid muscle (SCM), absence of head tremor, lack of sensory trick, and head tilt since infancy. We describe 3 patients with persistent CMT, who were successfully treated with botulinum toxin injections with long lasting benefit.
In their article "Importing Injectables" in the September 2014 issue of the Journal of Drugs in Dermatology, Dr. Kenneth Beer and Karen Rothschild highlighted the possible harm to patients and practitioners from the use of unapproved botulinum toxin products - eg, Botox, Dysport, Xeomin, and Myobloc - and other cosmetic prescription drug products purchased from foreign or unlicensed suppliers.1 In the intervening years, the accuracy of their critique has been repeatedly demonstrated, as the dangers to patients' health, as well as to cosmetic practitioners' liberty, has only increased.
Petracca, Martina; Guidubaldi, Arianna; Ricciardi, Lucia; Ialongo, Tàmara; Del Grande, Alessandra; Mulas, Delia; Di Stasio, Enrico; Bentivoglio, Anna Rita
In recent years, Botulinum Toxin has been shown to be efficacious and safe in the treatment of sialorrhea, but scanty data are available on its long term use. The aim of this study was to investigate adverse events, discriminate differences in safety, and evaluate the efficacy of long-term use of both abobotulinumtoxinA and rimabotulinumtoxinB ultrasound-guided injections for sialorrhea in a retrospective trial. Moreover we review the literature on this topic. Consecutive patients with severe sialorrhea and receiving at least two ultrasound-guided intrasalivary glands abobotulinumtoxinA 250 U or rimabotulinumtoxinB 2500 U injections were included. Clinical and demographic data were collected. Safety and tolerability were assessed on the basis of patients' self-reports. Efficacy was assessed by recording the duration of benefit and by the Drooling Severity Scale and Drooling Frequency Scale 4 weeks after intervention. A review of literature was performed using 'Botulinum Toxin' and/or 'drooling' and/or 'sialorrhea' and/or 'hypersalivation' as keywords. Sixty-five patients (32 Amyotrophic Lateral Sclerosis and 33 Parkinson's Disease) were treated in a total of 317 sessions (181 rimabotulinumtoxinB and 136 abobotulinumtoxinA). Both serotypes induced a clear-cut benefit in 89% of injections. Mean benefit duration was 87 days (range 30-240), similar for abobotulinumtoxinA and rimabotulinumtoxinB but significantly shorter in Amyotrophic Lateral Sclerosis group compared to Parkinson's Disease (p < 0.001). Older age was positively correlated to benefit duration (p = 0.003). Botulinum Toxin-related and injection-related side effects complicated respectively 8,2% and 1,5% of treatments. The only Botulinum Toxin-related adverse event was a change of saliva thickness, mostly rated mild to moderate and more frequent in Amyotrophic Lateral Sclerosis patients (p = NS). Both 250 U abobotulinumtoxinA and 2500 U rimabotulinumtoxinB administered by ultrasound-guided intrasalivary
Braz, André Vieira; Louvain, Dailana; Mukamal, Luana Vieira
With aging, anatomical changes are observed in the face. In the lower third, these changes are expressed as ptosis of the angle of the mouth, lip enhancement groove mentalis; decrease in concavity between the jaw and neck and very noticeable platysmal banding. The repeated contraction of muscles of the lateral-chin together with the band platysmal side form what are called a marionette groove. Treating the whole lateral-chin area can result in a more harmonious aspect of the face when compared with treatment of a marionette groove in isolation. In this paper we describe combined treatment of the lateral chin area using botulinum toxin and fillers. PMID:23539022
Green, Richard James; Endersby, Simon; Allen, John; Adams, James
Frey syndrome classically causes gustatory sweating and facial flushing. We describe 2 cases in which medical thermography was used to investigate the symptoms. Images were taken after patients chewed a sialagogue and 2 weeks later they were given injections of botulinum toxin A. Images taken 4 weeks after treatment showed a considerable reduction in sweating and facial flushing, which was supported by the results of quality of life questionnaires completed before and after treatment. Medical thermography is much cleaner than the Minor's starch iodine test. It identifies areas of gustatory sweating, changes in temperature, and vascular changes, which potentially enable treatment to be targeted accurately.
Madsen, Ea Serie Lundegaard; Sonne-Holm, Stig; Wong, Christian; Curtis, Derek; Bencke, Jesper
Over the latest 30 years there has been an increasing use of botulinum toxin A injections in the lower limbs in children with cerebral palsy. However, the conclusions regarding effect of treatment in both randomized controlled and non-controlled trials have been inconclusive. One explanation may be that children with cerebral palsy do not always exhibit pure spasticity and/or dystonia of the affected muscles. Furthermore, the dose, injection volume and injection technique may vary from study to study. The evidence for the effect is so small that careful consideration on whether to continue this treatment regimen or not is needed.
Kaku, Michelle; Simpson, David M
Poststroke spasticity affects up to one-half of stroke patients and has debilitating effects, contributing to diminished activities of daily living, quality of life, pain, and functional impairments. Botulinum toxin (BoNT) is proven to be safe and effective in the treatment of focal poststroke spasticity. The aim of this review is to highlight BoNT and its potential in the treatment of upper and lower limb poststroke spasticity. We review evidence for the efficacy of BoNT type A and B formulations and address considerations of optimal injection technique, patient and caregiver satisfaction, and potential adverse effects of BoNT.
Peyronnet, B; Sanson, S; Amarenco, G; Castel-Lacanal, E; Chartier-Kastler, E; Charvier, K; Damphousse, M; Denys, P; de Seze, M; Egon, G; Even, A; Forin, V; Karsenty, G; Kerdraon, J; le Normand, L; Loche, C-M; Manunta, A; Mouracade, P; Phe, V; Previnaire, J-G; Ruffion, A; Saussine, C; Schurch, B; Game, X
There is currently no guideline regarding the management of neurogenic detrusor overactivity (NDO) refractory to intra-detrusor botulinum toxin injections. The primary objective of the present study was to find a consensus definition of failure of botulinum toxin intra-detrusor injections for NDO. The secondary objective was to report current trends in the managment of NDO refractory to botulinum toxin. A survey was created, based on data drawn from current literature, and sent via e-mail to all the experts form the Group for research in neurourology in french language (GENULF) and from the comittee of neurourology of the French urological association (AFU). The experts who did not answer to the first e-mail were contacted again twice. Main results from the survey are presented and expressed as numbers and proportions. Out of the 42 experts contacted, 21 responded to the survey. Nineteen participants considered that the definition of failure should be a combination of clinical and urodynamics criteria. Among the urodynamics criteria, the persistence of a maximum detrusor pressure>40 cm H2O was the most supported by the experts (18/21, 85%). According to the vast majority of participants (19/21, 90.5%), the impact of injections on urinary incontinence should be included in the definition of failure. Regarding the management, most experts considered that the first line treatment in case of failure of a first intra-detrusor injection of Botox(®) 200 U should be a repeat injection of Botox(®) at a higher dosage (300 U) (15/20, 75%), regardless of the presence or not of urodynamics risk factors of upper tract damage (16/20, 80%). This work has provided a first overview of the definition of failure of intra-detrusor injections of botulinum toxin in the management of NDO. For 90.5% of the experts involved, the definition of failure should be clinical and urodynamic and most participants (75%) considered that, in case of failure of a first injection of Botox(®) 200 U
Stark, Thomas R; Perez, Cristina V; Okeson, Jeffrey P
Chronic recurrent temporomandibular joint (TMJ) dislocation is an uncommon condition that is painful and distressing to patients and uniquely challenging for clinicians. Sustained TMJ dislocation is not amenable to manual reduction alone when the etiology is muscular in nature. The purpose of this report was to describe the case of a child presenting with recurring temporomandibular joint dislocation secondary to muscle hyperactivity of unknown etiology that was managed with injections of botulinum toxin type A into the inferior lateral pterygoid muscles. The use of this peripheral antispasmoic neurotoxin is a reasonable, safe, and conservative, palliative treatment option for pediatric patients suffering from chronic recurring TMJ dislocation.
Suzuki, Tomonori; Miyazaki, Satoru
Many of biological system mediated through protein-protein interactions. Knowledge of protein-protein complex structure is required for understanding the function. The determination of huge size and flexible protein-protein complex structure by experimental studies remains difficult, costly and five-consuming, therefore computational prediction of protein structures by homolog modeling and docking studies is valuable method. In addition, MD simulation is also one of the most powerful methods allowing to see the real dynamics of proteins. Here, we predict protein-protein complex structure of botulinum toxin to analyze its property. These bioinformatics methods are useful to report the relation between the flexibility of backbone structure and the activity.
Kaku, Michelle; Simpson, David M
Poststroke spasticity affects up to one-half of stroke patients and has debilitating effects, contributing to diminished activities of daily living, quality of life, pain, and functional impairments. Botulinum toxin (BoNT) is proven to be safe and effective in the treatment of focal poststroke spasticity. The aim of this review is to highlight BoNT and its potential in the treatment of upper and lower limb poststroke spasticity. We review evidence for the efficacy of BoNT type A and B formulations and address considerations of optimal injection technique, patient and caregiver satisfaction, and potential adverse effects of BoNT. PMID:27022247
Safarpour, Yasaman; Mousavi, Tahereh; Jabbari, Bahman
Purpose of review The purpose of this review is to provide updated information on the role of botulinum neurotoxin (BoNT) therapy in multiple sclerosis (MS). This review aims to answer which symptoms of multiple sclerosis may be amenable to BoNT therapy. Recent findings We searched the literature on the efficacy of BoNTs for treatment of MS symptoms up to April 1st 2017 via the Yale University Library's search engine including but not limited to Pub Med and Ovis SP. The level of efficacy was defined according to the assessment's criteria set forth by the Subcommittee on Guideline Development of the American Academy of Neurology. Significant efficacy was found for two indications based on the available blinded studies (class I and II) and has been suggested for several others through open-label clinical trials. Summary There is level A evidence (effective- two or more class I) that injection of BoNT-A into the bladder's detrusor muscle improves MS-related neurogenic detrusor overactivity (NDO) and MS-related overactive (OA) bladder. There is level B evidence (probably effective- two class II studies) for utility of intramuscular BoNT-A injections for spasticity of multiple sclerosis. Emerging data based on retrospective class IV studies demonstrates that intramuscular injection of BoNTs may help other symptoms of MS such as focal tonic spasms, focal myokymia, spastic dysphagia, and double vision in internuclear ophthalmoplegia. There is no data on MS-related trigeminal neuralgia and sialorrhea, two conditions which have been shown to respond to BoNT therapy in non-MS population.
Chun, Chan Lan; Kahn, Chase I.; Borchert, Andrew J.; Byappanahalli, Muruleedhara N.; Whitman, Richard L.; Peller, Julie R.; Pier, Christina; Lin, Guangyun; Johnson, Eric A.; Sadowsky, Michael J.
The reemergence of avian botulism caused by Clostridium botulinum type E has been observed across the Great Lakes in recent years. Evidence suggests an association between the nuisance algae, Cladophoraspp., and C. botulinum in nearshore areas of the Great Lakes. However, the nature of the association between Cladophora and C. botulinum is not fully understood due, in part, to the complex food web interactions in this disease etiology. In this study, we extensively evaluated their association by quantitatively examining population size and serotypes of C. botulinum in algal mats collected from wide geographic areas in lakes Michigan, Ontario, and Erie in 2011–2012 and comparing them with frequencies in other matrices such as sand and water. A high prevalence (96%) of C. botulinum type E was observed inCladophora mats collected from shorelines of the Great Lakes in 2012. Among the algae samples containing detectable C. botulinum, the population size of C. Botulinum type E was 100–104 MPN/g dried algae, which was much greater (up to 103 fold) than that found in sand or the water column, indicating thatCladophora mats are sources of this pathogen. Mouse toxinantitoxin bioassays confirmed that the putativeC. botulinum belonged to the type E serotype. Steam treatment was effective in reducing or eliminating C. botulinum type E viable cells in Cladophora mats, thereby breaking the potential transmission route of toxin up to the food chain. Consequently, our data suggest that steam treatment incorporated with a beach cleaning machine may be an effective treatment of Cladophora-borne C. botulinum and may reduce bird mortality and human health risks.
Lan Chun, Chan; Kahn, Chase I; Borchert, Andrew J; Byappanahalli, Muruleedhara N; Whitman, Richard L; Peller, Julie; Pier, Christina; Lin, Guangyun; Johnson, Eric A; Sadowsky, Michael J
The reemergence of avian botulism caused by Clostridium botulinum type E has been observed across the Great Lakes in recent years. Evidence suggests an association between the nuisance algae, Cladophora spp., and C. botulinum in nearshore areas of the Great Lakes. However, the nature of the association between Cladophora and C. botulinum is not fully understood due, in part, to the complex food web interactions in this disease etiology. In this study, we extensively evaluated their association by quantitatively examining population size and serotypes of C. botulinum in algal mats collected from wide geographic areas in lakes Michigan, Ontario, and Erie in 2011-2012 and comparing them with frequencies in other matrices such as sand and water. A high prevalence (96%) of C. botulinum type E was observed in Cladophora mats collected from shorelines of the Great Lakes in 2012. Among the algae samples containing detectable C. botulinum, the population size of C. Botulinum type E was 10(0)-10(4) MPN/g dried algae, which was much greater (up to 10(3) fold) than that found in sand or the water column, indicating that Cladophora mats are sources of this pathogen. Mouse toxinantitoxin bioassays confirmed that the putative C. botulinum belonged to the type E serotype. Steam treatment was effective in reducing or eliminating C. botulinum type E viable cells in Cladophora mats, thereby breaking the potential transmission route of toxin up to the food chain. Consequently, our data suggest that steam treatment incorporated with a beach cleaning machine may be an effective treatment of Cladophora-borne C. botulinum and may reduce bird mortality and human health risks. Copyright © 2014 Elsevier B.V. All rights reserved.
Klein, Fernanda Homem de Mello de Souza; Brenner, Fabiane Mulinari; Sato, Maurício Shigeru; Robert, Fernanda Manfron Batista Rosas; Helmer, Karin Adriane
BACKGROUND Masseter hypertrophy has been treated with botulinum toxin injections because of esthetic complaints especially in Asians. OBJECTIVES The goal of the present study was to evaluate the efficacy of abobotulin toxin use in masseter hipertrophy treatment in Brazilians. METHODS Ten Brazilian female patients with masseter hypertrophy were subjected to injections of 90U of abobotulinum toxin A applied on each side respecting the safety zone stabilished in literature and were followed up for 24 weeks. RESULTS When analyzing the coefficients between measures of middle and lower third of the face obtained from standardized photographs, an increase was observed, with statistical significance at 2 weeks (p=0.005) and 12 weeks (p=0.001). The progression of lower third reduction was 3.94%, 5.26%, 11.99%, and 5.47% (2, 4, 12, and 24 weeks respectively). All patients showed improvement in bruxism after treatment. Observed adverse effects were masticatory fatigue, smile limitation, and smile asymmetry. CONCLUSION The use of abobotulinum toxin A for masseter hypertrophy is effective in Brazilians and reached its maximum effect of facial thinning at 12 weeks. Smile limitation had a higher incidence compared to that reported in the literature and may result from risorius muscle blockage caused by toxin dissemination. Despite its side effects, 80% of the patients would like to repeat the treatment. PMID:25387491
FUNDING NUMBERS ]involvement -of -a Botulinun toxin -sesftUv&2_2At6-d -- Protein in stinulated exocytosis of humnan neutrophi1s. WICD I. AUTHOR(S) Nath...Botulinum Toxin -Sensitive 22-kDa G Protein in Stimulated Exocytosis of Human Neutrophils jaymaree Nath,’ Annette Powledge, and Daniel G. Wright2...observed. Although both peslussis toxin and ST-O Inhibited excocytosis In FlMvLP-stimvulated PMNs, the inhibitory effects o( the two toxins were found to be
Fabuel Alcañiz, José Javier; Martínez Arcos, Laura; Jimenez Cidre, Miguel; Burgos Revilla, Francisco Javier
Bladder hyperactivity is described as the presence of "voiding urgency, generally associated with increased daytime frequency and nocturia, with or without urinary incontinence, in the absence of urinary tract infection or other obvious pathology". Onabotulinum toxin A (BTA) is a recommendable therapeutic option in case of failure, contraindication or refusal of the conservative therapy or other non-pharmacological therapies. The injection of BTA in the detrusor has been performed under local, regional or general anesthesia either in the conventional or major ambulatory surgery operative room or in the cystoscopy room. The objective of this paper is to describe the procedure to perform BTA therapy as an ambulatory operation under intravesical local anesthesia in the cystoscopy room, describing its advantages and limitations.
Matak, I; Lacković, Z; Relja, M
In the motor system, botulinum toxin type A (BoNT/A) actions were classically attributed to its well-known peripheral anticholinergic actions in neuromuscular junctions. However, the enzymatic activity of BoNT/A, assessed by the detection of cleaved synaptosomal-associated protein 25 (SNAP-25), was recently detected in motor and sensory regions of the brainstem and spinal cord after toxin peripheral injection in rodents. In sensory regions, the function of BoNT/A activity is associated with its antinociceptive effects, while in motor regions we only know that BoNT/A activity is present. Is it possible that BoNT/A presence in central motor nuclei is without any function? In this brief review, we analyze this question. Limited data available in the literature warrant further investigations of BoNT/A actions in motor nervous system.
Daifas, D P; Smith, J P; Blanchfield, B; Austin, J W
To determine the safety of a high moisture bakery product, packaged under modified atmospheres, challenge studies were done on English-style crumpets (water activity [a(w)] 0.990, pH 6.5) inoculated postbaking with Clostridium botulinum types A and proteolytic B spores (5 X 10(2) spores/g). Products were packaged either in air, in air with an Ageless FX200 oxygen absorbent, or in a CO2/N2 (60:40) gas mixture, stored at ambient temperature (25 degrees C), and monitored for toxicity daily. All inoculated crumpets were toxic within 4 to 6 days and were organoleptically acceptable at the time of toxigenesis. Counts of C. botulinum increased to approximately 10(5) CFU/g at the time of toxicity. To determine the effect of baking on product safety, subsequent challenge studies were done on crumpets inoculated with 5 x 10(2) spores/g (baked weight basis) prior to baking. All crumpets were toxic after only 6 days, irrespective of packaging conditions, and toxigenesis again preceded spoilage. Temperature profile studies showed that the maximum internal temperature reached during baking was 97 degrees C, and the total baking process was equivalent to 0.03 min at 121 degrees C. The actual time to toxin production in both studies (4 to 6 days) correlated well with the predicted time (3.4 days) using the U.S. Department of Agriculture Pathogen Modeling Program (version 5.1) for proteolytic strains of C. botulinum. These studies confirm that high moisture bakery products, if contaminated with C. botulinum spores either pre- or postbaking, could pose a public health hazard, if packaged in air (in a high gas barrier package where O2 was depleted and CO2 was generated during storage) or under modified atmosphere packaging conditions and stored at ambient temperature.
Orlova, O R; Akulov, M A; Usachev, D Iu; Taniashin, S V; Zakharov, V O; Saksonova, E V; Mingazova, L R; Surovykh, S V
To evaluate the role of botulinum toxin type A in the acute phase of facial nerve injury after neurosurgical surgery. The study involved 55 patients with acute facial muscle paresis caused by facial nerve injury during surgery on the posterior cranial fossa and cerebello-pontine angle (CPA). The first group consisted of 35 patients (mean age, 48.14±1.26 years) who were administered botulinum toxin type A (xeomin) at a dose of 2-3 U per point in muscles of the intact side of the face. The control group included 20 patients (mean age, 49.85±1.4 years) who underwent standard rehabilitation treatment of this pathology. The treatment efficacy was evaluated using the House-Brackmann Scale, the Yanagihara facial grading system, the Facial Disability Index (FDI), and the Sunnybrook Facial Grading (SFG) Scale. Before treatment, patients of both groups experienced severe dysfunction according to the House-Brackmann Scale. A month after the botulinium toxin type A therapy had been started, a significant improvement in the group of patients who received botulinum toxin was observed at all scales (p<0.05), whereas improvement in the facial nerve function in the second group was observed only by the 3rd month of rehabilitation treatment (p<0.05). The number of synkineses in the patients who did not receive botulinum toxin was 46% higher than that in the first group (p=0.019) one year after the surgery, and it was higher by 91% after 2 years (p<0.001). The use of botulinum toxin type A is reasonable in acute facial nerve injury and should be mandatory in combined therapy of these patients.
Hasegawa, Kimiko; Watanabe, Toshihiro; Sato, Hiroaki; Sagane, Yoshimasa; Mutoh, Shingo; Suzuki, Tomonori; Yamano, Akihito; Kouguchi, Hirokazu; Takeshi, Kouichi; Kamaguchi, Arihide; Fujinaga, Yukako; Oguma, Keiji; Ohyama, Tohru
A unique strain of Clostridium botulinum, serotype D 4947 (D-4947), produces a considerable amount of a 650 kDa toxin complex (L-TC) and a small amount of a 280 kDa M-TC, a 540 kDa TC, and a 610 kDa TC. The complexes are composed of only un-nicked components, including neurotoxin (NT), nontoxic nonhemagglutinin (NTNHA) and hemagglutinin subcomponents (HA-70, HA-33 and HA-17). Unlike other NTs from all serotype strains, separation of D-4947 NT from L-TC, except for M-TC, during chromatography required highly alkaline conditions around pH 8.8. The separated NT and NTNHA/HAs complex can be reconstituted to L-TC that is indistinguishable from the parent L-TC with respect to toxicity, hemagglutination activity and gel filtration profile. The isoelectric points of NT and NTNHA/HAs were close together depending on the number of HA-33/17 molecules. We have established a new method to separate the unique D-4947 NT from the complex, which will yield valuable information on structure of botulinum toxin.
Naicker, A S; Roohi, S A; Chan, J L L
A 56-year-old man became quadriplegic, bed bound, and carer-dependent secondary to cervical osteomyelitis. Three years later, he presented with generalised spasticity, crouched posture, and a large sacral pressure sore. The severe spasticity in his hips and knees prevented ischial sitting. Injections of botulinum toxin type A to both hamstrings and gastrosoleuii controlled the flexor spasticity of his lower limbs and facilitated rehabilitation and wound healing through proper positioning, wound care, stretching, and weight-bearing exercises. A few weeks later, the patient could better position himself in bed (prone lying) and on his wheelchair (ischial sitting). His spasm-related pain lessened and his mobility and activities of daily living improved. The sacral pressure sore healed completely a few months later. The patient could sleep better, feed with set-up and adaptive aids, groom, dress, and transfer himself with minimal assistance. The effects of botulinum toxin extended beyond just spasticity reduction. His upper extremity function, mobility, and social well-being were all improved through better positioning.
Kaplan, Julie Bass
Knowledge of variable anatomy is key for excellent outcomes from the administration of botulinum toxin for aesthetic purposes. One must understand the location and function of each facial muscle to predict the patient's desired outcome. One concept often overlooked by injectors is the understanding of the target muscle's depth. In addition, a firm understanding of where each facial muscle originates and attaches can be essential to correctly identifying and injecting the correct muscle with botulinum toxin. Facial muscles often overlap each other and cross various planes. For example, an injector may be unaware that the corrugator supercilii muscle lies in different depths medially and laterally. Novice injectors may miss the variability of this muscle and inject the lower frontalis muscle by mistake. This may lead to a heavy brow look, or it could drop the area between the brows, creating an appearance of anger. This article explores a three-dimensional anatomical approach to achieve excellent outcomes, rather than the two-dimensional approach traditionally discussed. Many of the injection techniques defined in this article are considered off-label by the Food and Drug Administration at the time of this publication but are commonly discussed in peer-reviewed literature and consensus opinion reports. Twelve facial muscles often injected for positive aesthetic outcomes will be outlined as well as seven facial muscles to generally avoid.
Jankovic, J; Schwartz, K; Donovan, D T
In the past five years, 477 patients with various focal dystonias and hemifacial spasm received 3,806 injections of botulinum A toxin for relief of involuntary spasms. A definite improvement with a global rating greater than or equal to 2 on a 0-4 scale, was obtained in all 13 patients with spasmodic dysphonia, 94% of 70 patients with blepharospasm, 92% of 13 patients with hemifacial spasm, 90% of 195 patients with cervical dystonia, 77% of 22 patients with hand dystonia, 73% of 45 patients with oromandibular dystonia, and in 90% of 21 patients with other focal dystonia who had adequate follow up. While the average duration of maximum improvement lasted about 11 weeks after an injection (range seven weeks in patients with hand dystonia to 15 weeks in patients with hemifacial spasm), some patients benefited for over a year. Only 16% of the 941 treatment visits with follow up were not successful. Except for transient focal weakness, there were very few complications or systemic effects attributed to the injections. This study supports the conclusion that botulinum toxin injections are a safe and effective therapy for patients with focal dystonia and hemifacial spasm. Images PMID:2213039
Criswell, Susan R; Crowner, Beth E; Racette, Brad A
Hypertonicity is a leading cause of disability for children with cerebral palsy (CP). Botulinum toxin A (BTA) chemically denervates muscle tissue and is commonly used in the management of lower-extremity hypertonicity in children with CP because of its focal effects and wide safety margin. Randomized controlled trials have demonstrated that BTA injections in the ankle flexors, hamstrings, and adductors reduce spasticity and result in improved passive and active range of motion. In other studies, improvements in gait and measurements of functional outcome were found in appropriately selected children who had been injected with BTA. A multidisciplinary treatment approach that includes physical therapists, occupational therapists, orthotists, neurologists, physicians with expertise in performing botulinum toxin injections, orthopedic surgeons, and neurosurgeons is critical to optimize care in children with lower-extremity tone due to CP. In this paper, the authors propose treatment algorithms based on clinical presentation, detailed dosing, and technical information to optimize the treatment of these children. With a multidisciplinary approach, children with lower-extremity hypertonicity due to CP can experience improvements in muscle tone and function.
Kober, Johanna; Schmid, Melanie; Buchberger, Elisabeth; Kamolz, Lars-Peter; Keck, Maike
Background: Botulinum (neuro)toxin A (BoNT) is widely used in the field of plastic and reconstructive surgery. Among treatment of pain, hyperhidrosis, or aesthetic purposes, it is also used to enhance wound healing and prevent excessive scar formation. Some clinical data already exist, but only little is known on a cellular level. The aim of this study was to evaluate the effect of BoNT on cells essential for wound healing in vitro. Therefore, primary human keratinocytes and endothelial cells were treated with different concentrations of BoNT and tested on proliferation, migration, and angiogenic behavior. Methods: BoNT was exposed to human keratinocytes and endothelial cells in a low (1 IU/mL), medium (10 IU/mL), and high (20 IU/mL) concentrations in cell culture. Proliferation and migration of the 2 cell types were observed and also the angiogenic potential of endothelial cells in vitro. Results: BoNT 20 IU/mL negatively influenced proliferation and migration of keratinocytes but not those of endothelial cells. Angiogenesis in vitro was less effective with the highest BoNT concentrations tested. Low concentrations of BoNT supported sprouting of endothelial cells. Conclusions: High concentrations of botulinum toxin interfered with wound closure as keratinocytes’ proliferation and migration were deteriorated. Furthermore, BoNT concentrations of 20 IU/mL constrain in vitro vessel formation but do not influence proliferation or migration of endothelial cells. PMID:27622105
Laria, Carlos; Merino-Suárez, María L; Piñero, David P; Gómez-Hurtado, Arantxa; Pérez-Cambrodí, Rafael J
We describe the case of an eight-year-old girl with complaints of headaches and blurred vision (uncorrected visual acuity: 0.1 decimal) that showed on examination miotic pupils, pseudomyopia, no ocular motility restrictions, and no associated neurological disease. After initial treatment with cyclopentolate for two months, pseudomyopia persisted with an intermittent and variable esotropia. Spectacles of +1 both eyes and atropine 1% one drop daily were then prescribed. The situation improved and remained stable for several weeks, with pseudomyopia and esotropia reappearing later. Finally, botulinum toxin (2.5 iu Botox) was injected in the medial rectus muscle on two occasions and a visual therapy program based on the stimulation of fusional divergence, diplopia, and stereopsis consciousness was recommended. This prescription was combined with the use of atropine during the first few weeks. Orthotropia and corrected distance visual acuity of 1.0 were found three months after treatment. The evolution and clinical results of this case report suggest that botulinum toxin in combination with other therapeutic alternatives may be useful in the treatment of spasm of the near reflex.
Zhang, Yi; Zhang, Haifeng; Lian, Ya-Jun; Ma, Yun-Qing; Xie, Nan-Chang; Cheng, Xuan; Zhang, Lu
Background. Short-lasting unilateral neuralgiform headache with conjunctival injection and tearing (SUNCT) syndrome is an unusual cause of headache, mainly described in older adults, and is rare in children. Pain attacks may be severe, frequent, and prolonged. The therapeutic benefits of many drugs are disappointing. Patient and Methods. A 12-year-old boy suffered severe headache and toothache for 20 days. As treatment with nonsteroidal anti-inflammatory drugs, anticonvulsants, and steroids proved ineffective, he was treated with ipsilateral multisite subcutaneous injections of botulinum toxin A 70 U around the orbit, the temporal area, and the upper gum. Results. The pain had reduced in frequency and severity by the fourth day after treatment and had completely disappeared after 7 days. There were no side effects or recurrence during a subsequent 17-month follow-up period. Conclusion. Botulinum toxin A can be used to treat the first episode of SUNCT in children over the age of 12 years. PMID:27445629
Rystedt, Alma; Karlqvist, Mattias; Bertilsson, Maria; Naver, Hans; Swartling, Carl
Dose-response studies of botulinum toxin for reduction of sweating are sparse in the literature. The aim of this study was to determine the most appropriate concentrations of Botox®, Dysport®, Xeomin® and NeuroBloc®, respectively, in order to achieve the greatest reduction in sweating, thus reducing the costs and increasing the safety of treatment. Four concentrations of each product were investigated. Intradermal injections of all products and concentrations were applied to the backs of 20 consenting subjects, in a randomized, double-blind manner. Areas of anhidrotic and hypohidrotic skin were measured with an iodine-starch test after 4, 8 and 12 weeks, respectively. Optimal concentrations were found to be 25 U/ml for Botox and Xeomin, approximately 100 U/ml for Dysport, and 50 U/ml for NeuroBloc. When comparing the mean anhidrotic area per unit for 100 U/ml of each product, the calculated dose conversion ratios were 1:1.6:1.2:1.3 (Botox:Dysport:Xeomin:NeuroBloc). If, instead, the optimal concentration for each product was compared, the dose conversion ratios were 1:4.8:1.3:2.2. Thus, it is crucial to consider botulinum toxin concentration in a treatment regimen.
Ghanbarzadeh, Kourosh; Tabatabaie, Omid Reza; Salehifar, Ebrahim; Amanlou, Massoud; Khorasani, Ghasemali
A suitable pharmacological substitute for the well-established surgical delay technique for random skin flaps to increase viability has been elusive. To evaluate the effects of nitroglycerin and botulinum toxin type A on random flap survival in a rat model. The present controlled experimental study was performed in the four groups of rats. One week after intervention in each group, the flap was raised and kept in situ, and flap necrosis was evaluated through follow-up. Group 1 received intradermal botulinum toxin type A (BTX-A) and topical nitroglycerin 2%; group 2 received BTX-A and topical Vaseline (Unilever, USA); group 3 received topical nitroglycerin and intradermal normal saline; and group 4 received topical Vaseline and intradermal normal saline. BTX-A reduced the area of necrosis compared with control (24% versus 56% respectively; P<0.001). Nitroglycerin application was associated with a trend toward improved flap viability (42% versus 56%; P=0.059). The combination of topical nitroglycerin and BTX-A, compared with Vaseline and BTX-A, was associated with decreased flap necrosis (16.1% versus 24%, respectively), although it was not statistically significant (P=0.45). BTX-A was effective in reducing distal flap necrosis. The effect of BTX-A was significantly more pronounced than nitroglycerin ointment.
Kim, Hong Geum; Chung, Myung Eun; Song, Dae Heon; Kim, Ju Yong; Sul, Bo Mi; Oh, Chang Hoon
Objective To determine the optimal injection site in the flexor digitorum longus (FDL) muscle for effective botulinum toxin injection. Methods Fourteen specimens from eight adult Korean cadavers were used in this study. The most proximal medial point of the tibia plateau was defined as the proximal reference point; the most distal tip of the medial malleolus was defined as the distal reference point. The distance of a line connecting the proximal and distal reference points was defined as the reference length. The X-coordinate was the distance from the proximal reference point to the intramuscular motor endpoint (IME), or motor entry point (MEP) on the reference line, and the Y-coordinate was the distance from the nearest point from MEP on the medial border of the tibia to the MEP. IME and MEP distances from the proximal reference point were evaluated using the raw value and the X-coordinate to reference length ratio was determined as a percentage. Results The majority of IMEs were located within 30%-60% of the reference length from the proximal reference point. The majority of the MEPs were located within 40%-60% of the reference length from the proximal reference point. Conclusion We recommend the anatomical site for a botulinum toxin injection in the FDL to be within a region 30%-60% of the reference length from the proximal reference point. PMID:25750869
Warner, Marvin G.; Dockendorff, Brian P.; Feldhaus, Michael J.; Anheier, Norman C.; Marks, James D.; Grate, Jay W.; Bruckner-Lea, Cindy J.
In this paper we will describe how high affinity reagents and a sensor configuration enabling rapid mass transport can be combined for rapid, sensitive biodetection. The system that we have developed includes a renewable surface immunoassay, which involves on-column detection of a fluorescently labeled secondary antibody in a sandwich immunoassay. Yeast display and directed molecular evolution were used to create high affinity antibodies to the botulinum toxin heavy chain receptor binding domain, AR1 and 3D12. A rotating rod renewable surface microcolumn was used to form a microliter-sized column containing beads functionalized with the capture antibody (AR1). The column was perfused with sample, wash solutions, and a fluorescently labeled secondary antibody (3D12) while the on-column fluorescence was monitored. Detection was accomplished in less than 5 minutes, with a total processing time of about 10 minutes. On-column detection of botulinum toxin was more sensitive and much faster than flow cytometry analysis on microbeads using the same reagents.
O'Neil, Luke M; Palme, Carsten E; Riffat, Faruque; Mahant, Neil
Recurrent parotitis is a rare manifestation of Sjögren syndrome. The management of recurrent parotitis is challenging because conservative methods may be of limited efficacy and invasive approaches carry the risk of complications. Botulinum toxin has been shown to reduce salivary flow, and consequently, the results of its use in the management of recurrent parotitis have been encouraging. A 65-year-old female patient with recurrent parotitis due to Sjögren syndrome was referred to us, complaining of weekly bouts of inflammation. She required a course of antibiotics monthly to control bacterial superinfections. We treated her with onabotulinumtoxinA injections into both parotid glands at regular intervals. After her second injection cycle, she denied further inflammatory bouts, has not required antibiotics in more than 36 months, and denied any side effects. Botulinum toxin may be a safe and effective method of treating Sjögren syndrome-associated recurrent parotitis. Copyright © 2016 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.
Singh, Ajay K; Sachdeva, Amita; Degrasse, Jeffrey A; Croley, Timothy R; Stanker, Larry H; Hodge, David; Sharma, Shashi K
Botulinum neurotoxins are produced as a toxin complex (TC) which consists of neurotoxin (NT) and neurotoxin associated proteins. The characterization of NT in its native state is an essential step for developing diagnostics and therapeutic countermeasures against botulism. The presence of NT genes was validated by PCR amplification of toxin specific fragments from genomic DNA of Clostridium botulinum strain PS-5 which indicated the presence of both serotype A and B genes on PS-5 genome. Further, TC was purified and characterized by Western blotting, Digoxin-enzyme linked immunosorbent assay, endopeptidase activity assay, and Liquid chromatography-Mass spectrometry. The data showed the presence of serotype A specific neurotoxin. Based on the analysis of neurotoxin genes and characterization of TC, PS-5 strain appears as a serotype A (B) strain of C. botulinum which produces only serotype A specific TC in the cell culture medium.
Carlin, F; Peck, M W
Seven strains of nonproteolytic Clostridium botulinum (types B, E, and F) were each inoculated into a range of anaerobic cooked puréed vegetables. After incubation at 10 degrees C for 15 to 60 days, all seven strains formed toxin in mushrooms, five did so in broccoli, four did so in cauliflower, three did so in asparagus, and one did so in kale. Growth kinetics of nonproteolytic C. botulinum type B in cooked mushrooms, cauliflower, and potatoes were determined at 16, 10, 8, and 5 degrees C. Growth and toxin production occurred in cooked cauliflower and mushrooms at all temperatures and in potatoes at 16 and 8 degrees C. The C. botulinum neurotoxin was detected within 3 to 5 days at 16 degrees C, 11 to 13 days at 10 degrees C, 10 to 34 days at 8 degrees C, and 17 to 20 days at 5 degrees C.
Midura, T; Taclindo, C; Nygaard, G S; Bodily, H L; Wood, R M
The appearance of Clostridium botulinum type E organisms and of toxin in experimentally inoculated packages of turkey roll was followed to study the time relationship between the presence of vegetative cells and the demonstration of toxin. The presence of vegetative cells was determined by immunofluorescence, and animal tests were used to assay toxin production. Growth initiated from detoxified spores of C. botulinum type E resulted in toxin formation within 24 hr. Presence of fluorescing vegetative cells and of toxin coincided from 1 to 14 days of incubation. Beginning with the next testing date, day 21, differences were observed. Toxin could be detected for a longer time than vegetative cells. Neither toxin nor organisms could be found after 56 days of incubation. The mouse lethal dose tests (MLD per gram of turkey roll) showed fluctuations in the amount of toxin present throughout the period of testing. Maximal amounts of toxin were present during the period when fluorescing organisms were also more numerous. The applications of immunofluorescence in the study and in the diagnosis of botulism is discussed.
Lunde, Hanne Marie Bøe; Torkildsen, Øivind; Bø, Lars; Bertelsen, Anne Kjørsvik
Trigeminal neuralgia (TN) is one of the most agonizing facial pain disorders that humans endure. Studies on onabotulinum toxin A (BTX-A) treatment for TN are limited, but promising with respect to TN of no identifiable cause. We aimed to investigate the efficiency and safety of BTX-A treatment in a 60-year-old male with diabetes mellitus who in March 2013 presented with TN caused by an exostosis in Meckel's cave. The patient was medically treatment refractory due to insufficient pain relief and adverse events of hyperglycemia, and surgery was declined due to complex anatomy. As a last resort, BTX-A was injected into the pain trigger zones of the trigeminal nerve (V5). Complete analgesia was reported 2 weeks after BTX-A injection. Pain medications were discontinued and laboratory values returned to acceptable levels. Regular BTX-A treatment during the next 28 months showed sustained analgesic effect. BTX-A has an excellent safety profile and may be efficient for patients with symptomatic TN not suited for conventional therapies. © 2016 American Headache Society.
Baguley, Ian J; Nott, Melissa T; Turner-Stokes, Lynne; De Graaff, Stephen; Katrak, Pesi; McCrory, Paul; de Abadal, Monica; Hughes, Andrew
Limited empirical information exists regarding botulinum toxin-A injector decision-making practices for adult upper limb post-stroke spasticity. The design of most studies prevents such an assessment, as injection sites and dosage are mandated by researcher protocols. This contrasts to usual injector practices, where individualized decision-making is the standard of care. Secondary data analysis from an Australian randomized controlled trial of 90 adults with upper limb post-stroke spasticity where experienced clinicians followed their standard clinical injecting practice rather than a mandated injection regimen. Clinicians were hypothesized to tailor their injection practices according to the subject's degree of spasticity and/or the type of functional gain desired. Hypothesis testing was conducted using non-parametric analysis. Muscle selection and botulinum toxin-A dosage were not significantly associated with spasticity severity or with patient-identified goals. Between-site differences in injection practices suggested that injector beliefs, rather than patient characteristics, were the dominant feature driving botulinum toxin-A injection strategy for post-stroke upper limb spasticity. This result looks into the "black box" of rehabilitation, revealing significant variation in injector beliefs. Findings suggest that further scientific work is required to maximize the efficacy of botulinum toxin-A injections in post-stroke upper limb spasticity management.
Lee, Li-Rong; Chuang, Yao-Chia; Yang, Baii-Jia; Hsu, Min-Jung; Liu, Ying-Hung
To compare the effect of equivalent doses of botulinum toxin type A given in high-volume or low-volume injections on lower limb spasticity in children with cerebral palsy. A total of 17 subjects whose modified Ashworth scale scores in the calf flexors bilaterally ranged from 2 to 3 were enrolled. The right gastrocnemius was injected with botulinum toxin type A using a high-volume preparation (100 IU/4 ml), and the left gastrocnemius was injected with a low-volume preparation (100 IU/1 ml). The amplitude and area of the compound muscle action potential for both medial gastrocnemius muscles, the dynamic muscle range, static muscle range, modified Ashworth scale for both ankles, and the Gross Motor Functional Classification System were assessed before and after treatment. Spasticity was reduced in both legs. There was no significant difference in the changes in the amplitude and area of compound muscle action potential (P = 0.74 and 0.30, respectively), dynamic muscle range (P = 0.7), static muscle range (P = 0.65), and modified Ashworth scale (P = 1) in the right vs. left legs after botulinum toxin type A injection. The high-volume preparation did not cause more pain. A higher volume preparation with a 4-fold dilution of botulinum toxin type A does not yield better results than a low-volume preparation.
Botulinum neurotoxins (BoNTs) are produced as a toxin complex (TC) which consists of neurotoxin (NT) and neurotoxin associated proteins (NAPs). The characterization of NT in its native state is an essential step for developing diagnostics and therapeutic countermeasures against botulism. The presenc...
Bakheit, Abdel Magid
Although there are sound theoretical reasons for the use of botulinum toxin (Btx) as early as possible in the management of severe childhood muscle spasticity, the experience with its safety in children younger than 2 years of age is limited and information about its possible effects on the development and maturation of the human motor system…
Kongsaengdao, Subsai; Maneeton, Benchalak; Maneeton, Narong
Objective This study aimed to identify possible improvements in disease-specific health-related quality of life (HRQoL) after multiple injections of botulinum toxin A over 24 weeks in Thai cervical dystonia (CD) patients. Materials and methods A 24-week prospective study comparing HRQoL of Thai CD patients before and after multiple injections of botulinum toxin A at 3-month intervals was performed. Disease-specific HRQoL was assessed by using the Cervical Dystonia Impact Profile-58 questionnaire (CDIP-58) and the Craniocervical Dystonia Questionnaire-24 (CDQ-24). General HRQoL was assessed by using the Medical Outcomes’ 36-Item Short Form Health Survey (SF-36) and the EuroQoL 5-dimension questionnaire (EQ-5D). All the assessments were performed before and after the 24-week treatment period. Results A total of 20 CD patients were enrolled in this study from April to December 2011. CDIP-58 and CDQ-24 scores, which assess disease-specific HRQoL, showed a significant improvement after 24 weeks of treatment by botulinum toxin A (P<0.001). However, EQ-5D and SF-36 scores, which assess general HRQoL, showed no significant improvement after the treatment (P>0.05). Conclusion CD patients’ disease-specific HRQoL improved after being treated with multiple botulinum toxin A injections. However, general HRQoL was not improved. PMID:28138245
Bakheit, Abdel Magid
Although there are sound theoretical reasons for the use of botulinum toxin (Btx) as early as possible in the management of severe childhood muscle spasticity, the experience with its safety in children younger than 2 years of age is limited and information about its possible effects on the development and maturation of the human motor system…
Hefter, Harald; Rosenthal, Dietmar
It has been hypothesized that altered trunk movements during gait in post-stroke patients or children with cerebral palsy are compensatory to lower limb impairment. Improvement of trunk movements and posture after injections of botulinum toxin into the affected arm would be at variance with this hypothesis and hint towards a multifactorial trunk control deficit. Clinical gait analysis was performed in 11 consecutively recruited hemiplegic patients immediately before and 4weeks after a botulinum toxin type A-injection into the affected arm. Kinematic data were collected using an 8 camera optical motion-capturing system and reflective skin-markers were attached according to a standard plug-in-gait model. Deviation of the trunk in lateral and forward direction and the trajectory of the C7-marker in a sacrum-fixed horizontal plane were analyzed in addition to classical gait parameters. The Wilson-signed-rank test was used for pre/post-botulinum toxin comparisons. After botulinum toxin injections a significant improvement of forearm flexion scores from 2.57 to 2.0 (p<0.014), and a reduced lateral deviation of the upper trunk from 3.5degrees to 2.5degrees (p<0.014) were observed. Free-walkers tended to walk faster (p<0.046, 1-sided), with reduced pre-swing duration of both legs and an increased step length of the non-affected leg. The C7-marker trajectory was shifted towards the midline. Injections of botulinum toxin into the affected arm of hemiplegic patients improve abnormal trunk lateral flexion. This shift of the center of mass of the upper body towards the midline improves various gait parameters including gait speed. Copyright © 2017. Published by Elsevier Ltd.
Placzek, Richard; Drescher, Wolf; Deuretzbacher, Georg; Hempfing, Axel; Meiss, A Ludwig
Radial epicondylitis (tennis elbow) is the most frequent type of myotendinosis. Patients can experience substantial loss of function, especially when this condition becomes chronic. A successful therapy has not yet been established. A preliminary study of injections of botulinum toxin A in patients with chronic epicondylitis has shown promising results. In the present prospective, controlled, double-blinded clinical trial, 130 patients were examined at sixteen study centers. A single injection of botulinum toxin A into the painful origin of the forearm extensor muscles was performed. Follow-up examinations were performed at two, six, twelve, and eighteen weeks. Clinical findings were documented with use of a new clinical pain score and with a visual analogue scale. A global assessment of the result of treatment was also provided by the patient and the attending doctor. Strength of extension of the third finger and the wrist was evaluated with use of the Brunner method, and grip strength (fist closure strength) was measured with a vigorimeter. The group treated with botulinum toxin A was found to have a significant improvement in the clinical findings, compared with those in the placebo group, as early as the second week after injection (p = 0.003). Subjective general assessment also showed improvement in that group, compared with the placebo group, at six weeks (p = 0.001) and at the time of the final examination (at eighteen weeks) (p = 0.001). There was a consistent increase in fist closure strength in both the group treated with botulinum toxin A and the control group, but there was no significant difference between groups. As was expected as a side effect, extension of the third finger was observed to be significantly weakened at two weeks but this complication had completely resolved at eighteen weeks. We concluded that local injection of botulinum toxin A is a beneficial treatment for radial epicondylitis (tennis elbow). The treatment can be performed in an
Lam, Kuen; Lau, Kwok Kwong; So, Kar Kui; Tam, Cheuk Kwan; Wu, Yee Ming; Cheung, Gloria; Liang, Ka Shing; Yeung, Kwan Mo; Lam, Kin Yip; Yui, Samuel; Leung, Christine
To evaluate whether botulinum toxin can decrease the burden for caregivers of long term care patients with severe upper limb spasticity. This was a double-blind placebo-controlled trial with a 24-week follow-up period. A 250-bed long term care hospital, the infirmary units of 3 regional hospitals, and 5 care and attention homes. Participants included 55 long term care patients with significant upper limb spasticity and difficulty in basic upper limb care. Patients were randomized into 2 groups that received either intramuscular botulinum toxin A or saline. The primary outcome measure was provided by the carer burden scale. Secondary outcomes included goal attainment scale, measure of spasticity by modified Ashworth score, passive range of movement for shoulder abduction, and elbow extension and finger extension. Pain was assessed using the Pain Assessment in Advanced Dementia Scale. A total of 55 patients (21 men; mean age = 69, SD =18) were recruited. At week 6 post-injection, 18 (60%) of 30 patients in the treatment group versus 2 (8%) of 25 patients in the control group had a significant 4-point reduction of carer burden scale (P < .001). There was also significant improvement in the goal attainment scale, as well as the modified Ashworth score, resting angle, and passive range of movement of the 3 regions (shoulder, elbow, and fingers) in the treatment group which persisted until week 24. There were also fewer spontaneous bone fractures after botulinum toxin injection, although this did not reach statistical significance. No significant difference in Pain Assessment in Advanced Dementia scale was found between the 2 groups. No serious botulinum toxin type A-related adverse effects were reported. Long term care patients who were treated for upper limb spasticity with intramuscular injections of botulinum toxin A had a significant decrease in the caregiver burden. The treatment was also associated with improved scores on patient-centered outcome measures
Olea, E; Fondarella, A; Sánchez, C; Iriarte, I; Almeida, M V; Martínez de Salinas, A
Evaluation of pain and degree of satisfaction in patients undergoing ultrasound-assisted peripheral regional block for the treatment of idiopathic palmar hyperhidrosis with botulinum toxin. A descriptive, observational study of patients with palmar hyperhidrosis treated with botulinum toxin A, who underwent ultrasound-guided peripheral regional block of the median and ulnar nerves with 3 ml of mepivacaine 1% in each one. The radial nerve block was injected in the anatomical snuffbox. After establishing blocking, the dermatologist performed a mapping and injected around 100 IU of botulinum toxin across the whole palm. The pain experienced during the injection of botulinum toxin was evaluated by verbal numerical scale (from 0 to 10), along with the degree of satisfaction with the anesthetic technique, and the post-anesthetic complications. A total of 40 patients were enrolled in the study, 11 men and 29 women with no significant differences. The pain intensity assessed with verbal numerical scale was 1.03 (standard deviation of 1.37). No patients had a value greater than 5. The degree of patient satisfaction with the anesthetic technique was very good for 85% of the patients, and good for 7.5%. There were no complications related to type of anesthesia. The ultrasound-assisted peripheral regional block could be a simple, effective and safe technique for patients undergoing palmar injection of botulinum toxin. Pain intensity was very low, and it provided a very good level of satisfaction in most patients. Copyright © 2013 Sociedad Española de Anestesiología, Reanimación y Terapéutica del Dolor. Published by Elsevier España. All rights reserved.
ideal system to evaluate such therapies is the blockade of neuromuscular transmission by botulinum neurotoxin type A (BoNT/A). Its light chain Zn 2...Brief Communications Adeno-Associated Virus Transfer of a Gene Encoding SNAP-25 Resistant to Botulinum Toxin A Attenuates Neuromuscular Paralysis...the neuromuscular paralysis induced by botulinum neurotoxin type A (BoNT/A) as a prototype disease. Furthermore, because human botulism, occasionally
Anderson, N M; Larkin, J W; Cole, M B; Skinner, G E; Whiting, R C; Gorris, L G M; Rodriguez, A; Buchanan, R; Stewart, C M; Hanlin, J H; Keener, L; Hall, P A
As existing technologies are refined and novel microbial inactivation technologies are developed, there is a growing need for a metric that can be used to judge equivalent levels of hazard control stringency to ensure food safety of commercially sterile foods. A food safety objective (FSO) is an output-oriented metric that designates the maximum level of a hazard (e.g., the pathogenic microorganism or toxin) tolerated in a food at the end of the food supply chain at the moment of consumption without specifying by which measures the hazard level is controlled. Using a risk-based approach, when the total outcome of controlling initial levels (H(0)), reducing levels (ΣR), and preventing an increase in levels (ΣI) is less than or equal to the target FSO, the product is considered safe. A cross-disciplinary international consortium of specialists from industry, academia, and government was organized with the objective of developing a document to illustrate the FSO approach for controlling Clostridium botulinum toxin in commercially sterile foods. This article outlines the general principles of an FSO risk management framework for controlling C. botulinum growth and toxin production in commercially sterile foods. Topics include historical approaches to establishing commercial sterility; a perspective on the establishment of an appropriate target FSO; a discussion of control of initial levels, reduction of levels, and prevention of an increase in levels of the hazard; and deterministic and stochastic examples that illustrate the impact that various control measure combinations have on the safety of well-established commercially sterile products and the ways in which variability all levels of control can heavily influence estimates in the FSO risk management framework. This risk-based framework should encourage development of innovative technologies that result in microbial safety levels equivalent to those achieved with traditional processing methods.
Park, Hoon; Shin, Soowan; Shin, Han Sol; Kim, Hyun Woo; Kim, Dong Wook; Lee, Dong Hoon
Reduced joint ROM and distraction-induced pain are common complaints of patients who have undergone gradual femoral lengthening. Attempts to reduce the effects of lengthening on joint motion have included the use of botulinum toxin to reduce the muscle forces that restrict motion. The benefits of this approach during femoral lengthening, however, have not been conclusively established. We wished to evaluate the effects of botulinum toxin type A (BtX-A) injection in the anterior thigh muscles during femoral distraction osteogenesis on adjacent joint ROM and distraction-induced pain. We asked: (1) Does injection of BtX-A in the quadriceps muscles lead to improved knee and hip motion during femoral lengthening? (2) Does injection of BtX-A reduce pain during femoral lengthening? A single-center, double-blind, randomized placebo-controlled trial was conducted. Forty-four patients (88 femurs) undergoing bilateral femoral lengthening for familial short stature were included in the study. BtX-A (200 IU) was injected intraoperatively in the quadriceps muscles of one thigh. An equal volume of sterile normal saline was injected in the other thigh as a control. Selection of the limb receiving the toxin was randomized. Clinical evaluation included a VAS score for pain measurement, ROM evaluation of the hips and knees, and measurement of thigh circumference. Side-to-side differences were analyzed throughout the entire consolidation phase. No patients were lost to followup, leaving 44 patients (88 femurs). The mean followup was 26 months (range, 14-40 months). The distraction rate and final length of gain were similar between treated and control limbs. A priori power analysis suggested that 44 legs were required in each group to achieve statistical significance of 0.05 with 90% power to detect a 50% difference in treatment effect between treatment and control groups. There were no differences in hip ROM, knee ROM, or maximal thigh circumference between the two lower extremities
Quantitative determination of biological activity of botulinum toxins utilizing compound muscle action potentials (CMAP), and comparison of neuromuscular transmission blockage and muscle flaccidity among toxins.
Torii, Yasushi; Goto, Yoshitaka; Takahashi, Motohide; Ishida, Setsuji; Harakawa, Tetsuhiro; Sakamoto, Takashi; Kaji, Ryuji; Kozaki, Shunji; Ginnaga, Akihiro
The biological activity of various types of botulinum toxin has been evaluated using the mouse intraperitoneal LD(50) test (ip LD(50)). This method requires a large number of mice to precisely determine toxin activity, and so has posed a problem with regard to animal welfare. We have used a direct measure of neuromuscular transmission, the compound muscle action potential (CMAP), to evaluate the effect of different types of botulinum neurotoxin (NTX), and we compared the effects of these toxins to evaluate muscle relaxation by employing the digit abduction scoring (DAS) assay. This method can be used to measure a broad range of toxin activities the day after administration. Types A, C, C/D, and E NTX reduced the CMAP amplitude one day after administration at below 1 ip LD(50), an effect that cannot be detected using the mouse ip LD(50) assay. The method is useful not only for measuring toxin activity, but also for evaluating the characteristics of different types of NTX. The rat CMAP test is straightforward, highly reproducible, and can directly determine the efficacy of toxin preparations through their inhibition of neuromuscular transmission. Thus, this method may be suitable for pharmacology studies and the quality control of toxin preparations.
Han, Yi; Stevens, Andrea L; Dashtipour, Khashayar; Hauser, Robert A; Mari, Zoltan
A systematic pair-wise comparison of all available botulinum toxin serotype A and B treatments for cervical dystonia (CD) was conducted, as direct head-to-head clinical trial comparisons are lacking. Five botulinum toxin products: Dysport(®) (abobotulinumtoxinA), Botox(®) (onabotulinumtoxinA), Xeomin(®) (incobotulinumtoxinA), Prosigne(®) (Chinese botulinum toxin serotype A) and Myobloc(®) (rimabotulinumtoxinB) have demonstrated efficacy for managing CD. A pair-wise efficacy and safety comparison was performed for all toxins based on literature-reported clinical outcomes. Multi-armed randomized controlled trials (RCTs) were identified for inclusion using a systematic literature review, and assessed for comparability based on patient population and efficacy outcome measures. The Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) was selected as the efficacy outcome measurement for assessment. A mixed treatment comparison (MTC) was conducted using a Bayesian hierarchical model allowing indirect comparison of the interventions. Due to the limitation of available clinical data, this study only investigated the main effect of toxin treatments without explicitly considering potential confounding factors such as gender and formulation differences. There was reasonable agreement between the number of unconstrained data points, residual deviance and pair-wise results. This research suggests that all botulinum toxin serotype A and serotype B treatments were effective compared to placebo in treating CD, with the exception of Prosigne. Based on this MTC analysis, there is no significant efficacy difference between Dysport, Botox, Xeomin and Myobloc at week four post injection. Of the adverse events measured, neither dysphagia nor injection site pain was significantly greater in the treatment or placebo groups.
Foynes, Susan; Holley, Jane L; Garmory, Helen S; Titball, Richard W; Fairweather, Neil F
The utility of the htrA, pagC and nirB promoters to direct the expression of the carboxy-terminal (H(C)) fragment of botulinum toxin F (FH(C)) in Salmonella enterica var Typhimurium has been evaluated. Only low levels of serum antibody were induced after immunisation, and some protection against botulinum toxin type F was demonstrated after oral immunisation of mice with two doses of any of these recombinant Salmonella. Immunisation with two doses of recombinant Salmonella expressing FH(C) from the htrA promoter gave the greatest protection, against up to 10,000 mouse lethal doses of botulinum toxin type F. These results demonstrate the feasibility of an orally delivered vaccine against botulinum toxin type F.
Kerkemeyer, L; Lux, G; Walendzik, A; Wasem, J; Neumann, A
Upper limb spasticity is a common complication following stroke. Cohort studies found 19% of post-stroke patients had upper limb spasticity at 3 months and 38% of patients at 12 months. For focal spasticity, intramuscular injections of botulinum toxin are indicated. In Germany, it is assumed that patients with the described indication are undersupplied with botulinum toxin. The aim of the present study is to evaluate the medical care of patients with upper limb spasticity post-stroke with the focus on the use of botulinum toxin as one treatment option. A standardized questionnaire was developed and a postal survey of a representative national random sample of 800 neurologists to capture the actual medical care situation. The response rate amounted to 37% (n = 292). 59% of the neurologists surveyed had never used botulinum toxin. In total, 87% of neurologists noticed barriers regarding the use of botulinum toxin, where the amount of the doctor's remuneration in 40% and the lack of reimbursement of costs in off-label use in 60% were the most commonly used answers. The achievement of an advanced training in using botulinum toxin was also stated as a general obstacle for resident neurologists. Due to a response rate of 37% for the postal survey a selection bias cannot be excluded. Although botulinum toxin is recommended in the national treatment guidelines, many neurologists do not use botulinum toxin. The reasons can be seen from the barriers described.
Barnes, Thomas G; Zafrani, Zakhi; Abdelrazeq, Ayman S
There is paucity of data on the long-term outcome of the combination of fissurectomy and botulinum toxin A injection for the management of chronic anal fissure. The aim of this study is to assess the safety, efficacy, and long-term outcome of the combination of fissurectomy and botulinum toxin A injection. This is a nonrandomized prospective cohort study. This study was conducted at a district general hospital in the United Kingdom. The cohort included all patients treated with fissurectomy and botulinum toxin A for chronic anal fissure between September 2008 and March 2012. The patients were treated with a combination of fissurectomy and botulinum toxin A injection. Symptomatic relief, fissure healing, complications, recurrence, and the need for further surgical intervention. One hundred and two patients received fissurectomy and botulinum toxin A injection for chronic anal fissure. At 12-week follow-up, 68 patients had resolution of symptoms and complete healing of chronic anal fissure, 29 patients had improvement of symptoms but incomplete healing and had further topical or botulinum toxin A treatment with subsequent complete healing. Ninety-five patients (93%) reported no postoperative complications. Seven patients reported a degree of incontinence in the immediate postoperative period. All reported normal continence at12-week follow-up. No local complications were observed or reported. At the mean follow-up of 33 months, there was no evidence of recurrence. Twelve-month follow-up was conducted via telephone interview only. This study is nonrandomized and did not examine the dose response of Botulinum Toxin A. Fissurectomy combined with high-dose botulinum toxin A is a safe, effective, and durable option for the management of chronic anal fissure and a promising alternative to surgical sphincterotomy.
Lin, Yu-Ching; Wu, Wei-Ting; Hsu, Yu-Chun; Han, Der-Sheng; Chang, Ke-Vin
To explore the effectiveness of botulinum toxin compared with non-surgical treatments in patients with lateral epicondylitis. Data sources including PubMed, Scopus, Embase and Airity Library from the earliest record to February 2017 were searched. Study design, patients' characteristics, dosage/brand of botulinum toxin, injection techniques, and measurements of pain and hand grip strength were retrieved. The standardized mean differences (SMDs) in pain relief and grip strength reduction were calculated at the following time points: 2-4, 8-12, and 16 weeks or more after injection. Six randomized controlled trials (321 participants) comparing botulinum toxin with placebo or corticosteroid injections were included. Compared with placebo, botulinum toxin injection significantly reduced pain at all three time points (SMD, -0.729, 95% confidence interval [CI], -1.286 to -0.171; SMD, -0.446, 95% CI, -0.740 to -0.152; SMD, -0.543, 95% CI, -0.978 to -0.107, respectively). Botulinum toxin was less effective than corticosteroid at 2-4 weeks (SMD, 1.153; 95% CI, 0.568-1.737) and both treatments appeared similar in efficacy after 8 weeks. Different injection sites and dosage/brand did not affect effectiveness. Botulinum toxin decreased grip strength 2-4 weeks after injection, and high equivalent dose could extend its paralytic effects to 8-12 weeks. When treating lateral epicondylitis, botulinum toxin was superior to placebo and could last for 16 weeks. Corticosteroid and botulinum toxin injections were largely equivalent, except the corticosteroid injections were better at pain relief in the early stages and were associated with less weakness in grip in the first 12 weeks.
Gibbons, John P; Nugent, Emmeline; O'Donohoe, Nollaig; Maher, Barry; Egan, Bridget; Feeley, Martin; Tierney, Sean
To estimate cost-effectiveness of botulinum toxin therapy for axillary hyperhidrosis compared to the standard surgical intervention of endoscopic thoracic sympathectomy (ETS). The validated dermatology life quality index questionnaire was given to patients attending for treatment over a 4 month period, to assess their quality of life (QoL) over the preceding week (n = 44). Follow-up was performed 4-6 weeks later by telephone using the same questionnaire to validate the effectiveness of the treatment. The duration of effect of the botulinum toxin treatment was also recorded and this data was used as the basis for cost effectiveness analysis. Using HIPE data, the baseline cost for single intervention using botulinum toxin and ETS was retrieved. Using figures provided by HIPE and expert opinion of the costs of complications, a stochastic model for 10,000 patients was used to evaluate the total costs for ETS including the complications. The results from the QoL analysis show that botulinum toxin therapy is a successful therapy for improvement of symptoms. It was revealed that the mean interval before recurrence of original symptoms after botulinum toxin therapy was 5.6 months. The baseline cost for both treatments are €389 for botulinum toxin and €9389 for uncomplicated ETS. The stochastic model yields a mean cost of €11,390 for ETS including complications. Treatments reached cost equivalence after 13.3 years. However, given the efficacy of the botulinum toxin therapy and the low risk we propose that botulinum toxin therapy for hyperhidrosis should be considered the gold standard. Copyright © 2015 Royal College of Surgeons of Edinburgh (Scottish charity number SC005317) and Royal College of Surgeons in Ireland. Published by Elsevier Ltd. All rights reserved.
Chaptini, Cassandra; Casey, Genevieve; Harris, Adam G; Wattchow, David; Gordon, Lynne; Murrell, Dedee F
We report a 20-year-old female with generalized, severe, recessive dystrophic epidermolysis bullosa who developed secondary chronic anal fissures. This resulted in anal sphincter spasm and severe, disabling pain. She was treated with five botulinum toxin A injections into the internal anal sphincter over a period of 2 years and gained marked improvement in her symptoms. This case demonstrates the successful use of botulinum toxin A injections to relieve anal sphincter spasm and fissuring, with long-term improvement.
Brin, Mitchell F; James, Charmaine; Maltman, John
Botulinum toxin type A (BoNTA) products are injectable biologic medications derived from Clostridium botulinum bacteria. Several different BoNTA products are marketed in various countries, and they are not interchangeable. Differences between products include manufacturing processes, formulations, and the assay methods used to determine units of biological activity. These differences result in a specific set of interactions between each BoNTA product and the tissue injected. Consequently, the products show differences in their in vivo profiles, including preclinical dose response curves and clinical dosing, efficacy, duration, and safety/adverse events. Most, but not all, published studies document these differences, suggesting that individual BoNTA products act differently depending on experimental and clinical conditions, and these differences may not always be predictable. Differentiation through regulatory approvals provides a measure of confidence in safety and efficacy at the specified doses for each approved indication. Moreover, the products differ in the amount of study to which they have been subjected, as evidenced by the number of publications in the peer-reviewed literature and the quantity and quality of clinical studies. Given that BoNTAs are potent biological products that meet important clinical needs, it is critical to recognize that their dosing and