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Ayoub N. Botulinum Toxin Therapy: A Comprehensive Review on Clinical and Pharmacological Insights. J Clin Med 2025; 14:2021. [PMID: 40142828 PMCID: PMC11943293 DOI: 10.3390/jcm14062021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2025] [Revised: 03/10/2025] [Accepted: 03/12/2025] [Indexed: 03/28/2025] Open
Abstract
Background: Botulinum toxin (BoNT), produced by Clostridium botulinum, has transitioned from being a lethal neurotoxin to a versatile therapeutic agent. Its ability to inhibit neurotransmitter release by targeting Soluble N-ethylmaleimide-sensitive factor Attachment Protein Receptor (SNARE) proteins underpins its applications in treating conditions such as spasticity, dystonia, chronic pain, and overactive bladder. The clinical and pharmacological properties of BoNT have been extensively studied, with significant advancements in its therapeutic use, safety profile, and understanding of associated adverse effects. Objective: This comprehensive review aims to consolidate historical developments, molecular mechanisms, clinical applications, and challenges associated with BoNT, with a focus on expanding its therapeutic scope while ensuring safety and efficacy. Method: A narrative approach was used to analyze and synthesize insights from 155 references spanning experimental studies, clinical trials, and reviews. Key topics included BoNT's historical milestones, mechanisms of action, therapeutic applications, and adverse events. Findings: BoNT demonstrates remarkable efficacy in a wide range of medical and cosmetic applications. In movement disorders such as dystonia and spasticity, it reduces muscle overactivity and improves functional outcomes. In chronic pain management, including migraines and neuropathic pain, BoNT significantly alleviates symptoms by modulating neurotransmitter activity. Cosmetic use for conditions like glabellar lines and hyperhidrosis highlights its precision and safety when administered appropriately. For conditions like strabismus and blepharospasm, BoNT effectively restores muscle control, reducing involuntary contractions. In urological applications, BoNT has proven to be an effective therapy for overactive bladder, offering significant symptom relief in refractory cases. However, concerns about long-distance effects, where the toxin may spread beyond the injection site to affect distant muscles or systems, have been reported in certain high-dose or sensitive populations. These findings emphasize the importance of dose optimization and patient-specific approaches. Adverse effects such as localized pain, hematoma, dysphagia, and systemic effects, particularly in high-risk groups, underscore the need for careful monitoring. The development of immunogenicity, leading to neutralizing antibodies, remains a challenge that impacts long-term therapeutic efficacy. Emerging research on novel serotypes, including BoNT/X, and innovations in delivery mechanisms, offer promising avenues to address current limitations. Advances in optimizing dosing regimens and refining injection techniques have also contributed to minimizing complications and improving outcomes across diverse patient populations. Conclusions: BoNT remains a cornerstone in neurology and cosmetic medicine, with its therapeutic potential still expanding. The balance between efficacy and safety, driven by innovations in formulation and application, underscores the importance of continued research. Future directions should focus on minimizing adverse effects, reducing immunogenicity, and exploring novel indications to further enhance its clinical utility.
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Affiliation(s)
- Nahla Ayoub
- Department of Pharmacology and Toxicology, Faculty of Medicine, Umm Al-Qura University, Makkah 24375, Saudi Arabia
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Niazi SK. A Critical Analysis of the FDA's Omics-Driven Pharmacodynamic Biomarkers to Establish Biosimilarity. Pharmaceuticals (Basel) 2023; 16:1556. [PMID: 38004421 PMCID: PMC10675618 DOI: 10.3390/ph16111556] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 09/25/2023] [Accepted: 09/29/2023] [Indexed: 11/26/2023] Open
Abstract
Demonstrating biosimilarity entails comprehensive analytical assessment, clinical pharmacology profiling, and efficacy testing in patients for at least one medical indication, as required by the U.S. Biologics Price Competition and Innovation Act (BPCIA). The efficacy testing can be waived if the drug has known pharmacodynamic (PD) markers, leaving most therapeutic proteins out of this concession. To overcome this, the FDA suggests that biosimilar developers discover PD biomarkers using omics technologies such as proteomics, glycomics, transcriptomics, genomics, epigenomics, and metabolomics. This approach is redundant since the mode-action-action biomarkers of approved therapeutic proteins are already available, as compiled in this paper for the first time. Other potential biomarkers are receptor binding and pharmacokinetic profiling, which can be made more relevant to ensure biosimilarity without requiring biosimilar developers to conduct extensive research, for which they are rarely qualified.
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Affiliation(s)
- Sarfaraz K Niazi
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois, Chicago, IL 60612, USA
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Safarpour D, Jabbari B. Botulinum toxin for motor disorders. HANDBOOK OF CLINICAL NEUROLOGY 2023; 196:539-555. [PMID: 37620089 DOI: 10.1016/b978-0-323-98817-9.00003-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/26/2023]
Abstract
Botulinum neurotoxins are a group of biological toxins produced by the gram-negative bacteria Clostridium botulinum. After intramuscular injection, they produce dose-related muscle relaxation, which has proven useful in the treatment of a large number of motor and movement disorders. In this chapter, we discuss the utility of botulinum toxin treatment in three major and common medical conditions related to the dysfunction of the motor system, namely dystonia, tremor, and spasticity. A summary of the existing literature is provided along with different techniques of injection including those recommended by the authors.
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Affiliation(s)
- Delaram Safarpour
- Department of Neurology, Oregon Health & Science University, Portland, OR, United States
| | - Bahman Jabbari
- Department of Neurology, Yale University School of Medicine, New Haven, CT, United States.
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Vergallo A, Cocco A, De Santis T, Lalli S, Albanese A. Eligibility criteria in clinical trials for cervical dystonia. Parkinsonism Relat Disord 2022; 104:110-114. [PMID: 36243553 DOI: 10.1016/j.parkreldis.2022.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 09/10/2022] [Accepted: 10/03/2022] [Indexed: 11/06/2022]
Abstract
INTRODUCTION Cervical dystonia (CD) is the most common form of adult-onset focal dystonia. Because of a heterogeneous clinical presentation, the diagnosis rests on clinical opinion. During the last decades, several clinical trials have tested safety and efficacy of medical and surgical treatments for CD. We analyzed all the published CD trials and reviewed the strategies adopted for patient enrollment. METHODS The review included clinical trials in patients with CD published in PubMed. Studies were excluded if reviews, meta-analyses, post-hoc analyses on pooled data, or if not reporting a treatment for CD. RESULTS A total of 174 articles were identified; 134 studies met inclusion criteria. Diagnosis of CD varied among studies and in most cases was based on clinical judgement, using different descriptors such as "cervical dystonia" (37 studies), "idiopathic or isolated CD" (35), "primary CD" (13), and "torticollis" (40). Clinical judgement was supported by a phenomenological description of dystonia in four studies, and by a specific diagnostic strategy in other four. Finally, one study adopted general diagnostic criteria for dystonia. Inclusion and exclusion criteria proved heterogeneous across trials and were defined only in 108 studies, mainly considering age or the phenomenological pattern of muscle involvement. CONCLUSION The review showed lack of consolidated diagnostic criteria and non-uniformity of eligibility criteria for CD across clinical trials. There is need to move beyond clinical judgement as diagnostic criterion for selecting participants. New trials assessing specific CD patient subgroups or comparing medical and surgical procedures will need grounds that are more consistent.
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Affiliation(s)
- Andrea Vergallo
- Department of Neurology, IRCCS Humanitas Research Hospital, Rozzano, Milano, Italy
| | - Antoniangela Cocco
- Department of Neurology, IRCCS Humanitas Research Hospital, Rozzano, Milano, Italy
| | - Tiziana De Santis
- Department of Neurology, IRCCS Humanitas Research Hospital, Rozzano, Milano, Italy
| | - Stefania Lalli
- Department of Neurology, IRCCS Humanitas Research Hospital, Rozzano, Milano, Italy
| | - Alberto Albanese
- Department of Neurology, IRCCS Humanitas Research Hospital, Rozzano, Milano, Italy.
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Kaji R, Endo A, Sugawara M, Ishii M. Efficacy of botulinum toxin type B (rimabotulinumtoxinB) in patients with cervical dystonia previously treated with botulinum toxin type A: A post-marketing observational study in Japan. eNeurologicalSci 2021; 25:100374. [PMID: 34877415 PMCID: PMC8627969 DOI: 10.1016/j.ensci.2021.100374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 09/26/2021] [Accepted: 10/24/2021] [Indexed: 11/17/2022] Open
Abstract
To date, efficacy data on botulinum toxin type B (rimabotulinumtoxinB) in patients with cervical dystonia (CD) previously treated with botulinum toxin type A in a large population are lacking; thus, we aimed to evaluate type B efficacy in this patient population. In a post-marketing observational cohort study, 150 patients previously treated with botulinum toxin type A were enrolled, of whom 138 were followed up for 1 year after the initial type B injection. Final observation data were available for 122 patients. Efficacy was evaluated using the Toronto Western Spasmodic Torticollis Rating Scale. Total score improved from 39.9 at baseline to 34.3 at 4 weeks after the first injection, and pain score improved from 8.9 to 7.9. Improvements were maintained through six further injections in two subpopulations: patients who showed resistance to botulinum toxin type A and patients who were not type A resistant but switched to type B. For a number of patients, even low doses (<5000 units) of botulinum toxin type B demonstrated efficacy. These findings support the efficacy of botulinum toxin type B in clinical settings for the management of CD symptoms, including pain, even at low doses, regardless of the patient's botulinum toxin type A resistance status.
Botulinum toxin type B improved cervical dystonia symptoms and pain after 4 weeks. Botulinum toxin type B was effective even at low doses (<5000 units). The efficacy of toxin type B is not affected by toxin type A resistance status.
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Affiliation(s)
- Ryuji Kaji
- National Hospital Organization Utano National Hospital, 8 Narutaki Ondoyama-cho, Ukyo-ku, Kyoto, Japan.,Institute of Health Biosciences, Tokushima University Graduate School, 3-18-15 Kuramotocho, Tokushima, Japan
| | - Akira Endo
- Clinical Planning and Development, Medical HQs, Eisai Co., Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo, Japan
| | - Michiko Sugawara
- Scientific Intelligence Group, Medical HQs, Eisai Co., Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo, Japan
| | - Mika Ishii
- Clinical Planning and Development, Medical HQs, Eisai Co., Ltd., 4-6-10 Koishikawa, Bunkyo-ku, Tokyo, Japan
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Low-Dose Neubotulinum Toxin A versus Low-Dose Abobotulinum Toxin A Injection for the Treatment of Cervical Dystonia: A Multicenter, 48-Week, Prospective, Double-Blinded, Randomized Crossover Design Study. Toxins (Basel) 2021; 13:toxins13100694. [PMID: 34678987 PMCID: PMC8541224 DOI: 10.3390/toxins13100694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 08/31/2021] [Accepted: 08/31/2021] [Indexed: 11/16/2022] Open
Abstract
Various types of botulinum toxin (BoNT) have been studied to treat cervical dystonia (CD). Although high-dose BoNT has proven efficacy, it increases the risk of adverse events. For this reason, this study was planned to identify the non-inferiority efficacy, tolerability, and safety of low-dose neubotulinum toxin A (Neu-BoNT-A) versus low-dose abobotulinum toxin A (Abo-BoNT-A) in CD treatment. The 48-week, prospective, randomized, controlled crossover design study of CD treatment, with 50-unit Neu-BoNT-A and 250-unit Abo-BoNT-A injections at 12-week intervals, was conducted over a 24-week treatment period. This study used the following standardized rating scales to assess the efficacy of BoNT: the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS); health-related quality of life (HRQoL); the Cervical Dystonia Impact Profile (CDIP-58); the Short Form 36 health survey questionnaire (SF-36); and, for the depressive symptoms of CD patients, the Center for Epidemiological Studies-Depression Scale (CES-D) and the Patient Health Questionnaire-9 (PHQ-9). Fifty-two CD patients were enrolled from October 2019 to January 2021. The mean scores of the TWSTRS total at the post-treatments in both Neu-BoNT-A and Abo-BoNT-A had a significant reduction from baseline (p = 0.008 and 0.002, respectively). However, the mean changes of the TWSTRS total at the 12- and 24-week treatments between the two treatment groups were not significantly different (p = 0.284 and 0.129, respectively). The mean scores of the HRQoL questionnaires (the CIDP-58 and the SF-36) and the depressive symptoms (the CES-D and the PHQ-9) in both treated groups at the post-treatments did not significantly decrease from baseline and were comparable. Two patients treated with Abo-BoNT-A (250 units) reported cervical tension and benign paroxysmal positional vertigo (BPPV). There were no serious adverse events reported. Though both low-dose BoNT-As were effective at improving clinical symptoms without significant side effects, both treatments did not predict change in quality of life and depression. With the non-inferiority criteria, low-dose Neu-BoNT-A has a similar efficacy, safety, and tolerability to Abo-BoNT-A.
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Systemic muscular weakness after botulinum toxin A administration: a review of the literature. DRUGS & THERAPY PERSPECTIVES 2021. [DOI: 10.1007/s40267-021-00842-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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Anandan C, Jankovic J. Botulinum Toxin in Movement Disorders: An Update. Toxins (Basel) 2021; 13:42. [PMID: 33430071 PMCID: PMC7827923 DOI: 10.3390/toxins13010042] [Citation(s) in RCA: 66] [Impact Index Per Article: 16.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 12/30/2020] [Accepted: 01/05/2021] [Indexed: 12/17/2022] Open
Abstract
Since its initial approval in 1989 by the US Food and Drug Administration for the treatment of blepharospasm and other facial spasms, botulinum toxin (BoNT) has evolved into a therapeutic modality for a variety of neurological and non-neurological disorders. With respect to neurologic movement disorders, BoNT has been reported to be effective for the treatment of dystonia, bruxism, tremors, tics, myoclonus, restless legs syndrome, tardive dyskinesia, and a variety of symptoms associated with Parkinson's disease. More recently, research with BoNT has expanded beyond its use as a powerful muscle relaxant and a peripherally active drug to its potential central nervous system applications in the treatment of neurodegenerative disorders. Although BoNT is the most potent biologic toxin, when it is administered by knowledgeable and experienced clinicians, it is one of the safest therapeutic agents in clinical use. The primary aim of this article is to provide an update on recent advances in BoNT research with a focus on novel applications in the treatment of movement disorders. This comprehensive review of the literature provides a critical review of evidence-based clinical trials and highlights recent innovative pilot studies.
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Affiliation(s)
| | - Joseph Jankovic
- Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA;
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Cisneros E, Stebbins GT, Chen Q, Vu JP, Benadof CN, Zhang Z, Barbano RL, Fox SH, Goetz CG, Jankovic J, Jinnah HA, Perlmutter JS, Adler CH, Factor SA, Reich SG, Rodriguez R, Severt LL, Stover NP, Berman BD, Comella CL, Peterson DA. It's tricky: Rating alleviating maneuvers in cervical dystonia. J Neurol Sci 2020; 419:117205. [PMID: 33160248 DOI: 10.1016/j.jns.2020.117205] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Revised: 10/12/2020] [Accepted: 10/20/2020] [Indexed: 10/23/2022]
Abstract
OBJECTIVES To investigate hypothesized sources of error when quantifying the effect of the sensory trick in cervical dystonia (CD) with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS-2), test strategies to mitigate them, and provide guidance for future research on the sensory trick. METHODS Previous analyses suggested the sensory trick (or "alleviating maneuver", AM) item be removed from the TWSTRS-2 because of its poor clinimetric properties. We hypothesized three sources of clinimetric weakness for rating the AM: 1) whether patients were given sufficient time to demonstrate their AM; 2) whether patients' CD was sufficiently severe for detecting AM efficacy; and 3) whether raters were inadvertently rating the item in reverse of scale instructions. We tested these hypotheses with video recordings and TWSTRS-2 ratings by one "site rater" and a panel of five "video raters" for each of 185 Dystonia Coalition patients with isolated CD. RESULTS Of 185 patients, 23 (12%) were not permitted sufficient testing time to exhibit an AM, 23 (12%) had baseline CD too mild to allow confident rating of AM effect, and 1 site- and 1 video-rater each rated the AM item with a reverse scoring convention. When these confounds were eliminated in step-wise fashion, the item's clinimetric properties improved. CONCLUSIONS The AM's efficacy can contribute to measuring CD motor severity by addressing identified sources of error during its assessment and rating. Given the AM's sensitive diagnostic and potential pathophysiologic significance, we also provide guidance on modifications to how AMs can be assessed in future CD research.
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Affiliation(s)
- Elizabeth Cisneros
- Institute for Neural Computation, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093, United States of America.
| | - Glenn T Stebbins
- Department of Neurological Sciences, Rush University Medical Center, 1620 W Harrison St, Chicago, IL 60612, United States of America.
| | - Qiyu Chen
- Institute for Neural Computation, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093, United States of America.
| | - Jeanne P Vu
- Institute for Neural Computation, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093, United States of America
| | - Casey N Benadof
- Institute for Neural Computation, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093, United States of America
| | - Zheng Zhang
- Institute for Neural Computation, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093, United States of America
| | - Richard L Barbano
- Department of Neurology, University of Rochester, 500 Joseph C. Wilson Blvd, Rochester, NY 14627, United States of America.
| | - Susan H Fox
- Movement Disorder Clinic, Toronto Western Hospital, 399 Bathurst Street, Toronto, ON M5T 2S8, Canada; Medical Sciences Building, 1 King's College Cir, Toronto, ON M5S 1A8, Canada.
| | - Christopher G Goetz
- Department of Neurological Sciences, Rush University Medical Center, 1620 W Harrison St, Chicago, IL 60612, United States of America.
| | - Joseph Jankovic
- Department of Neurology, Baylor College of Medicine, 1 Baylor Plaza, Houston, TX 77030, United States of America.
| | - Hyder A Jinnah
- Departments of Neurology and Human Genetics, Emory University, 1365 Clifton Rd building b suite 2200, Atlanta, GA 30322, United States of America.
| | - Joel S Perlmutter
- Department of Neurology, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110, United States of America; Departments of Radiology, Neuroscience, Physical Therapy, and Occupational Therapy, Washington University School of Medicine, 660 S Euclid Ave, St. Louis, MO 63110, United States of America.
| | - Charles H Adler
- Department of Neurology, Mayo Clinic College of Medicine, 200 1st St SW, Rochester, MN 55905, United States of America.
| | - Stewart A Factor
- Department of Neurology, Emory University School of Medicine, 201 Dowman Dr, Atlanta, GA 30322, United States of America.
| | - Stephen G Reich
- Department of Neurology, University of Maryland Medical Centre, 22 S Greene St, Baltimore, MD 21201, United States of America.
| | - Ramon Rodriguez
- UF Department of Neurology, 1149 Newell Dr, Gainesville, FL 32611, United States of America.
| | - Lawrence L Severt
- Department of Neurology, Beth Israel Medical Center, 529 W 42nd St # 6K, New York, NY 10036, United States of America
| | - Natividad P Stover
- Department of Neurology, The University of Alabama, Tuscaloosa, AL 35487, United States of America.
| | - Brian D Berman
- Department of Neurology, Virginia Commonwealth University, 1101 East Marshall Street, PO Box 980599, Richmond, VA 23298-0599, United States of America.
| | - Cynthia L Comella
- Department of Neurological Sciences, Rush University Medical Center, 1620 W Harrison St, Chicago, IL 60612, United States of America.
| | - David A Peterson
- Institute for Neural Computation, University of California, San Diego, 9500 Gilman Dr, La Jolla, CA 92093, United States of America; CNL-S, Salk Institute for Biological Studies, 10010 N Torrey Pines Rd, La Jolla, CA 92037, United States of America.
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Hefter H, Samadzadeh S, Moll M. Transient Improvement after Switch to Low Doses of RimabotulinumtoxinB in Patients Resistant to AbobotulinumtoxinA. Toxins (Basel) 2020; 12:toxins12110677. [PMID: 33121133 PMCID: PMC7693617 DOI: 10.3390/toxins12110677] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Revised: 10/24/2020] [Accepted: 10/25/2020] [Indexed: 11/16/2022] Open
Abstract
Botulinum toxin type B (BoNT/B) has been recommended as an alternative for patients who have become resistant to botulinum toxin type A (BoNT/A). This study aimed to compare the clinical effect, within a patient, of four injections with low doses of rimabotulinumtoxinB with the effect of the preceding abobotulinumtoxinA (aboBoNT/A) injections. In 17 patients with cervical dystonia (CD) who had become resistant to aboBoNT/A, the clinical effect of the first four rimabotulinumtoxinB (rimaBoNT/B) injections was compared to the effect of the first four aboBoNT/A injections using a global assessment scale and the TSUI score. After the first two BoNT/B injections, all 17 patients responded well and to a similar extent as to the first two BoNT/A injections, but with more side effects such as dry mouth and constipation. After the next BoNT/B injection, the improvement started to decline. The response to the fourth BoNT/B injection was significant (p < 0.048) lower than the fourth BoNT/A injection. Only three patients developed a complete secondary treatment failure (CSTF) and five patients a partial secondary treatment failure (PSTF) after four BoNT/B injections. In nine patients, the usual response persisted. With the use of low rimaBoNT/B doses, the induction of CSTF and PSTF to BoNT/B could not be avoided but was delayed in comparison to the use of higher doses. In contrast to aboBoNT/A injections, PSTF and CSTF occurred much earlier, although low doses of rimaBoNT/B had been applied.
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Affiliation(s)
- Harald Hefter
- Correspondence: ; Tel.: +49-211-811-7025; Fax: +49-211-810-4903
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Spiegel LL, Ostrem JL, Bledsoe IO. FDA Approvals and Consensus Guidelines for Botulinum Toxins in the Treatment of Dystonia. Toxins (Basel) 2020; 12:E332. [PMID: 32429600 PMCID: PMC7290737 DOI: 10.3390/toxins12050332] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Revised: 05/01/2020] [Accepted: 05/13/2020] [Indexed: 11/17/2022] Open
Abstract
In 2016, the American Academy of Neurology (AAN) published practice guidelines for botulinum toxin (BoNT) in the treatment of blepharospasm, cervical dystonia, adult spasticity, and headache. This article, focusing on dystonia, provides context for these guidelines through literature review. Studies that led to Food and Drug Administration (FDA) approval of each toxin for dystonia indications are reviewed, in addition to several studies highlighted by the AAN guidelines. The AAN guidelines for the use of BoNT in dystonia are compared with those of the European Federation of the Neurological Societies (EFNS), and common off-label uses for BoNT in dystonia are discussed. Toxins not currently FDA-approved for the treatment of dystonia are additionally reviewed. In the future, additional toxins may become FDA-approved for the treatment of dystonia given expanding research in this area.
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Affiliation(s)
| | | | - Ian O. Bledsoe
- Movement Disorders and Neuromodulation Center, Department of Neurology, University of California, San Francisco, CA 94115, USA; (L.L.S.); (J.L.O.)
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Abstract
Passive antibody therapies have a long history of use. In the 19th century, antibodies from xenographic sources of polyclonal antibodies were used to treat infections (diphtheria). They were used often as protection from infectious agents and toxins. Complications related to their use involved development of immune complexes and severe allergic reactions. As a result, human source plasma for polyclonal antibodies became the preferential source for antibodies. They are used to treat infection, remove toxins, prevent hemolytic disease of the newborn, modify inflammatory reactions, and control autoimmune diseases. Continued improvements in processing decreased the transfusion/infusion transmission of infections. In the late 20th century (∼1986), monoclonal antibodies were developed. The first monoclonal antibodies were of xenographic source and were wrought with problems of immunogenicity. These forms of antibodies did not gain favor until chimerization took pace in the mid-1990s and in 1998 two monoclonal antibodies were approved one to treat respiratory syncytial virus and the other for breast cancers. Further development of humanized and then fully human monoclonal antibodies has led to an evolution of therapies with these agents. Monoclonal antibodies are being researched or approved to treat a multitude of diseases to include oncologic, inflammatory, autoimmune, cardiovascular, respiratory, neurologic, allergic, benign hematologic, infections, orthopedic, coagulopathy, metabolic and to decrease morbidity of disease (diminution of pain), modify disease progression, and potentially anatomic development. In this chapter, we will review the history of use of these passive antibody therapies, their mechanism of action, pharmacologic-therapeutic classification, particular medical indication, adverse reactions, and potential future use of these medications.
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Tyślerowicz M, Jost WH. Injection into the Longus Colli Muscle via the Thyroid Gland. TREMOR AND OTHER HYPERKINETIC MOVEMENTS (NEW YORK, N.Y.) 2019; 9:tre-09-718. [PMID: 31867133 PMCID: PMC6898894 DOI: 10.7916/tohm.v0.718] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Accepted: 10/24/2019] [Indexed: 12/01/2022]
Abstract
Background Anterior forms of cervical dystonia are considered to be the most difficult to treat because of the deep cervical muscles that can be involved. Case Report We report the case of a woman with cervical dystonia who presented with anterior sagittal shift, which required injections through the longus colli muscle to obtain a satisfactory outcome. The approach via the thyroid gland was chosen. Discussion The longus colli muscle can be injected under electromyography (EMG), computed tomography (CT), ultrasonography (US), or endoscopy guidance. We recommend using both ultrasonography and electromyography guidance as excellent complementary techniques for injection at the C5-C6 level.
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Mittal SO, Lenka A, Jankovic J. Cervical dystonia: an update on therapeutics. Expert Opin Orphan Drugs 2019. [DOI: 10.1080/21678707.2019.1613978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Affiliation(s)
- Shivam Om Mittal
- , Parkinson's Disease and Movement Disorders Clinic, Cleveland Clinic, Abu Dhabi, UAE
| | - Abhishek Lenka
- Department of Neurology, MedStar Georgetown University Hospital, Washington, DC, USA
| | - Joseph Jankovic
- Department of Neurology, Baylor College of Medicine, Parkinson’s Disease Center and Movement Disorders Clinic, Houston, TX, USA
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Marciniec M, Szczepańska-Szerej A, Kulczyński M, Sapko K, Popek-Marciniec S, Rejdak K. Pain in cervical dystonia and the antinociceptive effects of botulinum toxin: what is currently known? Rev Neurosci 2019; 30:771-779. [DOI: 10.1515/revneuro-2018-0119] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2018] [Accepted: 01/25/2019] [Indexed: 12/14/2022]
Abstract
Abstract
Pain is the most common and disabling non-motor symptom in cervical dystonia (CD). Up to 88.9% of patients report pain at some point in the course of the disease. It is still a matter of debate whether CD-related pain originates only from prolonged muscle contraction. Recent data suggest that the alterations of transmission and processing of nociceptive stimuli play a crucial role in pain development. Botulinum toxin (BT) is the first-line therapy for CD. Despite fully elucidated muscle relaxant action, the antinociceptive effect of BT remains unclear and probably exceeds a simple decompression of the nerve fibers due to the reduction in muscle tone. The proposed mechanisms of the antinociceptive action of BT include inhibition of pain mediator release, inhibition of membrane sodium channels, retrograde axonal transport and impact on the other pain pathways. This article summarizes the current knowledge about the antinociceptive properties of BT and the clinical analgesic efficacy in the treatment of CD patients.
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Affiliation(s)
- Michał Marciniec
- Chair and Department of Neurology , Medical University of Lublin , Independent Public Clinical Hospital , No. 4, ul. Jaczewskiego 8 , 20-954 Lublin , Poland
| | | | - Marcin Kulczyński
- Chair and Department of Neurology , Medical University of Lublin , Lublin , Poland
| | - Klaudia Sapko
- Chair and Department of Neurology , Medical University of Lublin , Lublin , Poland
| | - Sylwia Popek-Marciniec
- Department of Cancer Genetics with Cytogenetics Laboratory , Medical University of Lublin , Lublin , Poland
| | - Konrad Rejdak
- Chair and Department of Neurology , Medical University of Lublin , Lublin , Poland
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Abstract
Dystonias are characterized by involuntary muscle contractions, twisting movements, abnormal postures, and often tremor in various body regions. However, in the last decade several studies have demonstrated that dystonias are also characterized by sensory abnormalities. While botulinum toxin is the gold standard therapy for focal dystonia, exactly how it improves this disorder is not entirely understood. Neurophysiological studies in animals and humans have clearly demonstrated that botulinum toxin improves dystonic motor manifestations by inducing chemodenervation, therefore weakening the injected muscles. In addition, neurophysiological and neuroimaging evidence also suggests that botulinum toxin modulates the activity of various neural structures in the CNS distant from the injected site, particularly cortical motor and sensory areas. Concordantly, recent studies have shown that in patients with focal dystonias botulinum toxin ameliorates sensory disturbances, including reduced spatial discrimination acuity and pain. Overall, these observations suggest that in these patients botulinum toxin-induced effects encompass complex mechanisms beyond chemodenervation of the injected muscles.
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Affiliation(s)
- Alfredo Berardelli
- Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy.
- IRCCS Neuromed, Pozzilli, IS, Italy.
| | - Antonella Conte
- Department of Human Neurosciences, Sapienza University of Rome, Rome, Italy
- IRCCS Neuromed, Pozzilli, IS, Italy
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Pain in focal dystonias – A focused review to address an important component of the disease. Parkinsonism Relat Disord 2018; 54:17-24. [DOI: 10.1016/j.parkreldis.2018.04.030] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Revised: 04/05/2018] [Accepted: 04/26/2018] [Indexed: 12/16/2022]
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Abstract
Botulinum neurotoxins (BoNTs) are now among the most widely used therapeutic agents in clinical medicine with indications applied to the fields of movement disorders, pain disorders, and autonomic dysfunction. In this literature review, the efficacy and utility of BoNTs in the field of movement disorders are assessed using the criteria of the Guideline Development Subcommittee of the American Academy of Neurology. The literature supports a level A efficacy (established) for BoNT therapy in cervical dystonia and a level B efficacy (probably effective) for blepharospasm, hemifacial spasm, laryngeal dystonia (spasmodic dysphonia), task-specific dystonias, essential tremor, and Parkinson rest tremor. It is the view of movement disorder experts, however, that despite the level B efficacy, BoNTs should be considered treatment of first choice for blepharospasm, hemifacial spasm, laryngeal, and task-specific dystonias. The emerging data on motor and vocal tics of Tourette syndrome and oromandibular dystonias are encouraging but the current level of efficacy is U (undetermined) due to lack of published high-quality studies.
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Affiliation(s)
- Yasaman Safarpour
- Division of Nephrology, Department of Medicine, University of California, Irvine, USA
| | - Bahman Jabbari
- Division of Movement Disorders, Department of Neurology, Yale University School of Medicine, New Haven-CT, 31 Silver Pine Drive, Newport Coast, CA, 92657, USA.
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Affiliation(s)
- Isabel Alfradique-Dunham
- Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA
| | - Joseph Jankovic
- Parkinson’s Disease Center and Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, Houston, TX, USA
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Zanetti G, Sikorra S, Rummel A, Krez N, Duregotti E, Negro S, Henke T, Rossetto O, Binz T, Pirazzini M. Botulinum neurotoxin C mutants reveal different effects of syntaxin or SNAP-25 proteolysis on neuromuscular transmission. PLoS Pathog 2017; 13:e1006567. [PMID: 28800600 PMCID: PMC5568444 DOI: 10.1371/journal.ppat.1006567] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2017] [Revised: 08/23/2017] [Accepted: 08/03/2017] [Indexed: 11/30/2022] Open
Abstract
Botulinum neurotoxin serotype C (BoNT/C) is a neuroparalytic toxin associated with outbreaks of animal botulism, particularly in birds, and is the only BoNT known to cleave two different SNARE proteins, SNAP-25 and syntaxin. BoNT/C was shown to be a good substitute for BoNT/A1 in human dystonia therapy because of its long lasting effects and absence of neuromuscular damage. Two triple mutants of BoNT/C, namely BoNT/C S51T/R52N/N53P (BoNT/C α-51) and BoNT/C L200W/M221W/I226W (BoNT/C α-3W), were recently reported to selectively cleave syntaxin and have been used here to evaluate the individual contribution of SNAP-25 and syntaxin cleavage to the effect of BoNT/C in vivo. Although BoNT/C α-51 and BoNT/C α-3W toxins cleave syntaxin with similar efficiency, we unexpectedly found also cleavage of SNAP-25, although to a lesser extent than wild type BoNT/C. Interestingly, the BoNT/C mutants exhibit reduced lethality compared to wild type toxin, a result that correlated with their residual activity against SNAP-25. In spite of this, a local injection of BoNT/C α-51 persistently impairs neuromuscular junction activity. This is due to an initial phase in which SNAP-25 cleavage causes a complete blockade of neurotransmission, and to a second phase of incomplete impairment ascribable to syntaxin cleavage. Together, these results indicate that neuroparalysis of BoNT/C at the neuromuscular junction is due to SNAP-25 cleavage, while the proteolysis of syntaxin provides a substantial, but incomplete, neuromuscular impairment. In light of this evidence, we discuss a possible clinical use of BoNT/C α-51 as a botulinum neurotoxin endowed with a wide safety margin and a long lasting effect. The seven established Botulinum Neurotoxins serotypes (BoNT/A to G) and the many BoNT subtypes, the causative agents of botulism, are the most poisonous substances known (lethal doses in the low ng/kg range). Due to their toxicological properties, BoNTs are Janus-faced toxins: potent pathogenic factors and potential bioterrorism agents as well as safe and efficacious therapeutics. BoNTs exert their neuroparalytic action by cleaving SNARE proteins, either SNAP-25 or synaptobrevin/VAMP, which mediate neurotransmitter release at the neuromuscular junction; BoNT/C is the only serotype shown to cleave SNAP-25 and syntaxin-1 in vitro. Our study shows for the first time that this parallel cleavage also occurs in vivo. By using mutated toxins reported to be syntaxin-selective, we found that SNAP-25 proteolysis at the neuromuscular junction is the key determinant of BoNT/C lethality as it completely blocks nerve-muscle transmission. Conversely, syntaxin-1 cleavage only attenuates nerve terminal activity without inactivating the synapse, leading to only a partial decrease of neuromuscular functionality. As a result, the BoNT/C mutants have dramatically reduced lethality, but still modulate neuromuscular junction activity upon intramuscular injection. This aspect is particularly relevant considering the possible use of syntaxin-specific BoNT/C derivatives to improve the present clinical utilization of BoNTs.
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Affiliation(s)
- Giulia Zanetti
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Stefan Sikorra
- Institut für Zellbiochemie, Medizinische Hochschule Hannover, Hannover, Germany
| | - Andreas Rummel
- Institut für Toxikologie, Medizinische Hochschule Hannover, Hannover, Germany
| | - Nadja Krez
- Institut für Toxikologie, Medizinische Hochschule Hannover, Hannover, Germany
| | - Elisa Duregotti
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Samuele Negro
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Tina Henke
- Institut für Zellbiochemie, Medizinische Hochschule Hannover, Hannover, Germany
| | - Ornella Rossetto
- Department of Biomedical Sciences, University of Padova, Padova, Italy
| | - Thomas Binz
- Institut für Zellbiochemie, Medizinische Hochschule Hannover, Hannover, Germany
| | - Marco Pirazzini
- Department of Biomedical Sciences, University of Padova, Padova, Italy
- * E-mail:
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Pirazzini M, Rossetto O, Eleopra R, Montecucco C. Botulinum Neurotoxins: Biology, Pharmacology, and Toxicology. Pharmacol Rev 2017; 69:200-235. [PMID: 28356439 PMCID: PMC5394922 DOI: 10.1124/pr.116.012658] [Citation(s) in RCA: 478] [Impact Index Per Article: 59.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
The study of botulinum neurotoxins (BoNT) is rapidly progressing in many aspects. Novel BoNTs are being discovered owing to next generation sequencing, but their biologic and pharmacological properties remain largely unknown. The molecular structure of the large protein complexes that the toxin forms with accessory proteins, which are included in some BoNT type A1 and B1 pharmacological preparations, have been determined. By far the largest effort has been dedicated to the testing and validation of BoNTs as therapeutic agents in an ever increasing number of applications, including pain therapy. BoNT type A1 has been also exploited in a variety of cosmetic treatments, alone or in combination with other agents, and this specific market has reached the size of the one dedicated to the treatment of medical syndromes. The pharmacological properties and mode of action of BoNTs have shed light on general principles of neuronal transport and protein-protein interactions and are stimulating basic science studies. Moreover, the wide array of BoNTs discovered and to be discovered and the production of recombinant BoNTs endowed with specific properties suggest novel uses in therapeutics with increasing disease/symptom specifity. These recent developments are reviewed here to provide an updated picture of the biologic mechanism of action of BoNTs, of their increasing use in pharmacology and in cosmetics, and of their toxicology.
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Affiliation(s)
- Marco Pirazzini
- Department of Biomedical Sciences, University of Padova, Italy (M.P., O.R., C.M.); Neurologic Department, University-Hospital S. Maria della Misericordia, Udine, Italy (R.E.); and Consiglio Nazionale delle Ricerche, Institute of Neuroscience, University of Padova, Italy (C.M.)
| | - Ornella Rossetto
- Department of Biomedical Sciences, University of Padova, Italy (M.P., O.R., C.M.); Neurologic Department, University-Hospital S. Maria della Misericordia, Udine, Italy (R.E.); and Consiglio Nazionale delle Ricerche, Institute of Neuroscience, University of Padova, Italy (C.M.)
| | - Roberto Eleopra
- Department of Biomedical Sciences, University of Padova, Italy (M.P., O.R., C.M.); Neurologic Department, University-Hospital S. Maria della Misericordia, Udine, Italy (R.E.); and Consiglio Nazionale delle Ricerche, Institute of Neuroscience, University of Padova, Italy (C.M.)
| | - Cesare Montecucco
- Department of Biomedical Sciences, University of Padova, Italy (M.P., O.R., C.M.); Neurologic Department, University-Hospital S. Maria della Misericordia, Udine, Italy (R.E.); and Consiglio Nazionale delle Ricerche, Institute of Neuroscience, University of Padova, Italy (C.M.)
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22
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Contarino MF, Van Den Dool J, Balash Y, Bhatia K, Giladi N, Koelman JH, Lokkegaard A, Marti MJ, Postma M, Relja M, Skorvanek M, Speelman JD, Zoons E, Ferreira JJ, Vidailhet M, Albanese A, Tijssen MAJ. Clinical Practice: Evidence-Based Recommendations for the Treatment of Cervical Dystonia with Botulinum Toxin. Front Neurol 2017; 8:35. [PMID: 28286494 PMCID: PMC5323428 DOI: 10.3389/fneur.2017.00035] [Citation(s) in RCA: 60] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2016] [Accepted: 01/25/2017] [Indexed: 12/14/2022] Open
Abstract
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.
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Affiliation(s)
- Maria Fiorella Contarino
- Department of Neurology, Haga Teaching Hospital, The Hague, Netherlands; Department of Neurology, Leiden University Medical Centre, Leiden, Netherlands
| | - Joost Van Den Dool
- Department of Neurology AB 51, University Medical Centre Groningen, Groningen, Netherlands; ACHIEVE Centre of Expertise, Faculty of Health, Amsterdam University of Applied Sciences, Amsterdam, Netherlands
| | - Yacov Balash
- Movement Disorders Unit of the Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Kailash Bhatia
- Sobell Department, Institute of Neurology, National Hospital for Neurology, University College London , London , UK
| | - Nir Giladi
- Movement Disorders Unit of the Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel; Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel
| | - Johannes H Koelman
- Department of Neurology/Clinical Neurophysiology, Academic Medical Center , Amsterdam , Netherlands
| | - Annemette Lokkegaard
- Department of Neurology, Copenhagen University Hospital Bispebjerg , Copenhagen , Denmark
| | - Maria J Marti
- Department of Neurology, Hospital Clinic i Universitari, Institut D'Investigacio Biomedica August Pi i Sunyer (IDIBAPS), CIBERNED , Barcelona , Spain
| | - Miranda Postma
- Department of Neurology/Clinical Neurophysiology, Academic Medical Center , Amsterdam , Netherlands
| | - Maja Relja
- Movement Disorders Center, Department of Neurology, Clinical Medical Center School of Medicine, Zagreb University , Zagreb , Croatia
| | - Matej Skorvanek
- Department of Neurology, P. J. Safarik University, Kosice, Slovakia; Department of Neurology, University Hospital of L. Pasteur, Kosice, Slovakia
| | - Johannes D Speelman
- Department of Neurology/Clinical Neurophysiology, Academic Medical Center , Amsterdam , Netherlands
| | - Evelien Zoons
- Department of Neurology/Clinical Neurophysiology, Academic Medical Center , Amsterdam , Netherlands
| | - Joaquim J Ferreira
- Clinical Pharmacology Unit, Faculty of Medicine, Instituto de Medicina Molecular, University of Lisbon , Lisbon , Portugal
| | - Marie Vidailhet
- Sorbonne University, UPMC Paris-6, Paris, France; Brain and Spine Institute - ICM, Centre for Neuroimaging Research - CENIR, UPMC UMR 1127, Paris, France; INSERM U 1127, Paris, France; CNRS UMR 7225, Team Control of Normal and Abnormal Movement, Paris, France; Department of Neurology, Salpêtriere Hospital, AP-HP, Paris, France
| | - Alberto Albanese
- Department of Neurology, Humanitas Research Hospital, Milano, Italy; Department of Neurology, Università Cattolica del Sacro Cuore, Milano, Italy
| | - Marina A J Tijssen
- Department of Neurology AB 51, University Medical Centre Groningen , Groningen , Netherlands
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23
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Jabbari B. History of Botulinum Toxin Treatment in Movement Disorders. Tremor Other Hyperkinet Mov (N Y) 2016; 6:394. [PMID: 27917308 PMCID: PMC5133258 DOI: 10.7916/d81836s1] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Accepted: 10/25/2016] [Indexed: 01/27/2023] Open
Abstract
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.
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Marques RE, Duarte GS, Rodrigues FB, Castelão M, Ferreira J, Sampaio C, Moore AP, Costa J, Cochrane Movement Disorders Group. Botulinum toxin type B for cervical dystonia. Cochrane Database Syst Rev 2016; 2016:CD004315. [PMID: 27176573 PMCID: PMC8552447 DOI: 10.1002/14651858.cd004315.pub3] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
BACKGROUND This is an update of a Cochrane review first published in 2004, and previously updated in 2009 (no change in conclusions). Cervical dystonia is a frequent and disabling disorder characterised by painful involuntary head posturing. Botulinum toxin type A (BtA) is usually considered the first line therapy for this condition, although botulinum toxin type B (BtB) is an alternative option. OBJECTIVES To compare the efficacy, safety and tolerability of botulinum toxin type B (BtB) versus placebo in people with cervical dystonia. SEARCH METHODS We identified studies for inclusion in the review using the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, reference lists of articles and conference proceedings, last run in October 2015. We ran the search from 1977 to 2015. The search was unrestricted by language. SELECTION CRITERIA Double-blind, parallel, randomised, placebo-controlled trials (RCTs) of BtB versus placebo in adults with cervical dystonia. DATA COLLECTION AND ANALYSIS 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 one meta-analysis for the comparison BtB versus placebo. We used random-effects models when there was heterogeneity and fixed-effect models when there was no heterogeneity. In addition, we performed pre-specified subgroup analyses according to BtB doses and BtA previous clinical responsiveness. The primary efficacy outcome was overall improvement on any validated symptomatic rating scale. The primary safety outcome was the number of participants with any adverse event. MAIN RESULTS We included four RCTs of moderate overall methodological quality, including 441 participants with cervical dystonia. Three studies excluded participants known to have poorer response to Bt treatment, therefore including an enriched population with a higher probability of benefiting from Bt treatment. None of the trials were independently funded. All RCTs evaluated the effect of a single Bt treatment session using doses between 2500 U and 10,000 U. BtB was associated with an improvement of 14.7% (95% CI 9.8% to 19.5) in the patients' baseline clinical status as assessed by investigators, with reduction of 6.8 points in the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS-total score) at week 4 after injection (95% CI 4.54 to 9.01). Mean difference (MD) in TWSTRS-pain score at week 4 was 2.20 (95% CI 1.25 to 3.15). Overall, both participants and clinicians reported an improvement of subjective clinical status. There were no differences between groups in the withdrawals rate due to adverse events or in the proportion of participants with adverse events. However, BtB-treated patients had a 7.65 (95% CI 2.75 to 21.32) and a 6.78 (95% CI 2.42 to 19.05) increased risk of treatment-related dry mouth and dysphagia, respectively. Statistical heterogeneity between studies was low to moderate for most outcomes. All tested dosages were efficacious against placebo without clear-cut evidence of a dose-response gradient. However, duration of effect (time until return to baseline TWSTRS-total score) and risk of dry mouth and dysphagia were greater in the subgroup of participants treated with higher BtB doses. Subgroup analysis showed a higher improvement with BtB among BtA-non-responsive participants, although there were no differences in the effect size between the BtA-responsive and non-responsive subgroups. AUTHORS' CONCLUSIONS A single BtB-treatment session is associated with a significant and clinically relevant reduction of cervical dystonia impairment including severity, disability and pain, and is well tolerated, when compared with placebo. However, BtB-treated patients are at an increased risk of dry mouth and dysphagia. There are no data from RCTs evaluating the effectiveness and safety of repeated BtB injection cycles. There are no RCT data to allow us to draw definitive conclusions on the optimal treatment intervals and doses, usefulness of guidance techniques for injection, and impact on quality of life.
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Affiliation(s)
- Raquel E Marques
- Faculdade de Medicina de LisboaLaboratório de Farmacologia Clínica e TerapêuticaAv. Professor Egas MonizLisboaPortugal1649‐028
- Instituto de Medicina MolecularClinical Pharmacology UnitAvenida Professor Egas MonizLisboaPortugal1649‐028
| | - Gonçalo S Duarte
- Faculdade de Medicina de LisboaLaboratório de Farmacologia Clínica e TerapêuticaAv. Professor Egas MonizLisboaPortugal1649‐028
- Instituto de Medicina MolecularClinical Pharmacology UnitAvenida Professor Egas MonizLisboaPortugal1649‐028
| | - Filipe B Rodrigues
- Faculdade de Medicina de LisboaLaboratório de Farmacologia Clínica e TerapêuticaAv. Professor Egas MonizLisboaPortugal1649‐028
- Instituto de Medicina MolecularClinical Pharmacology UnitAvenida Professor Egas MonizLisboaPortugal1649‐028
| | - Mafalda Castelão
- Faculdade de Medicina de LisboaLaboratório de Farmacologia Clínica e TerapêuticaAv. Professor Egas MonizLisboaPortugal1649‐028
- Instituto de Medicina MolecularClinical Pharmacology UnitAvenida Professor Egas MonizLisboaPortugal1649‐028
| | - Joaquim Ferreira
- Faculdade de Medicina de LisboaLaboratório de Farmacologia Clínica e TerapêuticaAv. Professor Egas MonizLisboaPortugal1649‐028
- Instituto de Medicina MolecularClinical Pharmacology UnitAvenida Professor Egas MonizLisboaPortugal1649‐028
| | - Cristina Sampaio
- CHDI Foundation155 Village BoulevardSuite 200PrincetonNJUSA08540
| | - A Peter Moore
- The Walton Centre NHS Foundation TrustLower LaneLiverpoolUKL9 7LJ
| | - João Costa
- Faculdade de Medicina de LisboaLaboratório de Farmacologia Clínica e TerapêuticaAv. Professor Egas MonizLisboaPortugal1649‐028
- Instituto de Medicina MolecularClinical Pharmacology UnitAvenida Professor Egas MonizLisboaPortugal1649‐028
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Han Y, Stevens AL, Dashtipour K, Hauser RA, Mari Z. A mixed treatment comparison to compare the efficacy and safety of botulinum toxin treatments for cervical dystonia. J Neurol 2016; 263:772-80. [PMID: 26914922 PMCID: PMC4826665 DOI: 10.1007/s00415-016-8050-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2015] [Revised: 01/23/2016] [Accepted: 01/25/2016] [Indexed: 12/17/2022]
Abstract
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.
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Affiliation(s)
- Yi Han
- WG Consulting, 200 Fifth Avenue, New York, NY, 10010, USA.
| | | | - Khashayar Dashtipour
- Faculty of Medical Offices, School of Medicine, Loma Linda University, 11370 Anderson, Suite B-100, Loma Linda, CA, 92354, USA
| | - Robert A Hauser
- Health Byrd Institute, University of South Florida, 4001 E. Fletcher Ave, 6th Floor, Tampa, FL, 33613, USA
| | - Zoltan Mari
- School of Medicine, Johns Hopkins University, 600 N. Wolfe Street, Meyer 6-181B, Baltimore, MD, 21287, USA
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Del Sorbo F, Albanese A. Botulinum neurotoxins for the treatment of focal dystonias: Review of rating tools used in clinical trials. Toxicon 2015; 107:89-97. [PMID: 26365917 DOI: 10.1016/j.toxicon.2015.09.010] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Revised: 08/26/2015] [Accepted: 09/08/2015] [Indexed: 12/14/2022]
Abstract
Botulinum neurotoxins (BoNTs) are used to achieve therapeutic benefit in focal dystonia. An expert panel recently reviewed published evidence on the efficacy of BoNTs for the treatment of focal dystonias and produced recommendations for clinical practice. Another panel reviewed the clinimetric properties of rating scales for dystonia and produced recommendations for current usage and future directions. Considering that the strength of evidence derives not only from the quality of the study design, but also from usage of validated outcome measures, we combined the information provided by these two recent reviews and assessed the appropriateness of the rating instruments used in clinical trials on BoNT treatment in focal dystonia. Data sources included all the publications on BoNT treatment for focal dystonias reviewed by the recent evidence-based analysis. We reviewed all rating instruments used to assess primary and secondary outcome following BoNT treatment. The publications were allocated into five topics according to the focal dystonia type reviewed in the meta-analysis: blepharospasm, oromandibular dystonia, cervical dystonia, upper limb dystonia, and laryngeal dystonia. For each topic, papers were divided, according to the terminology used in the meta-analysis, into placebo-controlled, active comparator and methodological or uncontrolled. For each topic we identified the rating tools used in each study class and annotated which were the mostly used in each focal dystonia type. Outcome measures included tools related to motor and non-motor features, such as pain and depression, and functional as well as health-related quality of life features. Patient- and investigator-reported outcomes were also included. Rating instruments were classified as recommended, suggested, listed or not included, based on recommendations produced by the rating scale task force. Both primary and secondary outcome measures were assessed. As a final step we compared current practice, as summarized by the meta-analysis, with the recommendations of the rating scales panel. For blepharospasm, three placebo-controlled trials used suggested scales, one active-comparator study used a recommended scale and three active-comparator studies used suggested scales. For oromandibular dystonia, one placebo-controlled study used a suggested scale. For cervical dystonia, six placebo-controlled trials used a recommended scale, four active-comparator trials used a recommended scale and one active-comparator study used a suggested scale. For upper limb and laryngeal dystonia, no trial used validated instruments. Appropriately designed studies should be based on recommended rating instruments. Therapeutic trials not using clinimetrically tested rating measures do not provide sufficient information on efficacy of BoNT treatment, even if the study design is robust. Further research is needed to develop and validate new tools to assess all types of focal dystonia and to apply them in prospective placebo-controlled clinical trials.
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Affiliation(s)
| | - Alberto Albanese
- Istituto di Neurologia, Istituto Clinico Humanitas, Rozzano, Milano, Italy; Istituto di Neurologia, Università Cattolica del Sacro Cuore, Milano, Italy.
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Bentivoglio AR, Del Grande A, Petracca M, Ialongo T, Ricciardi L. Clinical differences between botulinum neurotoxin type A and B. Toxicon 2015; 107:77-84. [PMID: 26260691 DOI: 10.1016/j.toxicon.2015.08.001] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2015] [Accepted: 08/04/2015] [Indexed: 12/23/2022]
Abstract
In humans, the therapeutic use of botulinum neurotoxin A (BoNT/A) is well recognized and continuously expanding. Four BoNTs are widely available for clinical practice: three are serotype A and one is serotype B: onabotulinumtoxinA (A/Ona), abobotulinumtoxinA (A/Abo) and incobotulinumtoxinA (A/Inco), rimabotulinumtoxinB (B/Rima). A/Abo, A/Inco, A/Ona and B/Rima are all licensed worldwide for cervical dystonia. In addition, the three BoNT/A products are approved for blepharospasm and focal dystonias, spasticity, hemifacial spasm, hyperhidrosis and facial lines, with remarkable regional differences. These toxin brands differ for specific activity, packaging, constituents, excipient, and storage. Comparative literature assessing the relative safety and efficacy of different BoNT products is limited, most data come from reports on small samples, and only a few studies meet criteria of evidence-based medicine. One study compared the effects of BoNT/A and BoNT/B on muscle activity of healthy volunteers, showing similar neurophysiological effects with a dose ratio of 1:100. In cervical dystonia, when comparing the effects of BoNT/A and BoNT/B, results are more variable, some studies reporting roughly similar peak effect and overall duration (at a ratio of 1:66, others reporting substantially shorter duration of BoNT/B than BoNT/A (at a ratio 1/24). Although the results of clinical studies are difficult to compare for methodological differences (dose ratio, study design, outcome measures), it is widely accepted that: BoNT/B is clinically effective using appropriate doses as BoNT/A (1:40-50), injections are generally more painful, in most of the studies on muscular conditions, efficacy is shorter, and immunogenicity higher. Since the earliest clinical trials, it has been reported that autonomic side effects are more frequent after BoNT/B injections, and this observation encouraged the use of BoNT/B for sialorrhea, hyperhidrosis and other non-motor symptoms. In these indications the efficacy of toxins A and B are comparable and dose ratio is 1:25-30.
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Affiliation(s)
| | | | - Martina Petracca
- Institute of Neurology, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Tamara Ialongo
- Institute of Neurology, Università Cattolica del Sacro Cuore, Roma, Italy
| | - Lucia Ricciardi
- Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, University College London, London, UK
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Langevin P, Peloso PMJ, Lowcock J, Nolan M, Weber J, Gross A, Roberts J, Goldsmith CH, Graham N, Burnie SJ, Haines T, Cochrane Back and Neck Group. WITHDRAWN: Botulinum toxin for subacute/chronic neck pain. Cochrane Database Syst Rev 2015; 2015:CD008626. [PMID: 25994306 PMCID: PMC10637244 DOI: 10.1002/14651858.cd008626.pub3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Withdrawn due to non‐compliance with The Cochrane Collaboration’s Commercial Sponsorship Policy The editorial group responsible for this previously published document have withdrawn it from publication.
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Affiliation(s)
- Pierre Langevin
- Département de réadaptation, Faculté de Médecine, Université LavalCliniques Physio Interactive3520 rue de l'HêtrièreSt‐Augustin‐de‐DesmauresQCCanadaG3A 2V4
| | - Paul Michael J Peloso
- MRL ‐ MerckDepartment of Clinical DevelopmentRY34‐B272126 E. Lincoln AveRahwayNJUSA07065
| | | | - May Nolan
- University of British ColumbiaSchool of Physiotherapy, Faculty of Medicine212‐2177 Westbrook MallVancouverBCCanadaV6T 1Z3
| | - Jeff Weber
- Family Physiotherapy Inc.G04, 7408 ‐ 139th AvenueEdmontonABCanadaT5C 3H7
| | - Anita Gross
- McMaster UniversitySchool of Rehabilitation Science & Department of Clinical Epidemiology and Biostatistics1400 Main Street WestHamiltonONCanadaL8S 1C7
| | - John Roberts
- University of Calgary Sport Medicine CentrePhysiotherapy Department302 838 4th Ave NWCalgaryABCanadaT2N 0M8
| | - Charles H Goldsmith
- Simon Fraser UniversityFaculty of Health SciencesBlossom Hall, Room 95108888 University DriveBurnabyBCCanadaV5A 1S6
| | - Nadine Graham
- McMaster UniversitySchool of Rehabilitation Science1200 Main Street WestHamiltonONCanada
| | - Stephen J Burnie
- Canadian Memorial Chiropractic CollegeDepartment of Clinical Education6100 Leslie StreetTorontoONCanadaM2H 3J1
| | - Ted Haines
- McMaster UniversityDepartment of Clinical Epidemiology and Biostatistics1200 Main Street WestHSC 3H54HamiltonONCanadaL8N 3Z5
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Peloso PMJ, Gross A, Haines T, Trinh K, Goldsmith CH, Burnie SJ, Cervical Overview Group, Cochrane Back and Neck Group. WITHDRAWN: Medicinal and injection therapies for mechanical neck disorders. Cochrane Database Syst Rev 2015; 2015:CD000319. [PMID: 25994305 PMCID: PMC10798413 DOI: 10.1002/14651858.cd000319.pub5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Withdrawn due to non‐compliance with The Cochrane Collaboration’s Commercial Sponsorship Policy The editorial group responsible for this previously published document have withdrawn it from publication.
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Affiliation(s)
- Paul Michael J Peloso
- MRL ‐ MerckDepartment of Clinical DevelopmentRY34‐B272126 E. Lincoln AveRahwayNJUSA07065
| | - Anita Gross
- McMaster UniversitySchool of Rehabilitation Science & Department of Clinical Epidemiology and Biostatistics1400 Main Street WestHamiltonONCanadaL8S 1C7
| | - Ted Haines
- McMaster UniversityDepartment of Clinical Epidemiology and Biostatistics1200 Main Street WestHSC 3H54HamiltonONCanadaL8N 3Z5
| | - Kien Trinh
- McMaster UniversityDeGroote School of Medicine, Office of MD Admissions1200 Main Street WestMDCL‐3112HamiltonONCanadaL8N 3Z5
| | - Charles H Goldsmith
- Simon Fraser UniversityFaculty of Health SciencesBlossom Hall, Room 95108888 University DriveBurnabyBCCanadaV5A 1S6
| | - Stephen J Burnie
- Canadian Memorial Chiropractic CollegeDepartment of Clinical Education6100 Leslie StreetTorontoONCanadaM2H 3J1
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A randomized, placebo controlled pilot trial of botulinum toxin for paratonic rigidity in people with advanced cognitive impairment. PLoS One 2014; 9:e114733. [PMID: 25536218 PMCID: PMC4275182 DOI: 10.1371/journal.pone.0114733] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2014] [Accepted: 11/05/2014] [Indexed: 11/19/2022] Open
Abstract
OBJECTIVE Evaluate safety and efficacy of Incobotulinumtoxin A in elderly patients with dementia and paratonia. SETTING University-affiliated hospital, spasticity management Clinic. PARTICIPANTS Ten subjects were enrolled. INCLUSION CRITERIA 1) severe cognitive impairment 2) diagnosis of Alzheimer's disease, vascular dementia, or frontotemporal dementia, and 3) score >3 on the paratonic assessment instrument, with posture in an arm(s) interfering with provision of care. EXCLUSION CRITERIA 1) alternate etiologies for increased tone and 2) injection with botulinum toxin within the 6 months preceding the study. DESIGN Single center, randomized, double blind, placebo-controlled, crossover trial with two treatment cycles of 16 weeks. Assessments occurred at 2, 6, 12 and16 weeks following injections. Subjects received up to 300 U of Incobotulinumtoxin A in arm(s). PRIMARY AND SECONDARY OUTCOME MEASURES Primary outcome measure was the modified caregiver burden scale (mCBS); exploratory secondary outcome measures were also performed. Analysis of variance and mixed modeling techniques were used to evaluate treatment effects. RESULTS Incobotulinumtoxin A treatment produced significant improvement in mCBS total score -1.11 (-2.04 to -0.18) (Treatment effect and 95% CI), dressing sub-score -0.36 (-0.59 to 0.12), and cleaning under the left and right armpits sub-score -0.5 (-0.96 to -0.04), -0.41 (-0.79 to -0.04) respectively. PROM in the left and right elbow increased by 27.67 degrees (13.32-42.02) and 22.07 degrees (9.76-34.39) respectively. PROM in the left and right shoulder increased by 11.92 degrees (5.46-18.38) and 8.58 degrees (3.73-13.43) respectively. No significant treatment effect was found for GAS, VAS and PAINAD scales or change in time to perform care. No adverse drug reactions occurred. CONCLUSIONS Administration of Incobotulinumtoxin A in elderly people with advanced dementia and paratonia may be an efficacious and safe treatment to increase range of motion and reduce functional burden. Further studies are needed to confirm results. TRIAL REGISTRATION ClinicalTrials.Gov NCT02212119.
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Microvascular decompression surgery is effective for the laterocollis subtype of spasmodic torticollis: a long-term follow-up result. Acta Neurochir (Wien) 2014; 156:1551-6. [PMID: 24838841 DOI: 10.1007/s00701-014-2120-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 04/29/2014] [Indexed: 10/25/2022]
Abstract
BACKGROUND Spasmodic torticollis (ST) is characterized by sustained, involuntary, and painful spasms of specific muscle (s), which results into abnormal posture of the neck and head. Although various treatments for ST have been introduced, none of them shows absolute effectiveness. Earlier research from our department showed that microvascular decompression (MVD) surgery is effective in the short-term for ST patients with confirmed accessory nerve compression. However, the long-term outcome of MVD remains unknown. METHOD Twelve ST patients with confirmed accessory nerve compression received MVD surgery of their accessory nerves. We utilized the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) to evaluate the long-term outcome (5.4 ± 0.87 years). RESULTS The MVD lowered total TWSTRS scores by 42.8 % in all ST patients. This result, however, only counted for moderate relief. Interestingly, we observed that the laterocollis (LC) subtypes of ST (n = 3) obtained a higher TWSTRS score improvement (86.9 ± 6.2 %), compared to that of the non-LC (28.1 ± 12 %) (P =0.0001). Additionally, the disability (92.7 ± 2 %) subscale score in the LC subtypes had the most prominent improvement compared to the pain (88.1 ± 5.1 %) and severity (81.3 ± 10.5 %). CONCLUSIONS In the cases of confirmed accessory nerve compression, the MVD could be considered as a treatment alternative for ST, especially for the LC subtypes.
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Albanese A, Sorbo FD, Comella C, Jinnah HA, Mink JW, Post B, Vidailhet M, Volkmann J, Warner TT, Leentjens AFG, Martinez-Martin P, Stebbins GT, Goetz CG, Schrag A. Dystonia rating scales: critique and recommendations. Mov Disord 2014; 28:874-83. [PMID: 23893443 DOI: 10.1002/mds.25579] [Citation(s) in RCA: 135] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2013] [Accepted: 05/22/2013] [Indexed: 01/04/2023] Open
Abstract
Many rating scales have been applied to the evaluation of dystonia, but only few have been assessed for clinimetric properties. The Movement Disorders Society commissioned this task force to critique existing dystonia rating scales and place them in the clinical and clinimetric context. A systematic literature review was conducted to identify rating scales that have either been validated or used in dystonia. Thirty-six potential scales were identified. Eight were excluded because they did not meet review criteria, leaving 28 scales that were critiqued and rated by the task force. Seven scales were found to meet criteria to be "recommended": the Blepharospasm Disability Index is recommended for rating blepharospasm; the Cervical Dystonia Impact Scale and the Toronto Western Spasmodic Torticollis Rating Scale for rating cervical dystonia; the Craniocervical Dystonia Questionnaire for blepharospasm and cervical dystonia; the Voice Handicap Index (VHI) and the Vocal Performance Questionnaire (VPQ) for laryngeal dystonia; and the Fahn-Marsden Dystonia Rating Scale for rating generalized dystonia. Two "recommended" scales (VHI and VPQ) are generic scales validated on few patients with laryngeal dystonia, whereas the others are disease-specific scales. Twelve scales met criteria for "suggested" and 7 scales met criteria for "listed." All the scales are individually reviewed in the online information. The task force recommends 5 specific dystonia scales and suggests to further validate 2 recommended generic voice-disorder scales in dystonia. Existing scales for oromandibular, arm, and task-specific dystonia should be refined and fully assessed. Scales should be developed for body regions for which no scales are available, such as lower limbs and trunk.
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Affiliation(s)
- Alberto Albanese
- Istituto di Neurologia, Università Cattolica del Sacro Cuore, Milano, Italy; Neurologia I, Istituto Neurologico Carlo Besta, Milano, Italy.
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Abstract
Selecting the appropriate treatment for dystonia begins with proper classification of disease based on age, distribution, and underlying etiology. The therapies available for dystonia include oral medications, botulinum toxin, and surgical procedures. Oral medications are generally reserved for generalized and segmental dystonia. Botulinum toxin revolutionized the treatment of focal dystonia when it was introduced for therapeutic purposes in the 1980s. Surgical procedures are available for medication-refractory dystonia, markedly affecting an individual's quality of life.
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Affiliation(s)
- Mary Ann Thenganatt
- Parkinson’s Disease Center & Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston, TX 77030 USA
| | - Joseph Jankovic
- Parkinson’s Disease Center & Movement Disorders Clinic, Department of Neurology, Baylor College of Medicine, 6550 Fannin, Suite 1801, Houston, TX 77030 USA
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Use of rimabotulinum toxin for focal hypertonicity management in children with cerebral palsy with nonresponse to onabotulinum toxin. Am J Phys Med Rehabil 2013; 92:898-904. [PMID: 23636084 DOI: 10.1097/phm.0b013e31829231fa] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
OBJECTIVE The aim of this study was to review the effect of rimabotulinum toxin (BoNT-B) for focal hypertonicity management in children with cerebral palsy and secondary nonresponse to onabotulinum toxin treated at the authors' tertiary care academic medical center. DESIGN A retrospective review of the medical treatment of children was conducted at the authors' institution (March 16, 2001, to August 2, 2002) using the key words botulinum toxin B and Myobloc (Solstice Neurosciences Inc, South San Francisco, CA). Demographic information was analyzed using descriptive statistics (number [percentage] and mean [range]). The Pearson χ test was used to evaluate differences in incidence of adverse events. RESULTS Eighty-two children had BoNT-B injections (116 treatments). Overall, 26.8% (19/71) of the children or their parents/guardians reported no or minimal response to the injections, with 89.5% (17/19) of these children having secondary nonresponse to onabotulinum toxin. Adverse events were frequent but did not require hospitalization of any patient. No significant differences were found in incidence of adverse events related to BoNT-B dosing, medical fragility, or Gross Motor Function Classification System level. CONCLUSIONS More than one-fourth of the children receiving BoNT-B injections had nonresponse, with most having previous nonresponse to onabotulinum toxin. Adverse events related to BoNT-B injections were frequent and unpredictable but not severe.
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Peña E. Treatment with botulinum toxin: An update. World J Neurol 2013; 3:29-41. [DOI: 10.5316/wjn.v3.i3.29] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/23/2013] [Revised: 07/10/2013] [Accepted: 08/06/2013] [Indexed: 02/06/2023] Open
Abstract
Botulinum neurotoxin (BoNT) is a potent toxin produced by the anaerobic bacterium clostridium botulinum. It causes flaccid, long-lasting, local and reversible paralysis. In addition, BoNT inhibits the secretion of the exocrine glands and could have properties in the control of pain. Thus, BoNT is useful in the treatment of many neuromuscular conditions where an increase of muscle tone is associated with the pathogenic mechanism. Furthermore, BoNT is recommended in the treatment of some hypersecretion disorders of the exocrine gland and could play a role in the treatment of migraine and other chronic pain conditions. In the BoNT therapy adverse effects are usually mild and reversible. However, repeated injections of BoNT can lead to the development of neutralizing antibodies that can subsequently inhibit the biological activity of the toxin. In this sense, many factors can influence the immunogenicity of the BoNT, such as product-related factors, the dose of BoNT used, the frequency of injection and the previous exposure to the toxin. In this review, we are going to discuss the current clinical applications of BoNT with a special focus on evidence, doses, injection technique and adverse effects for those applications more frequently used in neurology, namely spasticity, blepharospasm, hemifacial spasm, cervical dystonia and other focal dystonias, as well as chronic migraine, tremor, sialorrhea, facial palsy, neurogenic bladder and many other neurological condition.
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Dressler D, Paus S, Seitzinger A, Gebhardt B, Kupsch A. Long-term efficacy and safety of incobotulinumtoxinA injections in patients with cervical dystonia. J Neurol Neurosurg Psychiatry 2013; 84:1014-9. [PMID: 23687362 PMCID: PMC3756428 DOI: 10.1136/jnnp-2012-303608] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/02/2022]
Abstract
INTRODUCTION Previously, controlled trials have demonstrated the efficacy and tolerability of fixed doses of incobotulinumtoxinA (Xeomin, NT 201, botulinum toxin type A free from complexing proteins) to treat cervical dystonia (CD). To explore the clinical relevance of these findings, this study evaluated long-term use of flexible dosing regimens of incobotulinumtoxinA in a setting close to real-life clinical practice. METHODS Patients with CD received five injection sessions of incobotulinumtoxinA using flexible intervals (10-24 weeks) and dosing (≤300 Units) based on patients' needs. Outcome measures included Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), the Dystonia Discomfort Scale (DDS), Investigator Global Assessment of Efficacy (IGAE) and Patient Evaluation of Global Response (PEGR). RESULTS Of 76 patients enrolled (men: 34%; naïve to botulinum toxin: 25%), 64 completed the study, receiving treatment over a duration of 49.3-114.1 weeks (total maximum duration: 121 weeks). Mean TWSTRS-Total and DDS scores significantly improved from study baseline to 4 weeks after each injection session (ranges of improvement: TWSTRS-Total: -11.7 to -14.3; DDS: -20.2 to -23.0). Up to 81.6% of investigators rated the efficacy as 'good' or 'very good' (IGAE) and up to 78.9% of patients rated the treatment response as 'improved' (PEGR). The most common adverse events were dysphagia, nasopharyngitis and headache. CONCLUSIONS In this long-term study, incobotulinumtoxinA was administered using more flexible dosing regimens than those permitted in previous controlled trials. Repeated injections of highly purified incobotulinumtoxinA are effective and well tolerated for the treatment of CD in a setting close to real-life clinical practice.
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Affiliation(s)
- Dirk Dressler
- Movement Disorders Section, Department of Neurology, Hannover Medical School, Hannover, Germany.
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Wheeler A, Smith HS. Botulinum toxins: mechanisms of action, antinociception and clinical applications. Toxicology 2013; 306:124-46. [PMID: 23435179 DOI: 10.1016/j.tox.2013.02.006] [Citation(s) in RCA: 114] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Revised: 02/07/2013] [Accepted: 02/10/2013] [Indexed: 10/27/2022]
Abstract
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.
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Affiliation(s)
- Anthony Wheeler
- The Neurological Institute, 2219 East 7th Street, Charlotte, NC 28204, United States.
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Hallett M, Albanese A, Dressler D, Segal KR, Simpson DM, Truong D, Jankovic J. Evidence-based review and assessment of botulinum neurotoxin for the treatment of movement disorders. Toxicon 2013; 67:94-114. [PMID: 23380701 DOI: 10.1016/j.toxicon.2012.12.004] [Citation(s) in RCA: 151] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2012] [Revised: 11/28/2012] [Accepted: 12/05/2012] [Indexed: 01/28/2023]
Abstract
Botulinum neurotoxin (BoNT) can be injected to achieve therapeutic benefit across a large range of clinical conditions. To assess the efficacy and safety of BoNT injections for the treatment of certain movement disorders, including blepharospasm, hemifacial spasm, oromandibular dystonia, cervical dystonia, focal limb dystonias, laryngeal dystonia, tics, and essential tremor, an expert panel reviewed evidence from the published literature. Data sources included English-language studies identified via MEDLINE, EMBASE, CINAHL, Current Contents, and the Cochrane Central Register of Controlled Trials. Evidence tables generated in the 2008 Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology (AAN) review of the use of BoNT for movement disorders were also reviewed and updated. The panel evaluated evidence at several levels, supporting BoNT as a class, the serotypes BoNT-A and BoNT-B, as well as the four individual commercially available formulations: abobotulinumtoxinA (A/Abo), onabotulinumtoxinA (A/Ona), incobotulinumtoxinA (A/Inco), and rimabotulinumtoxinB (B/Rima). The panel ultimately made recommendations for each therapeutic indication, based upon the strength of clinical evidence and following the AAN classification scale. For the treatment of blepharospasm, the evidence supported a Level A recommendation for BoNT-A, A/Inco, and A/Ona; a Level B recommendation for A/Abo; and a Level U recommendation for B/Rima. For hemifacial spasm, the evidence supported a Level B recommendation for BoNT-A and A/Ona, a Level C recommendation for A/Abo, and a Level U recommendation for A/Inco and B/Rima. For the treatment of oromandibular dystonia, the evidence supported a Level C recommendation for BoNT-A, A/Abo, and A/Ona, and a Level U recommendation for A/Inco and B/Rima. For the treatment of cervical dystonia, the published evidence supported a Level A recommendation for all four BoNT formulations. For limb dystonia, the available evidence supported a Level B recommendation for both A/Abo and A/Ona, but no published studies were identified for A/Inco or B/Rima, resulting in a Level U recommendation for these two formulations. For adductor laryngeal dystonia, evidence supported a Level C recommendation for the use of A/Ona, but a Level U recommendation was warranted for B/Rima, A/Abo, and A/Inco. For the treatment of focal tics, a Level U recommendation was warranted at this time for all four formulations. For the treatment of tremor, the published evidence supported a level B recommendation for A/Ona, but no published studies were identified for A/Abo, A/Inco, or B/Rima, warranting a Level U recommendation for these three formulations. Further research is needed to address evidence gaps and to evaluate BoNT formulations where currently there is insufficient or conflicting clinical data.
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Affiliation(s)
- Mark Hallett
- The George Washington University School of Medicine and Health Sciences, Ross Hall, Department of Neurology, 2300 Eye Street, NW Suite 713W, Washington, DC 20037, USA.
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Abstract
OPINION STATEMENT Dystonia is characterized by repetitive twisting movements or abnormal postures due to involuntary muscle activity. When limited to a single body region it is called focal dystonia. Examples of focal dystonia include cervical dystonia (neck), blepharospasm (eyes), oromandibular dystonia, focal limb dystonia, and spasmodic dysphonia, which are discussed here. Once the diagnosis is established, the therapeutic plan is discussed with the patients. They are informed that there is no cure for dystonia and treatment is symptomatic. The main therapeutic option for treating focal dystonias is botulinum toxin (BoNT). There have been several attempts to characterize the procedure, the type of toxin, dosage, techniques, and combination with physical measures in each of the focal dystonia forms. The general treatment principles are similar. The affected muscles are injected at muscle sites based on evidence and experience using standard dosages based on the type of toxin used. The injections are repeated after 3 to 6 months based on the individual response duration. In the uncommon event of nonresponse with BoNT, the dose and site are reassessed. Oral drug treatment could be considered as an additional option. Once the condition is thought to be medically refractory, the opinion from the deep brain stimulation (DBS) team for the suitability of the patient for DBS is taken. The successful use of DBS in cervical dystonia has led to increased acceptance for trial in other forms of focal dystonias. DBS surgery in focal dystonias other than cervical is, however, still experimental. The patients may be offered the surgery with adequate explanation of the risks and benefits. Patient education and directing the patients towards dystonia support groups and relevant websites that provide scientific information may be useful for long-term compliance and benefit.
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Affiliation(s)
- Amit Batla
- The National Hospital for Neurology and Neurosurgery Queen Square, Box 13, London, WC1N 3BG, UK
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Rating scales for cervical dystonia: a critical evaluation of tools for outcome assessment of botulinum toxin therapy. J Neural Transm (Vienna) 2012; 120:487-96. [PMID: 22899277 PMCID: PMC3575559 DOI: 10.1007/s00702-012-0887-7] [Citation(s) in RCA: 70] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2012] [Accepted: 07/08/2012] [Indexed: 10/28/2022]
Abstract
Botulinum neurotoxin is the therapy of choice for all forms of cervical dystonia (CD), but treatment regimens still vary considerably. The interpretation of treatment outcome is mainly based on the clinical experience and on the scientific value of the rating scales applied. The aim of this review is to describe the historical development of rating scales for the assessment of CD and to provide an appraisal of their advantages and drawbacks. The Tsui score and the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) have been widely employed in numerous clinical studies as specific instruments for CD. The obvious advantage of the Tsui score is its simplicity so that it can be easily implemented in clinical routine. The TWSTRS allows a more sophisticated assessment of functional features of CD, but only the Tsui score includes a rating for tremor. Other benefits of the TWSTRS are the disability and pain subscales, but despite its value in clinical trials, it might be too complex for routine clinical practice. None of the rating scales used at present has been rigorously tested for responsiveness to detect significant changes in clinical status after therapeutic interventions. Moreover, clinical data support a new classification of CD leading to a differentiation between head and neck subtypes. As the current rating scales are not able to cover all these aspects of the disorder, further research is needed to develop a valid and reliable instrument which considers the most current classification of CD.
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Longer-acting and highly potent chimaeric inhibitors of excessive exocytosis created with domains from botulinum neurotoxin A and B. Biochem J 2012; 444:59-67. [PMID: 22360156 DOI: 10.1042/bj20120100] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Various human neurogenic hyper-excitability disorders are successfully treated with type A or B BoNT (botulinum neurotoxin). The BoNT/A complex is widely used because of its longer-lasting benefits; also, autonomic side-effects are more often reported for BoNT/B. To establish if this distinct effect of BoNT/B could be exploited therapeutically, BoNT/A was modified so that it would bind the more abundant BoNT/B acceptor in rodents while retaining its desirable persistent action. The advantageous protease and translocation domain of BoNT/A were recombinantly combined with the acceptor-binding moiety of type B [H(C)/B (C-terminal half of BoNT/B heavy chain)], creating the chimaera AB. This purified protein bound the BoNT/B acceptor, displayed enhanced capability relative to type A for intraneuronally delivering its protease, cleaved SNAP-25 (synaptosome-associated protein of 25 kDa) and induced a more prolonged neuromuscular paralysis than BoNT/A in mice. The BA chimaera, generated by substituting H(C)/A (C-terminal half of BoNT/A heavy chain) into BoNT/B, exhibited an extremely high specific activity, delivered the BoNT/B protease via the BoNT/A acceptor into neurons, or fibroblast-like synoviocytes that lack SNAP-25, cleaving the requisite isoforms of VAMP (vesicle-associated membrane protein). Both chimaeras inhibited neurotransmission in murine bladder smooth muscle. BA has the unique ability to reduce exocytosis from non-neuronal cells expressing the BoNT/A-acceptor and utilising VAMP, but not SNAP-25, in exocytosis.
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Delnooz CCS, van de Warrenburg BPC. Current and future medical treatment in primary dystonia. Ther Adv Neurol Disord 2012; 5:221-40. [PMID: 22783371 PMCID: PMC3388529 DOI: 10.1177/1756285612447261] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Dystonia is a hyperkinetic movement disorder, characterized by involuntary and sustained contractions of opposing muscles causing twisting movements and abnormal postures. It is often a disabling disorder that has a significant impact on physical and psychosocial wellbeing. The medical therapeutic armamentarium used in practice is quite extensive, but for many of these interventions formal proof of efficacy is lacking. Exceptions are the use of botulinum toxin in patients with cervical dystonia, some forms of cranial dystonia (in particular, blepharospasm) and writer's cramp; deep brain stimulation of the pallidum in generalized and segmental dystonia; and high-dose trihexyphenidyl in young patients with segmental and generalized dystonia. In order to move this field forward, we not only need better trials that examine the effect of current treatment interventions, but also a further understanding of the pathophysiology of dystonia as a first step to design and test new therapies that are targeted at the underlying biologic and neurophysiologic mechanisms.
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Affiliation(s)
- Cathérine C S Delnooz
- Radboud University Nijmegen Medical Centre, Department of Neurology, Donders Institute for Brain, Cognition and Behaviour, Centre for Neuroscience, the Netherlands
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Zhao Y, Kang L, Gao S, Gao X, Xin W, Wang J. PEG precipitation coupled with chromatography is a new and sufficient method for the purification of botulinum neurotoxin type B [corrected]. PLoS One 2012; 7:e39670. [PMID: 22761863 PMCID: PMC3386254 DOI: 10.1371/journal.pone.0039670] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2011] [Accepted: 05/25/2012] [Indexed: 11/18/2022] Open
Abstract
Clostridium botulinum neurotoxins are used to treat a variety of neuro-muscular disorders, as well as in cosmetology. The increased demand requires efficient methods for the production and purification of these toxins. In this study, a new purification process was developed for purifying type B neurotoxin. The kinetics of C.botulinum strain growth and neurotoxin production were determined for maximum yield of toxin. The neurotoxin was purified by polyethylene glycol (PEG) precipitation and chromatography. Based on design of full factorial experiment, 20% (w/v) PEG-6000, 4 °C, pH 5.0 and 0.3 M NaCl were optimal conditions to obtain a high recovery rate of 87% for the type B neurotoxin complex, as indicated by a purification factor of 61.5 fold. Furthermore, residual bacterial cells, impurity proteins and some nucleic acids were removed by PEG precipitation. The following purification of neurotoxin was accomplished by two chromatography techniques using Sephacryl™ S-100 and phenyl HP columns. The neurotoxin was recovered with an overall yield of 21.5% and the purification factor increased to 216.7 fold. In addition, a mouse bioassay determined the purified neurotoxin complex possessed a specific toxicity (LD(50)) of 4.095 ng/kg.
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Affiliation(s)
- Yao Zhao
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Fengtai District, Beijing, People’s Republic of China
| | - Lin Kang
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Fengtai District, Beijing, People’s Republic of China
| | - Shan Gao
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Fengtai District, Beijing, People’s Republic of China
| | - Xing Gao
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Fengtai District, Beijing, People’s Republic of China
| | - Wenwen Xin
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Fengtai District, Beijing, People’s Republic of China
| | - Jinglin Wang
- State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Fengtai District, Beijing, People’s Republic of China
- * E-mail:
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Muscle selection for treatment of cervical dystonia with botulinum toxin--a systematic review. Parkinsonism Relat Disord 2012; 18:731-6. [PMID: 22575237 DOI: 10.1016/j.parkreldis.2012.04.005] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/30/2011] [Revised: 03/30/2012] [Accepted: 04/04/2012] [Indexed: 12/19/2022]
Abstract
RATIONALE Cervical dystonia, also called spasmodic torticollis, is the most common form of (primary) dystonia. Intramuscular injections with botulinum toxin are the first line of treatment for cervical dystonia. To optimise the treatment response to botulinum toxin correct muscles should be selected. Clinical evaluation is important for muscle selection but the value of additional tests to identify dystonic muscles remains unclear. OBJECTIVE To evaluate all relevant literature regarding the best approach to select dystonic muscles for treatment with botulinum toxin. METHODS We conducted a systematic review of studies that had investigated methods of selecting muscles for treatment with botulinum toxin. In addition, we compared all prospective botulinum toxin trials using either clinical evaluation or polymyographic electromyography for muscle selection. RESULTS Forty relevant studies were included and polymyographic electromyography recordings were most often employed. In several studies, polymyographic electromyography revealed a different pattern of muscle involvement compared to that found during clinical evaluation. In one randomized controlled trial polymyographic electromyography significantly improved the outcome of botulinum toxin treatment. A limited number of studies used positron emission tomography -computed tomography imaging or frequency analysis of the electromyography signal to identify dystonic muscles but their effect on the outcome of treatment has never been studied. CONCLUSION Polymyographic electromyography may improve the outcome of botulinum toxin treatment in cervical dystonia, but evidence is limited and larger studies are needed.
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Truong D. Botulinum toxins in the treatment of primary focal dystonias. J Neurol Sci 2012; 316:9-14. [PMID: 22336699 DOI: 10.1016/j.jns.2012.01.019] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2011] [Revised: 01/05/2012] [Accepted: 01/19/2012] [Indexed: 11/18/2022]
Abstract
Focal dystonia, such as cervical dystonia, blepharospasm, oromandibular dystonia, laryngeal dystonia, and limb dystonia, is often observed in adult-onset primary dystonia syndromes that affect a specific area of the body and tend to have little or no spread. This review will examine the past, present, and future approaches to the treatment of focal dystonia. Botulinum toxin (BoNT) has emerged as the treatment of choice for the majority of focal dystonias. Currently four products are widely available commercially, three of BoNT/A type and one of BoNT/B type. Each has important pharmacological differences that give rise to markedly different dosing recommendations. The four approved BoNTs are safe and effective for treating focal dystonias, including long-term treatment. Adverse events are limited and transient and, for the most part, mild in severity. Potential problems with the use of BoNT agents are diffusion and neutralizing antibody formation; the latter can lead to treatment resistance. Because each BoNT product is developed from distinct purification and manufacturing procedures and has varying toxin complex size and structures, physicians need to be aware of these differences when choosing an agent.
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Affiliation(s)
- Daniel Truong
- Parkinson's and Movement Disorder Institute, 9940 Talbert Avenue, Suite 204, Fountain Valley, CA 92708, USA.
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Jabbari B, Machado D. Treatment of refractory pain with botulinum toxins--an evidence-based review. PAIN MEDICINE 2011; 12:1594-606. [PMID: 21958302 DOI: 10.1111/j.1526-4637.2011.01245.x] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
OBJECTIVES To provide updated information on the role of botulinum toxins in the treatment of refractory pain based on prospective, randomized, double-blind, placebo-controlled studies. DESIGN OF THE REVIEW: Class I and class II articles were searched online through PubMed (1966 to the end of January 2011) and OvidSP including ahead-of-print manuscripts. RESULTS Level A evidence (two or more class I studies-established efficacy): pain of cervical dystonia, chronic migraine, and chronic lateral epicondylitis. Level B evidence (one class I or two class II studies-probably effective and recommended): post-herpetic neuralgia, post-traumatic neuralgia, pain of plantar fasciitis, piriformis syndrome, and pain in total knee arthroplasty. Level C evidence (one class II study-possibly effective, may be used at discretion of clinician): allodynia of diabetic neuropathy, chronic low back pain, painful knee osteoarthritis, anterior knee pain with vastus lateralis imbalance, pelvic pain, post-operative pain in children with cerebral palsy after adductor hip release surgery, post-operative pain after mastectomy, and sphincter spasms and pain after hemorrhoidectomy. Level U evidence (efficacy not proven due to diverse class I and II results): myofascial pain syndrome and chronic daily headaches. Studies in episodic migraine and tension headaches have shown treatment failure (level A-negative). CONCLUSION Evidence-based data indicate that administration of botulinum toxin in several human conditions can alleviate refractory pain. The problems with some study designs and toxin dosage are critically reviewed.
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Affiliation(s)
- Bahman Jabbari
- Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA.
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Jabeen A, Kandadai RM, Kannikannan MA, Borgohain R. Guidelines for the use of botulinum toxin in movement disorders and spasticity. Ann Indian Acad Neurol 2011; 14:S31-4. [PMID: 21847327 PMCID: PMC3152173 DOI: 10.4103/0972-2327.83099] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2010] [Indexed: 11/26/2022] Open
Affiliation(s)
- Afshan Jabeen
- Department of Neurology, NIMS, Punjagutta, Hyderabad, Andhra Pradesh, India
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Langevin P, Peloso PMJ, Lowcock J, Nolan M, Weber J, Gross A, Roberts J, Goldsmith CH, Graham N, Burnie SJ, Haines T. Botulinum toxin for subacute/chronic neck pain. Cochrane Database Syst Rev 2011:CD008626. [PMID: 21735434 DOI: 10.1002/14651858.cd008626.pub2] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Neck disorders are common, disabling and costly. Botulinum toxin (BoNT) intramuscular injections are often used with the intention of treating neck pain. OBJECTIVES To systematically evaluate the literature on the treatment effectiveness of BoNT for neck pain, disability, global perceived effect and quality of life in adults with neck pain with or without associated cervicogenic headache, but excluding cervical radiculopathy and whiplash associated disorder. SEARCH STRATEGY We searched CENTRAL, MEDLINE, AMED, Index to Chiropractic Literature, CINAHL, LILACS, and EMBASE from their origin to 20 September 2010. SELECTION CRITERIA We included randomised and quasi-randomised controlled trials in which BoNT injections were used to treat subacute or chronic neck pain. DATA COLLECTION AND ANALYSIS A minimum of two review authors independently selected articles, abstracted data, and assessed risk of bias, using the Cochrane Back Review Group criteria. In the absence of clinical heterogeneity, we calculated standardized mean differences (SMD) and relative risks, and performed meta-analyses using a random-effects model. The quality of the evidence and the strength of recommendations were assigned an overall grade for each outcome. MAIN RESULTS We included nine trials (503 participants). Only BoNT type A (BoNT-A) was used in these studies.High quality evidence suggests there was little or no difference in pain between BoNT-A and saline injections at four weeks (five trials; 252 participants; SMD pooled -0.07 (95% confidence intervals (CI) -0.36 to 0.21)) and six months for chronic neck pain. Very low quality evidence indicated little or no difference in pain between BoNT-A combined with physiotherapeutic exercise and analgesics and saline injection with physiotherapeutic exercise and analgesics for patients with chronic neck pain at four weeks (two trials; 95 participants; SMD pooled 0.09 (95% CI -0.55 to 0.73)) and six months (one trial; 24 participants; SMD -0.56 (95% CI -1.39 to 0.27)). Very low quality evidence from one trial (32 participants) showed little or no difference between BoNT-A and placebo at four weeks (SMD 0.16 (95% CI -0.53 to 0.86)) and six months (SMD 0.00 (95% CI -0.69 to 0.69)) for chronic cervicogenic headache. Very low quality evidence from one trial (31 participants), showed a difference in global perceived effect favouring BoNT-A in chronic neck pain at four weeks (SMD -1.12 (95% CI: -1.89 to -0.36)). AUTHORS' CONCLUSIONS Current evidence fails to confirm either a clinically important or a statistically significant benefit of BoNT-A injection for chronic neck pain associated with or without associated cervicogenic headache. Likewise, there was no benefit seen for disability and quality of life at four week and six months.
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Affiliation(s)
- Pierre Langevin
- Cliniques Physio Interactive, Département de réadaptation, Faculté de Médecine, Université Laval, 1100 boul Chaudière, CP 75217, Quebec City, PQ, Canada, G1Y 3C7
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Flu-like symptoms following botulinum toxin therapy. Toxicon 2011; 58:1-7. [DOI: 10.1016/j.toxicon.2011.04.019] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2011] [Revised: 04/24/2011] [Accepted: 04/27/2011] [Indexed: 01/12/2023]
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Chinnapongse R, Pappert EJ, Evatt M, Freeman A, Birmingham W. An open-label, sequential dose-escalation, safety, and tolerability study of rimabotulinumtoxinb in subjects with cervical dystonia. Int J Neurosci 2011; 120:703-10. [PMID: 20942584 DOI: 10.3109/00207454.2010.515047] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
OBJECTIVES Evaluate the safety and efficacy of a sequential dose escalation of rimabotulinumtoxinB (BoNT-B) in cervical dystonia (CD) subjects. METHODS This multicenter, open-label, within-subject, sequential dose-escalation study (BoNT-B dosed at 10,000, 12,500, and 15,000 Units) evaluated subjects over each phase of treatment at preinjection and at periodic intervals postinjection. Adverse events, vital signs, and laboratory results were recorded. Efficacy measures included the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and three visual analog scales (VASs). RESULTS 119 out of 145 CD subjects received all three doses in sequence. Dry mouth and dysphagia were the most common adverse events, and both decreased in frequency by the final injection, despite the increasing doses of the escalation. TWSTRS-Total and subscale scores demonstrated significant improvements following all doses at the week 2, 4, 8, and 12 assessments, with the exception of disability and pain at week 12 with the lowest dose. All VAS scores demonstrated similar improvements following all doses. The mean number of weeks in each phase of the study was 12.1 weeks (10,000 Units), 12.9 weeks (12,500 Units), and 13.9 weeks (15,000 Units). CONCLUSION BoNT-B was well tolerated and efficacious at 10,000, 12,500, and 15,000 Units in this within-subject, sequential dose-escalation study in CD subjects.
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