Botulinum Toxin for the Treatment of Neurological Disorders—Where We Are and Where We Need to Go

A special issue of Toxins (ISSN 2072-6651). This special issue belongs to the section "Bacterial Toxins".

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 63619

Special Issue Editors

1. Department of Clinical Neurological Sciences, London Health Sciences Centre—Lawson Health Research Institute, 339 Windermere Road, A10-026, London, ON N6A 5A5, Canada
2. Schulich School of Medicine and Dentistry, University of Western, 1151 Richmond Street, London, ON N6A 3K7, Canada
Interests: botulinum toxins; movement disorders; smart technologies; computational neuroscience; motor control and machine learning
Movement Disorders Center, Toronto Western Hospital, University of Toronto, Toronto, ON M5T 2S8, Canada
Interests: botulinum toxins; phenomenology; neurophysiology and treatment of Parkinson’s disease; tremor and dystonia; infusion pumps and deep brain stimulation for Parkinson's disease; gait disorders

Special Issue Information

Dear Colleagues,

Over the past 30 years, botulinum toxin has seen an ever-expanding use in disorders afflicting the nervous system. Aside from the classical use of toxins for dystonia, its use for conditions such as spasticity and headache has reached the mainstream. In addition, technologies such as electromyography, ultrasound, and kinematics are reaching maturity for use in enhancing clinical assessment and injection. Finally, and equally importantly, newer toxins are potentially ready to reach market over the next decade. Given these advances and this growth, the goal of this Special Issue is to collect a number of articles that address the main theme of where we are (e.g., basic concepts, review articles of the current toxins, current indications) to where we are going (e.g., technologies, new indications, new research data, and new toxins).

Prof. Dr. Mandar Jog
Prof. Dr. Alfonso Fasano
Guest Editors

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Keywords

  • botulinum toxins
  • movement disorders
  • unmet clinical needs
  • objective measurement
  • new indications

Published Papers (12 papers)

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Editorial

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3 pages, 204 KiB  
Editorial
Editorial on the Special Issue “Botulinum Toxin for the Treatment of Neurological Disorders: Where We Are and Where We Need to Go”
by Mandar Jog and Alfonso Fasano
Toxins 2022, 14(1), 41; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins14010041 - 05 Jan 2022
Viewed by 1316
Abstract
Over the past 30 years, botulinum toxin (BoNT) has seen an ever-expanding use in disorders afflicting the nervous system [...] Full article

Research

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9 pages, 592 KiB  
Article
Factors Influencing the Surgical Decision in Dystonia Patients Referred for Deep Brain Stimulation
by Carolina Gorodetsky, Paula Azevedo, Carolina Candeias da Silva and Alfonso Fasano
Toxins 2021, 13(8), 511; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13080511 - 22 Jul 2021
Cited by 1 | Viewed by 3229
Abstract
There is no available data on the journey of dystonia patients once referred to a tertiary center to undergo deep brain stimulation (DBS). We hypothesized that some patients might be incorrectly diagnosed while others might decline the procedure or experience significant benefit with [...] Read more.
There is no available data on the journey of dystonia patients once referred to a tertiary center to undergo deep brain stimulation (DBS). We hypothesized that some patients might be incorrectly diagnosed while others might decline the procedure or experience significant benefit with switching to a different botulinum neurotoxin (BoNT). This is a single-center, retrospective study of dystonia patients who were referred to the DBS program between January 2014 and December 2018. We collected data on the surgical decision as well as factors influencing this decision. Sixty-seven patients were included (30 males, mean age: 48.3 ± 20.1 years, disease duration: 16.9 ± 15.3 years). Thirty-three (49%) patients underwent DBS. Four (6%) patients were awaiting the procedure while the remaining 30 patients (45%) did not undergo DBS. Reasons for DBS decline were patient refusal (17, 53%), functional dystonia (6, 20%), and successful use of AbobotulinumtoxinA (3, 10%) in patients who had failed other BoNTs. Our study highlights the importance of structured patient education to increase acceptance of DBS, as well as careful patient evaluation, particularly with respect to functional dystonia. Finally, changing BoNT formulation might be beneficial in some patients. Full article
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13 pages, 1222 KiB  
Article
Continuous Increase of Efficacy under Repetitive Injections of Botulinum Toxin Type/A beyond the First Treatment for Adult Spastic Foot Drop
by Harald Hefter, Werner Nickels, Dietmar Rosenthal, Sara Samadzadeh and Philipp Albrecht
Toxins 2021, 13(7), 466; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13070466 - 02 Jul 2021
Cited by 3 | Viewed by 2669
Abstract
The objective of this study was to quantify the increase in efficacy during the first four cycles of treatment with botulinum toxin type/A (BoNT/A) in 24 free-walking BoNT/A naïve adult patients with post-stroke hemispasticity and spastic foot drop. Patients were followed over 390 [...] Read more.
The objective of this study was to quantify the increase in efficacy during the first four cycles of treatment with botulinum toxin type/A (BoNT/A) in 24 free-walking BoNT/A naïve adult patients with post-stroke hemispasticity and spastic foot drop. Patients were followed over 390 days and received five injections of 800 U aboBoNT/A every three months. Patients assessed the treatment effect at eight visits using a global assessment scale, physicians scored the muscle tone at the ankle joint, measured active and passive ranges of motion (aRoMs, pRoMs) at the knee and ankle joint and determined the distance patients succeeded to walk during a minute. Patients’ assessments significantly (p < 0.006) increased with time and significantly correlated with all parameters measured. The best correlation (r = 0.927; p < 0.0001) was found with the sum of the aRoMs of knee and ankle joint. After one year of treatment outcome measures were better than and significantly correlated with the peak effect of the first injection. This correlation was higher for pRoMs (r = 0.855; p < 0.00001) compared to aRoMs (r = 0.567; p < 0.009). When BoNT/A treatment of the spastic foot in chronic hemispasticity is performed regularly every three months for at least one year, patients will experience a significant increase of benefit beyond the first treatment, but have to learn how to adapt to and use the new degree of freedom induced by the injections. Full article
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10 pages, 913 KiB  
Article
Developing a Consistent, Reproducible Botulinum Toxin Type A Dosing Method for Upper Limb Tremor by Kinematic Analysis
by Olivia Samotus, Jack Lee and Mandar Jog
Toxins 2021, 13(4), 264; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13040264 - 08 Apr 2021
Cited by 5 | Viewed by 1921
Abstract
Botulinum toxin type A (BoNT-A) injection patterns customized to each patient’s unique tremor characteristics produce better efficacy and lower adverse effects compared to the fixed-muscle-fixed-dose approach for Essential Tremor (ET) and Parkinson’s disease (PD) tremor therapy. This article outlined how a kinematic-based dosing [...] Read more.
Botulinum toxin type A (BoNT-A) injection patterns customized to each patient’s unique tremor characteristics produce better efficacy and lower adverse effects compared to the fixed-muscle-fixed-dose approach for Essential Tremor (ET) and Parkinson’s disease (PD) tremor therapy. This article outlined how a kinematic-based dosing method to standardize and customize BoNT-A injections for tremors was developed. Seven ET and eight PD participants with significant tremor reduction and minimal perceived weakness using optimized BoNT-A injections determined by clinical and kinematic guidance were retrospectively selected to develop the kinematic-based dosing method. BoNT-A dosages allocated per joint were paired to baseline tremor amplitudes per joint. The final kinematic-based dosing method was prospectively utilized to validate BoNT-A injection pattern selection without clinical/visual assessments in 31 ET and 47 PD participants with debilitating arm tremors (totaling 122 unique tremor patterns). Whole-arm kinematic tremor analysis was performed at baseline and 6-weeks post-injection. Correlation and linear regression analyses between baseline tremor amplitudes and the change in tremor amplitude 6-weeks post-injection, with BoNT-A dosages per joint, were performed. Injection patterns determined using clinical assessment and interpretation of kinematics produced significant associations between baseline tremor amplitudes and optimized BoNT-A dosages in all joints. The change in elbow tremor was only significantly associated with the elbow total dose as the change in the wrist and shoulder tremor amplitudes were not significantly associated with the wrist and shoulder dosages from the selected 15 ET and PD participants. Using the kinematic-based dosing method, significant associations between baseline tremor amplitudes and the change (6-weeks post-first treatment) in tremor at each joint with BoNT-A dosages for all joints was observed in all 78 ET and PD participants. The kinematic-based dosing method provided consistency in dose selection and subsequent tremor reduction and can be used to standardize tremor assessments for whole-arm tremor treatment planning. Full article
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15 pages, 2357 KiB  
Article
Tolerability and Efficacy of Customized IncobotulinumtoxinA Injections for Essential Tremor: A Randomized, Double-Blind, Placebo-Controlled Study
by Mandar Jog, Jack Lee, Astrid Scheschonka, Robert Chen, Farooq Ismail, Chris Boulias, Douglas Hobson, David King, Michael Althaus, Olivier Simon, Hanna Dersch, Steven Frucht and David M. Simpson
Toxins 2020, 12(12), 807; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12120807 - 20 Dec 2020
Cited by 8 | Viewed by 2368
Abstract
In this first, double-blind, randomized, placebo-controlled exploratory trial, we evaluate the efficacy and safety of incobotulinumtoxinA and feasibility of using kinematic tremor assessment to aid in the planning of muscle selection in a multicenter setting. Reproducibility of the planning technology to other clinical [...] Read more.
In this first, double-blind, randomized, placebo-controlled exploratory trial, we evaluate the efficacy and safety of incobotulinumtoxinA and feasibility of using kinematic tremor assessment to aid in the planning of muscle selection in a multicenter setting. Reproducibility of the planning technology to other clinical sites was explored. In this trial (NCT02207946), patients with upper-limb essential tremor (ET) were randomized 2:1 to a single treatment cycle of incobotulinumtoxinA or placebo. A tremor kinematic analytics investigational device was used to define a customized muscle set for injection, related to the pattern of the wrist, forearm, elbow, and shoulder tremor for each patient, and the incobotulinumtoxinA dose per muscle (total ≤ 200 U). Fahn–Tolosa–Marin (FTM) Part B motor performance score, Global Impression of Change Scale (GICS), and kinematic analysis-based efficacy evaluations were assessed. Thirty patients were randomized (incobotulinumtoxinA, n = 19; placebo, n = 11). FTM motor performance scores showed greater improvement with incobotulinumtoxinA versus placebo at Week 4 (p= 0.003) and Week 8 (p= 0.031). The physician-rated GICS score indicated improvement with incobotulinumtoxinA versus placebo at Week 4 (p < 0.05). IncobotulinumtoxinA also decreased accelerometric hand-tremor amplitude versus placebo from baseline to Week 4 (p= 0.004) and Week 8 (p < 0.001), with persistent tremor reduction up to 24 weeks post-injection. IncobotulinumtoxinA produced a slight and transient reduction of maximal grip strength versus placebo; two patients reported localized finger muscle weakness. Customized incobotulinumtoxinA injections decreased tremor severity and improved hand motor function in patients with upper-limb ET after a single injection cycle, with a favorable tolerability profile. The study showed that tremor kinematic analytics technology could be successfully scaled for use in other clinical sites. Full article
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12 pages, 478 KiB  
Article
Iron Deposits in Periaqueductal Gray Matter Are Associated with Poor Response to OnabotulinumtoxinA in Chronic Migraine
by Clara Domínguez Vivero, Yago Leira, Marta Saavedra Piñeiro, Xiana Rodríguez-Osorio, Pedro Ramos-Cabrer, Carmen Villalba Martín, Tomás Sobrino, Francisco Campos, José Castillo and Rogelio Leira
Toxins 2020, 12(8), 479; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12080479 - 28 Jul 2020
Cited by 12 | Viewed by 2788
Abstract
Previous studies have reported increased brain deposits of iron in patients with chronic migraine (CM). This study aims to determine the relation between iron deposits and outcome after treatment with OnabotulinumtoxinA (OnabotA). Demographic and clinical data were collected for this study through a [...] Read more.
Previous studies have reported increased brain deposits of iron in patients with chronic migraine (CM). This study aims to determine the relation between iron deposits and outcome after treatment with OnabotulinumtoxinA (OnabotA). Demographic and clinical data were collected for this study through a prospective cohort study including 62 CM patients treated with OnabotA in the Hospital Clínico Universitario de Santiago de Compostela (Spain). Demographic and clinical variables were registered. Selected biomarkers in plasma during interictal periods (calcitonin gene-related peptide (CGRP) and pentraxin-3 (PTX3)) and neuroimaging changes (iron deposits in the red nucleus (RN), substantia nigra (SN), globus pallidus (GP), and periaqueductal gray matter (PAG), and white matter lesions (WML)) were determined. Subjects were classified in responders (≥50% reduction in headache days) or non-responders (<50%). Responders to treatment were younger (mean age difference = 12.2; 95% confidence interval (CI): 5.4–18.9, p = 0.001), showed higher serum levels of CGRP (≥50 ng/mL) and PTX3 (≥1000 pg/mL) and smaller iron deposits in the GP and PAG (mean difference = 805.0; 95% CI: 37.9–1572.1 μL, p = 0.040 and mean difference = 69.8; 95% CI: 31.0–108.6 μL, p = 0.008; respectively). Differences in PAG iron deposits remained significant after adjusting for age (mean difference = 65.7; 95% CI: 22.8–108.6 μL, p = 0.003) and were associated with poor response to OnabotA after adjustment for clinical and biochemical variables (odds ratio (OR) = 0.963; 95% CI: 0.927–0.997, p = 0.041). We conclude that larger PAG iron deposits are associated with poor response to OnabotA in CM. Full article
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Review

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15 pages, 5035 KiB  
Review
The Role of Ultrasound for the Personalized Botulinum Toxin Treatment of Cervical Dystonia
by Urban M. Fietzek, Devavrat Nene, Axel Schramm, Silke Appel-Cresswell, Zuzana Košutzká, Uwe Walter, Jörg Wissel, Steffen Berweck, Sylvain Chouinard and Tobias Bäumer
Toxins 2021, 13(5), 365; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13050365 - 20 May 2021
Cited by 10 | Viewed by 4816
Abstract
The visualization of the human body has frequently been groundbreaking in medicine. In the last few years, the use of ultrasound (US) imaging has become a well-established procedure for botulinum toxin therapy in people with cervical dystonia (CD). It is now undisputed among [...] Read more.
The visualization of the human body has frequently been groundbreaking in medicine. In the last few years, the use of ultrasound (US) imaging has become a well-established procedure for botulinum toxin therapy in people with cervical dystonia (CD). It is now undisputed among experts that some of the most relevant muscles in this indication can be safely injected under visual US guidance. This review will explore the method from basic technical considerations, current evidence to conceptual developments of the phenomenology of cervical dystonia. We will review the implications of introducing US to our understanding of muscle function and anatomy of common cervical dystonic patterns. We suggest a flow chart for the use of US to achieve a personalized treatment of people with CD. Thus, we hope to contribute a resource that is useful in clinical practice and that stimulates the ongoing development of this valuable technique. Full article
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20 pages, 1068 KiB  
Review
Muscle Tone Physiology and Abnormalities
by Jacky Ganguly, Dinkar Kulshreshtha, Mohammed Almotiri and Mandar Jog
Toxins 2021, 13(4), 282; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13040282 - 16 Apr 2021
Cited by 41 | Viewed by 12607
Abstract
The simple definition of tone as the resistance to passive stretch is physiologically a complex interlaced network encompassing neural circuits in the brain, spinal cord, and muscle spindle. Disorders of muscle tone can arise from dysfunction in these pathways and manifest as hypertonia [...] Read more.
The simple definition of tone as the resistance to passive stretch is physiologically a complex interlaced network encompassing neural circuits in the brain, spinal cord, and muscle spindle. Disorders of muscle tone can arise from dysfunction in these pathways and manifest as hypertonia or hypotonia. The loss of supraspinal control mechanisms gives rise to hypertonia, resulting in spasticity or rigidity. On the other hand, dystonia and paratonia also manifest as abnormalities of muscle tone, but arise more due to the network dysfunction between the basal ganglia and the thalamo-cerebello-cortical connections. In this review, we have discussed the normal homeostatic mechanisms maintaining tone and the pathophysiology of spasticity and rigidity with its anatomical correlates. Thereafter, we have also highlighted the phenomenon of network dysfunction, cortical disinhibition, and neuroplastic alterations giving rise to dystonia and paratonia. Full article
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15 pages, 1521 KiB  
Review
Botulinum Toxin: An Update on Pharmacology and Newer Products in Development
by Supriyo Choudhury, Mark R. Baker, Suparna Chatterjee and Hrishikesh Kumar
Toxins 2021, 13(1), 58; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins13010058 - 14 Jan 2021
Cited by 50 | Viewed by 15526
Abstract
Since its introduction as a treatment for strabismus, botulinum toxin (BoNT) has had a phenomenal journey and is now recommended as first-line treatment for focal dystonia, despite short-term clinical benefits and the risks of adverse effects. To cater for the high demand across [...] Read more.
Since its introduction as a treatment for strabismus, botulinum toxin (BoNT) has had a phenomenal journey and is now recommended as first-line treatment for focal dystonia, despite short-term clinical benefits and the risks of adverse effects. To cater for the high demand across various medical specialties, at least six US Food and Drug Administration (FDA)-approved formulations of BoNT are currently available for diverse labelled indications. The toxo-pharmacological properties of these formulations are not uniform and thus should not be used interchangeably. Synthetic BoNTs and BoNTs from non-clostridial sources are not far from clinical use. Moreover, the study of mutations in naturally occurring toxins has led to modulation in the toxo-pharmacokinetic properties of BoNTs, including the duration and potency. We present an overview of the toxo-pharmacology of conventional and novel BoNT preparations, including those awaiting imminent translation from the laboratory to the clinic. Full article
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11 pages, 287 KiB  
Review
Botulinum Toxin in the Treatment of Headache
by Werner J. Becker
Toxins 2020, 12(12), 803; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12120803 - 17 Dec 2020
Cited by 25 | Viewed by 6715
Abstract
Botulinum toxin type A has been used in the treatment of chronic migraine for over a decade and has become established as a well-tolerated option for the preventive therapy of chronic migraine. Ongoing research is gradually shedding light on its mechanism of action [...] Read more.
Botulinum toxin type A has been used in the treatment of chronic migraine for over a decade and has become established as a well-tolerated option for the preventive therapy of chronic migraine. Ongoing research is gradually shedding light on its mechanism of action in migraine prevention. Given that its mechanism of action is quite different from that of the new monoclonal antibodies directed against calcitonin gene-related peptide (CGRP) or its receptor, it is unlikely to be displaced to any major extent by them. Both will likely remain as important tools for patients with chronic migraine and the clinicians assisting them. New types of botulinum toxin selective for sensory pain neurons may well be discovered or produced by recombinant DNA techniques in the coming decade, and this may greatly enhance its therapeutic usefulness. This review summarizes the evolution of botulinum toxin use in headache management over the past several decades and its role in the preventive treatment of chronic migraine and other headache disorders. Full article
9 pages, 530 KiB  
Review
Sialorrhea in Parkinson’s Disease
by Jonathan Isaacson, Sanskruti Patel, Yasar Torres-Yaghi and Fernando Pagán
Toxins 2020, 12(11), 691; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12110691 - 31 Oct 2020
Cited by 22 | Viewed by 4903
Abstract
Sialorrhea, or excessive saliva beyond the margin of the lip, is a common problem in many neurological diseases. Previously, sialorrhea has been underrecognized in Parkinson’s disease (PD) patients. Despite this, many patients rank sialorrhea as one of the most debilitating complaints of Parkinson’s [...] Read more.
Sialorrhea, or excessive saliva beyond the margin of the lip, is a common problem in many neurological diseases. Previously, sialorrhea has been underrecognized in Parkinson’s disease (PD) patients. Despite this, many patients rank sialorrhea as one of the most debilitating complaints of Parkinson’s disease. Previous treatment for sialorrhea has been suboptimal and has been plagued by significant side effects that are bothersome and can be dangerous in patients with a concurrent neurodegenerative disease. This review sought to review the anatomy, function, and etiology of sialorrhea in PD. It then sought to examine the evidence for the different treatments of sialorrhea in PD, and further examined newer evidence for safety and efficacy in minimally invasive treatment such as botulinum toxin. Full article
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27 pages, 623 KiB  
Review
Use of AbobotulinumtoxinA in Adults with Cervical Dystonia: A Systematic Literature Review
by Alfonso Fasano, Vijayashankar Paramanandam and Mandar Jog
Toxins 2020, 12(8), 470; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12080470 - 24 Jul 2020
Cited by 8 | Viewed by 2614
Abstract
Cervical dystonia (CD) is a neurological movement disorder characterized by sustained involuntary muscle contractions. First-line therapy for CD is intramuscular injections of botulinum neurotoxin (e.g., abobotulinumtoxinA) into the affected muscles. The objective of this systematic literature review is to assess the clinical evidence [...] Read more.
Cervical dystonia (CD) is a neurological movement disorder characterized by sustained involuntary muscle contractions. First-line therapy for CD is intramuscular injections of botulinum neurotoxin (e.g., abobotulinumtoxinA) into the affected muscles. The objective of this systematic literature review is to assess the clinical evidence regarding the effects of abobotulinumtoxinA for treatment of CD in studies of safety, efficacy, patient-reported outcomes, and economic outcomes. Using comprehensive electronic medical literature databases, a search strategy was developed using a combination of Medical Subject Heading terms and keywords. Results were reviewed by two independent reviewers who rated the level of evidence. The search yielded 263 publications, of which 232 were excluded for being duplicate publications, not meeting the selection criteria, or failing to meet predefined eligibility criteria, leaving a total of 31 articles. Clinical efficacy, patient-reported outcomes, and safety data were in 6 placebo-controlled trials (8 articles), 6 active-controlled trials, and 16 observational studies (17 articles). Data on health economic outcomes were provided in one of the clinical trials, in two of the observational studies, and in one specific cost-analysis publication. This review demonstrated that the routine use of abobotulinumtoxinA in CD is well-established, effective, and generally well-tolerated, with a relatively low cost of treatment. Full article
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