Botulinum Toxin: From Poison to Possible Treatment for Spasticity and Movement Disorder

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

Deadline for manuscript submissions: closed (31 October 2023) | Viewed by 26397

Special Issue Editors


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Guest Editor
Department of Biomedical Engineering, University of Houston, Houston, TX 77204, USA
Interests: neuroimaging; neuromodulation; neurorehabilitation; pelvic floor dysfunction assessment; computational modelling; EEG; EMG; fMRI; NIRS

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Guest Editor
Department of Physical Medicine and Rehabilitation, University of Texas Health Science Center – Houston, Houston, TX 77030, USA
Interests: spasticity; motor recovery; neuromodulation; neuropathic pain; neurorehabilitation

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Guest Editor
Faculty of Biomedical and Rehabilitation Engineering, University of Health and Rehabilitation Sciences, Qingdao 266071, China
Interests: biomedical signal processing; motor unit; EMG; neuromuscular electrophysiology; neurorehabilitation; myoelectric control

Special Issue Information

Dear Colleagues,

Botulinum Toxin (BoNT), produced by the bacterium clostridium botulinum, is a powerful inhibitor of pee-synaptic transmission of acetylcholine at the neuromuscular junctions (NMJ). Poisoning with BoNT can lead to a rare but serious systemic problem, i.e., botulism. Symptoms of botulism are weakness of muscles that control the limbs, trunk, throat, mouth, and eyes. Botulinum can weaken the muscles involved in breathing, leading to difficulty breathing, and even death. However, when a small dose of BoNT is precisely injected into a muscle, a locally confined and long-lasting neuromuscular block develops, leading to targeted muscle paralysis. As such, poisonous BoNT can be turned into therapeutic purposes. BoNT has a broad spectrum of clinical applications, including, but not limited to, management of limb spasticity, cervical dystonia, strabismus, bladder overactivity, chronic pelvic pain, and cosmetic applications.

Despite its proven potency and safety in the management of limb spasticity, BoNT injection can cause dosage-dependent adverse effects, and it has been clinically shown that injection of a minimum effective dose reduces the presence of adverse effects. BoNT treatment has also had problems with variable clinical effectiveness and high treatment cost.

This Special Issue of Toxins is focused on but not limited to novel and advanced NMJ-target injection technique development and application; advanced understanding of BoNT effects on the nervous system and neuromuscular system; and exploration of new therapeutic and nontherapeutic applications of BoNT.

Prof. Dr. Yingchun Zhang
Prof. Dr. Sheng Li
Prof. Dr. Ping Zhou
Guest Editors

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Keywords

  • Botulinum Toxin
  • neuromuscular junction
  • EMG
  • movement disorder
  • muscle spasticity
  • dystonia
  • muscle spasm
  • dermatology
  • pelvic floor muscle overactivity
  • overactive bladder

Published Papers (9 papers)

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Research

12 pages, 718 KiB  
Article
Effect of Botulinum Toxin on Masticatory Muscle Pain in Patients with Temporomandibular Disorders: A Randomized, Double-Blind, Placebo-Controlled Pilot Study
by So Ra Kim, Min Chang, Alec Hyung Kim and Seong Taek Kim
Toxins 2023, 15(10), 597; https://doi.org/10.3390/toxins15100597 - 4 Oct 2023
Cited by 5 | Viewed by 2132
Abstract
This study aimed to evaluate the efficacy of botulinum toxin type A (BoNT/A) in patients with temporomandibular disorders (TMDs) associated with masticatory muscle pain (MMP) and headaches. This randomized, double-blind, placebo-controlled pilot study is the first clinical trial to evaluate both disorders simultaneously. [...] Read more.
This study aimed to evaluate the efficacy of botulinum toxin type A (BoNT/A) in patients with temporomandibular disorders (TMDs) associated with masticatory muscle pain (MMP) and headaches. This randomized, double-blind, placebo-controlled pilot study is the first clinical trial to evaluate both disorders simultaneously. Twenty-one patients with myogenous TMD were randomly assigned to two groups. The experimental and control groups received injections of either BoNT/A or saline into the sites showing tenderness after palpation of a total of 16 muscle areas, including each masseter, a temporalis, splenius capitis, sternocleidomastoid, and trapezius muscle. During each visit, the clinical effects, based on the intensity of orofacial pain (OVAS), headache (HVAS), number of tender points (TPs), maximum mouth opening (MMO), and headache frequency (HF), were evaluated at four time points, namely, pre-injection and 4, 8, and 12 weeks after the injection, in both groups. Friedman and Mann–Whitney tests were used for the analyses. In the experimental group, the reductions in OVAS, TP, HVAS, and HF showed significant differences over time, excluding MMO, whereas there was no significant difference in any of the variables in the control group. In addition, the decline in TPs was significantly different between the experimental and control groups at all time points, especially after 4 and 12 weeks, compared to that during pre-injection. In conclusion, treatment with BoNT/A was relatively effective for masticatory muscle pain caused by TMDs and headache compared to the saline placebo. Full article
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18 pages, 2610 KiB  
Article
Treatment of Vestibulodynia with Submucosal Injections of IncobotulinumtoxinA into Targeted Painful Points: An Open-Label Exploratory Study
by Paula Villa-Muñoz, Monica Albaladejo-Belmonte, Francisco J. Nohales-Alfonso, Jose Alberola-Rubio and Javier Garcia-Casado
Toxins 2023, 15(8), 476; https://doi.org/10.3390/toxins15080476 - 25 Jul 2023
Viewed by 1278
Abstract
The studies carried out to date on vulvodynia treatment with botulinum neurotoxin type A (BoNT/A) have followed generic injection protocols and reported contradictory outcomes on its effects. The aim of the present study was thus to propose a protocol for injecting BoNT/A into [...] Read more.
The studies carried out to date on vulvodynia treatment with botulinum neurotoxin type A (BoNT/A) have followed generic injection protocols and reported contradictory outcomes on its effects. The aim of the present study was thus to propose a protocol for injecting BoNT/A into targeted painful points, to comprehensively assess the clinical effect of BoNT/A treatment and identify the risk/protective factors for successful treatment. Thirty-five vestibulodynia patients were treated with submucosal injections of incobotulinumtoxinA and assessed 8, 12 and 24 weeks after their treatment. Their clinical and pelvic statuses were assessed from self-reported questionnaires (Visual Analogue Scale (VAS), Female Sexual Function Index (FSFI), Marinoff’s Dyspareunia Scale (MDS), Hospital Anxiety and Depression Scale (HADS), Catastrophizing Scale (CS)), physical examinations and surface electromyography (sEMG). The patients reported a reduction in provoked vestibulodynia (<VAS, p < 0.01), improved sexual function (>FSFI, p < 0.01; <MDS, p = 0.01) and psychological status (<HADS, p < 0.01), and lower pelvic floor hyperactivity at rest (<sEMG amplitude, p = 0.01). Factors such as smoking, painful comorbidities, vulvar pain sensitivity and sexual function were significantly associated with successful treatment. The results indicate the beneficial effects of BoNT/A in treating vestibulodynia and reinforce the importance of adapting the treatment according to its clinical presentation and the patient’s medical background. Full article
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13 pages, 1303 KiB  
Article
Botulinum Toxin and Percutaneous Needle Electrolysis for the Treatment of Chronic Masticatory Myalgia
by Luis-Miguel Gonzalez-Perez, Ramon Vera-Martin, Enrique Montes-Latorre, Eusebio Torres-Carranza and Pedro Infante-Cossio
Toxins 2023, 15(4), 278; https://doi.org/10.3390/toxins15040278 - 10 Apr 2023
Cited by 4 | Viewed by 2167
Abstract
Botulinum toxin type A (BTA) is applied in muscle hyperactivity disorders and injected into affected muscles, producing deep and persistent muscle relaxation. Several multidisciplinary groups investigated the treatment of temporomandibular disorders for several years, and there is currently some data on the beneficial [...] Read more.
Botulinum toxin type A (BTA) is applied in muscle hyperactivity disorders and injected into affected muscles, producing deep and persistent muscle relaxation. Several multidisciplinary groups investigated the treatment of temporomandibular disorders for several years, and there is currently some data on the beneficial effects of BTA in specific cases of chronic masticatory myalgia. Percutaneous needle electrolysis (PNE), which applies a low-intensity galvanic current to promote tissue regeneration, has been shown to be effective in reducing pain and improving masticatory function. The purpose of this study was to investigate the efficacy and safety of BTA and to assess whether its application in patients with localized masticatory myalgia can significantly reduce pain and improve function compared to a group treated with PNE. Fifty-two patients with long-term refractory masticatory myalgia were randomly assigned to two groups. The BTA group (n = 26) received a bilateral botulinum toxin injection and the PNE group (n = 26) received percutaneous electrolysis. The dose of BTA injected was 100 units distributed among the main primary masticatory muscles, and PNE was administered at 0.5 mA/3 s/3 consecutive times in a single session. Patient assessments were performed prior to treatment and one, two, and three months after treatment. The results revealed good therapeutic response in both groups. In the long term, both BTA and PNE showed high efficacy and safety in reducing pain and improving muscle function for the treatment of chronic masticatory myalgia. This improvement was sustained over a three-month period in both groups. Therefore, the use of BTA and PNE could be considered a valid and safe therapeutic alternative among the available options to treat refractory and localized masticatory myalgia when a better therapeutic response is expected as it demonstrated high efficacy. Full article
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11 pages, 8689 KiB  
Article
Botulinum Neurotoxin Injections in Children with Self-Injurious Behaviors
by Mariam Hull, Mered Parnes and Joseph Jankovic
Toxins 2023, 15(4), 236; https://doi.org/10.3390/toxins15040236 - 23 Mar 2023
Cited by 1 | Viewed by 1664
Abstract
Self-injurious behaviors are repetitive, persistent actions directed toward one’s body that threaten or cause physical harm. These behaviors are seen within a broad spectrum of neurodevelopmental and neuropsychiatric conditions, often associated with intellectual disability. Injuries can be severe and distressing to patients and [...] Read more.
Self-injurious behaviors are repetitive, persistent actions directed toward one’s body that threaten or cause physical harm. These behaviors are seen within a broad spectrum of neurodevelopmental and neuropsychiatric conditions, often associated with intellectual disability. Injuries can be severe and distressing to patients and caregivers. Furthermore, injuries can be life-threatening. Often, these behaviors are challenging to treat and require a tiered, multimodal approach which may include mechanical/physical restraints, behavioral therapy, pharmacotherapy, or in some cases, surgical management, such as tooth extraction or deep brain stimulation. Here, we describe a series of 17 children who presented to our institution with self-injurious behaviors in whom botulinum neurotoxin injections were found helpful in preventing or lessening self-injury. Full article
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7 pages, 1700 KiB  
Communication
Stiff Knee Gait Disorders as Neuromechanical Consequences of Spastic Hemiplegia in Chronic Stroke
by Sheng Li
Toxins 2023, 15(3), 204; https://doi.org/10.3390/toxins15030204 - 7 Mar 2023
Cited by 2 | Viewed by 6896
Abstract
Stiff knee gait (SKG) is defined as decreased knee flexion during the swing phase. It is one of the most common gait disorders following stroke. Knee extensor spasticity is commonly accepted as the primary cause. Clinical management has focused on the reduction in [...] Read more.
Stiff knee gait (SKG) is defined as decreased knee flexion during the swing phase. It is one of the most common gait disorders following stroke. Knee extensor spasticity is commonly accepted as the primary cause. Clinical management has focused on the reduction in knee extensor spasticity. Recent advances in understanding of post-stroke hemiplegic gait suggest that SKG can present as mechanical consequences between muscle spasticity, weakness, and their interactions with ground reactions during walking. Various underlying mechanisms are presented through sample cases in this article. They include ankle plantar flexor spasticity, knee extensor spasticity, knee flexor and extensor coactivation, and hip flexor spasticity. Careful and thorough clinical assessment is advised to determine the primary cause for each patient. Understanding of these various presentations of SKG is helpful to guide clinical assessment and select appropriate target muscles for interventions. Full article
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14 pages, 1610 KiB  
Article
Canadian Physicians’ Use of Intramuscular Botulinum Toxin Injections for Shoulder Spasticity: A National Cross-Sectional Survey
by Farris Kassam, Brendan Lim, Sadia Afroz, Ève Boissonnault, Rajiv Reebye, Heather Finlayson and Paul Winston
Toxins 2023, 15(1), 58; https://doi.org/10.3390/toxins15010058 - 10 Jan 2023
Cited by 2 | Viewed by 4071
Abstract
Spasticity of the upper extremity can result in severe pain, along with many complications that can impair a patient’s activities of daily living. Failure to treat patients with spasticity of the upper limb can result in a decrease in the range of motion [...] Read more.
Spasticity of the upper extremity can result in severe pain, along with many complications that can impair a patient’s activities of daily living. Failure to treat patients with spasticity of the upper limb can result in a decrease in the range of motion of joints and contracture development, leading to further restriction in daily activities. We aimed to investigate the practice patterns of Canadian physicians who utilize Botulinum toxin type-A (BoNT-A) injections in the management of shoulder spasticity. 50 Canadian Physical Medicine and Rehabilitation (PM&R) physicians completed a survey with an estimated completion rate of (36.23%). The demographics of the survey participants came from a variety of provinces, clinical settings, and patient populations. The most common muscle injected for shoulder adduction and internal rotation spasticity was the pectoralis major, this was followed by latissimus dorsi, pectoralis minor, subscapularis and teres major. Injection of BoNT-A for problematic post-stroke shoulder spasticity was common, with (81.48%) of participants responding that it was always or often used in their management of post-stroke spasticity (PSS). Dosing of BoNT-A demonstrated variability for the muscle injected as well as the type of toxin used. The goals of the patients, caregivers, and practitioners were used to help guide the management of these patients. As a result, the practice patterns of Canadian physicians who treat shoulder spasticity are varied, due to numerous patient factors. Future studies are needed to analyze optimal treatment patterns, and the development of algorithms to standardize care. Full article
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11 pages, 2236 KiB  
Article
Early Detrusor Application of Botulinum Toxin A Results in Reduced Bladder Hypertrophy and Fibrosis after Spinal Cord Injury in a Rodent Model
by Juliana Y. Bushnell, Lindsay N. Cates, Jeffrey E. Hyde, Christoph P. Hofstetter, Claire C. Yang and Zin Z. Khaing
Toxins 2022, 14(11), 777; https://doi.org/10.3390/toxins14110777 - 10 Nov 2022
Cited by 6 | Viewed by 1994
Abstract
Following spinal cord injury (SCI), pathological reflexes develop that result in altered bladder function and sphincter dis-coordination, with accompanying changes in the detrusor. Bladder chemodenervation is known to ablate the pathological reflexes, but the resultant effects on the bladder tissue are poorly defined. [...] Read more.
Following spinal cord injury (SCI), pathological reflexes develop that result in altered bladder function and sphincter dis-coordination, with accompanying changes in the detrusor. Bladder chemodenervation is known to ablate the pathological reflexes, but the resultant effects on the bladder tissue are poorly defined. In a rodent model of contusion SCI, we examined the effect of early bladder chemodenervation with botulinum toxin A (BoNT-A) on bladder histopathology and collagen deposition. Adult female Long Evans rats were given a severe contusion SCI at spinal level T9. The SCI rats immediately underwent open laparotomy and received detrusor injections of either BoNT-A (10 U/animal) or saline. At eight weeks post injury, the bladders were collected, weighed, and examined histologically. BoNT-A injected bladders of SCI rats (SCI + BoNT-A) weighed significantly less than saline injected bladders of SCI rats (SCI + saline) (241 ± 25 mg vs. 183 ± 42 mg; p < 0.05). Histological analyses showed that SCI resulted in significantly thicker bladder walls due to detrusor hypertrophy and fibrosis compared to bladders from uninjured animals (339 ± 89.0 μm vs. 193 ± 47.9 μm; p < 0.0001). SCI + BoNT-A animals had significantly thinner bladder walls compared to SCI + saline animals (202 ± 55.4 μm vs. 339 ± 89.0 μm; p < 0.0001). SCI + BoNT-A animals had collagen organization in the bladder walls similar to that of uninjured animals. Detrusor chemodenervation soon after SCI appears to preserve bladder tissue integrity by reducing the development of detrusor fibrosis and hypertrophy associated with SCI. Full article
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8 pages, 466 KiB  
Article
Persistence with Botulinum Toxin Treatment for Spasticity Symptoms in Multiple Sclerosis
by Federica Novarella, Antonio Carotenuto, Paolo Cipullo, Rosa Iodice, Emanuele Cassano, Antonio Luca Spiezia, Nicola Capasso, Maria Petracca, Fabrizia Falco, Carmine Iacovazzo, Giuseppe Servillo, Roberta Lanzillo, Vincenzo Brescia Morra and Marcello Moccia
Toxins 2022, 14(11), 774; https://doi.org/10.3390/toxins14110774 - 9 Nov 2022
Cited by 4 | Viewed by 2116
Abstract
Botulinum toxin (BT) is an effective treatment for spasticity symptoms in multiple sclerosis (MS). Despite its wide use in clinical practices, only few studies have explored long-term persistence. We aim to evaluate the rate of discontinuation of BT treatment and the correlation with [...] Read more.
Botulinum toxin (BT) is an effective treatment for spasticity symptoms in multiple sclerosis (MS). Despite its wide use in clinical practices, only few studies have explored long-term persistence. We aim to evaluate the rate of discontinuation of BT treatment and the correlation with MS, spasticity, and injection variables. This retrospective study on 3-year prospectively collected data included 122 MS patients receiving BT injections for spasticity. We collected MS clinical variables (disease durations, Expanded Disability Status Scales [EDSSs], disease-modifying treatments [DMT], and Symbol Digit Modalities Tests [SDMTs]), modified Ashworth scales [MASs], concomitant treatments, and injection variables (formulation, dose, number of injections, and intervals between injections). A total of 14 out of the 122 patients discontinued BT after a mean time of 3.0 ± 1.5 years. In the Cox regression model including the MS clinical variables, the probability of BT discontinuations increased in patients with DMT changes during follow-ups (HR = 6.34; 95%Cl = 2.47, 18.08; p < 0.01) and with impaired SDMTs (HR = 1.20; 95%Cl = 1.04, 1.96; p < 0.01). In the model including the spasticity variables, there were no associations between BT discontinuation and MAS or other spasticity treatments. In the model including the injection variables, the probability of discontinuation decreased by 80% for each cumulative injection (HR = 0.16; 95%Cl = 0.05, 0.45; p < 0.01), but increased by 1% for each additional day over the 3-month interval between injections (HR = 1.27; 95%Cl = 1.07, 1.83; p < 0.01). BT discontinuation was associated with concomitant MS-related issues (e.g., treatment failure and DMT change) and the presence of cognitive impairment, which should be accounted for when planning injections. The interval between injections should be kept as short as possible from regulatory and clinical perspectives to maximize the response across all of the spasticity symptoms and to reduce discontinuation in the long term. Full article
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4 pages, 235 KiB  
Communication
High Doses of Botulinum Toxin Type A for the Treatment of Post-Stroke Spasticity: Rationale for a Real Benefit for the Patients
by Andrea Santamato
Toxins 2022, 14(5), 332; https://doi.org/10.3390/toxins14050332 - 6 May 2022
Cited by 2 | Viewed by 2399
Abstract
In the past few years, there was a great interest in the use of higher doses of botulinum toxin type A, especially in case of upper and lower limb severe spasticity. To date, only one prospective, non-randomized, single-arm, multicenter, open-label, dose-titration study with [...] Read more.
In the past few years, there was a great interest in the use of higher doses of botulinum toxin type A, especially in case of upper and lower limb severe spasticity. To date, only one prospective, non-randomized, single-arm, multicenter, open-label, dose-titration study with the employment of incobotulinum toxin up to 800 U has been published, and the authors investigated safety and tolerability. Other researches showed efficacy in spasticity reduction, but there is a lack of evidence about the reasons to use high doses of botulinum toxin. This short communication highlights the benefits of higher doses for subjects with upper and lower limb spasticity. Full article
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