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Special Issue "Botulinum Toxin Treatment of Movement Disorders"

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

Deadline for manuscript submissions: closed (31 December 2018)

Special Issue Editor

Guest Editor
Prof. Dr. Markus Naumann

Department of Neurology and Clinical Neurophysiology, Academic Hospital, Klinikum Augsburg, Augsburg 86156, Germany
Website | E-Mail
Interests: movement disorders; botulinum toxin; autonomic disorders; neurophysiology; neuroimaging

Special Issue Information

Dear Colleagues,

Botulinum toxin has been approved for many disorders, including movement disorders, autonomic disorders (i.e., secretory, bladder), pain, and ophthalmologic uses. Among movement disorders, it has revolutionized the treatment of focal spasticity of upper and lower limbs, focal dystonias, and some other rare conditions. In spasticity and dystonia, the mode of action of botulinum toxin is complex, and is not only based on a blockage of acetylcholine release at the neuromuscular junction, leading to muscle weakness. Due to its effect on muscle spindles, it exerts an additional effect on different pathways to the central nervous system, thereby markedly contributing to beneficial clinical effects. There is increasing evidence that treatment outcomes can be optimized using guided injection techniques.

The focus of this Special Issue of Toxins will be on botulinum toxin treatment of movement disorders, in all its aspects: Treatment outcomes in focal spasticity, dystonias, tremors, and other movement disorders; effects of different serotypes; dosing and side effects; antigenicity; evidence-based medicine; guided injection techniques (ultrasound, EMG, stimulation, imaging); sensorimotor aspects of mode of action; and others.

Prof. Dr. Markus Naumann
Guest Editor

Manuscript Submission Information

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Keywords

  • botulinum toxin
  • spasticity
  • dystonia
  • mode of action
  • guidance
  • outcome

Published Papers (11 papers)

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Research

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Open AccessArticle Botulinum Neurotoxin Therapy for Lingual Dystonia Using an Individualized Injection Method Based on Clinical Features
Received: 14 December 2018 / Revised: 11 January 2019 / Accepted: 15 January 2019 / Published: 17 January 2019
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Abstract
Lingual dystonia is a debilitating type of oromandibular dystonia characterized by involuntary, often task-specific, contractions of the tongue muscle activated by speaking or eating. Botulinum neurotoxin (BoNT) has been used to treat lingual dystonia; however, it is known to cause serious complications, such [...] Read more.
Lingual dystonia is a debilitating type of oromandibular dystonia characterized by involuntary, often task-specific, contractions of the tongue muscle activated by speaking or eating. Botulinum neurotoxin (BoNT) has been used to treat lingual dystonia; however, it is known to cause serious complications, such as dysphasia and aspiration. The purpose of this study was to evaluate the efficacy and adverse effects of individualized BoNT therapy for lingual dystonia. One-hundred-and-seventy-two patients (102 females and 70 males, mean age: 46.2 years) with lingual dystonia were classified into four subtypes based on symptoms of involuntary tongue movements: protrusion (68.6%), retraction (16.9%), curling (7.6%), and laterotrusion (7.0%). Patients were treated with BoNT injection into the genioglossus and/or intrinsic muscles via individualized submandibular and/or intraoral routes. Results were compared before and after BoNT therapy. Botulinum neurotoxin was injected in 136 patients (mean: 4.8 injections). Clinical sub-scores (mastication, speech, pain, and discomfort) in a disease-specific rating scale were reduced significantly (p < 0.001) after administration. Comprehensive improvement after BoNT injection, assessed using the rating scale, was 77.6%. The curling type (81.9%) showed the greatest improvement, while the retraction type showed the least improvement (67.9%). Mild and transient dysphasia occurred in 12.5% of patients (3.7% of total injections) but disappeared spontaneously within several days to two weeks. No serious side effects were observed. With careful diagnosis of subtypes and a detailed understanding of lingual muscle anatomy, individualized BoNT injection into dystonic lingual muscles can be effective and safe. Full article
(This article belongs to the Special Issue Botulinum Toxin Treatment of Movement Disorders)
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Open AccessArticle Effects of Ultrasound-Guided Administration of Botulinum Toxin (IncobotulinumtoxinA) in Patients with Lateral Epicondylitis
Received: 3 October 2018 / Revised: 7 January 2019 / Accepted: 11 January 2019 / Published: 15 January 2019
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Abstract
How effective and safe are incobotulinumtoxinA injections in adult patients with lateral epicondylitis refractory to other treatments? In this experimental study, ultrasound-guided incobotulinumtoxinA 10–30 U/muscle was injected into extensor carpi ulnaris, extensor digiti minimi, extensor digitorum longus and extensor carpi radialis brevis muscles. [...] Read more.
How effective and safe are incobotulinumtoxinA injections in adult patients with lateral epicondylitis refractory to other treatments? In this experimental study, ultrasound-guided incobotulinumtoxinA 10–30 U/muscle was injected into extensor carpi ulnaris, extensor digiti minimi, extensor digitorum longus and extensor carpi radialis brevis muscles. Pain (visual analogue scale [VAS], 0 to 10 [no pain to severe pain]) and upper-limb functionality (QuickDASH scale, 0 to 100 [best to worst]), assessed at baseline, 1, 3 and 6 months post-treatment, were analysed using repeated-measures analysis of variance (ANOVA) and Tukey post-hoc tests. Secondary analyses stratifying patient population by sex and baseline VAS were performed. Adverse events were reported. Twenty-four patients (mean [standard deviation] age 46.8 years) were included. Compared with baseline, mean VAS and QuickDASH scores improved at all follow-ups (p < 0.001 and p = 0.001, respectively; repeated-measures ANOVA). Secondary analyses revealed significant differences between baseline and all follow-ups in the group with baseline VAS ≥ 6 and in males and females (all p < 0.05, Tukey post-hoc test). No adverse events, except for the expected third finger weakness, were reported. In conclusion, ultrasound-guided incobotulinumtoxinA injections may be an effective treatment for lateral epicondylitis in the appropriate patient population. Full article
(This article belongs to the Special Issue Botulinum Toxin Treatment of Movement Disorders)
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Open AccessArticle Spatiotemporal Gait Analysis and Lower Limb Functioning in Foot Dystonia Treated with Botulinum Toxin
Toxins 2018, 10(12), 532; https://doi.org/10.3390/toxins10120532
Received: 17 November 2018 / Revised: 9 December 2018 / Accepted: 10 December 2018 / Published: 12 December 2018
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Abstract
Foot dystonia (FD) is a disabling condition causing pain, spasm and difficulty in walking. We treated fourteen (14) adult patients experiencing FD with onabotulinum toxin A injection into the dystonic foot muscles. We analyzed the spatiotemporal gait utilizing the GaitRite system pre- and [...] Read more.
Foot dystonia (FD) is a disabling condition causing pain, spasm and difficulty in walking. We treated fourteen (14) adult patients experiencing FD with onabotulinum toxin A injection into the dystonic foot muscles. We analyzed the spatiotemporal gait utilizing the GaitRite system pre- and 3 weeks post-botulinum toxin injection along with measuring dystonia by the Fahn–Marsden Dystonia Scale (FMDS), pain by the Visual Analog Scale (VAS) and other lower limb functional outcomes such as gait velocity, the Berg Balance Scale (BBS), the Unified Parkinson’s Disease Rating Scale–Lower Limb Score (UPDRS–LL), the Timed Up and Go (TUG) test and the Goal Attainment Scale (GAS). We found that stride length increased significantly in both the affected (p = 0.02) and unaffected leg (p = 0.01) after treatment, and the improvement in stride length was roughly the same in each leg. Similar results were found for step length (p = 0.02) with improvement in the step length differential (p = 0.01). The improvements in the lower limb functional outcomes were also significant—FMDS, VAS, TUG, and UPDRS–LL decreased significantly after treatment (all p < 0.001), and BBS (p = 0.001), GAS (p < 0.001) except cadence (p = 0.37). BT injection improved walking in foot dystonia as evidenced through gait analysis, pain and lower limb functional outcomes. Main study limitations were small sample size and lack of control. Full article
(This article belongs to the Special Issue Botulinum Toxin Treatment of Movement Disorders)
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Open AccessArticle Botulinum Toxin in Restless Legs Syndrome—A Randomized Double-Blind Placebo-Controlled Crossover Study
Toxins 2018, 10(10), 401; https://doi.org/10.3390/toxins10100401
Received: 6 September 2018 / Revised: 27 September 2018 / Accepted: 27 September 2018 / Published: 29 September 2018
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Abstract
Background: Restless Legs Syndrome (RLS) is a common movement disorder with an estimated prevalence of up to 12%. Previous small studies with onabotulinumtoxin A (OnaA) for RLS have shown inconsistent results. Methods: Twenty-four patients with an International RLS score (IRLS) of >11 (moderate-severe) [...] Read more.
Background: Restless Legs Syndrome (RLS) is a common movement disorder with an estimated prevalence of up to 12%. Previous small studies with onabotulinumtoxin A (OnaA) for RLS have shown inconsistent results. Methods: Twenty-four patients with an International RLS score (IRLS) of >11 (moderate-severe) were enrolled in this blinded, placebo-controlled crossover study. Twenty-one patients completed the evaluations at 4, 6, and 8 weeks after each injection. One-hundred units of Incobotulinumtoxin A (IncoA) or normal saline were injected into tibialis anterior, gastrocnemius, and biceps femoris muscles each side. Results: Improvement from a severe (IRLS >21) to a mild/moderate (IRLS ≤20) score was significant at four weeks (p = 0.0036) and six weeks (p = 0.0325) following IncoA administration compared to placebo. Additionally, there was significant improvement in pain score at six weeks as measured by Visual Analogue Scale (p = 0.04) and the Johns Hopkins Quality of Life Questionnaire (p = 0.01) in the IncoA group. Definite or marked improvement on Patient Global Impression of Change was seen in 7 out of 21 patients in the IncoA group vs. 1 out of 21 patients in the placebo group at 4 weeks (p = 0.012). Conclusion: IncoA injection lead to a reduction in severity of RLS symptoms, pain score, and quality of life, without any adverse effects. Full article
(This article belongs to the Special Issue Botulinum Toxin Treatment of Movement Disorders)
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Open AccessArticle Repeated Intrastriatal Botulinum Neurotoxin-A Injection in Hemiparkinsonian Rats Increased the Beneficial Effect on Rotational Behavior
Received: 22 August 2018 / Revised: 4 September 2018 / Accepted: 8 September 2018 / Published: 11 September 2018
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Abstract
Injection of botulinum neurotoxin-A (BoNT-A) into the striatum of hemiparkinsonian (hemi-PD) rats reduced apomorphine-induced rotation behavior significantly, for at least 3 months. Thereafter, rotation behavior increased again. We injected hemi-PD rats with 1 ng BoNT-A twice, the second injection following 6 months after [...] Read more.
Injection of botulinum neurotoxin-A (BoNT-A) into the striatum of hemiparkinsonian (hemi-PD) rats reduced apomorphine-induced rotation behavior significantly, for at least 3 months. Thereafter, rotation behavior increased again. We injected hemi-PD rats with 1 ng BoNT-A twice, the second injection following 6 months after the first one and tested the rats for apomorphine-induced rotations and spontaneous motor behaviors, i.e., corridor task and stepping test. To test the hypothesis that BoNT-A reduced striatal hypercholinism in hemi-PD rats, the acetylcholinesterase inhibitor donepezil was injected prior to separate apomorphine-induced rotation tests. In hemi-PD rats, the first BoNT-A injection led to a clear reduction of the apomorphine-induced rotations, and the second BoNT-A injection to a more massive and prolonged reaction. In hemi-PD rats whose apomorphine-induced rotation behavior was strongly reduced by an intrastriatal BoNT-A, subsequent donepezil injections led to significant increases of the rotation rate. Concerning corridor task and stepping test, neither first nor second BoNT-A injections changed hemi-PD rats’ behavior significantly. The data give evidence for the possibility of repeated intrastriatal administrations of BoNT-A, for treatment of motor symptoms in experimental hemi-PD over a longer time. Full article
(This article belongs to the Special Issue Botulinum Toxin Treatment of Movement Disorders)
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Open AccessArticle The Effect of Repeated Botulinum Toxin A Therapy Combined with Intensive Rehabilitation on Lower Limb Spasticity in Post-Stroke Patients
Received: 15 August 2018 / Revised: 28 August 2018 / Accepted: 30 August 2018 / Published: 31 August 2018
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Abstract
Objectives: This study is a retrospective investigation of the effects of repetitive botulinum toxin A therapy (BoNT-A) and intensive rehabilitation (IR) on lower limb spasticity in post-stroke patients. Methods: Thirty-five post-stroke patients was included in this study and received BoNT-A for the first [...] Read more.
Objectives: This study is a retrospective investigation of the effects of repetitive botulinum toxin A therapy (BoNT-A) and intensive rehabilitation (IR) on lower limb spasticity in post-stroke patients. Methods: Thirty-five post-stroke patients was included in this study and received BoNT-A for the first time. A 12-day inpatient protocol was with 4 cycles of the treatment protocol. The severity of spasticity, motor function and brace status were evaluated. Results: The modified Ashworth Scale (MAS) score of ankle dorsiflexors, range of motion, walking speed and balancing ability were significantly improved after cycle 1. The improvement of spasticity and motor function was persistent through cycles 2–4. One-third of brace users were able to discontinue the use of a brace. All of these brace users showed a forward gait pattern prior to therapy. Conclusions: Repeated BoNT-A combined with IR improved lower limb spasticity in post-stroke patients. Our results suggest that patients who show the forward gait pattern prior to therapy may be able to discontinue the use of their brace after therapy. Full article
(This article belongs to the Special Issue Botulinum Toxin Treatment of Movement Disorders)
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Open AccessArticle Incobotulinumtoxin A for Sialorrhea in Neurological Disorders: A Real-Life Experience
Received: 10 May 2018 / Revised: 25 May 2018 / Accepted: 25 May 2018 / Published: 28 May 2018
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Abstract
Botulinum toxin type A is one of the most useful treatments of sialorrhea in neurological disorders. Evidence for the use of incobotulinumtoxin A (inco-A) in the treatment of sialorrhea is limited. Thirty-six patients with sialorrhea were treated with infiltrations of inco-A into both [...] Read more.
Botulinum toxin type A is one of the most useful treatments of sialorrhea in neurological disorders. Evidence for the use of incobotulinumtoxin A (inco-A) in the treatment of sialorrhea is limited. Thirty-six patients with sialorrhea were treated with infiltrations of inco-A into both parotid glands. The severity of sialorrhea was evaluated by the Drooling Severity Scale (DSS), and the Drooling Frequency Scale (DFS). Patients’ perceptions of clinical benefit were recorded via the Patient Global Impression of Improvement (PGI-I) scale. Following treatment, there was a significant difference in both the DFS and the DSS (p < 0.001). Clinical benefits on the basis of the PGI-I were present in up to 90% of patients. Full article
(This article belongs to the Special Issue Botulinum Toxin Treatment of Movement Disorders)
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Open AccessArticle Botulinum Toxin Type A Injection for Cervical Dystonia in Adults with Dyskinetic Cerebral Palsy
Received: 9 April 2018 / Revised: 4 May 2018 / Accepted: 15 May 2018 / Published: 16 May 2018
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Abstract
We aimed to evaluate the efficacy and safety of injecting botulinum toxin A (BoNT-A) into the neck muscles to treat cervical dystonia (CD) in patients with dyskinetic cerebral palsy (CP). This was a randomized, double-blinded, placebo-controlled trial with cross-over design. We prospectively enrolled [...] Read more.
We aimed to evaluate the efficacy and safety of injecting botulinum toxin A (BoNT-A) into the neck muscles to treat cervical dystonia (CD) in patients with dyskinetic cerebral palsy (CP). This was a randomized, double-blinded, placebo-controlled trial with cross-over design. We prospectively enrolled adults with dyskinetic CP who were over 20 years old and had been clinically diagnosed with CD for more than one year. The primary outcome measure was the change in Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) at four weeks from the baseline TWSTRS. Seventeen patients were initially enrolled, but one patient was excluded after the final evaluation because of a violation of the study protocol. At four weeks, the BoNT-A injections showed significant improvement in TWSTRS total scores compared to the saline injections (p = 0.0286 for ANCOVA). At 12 weeks, the BoNT-A injections resulted in greater improvements in TWSTRS total scores than the saline injections without statistical significance (p = 0.0783 for ANCOVA). Dysphagia occurred in three out of 16 patients: two after BoNT-A and one after saline. The dysphagia was transient and improved naturally within two weeks without any special treatment. BoNT-A injection for CD in adults with dyskinetic CP is relatively safe and improves pain and disability. Full article
(This article belongs to the Special Issue Botulinum Toxin Treatment of Movement Disorders)
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Review

Jump to: Research

Open AccessReview Mandibular Bone Loss after Masticatory Muscles Intervention with Botulinum Toxin: An Approach from Basic Research to Clinical Findings
Received: 30 December 2018 / Revised: 23 January 2019 / Accepted: 28 January 2019 / Published: 1 February 2019
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Abstract
The injection of botulinum toxin type A (BoNT/A) in the masticatory muscles, to cause its temporary paralysis, is a widely used intervention for clinical disorders such as oromandibular dystonia, sleep bruxism, and aesthetics (i.e., masseteric hypertrophy). Considering that muscle contraction is required for [...] Read more.
The injection of botulinum toxin type A (BoNT/A) in the masticatory muscles, to cause its temporary paralysis, is a widely used intervention for clinical disorders such as oromandibular dystonia, sleep bruxism, and aesthetics (i.e., masseteric hypertrophy). Considering that muscle contraction is required for mechano-transduction to maintain bone homeostasis, it is relevant to address the bone adverse effects associated with muscle condition after this intervention. Our aim is to condense the current and relevant literature about mandibular bone loss in fully mature mammals after BoNT/A intervention in the masticatory muscles. Here, we compile evidence from animal models (mice, rats, and rabbits) to clinical studies, demonstrating that BoNT/A-induced masticatory muscle atrophy promotes mandibular bone loss. Mandibular bone-related adverse effects involve cellular and metabolic changes, microstructure degradation, and morphological alterations. While bone loss has been detected at the mandibular condyle or alveolar bone, cellular and molecular mechanisms involved in this process must still be elucidated. Further basic research could provide evidence for designing strategies to control the undesired effects on bone during the therapeutic use of BoNT/A. However, in the meantime, we consider it essential that patients treated with BoNT/A in the masticatory muscles be warned about a putative collateral mandibular bone damage. Full article
(This article belongs to the Special Issue Botulinum Toxin Treatment of Movement Disorders)
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Open AccessReview Central Effects of Botulinum Neurotoxin—Evidence from Human Studies
Received: 12 December 2018 / Revised: 25 December 2018 / Accepted: 31 December 2018 / Published: 6 January 2019
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Abstract
For more than three decades, Botulinum neurotoxin (BoNT) has been used to treat a variety of clinical conditions such as spastic or dystonic disorders by inducing a temporary paralysis of the injected muscle as the desired clinical effect. BoNT is known to primarily [...] Read more.
For more than three decades, Botulinum neurotoxin (BoNT) has been used to treat a variety of clinical conditions such as spastic or dystonic disorders by inducing a temporary paralysis of the injected muscle as the desired clinical effect. BoNT is known to primarily act at the neuromuscular junction resulting in a biochemical denervation of the treated muscle. However, recent evidence suggests that BoNT’s pharmacological properties may not only be limited to local muscular denervation at the injection site but may also include additional central effects. In this review, we report and discuss the current evidence for BoNT’s central effects based on clinical observations, neurophysiological investigations and neuroimaging studies in humans. Collectively, these data strongly point to indirect mechanisms via changes to sensory afferents that may be primarily responsible for the marked plastic effects of BoNT on the central nervous system. Importantly, BoNT-related central effects and consecutive modulation and/or reorganization of the brain may not solely be considered “side-effects” but rather an additional therapeutic impact responsible for a number of clinical observations that cannot be explained by merely peripheral actions. Full article
(This article belongs to the Special Issue Botulinum Toxin Treatment of Movement Disorders)
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Open AccessReview Botulinum Toxin Induced Atrophy: An Uncharted Territory
Received: 4 July 2018 / Revised: 30 July 2018 / Accepted: 31 July 2018 / Published: 2 August 2018
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Abstract
Botulinum neurotoxins (BoNTs) produce local chemo-denervation by cleaving soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) proteins. Botulinum neurotoxins are therapeutically indicated in several neurological disorders and have been in use for three decades. The long-term efficacy, safety, and side effects of BoNTs have [...] Read more.
Botulinum neurotoxins (BoNTs) produce local chemo-denervation by cleaving soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE) proteins. Botulinum neurotoxins are therapeutically indicated in several neurological disorders and have been in use for three decades. The long-term efficacy, safety, and side effects of BoNTs have been well documented in the literature. However, the development of muscle atrophy following chronic exposure to BoNTs has not received sufficient attention. Muscle atrophy is not only cosmetically distressing, but also has an impact on future injections. An extensive literature search was conducted on atrophy and mechanisms of atrophy. Five hundred and four relevant articles in the English language were reviewed. This review revealed the surprising lack of documentation of atrophy within the literature. In addition, as demonstrated in this review, the mechanisms and the clinical factors that may lead to atrophy have also been poorly studied. However, even with this limited information it is possible to indicate factors that could modify the clinical approach to botulinum toxin injections. This review highlights the need for further study of atrophy following BoNT injections. Full article
(This article belongs to the Special Issue Botulinum Toxin Treatment of Movement Disorders)
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