Special Issue "Effects of Botulinum Toxin on Functional Recovery after Injuries of Nervous System"

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

Deadline for manuscript submissions: closed (31 May 2020).

Special Issue Editor

Dr. Siro Luvisetto
E-Mail Website
Guest Editor
Institute of Biochemistry and Cell Biology (IBBC), National Research Council (CNR) of Italy, 00015 - Monterotondo Scalo, Roma, Italy
Interests: botulinum neurotoxins; neuropathic pain; peripheral nerve; motor function; functional recovery; animal model; glial cells; Schwann cells
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Special Issue Information

Dear Colleagues,

Botulinum toxins (BoNTs) are extensively used for their therapeutic efficacy in a variety of human pathologies, most of them difficult to treat with other drugs, characterized by excessive muscle contractions due to hypercholinergic dysfunctions. This effect resides in the capacity of BoNTs to block the cholinergic transmission at the neuromuscular junction. Nowadays, the list of human disorders in which treatments with BoNTs have produced, or are expected to produce, favorable results is long and continuously growing, comprising also pathologies where the expected therapeutic action is not only at the level of the neuromuscular junction, but it is also attributable to the interaction of the toxins with other structures,  including peripheral nerves, spinal cord, central neurons, non-neural cells, and so on. In more recent years, a number of experimental and clinical studies provided positive evidences for the efficacy of BoNTs in facilitating motor and functional recovery after traumatic injuries of nervous systems. This Special Issue on “The Effect of Botulinum Toxin on Functional Recovery after Injuries of Nervous System” is particularly devoted to collecting the most recent research on the effects of BoNTs in all those conditions where impairments of motor function are the consequence of traumatic injuries on the nervous system. Both review and research articles are welcome, not only from animal studies but also from clinical trials or case reports. The ambitious purpose of this Special Issue is to provide an up-to-date picture of the state of art on the development of novel BoNT applications to ameliorate the functional recovery after motor impairment resulting from trauma to the brain, the spinal cord or the peripheral nerves, such as spasticity after stroke, paralysis after spinal cord injury, hemiparesis after peripheral nerves degeneration, and so on.

Dr. Siro Luvisetto
Guest Editor

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Keywords

  • Botulinum neurotoxins
  • Peripheral nerve injury
  • Spinal cord injury
  • Post-stroke spasticity
  • Axonal regeneration
  • Functional recovery
  • Experimental models
  • Clinical studies
  • Rehabilitation

Published Papers (8 papers)

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Research

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Article
The Effects of Botulinum Toxin Injections on Spasticity and Motor Performance in Chronic Stroke with Spastic Hemiplegia
Toxins 2020, 12(8), 492; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12080492 - 31 Jul 2020
Cited by 2 | Viewed by 1513
Abstract
Spastic muscles are weak muscles. It is known that muscle weakness is linked to poor motor performance. Botulinum neurotoxin (BoNT) injections are considered as the first-line treatment for focal spasticity. The purpose of this study was to quantitatively investigate the effects of BoNT [...] Read more.
Spastic muscles are weak muscles. It is known that muscle weakness is linked to poor motor performance. Botulinum neurotoxin (BoNT) injections are considered as the first-line treatment for focal spasticity. The purpose of this study was to quantitatively investigate the effects of BoNT injections on force control of spastic biceps brachii muscles in stroke survivors. Ten stroke survivors with spastic hemiplegia (51.7 ± 11.5 yrs; 5 men) who received 100 units of incobotulinumtoxinA or onabotulinumtoxinA to the biceps brachii muscles participated in this study. Spasticity assessment (Modified Ashworth Scale (MAS) and reflex torque) and muscle strength of elbow flexors, as well as motor performance assessment (force variability of submaximal elbow flexion) were performed within one week before (pre-injection) and 3~4 weeks (3-wk) after BoNT injections. As expected, BoNT injections reduced the MAS score and reflex torque, and elbow flexor strength on the spastic paretic side. However, motor performance remained within similar level before and after injections. There was no change in muscle strength or motor performance on the contralateral arm after BoNT injections. The results of this study provide evidence that BoNT injections can reduce spasticity and muscle strength, while motor performance of the weakened spastic muscle remains unchanged. Full article
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Article
Revealing the Therapeutic Potential of Botulinum Neurotoxin Type A in Counteracting Paralysis and Neuropathic Pain in Spinally Injured Mice
Toxins 2020, 12(8), 491; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12080491 - 31 Jul 2020
Cited by 1 | Viewed by 1348
Abstract
Botulinum neurotoxin type A (BoNT/A) is a major therapeutic agent that has been proven to be a successful treatment for different neurological disorders, with emerging novel therapeutic indications each year. BoNT/A exerts its action by blocking SNARE complex formation and vesicle release through [...] Read more.
Botulinum neurotoxin type A (BoNT/A) is a major therapeutic agent that has been proven to be a successful treatment for different neurological disorders, with emerging novel therapeutic indications each year. BoNT/A exerts its action by blocking SNARE complex formation and vesicle release through the specific cleavage of SNAP-25 protein; the toxin is able to block the release of pro-inflammatory molecules for months after its administration. Here we demonstrate the extraordinary capacity of BoNT/A to neutralize the complete paralysis and pain insensitivity induced in a murine model of severe spinal cord injury (SCI). We show that the toxin, spinally administered within one hour from spinal trauma, exerts a long-lasting proteolytic action, up to 60 days after its administration, and induces a complete recovery of muscle and motor function. BoNT/A modulates SCI-induced neuroglia hyperreactivity, facilitating axonal restoration, and preventing secondary cells death and damage. Moreover, we demonstrate that BoNT/A affects SCI-induced neuropathic pain after moderate spinal contusion, confirming its anti-nociceptive action in this kind of pain, as well. Our results provide the intriguing and real possibility to identify in BoNT/A a therapeutic tool in counteracting SCI-induced detrimental effects. Because of the well-documented BoNT/A pharmacology, safety, and toxicity, these findings strongly encourage clinical translation. Full article
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Article
Botulinum Toxin Type A Injections Impact Hamstring Muscles and Gait Parameters in Children with Flexed Knee Gait
Toxins 2020, 12(3), 145; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12030145 - 27 Feb 2020
Cited by 1 | Viewed by 1152
Abstract
The aim of this study was to determine if botulinum toxin type A (BoNT-A) injection into the medial hamstring can improve gait kinematics and muscle-tendon length in spastic cerebral palsy (CP) with a flexed knee gait (FKG). Twenty-nine children with spastic CP (Gross [...] Read more.
The aim of this study was to determine if botulinum toxin type A (BoNT-A) injection into the medial hamstring can improve gait kinematics and muscle-tendon length in spastic cerebral palsy (CP) with a flexed knee gait (FKG). Twenty-nine children with spastic CP (Gross Motor Function Classification System I–III) with FKG were recruited for this prospective study. BoNT-A was injected into the semitendinosus and semimembranosus (SM) muscles under ultrasonography guidance. Assessments included Gross Motor Function Measure (GMFM), Modified Ashworth Scale (MAS), Modified Tardieu Scale (MTS), 3-dimensional computerized gait analysis, calculated SM muscle-tendon length and lengthening velocity during gait using musculoskeletal modeling at baseline, 4 and 16 weeks after the injection. Compared to baseline data, significant improvements in GMFM, MAS, and MTS were demonstrated at weeks 4 and 16, and also a significant increase in maximum knee extension during the stance phase was observed at week 4. In addition, the mean lengthening velocity during the swing phase was increased at week 16 without a change in the SM muscle length. Furthermore, there was a significant increase in anterior pelvic tilt at week 4, compared to baseline data. The significant decrease in hip internal rotation after injection was observed only in children with excessive hip internal rotation at initial contact before injection. BoNT-A injection into hamstrings leads to a significant increase in knee extension and anterior pelvic tilt with an increase in lengthening velocity of SM in spastic CP with FKG. Full article
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Article
Botulinum Toxin Injection in Children with Hemiplegic Cerebral Palsy: Correction of Growth through Comparison of Treated and Unaffected Limbs
Toxins 2019, 11(12), 688; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11120688 - 23 Nov 2019
Cited by 2 | Viewed by 1174
Abstract
Botulinum toxin type A (BoNT-A) injections in children with cerebral palsy (CP) may negatively affect muscle growth and strength. We injected BoNT-A into the affected limbs of 14 children (4.57 ± 2.28 years) with hemiplegic CP and exhibiting tip-toeing gait on the affected [...] Read more.
Botulinum toxin type A (BoNT-A) injections in children with cerebral palsy (CP) may negatively affect muscle growth and strength. We injected BoNT-A into the affected limbs of 14 children (4.57 ± 2.28 years) with hemiplegic CP and exhibiting tip-toeing gait on the affected side and investigated the morphological alterations in the medial head of the gastrocnemius muscle (GCM). We assessed thickness of the GCM, fascicle length, and fascicle angle on the affected and unaffected sides at baseline at 4 and 12 weeks after BoNT-A injections. The primary outcome measure was the change (percentage) in GCM thickness in the affected side treated with BoNT-A in comparison with the unaffected side. The percentage of treated GCM thickness became significantly thinner at 4 and 12 weeks after BoNT-A injection than baseline. However, the percentage of fascicle length and angle in treated limbs showed no significant change from baseline 4 and 12 weeks after the injection. BoNT-A injections might reduce muscle thickness in children with spastic hemiplegic CP. Fascicle length and angle might not be affected by BoNT-A injections after correction of normal growth of the children. Full article
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Article
The Effect of Botulinum Toxin Injections on Gross Motor Function for Lower Limb Spasticity in Children with Cerebral Palsy
Toxins 2019, 11(11), 651; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11110651 - 08 Nov 2019
Cited by 5 | Viewed by 1336
Abstract
The aim of this study was to investigate the use of botulinum toxin type A (BoNT-A) injections and their efficacy on gross motor function for lower limb spasticity in children with spastic cerebral palsy (CP). This retrospective study included 919 injection occasions from [...] Read more.
The aim of this study was to investigate the use of botulinum toxin type A (BoNT-A) injections and their efficacy on gross motor function for lower limb spasticity in children with spastic cerebral palsy (CP). This retrospective study included 919 injection occasions from 591 children with CP who received a lower limb BoNT-A injection between 2006 and 2016. The Gross Motor Function Measure (GMFM-88), the Modified Ashworth Scale, and the Modified Tardieu Scale were administered before and after injections. Injections were predominantly administered to children under the age of 6 years. The most common muscle injection site was the calf muscle for dynamic foot deformity. The second most commonly injected muscle was the hip adductor among 2–3 year olds and the hamstring muscle among 4–6 year olds. Distal injections were predominantly administered to high-functioning children, whereas proximal injections were typically administered to low-functioning children. Multilevel injections were mostly administered to midfunctioning children. GMFM-88 scores significantly increased post-injection for both high- and low-functioning groups. Younger age at injection and distal injection type were associated with larger improvements on the GMFM-88 at both short- and midterm follow-up. The target muscles for injection varied depending on gross motor functioning and age. Younger age at injection and distal injection type were significantly related with greater gain in gross motor function. Full article
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Review

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Review
Botulinum Toxin and Neuronal Regeneration after Traumatic Injury of Central and Peripheral Nervous System
Toxins 2020, 12(7), 434; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12070434 - 02 Jul 2020
Viewed by 1990
Abstract
Botulinum neurotoxins (BoNTs) are toxins produced by the bacteria Clostridium botulinum, the causing agent for botulism, in different serotypes, seven of which (A–G) are well characterized, while others, such as H or FA, are still debated. BoNTs exert their action by blocking [...] Read more.
Botulinum neurotoxins (BoNTs) are toxins produced by the bacteria Clostridium botulinum, the causing agent for botulism, in different serotypes, seven of which (A–G) are well characterized, while others, such as H or FA, are still debated. BoNTs exert their action by blocking SNARE (soluble N-ethylmale-imide-sensitive factor-attachment protein receptors) complex formation and vesicle release from the neuronal terminal through the specific cleavage of SNARE proteins. The action of BoNTs at the neuromuscular junction has been extensively investigated and knowledge gained in this field has set the foundation for the use of these toxins in a variety of human pathologies characterized by excessive muscle contractions. In parallel, BoNTs became a cosmetic drug due to its power to ward off facial wrinkles following the activity of the mimic muscles. Successively, BoNTs became therapeutic agents that have proven to be successful in the treatment of different neurological disorders, with new indications emerging or being approved each year. In particular, BoNT/A became the treatment of excellence not only for muscle hyperactivity conditions, such as dystonia and spasticity, but also to reduce pain in a series of painful states, such as neuropathic pain, lumbar and myofascial pain, and to treat various dysfunctions of the urinary bladder. This review summarizes recent experimental findings on the potential efficacy of BoNTs in favoring nerve regeneration after traumatic injury in the peripheral nervous system, such as the injury of peripheral nerves, like sciatic nerve, and in the central nervous system, such as spinal cord injury. Full article
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Review
Use of Botulinum Toxin in Orofacial Clinical Practice
Toxins 2020, 12(2), 112; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins12020112 - 11 Feb 2020
Cited by 2 | Viewed by 2468
Abstract
Introduction: Botulinum neurotoxin (BoNT) is a potent biological toxin and powerful therapeutic tool for a growing number of clinical orofacial applications. BoNT relaxes striated muscle by inhibiting acetylcholine’s release from presynaptic nerve terminals, blocking the neuromuscular junction. It also has an antinociceptive effect [...] Read more.
Introduction: Botulinum neurotoxin (BoNT) is a potent biological toxin and powerful therapeutic tool for a growing number of clinical orofacial applications. BoNT relaxes striated muscle by inhibiting acetylcholine’s release from presynaptic nerve terminals, blocking the neuromuscular junction. It also has an antinociceptive effect on sensory nerve endings, where BoNT and acetylcholine are transported axonally to the central nervous system. In dentistry, controlled clinical trials have demonstrated BoNT’s efficiency in pathologies such as bruxism, facial paralysis, temporomandibular joint (TMJ) disorders, neuropathic pain, sialorrhea, dystonia and more. Aim: This study’s aim was to conduct a systematic literature review to assess the most recent high-level clinical evidence for BoNT’s efficacy and for various protocols (the toxin used, dilution, dosage and infiltration sites) used in several orofacial pathologies. Materials and methods: We systematically searched the MedLine database for research papers published from 2014 to 2019 with randomly allocated studies on humans. The search included the following pathologies: bruxism, dislocation of the TMJ, orofacial dystonia, myofascial pain, salivary gland disease, orofacial spasm, facial paralysis, sialorrhea, Frey syndrome and trigeminal neuralgia. Results: We found 228 articles, of which only 20 met the inclusion criteria: bruxism (four articles), orofacial dystonia (two articles), myofascial pain (one article), salivary gland disease (one article), orofacial spasm (two articles), facial paralysis (three articles), sialorrhea (four articles) or trigeminal neuralgia (three articles). Discussion: The clinical trials assessed showed variations in the dosage, application sites and musculature treated. Thus, applying BoNT can reduce symptoms related to motor muscular activity in the studied pathologies efficiently enough to satisfy patients. We did not identify the onset of any important side effects in the literature reviewed. We conclude that treatment with BoNT seems a safe and effective treatment for the reviewed pathologies. Full article
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Review
Botulinum Toxin Therapy Combined with Rehabilitation for Stroke: A Systematic Review of Effect on Motor Function
Toxins 2019, 11(12), 707; https://0-doi-org.brum.beds.ac.uk/10.3390/toxins11120707 - 05 Dec 2019
Cited by 8 | Viewed by 2631
Abstract
Aim: The purpose of this study was to examine the effectiveness of botulinum toxin A (BoNT-A) therapy combined with rehabilitation on motor function in post-stroke patients. Methods: The following sources up to December 31, 2018, were searched from inception for articles in English: [...] Read more.
Aim: The purpose of this study was to examine the effectiveness of botulinum toxin A (BoNT-A) therapy combined with rehabilitation on motor function in post-stroke patients. Methods: The following sources up to December 31, 2018, were searched from inception for articles in English: Pubmed, Scopus, CINAHL, Embase, PsycINFO, and CENTRAL. Trials using injections of BoNT-A for upper and lower limb rehabilitation were examined. We excluded studies that were not performed for rehabilitation or were not evaluated for motor function. Results: Twenty-six studies were included. In addition to rehabilitation, nine studies used adjuvant treatment to improve spasticity or improve motor function. In the upper limbs, two of 14 articles indicated that significant improvement in upper limb motor function was observed compared to the control group. In the lower limbs, seven of 14 articles indicated that significant improvement in lower limb motor function was observed compared to the control group. Conclusions: The effect of combined with rehabilitation is limited after stroke, and there is not sufficient evidence, but results suggest that BoNT-A may help to improve motor function. In future studies, the establishment of optimal rehabilitation and evaluation times of BoNT-A treatment will be necessary for improving motor function and spasticity. Full article
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