Toxins

Editorial

5 pages, 193 KiB

Open AccessEditorial

Introduction to the Toxins Special Issue on Botulinum Neurotoxins in the Nervous System: Future Challenges for Novel Indications

by Siro Luvisetto

Toxins 2020, 12(9), 601; https://doi.org/10.3390/toxins12090601 - 17 Sep 2020

Cited by 2 | Viewed by 2166

Abstract

Botulinum toxins (BoNTs) are a true wonder of nature [...] Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

Research

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11 pages, 539 KiB

Open AccessArticle

Botulinum Toxin Injections and Electrical Stimulation for Spastic Paresis Improve Active Hand Function Following Stroke

by Jong-Min Lee, Jean-Michel Gracies, Si-Bog Park, Kyu Hoon Lee, Ji Yeong Lee and Joon-Ho Shin

Toxins 2018, 10(11), 426; https://doi.org/10.3390/toxins10110426 - 25 Oct 2018

Cited by 20 | Viewed by 5777

Abstract

Botulinum toxin type A (BTX-A) injections improve muscle tone and range of motion (ROM) among stroke patients with upper limb spasticity. However, the efficacy of BTX-A injections for improving active function is unclear. We aimed to determine whether BTX-A injections with electrical stimulation [...] Read more.

Botulinum toxin type A (BTX-A) injections improve muscle tone and range of motion (ROM) among stroke patients with upper limb spasticity. However, the efficacy of BTX-A injections for improving active function is unclear. We aimed to determine whether BTX-A injections with electrical stimulation (ES) of hand muscles could improve active hand function (AHF) among chronic stroke patients. Our open-label, pilot study included 15 chronic stroke patients. Two weeks after BTX-A injections into the finger and/or wrist flexors, ES of finger extensors was performed while wearing a wrist brace for 4 weeks (5 days per week; 30-min sessions). Various outcomes were assessed at baseline, immediately before BTX-A injections, and 2 and 6 weeks after BTX-A injections. After the intervention, we noted significant improvements in Box and Block test results, Action Research Arm Test results, the number of repeated finger flexions/extensions, which reflect AHF, and flexor spasticity. Moreover, significant improvements in active ROM of wrist extension values were accompanied by marginally significant changes in Medical Research Council wrist extensor and active ROM of wrist flexion values. In conclusion, BTX-A injections into the finger and/or wrist flexors followed by ES of finger extensors improve AHF among chronic stroke patients. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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10 pages, 1145 KiB

Open AccessArticle

Transitioning from Unilateral to Bilateral Upper Limb Tremor Therapy for Parkinson’s Disease and Essential Tremor Using Botulinum Toxin: Case Series

by Olivia Samotus, Jack Lee and Mandar Jog

Toxins 2018, 10(10), 394; https://doi.org/10.3390/toxins10100394 - 27 Sep 2018

Cited by 6 | Viewed by 3792

Abstract

Botulinum toxin type A (BoNT-A) injections guided by kinematic analysis for unilateral upper limb essential tremor (ET) and Parkinson’s disease (PD) tremor therapy has demonstrated efficacy, improvements in quality of life (QoL) and arm functionality. In this open-label pilot trial, 5 ET and [...] Read more.

Botulinum toxin type A (BoNT-A) injections guided by kinematic analysis for unilateral upper limb essential tremor (ET) and Parkinson’s disease (PD) tremor therapy has demonstrated efficacy, improvements in quality of life (QoL) and arm functionality. In this open-label pilot trial, 5 ET and 2 PD participants decided to switch from receiving long-term unilateral arm treatment to now bilateral BoNT-A arm therapy in their other tremulous arm which worsened over time. Injection patterns were based on kinematic analysis. Efficacy endpoints including kinematic analysis, Fahn-Tolosa-Marin tremor rating scale, QoL questionnaire, and maximal grip strength were collected over 2 treatments and 2 follow-up visits totaling 18-weeks. BoNT-A decreased wrist tremor amplitude by 84.6% and 89.6% 6-weeks following the 1st injection in the newly-treated limb in ET and PD participants, respectively. PD participants started with worse QoL but demonstrated an additional improvement in QoL by 29.9% for switching to bilateral treatment, whereas ET participants did not. Left and right arm tremor also did not share commonalities in severity or dose. This preliminary finding suggests trends for transitioning to bilateral therapy and warrants further studies to evaluate efficacy of bilateral tremor BoNT-A therapy in a larger cohort of PD and ET patients. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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10 pages, 684 KiB

Open AccessFeature PaperArticle

Botulinum Toxin for the Treatment of Hand Tremor

by Nicki Niemann and Joseph Jankovic

Toxins 2018, 10(7), 299; https://doi.org/10.3390/toxins10070299 - 19 Jul 2018

Cited by 45 | Viewed by 7459

Abstract

The aim of this study is to review our longitudinal experience with onabotulinumtoxinA (onaBoNT-A) injections for medically refractory hand tremor. We performed a retrospective review of our database of patients treated with onaBoNT-A for hand tremor evaluated between 2010 and 2018 in at [...] Read more.

The aim of this study is to review our longitudinal experience with onabotulinumtoxinA (onaBoNT-A) injections for medically refractory hand tremor. We performed a retrospective review of our database of patients treated with onaBoNT-A for hand tremor evaluated between 2010 and 2018 in at least 2 sessions with follow-up. The majority were injected into the forearm flexors (FF), although treatment was individualized. During the specified period, 91 patients (53 essential tremor, 31 dystonic tremor, 6 Parkinson’s disease tremor, and 1 cerebellar outflow tremor) met our inclusion criteria. The mean age (SD) was 64.8 years (12.8), and mean duration of follow-up was 29.6 months (25.1) with mean of 7.7 (6.3) treatment visits. FF were injected in 89 (97.8%) patients, exclusively in 74 (81.3%), and 15 (16.5%) were injected in FF and other muscles. EMG guidance was used in 5 patients (5.5%). On a 0–4 “peak effect” rating scale (0 = no effect, 4 = marked improvement in severity and function), 80.2% and 85.7% of patients reported moderate or marked improvement (score 3 or 4) at their first and last follow-up visit, respectively. There was no statistically significant difference in the outcomes between first and last visit: average “peak effect” rating score (3.2 versus 3.4), “global” rating score (3.0 versus 3.2), latency of response (4.5 versus 3.8 days), and total duration of response (12.7 versus 12.8 weeks), except onaBoNT-A dose (65.0 versus 78.6 U/limb, p = 0.002). Of 1095 limb injections, there were 134 (12.2%) non-disabling and transient (mean 36 days) adverse events (132 limb weakness, 2 pain). OnaBoNT-A injections are safe and effective in the treatment of hand tremor. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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22 pages, 1734 KiB

Open AccessArticle

Unilateral Botulinum Neurotoxin-A Injection into the Striatum of C57BL/6 Mice Leads to a Different Motor Behavior Compared with Rats

by Veronica Antipova, Andreas Wree, Carsten Holzmann, Teresa Mann, Nicola Palomero-Gallagher, Karl Zilles, Oliver Schmitt and Alexander Hawlitschka

Toxins 2018, 10(7), 295; https://doi.org/10.3390/toxins10070295 - 17 Jul 2018

Cited by 9 | Viewed by 5533

Abstract

Different morphological changes in the caudate-putamen (CPu) of naïve rats and mice were observed after intrastriatal botulinum neurotoxin-A (BoNT-A) injection. For this purpose we here studied various motor behaviors in mice (n = 46) longitudinally up to 9 months after intrastriatal BoNT-A [...] Read more.

Different morphological changes in the caudate-putamen (CPu) of naïve rats and mice were observed after intrastriatal botulinum neurotoxin-A (BoNT-A) injection. For this purpose we here studied various motor behaviors in mice (n = 46) longitudinally up to 9 months after intrastriatal BoNT-A administration as previously reported for rats, and compared both outcomes. Apomorphine- and amphetamine-induced rotational behavior, spontaneous motor behavior, as well as lateralized neglect were studied in mice after the injection of single doses of BoNT-A into the right CPu, comparing them with sham-injected animals. Unilateral intrastriatal injection of BoNT-A in mice induced significantly increased contralateral apomorphine-induced rotations for 1 to 3 months, as well as significantly increased contralateral amphetamine-induced rotations 1 to 9 months after injection. In rats (n = 28), unilateral BoNT-A injection also induced significantly increased contralateral apomorphine-induced rotations 3 months after injection, but did not provoke amphetamine-induced rotations at all. Lateralized sensorimotor integration, forelimb preference, and forelimb stepping were significantly impaired on the left side. The differences in motor behaviors between rats and mice may be caused by different BoNT-A effects on cholinergic and catecholaminergic fibers in rat and mouse striata, interspecies differences in striatal receptor densities, and different connectomes of the basal ganglia. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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12 pages, 1108 KiB

Open AccessArticle

Early AbobotulinumtoxinA (Dysport^®) in Post-Stroke Adult Upper Limb Spasticity: ONTIME Pilot Study

by Raymond L Rosales, Jovita Balcaitiene, Hugues Berard, Pascal Maisonobe, Khean Jin Goh, Witsanu Kumthornthip, Mazlina Mazlan, Lydia Abdul Latif, Mary Mildred D. Delos Santos, Chayaporn Chotiyarnwong, Phakamas Tanvijit, Odessa Nuez and Keng He Kong

Toxins 2018, 10(7), 253; https://doi.org/10.3390/toxins10070253 - 21 Jun 2018

Cited by 34 | Viewed by 6224

Abstract

The ONTIME study investigated whether early post-stroke abobotulinumtoxinA injection delays appearance or progression of upper limb spasticity (ULS) symptoms. ONTIME (NCT02321436) was a 28-week, exploratory, double-blind, randomized, placebo-controlled study of abobotulinumtoxinA 500U in patients with ULS (Modified Ashworth Scale [MAS] score ≥ 2) [...] Read more.

The ONTIME study investigated whether early post-stroke abobotulinumtoxinA injection delays appearance or progression of upper limb spasticity (ULS) symptoms. ONTIME (NCT02321436) was a 28-week, exploratory, double-blind, randomized, placebo-controlled study of abobotulinumtoxinA 500U in patients with ULS (Modified Ashworth Scale [MAS] score ≥ 2) 2–12 weeks post-stroke. Patients were either symptomatic or asymptomatic (only increased MAS) at baseline. Primary efficacy outcome measure: time between injection and visit at which re-injection criteria were met (MAS ≥ 2 and ≥1, sign of symptomatic spasticity: pain, involuntary movements, impaired active or passive function). Forty-two patients were randomized (abobotulinumtoxinA 500U: n = 28; placebo: n = 14) with median 5.86 weeks since stroke. Median time to reach re-injection criteria was significantly longer for abobotulinumtoxinA (156 days) than placebo (32 days; log-rank: p = 0.0176; Wilcoxon: p = 0.0480). Eleven (39.3%) patients receiving abobotulinumtoxinA did not require re-injection for ≥28 weeks versus two (14.3%) in placebo group. In this exploratory study, early abobotulinumtoxinA treatment significantly delayed time to reach re-injection criteria compared with placebo in patients with post-stroke ULS. These findings suggest an optimal time for post-stroke spasticity management and help determine the design and sample sizes for larger confirmatory studies. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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9 pages, 2916 KiB

Open AccessCommunication

Detection of Clostridium tetani Neurotoxins Inhibited In Vivo by Botulinum Antitoxin B: Potential for Misleading Mouse Test Results in Food Controls

by Luca Bano, Elena Tonon, Ilenia Drigo, Marco Pirazzini, Angela Guolo, Giovanni Farina, Fabrizio Agnoletti and Cesare Montecucco

Toxins 2018, 10(6), 248; https://doi.org/10.3390/toxins10060248 - 19 Jun 2018

Cited by 4 | Viewed by 5275

Abstract

The presence of botulinum neurotoxin-producing Clostridia (BPC) in food sources is a public health concern. In favorable environmental conditions, BPC can produce botulinum neurotoxins (BoNTs) outside or inside the vertebrate host, leading to intoxications or toxico-infectious forms of botulism, respectively. BPC in food [...] Read more.

The presence of botulinum neurotoxin-producing Clostridia (BPC) in food sources is a public health concern. In favorable environmental conditions, BPC can produce botulinum neurotoxins (BoNTs) outside or inside the vertebrate host, leading to intoxications or toxico-infectious forms of botulism, respectively. BPC in food are almost invariably detected either by PCR protocols targeted at the known neurotoxin-encoding genes, or by the mouse test to assay for the presence of BoNTs in the supernatants of enrichment broths inoculated with the tested food sample. The sample is considered positive for BPC when the supernatant contains toxic substances that are lethal to mice, heat-labile and neutralized in vivo by appropriate polyclonal antibodies raised against purified BoNTs of different serotypes. Here, we report the detection in a food sample of a Clostridium tetani strain that produces tetanus neurotoxins (TeNTs) with the above-mentioned characteristics: lethal for mice, heat-labile and neutralized by botulinum antitoxin type B. Notably, neutralization occurred with two different commercially available type B antitoxins, but not with type A, C, D, E and F antitoxins. Although TeNT and BoNT fold very similarly, evidence that antitoxin B antiserum can neutralize the neurotoxic effect of TeNT in vivo has not been documented before. The presence of C. tetani strains in food can produce misleading results in BPC detection using the mouse test. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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7 pages, 2108 KiB

Open AccessArticle

Monocentric Prospective Study into the Sustained Effect of Incobotulinumtoxin A (XEOMIN^®) Botulinum Toxin in Chronic Refractory Migraine

by Ioana Ion, Dimitri Renard, Anne Le Floch, Marie De Verdal, Stephane Bouly, Anne Wacongne, Alessandro Lozza and Giovanni Castelnovo

Toxins 2018, 10(6), 221; https://doi.org/10.3390/toxins10060221 - 1 Jun 2018

Cited by 9 | Viewed by 5275

Abstract

Refractory chronic migraine is a disabling disorder impacting quality of life. BOTOX^® (Onabotulinumtoxin A) is approved as a prophylactic treatment of chronic migraine in patients unresponsive to at least three prior preventive treatments. The objective of this study was to determine the [...] Read more.

Refractory chronic migraine is a disabling disorder impacting quality of life. BOTOX^® (Onabotulinumtoxin A) is approved as a prophylactic treatment of chronic migraine in patients unresponsive to at least three prior preventive treatments. The objective of this study was to determine the prophylactic effect of 145 U XEOMIN^® (Incobotulinumtoxin A) injected at 31 specific sites in adult patients with refractory chronic migraine. Sixty-one patients (8 men and 53 women, mean age 50) with migraine were recruited, including 20 patients with isolated chronic migraine, 18 patients with chronic migraine associating tension-type headache, 12 patients with migraine associating medication overuse headache, and 11 patients with episodic disabling migraine. The mean number of injections and duration of treatment per patient was 3.5 (range 2–13) and 21 (6–68) months, respectively. From baseline to first injection, 44 patients (73%) had >50% reduction in frequency of migraine episodes, 29 patients (48%) showed >50% reduction in number of headache days, and 28 patients (46%) had a >50% reduction in drug intake. Stable response for all three parameters was observed after the last injection. XEOMIN^® thus seems to represent an effective and sustained prophylactic treatment of chronic migraine. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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13 pages, 980 KiB

Open AccessArticle

Botulinum Neurotoxin Injection for the Treatment of Recurrent Temporomandibular Joint Dislocation with and without Neurogenic Muscular Hyperactivity

by Kazuya Yoshida

Toxins 2018, 10(5), 174; https://doi.org/10.3390/toxins10050174 - 25 Apr 2018

Cited by 32 | Viewed by 9611

Abstract

The aim of this study was to compare treatment outcomes following intramuscular injection of botulinum neurotoxin (BoNT) in patients with recurrent temporomandibular joint dislocation, with and without muscle hyperactivity due to neurological diseases. Thirty-two patients (19 women and 13 men, mean age: 62.3 [...] Read more.

The aim of this study was to compare treatment outcomes following intramuscular injection of botulinum neurotoxin (BoNT) in patients with recurrent temporomandibular joint dislocation, with and without muscle hyperactivity due to neurological diseases. Thirty-two patients (19 women and 13 men, mean age: 62.3 years) with recurrent temporomandibular joint dislocation were divided into two groups: neurogenic (8 women and 12 men) and habitual (11 women and 1 man). The neurogenic group included patients having neurological disorders, such as Parkinson’s disease or oromandibular dystonia, that are accompanied by muscle hyperactivity. BoNT was administered via intraoral injection to the inferior head of the lateral pterygoid muscle. In total, BoNT injection was administered 102 times (mean 3.2 times/patient). The mean follow-up duration was 29.5 months. The neurogenic group was significantly (p < 0.001) younger (47.3 years) than the habitual group (84.8 years) and required significantly (p < 0.01) more injections (4.1 versus 1.7 times) to achieve a positive outcome. No significant immediate or delayed complications occurred. Thus, intramuscular injection of BoNT into the lateral pterygoid muscle is an effective and safe treatment for habitual temporomandibular joint dislocation. More injections are required in cases of neurogenic temporomandibular joint dislocation than in those of habitual dislocation without muscle hyperactivity. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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8 pages, 3674 KiB

Open AccessArticle

Lumbar Sympathetic Block with Botulinum Toxin Type A and Type B for the Complex Regional Pain Syndrome

by Yongki Lee, Chul Joong Lee, Eunjoo Choi, Pyung Bok Lee, Ho-Jin Lee and Francis Sahngun Nahm

Toxins 2018, 10(4), 164; https://doi.org/10.3390/toxins10040164 - 19 Apr 2018

Cited by 32 | Viewed by 6855

Abstract

A lumbar sympathetic ganglion block (LSB) is a therapeutic method for complex regional pain syndrome (CRPS) affecting the lower limbs. Recently, LSB with botulinum toxin type A and B was introduced as a novel method to achieve longer duration of analgesia. In this [...] Read more.

A lumbar sympathetic ganglion block (LSB) is a therapeutic method for complex regional pain syndrome (CRPS) affecting the lower limbs. Recently, LSB with botulinum toxin type A and B was introduced as a novel method to achieve longer duration of analgesia. In this study, we compared the botulinum toxin type A (BTA) with botulinum toxin type B (BTB) in performing LSB on patients with CRPS. LSB was performed with either BTA or BTB on patients with CRPS in their lower extremities. The length of time taken for patients to return to the pre-LSB pain score and the adverse effect of LSB with BTA/BTB were investigated. The median length of time taken for the patients to return to the pre-LSB pain score was 15 days for the BTA group and 69 days for the BTB group (P = 0.002). Scores on a visual analogue scale decreased in the patients of both groups, and no significant adverse effects were experienced. In conclusion, the administration of either BTA or BTB for LSB is a safe method to prolong the sympathetic blocking effect in patients with CRPS. BTB is more effective than BTA to prolong the sympathetic blocking effect in CRPS patients. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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12 pages, 4872 KiB

Open AccessArticle

“Appropriate Treatment” and Therapeutic Window in Spasticity Treatment with IncobotulinumtoxinA: From 100 to 1000 Units

by Giancarlo Ianieri, Riccardo Marvulli, Giulia Alessia Gallo, Pietro Fiore and Marisa Megna

Toxins 2018, 10(4), 140; https://doi.org/10.3390/toxins10040140 - 28 Mar 2018

Cited by 9 | Viewed by 6384

Abstract

Many neurological diseases (ischemic and hemorrhagic stroke, multiple sclerosis, infant cerebral palsy, spinal cord injuries, traumatic brain injury, and other cerebrovascular disorders) may cause muscle spasticity. Different therapeutic strategies have been proposed for the treatment of spasticity. One of the major treatments for [...] Read more.

Many neurological diseases (ischemic and hemorrhagic stroke, multiple sclerosis, infant cerebral palsy, spinal cord injuries, traumatic brain injury, and other cerebrovascular disorders) may cause muscle spasticity. Different therapeutic strategies have been proposed for the treatment of spasticity. One of the major treatments for tone modulation is botulinum toxin type A (BTX-A), performed in addition to other rehabilitation strategies based on individualized multidisciplinary programs aimed at achieving certain goals for each patient. Therapeutic plans must be precisely defined as they must balance the reduction of spastic hypertonia and retention of residual motor function. To perform and optimize the treatment, an accurate clinical and instrumental evaluation of spasticity is needed to determine how this symptom is invalidating and to choose the best doses, muscles and times of injection in each patient. We introduce an “appropriate treatment” and no “standard or high dosage treatment” concept based on our retrospective observational study on 120 patients lasting two years, according to the larger Therapeutic Index and Therapeutic Window of Incobotulinumtoxin A doses from 100 to 1000 units. We studied the efficiency and safety of this drug considering the clinical spasticity significance for specialist physicians and patients. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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13 pages, 8008 KiB

Open AccessFeature PaperArticle

A Study and Review of Effects of Botulinum Toxins on Mast Cell Dependent and Independent Pruritus

by Roshni Ramachandran, Marc J. Marino, Snighdha Paul, Zhenping Wang, Nicholas L. Mascarenhas, Sabine Pellett, Eric A. Johnson, Anna DiNardo and Tony L. Yaksh

Toxins 2018, 10(4), 134; https://doi.org/10.3390/toxins10040134 - 23 Mar 2018

Cited by 14 | Viewed by 5690

Abstract

Pruriceptive itch originates following activation of peripheral sensory nerve terminals when pruritogens come in contact with the skin. The ability of botulinum neurotoxins (BoNTs) to attenuate transmitter release from afferent terminals provides a rationale for studying its effect on pruritus. This study investigated [...] Read more.

Pruriceptive itch originates following activation of peripheral sensory nerve terminals when pruritogens come in contact with the skin. The ability of botulinum neurotoxins (BoNTs) to attenuate transmitter release from afferent terminals provides a rationale for studying its effect on pruritus. This study investigated the effects of BoNT/A1 and BoNT/B1 on mast cell dependent (Compound 48/80:48/80) and independent (Chloroquine:CQ) scratching. C57Bl/6 male mice received intradermal injection of 1.5 U of BoNT/A1, BoNT/B1 or saline 2, 7, 14 and 21 days prior to ipsilateral 48/80 or CQ at the nape of the neck. Ipsilateral hind paw scratching was determined using an automated recording device. The effect of BoNTs on 48/80 mediated mast cell degranulation was analyzed in human and murine mast cells and the presence of SNAREs was determined using qPCR, immunostaining and Western blot. Pre-treatment with BoNT/A1 and BoNT/B1 reduced 48/80 and CQ induced scratching behavior starting on day 2 with reversal by day 21. Both serotypes inhibited 48/80 induced mast cell degranulation. qPCR and immunostaining detected SNAP-25 mRNA and protein, respectively, in mast cells, however, Western blots did not. This study demonstrates the long-lasting anti-pruritic effects of two BoNT serotypes, in a murine pruritus model using two different mechanistically driven pruritogens. These data also indicate that BoNTs may have a direct effect upon mast cell degranulation. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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17 pages, 9304 KiB

Open AccessArticle

Botulinum Toxin B Affects Neuropathic Pain but Not Functional Recovery after Peripheral Nerve Injury in a Mouse Model

by Alba Finocchiaro, Sara Marinelli, Federica De Angelis, Valentina Vacca, Siro Luvisetto and Flaminia Pavone

Toxins 2018, 10(3), 128; https://doi.org/10.3390/toxins10030128 - 18 Mar 2018

Cited by 16 | Viewed by 5974

Abstract

Clinical use of neurotoxins from Clostridium botulinum is well established and is continuously expanding, including in treatment of pain conditions. Background: The serotype A (BoNT/A) has been widely investigated, and current data demonstrate that it induces analgesia and modulates nociceptive processing initiated [...] Read more.

Clinical use of neurotoxins from Clostridium botulinum is well established and is continuously expanding, including in treatment of pain conditions. Background: The serotype A (BoNT/A) has been widely investigated, and current data demonstrate that it induces analgesia and modulates nociceptive processing initiated by inflammation or nerve injury. Given that data concerning the serotype B (BoNT/B) are limited, the aim of the present study was to verify if also BoNT/B is able not only to counteract neuropathic pain, but also to interfere with inflammatory and regenerative processes associated with the nerve injury. Methods: As model of neuropathic pain, chronic constriction injury (CCI) of the sciatic nerve was performed in CD1 male mice. Mice were intraplantarly injected with saline (control) or BoNT/B (5 or 7.5 pg/mouse) into the injured hindpaw. For comparison, another mouse group was injected with BoNT/A (15 pg/mouse). Mechanical allodynia and functional recovery of the injured paw was followed for 101 days. Spinal cords and sciatic nerves were collected at day 7 for immunohistochemistry. Results and Conclusions: The results of this study show that BoNT/B is a powerful biological molecule that, similarly to BoNT/A, can reduce neuropathic pain over a long period of time. However, the analgesic effects are not associated with an improvement in functional recovery, clearly highlighting an important difference between the two serotypes for the treatment of this chronic pain state. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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14 pages, 2578 KiB

Open AccessArticle

The Effect of Botulinum Neurotoxin Serotype a Heavy Chain on the Growth Related Proteins and Neurite Outgrowth after Spinal Cord Injury in Rats

by Ya-Fang Wang, Fu Liu, Jing Lan, Juan Bai and Xia-Qing Li

Toxins 2018, 10(2), 66; https://doi.org/10.3390/toxins10020066 - 2 Feb 2018

Cited by 8 | Viewed by 5973

Abstract

(1) Background: The botulinum toxin A (BoNT-A) heavy chain (HC) can stimulate the growth of primary motor neurites. (2) Methods: A recombinant BoNT/A HC was injected locally plus interval intrathecal catheter of BoNT/A HC to rats with ipsilateral semi-dissociated lumbar spinal cord injuries [...] Read more.

(1) Background: The botulinum toxin A (BoNT-A) heavy chain (HC) can stimulate the growth of primary motor neurites. (2) Methods: A recombinant BoNT/A HC was injected locally plus interval intrathecal catheter of BoNT/A HC to rats with ipsilateral semi-dissociated lumbar spinal cord injuries (SCIs). First, 2D gel with a silver nitrate stain was applied to detect the general pattern of protein expression. Growth associated protein 43 (GAP-43) and superior cervical ganglion 10 (SCG10) were chosen to represent the altered proteins, based on their molecular weight and pI, and were used to further detect their expression. Meanwhile, the neuronal processes were measured. The measurements of thermal hyperalgesia and grasp power at the ipsilateral hindlimb were used to evaluate spinal sensory and motor function, respectively. (3) Results: The local injection of BoNT/A HC followed by its intrathecal catheter intervally altered the spinal protein expression pattern after an SCI; protein expression was similar to normal levels or displayed a remarkable increase. The changes in the expression and distribution of phosphorylated growth associated protein 43(p-GAP 43) and superior cervical ganglion 10 (SCG 10) indicated that the administration of BoNT/A HC to the SCI significantly amplified the expression of p-GAP43 and SCG10 (p < 0.05). Meanwhile, the positive immunofluorescent staining for both p-GAP43 and SCG10 was mainly present near the rostral aspect of the injury, both in the cytoplasm and the neuronal processes. Moreover, the outgrowth of neurites was stimulated by the BoNT/A HC treatment; this was evident from the increase in neurite length, number of branches and the percentage of cells with neuronal processes. The results from the spinal function tests suggested that the BoNT/A HC did not affect sensation, but had a large role in improving the ipsilateral hindlimb grasp power (p < 0.05). (4) Conclusions: The local injection with the intermittent intrathecal administration of BoNT/A heavy chain to rats with SCI increased the local expression of GAP-43 and SCG 10, which might be affiliated with the regeneration of neuronal processes surrounding the injury, and might also be favorable to the relief of spinal motor dysfunction. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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9 pages, 1082 KiB

Open AccessArticle

Botulinum Toxin A for Sialorrhoea Associated with Neurological Disorders: Evaluation of the Relationship between Effect of Treatment and the Number of Glands Treated

by Domenico A. Restivo, Mariangela Panebianco, Antonino Casabona, Sara Lanza, Rosario Marchese-Ragona, Francesco Patti, Stefano Masiero, Antonio Biondi and Angelo Quartarone

Toxins 2018, 10(2), 55; https://doi.org/10.3390/toxins10020055 - 27 Jan 2018

Cited by 30 | Viewed by 5163

Abstract

Background: Sialorrhoea and drooling are disabling manifestations of different neurological disorders. The aim of this study was to evaluate the effects of botulinum neurotoxin type A (BoNT/A) injection on hypersalivation in 90 patients with neurological diseases of different aetiologies, and to define [...] Read more.

Background: Sialorrhoea and drooling are disabling manifestations of different neurological disorders. The aim of this study was to evaluate the effects of botulinum neurotoxin type A (BoNT/A) injection on hypersalivation in 90 patients with neurological diseases of different aetiologies, and to define the minimum number of injected salivary glands to reduce sialorrhoea. Determining the minimum number of glands that need to be engaged in order to have a significant reduction in drooling may be very useful for establishing the minimum total dosage of BoNT/A that may be considered effective in the treatment of hypersalivation. Methods: Twenty-five mouse units (MU) of BoNT/A (onabotulinumtoxin A, Botox; Allergan, Irvine, CA, USA; 100 MU/2 mL, 0.9% saline; or incobotulinumtoxin A, Xeomin; Merz Pharma, Germany; 100 MU/2 mL, 0.9% saline) were percutaneously injected into the parotid (p) glands and/or submandibular (s) glands under ultrasound control. On this basis, patients were divided into three groups. In group A (30 patients), BoNT/A injections were performed into four glands; in group B (30 patients), into three glands, and in group C (30 patients), into two glands. Patients treated in three glands (group B) were divided into two subgroups based on the treated glands (2 p + 1 s = 15 patients; 2 s + 1 p = 15 patients). Similarly, patients being injected in two glands (group C) were subdivided into three groups (2 p = 10 patients; 1 p + 1 s = 10 patients; 2 s = 10 patients). In patients who were injected in three and two salivary glands, saline solution was injected into the remaining one and two glands, respectively. Assessments were performed at baseline and at 2 weeks after the injections. Results: BoNT/A significantly reduced sialorrhoea in 82 out of 90 patients. The effect was more evident in patients who had four glands injected than when three or two glands were injected. The injections into three glands were more effective than injections into two glands. Conclusions: Our results have shown that BoNT/A injections induced a significant reduction in sialorrhoea in most patients (91%). In addition, we demonstrated that sialorrhoea associated with different neurological diseases was better controlled when the number of treated glands was higher. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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Review

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11 pages, 238 KiB

Open AccessReview

Novel Applications of OnabotulinumtoxinA in Lower Urinary Tract Dysfunction

by Jia-Fong Jhang and Hann-Chorng Kuo

Toxins 2018, 10(7), 260; https://doi.org/10.3390/toxins10070260 - 26 Jun 2018

Cited by 16 | Viewed by 3879

Abstract

OnabotulinumtoxinA (BoNT-A) was first used to treat neurogenic lower urinary tract dysfunction (LUTD) 30 years ago. Recently, application of BoNT-A in LUTD have become more common since the approval of intravesical BoNT-A injection for patients with both overactive bladders (OAB) and neurogenic detrusor [...] Read more.

OnabotulinumtoxinA (BoNT-A) was first used to treat neurogenic lower urinary tract dysfunction (LUTD) 30 years ago. Recently, application of BoNT-A in LUTD have become more common since the approval of intravesical BoNT-A injection for patients with both overactive bladders (OAB) and neurogenic detrusor overactivity (NDO) by regulatory agencies in many countries. Although unlicensed, BoNT-A has been recommended to treat patients with interstitial cystitis/bladder pain syndrome (IC/BPS) under different guidelines. BoNT-A delivery with liposome-encapsulation and gelation hydrogel intravesical instillation provided a potentially less invasive and more convenient form of application for patients with OAB or IC/BPS. BoNT-A injections into the urethral sphincter for spinal cord injury patients with detrusor-sphincter dyssynergia have been used for a long time. New evidence revealed that it could also be applied to patients with non-neurogenic dysfunctional voiding. Previous studies and meta-analyses suggest that BoNT-A injections for patients with benign prostate hyperplasia do not have a better therapeutic effect than placebo. However, new randomized and placebo-controlled trials revealed intraprostatic BoNT-A injection is superior to placebo in specific patients. A recent trial also showed intraprostatic BoNT-A injection could significantly reduce pain in patients with chronic prostatitis. Both careful selection of patients and prudent use of urodynamic evaluation results to confirm diagnoses are essential for successful outcomes of BoNT-A treatment for LUTD. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

14 pages, 489 KiB

Open AccessReview

Botulinum Toxin for Central Neuropathic Pain

by Jihye Park and Myung Eun Chung

Toxins 2018, 10(6), 224; https://doi.org/10.3390/toxins10060224 - 1 Jun 2018

Cited by 53 | Viewed by 10073

Abstract

Botulinum toxin (BTX) is widely used to treat muscle spasticity by acting on motor neurons. Recently, studies of the effects of BTX on sensory nerves have been reported and several studies have been conducted to evaluate its effects on peripheral and central neuropathic [...] Read more.

Botulinum toxin (BTX) is widely used to treat muscle spasticity by acting on motor neurons. Recently, studies of the effects of BTX on sensory nerves have been reported and several studies have been conducted to evaluate its effects on peripheral and central neuropathic pain. Central neuropathic pain includes spinal cord injury-related neuropathic pain, post-stroke shoulder pain, multiple sclerosis-related pain, and complex regional pain syndrome. This article reviews the mechanism of central neuropathic pain and assesses the effect of BTX on central neuropathic pain. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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27 pages, 954 KiB

Open AccessReview

The Expanding Therapeutic Utility of Botulinum Neurotoxins

by Elena Fonfria, Jacquie Maignel, Stephane Lezmi, Vincent Martin, Andrew Splevins, Saif Shubber, Mikhail Kalinichev, Keith Foster, Philippe Picaut and Johannes Krupp

Toxins 2018, 10(5), 208; https://doi.org/10.3390/toxins10050208 - 18 May 2018

Cited by 85 | Viewed by 9187

Abstract

Botulinum neurotoxin (BoNT) is a major therapeutic agent that is licensed in neurological indications, such as dystonia and spasticity. The BoNT family, which is produced in nature by clostridial bacteria, comprises several pharmacologically distinct proteins with distinct properties. In this review, we present [...] Read more.

Botulinum neurotoxin (BoNT) is a major therapeutic agent that is licensed in neurological indications, such as dystonia and spasticity. The BoNT family, which is produced in nature by clostridial bacteria, comprises several pharmacologically distinct proteins with distinct properties. In this review, we present an overview of the current therapeutic landscape and explore the diversity of BoNT proteins as future therapeutics. In recent years, novel indications have emerged in the fields of pain, migraine, overactive bladder, osteoarthritis, and wound healing. The study of biological effects distal to the injection site could provide future opportunities for disease-tailored BoNT therapies. However, there are some challenges in the pharmaceutical development of BoNTs, such as liquid and slow-release BoNT formulations; and, transdermal, transurothelial, and transepithelial delivery. Innovative approaches in the areas of formulation and delivery, together with highly sensitive analytical tools, will be key for the success of next generation BoNT clinical products. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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11 pages, 300 KiB

Open AccessFeature PaperReview

Exploiting Botulinum Neurotoxins for the Study of Brain Physiology and Pathology

by Matteo Caleo and Laura Restani

Toxins 2018, 10(5), 175; https://doi.org/10.3390/toxins10050175 - 25 Apr 2018

Cited by 15 | Viewed by 4898

Abstract

Botulinum neurotoxins are metalloproteases that specifically cleave N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in synaptic terminals, resulting in a potent inhibition of vesicle fusion and transmitter release. The family comprises different serotypes (BoNT/A to BoNT/G). The natural target of these toxins [...] Read more.

Botulinum neurotoxins are metalloproteases that specifically cleave N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) proteins in synaptic terminals, resulting in a potent inhibition of vesicle fusion and transmitter release. The family comprises different serotypes (BoNT/A to BoNT/G). The natural target of these toxins is represented by the neuromuscular junction, where BoNTs block acetylcholine release. In this review, we describe the actions of botulinum toxins after direct delivery to the central nervous system (CNS), where BoNTs block exocytosis of several transmitters, with near-complete silencing of neural networks. The use of clostridial neurotoxins in the CNS has allowed us to investigate specifically the role of synaptic activity in different physiological and pathological processes. The silencing properties of BoNTs can be exploited for therapeutic purposes, for example to counteract pathological hyperactivity and seizures in epileptogenic brain foci, or to investigate the role of activity in degenerative diseases like prion disease. Altogether, clostridial neurotoxins and their derivatives hold promise as powerful tools for both the basic understanding of brain function and the dissection and treatment of activity-dependent pathogenic pathways. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

29 pages, 19193 KiB

Open AccessReview

Therapeutic Approaches of Botulinum Toxin in Gynecology

by Marius Alexandru Moga, Oana Gabriela Dimienescu, Andreea Bălan, Ioan Scârneciu, Barna Barabaș and Liana Pleș

Toxins 2018, 10(4), 169; https://doi.org/10.3390/toxins10040169 - 21 Apr 2018

Cited by 19 | Viewed by 8384

Abstract

Botulinum toxins (BoNTs) are produced by several anaerobic species of the genus Clostridium and, although they were originally considered lethal toxins, today they find their usefulness in the treatment of a wide range of pathologies in various medical specialties. Botulinum neurotoxin has been [...] Read more.

Botulinum toxins (BoNTs) are produced by several anaerobic species of the genus Clostridium and, although they were originally considered lethal toxins, today they find their usefulness in the treatment of a wide range of pathologies in various medical specialties. Botulinum neurotoxin has been identified in seven different isoforms (BoNT-A, BoNT-B, BoNT-C, BoNT-D, BoNT-E, BoNT-F, and BoNT-G). Neurotoxigenic Clostridia can produce more than 40 different BoNT subtypes and, recently, a new BoNT serotype (BoNT-X) has been reported in some studies. BoNT-X has not been shown to actually be an active neurotoxin despite its catalytically active LC, so it should be described as a putative eighth serotype. The mechanism of action of the serotypes is similar: they inhibit the release of acetylcholine from the nerve endings but their therapeutically potency varies. Botulinum toxin type A (BoNT-A) is the most studied serotype for therapeutic purposes. Regarding the gynecological pathology, a series of studies based on the efficiency of its use in the treatment of refractory myofascial pelvic pain, vaginism, dyspareunia, vulvodynia and overactive bladder or urinary incontinence have been reported. The current study is a review of the literature regarding the efficiency of BoNT-A in the gynecological pathology and on the long and short-term effects of its administration. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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11 pages, 283 KiB

Open AccessReview

Analgesic Effects of Botulinum Toxin in Children with CP

by Josephine Sandahl Michelsen, Gitte Normann and Christian Wong

Toxins 2018, 10(4), 162; https://doi.org/10.3390/toxins10040162 - 19 Apr 2018

Cited by 19 | Viewed by 4579

Abstract

Experiencing pain is the greatest contributor to a reduced quality of life in children with cerebral palsy (CP). The presence of pain is quite common (~60%) and increases with age. This leads to missed school days, less participation, and reduced ambulation. Despite these [...] Read more.

Experiencing pain is the greatest contributor to a reduced quality of life in children with cerebral palsy (CP). The presence of pain is quite common (~60%) and increases with age. This leads to missed school days, less participation, and reduced ambulation. Despite these alarming consequences, strategies to relieve the pain are absent and poorly studied. Moreover, it is difficult to evaluate pain in this group of children, especially in cases of children with cognitive deficits, and tools for pain evaluation are often inadequate. Botulinum toxin has been shown to alleviate pain in a variety of disorders and could potentially have an analgesic effect in children with CP as well. Even though most of the studies presented here show promising results, many also have limitations in their methodology as it is unlikely to capture all dimensions of pain in this heterogeneous group using only one assessment tool. In this review, we present a new way of examining the analgesic effect of botulinum toxin in children with CP using a variety of pain scores. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

12 pages, 4099 KiB

Open AccessFeature PaperReview

Botulinum Toxin Type A—A Modulator of Spinal Neuron–Glia Interactions under Neuropathic Pain Conditions

by Ewelina Rojewska, Anna Piotrowska, Katarzyna Popiolek-Barczyk and Joanna Mika

Toxins 2018, 10(4), 145; https://doi.org/10.3390/toxins10040145 - 2 Apr 2018

Cited by 33 | Viewed by 7690

Abstract

Neuropathic pain represents a significant clinical problem because it is a chronic condition often refractory to available therapy. Therefore, there is still a strong need for new analgesics. Botulinum neurotoxin A (BoNT/A) is used to treat a variety of clinical diseases associated with [...] Read more.

Neuropathic pain represents a significant clinical problem because it is a chronic condition often refractory to available therapy. Therefore, there is still a strong need for new analgesics. Botulinum neurotoxin A (BoNT/A) is used to treat a variety of clinical diseases associated with pain. Glia are in continuous bi-directional communication with neurons to direct the formation and refinement of synaptic connectivity. This review addresses the effects of BoNT/A on the relationship between glia and neurons under neuropathic pain. The inhibitory action of BoNT/A on synaptic vesicle fusion that blocks the release of miscellaneous pain-related neurotransmitters is known. However, increasing evidence suggests that the analgesic effect of BoNT/A is mediated through neurons and glial cells, especially microglia. In vitro studies provide evidence that BoNT/A exerts its anti-inflammatory effect by diminishing NF-κB, p38 and ERK1/2 phosphorylation in microglia and directly interacts with Toll-like receptor 2 (TLR2). Furthermore, BoNT/A appears to have no more than a slight effect on astroglia. The full activation of TLR2 in astroglia appears to require the presence of functional TLR4 in microglia, emphasizing the significant interaction between those cell types. In this review, we discuss whether and how BoNT/A affects the spinal neuron–glia interaction and reduces the development of neuropathy. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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17 pages, 379 KiB

Open AccessFeature PaperReview

Antipruritic Effects of Botulinum Neurotoxins

by Parisa Gazerani

Toxins 2018, 10(4), 143; https://doi.org/10.3390/toxins10040143 - 29 Mar 2018

Cited by 15 | Viewed by 5027

Abstract

This review explores current evidence to demonstrate that botulinum neurotoxins (BoNTs) exert antipruritic effects. Both experimental and clinical conditions in which botulinum neurotoxins have been applied for pruritus relief will be presented and significant findings will be highlighted. Potential mechanisms underlying antipruritic effects [...] Read more.

This review explores current evidence to demonstrate that botulinum neurotoxins (BoNTs) exert antipruritic effects. Both experimental and clinical conditions in which botulinum neurotoxins have been applied for pruritus relief will be presented and significant findings will be highlighted. Potential mechanisms underlying antipruritic effects will also be discussed and ongoing challenges and unmet needs will be addressed. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

14 pages, 5464 KiB

Open AccessReview

Correction of Malocclusion by Botulinum Neurotoxin Injection into Masticatory Muscles

by Hyun Seok and Seong-Gon Kim

Toxins 2018, 10(1), 27; https://doi.org/10.3390/toxins10010027 - 2 Jan 2018

Cited by 16 | Viewed by 10167

Abstract

Botulinum toxin (BTX) is a neurotoxin, and its injection in masticatory muscles induces muscle weakness and paralysis. This paralytic effect of BTX induces growth retardation of the maxillofacial bones, changes in dental eruption and occlusion state, and facial asymmetry. Using masticatory muscle paralysis [...] Read more.

Botulinum toxin (BTX) is a neurotoxin, and its injection in masticatory muscles induces muscle weakness and paralysis. This paralytic effect of BTX induces growth retardation of the maxillofacial bones, changes in dental eruption and occlusion state, and facial asymmetry. Using masticatory muscle paralysis and its effect via BTX, BTX can be used for the correction of malocclusion after orthognathic surgery and mandible fracture. The paralysis of specific masticatory muscles by BTX injection reduces the tensional force to the mandible and prevents relapse and changes in dental occlusion. BTX injection in the anterior belly of digastric and mylohyoid muscle prevents the open-bite and deep bite of dental occlusion and contributes to mandible stability after orthognathic surgery. The effect of BTX injection in masticatory muscles for maxillofacial bone growth and dental occlusion is reviewed in this article. The clinical application of BTX is also discussed for the correction of dental malocclusion and suppression of post-operative relapse after mandibular surgery. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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251 KiB

Open AccessReview

Botulinum Toxin in the Field of Dermatology: Novel Indications

by Yoon Seob Kim, Eun Sun Hong and Hei Sung Kim

Toxins 2017, 9(12), 403; https://doi.org/10.3390/toxins9120403 - 16 Dec 2017

Cited by 40 | Viewed by 6621

Abstract

Since its approval by the US Food and Drug Administration in 2002 for glabellar wrinkles, botulinum toxin (BTX) has been widely used to correct facial wrinkles. As a result, many consider BTX synonymous with cosmetic dermatology. Recent studies indicate that BTX elicits biological [...] Read more.

Since its approval by the US Food and Drug Administration in 2002 for glabellar wrinkles, botulinum toxin (BTX) has been widely used to correct facial wrinkles. As a result, many consider BTX synonymous with cosmetic dermatology. Recent studies indicate that BTX elicits biological effects on various skin cell types via the modulation of neurotransmitter release, and it seems that BTX has a wider zone of dermatologic influence than originally understood. Clinicians and researchers are now beginning to explore the potential of BTX beyond the amelioration of facial lines and encouraging results are seen with BTX in a variety of skin conditions. In this paper, we review novel dermatological indications of BTX which includes (but not limited to) scar prevention, facial flushing, post-herpetic neuralgia and itch. These areas show great promise, but there is definite need for larger, double-blinded, randomized control trials against established treatments before BTX becomes a clinical reality. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

214 KiB

Open AccessFeature PaperReview

Botulinum Toxin in Management of Limb Tremor

by Elina Zakin and David Simpson

Toxins 2017, 9(11), 365; https://doi.org/10.3390/toxins9110365 - 10 Nov 2017

Cited by 16 | Viewed by 5145

Abstract

Essential tremor is characterized by persistent, usually bilateral and symmetric, postural or kinetic activation of agonist and antagonist muscles involving either the distal or proximal upper extremity. Quality of life is often affected and one’s ability to perform daily tasks becomes impaired. Oral [...] Read more.

Essential tremor is characterized by persistent, usually bilateral and symmetric, postural or kinetic activation of agonist and antagonist muscles involving either the distal or proximal upper extremity. Quality of life is often affected and one’s ability to perform daily tasks becomes impaired. Oral therapies, including propranolol and primidone, can be effective in the management of essential tremor, although adverse effects can limit their use and about 50% of individuals lack response to oral pharmacotherapy. Locally administered botulinum toxin injection has become increasingly useful in the management of essential tremor. Targeting of select muscles with botulinum toxin is an area of active research, and muscle selection has important implications for toxin dosing and functional outcomes. The use of anatomical landmarks with palpation, EMG guidance, electrical stimulation, and ultrasound has been studied as a technique for muscle localization in toxin injection. Earlier studies implemented a standard protocol for the injection of (predominantly) wrist flexors and extensors using palpation and EMG guidance. Targeting of muscles by selection of specific activators of tremor (tailored to each patient) using kinematic analysis might allow for improvement in efficacy, including functional outcomes. It is this individualized muscle selection and toxin dosing (requiring injection within various sites of a single muscle) that has allowed for success in the management of tremors. Full article

(This article belongs to the Special Issue Botulinum Neurotoxins and Nervous System: Future Challenges for Novel Indications)

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