Beyond Wrinkles: A Comprehensive Review of the Uses of Botulinum Toxin.

BACKGROUND: Botulinum neurotoxin (BoNT) exhibits inhibitory effects on the neuromuscular junction, and its use is well established in cosmetic dermatology. Our review aims to analyze the evidence for its use in the treatment of various dermatological, neurological, gastroenterological, ophthalmological, otorhinolaryngological, dental, urological, gynecological, and cardiovascular disorders. METHODS: A systematic review of the literature was performed for studies published between 2012 and 2022 that discussed the therapeutic use of BoNT in human participants. A total of 58 studies were selected for inclusion in this review.  Results: We discovered a large range of therapeutic applications of BoNT toxin beyond aesthetic and US Food and Drug Administration (FDA)-approved non-aesthetic uses.  Conclusions: BoNT is a powerful neurotoxin that has varied FDA-approved indications and has been studied in a wide range of therapeutic applications. Further investigation through higher power studies is needed to assess the potential of BoNT and expand its versatility across other medical specialties.  J Drugs Dermatol. 2024;23(3):173-186. doi:10.36849/JDD.7243e.

Do repetitive botulinum neurotoxin injections induce muscle fibrosis? Sonographic observation of the masseter muscle.

OBJECTIVE: In the esthetic field, the masseter muscle is commonly targeted by botulinum neurotoxin for facial contouring. However, multiple botulinum neurotoxin injections have been reported to cause muscle fibrosis. Ultrasonography can be useful for clinical consideration in such cases. MATERIALS AND METHODS: This study presents nine cases of masseteric fibrosis caused by repeated botulinum neurotoxin injections with ultrasonographic analysis of full and partial masseteric fibrosis. RESULTS: Repetitive botulinum neurotoxin injections resulted in reduced masseter muscle volume, which frequently appeared hyperechoic on ultrasonography. The hyperechoic region was mostly located in the deep and posterior portions; however, in some cases, it was observed throughout the muscle, including the superficial, deep, or both areas. CONCLUSION: The fibrotic masseter muscles appear hyperechoic, and ultrasonography is necessary to analyze the degree and location of fibrosis. Predictions can be made for cases in which botulinum neurotoxin injections may have less of an effect after ultrasonography. Because muscle fibrosis can be localized, it is necessary to confirm the degree and location of fibrosis before determining the effective area of injection. In clinical practice, muscle fibrosis may be visible in a specific area where blind injections are administered.

Comparing the evidence for botulinum neurotoxin injections in paediatric anterior drooling: a scoping review.

Paediatric anterior drooling has a major impact on the daily lives of children and caregivers. Intraglandular botulinum neurotoxin type-A (BoNT-A) injections are considered an effective treatment to diminish drooling. However, there is no international consensus on which major salivary glands should be injected to obtain optimal treatment effect while minimizing the risk of side effects. This scoping review aimed to explore the evidence for submandibular BoNT-A injections and concurrent submandibular and parotid (i.e. four-gland) injections, respectively, and assess whether outcomes could be compared across studies to improve decision making regarding the optimal initial BoNT-A treatment approach for paediatric anterior drooling. PubMed, Embase, and Web of Science were searched to identify relevant studies (until October 1, 2023) on submandibular or four-gland BoNT-A injections for the treatment of anterior drooling in children with neurodevelopmental disabilities. Similarities and differences in treatment, patient, outcome, and follow-up characteristics were assessed. Twenty-eight papers were identified; 7 reporting on submandibular injections and 21 on four-gland injections. No major differences in treatment procedures or timing of follow-up were found. However, patient characteristics were poorly reported, there was great variety in outcome measurement, and the assessment of side effects was not clearly described.   Conclusion: This review highlights heterogeneity in outcome measures and patient population descriptors among studies on paediatric BoNT-A injections, limiting the ability to compare treatment effectiveness between submandibular and four-gland injections. These findings emphasize the need for more extensive and uniform reporting of patient characteristics and the implementation of a core outcome measurement set to allow for comparison of results between studies and facilitate the optimization of clinical practice guidelines. What is Known: • There is no international consensus on which salivary glands to initially inject with BoNT-A to treat paediatric drooling. What is New: • Concluding on the optimal initial BoNT-A treatment based on literature is currently infeasible. There is considerable heterogeneity in outcome measures used to quantify anterior drooling.and clinical characteristics of children treated with intraglandular BoNT-A are generally insufficiently reported. • Consensus-based sets of outcome measures and patient characteristics should be developed and implemented.

Neuromodulators for Skin.

Neurotoxins are the most popular nonsurgical aesthetic procedure for men and women of all ages. Five botulinum toxin A (BoNTA) products represent the current palette of available BoNTA for cosmetic use. Off-label uses of BoNTA continue to expand and are now used for skin rejuvenation, to treat various skin disorders, and in facial nerve paralysis. Dermal and subdermal injections of dilute BoNTA has grown in popularity and been shown to improve skin texture and quality. Common targets for chemodenervation in facial nerve synkinesis are ipsilateral orbicularis oculi, mentalis, depressor anguli oris, buccinator, corrugator muscles, and the ipsilateral and/or contralateral frontalis.

"Pseudo"-Secondary Treatment Failure Explained via Disease Progression and Effective Botulinum Toxin Therapy: A Pilot Simulation Study.

BACKGROUND: The objective of this study was to provide evidence from a simple simulation. In patients with focal dystonia, an initial good response to botulinum neurotoxin (BoNT) injections followed by a secondary worsening does not necessarily arise from an antibody-induced secondary treatment failure (NAB-STF), but may stem from a "pseudo"-secondary treatment failure (PSEUDO-STF). METHODS: The simulation of the outcome after BoNT long-term treatment was performed in four steps: 1. The effect of the first single BoNT injection (SI curve) was displayed as a 12-point graph, corresponding to the mean improvement from weeks 1 to 12. 2. The remaining severity of the dystonia during the nth injection cycle was calculated by subtracting the SI curve (weighted by the outcome after n - 1 cycles) from the outcome after week 12 of the (n - 1)th cycle. 3. A graph was chosen (the PRO curve), which represents the progression of the severity of the underlying disease during BoNT therapy. 4. The interaction between the outcome during the nth BoNT cycle and the PRO curve was determined. RESULTS: When the long-term outcome after n cycles of BoNT injections (applied every 3 months) was simulated as an interactive process, subtracting the effect of the first cycle (weighted by the outcome after n - 1 cycles) and adding the progression of the disease, an initial good improvement followed by secondary worsening results. This long-term outcome depends on the steepness of the progression and the duration of action of the first injection cycle. We termed this response behavior a "pseudo"-secondary treatment failure, as it can be compensated via a dose increase. CONCLUSION: A secondary worsening following an initial good response in BoNT therapy of focal dystonia might not necessarily indicate neutralizing antibody induction but could stem from a "PSEUDO"-STF (a combination of good response behavior and progression of the underlying disease). Thus, an adequate dose adaptation must be conducted before diagnosing a secondary treatment failure in the strict sense.

Introduction to the Toxins Special Issue on Botulinum Toxins: New Uses in the Treatment of Diseases.

Studies on animals and humans have amply demonstrated the therapeutic efficacy of botulinum neurotoxins (BoNTs) in many pathologies [...].

Beyond Wrinkles: A Comprehensive Review of the Uses of Botulinum Toxin.

BACKGROUND: Botulinum neurotoxin (BoNT) exhibits inhibitory effects on the neuromuscular junction, and its use is well established in cosmetic dermatology. Our review aims to analyze the evidence for its use in the treatment of various dermatological, neurological, gastroenterological, ophthalmological, otorhinolaryngological, dental, urological, gynecological, and cardiovascular disorders. METHODS: A systematic review of the literature was performed for studies published between 2012 and 2022 that discussed the therapeutic use of BoNT in human participants. A total of 58 studies were selected for inclusion in this review. RESULTS: We discovered a large range of therapeutic applications of BoNT toxin beyond aesthetic and US Food and Drug Administration (FDA)-approved non-aesthetic uses. CONCLUSIONS: BoNT is a powerful neurotoxin that has varied FDA-approved indications and has been studied in a wide range of therapeutic applications. Further investigation through higher power studies is needed to assess the potential of BoNT and expand its versatility across other medical specialties. J Drugs Dermatol. 2023;22(9): doi:10.36849/JDD.7243e.

Placement of High Dose Neurotoxins for Treatment-Resistant Rosacea.

Rosacea is a chronic inflammatory skin condition characterized by facial flushing, erythema, telangiectasias, and papulopustular lesions. Treatment for rosacea includes limiting inciting factors and reducing inflammation with topical and oral therapies. Traditional therapies primarily focus on the papulopustular or background erythematotelangiectatic component of rosacea, leaving symptoms of flushing poorly controlled and profoundly impacting the quality of life of patients. Neuromodulators have been speculated to improve the flushing component of rosacea by reducing mast cell degranulation and the release of neuropeptides. However, its use for symptomatic relief in refractory flushing rosacea has been limited by side effects such as facial muscle weakness or paralysis. We present the use of strategic placement of high-dose neuromodulators for treatment-resistant rosacea. This approach has resulted in the gradual stabilization of symptoms, improved quality of life, and superior side effect profile. Silence C, Kourosh AS, Gilbert E. Placement of high-dose neurotoxins for treatment-resistant rosacea. J Drugs Dermatol. 2023;22(6):605-606. doi:10.36849/JDD.7237.

Botulinum Neurotoxin Injections in Children with Self-Injurious Behaviors.

Self-injurious behaviors are repetitive, persistent actions directed toward one's body that threaten or cause physical harm. These behaviors are seen within a broad spectrum of neurodevelopmental and neuropsychiatric conditions, often associated with intellectual disability. Injuries can be severe and distressing to patients and caregivers. Furthermore, injuries can be life-threatening. Often, these behaviors are challenging to treat and require a tiered, multimodal approach which may include mechanical/physical restraints, behavioral therapy, pharmacotherapy, or in some cases, surgical management, such as tooth extraction or deep brain stimulation. Here, we describe a series of 17 children who presented to our institution with self-injurious behaviors in whom botulinum neurotoxin injections were found helpful in preventing or lessening self-injury.

A Bayesian Network Meta-Analysis and Systematic Review of Guidance Techniques in Botulinum Toxin Injections and Their Hierarchy in the Treatment of Limb Spasticity.

Accurate targeting of overactive muscles is fundamental for successful botulinum neurotoxin (BoNT) injections in the treatment of spasticity. The necessity of instrumented guidance and the superiority of one or more guidance techniques are ambiguous. Here, we sought to investigate if guided BoNT injections lead to a better clinical outcome in adults with limb spasticity compared to non-guided injections. We also aimed to elucidate the hierarchy of common guidance techniques including electromyography, electrostimulation, manual needle placement and ultrasound. To this end, we conducted a Bayesian network meta-analysis and systematic review with 245 patients using the MetaInsight software, R and the Cochrane Review Manager. Our study provided, for the first time, quantitative evidence supporting the superiority of guided BoNT injections over the non-guided ones. The hierarchy comprised ultrasound on the first level, electrostimulation on the second, electromyography on the third and manual needle placement on the last level. The difference between ultrasound and electrostimulation was minor and, thus, appropriate contextualization is essential for decision making. Taken together, guided BoNT injections based on ultrasound and electrostimulation performed by experienced practitioners lead to a better clinical outcome within the first month post-injection in adults with limb spasticity. In the present study, ultrasound performed slightly better, but large-scale trials should shed more light on which modality is superior.

Botulinum neurotoxin: A therapeutic powerhouse with broad clinical implications.

ABSTRACT: Clostridium botulinum is a Gram-positive bacterium that produces one of the most deadly chemodenervating toxins in the world. To date, six distinct neurotoxins are available for prescription use in the United States. Decades of data across aesthetic therapeutic areas and therapeutic disease states support the safety and efficacy of C. botulinum, providing good symptom management and improved quality of life in appropriately chosen patients. Unfortunately, many clinicians are slow to progress patients to toxin therapy from more conservative measures, and others wrongly interchange the products despite characteristics unique to each. Commensurate with an improved understanding of the complex pharmacology and clinical implications of botulinum neurotoxins is the importance for clinicians to appropriately identify, educate, refer, and/or treat candidate patients. This article provides an overview of the history, mechanism of action, differentiation, indications, and uses for botulinum neurotoxins.

A Pilot Study of A2NTX, a Novel Low-Molecular-Weight Neurotoxin Derived from Subtype A2 for Post-Stroke Lower Limb Spasticity: Comparison with OnabotulinumtoxinA.

All the currently used type A botulinum neurotoxins for clinical uses are of subtype A1. We compared the efficacy and safety for the first time head-to-head between a novel botulinum toxin A2NTX prepared from subtype A2 and onabotulinumtoxinA (BOTOX) derived from A1 for post-stroke spasticity. We assessed the modified Ashworth scale (MAS) of the ankle joint, the mobility scores of Functional Independence Measure (FIM), and the grip power of the unaffected hand before and after injecting 300 units of BOTOX or A2NTX into calf muscles. The procedure was done in a blinded manner for the patient, the injecting physician, and the examiner. Stroke patients with chronic spastic hemiparesis (15 for A2NTX and 16 for BOTOX) were enrolled, and 11 for A2NTX and 13 for BOTOX (MAS of ankle; > or = 2) were entered for the MAS study. Area-under-curves of changes in MAS (primary outcome) were greater for A2NTX by day 30 (p = 0.044), and were similar by day 60. FIM was significantly improved in the A2NTX group (p = 0.005), but not in the BOTOX group by day 60. The hand grip of the unaffected limb was significantly decreased in the BOTOX-injected group (p = 0.002), but was unaffected in the A2NTX-injected group by day 60, suggesting there was less spread of A2NTX to the upper limb than there was with BOTOX. Being a small-sized pilot investigation with an imbalance in the gender of the subjects, the present study suggested superior efficacy and safety of A2NTX, and warrants a larger scale clinical trial of A2NTX to confirm these preliminary results.

[Research progress of botulinum toxin type A in the treatment of chronic rhinitis].

Botulinum toxin（BoNT）, a superfamily of neurotoxins produced by the bacterium Clostridium botulinum, disturbs the signal transmission at the neuromuscular and neuroglandular junctions by inhibiting the neurotransmitter release from the presynaptic nerve terminal. BoNT has been widely used in neuromuscular, hypersecretory, and autonomic nerve system disorders. In recent years, botulinum toxin type A（BoNT-A） has been used to treat chronic rhinitis. Studies have shown that intranasal administration of BoNT-A is safe and effective, and can reduce nasal symptoms in rhinitis patients with long-lasting effects. This article reviews the research progress of BoNT-A in the treatment of chronic rhinitis.

Does Ultrasound Guidance Improve the Effectiveness of Neurotoxin Injections in Patients with Cervical Dystonia? (A Prospective, Partially-Blinded, Clinical Study).

AIM: The aim of this study was to evaluate the efficacy of ultrasound guidance (US) in the treatment of cervical dystonia (CD) with botulinum neurotoxin type A (BoNT-A) injections in comparison to anatomical landmarks (AL). To date, US is routinely used in many centers, but others deny its usefulness. MATERIALS AND METHODS: Thirty-five patients (12 males, 23 females) with a clinical diagnosis of CD were included in the study. Intramuscular administration of BoNT-A was performed using either US guidance, or with AL, in two separate therapeutic sessions. The efficacy of BoNT-A administration was assessed with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), Tsui modified scale, Craniocervical Dystonia Questionnaire (CDQ-24) and Clinical Global Impression-Improvement scale (CGI-I). Additionally, patients at therapeutic sessions were digitally recorded and evaluated by two blinded and independent raters. RESULTS: A significant decrease in total TWSTRS, severity subscale TWSTRS, Tsui score, and CDQ-24 was found in both the AL and US group; however, in the TWSTRS disability and pain subscales, a significant decrease was found only in the US group. Moreover, US guided treatment also resulted in a greater decrease in TWSTRS, Tsui score and CDQ-24 compared to anatomical landmarks use only. CONCLUSIONS: US guidance might be helpful in improving the results of BoNT-A injections in cervical dystonia, reducing associated pain and disability; however, more studies are needed to evaluate its clinical efficacy.

Botulinum Neurotoxins beyond Neurons: Interplay with Glial Cells.

In recent years, numerous studies have highlighted the significant use of botulinum neurotoxins (BoNTs) in the human therapy of various motor and autonomic disorders. The therapeutic action is exerted with the selective cleavage of specific sites of the SNARE's protein complex, which plays a key role in the vesicular neuroexocytosis which is responsible for neural transmission. The primary target of the BoNTs' action is the peripheral neuromuscular junction (NMJ), where, by blocking cholinergic neurons releasing acetylcholine (ACh), they interfere with neural transmission. A great deal of experimental evidence has demonstrated that BoNTs are also effective in blocking the release of other neurotransmitters or neuromodulators, such as glutamate, substance-P, and CGRP, and they can interfere with the function of glial cells, both at the peripheral and central level. The purpose of this review is to provide an update on the available experimental data from animal models that suggest or confirm the direct interactions between BoNTs and glial cells. From the data collected, it appears evident that, through mechanisms that are not yet fully understood, BoNTs can block the activation of spinal glial cells and their subsequent release of pro-inflammatory factors. BoNTs are also able to promote peripheral regeneration processes after nerve injury by stimulating the proliferation of Schwann cells. The data will be discussed in consideration of the possible therapeutic implications of the use of BoNTs on those pathological conditions where the contribution of glial cell activation is fundamental, such as in peripheral and central neuropathies.

Short- and Long-term Central Action of Botulinum Neurotoxin Treatment in Laryngeal Dystonia.

BACKGROUND AND OBJECTIVES: Laryngeal dystonia (LD) is isolated task-specific focal dystonia selectively impairing speech production. The first choice of LD treatment is botulinum neurotoxin (BoNT) injections into the affected laryngeal muscles. However, whether BoNT has a lasting therapeutic effect on disorder pathophysiology is unknown. We investigated short-term and long-term effects of BoNT treatment on brain function in patients with LD. METHODS: A total of 161 participants were included in the functional MRI study. Statistical analyses examined central BoNT effects in patients with LD who were stratified based on the effectiveness and duration of treatment. RESULTS: Patients with LD who were treated and benefited from BoNT injections had reduced activity in the left precuneus compared with BoNT-naive and treatment nonbenefiting patients. In addition, BoNT-treated patients with adductor LD had decreased activity in the right thalamus, whereas BoNT-treated abductor patients with LD had reduced activity in the left inferior frontal cortex. No statistically significant differences in brain activity were found between patients with shorter (1-5 years) and longer (13-28 years) treatment durations. However, patients with intermediate treatment duration of 6-12 years showed reduced activity in the right cerebellum compared with patients with both shorter and longer treatment durations and reduced activity in the right prefrontal cortex compared with patients with shorter treatment duration. DISCUSSION: Our findings suggest that the left precuneus is the site of short-term BoNT central action in patients with LD, whereas the prefrontal-cerebellar axis is engaged in the BoNT response in patients with intermediate treatment duration of 6-12 years. Involvement of these structures points to indirect action of BoNT treatment on the dystonic sensorimotor network through modulation of motor sequence planning and coordination.

Botulinum Toxin-A Injection in Chronic Pelvic Pain Syndrome Treatment: A Systematic Review and Pooled Meta-Analysis.

INTRODUCTION: Pain management of patients with chronic pelvic pain syndrome (CPPS) is challenging, because pain is often refractory to conventional treatments. Botulinum toxin A (BTX-A) may represent a promising therapeutic strategy for these patients. The aim of this systematic review was to investigate the role of BTX-A in CPPS treatment. METHODS: We reviewed the literature for prospective studies evaluating the use of BTX-A in the treatment of CPPS. A comprehensive search in the PubMed, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials databases was performed from English language articles published between January 2000 and October 2021. The primary outcome was to evaluate pain improvement in CPPS after BTX-A treatment. Pooled meta-analysis of the included studies, considering the effect of BTX-A on pain evaluated at last available follow-up compared to baseline values, was performed together with meta-regression analysis. RESULTS: After screening 1001 records, 18 full-text manuscripts were selected, comprising 13 randomized clinical trials and five comparative studies. They covered overall 896 patients of both sexes and several subtype of CPPS (interstitial cystitis/bladder pain syndrome, chronic prostatitis/prostate pain syndrome, chronic scrotal pain, gynecological pelvic pain, myofascial pelvic pain). The clinical and methodological heterogeneity of studies included makes it difficult to do an overall estimation of the real effect of BTX-A on pain and other functional outcomes of various CPPS subtypes. However, considering pooled meta-analysis results, a benefit in pain relief was showed for BTX-A-treated patients both in the overall studies populations and in the overall cohorts of patients with CPP due to bladder, prostate, and gynecological origin. CONCLUSIONS: BTX-A could be an efficacious treatment for some specific CPPS subtypes. Higher level studies are needed to assess the efficacy and safety of BTX-A and provide objective indications for its use in CPPS management.

Editorial on the Special Issue "Botulinum Toxin for the Treatment of Neurological Disorders: Where We Are and Where We Need to Go".

Over the past 30 years, botulinum toxin (BoNT) has seen an ever-expanding use in disorders afflicting the nervous system [...].

Design and Rationale of a Phase 2 Study of NeurOtoxin (Botulinum Toxin Type A) for the PreVention of Post-Operative Atrial Fibrillation - The NOVA Study.

BACKGROUND: Post-operative AF (POAF) is the most common complication following cardiac surgery, occurring in 30% to 60% of patients undergoing bypass and/or valve surgery. POAF is associated with longer intensive care unit/hospital stays, increased healthcare utilization, and increased morbidity and mortality. Injection of botulinum toxin type A into the epicardial fat pads resulted in reduction of AF in animal models, and in two clinical studies of cardiac surgery patients, without new safety observations. METHODS: The objective of NOVA is to assess the use of AGN-151607 (botulinum toxin type A) for prevention of POAF in cardiac surgery patients. This randomized, multi-site, placebo-controlled trial will study one-time injections of AGN-151607 125 U (25 U / fat pad) and 250 U (50 U / fat pad) or placebo during cardiac surgery in ∼330 participants. Primary endpoint: % of patients with continuous AF ≥ 30 s. Secondary endpoints include several measures of AF frequency, duration, and burden. Additional endpoints include clinically important tachycardia during AF, time to AF termination, and healthcare utilization. Primary and secondary efficacy endpoints will be assessed using continuous ECG monitoring for 30 days following surgery. All patients will be followed for up to 1 year for safety. CONCLUSIONS: The NOVA Study will test the hypothesis that injections of AGN-151607 will reduce the incidence of POAF and associated resource utilization. If demonstrated to be safe and effective, the availability of a one-time therapy for the prevention of POAF would represent an important treatment option for patients undergoing cardiac surgery.

Prediction Model for Identifying Computational Phenotypes of Children with Cerebral Palsy Needing Neurotoxin Treatments.

Factors associated with neurotoxin treatments in children with cerebral palsy (CP) are poorly studied. We developed and externally validated a prediction model to identify the prognostic phenotype of children with CP who require neurotoxin injections. We conducted a longitudinal, international, multicenter, double-blind descriptive study of 165 children with CP (mean age 16.5 ± 1.2 years, range 12−18 years) with and without neurotoxin treatments. We collected functional and clinical data from 2005 to 2020, entered them into the BTX-PredictMed machine-learning model, and followed the guidelines, "Transparent Reporting of a Multivariable Prediction Model for Individual Prognosis or Diagnosis". In the univariate analysis, neuromuscular scoliosis (p = 0.0014), equines foot (p < 0.001) and type of etiology (prenatal > peri/postnatal causes, p = 0.05) were linked with neurotoxin treatments. In the multivariate analysis, upper limbs (p < 0.001) and trunk muscle tone disorders (p = 0.02), the presence of spasticity (p = 0.01), dystonia (p = 0.004), and hip dysplasia (p = 0.005) were strongly associated with neurotoxin injections; and the average accuracy, sensitivity, and specificity was 75%. These results have helped us identify, with good accuracy, the clinical features of prognostic phenotypes of subjects likely to require neurotoxin injections.