Clinical Conditions Targeted by OnabotulinumtoxinA in Different Ways in Medicine.

OnabotulinumtoxinA (BT-A) is used in different medical fields for its beneficial effects. BT-A, a toxin originally produced by the bacterium Clostridium botulinum, is widely known for its ability to temporarily paralyze muscles by blocking the release of acetylcholine, a neurotransmitter involved in muscle contraction. The literature continually reports new hypotheses regarding potential applications that do not consider blockade of acetylcholine release at the neuromuscular junction as a common pathway. In this opinion article, it is our aim to investigate the different pathway targets of BT-A in different medical applications. First of all, the acetylcholine effect of BT-A is used to reduce wrinkles for cosmetic purposes, in the treatment of urological problems, excessive sweating, temporomandibular joint disorders, obesity, migraine, spasticity in neurological diseases, and in various cases of muscle overactivity such as cervical dystonia, blepharospasm, and essential head tremor. In another potential pathway, glutamate A, CGRP, and substance P are targeted for pain inhibition with BT-A application in conditions such as migraine, trigeminal neuralgia, neuropathic pain, and myofascial pain syndrome. On the other hand, as a mechanism different from acetylcholine and pain mediators, BT-A is used in the treatment of hair loss by increasing oxygenation and targeting transforming growth factor-beta 1 cells. In addition, the effect of BT-A on the apoptosis of cancer cells is also known and is being developed. The benefits of BT-A applied in different doses to different regions for different medical purposes are shown in literature studies, and it is also emphasized in those studies that repeating the applications increases the benefits in the long term. The use of BT-A continues to expand as researchers discover new potential therapeutic uses for this versatile toxin.

OnabotulinumtoxinA as a promising treatment for primary trochlear headache: A retrospective case series.

OBJECTIVES: To report the efficacy of onabotulinumtoxinA (BoNTA) injections in relieving pain in patients with primary trochlear headache (PRTH). METHODS: Examination of medical records for patients diagnosed with PRTH according to the International Classification of Headache Disorders, 3rd edition criteria and treated with BoNTA. Data were collected for variables related to pain relief, duration of effectiveness, and adverse effects. RESULTS: Six patients were included in the study. All had previously undergone standard care interventions, including infiltrations or oral treatments, yet experienced treatment failure or symptom recurrence. All patients received 20 units of BoNTA, administered in the corrugator and procerus muscles. Subsequent to the BoNTA injections, all six patients reported substantial pain relief, with five achieving complete remission of symptoms. The analgesic effect persisted for a duration of 3 months. No adverse events were reported in any of the cases. CONCLUSIONS: Our case series presents the first evidence of the potential of BoNTA as a safe and effective treatment option for PRTH. From a clinical standpoint, having a safer alternative is of paramount significance for patients with limited treatment options, such as those with PRTH. Further research is warranted to validate these findings and explore the long-term efficacy of BoNTA in PRTH management.

Therapeutic outcome of active management in male patients with detrusor underactivity based on clinical diagnosis and videourodynamic classification.

Detrusor underactivity (DU) could be resulted from many different etiologies. Patients with DU might have reduced bladder sensation, low detrusor contractility, and large post-void residual volume. This study analyzed therapeutic outcome of active management for male DU patients, based on clinical and urodynamic characteristics. Male DU patients aged > 18 years old were retrospectively reviewed from the videourodynamic study (VUDS) records in recent 10 years. The patients' demographics, VUDS results, treatment modalities, and treatment outcome were analyzed. The treatment outcomes were compared among patients with different DU subgroups, clinical diagnosis and treatment modalities. Patients with voiding efficiency of > 66.7% were considered having a successful treatment outcome. For comparison, 30 men with normal VUDS finding served as the control arm. Most of the DU patients had reduced bladder sensation. The reduced bladder sensation is closely associated with low detrusor contractility. After active treatment, a successful outcome was achieved in 68.4% of patients after bladder outlet surgery, 59.1% after urethral botulinum toxin A injection, and 57.6% after medical treatment, but only 18.2% after conservative treatment. A successful treatment outcome was achieved in patients with an intact detrusor contractility, either low (69.2%) or normal voiding pressure (81.8%), and in patients with a normal or increased bladder sensation (78.1%). However, patients with detrusor acontractile (41.3%) or absent bladder sensation (17.9%) had less favorable treatment outcome after any kind of urological management. This study revealed that active management can effectively improve voiding efficiency in patients with DU. The normal bladder sensation, presence of adequate detrusor contractility, and bladder outlet narrowing during VUDS provide effective treatment strategy for DU patients. Among all management, BOO surgery provides the best treatment outcome.

Botulinum Neurotoxin Type A in the Treatment of Facial Seborrhea and Acne: Evidence and a Proposed Mechanism.

Intradermal injection of botulinum neurotoxin is a frequently performed procedure in aesthetic dermatology to improve facial skin tone, texture, fine wrinkles, and enlarged pores. In practice, botulinum neurotoxin type A is also used to reduce skin oiliness of the face. There is increasing evidence that acetylcholine plays specific roles in sebum production, suggesting that botulinum neurotoxin type A may reduce sebum production by interfering with cholinergic transmission between sebaceous glands and autonomic nerve terminals. Botulinum neurotoxins can also inhibit several pathogenetic components of acne development, suggesting that botulinum neurotoxins can be used as a safe and effective treatment modality for acne and other skin disorders related to overactivity of sebaceous glands. This review aims to explore the current evidence behind the treatment of facial seborrhea and acne with botulinum neurotoxin type A.

Low-Dose Neubotulinum Toxin A versus Low-Dose Abobotulinum Toxin A Injection for the Treatment of Cervical Dystonia: A Multicenter, 48-Week, Prospective, Double-Blinded, Randomized Crossover Design Study.

Various types of botulinum toxin (BoNT) have been studied to treat cervical dystonia (CD). Although high-dose BoNT has proven efficacy, it increases the risk of adverse events. For this reason, this study was planned to identify the non-inferiority efficacy, tolerability, and safety of low-dose neubotulinum toxin A (Neu-BoNT-A) versus low-dose abobotulinum toxin A (Abo-BoNT-A) in CD treatment. The 48-week, prospective, randomized, controlled crossover design study of CD treatment, with 50-unit Neu-BoNT-A and 250-unit Abo-BoNT-A injections at 12-week intervals, was conducted over a 24-week treatment period. This study used the following standardized rating scales to assess the efficacy of BoNT: the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS); health-related quality of life (HRQoL); the Cervical Dystonia Impact Profile (CDIP-58); the Short Form 36 health survey questionnaire (SF-36); and, for the depressive symptoms of CD patients, the Center for Epidemiological Studies-Depression Scale (CES-D) and the Patient Health Questionnaire-9 (PHQ-9). Fifty-two CD patients were enrolled from October 2019 to January 2021. The mean scores of the TWSTRS total at the post-treatments in both Neu-BoNT-A and Abo-BoNT-A had a significant reduction from baseline (p = 0.008 and 0.002, respectively). However, the mean changes of the TWSTRS total at the 12- and 24-week treatments between the two treatment groups were not significantly different (p = 0.284 and 0.129, respectively). The mean scores of the HRQoL questionnaires (the CIDP-58 and the SF-36) and the depressive symptoms (the CES-D and the PHQ-9) in both treated groups at the post-treatments did not significantly decrease from baseline and were comparable. Two patients treated with Abo-BoNT-A (250 units) reported cervical tension and benign paroxysmal positional vertigo (BPPV). There were no serious adverse events reported. Though both low-dose BoNT-As were effective at improving clinical symptoms without significant side effects, both treatments did not predict change in quality of life and depression. With the non-inferiority criteria, low-dose Neu-BoNT-A has a similar efficacy, safety, and tolerability to Abo-BoNT-A.

Contribution of Single-Fiber Evaluation on Monitoring Outcomes Following Injection of Botulinum Toxin-A: A Narrative Review of the Literature.

Botulinum toxin-A (BoNT-A) blocks acetylcholine release at the neuromuscular junction (NMJ) and is widely used for neuromuscular disorders (involuntary spasms, dystonic disorders and spasticity). However, its therapeutic effects are usually measured by clinical scales of questionable validity. Single-fiber electromyography (SFEMG) is a sensitive, validated diagnostic technique for NMJ impairment such as myasthenia. The jitter parameter (µs) represents the variability of interpotential intervals of two muscle fibers from the same motor unit. This narrative review reports SFEMG use in BoNT-A treatment. Twenty-four articles were selected from 175 eligible articles searched in Medline/Pubmed and Cochrane Library from their creation until May 2020. The results showed that jitter is sensitive to early NMJ modifications following BoNT-A injection, with an increase in the early days' post-injection and a peak between Day 15 and 30, when symptoms diminish or disappear. The reappearance of symptoms accompanies a tendency for a decrease in jitter, but always precedes its normalization, either delayed or nonexistent. Increased jitter is observed in distant muscles from the injection site. No dose effect relationship was demonstrated. SFEMG could help physicians in their therapeutic evaluation according to the pathology considered. More data are needed to consider jitter as a predictor of BoNT-A clinical efficacy.

Mechanism and Priority of Botulinum Neurotoxin A versus Sacral Neuromodulation for Refractory Overactive Bladder: A Review.

BACKGROUND: The treatment of common overactive bladder (OAB) has reached a consensus, but there is not a clear answer to the treatment of refractory OAB (ROAB). ROAB is defined as nonresponsive to treatment with behavioural and oral therapies. The disease can influence the physical and mental health of patients, cause poor quality of life, and create an urgent socio-economic burden. With the advancement of medical treatment, the treatment of OAB has improved significantly in the last 2 decades, especially ROAB, by the usage of botulinum neurotoxin A (BoNT-A) and sacral neuromodulation (SNM). Many studies have demonstrated their effectiveness and safety. However, which therapy is the optimal method remains unclear for patients with ROAB, and the exact mechanism involved in the procedures is still unknown. SUMMARY: This review is to clarify the mechanisms, advantages, and disadvantages of SNM and BoNT-A in treatment of ROAB, and determine whether there is an order effect of SNM and BoNT-A in managing ROAB. Key Messages: BoNT-A and SNM mainly act on the peripheral nervous system and central nervous system, respectively. But BoNT-A and SNM may partly act on the central and peripheral nervous systems, separately. SNM may be a better choice than BoNT-A in the long time. At the same time, BoNT-A and SNM can treat the ROAB as the first and next steps, and the sequence of both would not affect the effectiveness of each other.

Botulinum Injections for Idiopathic Cervical Dystonia: a Longitudinal Study.

Botulinum toxin (BT) injections into the cervical muscles are an effective and commonly practiced treatment approach for cervical dystonia. In this retrospective longitudinal study, we collected data from the Sheba electronic medical records on consecutive patients with idiopathic cervical dystonia (ICD), treated regularly with periodic BT injections between the years 2008-2020. All treatment visits were analyzed regarding type of toxin, dose injected, and clinical outcomes. The vast majority of patients were treated with abobotulinum toxin A. Sixty-four ICD patients (51 (79.7%) females, onset at age 45.8 ± 13.7 years) were treated over 17.1 ± 13.9 (range 3 to 49) visits per patient; BT treatment efficacy increased gradually from initial treatment sessions to visit 13, when it achieved a steady state. While the subjective report of percentage improvement and its duration were around 78.9 ± 17.1% for 2.8 ± 1.0 months, respectively, the dose of BT increased significantly over the years (p = 0.006). Side effects (SE) were not rare, and commonly recurred after subsequent sessions and were usually mild and short-lasting, with dysphagia being the most common (~17.5%), followed by neck/arm weakness (11.9%) and cervical pain (8.9%). Repeated injections of BT for ICD remain beneficial for patients over several years of therapy, and despite mild SE, patients tend to adhere to a 3-4 months interval schedule.

Long-term efficacy and safety of botulinum toxin treatment for cervical dystonia: a critical reappraisal.

Introduction: Botulinum toxin (BoNT) injections represent the gold standard treatment for cervical dystonia (CD). Different types of BoNT have been used for the treatment of CD, but only two serotypes, BoNT type A (BoNT-A) and type B (BoNT-B), have been approved by regulatory agencies. Efficacy and safety of BoNT have been well documented by many short-term studies, but the longterm effects have been investigated only relatively recently.Areas covered: In the present review, we aimed to critically reappraise the existing evidence on the long-term efficacy and safety of BoNT treatment in CD. The examined studies mainly explored BoNT-A serotypes. Only a few studies examined the long-term effects of BoNT-B serotypes, and only one head-to-head comparison between BoNT-A and BoNT-B was found. BoNT was consistently reported to be an effective and safe treatment for CD patients, with good outcomes and a few adverse events in the long-term. However about a third of patients still drop out from the treatment during a long-term follow-up.Expert opinion: We conclude that BoNT is safe and effective in the long-term treatment of patients with CD. Additional studies are needed to further explore patients real-life experiences and perspectives to better understand the long-term outcomes and reasons for discontinuation of treatment.

Novel Combined Approach for Digital Necrosis Secondary to Raynaud's Phenomenon.

The presence of severe Raynaud's Phenomenon (RP), with permanent pain or digital necrosis is a rare condition. Cervical sympathectomy or distal sympathectomy or A botulinum toxin have demonstrated efficacy after medical treatment failure. We report the case of a 38-year-old female patient with an acute onset of severe RP in both hands secondary to systemic sclerosis. Medical treatment failed, so a novel approach by a combination of a modified distal sympathectomy and injection of A botulinum toxin on digital neuromuscular bundles was performed. Remission of the pain occurred immediately after the procedure and 45 days later she had complete healing of the digital wounds and recovered full mobilization of both hands. The patient remained asymptomatic 6 month after the procedure, and a Doppler ultrasound showed tri-phasic flows distal to the surgical site. This novel technique is described, and a brief review of the literature is performed.

Developing a Consistent, Reproducible Botulinum Toxin Type A Dosing Method for Upper Limb Tremor by Kinematic Analysis.

Botulinum toxin type A (BoNT-A) injection patterns customized to each patient's unique tremor characteristics produce better efficacy and lower adverse effects compared to the fixed-muscle-fixed-dose approach for Essential Tremor (ET) and Parkinson's disease (PD) tremor therapy. This article outlined how a kinematic-based dosing method to standardize and customize BoNT-A injections for tremors was developed. Seven ET and eight PD participants with significant tremor reduction and minimal perceived weakness using optimized BoNT-A injections determined by clinical and kinematic guidance were retrospectively selected to develop the kinematic-based dosing method. BoNT-A dosages allocated per joint were paired to baseline tremor amplitudes per joint. The final kinematic-based dosing method was prospectively utilized to validate BoNT-A injection pattern selection without clinical/visual assessments in 31 ET and 47 PD participants with debilitating arm tremors (totaling 122 unique tremor patterns). Whole-arm kinematic tremor analysis was performed at baseline and 6-weeks post-injection. Correlation and linear regression analyses between baseline tremor amplitudes and the change in tremor amplitude 6-weeks post-injection, with BoNT-A dosages per joint, were performed. Injection patterns determined using clinical assessment and interpretation of kinematics produced significant associations between baseline tremor amplitudes and optimized BoNT-A dosages in all joints. The change in elbow tremor was only significantly associated with the elbow total dose as the change in the wrist and shoulder tremor amplitudes were not significantly associated with the wrist and shoulder dosages from the selected 15 ET and PD participants. Using the kinematic-based dosing method, significant associations between baseline tremor amplitudes and the change (6-weeks post-first treatment) in tremor at each joint with BoNT-A dosages for all joints was observed in all 78 ET and PD participants. The kinematic-based dosing method provided consistency in dose selection and subsequent tremor reduction and can be used to standardize tremor assessments for whole-arm tremor treatment planning.

Ergonomic Recommendations in Ultrasound-Guided Botulinum Neurotoxin Chemodenervation for Spasticity: An International Expert Group Opinion.

Ultrasound (US)-guided botulinum neurotoxin (BoNT) injections are becoming a mainstay in the treatment of muscle spasticity in upper motor neuron syndromes. As a result, there has been a commensurate increase in US-guided BoNT injection for spasticity training courses. However, many of these courses do not emphasize the importance of ergonomics. This paper aims to highlight the importance of ultrasound ergonomics and presents ergonomic recommendations to optimize US-guided BoNT injection techniques in spasticity management. Expert consensus opinion of 11 physicians (4 different continents; representing 8 countries, with an average of 12.6 years of practice using US guidance for BoNT chemodenervation (range 3 to 22 years)). A search using PubMed, College of Physicians and Surgeons of British Columbia database, EMbase was conducted and found no publications relating the importance of ergonomics in US-guided chemodenervation. Therefore, recommendations and consensus discussions were generated from the distribution of a 20-question survey to a panel of 11 ultrasound experts. All 11 surveyed physicians considered ergonomics to be important in reducing physician injury. There was complete agreement that physician positioning was important; 91% agreement that patient positioning was important; and 82% that ultrasound machine positioning was important. Factors that did not reach our 80% threshold for consensus were further discussed. Four categories were identified as being important when implementing ultrasound ergonomics for BoNT chemodenervation for spasticity; workstation, physician, patient and visual ergonomics. Optimizing ergonomics is paramount when performing US-guided BoNT chemodenervation for spasticity management. This includes proper preparation of the workspace and allowing for sufficient pre-injection time to optimally position both the patient and the physician. Lack of awareness of ergonomics for US-guided BoNT chemodenervation for spasticity may lead to suboptimal patient outcomes, increase work-related injuries, and patient discomfort. We propose key elements for optimal positioning of physicians and patients, as well as the optimal setup of the workspace and provide clinical pearls in visual identification of spastic muscles for chemodenervation.

Therapeutic Applications of Botulinum Neurotoxin for Autonomic Symptoms in Parkinson's Disease: An Updated Review.

Parkinson's disease is the most common age-related motoric neurodegenerative disease. In addition to the cardinal motor symptoms of tremor, rigidity, bradykinesia, and postural instability, there are numerous non-motor symptoms as well. Among the non-motor symptoms, autonomic nervous system dysfunction is common. Autonomic symptoms associated with Parkinson's disease include sialorrhea, hyperhidrosis, gastrointestinal dysfunction, and urinary dysfunction. Botulinum neurotoxin has been shown to potentially improve these autonomic symptoms. In this review, the varied uses of botulinum neurotoxin for autonomic dysfunction in Parkinson's disease are discussed. This review also includes discussion of some additional indications for the use of botulinum neurotoxin in Parkinson's disease, including pain.

Effective Treatment of Neurological Symptoms with Normal Doses of Botulinum Neurotoxin in Wilson's Disease: Six Cases and Literature Review.

BACKGROUND: Recent cell-based and animal experiments have demonstrated an effective reduction in botulinum neurotoxin A (BoNT/A) by copper. AIM: We aimed to analyze whether the successful symptomatic BoNT/A treatment of patients with Wilson's disease (WD) corresponds with unusually high doses per session. METHODS: Among the 156 WD patients regularly seen at the outpatient department of the university hospital in Düsseldorf (Germany), only 6 patients had been treated with BoNT/A during the past 5 years. The laboratory findings, indications for BoNT treatment, preparations, and doses per session were extracted retrospectively from the charts. These parameters were compared with those of 13 other patients described in the literature. RESULTS: BoNT/A injection therapy is a rare (<4%) symptomatic treatment in WD, only necessary in exceptional cases, and is often applied only transiently. In those cases for which dose information was available, the dose per session and indication appear to be within usual limits. CONCLUSION: Despite the evidence that copper can interfere with the botulinum toxin in preclinical models, patients with WD do not require higher doses of the toxin than other patients with dystonia.

BoNT-A for Post-Stroke Spasticity: Guidance on Unmet Clinical Needs from a Delphi Panel Approach.

There is extensive literature supporting the efficacy of botulinum toxin (BoNT-A) for the treatment of post-stroke spasticity, however, there remain gaps in the routine management of patients with post-stroke spasticity. A panel of 21 Italian experts was selected to participate in this web-based survey Delphi process to provide guidance that can support clinicians in the decision-making process. There was a broad consensus among physicians that BoNT-A intervention should be administered as soon as the spasticity interferes with the patients' clinical condition. Patients monitoring is needed over time, a follow-up of 4-6 weeks is considered necessary. Furthermore, physicians agreed that treatment should be offered irrespective of the duration of the spasticity. The Delphi consensus also stressed the importance of patient-centered goals in order to satisfy the clinical needs of the patient regardless of time of onset or duration of spasticity. The findings arising from this Delphi process provide insights into the unmet needs in managing post-stroke spasticity from the clinician's perspective and provides guidance for physicians for the utilization of BoNT-A for the treatment of post-stroke spasticity in daily practice.

The Five-Year Prospective Study of Quality of Life in Hemifacial Spasm Treated with Abo-Botulinum Toxin A.

This study aimed to determine the long-term quality of life (QoL) in hemifacial spasm (HFS) patients after treating with Abo-botulinum toxin A (Abo-BTX). The study assessed the disease-specific QoL (hemifacial spasm questionnaire 30 items; HFS 30), the involuntary movements (abnormal involuntary movement scale; AIMS), general health QoL (Medical Outcomes 36-Item Short Form Health Survey; SF-36), and Depression (the Center of Epidemiologic Studies-Depression questionnaire; CES-D). A total of 74 HFS patients were enrolled from 2012 to 2017. The disease-specific QoL; involuntary movements; and the general health domain of SF 36 were significantly improved after injections of Abo-BTX A in the first few years (p < 0.04), but significantly decreased at the fifth year of treatment without significant clinical resistance observed (p < 0.001). Only the general health domain of SF 36 showed persistent improvement over five years (p = 0.02). In summary, Abo-BTX A can improved quality of life in the first few years; however only the general health domain of SF-36 showed significant improvement over five years (p = 0.02). No clinical resistance was observed.

Botulinum Toxin Type A to Improve Facial Symmetry in Facial Palsy: A Practical Guideline and Clinical Experience.

Unilateral peripheral facial nerve palsy jeopardizes quality of life, rendering psychological consequences such as low self-esteem, social isolation, anxiety, and depression. Among therapeutical approaches, use of Botulinum toxin type A (BoNT-A) on the nonparalyzed side has shown promising results and improvement of quality of life. Nevertheless, the correct technique is paramount, since over-injection of the muscles can result in lack of function, leading to a "paralyzed" appearance, and even worse, functional incompetence, which may cause greater distress to patients. Therefore, the objective of this article is to provide a practical guideline for botulinum toxin use in facial palsy. To this aim, adequate patient assessment, BoNT-A choice, injection plan and dosage, and injection techniques are covered.

First Bite Syndrome: What Neurologists Need to Know.

PURPOSE OF REVIEW: Though first bite syndrome is well known in surgical settings, it is not commonly included in the differential for sharp paroxysmal facial pain in the neurology literature. This paper will highlight the clinical features and relevant anatomy of first bite syndrome, with the goal of helping clinicians differentiate this from other similar facial pain disorders. RECENT FINDINGS: First bite syndrome is severe sharp or cramping pain in the parotid region occurring with the first bite of each meal and improving with subsequent bites. Pathophysiology has been attributed to imbalanced sympathetic/parasympathetic innervation of the parotid gland. This is seen most typically in the post-surgical setting following surgery in the parotid or parapharyngeal region, but neoplastic etiologies have also been reported. It is common for patients to present with concurrent great auricular neuropathy and/or Horner's syndrome. Evidence regarding treatment is limited to case reports/series, however, botulinum toxin injections and neuropathic medicines have been helpful in select cases. It is critical for clinicians to be able to differentiate first bite syndrome from other paroxysmal facial pain. To help with this, we have proposed diagnostic criteria for clinical assessment. Patients often improve gradually over time, but symptomatic treatment with botulinum toxin or neuropathic medicine may be required.

Botulinum Neurotoxin Injections in Childhood Opisthotonus.

Opisthotonus refers to abnormal axial extension and arching of the trunk produced by excessive contractions of the paraspinal muscles. In childhood, the abnormal posture is most often related to dystonia in the setting of hypoxic injury or a number of other acquired and genetic etiologies. The condition is often painful, interferes with ambulation and quality of life, and is challenging to treat. Therapeutic options include oral benzodiazepines, oral and intrathecal baclofen, botulinum neurotoxin injections, and deep brain stimulation. Management of opisthotonus within the pediatric population has not been systematically reviewed. Here, we describe a series of seven children who presented to our institution with opisthotonus in whom symptom relief was achieved following administration of botulinum neurotoxin injections.