Botulinum Toxin for the Treatment of Hemifacial Spasm: An Update on Clinical Studies.

Hemifacial spasm (HFS) is a movement disorder characterized by involuntary contractions of the facial muscles innervated by the seventh cranial nerve. Generally, it is associated with a poor quality of life due to social embarrassment and can lead to functional blindness. Moreover, it is a chronic condition, and spontaneous recovery is rare. Intramuscular injections of Botulinum Toxin (BoNT) are routinely used as HFS treatment. METHODS: We reviewed published articles between 1991 and 2021 regarding the effectiveness and safety of BoNT in HFS as well as any reported differences among BoNT formulations. RESULTS: The efficacy of BoNT for HFS treatment ranged from 73% to 98.4%. The mean duration of the effect was around 12 weeks. Effectiveness did not decrease over time. Adverse effects were usually mild and transient. The efficacy and tolerability of the different preparations appeared to be similar. Among the studies, dosage, injected muscles, intervals of treatment, and rating scales were variable, thus leading to challenges in comparing the results. CONCLUSIONS: BoNT was the treatment of choice for HFS due to its efficacy and safety profile. Further studies are needed to investigate the factors that influence the outcome, including the optimal timing of treatment, injection techniques, dosage, and the best selection criteria for formulations.

Evaluation of the efficiency and safety of botulinum toxin A injection on improving facial scars: A protocol for systematic review and meta-analysis.

BACKGROUND: Botulinum toxin A injection is an established method of treatment. Clinical practitioners use it widely in their practice to prevent the occurrence of facial scars. However, the effectiveness and safeness of has not been comprehensively established. The objective of the current systematic review is to evaluate the efficacy and safety of using botulinum toxin A injection to improve facial scars. METHODS AND ANALYSIS: This systematic review involves browsing a number of electronic databases to search for related articles. The search will include databases in both English (PubMed, EMBASE, Web of Science, Spocus, and Cochrane Central Register of Controlled Trials) and Chinese (WanFang database, China Nation Knowledge Infrastructure, and VIP database), the periods of searching will be from inception till the 15th of September 2020. Completing the search in databases allows to consider randomized controlled studies that compares botulinum toxin A interventions to any comparison interventions in those who have facial scars. The review will be inclusive of papers in both languages, English and Chinese. The independent screening of studies for eligibility is conducted by 2 independent authors. Discussion was used to resolve discrepancies between the authors. The Cochrane Risk of Bias Tool V.2.0 is adopted for evaluating the methodological quality of each study. Data extraction was performed by 2 independent authors. For dichotomous outcomes, the were expressed as relative risk (RR) with 95% confidence intervals (CI). For continuous outcomes the results were expressed as the mean difference (MD) or standardized mean difference (SMD) with 95% CI. The statistical analysis of the present study is carried out in RevMan 5.3 software. RESULTS: This study will output a comprehensive synthesis of existing evidence in relation to botulinum toxin A. Moreover, the results will also provide an interpretation of the effectiveness and safety of botulinum toxin A. CONCLUSION: The present review contributes to the existing body of knowledge by adding more evidence to evaluate if botulinum toxin A is effective and safe to be used as an intervention for improving facial scars. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/94TXP (https://osf.io/94TXP/).

Providing Optimal Rejuvenation to the Periocular Area Using Botulinum Toxin A Neuromodulators and Hyaluronic Acid Dermal Fillers.

The periorbital area is the first area of the face to show signs of aging. To provide safe and natural looking rejuvenation of the delicate eyelids, and supporting structures, an advanced understanding of anatomy, ideal facial proportions, and the most effective methods for rejuvenation is discussed. Periocular rejuvenation is particularly challenging due to the intricate and delicate anatomy of the periocular area. To ensure safe and successful outcomes, it is crucial that injectors use a global approach when providing treatments and that they consider soft tissue, vasculature, and bone structure of the periocular region before administering treatments for aesthetic rejuvenation. Neuromodulators, specifically botulinum toxin A (BoNT-A), and hyaluronic acid (HA) dermal fillers are 2 nonsurgical treatments frequently used to address signs of aging in the periocular area. The objective of this article is to review different BoNT-A and HA filler treatments and discuss how these treatments can be used for optimal rejuvenation of the periocular area.

Management of Chronic Migraine and Occipital Neuralgia in Post 9/11 Combat Veterans.

INTRODUCTION: The rate of chronic migraine (CM) has been shown to be 20% or greater in the post 9/11 combat veteran population with a history of traumatic brain injury, while the rate is much lower at 3-5% in the general population. Studies have shown that medications such as oral topiramate or intramuscular injections of onabotulinum toxin A (Botox) have been used for CM prevention, and occipital blocks have been shown to be helpful in treating occipital neuralgia and short-term relief of CM. However, there are no known studies that have specifically evaluated the use of Botox and occipital blocks for reducing headache frequency in the US veteran population. The purpose of this study was to evaluate the effectiveness of using occipital blocks and Botox as dual therapy for reducing headache frequency in post 9/11 combat veterans with CM, occipital neuralgia, and a history of TBI or neck trauma. MATERIALS AND METHODS: Following Institutional Review Board approval, a retrospective chart review was completed on post 9/11 combat veterans treated in a headache clinic located at the Central Texas Veteran Health Care System. The electronic medical record was used to retrieve the charts of post 9/11 combat veterans who (1) had a confirmed deployment-related history of TBI or neck trauma; (2) were diagnosed with CM and occipital neuralgia; and (3) were treated in the headache clinic between January 1, 2014 and December 31, 2015 with the administration of occipital blocks and Botox within the first six months. Of 282 charts that were reviewed, a total of 30 (N = 30) veterans fit the criteria. The mean number of self-reported headache days per month (28 days) for the month prior to starting treatment was compared to the number of headache days per month (28 days) 6 months after initiation of therapy. RESULTS: Results revealed that the mean number of headache days in the month prior to treatment was 24.1 (22.0, 25.7). The mean number of headache days in the month post-treatment (6 months after the initiation of dual therapy with occipital blocks and Botox) was 12.9 (9.7, 16.4). The mean difference in the number of headache days from pre- to post-treatment (pre-treatment minus post-treatment) was 11.2 (8.2, 14.2). CONCLUSION: This study evaluated the effectiveness of using occipital blocks and Botox as dual therapy for reducing headache frequency for post 9/11 combat veterans with CM, occipital neuralgia, and a history of TBI or neck trauma. Results revealed a statistically significant reduction in the number of headache days per month after the dual therapy. There were multiple limitations to the study to include a small sample size, lack of a control group, self-reported headaches for only 1 month pre-and post-treatment, and no control for other interventions or events which may have influenced the outcome. There is a strong need for randomized, double blinded, placebo- controlled studies involving dual therapy in this population. This study, though small, may be helpful in stimulating additional studies and treatments in this veteran population.

Absence of bacterial or fungal growth in vials of reconstituted botulinum toxin type A after storage.

BACKGROUND: Botulinum toxin type A (BTX-A; Botox) is supplied as individual freeze-dried preparations that should be administered within 24 hours after reconstitution. To avoid wasting this expensive drug, some physicians have resorted to storing vials of reconstituted BTX-A beyond the recommended duration. However, there is insufficient evidence to indicate that the sterility of previously reconstituted BTX-A is maintained during storage. OBJECTIVES: The authors sought to determine whether bacterial and/or fungal proliferation occurred in vials of reconstituted BTX-A and subsequent storage of the remaining solution under refrigeration for 4 weeks. METHODS: A portion of the contents of 88 consecutive 100-U vials of BTX-A was administered aseptically to 108 patients for essential blepharospasm, hemifacial spasm, or facial rejuvenation. The vials were then stored for 4 weeks in a refrigerator, after which the contents were transferred to various media (blood agar, chocolate agar, Sabouraud agar, brain-heart infusion medium, and thioglycolate broth) and assessed for bacterial and/or fungal growth by standard methods. RESULTS: None of the BTX-A vials contained detectable bacterial or fungal contamination after 4 weeks of storage. CONCLUSIONS: Storing vials of reconstituted BTX-A for 4 weeks after administration to patients was not associated with detectable growth of bacteria or fungi.

A guide to dosing in the treatment of cervical dystonia and blepharospasm with Xeomin®: a new botulinum neurotoxin A.

Xeomin(®) (incobotulinumtoxinA; Merz Pharmaceuticals, Frankfurt am Main, Germany) was first introduced in Germany for movement disorders in 2005. In 2010, it was approved for use in the United States by the FDA for the treatment of cervical dystonia (CD) and blepharospasm. It is a unique botulinum type A formulation free of any complexing proteins and contains only the pure 150 kD neurotoxin. Thus, the formation of neutralizing antibodies is not induced even after long-term treatment. The purpose of this report is to review the safety profile and dosing schedule for Xeomin for the treatment of CD and blepharospasm. The recommended dose for patients with CD is 120 U/treatment, with administration intervals normally between 3 and 6 months. However, clinical studies have found Xeomin to be safe and effective at doses up to 400 U in both previously treated and treatment-naïve patients. The recommended starting dose in patients with blepharospasm is 2.5-5.0 U/injection site. Patients can be switched using a 1:1 conversion ratio from Botox(®) (onabotulinumtoxinA, Allergen Inc., Irvine, CA, USA) to Xeomin without any loss of efficacy or safety concerns. Xeomin does not differ from Botox in terms of its potency, onset, diffusion profile, or duration and waning of effect. It is the only botulinum treatment that is stable for up to 3 years at room temperature. Xeomin offers a new and important treatment option for movement disorders.

Guidelines on the use of botulinum toxin type A.

UNLABELLED: Botulinum toxin is available as types A and B. These two different forms need different dosages and hence, the physician needs to be familiar with the formulations. A thorough knowledge of the anatomy and physiology of the muscles in the area to be injected is essential. INDICATIONS FOR BOTULINUM TOXIN: Dynamic wrinkles caused by persistent muscular contractions are the main aesthetic indications for the use of Botulinum toxin. These include forehead lines, glabellar lines, crow's feet, bunny lines, perioral wrinkles, and platysmal bands. Non-aesthetic indications include hyperhidrosis of the palms, soles and axillae. PHYSICIANS' QUALIFICATIONS: Any qualified dermatologist may practice the technique after receiving adequate training in the field. This may be obtained either during post-graduation or at any workshops dedicated to this subject. FACILITY: Botulinum toxin can be administered in the dermatologist's minor procedure room. PREOPERATIVE COUNSELING AND INFORMED CONSENT: Detailed counseling with respect to the treatment, desired effects, and longevity of the results should be discussed with the patient. The patient should be given brochures to study and adequate opportunity to seek information. A detailed consent form needs to be completed by the patient. The consent form should include the type of botulinum toxin, longevity expected and possible postoperative complications. Pre- and postoperative photography is recommended. Dosage depends on the area, muscle mass, gender and other factors outlined in these guidelines. It is recommended that beginners should focus on the basic indications in the upper third of the face and that they treat the middle and lower parts of the face only after garnering adequate experience.

Microbial growth in vials of Botulinum toxin following use in clinic.

PURPOSE: Botulinum toxin has various applications in ophthalmology and is used in the outpatient department, where it is often exposed to room temperatures for 3-4 h. The manufacturer's recommendations are that the reconstituted toxin be stored in a refrigerator when not in use and discarded 4 h after reconstitution. The aim of our study was to examine such used bottles of Botulinum toxin for microbial growth after 4 h at room temperature. METHODS AND RESULTS: Eleven consecutive bottles of Botulinum toxin used with aseptic precautions in the Ophthalmology outpatient clinics were exposed to room temperatures for 4 h. These were subsequently analysed for microbial growth. No growth was directly obtained from any of the Botulinum toxin bottles during our study. CONCLUSIONS: This pilot study suggests that if aseptic precautions are followed during the use of Botulinum toxin, the contents of the bottle remain sterile despite being exposed to room temperatures for up to 4 h. This has implications on the use of the reconstituted toxin after the recommended 4 h.

Botulism in 4 adults following cosmetic injections with an unlicensed, highly concentrated botulinum preparation.

CONTEXT: Botulism is a potentially lethal paralytic disease caused primarily by toxins of the anaerobic, spore-forming bacterium Clostridium botulinum. Although botulinum toxin A is available by prescription for cosmetic and therapeutic use, no cases of botulism with detectable serum toxin have previously been attributed to cosmetic or therapeutic botulinum toxin injections. On November 27, 2004, 4 suspected botulism case-patients with a link to cosmetic botulinum toxin injections were reported to the Centers for Disease Control and Prevention. OBJECTIVE: To investigate the clinical, epidemiological, and laboratory aspects of 4 suspected cases of iatrogenic botulism. DESIGN, SETTING, AND PATIENTS: Case series on 4 botulism case-patients. MAIN OUTCOME MEASURES: Clinical characteristics of the 4 case-patients, epidemiological associations, and mouse bioassay neutralization test results from case-patient specimens and a toxin sample. RESULTS: Clinical characteristics of the 4 case-patients were consistent with those of naturally occurring botulism. All case-patients had been injected with a highly concentrated, unlicensed preparation of botulinum toxin A and may have received doses 2857 times the estimated human lethal dose by injection. Pretreatment serum toxin levels in 3 of the 4 case-patients were equivalent to 21 to 43 times the estimated human lethal dose; pretreatment serum from the fourth epidemiologically linked case-patient was not available. A 100-microg vial of toxin taken from the same manufacturer's lot as toxin administered to the case-patients contained a toxin amount sufficient to kill approximately 14,286 adults by injection if disseminated evenly. CONCLUSIONS: These laboratory-confirmed cases of botulism demonstrate that clinical use of unlicensed botulinum toxin A can result in severe, life-threatening illness. Further education and regulation are needed to prevent the inappropriate marketing, sale, and clinical use of unlicensed botulinum toxin products.

Progress in applying the Three Rs to the potency testing of Botulinum toxin type A.

Botulinum toxin type A (BTA) is being increasingly used for a range of therapeutic purposes and also for cosmetic reasons. For many years, the potency of BTA has been measured by using an LD50 assay in mice. This assay is a cause for concern due to its unpleasant nature and extreme severity, and the requirement for high numbers of mice to be used. Alternatives to this potency assay are presently reviewed with particular reference to the work at the National Institute for Biological Standards and Control (NIBSC), and to recent work by the UK manufacturer of the substance. An in vivo local paralysis assay with considerably less severity has been developed and is in use at the NIBSC. Alternative, ex vivo functional assays in use include the measurement of BTA-induced paralysis of neurally-stimulated rodent diaphragm or rat intercostal muscle. The latter method has the advantage of allowing more preparations to be derived from one animal. However, these ex vivo methods have not yet been fully validated and accepted by regulatory agencies as potency assays. Endopeptidase assays, although not measuring muscle paralysis directly, may provide a very useful consistency test for batch release and may replace the routine use of the LD50 test for that purpose. These assays measure the cleavage of the SNAP-25 protein (the final stage of BTA action), and have been validated for batch release by the National Control Laboratory (NIBSC), and are in regular use there. ELISA assays, used alongside the endopeptidase assay, also provide useful confirmatory information on the amounts of functional (and non-functional) BTA present. The UK manufacturer is further validating its endopeptidase assay, an ex vivo muscle assay and an ELISA. It is anticipated that their work will lead to a change in the product license, hopefully within the next two years, and will form a critical milestone towards the end of the LD50 potency test.

Sterility assessment of multiple use botulinum A exotoxin vials: a prospective simulation.

BACKGROUND: A preponderance of evidence now indicates that storage of reconstituted botulinum toxin solution for longer than the 4 hours recommended by the manufacturer does not result in loss of effectiveness. OBJECTIVE: Then purpose of this study was to assess whether serial re-extraction of reconstituted botulinum toxin solution from vials undergoing prolonged storage is associated with increased risk of microbial contamination. METHODS: Consecutive 100-U vials of botulinun A exotoxin were reconstituted with 2.5 mL each of normal saline with preservative (benzyl alcohol). Within 1 week after reconstitution, each vial was used to treat 1 to 3 patients, for a total of 60 to 80 U used. Thereafter, each vial was stored in a plastic kidney basin in an unlocked, multiuse medication refrigerator. Two weeks later, a randomly assigned nurse removed the vial from the refrigerator and withdrew and discarded 0.1 mL (5 U) using the same technique used for therapeutic extractions. Iterations of this withdrawal and discarding procedure were continued until a 0.1-mL aliquot could not be withdrawn without prying off the metal cover. Once this threshold was reached, the vial was sent to the microbiology laboratory for sterility testing using a thioglycolate broth. RESULTS: In all, 127 vials were handled per protocol. On average (mean), vials underwent 4.5 access procedures, including 1.6 therapeutic extractions for a total of 76 U removed during a period of 7 weeks. Sterility analysis with thioglycolate broth indicated no evidence of contamination. LIMITATIONS: Preservative-containing saline was used for reconstitution. CONCLUSION: Routine refrigerator storage of medication vials containing reconstituted botulinum toxin does not result in microbial contamination of the contents even after serial re-extraction of solution from these vials, and after handling of such vials by multiple personnel. Storage and subsequent reuse of botulinum toxin appears safe for at least 7 weeks after reconstitution.

Role for standards in assays of botulinum toxins: international collaborative study of three preparations of botulinum type A toxin.

The biological activity of therapeutic preparations of botulinum type A toxin is currently expressed in units defined on the basis of the median lethal intraperitoneal dose of that preparation in mice at 72 h, the LD50 dose. In this study we describe the comparison, by ten laboratories in five countries, of three different formulations of botulinum type A toxin using the mouse lethality test, and also using the relative activities of the preparations. The results of this study show that use of a standard preparation and expression of relative potency gives substantially greater consistency between and within laboratories than when mouse LD50 unit is used to define activity of botulinum toxin.

Efficacy of reconstituted and stored botulinum toxin type A: an electrophysiologic and visual study in the auricular muscle of the rabbit.

Once botulinum toxin type A is reconstituted, the manufacturer recommends that it be used in approximately 4 hours. As a result, a significant amount of this costly drug is often discarded because it is not completely used in the recommended period. The purpose of the present study was to compare fresh versus stored reconstituted botulinum toxin type A for (1) initial potency, (2) duration of action, and (3) bacterial colonization. Using a rabbit model, 20 New Zealand White rabbits were divided into four groups (I to IV). All rabbits had an injection of 2.5 U of reconstituted botulinum toxin into the right anterior auricular muscle. The first group was injected with botulinum toxin type A that was freshly reconstituted and served as the control. The second, third, and fourth groups were injected with botulinum toxin type A that had been reconstituted and stored for 2, 6, and 12 weeks, respectively, in a conventional freezer. Each rabbit had daily visual evaluation of the ear, with the position of auricle being graded from I to III. In addition, each rabbit had a nerve conduction study performed on the right anterior auricular muscle before injection and every 2 weeks after injection. Amplitude was chosen as the principal variable in the data analysis because it is the best predictor of physiologic changes at the muscle motor unit level. The endpoint of the study was defined as the time at which the nerve conduction studies and the visual inspections returned to baseline, preinjection levels. Botulinum toxin type A was also cultured before injection into each group.Overall, the nerve conduction data revealed a trend with a faster recovery (return to baseline) with the stored botulinum toxin. Groups IV and III returned to baseline first, followed by groups II and I. However, there was no significant difference among the groups at 2 and 4 weeks after injection, indicating that initial potency was unchanged. The differences between the groups became significant (p < 0.05) at 6 weeks and onward, suggesting that the duration was affected. Group I (fresh botulinum toxin) and group II (toxin stored for 2 weeks) had comparable outcomes and were not significantly different at any time period. Under visual inspection, the mean recovery time for each group was as follows: group IV, 5.4 weeks; group III, 7.0 weeks; group II, 6.75 weeks; and group I, 7.80 weeks. The results showed significance (p < 0.05) beginning after 3 weeks among some groups. Again, there was an overall quicker trend to return to baseline with the longer storage of the botulinum toxin (groups III and IV). These results support the authors' conduction study data, which suggest that the initial potency is not affected but the duration of action is. Again, groups I and II had comparable results. Microbiology cultures showed no growth of either aerobic or anaerobic bacteria at 7 days. In conclusion, using the rabbit model, it seems that reconstituted and stored botulinum toxin type A has the same initial potency but the duration of action is affected sometime after 2 weeks of storage. No bacterial contamination was associated with storing unpreserved reconstituted botulinum toxin type A for up to 12 weeks.

Validation of in vitro assays for botulinum toxin: a case study.

Ensuring the reliability and precision of assay results requires careful attention to assay design. In this case study we describe validation studies of an in vitro assay for botulinum neurotoxin type A based on its endopeptidase activity towards immobilised synthetic substrate. This assay, in common with many in vitro assays, is sensitive to changes in reagents and assay conditions and is time dependent. In addition, the toxin is not stable in solution. Differences in estimates of potency, resulting from positional factors, which are not significant in individual assays, are shown to be consistent and statistically significant over a longer series of assays. This study emphasizes that assay validation should not be viewed as a single step in assay development but must be considered as a continuing process if assay results are to be reliable and reproducible.