Long-term safety and efficacy of deutetrabenazine for the treatment of tardive dyskinesia.

OBJECTIVE: To evaluate the long-term safety and efficacy of deutetrabenazine in patients with tardive dyskinesia (TD). METHOD: Patients with TD who completed the 12 week, phase 3, placebo-controlled trials were eligible to enter this open-label, single-arm study. The open-label study consisted of a 6 week dose-escalation phase and a long-term maintenance phase (clinic visits at Weeks 4, 6 and 15, and every 13 weeks until Week 106). Patients began deutetrabenazine at 12 mg/day, titrating up to a dose that was tolerable and provided adequate dyskinesia control, based on investigator judgement, with a maximum allowed dose of 48 mg/day (36 mg/day for patients taking strong cytochrome P450 2D6 (CYP2D6) inhibitors). Safety measures included incidence of adverse events (AEs) and scales used to monitor parkinsonism, akathisia/restlessness, anxiety, depression, suicidality and somnolence/sedation. Efficacy endpoints included the change in Abnormal Involuntary Movement Scale (AIMS) score (items 1 to 7) from baseline and the proportion of patients rated as 'Much Improved' or 'Very Much Improved' on the Clinical Global Impression of Change. RESULTS: A total of 343 patients enrolled in the extension study, and there were 331 patient-years of exposure in this analysis. The exposure-adjusted incidence rates of AEs with long-term treatment were comparable to or lower than those observed in the phase 3 trials. The mean (SE) change in AIMS score was -4.9 (0.4) at Week 54 (n = 146), - 6.3 (0.7) at Week 80 (n = 66) and -5.1 (2.0) at Week 106 (n = 8). CONCLUSIONS: Overall, long-term treatment with deutetrabenazine was efficacious, safe, and well tolerated in patients with TD. TRIAL REGISTRATION NUMBER: NCT02198794.

Update on treatments for dystonia.

Oral medication, botulinum toxin injections, and deep brain stimulation are the current mainstays of treatment for dystonia. In addition, physical and other supportive therapies may help prevent further complications (eg, contractures) and improve function. This review discusses evidence-based medical treatment of dystonia with an emphasis on recent advances in treatment. We will also review the current treatment approaches and suggest ways in which these therapies can be applied to individuals with dystonia.

Botulinum toxin type B in the spastic arm: a randomized, double-blind, placebo-controlled, preliminary study.

OBJECTIVE: To determine the efficacy and safety of 2 doses of botulinum toxin type B (rimabotulinumtoxinB, BoNT/B) in spastic upper limb muscles. DESIGN: Randomized, double-blind, placebo-controlled trial with a 3-month follow-up. SETTING: Tertiary care center. PARTICIPANTS: Referred sample of adult hemiparetic patients (N=24) with disabling elbow flexor overactivity after stroke or traumatic brain injury. INTERVENTIONS: Injection of 10,000U of rimabotulinumtoxinB (fixed 2500U dose into elbow flexors; n=8), 15,000U (5000U into elbow flexors; n=8), or placebo (n=8) into overactive upper limb muscles selected as per investigator's discretion. MAIN OUTCOME MEASURES: At 1 month postinjection, active range of elbow extension (goniometry; primary outcome); active upper limb function (Modified Frenchay Scale [MFS]); subjective global self-assessment (GSA) of arm pain, stiffness, and function; rapid alternating elbow flexion-extension movement frequency over the maximal range; elbow flexor spasticity grade and angle (Tardieu), and tone (Ashworth). RESULTS: No adverse effects were associated with either BoNT/B dose. Both doses improved active elbow extension versus placebo (+8.3°; 95% confidence interval, 1.1°-15.5°; analysis of covariance, P=.028). The high dose of BoNT/B also improved subject-perceived stiffness (P=.005) and the composite pain, stiffness, and function GSA (P=.017), effects that persisted 3 months from injection. No MFS change was demonstrated, although subjects with a baseline MFS <70/100 seemed more likely to benefit from BoNT/B. CONCLUSIONS: In this short-term study, BoNT/B up to 15,000U into spastic upper limb muscles, including the elbow flexors, was well tolerated and improved active elbow extension and subject-perceived stiffness.

[The experience of treatment with medicines of botulinum toxin of type A Lantox of chronic anal fissure with sphincter spasm].

The original material of monitoring of 118 patients with chronic anal fissure is presented in the article. Patients' mean age was 48.9+-10.5 years. It was used injections of medicine of botulinum toxin of type A (Lantox) by its introduction in internal anal sphincter in all patients. There was granulating wound with signs of marginal epithelialization in 59.3% of cases on the 10th day after injection. It was detected complete epithelialization of dermis defect in 93.2% of cases on the 21st day, after six weeks - in 100% of cases. According to anorectal profilometry the index of maximal and average pressure in the anal canal at the level of the internal sphincter in patients at rest decreased to norm. Lantox introduction leads to rapid and persistent reduction of pain intensity. "Lantox" use in ambulatory practice permits to minimize the indications for surgical treatment.

Long-term efficacy and safety of incobotulinumtoxinA injections in patients with cervical dystonia.

INTRODUCTION: Previously, controlled trials have demonstrated the efficacy and tolerability of fixed doses of incobotulinumtoxinA (Xeomin, NT 201, botulinum toxin type A free from complexing proteins) to treat cervical dystonia (CD). To explore the clinical relevance of these findings, this study evaluated long-term use of flexible dosing regimens of incobotulinumtoxinA in a setting close to real-life clinical practice. METHODS: Patients with CD received five injection sessions of incobotulinumtoxinA using flexible intervals (10-24 weeks) and dosing (≤300 Units) based on patients' needs. Outcome measures included Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS), the Dystonia Discomfort Scale (DDS), Investigator Global Assessment of Efficacy (IGAE) and Patient Evaluation of Global Response (PEGR). RESULTS: Of 76 patients enrolled (men: 34%; naïve to botulinum toxin: 25%), 64 completed the study, receiving treatment over a duration of 49.3-114.1 weeks (total maximum duration: 121 weeks). Mean TWSTRS-Total and DDS scores significantly improved from study baseline to 4 weeks after each injection session (ranges of improvement: TWSTRS-Total: -11.7 to -14.3; DDS: -20.2 to -23.0). Up to 81.6% of investigators rated the efficacy as 'good' or 'very good' (IGAE) and up to 78.9% of patients rated the treatment response as 'improved' (PEGR). The most common adverse events were dysphagia, nasopharyngitis and headache. CONCLUSIONS: In this long-term study, incobotulinumtoxinA was administered using more flexible dosing regimens than those permitted in previous controlled trials. Repeated injections of highly purified incobotulinumtoxinA are effective and well tolerated for the treatment of CD in a setting close to real-life clinical practice.

Analysis of CYP2D6 genotype and response to tetrabenazine.

Tetrabenazine is effective in the treatment of the chorea associated with Huntington disease and other hyperkinetic movement disorders. Following oral administration, tetrabenazine is hepatically transformed into 2 active metabolites that are CYP2D6 substrates. There are 4 CYP2D6 genotypes: poor metabolizers, intermediate metabolizers, extensive metabolizers, and ultrarapid metabolizers. CYP2D6 genotyping was performed on sequential subjects treated with tetrabenazine, but results were not known at the time of titration. Duration of titration to a stable dose, total daily dose, response rating scores, and adverse events were retrospectively collected and subsequently analyzed. Of 127 patients, the majority (n = 100) were categorized as extensive metabolizers, 14 as intermediate metabolizers, 11 as poor metabolizers, and 2 as ultrarapid metabolizers. Ultrarapid metabolizer patients needed a longer titration (8 vs 3.3, 4.4, and 3 weeks, respectively; P < .01) to achieve optimal benefit and required a higher average daily dose than the other patients, but this difference did not reach statistical significance. The treatment response was less robust in the intermediate metabolizer group when compared with the extensive metabolizer patients (P = .013), but there were no statistically significant differences between the various groups with regard to adverse effects. Our findings demonstrate that, aside from the need for a longer titration in the ultrarapid metabolizers, there are no distinguishing features of patients with various CYP2D6 genotypes, and therefore the current recommendation to systematically genotype all patients prescribed more than 50 mg/day of tetrabenazine should be reconsidered.

The role of Botulinum toxin injection in the management of achalasia.

PURPOSE OF REVIEW: Botulinum toxin injection into the lower esophageal sphincter is an established therapy for the treatment of achalasia. This review will highlight recent studies that shed light on the role of Botulinum toxin injection in the management of achalasia. RECENT FINDINGS: Recent studies have shown that Botulinum toxin injection is the most common initial endoscopic therapy for achalasia, most likely due to its safety and ease of administration. However, this trend represents a deviation from recent guidelines which consider Botulinum toxin injection less efficacious than alternative treatments like pneumatic dilation and laparoscopic Heller myotomy. Over the past decade, multiple commercial formulations of Botulinum toxin injection have been introduced, but the techniques, indications, and therapeutic efficacy for Botulinum toxin have largely remained unchanged. This review will evaluate recent guidelines, consensus articles, meta-analyses, and landmark studies to expound on the short and long-term efficacy of Botulinum toxin, injection dosages, and technique, as well as its efficacy compared to pneumatic dilation, myotomy, and combination therapy. SUMMARY: Despite its relatively poor long-term efficacy, Botulinum toxin injection continues to play an important role in elderly patients with comorbidities and as salvage therapy for achalasia.

Ischiorectal fossa abscess after pelvic floor injection of botulinum toxin.

Botulinum toxin is used to treat pelvic floor tension myalgia; however, its safety profile is poorly understood. We report an ischiorectal fossa abscess after pelvic floor injections of botulinum toxin. Physicians need to be aware of this possible complication, consider alternate injection techniques and antiseptic preparation before injection.

Survey of practices employed by neurologists for the definition and management of secondary non-response to botulinum toxin in cervical dystonia.

Secondary non-response (SNR) to botulinum toxin (BoNT) in cervical dystonia (CD) lacks a universal definition. We conducted a retrospective survey to develop a definition based on clinicians' practice. Fifty-seven neurologists completed a 17-item questionnaire. In defining SNR, insufficiently improved posture was considered to be more relevant (98% of physicians) than insufficiently improved pain (86%). The most frequently used diagnostic test for SNR was the frontalis test (68%); antibody testing was performed by only 13% of physicians. Three consecutive unsuccessful injection cycles were considered the most appropriate indicator of SNR (55% of physicians). Physicians reported that 5.9% (median) of patients treated in 2008 became secondary non-responders to BoNT-A. The most common strategy for SNR was optimization of physiotherapy, considered by 98% of the physicians. On the basis of our findings, SNR can be defined as insufficiently improved posture after ≥3 unsuccessful injection cycles in CD patients previously achieving satisfactory results.

Women's perspective of botulinum toxin treatment for overactive bladder symptoms.

INTRODUCTION AND HYPOTHESIS: This study aimed to evaluate the women's' views and expectations about outcomes and complications of botulinum toxin treatment for overactive bladder (OAB) symptoms. METHODS: Consecutive women with OAB symptoms and detrusor overactivity were requested to fill out a multiple choice questionnaire to assess whether they would consider botulinum and what outcomes as well as complications they would find acceptable to undergo this treatment. RESULTS: Two hundred sixty-one women, mean age of 58 (range, 38-78) years, were studied. Two hundred twenty-four were treatment-naive women (group A), while 37 were no responders to anticholinergics (group B). Only 49.6% of women in group A and 54% in group B would accept botulinum toxin. No significant differences were found between treatment-naive women and non-responders to anticholinergics (p > 0.05). CONCLUSIONS: Acceptance of botulinum toxin treatment involves a complex interaction of efficacy and possible complications. The balance of these factors changes the acceptability of the treatment.

PPARγ receptors are involved in the effects of cannabidiol on orofacial dyskinesia and cognitive dysfunction induced by typical antipsychotic in mice.

Tardive dyskinesia (TD) is a movement disorder that appears after chronic use of drugs that block dopaminergic receptors such as antipsychotics. Besides the motor symptoms, patients with TD also present cognitive deficits. Neuroinflammatory mechanisms could be involved in the development of these symptoms. A previous study showed that cannabidiol (CBD), the major non-psychotomimetic compound of Cannabis sativa plant, prevents orofacial dyskinesia induced by typical antipsychotics by activating peroxisome proliferator-activated receptors gamma (PPARγ). Here, we investigated if CBD would also reverse haloperidol-induced orofacial dyskinesia and associated cognitive deficits. We also verified if these effects depend on PPARγ receptor activation. Daily treatment with haloperidol (3 mg/kg, 21 days) increased the frequency of vacuous chewing movements (VCM) and decreased the discrimination index in the novel object recognition test in male Swiss mice. CBD (60 mg/kg/daily) administered in the last 7 days of haloperidol treatment attenuated both behavioral effects. Furthermore, haloperidol increased IL-1ß and TNF-α levels in the striatum and hippocampus while CBD reverted these effects. The striatal and hippocampal levels of proinflammatory cytokines correlated with VCM frequency and discrimination index, respectively. Pretreatment with the PPARγ antagonist GW9662 (2 mg/kg/daily) blocked the behavioral effects of CBD. In conclusion, these results indicated that CBD could attenuate haloperidol-induced orofacial dyskinesia and improve non-motor symptoms associated with TD by activating PPARγ receptors.

An open-label, sequential dose-escalation, safety, and tolerability study of rimabotulinumtoxinb in subjects with cervical dystonia.

OBJECTIVES: Evaluate the safety and efficacy of a sequential dose escalation of rimabotulinumtoxinB (BoNT-B) in cervical dystonia (CD) subjects. METHODS: This multicenter, open-label, within-subject, sequential dose-escalation study (BoNT-B dosed at 10,000, 12,500, and 15,000 Units) evaluated subjects over each phase of treatment at preinjection and at periodic intervals postinjection. Adverse events, vital signs, and laboratory results were recorded. Efficacy measures included the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) and three visual analog scales (VASs). RESULTS: 119 out of 145 CD subjects received all three doses in sequence. Dry mouth and dysphagia were the most common adverse events, and both decreased in frequency by the final injection, despite the increasing doses of the escalation. TWSTRS-Total and subscale scores demonstrated significant improvements following all doses at the week 2, 4, 8, and 12 assessments, with the exception of disability and pain at week 12 with the lowest dose. All VAS scores demonstrated similar improvements following all doses. The mean number of weeks in each phase of the study was 12.1 weeks (10,000 Units), 12.9 weeks (12,500 Units), and 13.9 weeks (15,000 Units). CONCLUSION: BoNT-B was well tolerated and efficacious at 10,000, 12,500, and 15,000 Units in this within-subject, sequential dose-escalation study in CD subjects.

Reverse sensory geste in cervical dystonia.

Sensory gestes (SG) are a pathognomonic sign of dystonia, which can be detected in up to two thirds of patients with cervical dystonia (CD). They reduce dystonia severity markedly but transiently. We report a patient whose CD substantially worsened with sensory input to the back of the head and neck in different body postures, a phenomomen recently termed "reverse" sensory geste (rSG) in craniocervical dystonia. In a cohort of CD outpatients, screening for "reverse" effects of SG on dystonia yielded a prevalence of 12.8% (n = 6/47). The most frequent rSG pattern was increased dystonic activity in a supine, resting position while trying to fall asleep. The response to rSG persisted throughout the course of the disease arguing for an impairment of central integration of neck proprioception. Assessment of rSG should be included in the routine examination of CD patients, since BTX treatment may have to beadjusted accordingly to be efficacious.

Xeomin: an innovative new botulinum toxin type A.

Botulinum toxin type A (BoNT/A) is a well-established treatment for conditions characterized by muscle and autonomic nerve terminal overactivity, such as cervical dystonia and blepharospasm, and hyperhidrosis, respectively. BoNT/A is not digested in the gastrointestinal tract as it forms a complex with several proteins that protect and stabilize the neurotoxin. However, the pure neurotoxin is solely responsible for the therapeutic effect, and the complexing proteins have been shown to exhibit immunostimulating activity. The complexing proteins are not required for the stabilization of the neurotoxin in a formulation; the complexing proteins immediately dissociate from the neurotoxin at a physiologic pH, so they do not influence the spread of the neurotoxin. Xeomin is the only botulinum toxin that is free from complexing proteins and is stable at room temperature for a period of 4 years. When injected directly into muscles, Xeomin inhibits local neuromuscular cholinergic transmission, causing focal weakness. It binds to motor nerve terminal pre-synaptic receptors, is internalized via receptor-mediated endocytosis and then selectively cleaves a protein called SNAP-25. This is one of several so-called 'SNARE' proteins involved in exocytosis. Cleavage of SNAP-25 inhibits the secretion of acetylcholine causing the paralysis of the muscle. The clinical effects begin 24-72 h after injection, peak at approximately 4-6 weeks and are sustained for several months.

Xeomin in the treatment of cervical dystonia.

BACKGROUND AND PURPOSE: Botulinum toxin type A (BoNT/A) is a highly effective and well-tolerated treatment for focal dystonias. The BoNT/A in Botox and Dysport is part of a high-molecular-weight complex that contains hemagglutinins and other non-toxic proteins, whilst Xeomin is a highly purified BoNT/A free of such complexing proteins. In the largest controlled study of BoNT/A published to date (Neurology 2005; 64: 1949), it was demonstrated that Xeomin is non-inferior to Botox and has 1:1 efficacy in the treatment of cervical dystonia. A possible limitation of continued BoNT/A treatment is antibody development. Based on its physiochemical properties and toxicological evidence, Xeomin is expected to have a reduced incidence of non-responders after long-term treatment compared with other marketed BoNT/A products. METHODS AND RESULTS: In our ongoing open-label study, 100 patients suffering from cervical dystonia are continuously treated with Xeomin; 50 patients were treated de novo, the remaining patients had been previously treated with Botox, Dysport or NeuroBloc/Myobloc. All patients showed negative results in antibody testing at the beginning of Xeomin treatment. During continuous treatment with Xeomin up to 2 years, patients continued to respond well to Xeomin treatment. CONCLUSION: The treatment was well tolerated and no patient has developed neutralizing antibodies as measured using the sensitive mouse hemidiaphragma assay within these first 2 years.

Clinical efficacy and tolerability of Xeomin in the treatment of blepharospasm.

BACKGROUND AND PURPOSE: Blepharospasm is classified as a focal dystonia, and botulinum toxin type A (BoNT/A) has been shown to be a highly effective and well-tolerated symptomatic treatment. Xeomin, the latest addition to BoNT/A preparations, is a purified, freeze-dried BoNT/A that is free from complexing proteins. METHODS AND RESULTS: In a double-blind, parallel-group, multicentre study, 300 patients with blepharospasm received either Xeomin or Botox 15-80 U (J Neural Transm 2006; 113: 303). Both treatments produced statistically significant improvements from baseline in the Jankovic Rating Scale at week 3 (primary efficacy variable; Xeomin: -2.90; Botox: -2.67; P < 0.0001 from baseline for both), with the difference between treatments (-0.23) indicating that Xeomin was clinically non-inferior to Botox. No significant differences were found between Xeomin and Botox for all secondary variables. There were no clinically relevant differences between Xeomin and Botox in safety parameters, with 40 of 148 patients (27.0%) treated with Xeomin reporting adverse events versus 45 of 155 patients (29.0%) treated with Botox. The most common adverse event was ptosis (6.1% Xeomin and 4.5% Botox). CONCLUSION: Clinical evidence to date suggests that Xeomin is an effective treatment for blepharospasm that does not differ from Botox in terms of its potency, duration of effect or adverse reaction profile.

Routine use of Xeomin in patients previously treated with Botox: long term results.

BACKGROUND AND PURPOSE: Based upon large and carefully performed studies Xeomin was first registered in 2005. However, its real potential can only be assessed, when it is used outside of study design restrictions, in an independent setting, in off-label indications and during continued use. METHODS AND RESULTS: Two hundred and sixty-three patients (91 with dystonia, 84 with spasticity, 17 with hemifacial spasm and re-innervation synkinesias, 64 with hyperhidrosis, 7 with hypersalivation), who were previously treated with Botox for at least 1 year under stable conditions, were converted in a blinded fashion to Xeomin using a 1:1 conversion ratio and identical treatment parameters. Therapeutic outcome and adverse effects were monitored by neurological examination and structuralised interviews. In 223 patients (all except those with axillary hyperhidrosis) Xeomin was used continuously throughout a 3 year period. Altogether 1050 injection series were performed. Patients with dystonia received 261.5 +/- 141.0 MU Botox/Xeomin, patients with spasticity 450.5 +/- 177.1 MU, patients with hemifacial spasm and reinnervation synkinesias 44.7 +/- 19.5 MU and patients with hyperhidrosis 286.9 +/- 141.6 MU. The maximum botulinum toxin dose applied was 840 MU. There were no subjective or objective differences between Botox and Xeomin treatments with respect to onset latency, maximum and duration of their therapeutic effects and their adverse effect profiles. Long-term use did not reveal additional safety relevant aspects. None of the patients lost therapeutic efficacy during the observation period. CONCLUSIONS: Xeomin can be used safely in doses of up to 840 MU. Even when applied in high doses it did not produce secondary therapy failure. There were no diffusion differences between Botox and Xeomin. Using a conversion ratio of 1:1 Xeomin and Botox can easily be exchanged in a continued treatment.

Pimozide for tics in Tourette's syndrome.

BACKGROUND: Neuroleptic drugs with potent D-2 receptor blocking properties have been the traditional treatment for tics caused by Tourette Syndrome. Pimozide is the most studied of these. Use of these medications is declining because of concerns about side effects, and new atypical neuroleptics are now available. The true benefit and risks associated with pimozide compared to other drugs is not known. OBJECTIVES: To evaluate the efficacy and harms of pimozide in comparison to placebo or other medications in the treatment of tics in Tourette Syndrome. SEARCH STRATEGY: We cross-referenced pimozide and its proprietary names with Tourette Syndrome and its derivations, as MeSH headings and as text words, and searched the Cochrane Movement Disorders Group Trials Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library 2007, Issue 4), MEDLINE (1950-April 2007), and EMBASE (1980-April 2007). Reference lists of relevant articles were reviewed for additional trials. SELECTION CRITERIA: All randomized, controlled, double blind studies comparing pimozide to placebo or other medications for the treatment of tics in Tourette Syndrome were considered for inclusion in this review. Both parallel group and crossover studies of children or adults, at any dose and for any duration, were included. DATA COLLECTION AND ANALYSIS: Data was abstracted independently by two authors onto standardized forms and disagreements were resolved by discussion. MAIN RESULTS: Six randomized controlled trials were included (total 162 participants, age range 7 to 53 years). Pimozide was compared with: placebo and haloperidol (two trials), placebo (one trial), haloperidol (one trial), and risperidone (two trials). Methodological quality was rated 'fair' for all studies. Studies used different outcome measurement scales for assessing tic severity and adverse effects. Significant clinical heterogeneity made meta-analysis inappropriate. Pimozide was superior to placebo in three studies, though it caused more side effects than placebo in one of these. Pimozide was inferior to haloperidol in one of three studies (the other two showed no significant difference between the drugs), which also showed significantly fewer side effects associated with pimozide. No significant differences between pimozide and risperidone were detected. AUTHORS' CONCLUSIONS: Pimozide is an effective treatment for tics in Tourette Syndrome, though the number of trials comparing its effect to placebo and other drugs is limited. Trials of longer duration (minimum six months) are needed to investigate the longer-term effects of pimozide compared to atypical neuroleptics. Future trials should use the Yale Global Tic Severity Scale to assess the main outcome measure, and quantify adverse events with the Extrapyramidal Symptoms Rating Scale.

Unilateral ptosis: a rare presentation.

We report a case of unilateral gradual drooping of right upper eyelid. It was mild to moderate in intensity and variable during the day. Examination was suggestive of myogenic ptosis (with slightly reduced levator palpebrae superioris function). She was screened for myasthenia gravis with negative tensilon test and oral trial of pyridostigmine for few weeks without any improvement, and was advised surgery at an overseas center. A second opinion was taken before surgery. A detailed history revealed that local administration of Botulinum toxin was done four months ago by a plastic surgeon. This along with mildly compromised levator function without any systemic features and negative tensilon test, led us to believe that ptosis was secondary to injection Botulinum toxin. Patient was reassured and advised to use crutch glasses for a month and then report any spontaneous improvement. She reported improvement in the right eye after six weeks, with reappearance of forehead lines.

Botulinum toxin: description of injection techniques and examination of controversies surrounding toxin diffusion.

The benefits derived from botulinum toxin (BTX) injections may be negated by unintentional weakness of adjacent uninjected muscles. Such weakness may be the result of inaccurate targeting, or diffusion of BTX to surrounding muscles. Several techniques, using electromyographic, endoscopic or imaging guidance are purported to increase the accuracy of targeting. Diffusion of BTX is thought to be influenced by factors such as dose, concentration, injectate volume, number of injections, site and rate of injection, needle gauge, muscle size, muscular fascia, distance of needle tip from the neuromuscular junction, and protein content of the BTX formulation. This article describes techniques that aim to increase the accuracy of BTX injections and examines the controversies surrounding diffusion of BTX following injection.