Botulinum Neurotoxin Type A Research Articles

Characterization of diffusion and duration of action of a new botulinum toxin type A formulation

RT002, an injectable form of botulinum neurotoxin type A (BoNTA), comprised of a purified 150 kDa neurotoxin formulated in a novel formulation, is designed to limit the extent of diffusion and permit safe administration of longer acting doses. The aim of this study was to evaluate the degree of diffusion of RT002 in comparison to another commercially available BoNTA product, Botox® Cosmetic (OnabotulinumtoxinA, Allergan, Inc., Irvine, CA, USA), and establish the relative duration of effect for diffusion matched doses of the two BoNTA formulations using quantitative measurements in mice.Measurement of muscle paralysis by muscle force generation (MFG) in mice at the injected gastrocnemius muscles indicated that RT002 and Botox are equipotent. Measurements of MFG inhibition in an adjacent muscle, the tibialis anterior muscle, indicated significantly less diffusion for RT002 as compared to Botox. When RT002 and Botox were dosed using the established diffusion matched doses, RT002 treatment resulted in an extended duration of drug effect as compared to Botox by 58–100% as assessed by either partial or complete recovery endpoints. Use of a daily voluntary running activity model provided confirmation that the two BoNTA formulations are equipotent by daily running distance and further confirmed the diffusion matched dose ratio assessed by degree of drug effect on body weight gain. Using these diffusion matched doses, RT002 treatment resulted in an extended duration of drug effect as compared to Botox (100–126% increase in duration) as assessed by either partial or complete recovery endpoints. Use of this model provides further evidence that the RT002 formulation limits diffusion with equipotency and thereby may permit safe administration of higher and more efficacious doses. In summary, data from two murine models suggest that RT002 may represent a next generation of BoNTA drug formulation offering superior degree and duration of effect at the intended target while controlling the unwanted diffusion and accompanying adverse effects of BoNTA at neighboring muscles and distal systemic targets.

Immunization of mice with the non-toxic HC50 domain of botulinum neurotoxin presented by rabies virus particles induces a strong immune response affording protection against high-dose botulinum neurotoxin challenge

We previously showed that rabies virus (RABV) virions are excellent vehicles for antigen presentation. Here, a reverse genetic approach was applied to generate recombinant RABV that express a chimeric protein composed of the heavy chain carboxyterminal half (HC50) of botulinum neurotoxin type A (BoNT/A) and RABV glycoprotein (G). To promote surface expression and incorporation of HC50/A into RABV virions, the RABV glycoprotein (G) ER translocation sequence, various fragments of RABV ectodomain (ED) and cytoplasmic domain were fused to HC50/A. The HC50/A chimeric proteins were expressed on the surface of cells infected with all of the recombinant RABVs, however, the highest level of surface expression was detected by utilizing 30 amino acids of the RABV G ED (HV50/A-E30). Our results also indicated that this chimeric protein was effectively incorporated into RABV virions. Immunization of mice with inactivated RABV-HC50/A-E30 virions induced a robust anti-HC50/A IgG antibody response that efficiently neutralized circulating BoNT/A in vivo, and protected mice against 1000 fold the lethal dose of BoNT/A.

Re-Assembled Botulinum Neurotoxin Inhibits CNS Functions without Systemic Toxicity

The therapeutic potential of botulinum neurotoxin type A (BoNT/A) has recently been widely recognized. BoNT/A acts to silence synaptic transmission via specific proteolytic cleavage of an essential neuronal protein, SNAP25. The advantages of BoNT/A-mediated synaptic silencing include very long duration, high potency and localized action. However, there is a fear of possible side-effects of BoNT/A due to its diffusible nature which may lead to neuromuscular blockade away from the injection site. We recently developed a “protein-stapling” technology which allows re-assembly of BoNT/A from two separate fragments. This technology allowed, for the first time, safe production of this popular neuronal silencing agent. Here we evaluated the re-assembled toxin in several CNS assays and assessed its systemic effects in an animal model. Our results show that the re-assembled toxin is potent in inhibiting CNS function at 1 nM concentration but surprisingly does not exhibit systemic toxicity after intraperitoneal injection even at 200 ng/kg dose. This shows that the re-assembled toxin represents a uniquely safe tool for neuroscience research and future medical applications.

Botulinum toxin type-A effect as a preemptive treatment in a model of acute trigeminal pain: a pre-clinical double-blind and placebo-controlled study

The purpose of this study was to investigate if botulinum neurotoxin type-A (BoNT/A) had a preemptive antinociceptive effect in a formalin-induced orofacial pain model (FT). To test this hypothesis, male Rattus norvegicus were injected with isotonic saline solution 0.9% or BoNT/A administered as a 40 μl bolus, lateral to their nose, at 24 hours, 8, 15, 22, 29 or 36 days pre-FT. The procedures were repeated 42 days later. Influence on motor activity was assessed through the open-field test. Pain scores corresponded to the time spent rubbing and flicking the injected area. Animals pre-treated with BoNT/A at the first protocol (8 days subgroup) showed reduced inflammatory scores (p=0.011). For the other groups no significant results were observed at any phase. Motor activity was similar in both groups. BoNT/A showed to be effective preventing inflammatory pain up to eight days after the first treatment, an effect not reproduced on the second dose administration.

Botulinum toxin A versus B in sialorrhea: A prospective, randomized, double-blind, crossover pilot study in patients with amyotrophic lateral sclerosis or Parkinson's disease

Either botulinum toxins (BoNTs) A and B have been used for improving drooling in different neurological conditions. Consecutive patients affected by Amyotrophic Lateral Sclerosis (ALS) or Parkinson's Disease (PD) accompanied by severe drooling were randomized to receive botulinum neurotoxin type A (BoNT-A) or B (BoNT-B) injections into the salivary glands. Following the first treatment, when sialorrhea returned to baseline (at least three months after the first injection), subjects were re-treated with the other serotype. Ultrasound-guided injections into parotid and submandibular glands were bilaterally performed: total doses were 250 U BoNT-A (Dysport) and 2500 U BoNT-B (Neurobloc). Objective (cotton roll weight) and subjective (ad hoc clinical scales) evaluations were performed at baseline, after 1 and 4 weeks, and every 4 weeks until drooling returned to baseline. Twenty-seven patients (15 ALS and 12 PD) were enrolled, fourteen completed the study. BoNT-A and BoNT-B treatments gave both subjective and objective improvements in all patients. The latency was significantly shorter after BoNT-B treatments (3.2 ± 3.7 days) compared to BoNT-A (6.6 ± 4.1 days; P = 0.002). The mean benefit duration was similar at 75 and 90 days for BoNT-A and BoNT-B, respectively (P = NS). The only toxin-related side effect was a change to saliva thickness. Either 250 U Dysport or 2500 U Neurobloc have similar effectiveness and safety in controlling sialorrhea. BoNT-B has a shorter latency and comparable duration. Cost analysis, considering the doses used in this study protocol favored BoNT-B treatment.

Botulinum neurotoxin A for male lower urinary tract symptoms

Lower urinary tract symptoms (LUTS) related to benign prostatic hyperplasia (BPH) affects a large number of male patients from 45 years onward, increasing with age. Routine medical treatment is mainly limited to plant extracts, α-blockers, and 5-α-reductase inhibitors. Although all types of drug have a proven efficacy, they often do not sufficiently treat all aspects of LUTS related to BPH. Thus, there is a need for alternatives. Intraprostatic injections with botulinum neurotoxin type A (BoNT/A) seem to be a promising alternative. The purpose of this review is to summarize the most recent findings from basic science and clinical studies in relation to BoNT/A application in BPH-related LUTS, thereby providing insight into the putative mechanism of action, the rationale for the use of BoNT/A in BPH-related LUTS, and the clinical outcomes. There is some evidence that BoNT/A intraprostatic injections affect both, the static and dynamic component of BPH-related LUTS by reducing the prostate volume and by downregulation of α-1A-adrenoreceptors. Clinical trials demonstrated an easy and minimally invasive intraprostatic application of BoNT/A with a favourable safety profile. Efficacy seems to be good with significant improvements for several months in symptoms, urinary flow rate and reduction in postvoid residual, prostate volume, and also prostate-specific antigen in some studies. BoNT/A seems to be a promising alternative in the treatment of BPH-related LUTS with a good tolerance and safety profile. However, the level of evidence is still low and further randomized controlled studies are mandatory.

Profile of Xeomin® (incobotulinumtoxinA) for the treatment of blepharospasm

Even though conventional botulinum neurotoxin (BoNT) products have shown successful treatment results in patients with benign blepharospasm (BEB), the main, potential long-term side effect of BoNT use is the development of immunologic resistance due to the production of neutralizing antibody to the neurotoxin after repeated injections. Xeomin® (incobotulinumtoxinA), a unique botulinum neurotoxin type A (BoNT/A) drug free of complexing proteins otherwise contained in all conventional BoNT/A drugs, was recently approved by US Food and Drug Administration for the treatment of cervical dystonia or blepharospasm in adults. The newly approved BoNT/A drug may overcome this limitation of previous conventional products, since it contains pure neurotoxin (150 kDa) through a manufacturing process that separates it from complexing proteins such as hemagglutinins produced by fermentation of Clostridium botulinum. Many studies have also shown that Xeomin® has the same efficacy and safety profile as complexing protein-containing products such as Botox® and is exchangeable with Botox® using a simple 1:1 conversion ratio. Xeomin® represents a new treatment option for the repeated treatment of patients with blepharospasm in that it may reduce antibody-induced therapy failure. But, long-term comparative trials in naïve patients between Xeomin® and conventional BoNT/A drugs are required to confirm the low immunogenicity of Xeomin®.

Evolution of dose and response to botulinum toxin A in cervical dystonia: a multicenter study

Botulinum neurotoxin (BoNT) is an effective treatment for cervical dystonia (CD). Long-term changes of several variables, including the dose of BoNT, in these patients is largely unknown. We reviewed the clinical charts of 275 patients with CD treated with BoNT type A (BoNT-A) for at least 5 years since 1989 at ten tertiary centers. The mean dose of BoNT-A per session during the first 5 years of treatment was calculated and the appearance of resistance was noted. The dose of BoNT-A for the whole group showed a significant trend to increase over time (year 1: 180 ± 65 U; year 5: 203 ± 63 U; ANOVA: p < 0.0001). However, when we studied the evolution of the dose of BoNT-A for those patients (n = 49) first injected after 2000 (introduction of current BOTOX preparation in our country), there was no significant increase in dose (year 1: 181.8 ± 75 U; year 5: 181.7 ± 75 U; ANOVA p: ns). A total of 19 patients became secondary nonresponders; all but one of these patients began BoNT-A treatment before 2000. In summary, there is a statistically significant increase of mean dose of BoNT-A per session over time, and this could be explained by the appearance of secondary nonresponders. On the other hand, those patients initially treated after 2000 did not show any statistically significant increase in dose for 5 years. This could be explained by better experience and techniques, fewer immunogenic problems with the current BoNT-A, and also less variability of the dose per vial.

Botulinum toxin has an increased effect when targeted toward the muscle’s endplate zone: A high-density surface EMG guided study

Objectives To compare the effect of endplate-targeted injections of a low Botulinum neurotoxin type A (BoNT-A) dose with that of injections at defined distances from the motor endplate zone. Methods In eight healthy volunteers, the main endplate zones of the right and left extensor digitorum brevis (EDB) muscles were localized using high-density surface EMG. On the study side BoNT-A was injected at fixed distances from the endplate zone. On the control side, BoNT-A was administered into the endplate zone. Compound muscle action potential (CMAP) prior to the injection and 2, 12, and 24 weeks later were recorded. Results On the control side, the mean CMAP reduction 2 weeks after BoNT-A injection was 79.3%. The difference in CMAP reduction between both EDB muscles was significantly related to the injection distance from the endplate zone. Increasing the injection distance by 1 cm reduced the effect of BoNT-A by 46%. Conclusions Guided injection of a reduced BoNT-A dose into the muscle’s endplate zone(s) is a promising strategy for optimizing the therapeutic effectiveness of BoNT-A and for minimizing side-effects such as unwanted weakness of adjacent muscles. Significance Precise endplate-targeted injections increase the effect of BoNT-A and may thus prove to reduce required dosage and treatment costs.

Intrathecal Administration of Botulinum Neurotoxin Type A Attenuates Formalin-Induced Nociceptive Responses in Mice

Botulinum neurotoxin type A (BoNT/A) has been used as an analgesic for myofascial pain syndromes, migraine, and other types of headaches. Although an antinociceptive effect of central or peripheral administration of BoNT/A is suggested, the effect at the spinal level is still unclear. In this study, we evaluated the antinociceptive effect of intrathecally administered BoNT/A on the ICR mice during the formalin test. BoNT/A (0.01 U/mouse) was injected intrathecally in ICR mice, and we observed formalin-induced inflammatory pain behaviors at days 1, 4, 7, 10, 14, 21, and 28 after the injection. We also examined the level of calcitonin gene-related peptide (CGRP), phosphorylated extracellullar signal-regulated kinases (p-ERK), and phosphorylated Ca(2+)/calmodulin-dependent protein kinase type 2 (p-CaMK-II) using immunoblot or immunohistochemical analyses before and after BoNT/A intrathecal injection. Even a single intrathecal injection of BoNT/A significantly decreased the nociceptive responses in the first phase (10 and 14 days later) and in the second phase of the formalin test at 1, 4, 7, 10, and 14 days later (P < 0.05) without any locomotor changes. Interestingly, intrathecal BoNT/A attenuated the expression level of CGRP, p-ERK, and p-CaMK-II in the 4th and 5th lumbar spinal dorsal horn at 10 days after injection in comparison with control. We showed that intrathecally administered BoNT/A may have a central analgesic effect on inflammatory pain through the modulation of central sensitization. BoNT/A, with its long-lasting antinociceptive effect, may be a useful analgesic in inflammatory pain.

Insulin-resistance reduces botulinum neurotoxin-type A induced prostatic atrophy and apoptosis in rats

Botulinum neurotoxin-type A (BoNTA) is an emerging therapeutic option for the treatment of benign prostatic hyperplasia. Recent reports indicate increased incidence of benign prostatic hyperplasia in the insulin-resistant individuals. Insulin-resistance is associated with the compensatory rise in the plasma insulin, which is known to have growth-promoting effects. The present study investigated the effect of insulin-resistance on the effectiveness of BoNTA in inducing prostatic atrophy in rats. Sprague-Dawley rats (200–220 g), maintained on normal-pellet or high-fat diet, were injected in the ventral prostate with 200 μl of saline or the same volume containing 5U BoNTA at the end of 9 weeks and were sacrificed 3 weeks later. Ventral prostate was carefully isolated, weighed, fixed and stained to examine the cellular morphology, cell death and proliferation. High-fat diet produced insulin-resistance, hyperinsulinemia and prostatic enlargement in rats. BoNTA caused prostatic atrophy and apoptosis in both insulin-resistant and insulin-sensitive rats. However, the effect of BoNTA was more prominent in insulin-sensitive rats (apoptosis-2 fold, prostatic atrophy-3 fold) as compared to the insulin-resistant rats. Significant increase in the phosphorylation of ERK-1/2 and expression of the proliferating cell nuclear antigen was observed in the prostate of insulin-resistant rats. In the present investigation we report that diet-induced insulin-resistance activates mitogenic signaling of insulin, increases cellular proliferation and reduces BoNTA-induced prostatic atrophy and apoptosis in rats. Results of the present study indicate that the insulin-resistance can affect the therapeutic outcome of BoNTA.

Botulinum Neurotoxin Type A Induces Skeletal Muscle Atrophy Without Altering Heat Shock Protein 70 Expression.

Botulinum neurotoxin type A (BoNT/A) is commonly used as a therapeutic treatment for a number of conditions associated with muscle spasticity in humans. BoNT/A creates a partial paralysis in skeletal muscle by inhibiting release of acetylcholine at the neuromuscular junction; effectively creating a chemical denervation. Like mechanical denervation, this results in significant skeletal muscle atrophy. Our prior studies have shown that heat shock protein 70 (Hsp70) is significantly reduced during various models of skeletal muscle atrophy and, if overexpressed, provides protection against atrophy. PURPOSE: To determine the effect of BoNT/A on Hsp70 expression and CSA in skeletal muscle. METHODS: Male, Sprague-Dawley rats were injected with either a control buffer or three units of Botulinum type A in the triceps surae muscle group. Hindlimbs were then stimulated to confirm force deficit in the triceps surae group and animals were allowed to ambulate normally for either 7 or 14 days. Soleus, plantaris, and gastrocnemius muscles were removed, weighed, and rapidly frozen for cross sectional analysis and Hsp70 protein expression. RESULTS: Force deficits of ∼80% confirmed chemical denervation of the triceps surae muscle group. Gastrocnemius, soleus, and plantaris muscle weights were all significantly decreased (∼36%; ∼31%; ∼54%, respectively) 14 days after injection. Similarly, soleus muscle fiber CSA was significantly decreased (∼25%) in injected limbs. Hsp70 protein expression remained unchanged in the plantaris and soleus muscles 7 and 14 days after BoNT/A injection. CONCLUSION: These data suggest that small doses of BoNT/A cause significant muscle atrophy in a short time period. Unlike other reduced-use models of atrophy, BoNT/A does not cause a reduction in Hsp70. Supported by Ipsen Pharmaceuticals, Ltd.

Bone changes in the mandible following botulinum neurotoxin injections

In this study, botulinum neurotoxin type A (BoTx/A) was injected into the temporalis and masseter muscles of growing rats to induce masticatory hypoactivity. Sixty, 30-day-old, male Long-Evans rats were randomly divided into four groups. BoTx/A was bilaterally injected in the masseter muscles in group I, in the temporalis muscles in group II, and into both the masseter and the temporalis muscles in group III. Group IV served as the control in which saline was bilaterally injected into both muscles. Forty-five days after the injections, the rats were sacrificed. Observation of cortical bone thickness from bone biopsies of the right halves of the mandibles, evaluation of the volume of masseter and temporalis muscles with a plethysmometer, and scanning of bone mineral density (BMD) of the skull and mandibular bone structure with dual-energy X-ray absorptiometry were performed. One-way analysis of variance was employed to analyse measurements of muscle volume, BMD, and cortical bone thickness among the groups. The least square difference was then used to determine significance. Reduced cortical bone thickness and BMD of the skull and mandibular bone structure were observed. The volumes of the temporalis and masseter muscles injected with BoTx/A were smaller. Masticatory hypofunction affects bone structure during development.

Utilisation de la toxine botulinique dans les cervicalgies postopératoires en chirurgie rachidienne : résultats préliminaires

Background and purpose Postoperative neck pain after cervical spinal surgery is a common occurrence, the prevalence of which can reach up to 60%. Since 2005 a prospective study, still in progress, is attempting to show the efficacy of botulinum toxin injections in its treatment. Methods Two hundred and fifteen patients operated on in the same institution for cervical spondylotic myelopathy were prospectively followed-up; 38 of them presented postoperative neck pain and were enrolled either in a course of botulinum toxin injections (19) or in conservative treatment (19). The muscles injected, in descending order, were: trapezius, supraspinalis, splenius capitis, and rhomboids. Injections were made using Type A-botulinum toxin (Botox*-Allergan Pharmaceuticals, Westport, Ireland), increasing from 20 to 100U Botox* without exceeding 300 U once in the same patient, performed every 3 months if necessary. The conservative treatment consisted of a course of thiocolchicoside (16 mg/day) and physical rehabilitation. The lordosis angle was calculated on lateral sitting radiographs in the neutral position immediately postoperatively and 1.5 months after injection and correlated to pain improvement evaluated by the visual analogic scale (VAS). Results No visible improvement was found on x-rays in three patients after injection, and in 11 after conservative treatment. In 16 cases, after an average of three injections, the gain in lordosis averaged 11.3° and the VAS score was decreased by 4.6 points versus 4.7° and a decrease of 0.6 points after conservative treatment. Conclusion Regardless of its limitations, the present study would seem to show potential value in the use of botulinum toxin in the treatment of postoperative pain after cervical spinal surgery.

Botulinum toxin improves dysphagia associated with multiple sclerosis

To evaluate the efficacy of botulinum neurotoxin type A (BoNT/A) for severe oro-pharyngeal dysphagia associated with multiple sclerosis (MS). BoNT/A was injected percutaneously into the hyperactive cricopharyngeal muscle of 14 dysphagic MS patients under electromyographic control. Patients were evaluated by videofluoroscopic and electromyographic examinations and by the Penetration/Aspiration Scale (PAS), at week 1, 4, 12, 16, 18, and 24 after BoNT/A injection. All patients showed a significant improvement in all the swallowing outcome measures. No specific treatment for oro-pharyngeal dysphagia related to MS has been described to date. Our preliminary findings suggest a potential benefit from BoNT/A treatment in MS patients with dysphagia associated with upper esophageal sphincter hyperactivity.

Botulinum neurotoxin type A (BoNTA) decreases the mechanical sensitivity of nociceptors and inhibits neurogenic vasodilation in a craniofacial muscle targeted for migraine prophylaxis

The mechanism by which intramuscular injection of BoNTA into the craniofacial muscles decreases migraine headaches is not known. In a blinded study, the effect of BoNTA on the mechanical and chemical responsiveness of individual temporalis muscle nociceptors and muscle neurogenic vasodilation was investigated in female rats. Mechanical threshold was measured for 3h following intramuscular injection of BoNTA or vehicle, and for 10min after a subsequent injection of the algogen glutamate. Injection of BoNTA significantly increased the mechanical threshold of muscle nociceptors without altering the muscle surface temperature and blocked glutamate-induced mechanical sensitization and neurogenic vasodilation. None of these effects were reproduced by pancuronium-induced muscle paralysis. Western blot analysis of temporalis muscles indicated that BoNTA significantly decreased SNAP-25. Measurement of interstitial glutamate concentration with a glutamate biosensor indicated that BoNTA significantly reduced glutamate concentrations. The mechanical sensitivity of muscle nociceptors is modulated by glutamate concentration through activation of peripheral NMDA receptors. Immunohistochemical experiments were conducted and they indicated that half of the NMDA-expressing temporalis nerve fibers co-expressed substance P or CGRP. Additional electrophysiology experiments examined the effect of antagonists for NMDA, CGRP and NK1 receptors on glutamate-induced effects. Glutamate-induced mechanical sensitization was only blocked by the NMDA receptor antagonist, but muscle neurogenic vasodilation was attenuated by NMDA or CGRP receptor antagonists. These data suggest that injection of BoNTA into craniofacial muscles acts to decrease migraine headaches by rapidly decreasing the mechanical sensitivity of temporalis muscle nociceptors through inhibition of glutamate release and by attenuating the provoked release of CGRP from muscle nociceptors.

Characterization of SNARE Cleavage Products Generated by Formulated Botulinum Neurotoxin Type-A Drug Products

The study evaluated substrate cleavage product(s) generated by three botulinum neurotoxin serotype A (BoNT/A) medicinal drug products utilizing a novel and highly specific, light-chain activity, high-performance liquid chromatography (LCA-HPLC) method. Samples were reacted with a commercially available BoNT/A fluorescent substrate derived from the SNAP-25 sequence. Reaction products were separated by reversed-phase HPLC. The method detected an atypical cleavage pattern by one of the formulated drug products. IncobotulinumtoxinA produced two cleavage fragments rather than the single fragment typically generated by BoNT/A. Identification confirmed the secondary cleavage at a position corresponding to SNAP-25 Arg198–Ala199 (normal BoNT/A cleavage is Gln197–Arg198). Arg198–Ala199 is also the cleavage site for trypsin and serotype C toxin. Normal cleavage was observed for all other BoNT/A drug product samples, as well as 900-kD and 150-kD bulk toxin BoNT/A. The reason for this unexpected secondary cleavage pattern by one formulated BoNT/A drug product is unknown. Possible explanations include a contaminating protease and/or damage to the 150-kD type-A toxin causing nonspecific substrate recognition and subsequent cleavage uncharacteristic of type-A toxin. The BoNT/A drug products were also analyzed via the LCA-HPLC assay using a commercial BoNT/C fluorescent substrate derived from the syntaxin sequence. Cleavage of the serotype C substrate by incobotulinumtoxinA was also confirmed whilst neither of the other drug products cleaved the syntaxin substrate.

Botulinum toxin assessment, intervention and aftercare for paediatric and adult drooling: international consensus statement

Many individuals with neurological problems or anatomical abnormalities of the jaw, lips or oral cavity may drool, which can impact on health and quality of life. A thorough evaluation of the patient's history, examination of the oral region by a speech pathologist and, in individuals over 3 years, a dental examination is warranted. Questionnaires with established validity such as the Drooling Impact Scale are useful assessment tools. A hierarchical approach to treatment is taken from least invasive therapies, such as speech pathology, to more invasive, such as injection of botulinum neurotoxin type-A (BoNT-A) into the salivary glands (parotid and submandibular). The wishes of the individual and their carer are crucial considerations in determining the suitability of the intervention for the patient. In the presence of dysphagia and cerebral palsy (CP), careful assessment is required prior to the injection of BoNT-A. Favourable responses to intervention include a reduction in the secretion of saliva and in drooling, as well as psychosocial improvements. BoNT-A is usually well tolerated, although potential side effects should be discussed with the patient and carer.

Botulinum toxin assessment, intervention and aftercare for paediatric and adult niche indications including pain: international consensus statement

Evidence is emerging for the use of botulinum neurotoxin type-A (BoNT-A) for niche indications including pain independent of spasticity. Pain indications such as chronic nociceptive back pain, piriformis syndrome, chronic myofascial pain, pelvic pain, complex regional pain syndrome, facial pain and neuropathic pain are outlined in this paper. Of these, class I evidence is available for the treatment of chronic nociceptive low back pain, piriformis syndrome, myofascial pain, facial pain, neuropathic pain and plantar fasciitis. Peri-operative use of BoNT-A is emerging, with indications including planning for surgery and facilitating surgery, as well as healing and improving analgesia post-operatively. Evidence is limited, although there are some reports that clinicians are successfully using BoNT-A peri-operatively. There is class I evidence showing pre-operative use of BoNT-A has a beneficial effect on outcomes following adductor-release surgery. The use of BoNT for treatment of tremor, other than neck tremor in the setting of cervical dystonia, including evidence for upper limb tremor, cranial tremor and non-dystonic neck tremor is reviewed. The evidence is variable at this stage, and further study is required to develop definitive recommendations for the clinical utility of BoNT-A for these indications.

Botulinum toxin assessment, intervention and aftercare for lower limb disorders of movement and muscle tone in adults: international consensus statement

Lower limb disorders of movement and muscle tone in adults significantly impact quality of life. The management of the patient with hypertonia is complex and requires a multidisciplinary team working with the patient and family/carers. Botulinum neurotoxin type A (BoNT-A) has been used as a component of this management to reduce lower limb hypertonia, increase passive range of motion and reduce associated pain and requirements for bracing. Adjunctive treatments to augment the effect of BoNT-A include electrical muscle stimulation of the injected muscles and stretching. When determining suitability for injection, the patient's main goals for intervention need to be established. Muscle overactivity must be distinguished from contracture, and the effect of underlying muscle weakness taken into account. Explanation of the injection process, potential adverse effects and post-injection interventions is essential. Assessment at baseline and post-treatment of impairments such as hypertonia, range of motion and muscle spasm are appropriate; however, the Goal Attainment Scale and other validated patient-centred scales can also be useful to assess therapy outcomes. In the future, initiatives should be directed towards examining the effectiveness of BoNT treatment to assist with achievement of functional and participation goals in adults with hypertonia and dystonia affecting the lower limb.