Botulinum Toxin and Smile Design

Biological macromolecules Alginate-Carboxymethyl Cellulose (Alg-CMC) hydrogel loaded with Botulinum toxin type A for skin wound treatment and functional tissue regeneration.

Botulinum Toxin as a medical therapy was introduced by Dr Alan Scott more than 20 years ago. The first clinical applications of Botulinum Toxin type A (BT-A) were for the treatment of strabismus and for periocular spasms. Botulinum Toxin type A is often effective in small to moderate angle convergent strabismus (esotropia) of any cause, and may be an alternative to surgery in these cases. Botulinum Toxin type A may have a role in acute or chronic fourth and sixth nerve palsy, childhood strabismus and thyroid eye disease. The use of BT-A for strabismus varies enormously in different cities and countries for no apparent reason. Botulinum Toxin type A may be particularly useful in situations where strabismus surgery is undesirable. This may be in elderly patients unfit for general anaesthesia, when the clinical condition is evolving or unstable, or if surgery has not been successful. Botulinum Toxin type A can give temporary symptomatic relief in many instances of bothersome diplopia irrespective of the cause. Ptosis and acquired vertical deviations are the commonest complications encountered. Vision-threatening complications are rare. Repeated use of BT-A is safe.

Correction of overactive bladder with botulinum toxin type A (BTX-A)

Botulinum toxin type A ameliorates adjuvant-arthritis pain by inhibiting microglial activation-mediated neuroinflammation and intracellular molecular signaling

Skin aging is commonly characterized by increased wrinkles, loss of elasticity, and hyperpigmentation, significantly affecting personal appearance and quality of life. Although botulinum toxin type A (BTX-A) has been widely applied in cosmetic anti-wrinkle treatments, its intrinsic cytotoxicity limits broader clinical applications. In this study, we developed a novel exosome-based BTX-A composite delivery system designed to synergize the anti-aging properties of exosomes with the wrinkle-reducing effects of BTX-A while reducing toxicity. Human adipose-derived mesenchymal stem cells were genetically modified via lentiviral transduction to overexpress Synaptic Vesicle Glycoprotein 2C (SV2C), the receptor of BTX-A, thereby producing SV2C-enriched functionalized exosomes (EXOSV2C). These exosomes (2.0 × 107 particles/mL) were incubated with BTX-A (3 U/mL) to generate the EXOSV2C-BTX-A complex. In vitro, EXOSV2C-BTX-A significantly promoted the proliferation and migration of human dermal fibroblasts and effectively alleviated D-galactose (D-gal)-induced cellular senescence and collagen type I loss. These effects were superior to those observed with either BTX-A or exosomes alone. In vivo, intradermal injection of EXOSV2C-BTX-A for 28 days markedly suppressed D-gal-induced skin aging in 8-week-old male KM mice, as evidenced by reduced malondialdehyde levels in dermal tissue, enhanced collagen type I expression, and preserved skin structure. Notably, the composite exhibited significantly lower toxicity compared to free BTX-A. Collectively, these findings highlight EXOSV2C-BTX-A as a promising exosome-mediated BTX-A delivery platform with enhanced anti-aging efficacy and improved biocompatibility, offering a potential therapeutic strategy for skin rejuvenation.

Botulinum toxin type A for failed back syndrome

Recently, botulinum toxin type B (BT-B) was introduced for treatment of cervical dystonia (CD). We wish to report on experience with BT-B derived from registration studies and from our own preliminary clinical experience. Botulinum toxin type B can be used successfully in CD patients with antibody-induced failure of botulinum toxin type A therapy (antibody patients). In our own 15 antibody patients, 11835 +/- 2,039 mouse units of BT-B (NeuroBloc) reduced the Toronto Western spasmodic torticollis rating scale (TWSTRS) score from 20.5 +/- 3.6 to 13.1 +/- 5.4. BT-B can also be used successfully in CD patients not previously exposed to BT-A or BT-B (de novo patients). In our own nine de novo patients, 10436 +/- 3,320 mouse units of BT-B reduced the TWSTRS score from 18.4 +/- 5.4 to 9.2 +/- 4.8. Altogether, dryness of the mouth occurred in 21 CD patients (severe 10, moderate 7, mild 4), accommodation difficulties in seven, conjunctival irritation in five, reduced sweating in four, swallowing difficulties in three, heartburn in three, constipation in three, bladder voiding difficulties in two, and dryness of nasal mucosa, head instability, and thrush in one each. BT-B produces substantially more systemic autonomic side effects than BT-A. It can be considered the therapy of choice in antibody patients. For de novo patients and for BT-A-treated CD patients, BT-B cannot be recommended currently.

SummaryThis analysis compared children with cerebral palsy treated with botulinum toxin type A (BTX-A) versus those not treated with BTX-A to assess the total cost of care and utilisation in a state run Medicaid program in the United States. A retrospective pre/post design was used with nested case-control matching based on propensity scores. Data for the study were extracted from the paid claims for South Carolina Medicaid recipients from 1995 through 2001. Extracted variables included cost of services, procedures performed and diagnoses. It was hypothesised that BTX-A use would not increase the total cost of care but would be related to cerebral palsy diagnosis (e.g. diplegia, hemiplegia, quadriplegia) when demographic covariates (age, race, gender), comorbid conditions (analgesic use, scoliosis, hydrocephalus, hip dysplasia, mental retardation, seizures) and hospitalisations were controlled. Conditional logistic regression via a Cox regression model was used to estimate the relationship between BTX-A use and the aforementioned variables. A total of 2,364 patients met the study inclusion and exclusion criteria. After 1:6 matching, a total of 406 patients were used in the analyses (58 cases and 348 matched controls). After matching, no significant differences were noted between the groups on any of the study variables. Regression results indicated that cerebral palsy diagnosis, but not cost, was significantly related to BTX-A treatment. The cerebral palsy categories of diplegia (β=2.55; hazard ratio [HR]=5.91), hemiplegia (β=5.43; HR=23.88) and quadriplegia (β=4.23; HR=10.22) were all significant in the model (p < 0.01). The mean 2-year cost of treatment for BTX-A users (in US$) was $44,761 (sd $56,643) versus $41,553 (sd $57,844) for non-BTX-A users. These results indicate that, over the 24 months studied, BTX-A did not add to the total cost of care. Whilst the number of subjects is small, it represents the entire population of cerebral palsy patients treated over the study period.

Botulinum toxin type A (BoNT/A) has been proposed as an alternative treatment for sialorrhoea in patients with amyotrophic lateral sclerosis (ALS). In an open-label prospective study, BoNT/A was injected into the parotid glands bilaterally using anatomic landmarks in 26 ALS patients with bulbar symptoms. Two weeks after injection the severity of sialorrhoea and the related disability were evaluated subjectively and objectively. A group of healthy subjects acted as controls for saliva production. Patients also underwent electrophysiological tests to evaluate possible toxin effects in the nearby non-injected muscles by comparing the amplitude of compound motor action potentials (cMAPs) elicited by electrical stimulation and recorded from the orbicularis oculi and masseter muscles. After BoNT/A injections, of the 26 patients treated, 23 reported that the severity of sialorrhoea improved and the disabling symptoms diminished. Cotton roll weight also decreased after BoNT/A injection, suggesting a reduction in saliva production. Two patients complained of dry mouth. BoNT/A injection left the cMAP amplitude unchanged, suggesting that botulinum toxin does not significantly affect the non-injected facial and masticatory muscles. In conclusion, intraparotid anatomically-guided BoNT/A injection is an effective, easy, and safe treatment for sialorrhoea in patients with bulbar symptoms related to ALS.

Expanding use of botulinum toxin

Recently, botulinum toxin type B (BT-B) became commercially available for treatment of cervical dystonia. It is the aim of this study to explore its use for treatment of bilateral axillar hyperhydrosis (HH). For this we directly compared the antihyperhydrotic effect of BT-B (NeuroBloc)/MyoBloc) with that of botulinum toxin type A (BT-A) (Botox). 9 patients (HD group) received BT-A 100MU unilaterally and BT-B 4000MU contralaterally. 10 patients (LD group) received BT-A 100MU and BT-B 2000MU. All patients were blinded as to which preparation was used in which side. All patients except one reported excellent HH improvement in both axillae. None of the patients had residual HH on clinical examination. The duration of HH improvement until first recurrence in the HD group was 16.0 +/-4.3 weeks in the BT-A treated axillar and 16.4 +/-4.5 weeks in the BT-B treated axillae (Wilcoxon rank-sum test, p = 0.336). In the LD group it was 16.4 +/-5.3 weeks in the BT-B treated axillae and 17.1 +/-5.7 weeks in the BT-A treated axillae (Wilcoxon rank-sum test, p = 0.059). There was also no difference in the duration of HH improvement between the axillae treated with BT-B 4000MU and BT-B 2000MU (Wilcoxon rank-sum test, p = 0.712). 5 out of 9 patients in the HD group (chi-square test, p = 0.025) and 7 out of 10 patients in the LD group (chi-square test, p = 0.008) reported more application discomfort in the BT-B treated axillae. In 6 out of 9 patients in the HD group (chi-square test, p = 0.014) and in 6 out of 10 patients in the LD group (chi-square test, p = 0.014) the onset of HH improvement appeared earlier in the BT-B treated axillae. One patient in the HD group reported dryness of the mouth and eyes and accomodation difficulties.BT-B is a safe and efficient treatment for axillar HH. Doses of BT-B 2000MU per axilla seem sufficient indicating a conversion factor between BT-A and BT-B in the order of 1:20. With a conversion factor for cervical dystonia in the order of 1:40 the autonomic nervous system seems to be relatively more sensitive to BT-B than to BT-A compared with the motor system.

Botulinum toxin type a intralesional monotherapy for treating human hypertrophic scar in a dose-dependent manner: In an animal model

Botulinum toxin type A (BTX‐A) has been used successfully to manage spasticity in children with cerebral palsy. Little has been done to evaluate treatment outcome and satisfaction from the patients' and parents' points of view. The aim of this study was to investigate the parents' perceptions of the benefits of BTX‐A on movement disorders in children with cerebral palsy. Twenty‐six children with adductor spasticity were enrolled into an open‐label, prospective study. Patients received intramuscular injections of BTX‐A, and assessments of joint mobility (passive range of motion), degree of spasticity (Modified Ashworth Scale) and functional benefit (Gross Motor Function Measure) were made before and 12–18 weeks after treatment. Parents' assessment of treatment outcomes were evaluated using a standardised questionnaire. BTX‐A was shown to be effective in reducing muscular hyperactivity and functional limitations. Parents' satisfaction with the treatment outcome was high. For non‐ambulatory patients, the reported benefits included facilitation of daily care, ease of positioning and reduction of pain. For patients who were disabled to a lesser extent, improvements in gait and posture included sitting with improved comfort, standing for longer periods of time and/or walking longer distances. The parents' responses supported the impressions of the therapists, demonstrating that BTX‐A produced beneficial effects on daily activities, according to both objective measures and parents' observation.

HIV-associated progressive encephalopathy in vertically HIV-infected children may manifest early with a failure to attain or loss of developmental milestones, impaired brain growth or acquired progressive symmetric motor abnormalities [1]. The risk of developing progressive encephalopathy increases with the early age of infection and high viral loads [2,3]. Recent evidence suggests that highly active antiretroviral therapy (HAART) may halt or even partially reverse progressive encephalopathy, often leaving sequelae similar to those observed in static encephalopathies, including limb spasticity, usually with normal or mildly affected cognition [4]. Botulinum toxin type A (BT-A) injection has been proved to be a well-tolerated, safe and effective procedure in the treatment of children with cerebral palsy [5,6]. To our knowledge, no data regarding the use of BT-A in HIV-infected children has been reported to date. We report the cases of four vertically HIV-infected children in whom progressive encephalopathy developed severely during infancy and was the first AIDS-defining condition, leading to the diagnosis of HIV infection in their mothers. All of them showed good clinical and immunological responses to HAART. However, the sequelae from progressive encephalopathy included severe motor deficits in all cases, especially involving the lower limbs. The long-term treatment for the HIV-induced spasticity that affects these patients includes a physiotherapy programme, orthoses and sessions of BT-A (Dysport, Ipsen, Berks, UK or Botox, Allergan, Irvine, CA, USA) local injections every 4–6 months from the age of 3 years. An improvement in measures of gross motor function and functional mobility for daily living was observed in all cases, and our patients are now able to walk. No major side-effects have been observed to date. Clinical data and BT-A treatment characteristics are summarized in Table 1.Table 1: Clinical data and botulinum toxin type A treatment characteristics.BT-A is an exotoxin derived from Clostridium botulinum that is rapidly bound by the receptors in the presynaptic membranes of cholinergic motor neurones, preventing the discharge of acetylcholine and leading to a chemical denervation. The peak effect is usually noticed by 1–2 weeks after the injection, but the period of clinically useful relaxation lasts 12–16 weeks. Treatment-related adverse events are rare, mild and transient, local pain or weakening of the injected muscle being the most common, as once happened in one of our patients. The optimal timing for BT-A treatment in the lower extremity is between 2 and 5 years of age, the period of dynamic motor development, when there is the greatest chance to modify the natural course of the disease, reducing muscle contracture and the need for surgery. BT-A should always be used together with adjunctive treatments such as active motor training and orthotic treatment, in order to increase the injected muscle length and flexibility. Moreover, new motor skills will have to be achieved and retained at such early ages [5]. The pathogenic characteristics of HIV-related progressive encephalopathy spasticity are not different from those of more common causes of cerebral palsy. The patients we report have been treated according to our protocol for the treatment of spasticity in the paediatric population (dose, muscles injected, age at injection and interval between injections), which follows international recommendations [5] and has been applied to over 300 paediatric patients, with good functional results in most of them. It is remarkable that these four patients have shown an optimal clinical and immunological evolution after the initiation of HAART, with undetectable viral loads and normal CD4 T-cell counts over time. Whether BT-A treatment is also applicable to HIV-infected children with some degree of immunosuppression remains uncertain. In conclusion, BT-A seems to be effective as an adjunctive therapy in ameliorating progressive encephalopathy-related spasticity in HIV-infected children with good immunological status, and shows a good safety profile.

Botulinum toxin type B (BT-B) therapy failure due to formation of botulinum toxin type B antibodies (BT-B-AB) has only been reported in patients with botulinum toxin type A antibodies (BT-A-AB). We are reporting BT-B-AB-induced therapy failure in 2 patients with no previous exposure to botulinum toxin. In patient 1 complete therapy failure occurred after a single exposure to 14,400 mouse units (MU) BT-B (NeuroBloc™). The mouse diaphragm assay (MDA) revealed a BT-B-AB titre in excess of 10 mU/ml. Doubling the BT-B dose did not elicit any effects. Application of 360 MU BT-A (Botox^®) produced the original therapeutic effect, but the second BT-A application was followed by partial and the third by complete therapy failure. Doubling the BT-A dose did not elicit any effects. MDA testing showed a BT-A-AB titre in excess of 10 mU/ml. In patient 2 a single exposure to 7,200 MU BT-B lead to a complete therapy failure. MDA testing revealed a BT-B-AB titre in excess of 10 mU/ml. Doubling the BT-B dose did not elicit any effects. Application of 180 MU BT-A (Botox) produced the original response on 3 consecutive applications. Antibody formation can occur after a single exposure to botulinum toxin. However, this is highly unusual. Since therapy failure occurred after the first-ever botulinum toxin exposure, short intervals between injections and use of booster injections can be excluded as causes for BT-B-AB formation in both patients. A more likely cause may be the substantially higher amount of antigenic protein administered in BT-B therapy compared to BT-A therapy. Further studies are necessary to compare the incidence of antibody formation in BT-B and BT-A therapy.