Role of Diagnostic Nerve Blocks in the Goal-Oriented Treatment of Spasticity with Botulinum Toxin Type A: A Case-Control Study.

The goal-setting process is pivotal in managing patients with disabling spasticity. This case-control study assessed the role of diagnostic nerve blocks in guiding the goal-setting process within goal-targeted treatment of spasticity with botulinum neurotoxin-A. In this case-control study, patients with disabling spasticity underwent either a goal-setting process based on the patient's needs and clinical evaluation (control group) or additional diagnostic nerve block procedures (case group). All enrolled patients underwent a focal treatment with botulinum neurotoxin-A injection and a 1-month follow-up evaluation during which goal achievement was quantified using the goal attainment scaling-light score system. Data showed a higher goal achievement rate in the case group (70%) than in the control group (40%). In conclusion, diagnostic nerve blocks may help guide the goal-setting process within goal-targeted treatment of spasticity with botulinum neurotoxin-A towards more realistic and achievable goals, thereby improving the outcomes of botulinum neurotoxin-A injection. Future studies should better explore the role of diagnostic nerve blocks to further personalize botulinum neurotoxin-A according to individual patients' preferences and requirements.

Proteomic changes of botulinum neurotoxin injection on muscle growth in children with spastic cerebral palsy.

PURPOSE: The study aims to explore the proteomic profile and specific target proteins associated with muscle growth in response to botulinum neurotoxin A (BoNT-A) treatment, in order to improve spasticity management in children with cerebral palsy (CP). EXPERIMENTAL DESIGN: A total of 54 participants provided 60 plasma samples for proteomic analysis. Among them, six children were sampled before and after receiving their first BoNT-A injection. In addition, 48 unrelated children were enrolled, among whom one group had never received BoNT-A injections and another group was sampled after their first BoNT-A injection. Differentially expressed proteins were identified using the data-independent acquisition (DIA) mass spectrometry approach. Gene Ontology (GO), protein-protein interaction network, and Kyoto Encyclopedia of Genes and Genome analysis were conducted to explore the function and relationship among differentially expressed proteins. The expression levels of target proteins were verified by quantitative real-time PCR and western blotting. RESULTS: Analysis identified significant differential expression of 90 proteins across two time points, including 48 upregulated and 42 downregulated proteins. The upregulated thioredoxin, α-actinin-1, and aggrecan, and the downregulated integrin beta-1 may affect the growth of muscles affected by spasticity 3 months after BoNT-A injection. This effect is potentially mediated through the activation or inhibition of PI3K-Akt, focal adhesion, and regulation of actin cytoskeleton signaling pathways. CONCLUSION AND CLINICAL RELEVANCE: BoNT-A injection could lead to a disruption of protein levels and signaling pathways, a condition subsequently associated with muscle growth. This finding might aid clinicians in optimizing the management of spasticity in children with CP.

Synergic actions of botulinum neurotoxin A and oxaliplatin on colorectal tumour cell death through the upregulation of TRPM2 channel-mediated oxidative stress.

Botulinum neurotoxin A (BoNT) is being shown to have anticancer action as a potential adjuvant treatment. The transient receptor potential (TRP) melastatin 2 (TRPM2) stimulator action of BoNT was reported in glioblastoma cells, but not in colorectal cancer (HT29) cells. By activating TRPM2, we evaluated the impacts of BoNT and oxaliplatin (OXA) incubations on oxidant and apoptotic values within the HT29 cells. Control, BoNT (5 IU for 24 h), OXA (50 µM for 24 h) and their combinations were induced. We found that TRPM2 protein is upregulated and mediates enhanced BoNT and OXA-induced Ca2+ entry in cells as compared to control cells. The increase of free reactive oxygen species (ROS), but the decrease of glutathione is the main ROS responsible for TRPM2 activation on H29 exposure to oxidative stress. BoNT and OXA-mediated Ca2+ entry through TRPM2 stimulation in response to H2 O2 results in mitochondrial Ca2+ overload, followed by mitochondrial membrane depolarization, apoptosis and caspase-3/-8/-9, although they were diminished in the TRPM2 antagonist groups (N-(p-amylcinnamoyl)anthranilic acid and carvacrol). In conclusion, by increasing the susceptibility of HT29 tumour cells to oxidative stress and apoptosis, the combined administration of BoNT and OXA via the targeting of TRPM2 may offer a different approach to kill the tumour cells.

Complexing Protein-Free Botulinum Neurotoxin A Formulations: Implications of Excipients for Immunogenicity.

The formation of neutralizing antibodies is a growing concern in the use of botulinum neurotoxin A (BoNT/A) as it may result in secondary treatment failure. Differences in the immunogenicity of BoNT/A formulations have been attributed to the presence of pharmacologically unnecessary bacterial components. Reportedly, the rate of antibody-mediated secondary non-response is lowest in complexing protein-free (CF) IncobotulinumtoxinA (INCO). Here, the published data and literature on the composition and properties of the three commercially available CF-BoNT/A formulations, namely, INCO, Coretox® (CORE), and DaxibotulinumtoxinA (DAXI), are reviewed to elucidate the implications for their potential immunogenicity. While all three BoNT/A formulations are free of complexing proteins and contain the core BoNT/A molecule as the active pharmaceutical ingredient, they differ in their production protocols and excipients, which may affect their immunogenicity. INCO contains only two immunologically inconspicuous excipients, namely, human serum albumin and sucrose, and has demonstrated low immunogenicity in daily practice and clinical studies for more than ten years. DAXI contains four excipients, namely, L-histidine, trehalosedihydrate, polysorbate 20, and the highly charged RTP004 peptide, of which the latter two may increase the immunogenicity of BoNT/A by introducing neo-epitopes. In early clinical studies with DAXI, antibodies against BoNT/A and RTP004 were found at low frequencies; however, the follow-up period was critically short, with a maximum of three injections. CORE contains four excipients: L-methionine, sucrose, NaCl, and polysorbate 20. Presently, no data are available on the immunogenicity of CORE in human beings. It remains to be seen whether all three CF BoNT/A formulations demonstrate the same low immunogenicity in patients over a long period of time.

Onabotulinum Toxin A (BoNT-A) for Drooling in Children: A Systematic Review and Meta-Analysis.

INTRODUCTION: Sialorrhea, also known as drooling, hypersalivation, or ptyalism, has a significant impact on the medical and psychosocial well-being of children. Onabotulinum toxin A (BoNT-A) is the most commonly used botulinum toxin worldwide for the treatment of sialorrhea in children. OBJECTIVES: To conduct a comprehensive systematic review and meta-analysis to assess the clinical efficacy and potential adverse effects of BoNT-A as a treatment for drooling in children. METHODS: Cochrane, Embase, and Medline databases were systematically searched (up to May 2023). Out of 535 identified publications, 20 were found eligible for inclusion. A systematic review and meta-analysis were performed to determine the efficacy of BoNT-A treatment in children in reducing the frequency and severity of drooling. RESULTS: Out of the 20 studies included, a meta-analysis was conducted on the complete dataset of eight studies involving 131 patients. BoNT-A was found to significantly decrease the severity of drooling in patients with sialorrhea (standardized mean difference [SMD], -2.07; 95% confidence interval [CI], -2.91 to -1.23; p < 0.0001) when compared with the conditions before injections using random-effects models. Six studies out of 20 reported dysphagia as an adverse effect after injection. Other side effects included thickness of saliva and pain at the site of injection. CONCLUSION: BoNT-A is a clinically effective therapy that improves drooling severity in children with sialorrhea. Although there were some adverse side effects reported, they were transient and not severe. Future studies are needed to further evaluate the best techniques and to identify the ideal dosages required to achieve the optimal outcomes. Laryngoscope, 134:3012-3017, 2024.

Functional outcomes between headache surgery and targeted botox injections: A prospective multicenter pilot study.

Introduction: Chronic migraine headaches (MH) are a principal cause of disability worldwide. This study evaluated and compared functional outcomes after peripheral trigger point deactivation surgery or botulinum neurotoxin A (BTA) treatment in patients with MH. Methods: A long-term, multicenter, and prospective study was performed. Patients with chronic migraine were recruited at the Ohio State University and Massachusetts General Hospital and included in each treatment group according to their preference (BTA or surgery). Assessment tools including the Migraine Headache Index (MHI), Migraine Disability Assessment Questionnaire (MIDAS) total, MIDAS A, MIDAS B, Migraine Work and Productivity Loss Questionnaire-question 7 (MWPLQ7), and Migraine-Specific Quality of Life Questionnaire (MSQ) version 2.1 were used to evaluate functional outcomes. Patients were evaluated prior to treatment and at 1, 2, and 2.5 years after treatment. Results: A total of 44 patients were included in the study (surgery=33, BTA=11). Patients treated surgically showed statistically significant improvement in headache intensity as measured on MIDAS B (p = 0.0464) and reduced disability as measured on MWPLQ7 (p = 0.0120) compared to those treated with BTA injection. No statistical difference between groups was found for the remaining functional outcomes. Mean scores significantly improved over time independently of treatment for MHI, MIDAS total, MIDAS A, MIDAS B, and MWPLQ 7 (p<0.05). However, no difference in mean scores over time was observed for MSQ. Conclusions: Headache surgery and targeted BTA injections are both effective means of addressing peripheral trigger sites causing headache pain. However, lower pain intensity and work-related disabilities were found in the surgical group.

Industrial Production and Therapeutic Application of Botulinum Neurotoxin: The Role of C. botulinum Type A.

Botulinum neurotoxin has remarkably transitioned from a food safety hazard and biological warfare to an effective therapeutic drug. Currently, botulinum neurotoxins have seven serotypes (BoNT/A-G) in the form of protein complexes produced by Clostridium, a gram-positive and spore-forming bacteria. The conversion of toxins into useful drug substances of choice using the biotechnological process is tremendously increasing. Recent studies have shown that Botulinum neurotoxin-A (BoNT/A) has different biological activities and potencies in experimental and clinical conditions. They also indicate that the manufacturing process influences the potency and efficacy of BoNT/A drugs. Thus, this review focuses on the following criteria: detailed Fed-batch operation that includes the upstream and downstream processing of BoNT/A, the underlying mechanism behind the neurotoxic effect, and commercially available FDA-approved BoNT/A products and their therapeutic uses. Still, some research gaps exist in the mechanism for the treatment of psychiatric disorders.

Layer-Specific BTX-A Delivery to the Gastric Muscularis Achieves Effective Weight Control and Metabolic Improvement.

The rising incidence of health-endangering obesity constantly calls for more effective treatments. Gastric intramural injection of botulinum neurotoxin A (BTX-A) as a new modality carries great promise yet inconsistent therapeutic efficacy. A layer-specific delivery strategy enabled by dissolving microneedles is hence pioneered to investigate the working site of BTX-A and the resulting therapeutic effects. The drug-loaded tips of the layer-specific gastric paralysis microneedles (LGP-MN) rapidly release and achieve uniform distribution of BTX-A within the designated gastric wall layers. In an obesity rat model, the LGP-MNs not only prove safer than conventional injection, but also demonstrate consistently better therapeutic effects with muscular layer delivery, including 16.23% weight loss (3.06-fold enhancement from conventional injection), 55.20% slower gastric emptying rate, improved liver steatosis, lowered blood lipids, and healthier gut microbiota. Further hormonal study reveals that the elevated production of stomach-derived glucagon-like peptide-1 due to the muscularis-targeting LGP-MN treatment is an important contributor to its unique glucose tolerance-improving effect. This study provides clear indication of the gastric muscularis as the most favorable working site of BTX-A for weight loss and metabolic improvement purposes, and meanwhile suggests that the LGP-MNs could serve as a novel clinical approach to treat obesity and metabolic syndromes.

Addressing the Real-World Challenges of Immunoresistance to Botulinum Neurotoxin A in Aesthetic Practice: Insights and Recommendations from a Panel Discussion in Hong Kong.

With increasing off-label aesthetic indications using higher botulinum neurotoxin A (BoNT-A) doses and individuals starting treatment at a younger age, particularly in Asia, there is a greater risk of developing immunoresistance to BoNT-A. This warrants more in-depth discussions by aesthetic practitioners to inform patients and guide shared decision-making. A panel comprising international experts and experienced aesthetic practitioners in Hong Kong discussed the implications and impact of immunoresistance to BoNT-A in contemporary aesthetic practice, along with practical strategies for risk management. Following discussions on a clinical case example and the results of an Asia-Pacific consumer study, the panel concurred that it is a priority to raise awareness of the possibility and long-term implications of secondary non-response due to immunoresistance to BoNT-A. Where efficacy and safety are comparable, a formulation with the lowest immunogenicity is preferred. The panel also strongly favored a thorough initial consultation to establish the patient's treatment history, explain treatment side effects, including the causes and consequences of immunoresistance, and discuss treatment goals. Patients look to aesthetic practitioners for guidance, placing an important responsibility on practitioners to adopt risk-mitigating strategies and adequately communicate important risks to patients to support informed and prudent BoNT-A treatment decisions.

Botox for the prevention of radiation-induced Sialadenitis and xerostomia in head and neck cancer patients: A pilot study.

BACKGROUND: To determine the safety of Botox and its potential effect on alleviating radiation therapy (RT)-induced sialadenitis in head and neck cancer patients. METHODS: Twenty patients with stage III/IV head and neck cancer were randomized to receive Botox or saline injections into both submandibular glands (SMG). There were three visits: one before RT (V1); 1 week after RT (V2); and 6 weeks after RT (V3), each of which included saliva collection, a 24-h dietary recall, and a quality-of-life survey. RESULTS: No adverse events were observed. While the control group was much older, the Botox group more commonly underwent induction chemotherapy compared with controls. From V1 to V2, salivary flow decreased in both groups, but only in the control group from V1 to V3. CXCL-1 (GRO), a neutrophil chemoattractant, was lower in the Botox group compared with the control group at V3. CONCLUSION: Botox can be safely administered to the salivary glands prior to external beam radiation without observed complications or side-effects. After an initial reduction in salivary flow following RT, the Botox group showed lack of further flow reduction compared with controls. The inflammatory marker CXCL 1, which was reduced in the in Botox group at V3, may be a candidate for further studies of radiation-induced sialadenitis.

Increasing relief with repeated botulinum neurotoxin A injections in a rare case of hemi facial spasm with contralateral trigeminal autonomic orofacial pain and occipital neuralgia: A case report.

Ipsilateral hemi facial spasm, trigeminal autonomic orofacial pain and occipital neuralgia may occur due to close proximity of V and VII nerves in pons and inter-neuronal interconnections of trigeminocervical complex. In this report, we describe management of a patient with long standing untreated left hemi facial spasm of ten years with contralateral trigeminal autonomic orofacial pain and occipital neuralgia present for last five years. Repeated intramuscular injections of Botulinum neurotoxin A were given for hemi facial spasm which completely resolved the twitches for 5-8 months with decreased baseline twitches noted before next cycle of injections. Addition of Botulinum neurotoxin A in nerve block injections for occipital neuralgia resulted in prolonged relief of five months and decreased baseline pain scores. Addition of Botulinum neurotoxin A to nerve block injections for trigeminal autonomic orofacial pain decreased autonomic features and baseline pain scores.

Botulinum neurotoxin A ameliorates depressive-like behavior in a reserpine-induced Parkinson's disease mouse model via suppressing hippocampal microglial engulfment and neuroinflammation.

Depression is one of the common non-motor symptoms of Parkinson's disease (PD). In the clinic, botulinum neurotoxin A (BoNT/A) has been used to treat depression. In this study, we investigated the mechanisms underlying the anti-depressive effect of BoNT/A in a PD mouse model. Mice were administered reserpine (3 µg/mL in the drinking water) for 10 weeks. From the 10th week, BoNT/A (10 U·kg-1·d-1) was injected into the cheek for 3 consecutive days. We showed that chronic administration of reserpine produced the behavioral phenotypes of depression and neurochemical changes in the substantia nigra pars compacta (SNpc) and striatum. BoNT/A treatment significantly ameliorated the depressive-like behaviors, but did not improve TH activity in SNpc of reserpine-treated mice. We demonstrated that BoNT/A treatment reversed reserpine-induced complement and microglia activation in the hippocampal CA1 region. Furthermore, BoNT/A treatment significantly attenuated the microglial engulfment of presynaptic synapses, thus ameliorating the apparent synapse and spine loss in the hippocampus in the reserpine-treated mice. Moreover, BoNT/A treatment suppressed microglia-mediated expression of pro-inflammatory cytokines TNF-α and IL-1ß in reserpine-treated mice. In addition, we showed that BoNT/A (0.1 U/mL) ameliorated reserpine-induced complement and microglia activation in mouse BV2 microglial cells in vitro. We conclude that BoNT/A ameliorates depressive-like behavior in a reserpine-induced PD mouse model through reversing the synapse loss mediated by classical complement induced-microglial engulfment as well as alleviating microglia-mediated proinflammatory responses. BoNT/A ameliorates depressive-like behavior, and reverses synapse loss mediated by classical complement pathway-initiated microglia engulfment as well as alleviates microglia-mediated proinflammatory response in the reserpine-induced Parkinson's disease mouse model.

Distribution of Cleaved SNAP-25 in the Rat Brain, following Unilateral Injection of Botulinum Neurotoxin-A into the Striatum.

In Parkinson's disease, hypercholinism in the striatum occurs, with the consequence of disturbed motor functions. Direct application of Botulinum neurotoxin-A in the striatum of hemi-Parkinsonian rats might be a promising anticholinergic therapeutic option. Here, we aimed to determine the spread of intrastriatally injected BoNT-A in the brain as well as the duration of its action based on the distribution of cleaved SNAP-25. Rats were injected with 1 ng of BoNT-A into the right striatum and the brains were examined at different times up to one year after treatment. In brain sections immunohistochemically stained for BoNT-A, cleaved SNAP-25 area-specific densitometric analyses were performed. Increased immunoreactivity for cleaved SNAP-25 was found in brain regions other than the unilaterally injected striatum. Most cleaved SNAP-25-ir was found in widespread areas ipsilateral to the BoNT-A injection, in some regions, however, immunoreactivity was also measured in the contralateral hemisphere. There was a linear relationship between the distance of a special area from the injected striatum and the time until its maximum averaged immunoreactivity was reached. Moreover, we observed a positive relationship for the area-specific distance from the injected striatum and its maximum immunoreactivity as well as for the connection density with the striatum and its maximum immunoreactivity. The results speak for a bidirectional axonal transport of BoNT-A after its application into the striatum to its widespread connected parts of the brain. Even one year after BoNT-A injection, cleaved SNAP-25 could still be detected.

Functional Polymorphism in the ADRB3 Gene, Encoding the Beta-3 Adrenergic Receptor, and Response to Intra-Detrusor Injection of Botulinum Toxin-A in Women with Overactive Bladder.

BACKGROUND: There are reports suggesting an association between the rs4994 polymorphism in the ADRB3 gene encoding the beta-3 adrenergic receptor and OAB risk in females. The injection of botulinum toxin-A into the bladder wall is recommended as a possible treatment for OAB patients in whom first-line therapies have failed. The aim of our study was to analyze the possible association between the ADRB3:rs4994 polymorphism and the patient-perceived response to a single intra-detrusor injection of botulinum toxin-A in Polish women with overactive bladder. METHODS: The study group consisted of 115 consecutive female patients with OAB. The response to botulinum toxin-A was evaluated at three months after injection, as absolute or relative reductions in OAB symptoms or in scores from questionnaires ICIQ-OAB (parts A and B) and ICIQ-LUTS-QoL (parts A and B). ADRB3:rs4994 variants were identified by the sequencing of genomic DNA extracted from buccal swabs. RESULTS: There were no statistically significant differences between ADRB3:rs4994 [T];[T] homozygotes and [T];[C]+[C];[C] subjects for absolute or relative reductions in symptoms or in scores from all four questionnaire parts at three months after the injection of botulinum toxin-A. CONCLUSIONS: Our results do not support the hypothesis that ADRB3:rs4994 polymorphism is associated with the response to the intra-detrusor injection of botulinum toxin-A in Polish females with overactive bladder.

Botulinum Neurotoxin A in the Treatment of Pharyngocutaneous Fistula after Salvage Surgery in Head and Neck Cancer Patients: Our Preliminary Results.

Objective: To analyze the effect of intraparotid injection of botulinum neurotoxin A (BoNT-A) on salivary production and the course of pharyngocutaneous fistula (PCF) in post-radiation therapy salvage surgery. Methods: A total of 13 patients who had undergone total laryngectomy or pharyngolaryngectomy were treated with BoNT-A to both parotid glands, within three days from PCF onset. The salivary flow was evaluated using a subjective rating scale as the percentage of normal function from 0% (no saliva) to 100% (normal saliva flow), before injection, every day for 2 weeks, and once a week for three months. PCFs were monitored daily. Results: Spontaneous closure of PCF occurred in 7/13 (53.84%) cases 13.6 days (range: 7-18) after treatment; 6/13 (46.16%) patients needed revision surgery. Salivary flow significantly decreased in all patients seven days after injection (from 67.2% to 36.4%; p < 0.05). Patients who had undergone either conservative or surgical treatment did not differ in salivary flow before injection, whereas the mean percentages of salivary flow calculated at each time point after injection were different (p < 0.05). Conclusions: BoNT-A contributed to the closure of the fistula in most of our cases. The subjective perception of salivary flow predicted the closure of PCF. The mean time to closure may contribute to establishing the timing of PCF surgical treatment.

Preclinical Evidence for the Role of Botulinum Neurotoxin A (BoNT/A) in the Treatment of Peripheral Nerve Injury.

Traumatic peripheral nerve injuries tend to be more common in younger, working age populations and can lead to long-lasting disability. Peripheral nerves have an impressive capacity to regenerate; however, successful recovery after injury depends on a number of factors including the mechanism and severity of the trauma, the distance from injury to the reinnervation target, connective tissue sheath integrity, and delay between injury and treatment. Even though modern surgical procedures have greatly improved the success rate, many peripheral nerve injuries still culminate in persistent neuropathic pain and incomplete functional recovery. Recent studies in animals suggest that botulinum neurotoxin A (BoNT/A) can accelerate nerve regeneration and improve functional recovery after injury to peripheral nerves. Possible mechanisms of BoNT/A action include activation or proliferation of support cells (Schwann cells, mast cells, and macrophages), increased angiogenesis, and improvement of blood flow to regenerating nerves.

Tear meniscus, corneal topographic and aberrometric changes after botulinum toxin-a injection in patients with blepharospasm and hemifacial spasm.

PURPOSE: To investigate the effect of botulinum neurotoxin-A (BTX-A) treatment on dry eye symptoms, tear meniscus, corneal topography and corneal aberrometry in patients with benign essential blepharospasm (BEB) and hemifacial spasm (HFS). MATERIALS AND METHODS: This prospective study comprised of 6 patients with BEB and 20 patients with HFS. Tear meniscus height (TMH) and depth (TMD), tear break-up time (TBUT), corneal fluorescein staining score (CFSS), Schirmer I test, ocular surface disease index (OSDI) score, corneal topography [corneal power of flat axis (K1), corneal power of steep axis (K2), mean corneal power (Km), astigmatism and thinnest pachymetry] and anterior corneal aberrometry [spherical aberration (SA), vertical coma (vcoma), horizontal coma (hcoma), higher order root mean square (hRMS) and total RMS] were evaluated before BTX-A treatment, 3 weeks after BTX-A treatment and 2 months after BTX-A treatment. RESULTS: Six patients with BEB and 20 patients with HFS treated with BTX-A were evaluated in this study. Twenty contralateral spasm free eyes of 20 HFS patients were taken as control group. TMH and TMD were found to be significantly higher in eyes with spasm at both 3 weeks and 2 months after injection (TMH: 279.0 ± 123.2 at pretreatment, 380.5 ± 174.7 at third week and 317.0 ± 125.5 at second month p < 0.001 and p = 0.02, respectively), (TMD: 183.7 ± 59.7 at pretreatment, 235.7 ± 91.1 at third week and 209.8 ± 77.1 at second month p < 0.01 and p = 0.015, respectively). TBUT, CFSS, Schirmer I test values were similar (p > 0.05). OSDI scores decreased significantly from 29.6 ± 25.3 to 19.8 ± 20. p = 0.03 at third week and increased again by second month. K2 (43.9 ± 1.7 vs. 43.7 ± 1.6, p = 0.03) and astigmatism (0.8 ± 0.5 vs. 0.6 ± 0.4, p = 0.04) values were significantly lower at third week and increased again by second month. Pachymetry and aberrometric values did not change significantly. In the control group only Schirmer I test value decreased significantly at second month (10.5 ± 6.5 vs. 7.2 ± 5.6, p = 0.008), other parameters did not change. CONCLUSION: BTX-A injection increases tear meniscus and decrease symptoms related to dry eye disease in BEB and HFS patients. It decrease astigmatism and keratometry values, it does not cause a significant change in corneal aberrations. However the positive effects of BTX-A injection on ocular surface is temporary.

The Isolated Mouse Jejunal Afferent Nerve Assay as a Tool to Assess the Effect of Botulinum Neurotoxins in Visceral Nociception.

For the past two decades, botulinum neurotoxin A (BoNT/A) has been described as a strong candidate in the treatment of pain. With the production of modified toxins and the potential new applications at the visceral level, there is a real need for tools allowing the assessment of these compounds. In this study, we evaluated the jejunal mesenteric afferent nerve assay to investigate BoNT/A effects on visceral nociception. This ex vivo model allowed the continuous recording of neuronal activity in response to various stimuli. BoNT/A was applied intraluminally during three successive distensions, and the jejunum was distended every 15 min for 3 h. Finally, samples were exposed to external capsaicin. BoNT/A intoxication was validated at the molecular level with the presence of cleaved synaptosomal-associated protein of 25 (SNAP25) in nerve terminals in the mucosa and musculosa layers 3 h after treatment. BoNT/A had a progressive inhibitory effect on multiunit discharge frequency induced by jejunal distension, with a significant decrease from 1 h after application without change in jejunal compliance. The capsaicin-induced discharge was also affected by the toxin. This assay allowed the description of an inhibitory effect of BoNT/A on afferent nerve activity in response to distension and capsaicin, suggesting BoNT/A could alleviate visceral nociception.

Olfactory Bulb D2/D3 Receptor Availability after Intrastriatal Botulinum Neurotoxin-A Injection in a Unilateral 6-OHDA Rat Model of Parkinson's Disease.

Olfactory deficits occur as early non-motor symptoms of idiopathic Parkinson's disease (PD) in humans. The first central relay of the olfactory pathway, the olfactory bulb (OB), depends, among other things, on an intact, functional crosstalk between dopaminergic interneurons and dopamine receptors (D2/D3R). In rats, hemiparkinsonism (hemi-PD) can be induced by unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle (MFB), disrupting dopaminergic neurons of the substantia nigra pars compacta (SNpc). In a previous study, we showed that subsequent injection of botulinum neurotoxin-A (BoNT-A) into the striatum can reverse most of the pathological motor symptoms and normalize the D2/D3R availability. To determine whether this rat model is suitable to explain olfactory deficits that occur in humans with PD, we examined the availability of D2/D3R by longitudinal [18F]fallypride-PET/CT, the density of tyrosine hydroxylase immunoreactivity in the OB, olfactory performance by an orienting odor identification test adapted for rats, and a connectome analysis. PET/CT and immunohistochemical data remained largely unchanged after 6-OHDA lesion in experimental animals, suggesting that outcomes of the 6-OHDA hemi-PD rat model do not completely explain olfactory deficits in humans. However, after subsequent ipsilateral BoNT-A injection into the striatum, a significant 8.5% increase of the D2/D3R availability in the ipsilateral OB and concomitant improvement of olfactory performance were detectable. Based on tract-tracing meta-analysis, we speculate that this may be due to indirect connections between the striatum and the OB.

Video-Urodynamic Characteristics and Predictors of Switching from Botulinum Neurotoxin a Injection to Augmentation Enterocystoplasty in Spinal Cord Injury Patients.

Botulinum neurotoxin type A (BoNT-A) injection and augmentation enterocystoplasty (AE) are alternative and effective management strategies for neurogenic detrusor overactivity (NDO) refractory to pharmacotherapy. A great majority of patients with spinal cord injury (SCI) may, however, prefer BoNT-A injections to AE, due to the less invasive characteristics. In this study we evaluated the influence of various video-urodynamic study (VUDS) parameters in SCI patients who continuously received repeat BoNT-A detrusor injections or switched to AE to improve their bladder conditions. We compared the changes in the urodynamic parameters before and after each mode of treatment. In this retrospective study, all SCI patients with refractory NDO who had received at least one BoNT-A injection were enrolled. VUDS was performed before and after both BoNT-A injection and AE. All of the urodynamic parameters of the storage and micturition-including the bladder capacity of every sensation, maximal flow rate (Qmax), post-voiding residual volume, detrusor pressure at Qmax, and bladder contractility index-were recorded. A total of 126 patients, including 46 women and 80 men, with a mean age of 41.8 ± 13.1 years, were recruited for this study. All of the patients receiving either BoNT-A injection or AE had a statistically significant increase of bladder capacity at every time-point during filling and a decrease in detrusor pressure at Qmax during voiding. Patients who switched from BoNT-A to AE had greater improvements in their urodynamic parameters when compared with those who continued with BoNT-A injections. Accordingly, SCI patients receiving BoNT-A injections but experiencing few improvements in their urodynamic parameters should consider switching to AE to achieve a better storage function and bladder capacity.