Excitation-contraction coupling inhibitors potentiate the actions of botulinum neurotoxin type A at the neuromuscular junction.

BACKGROUND AND PURPOSE: Botulinum neurotoxin type A1 (BoNT/A) is one of the most potent neurotoxins known. At the same time, it is also one of the safest therapeutic agents used for the treatment of several human disorders and in aesthetic medicine. Notwithstanding great effectiveness, strategies to accelerate the onset and prolong BoNT/A action would significantly ameliorate its pharmacological effects with beneficial outcomes for clinical use. EXPERIMENTAL APPROACH: Here, we combined BoNT/A with two fast-acting inhibitors of excitation-contraction coupling inhibitors (ECCI), either the µ-conotoxin CnIIIC or dantrolene, and tested the effect of their co-injection on a model of hind-limb paralysis in rodents using behavioural, biochemical, imaging and electrophysiological assays. KEY RESULTS: The BoNT/A-ECCI combinations accelerated the onset of muscle relaxation. Surprisingly, they also potentiated the peak effect and extended the duration of the three BoNT/A commercial preparations OnabotulinumtoxinA, AbobotulinumtoxinA and IncobotulinumtoxinA. ECCI co-injection increased the number of BoNT/A molecules entering motoneuron terminals, which induced a faster and greater cleavage of SNAP-25 during the onset and peak phases, and prolonged the attenuation of nerve-muscle neurotransmission during the recovery phase. We estimate that ECCI co-injection yields a threefold potentiation in BoNT/A pharmacological activity. CONCLUSIONS AND IMPLICATIONS: Overall, our results show that the pharmacological activity of BoNT/A can be combined and synergized with other bioactive molecules and uncover a novel strategy to enhance the neuromuscular effects of BoNT/A without altering the neurotoxin moiety or intrinsic activity, thus maintaining its exceptional safety profile.

Ultrasonographic study and anatomical guidelines for botulinum neurotoxin injection into the parotid gland.

Benign enlargement of the parotid gland hypertrophy results in a bulky lateral facial contour and esthetic appearance. This study aimed to determine the depth from the skin surface to the parotid fascia, which encompasses the parotid gland. The anatomical properties of the parotid glands were evaluated in 40 patients using ultrasonography. An up-to-date understanding of the localization of botulinum neurotoxin (BoNT) injection based on anatomy could lead to better localization of the injection into the parotid gland through morphological measurements using data previously published from cadaveric studies. Measurement using the otobasion inferius as a landmark revealed parotideomasseteric fascia thickness averaging 4-6 mm from the skin surface, with the parotid gland extending approximately 15 mm anteriorly. Analysis showed a 3-7 mm thickness range, indicating an optimal injection depth for safety and efficacy in BoNT procedures. Utilizing the otobasion inferius as an anatomical landmark offers a practical approach for measuring parotideomasseteric fascia thickness, addressing cadaveric study limitations. These guidelines aim to maximize the effects of BoNT therapy, which can be useful in clinical settings, by minimizing its deleterious effects.

Case Report: Tissue Expanders-Another Tool in the Armamentarium for the Treatment of Complex Ventral Hernia.

Complex abdominal wall hernias represent a significant reconstructive challenge to the general surgeon. In patients with loss of abdominal domain, standard surgical techniques such as anterior component separation or transversus abdominus muscle release may not allow for primary fascial closure. In complex ventral wall hernias, visceroabdominal disproportion may need to be addressed prior to an attempt at hernia repair. Tissue expanders placed in the intermuscular space is a novel technique used to increase intraabdominal volume and safely allow reduction of viscera with subsequent closure of the myofascia. We present the case of an adult patient with complications of an untreated congenital omphalocele who underwent a successful two stage operation using tissue expanders in the abdominal wall combined with anterior component separation.

New Engineered-Chimeric Botulinum Neurotoxin Mutant Acts as an Effective Bivalent Vaccine Against Botulinum Neurotoxin Serotype A and E.

Botulinum neurotoxins (BoNTs), including serotypes A and E, are potent biotoxins known to cause human poisoning. In addition to the critical protective antigen found in the full BoNT molecule, the receptor binding domain (Hc domain), BoNTs also harbour another essential protective antigen-the light chain-translocation domain (L-HN domain). Leveraging these pivotal protective antigens, we genetically engineered a series of inactivated chimeric molecules incorporating L-HN and Hc domains of BoNT/A and E. The structure of these chimeric molecules, mirror BoNT/A and E, but are devoid of enzyme activity. Experimental findings demonstrated that a lead candidate mEL-HN-mAHc harnessing the inactivated protease LCHN/E with the mutated gangliosides binding site Hc/A (mE-mA) elicited robust immune protection against BoNT/A and E simultaneously in a mouse model, requiring low immune dosages and minimal immunisations. Moreover, mE-mA exhibited high protective efficacy against BoNT/A and E in guinea pigs and New Zealand white rabbits, resulting in elevated neutralising antibody titres. Furthermore, mE-mA proved to be a more stable and safer vaccine compared to formaldehyde-inactivated toxoid. Our data underscore the genetically engineered mE-mA as a highly effective bivalent vaccine against BoNT/A and E, paving the way for the development of polyvalent vaccines against biotoxins.

Novel platform for engineering stable and effective vaccines against botulinum neurotoxins A, B and E.

Botulinum neurotoxin (BoNT), produced by Clostridium botulinum, is the most toxic protein known, capable of causing severe paralysis and posing a significant bioterrorism threat due to its extreme lethality even in minute quantities. Despite this, there are currently no FDA-approved vaccines for widespread public use. To address this urgent need, we have developed an innovative vaccine platform by fusing the neuronal binding domain of BoNT/E (Hc/E) with core-streptavidin (CS), resulting in a stable CS-Hc/E vaccine. Mice vaccinated with CS-Hc/E exhibited superior antibody titers compared to those receiving Hc/E alone. To develop a trivalent vaccine against BoNT/A, BoNT/B, and BoNT/E- key contributors to the vast majority of human botulism-we conjugated CS-Hc/E with a biotinylated atoxic chimeric protein incorporating neutralizing epitopes from BoNT/A and BoNT/B. This chimeric protein includes the binding domain of BoNT/A, along with the protease-inactive light chain and translocation domains of BoNT/B. The interaction between CS and biotin formed a stable tetrameric antigen, EBA. Vaccination with EBA in mice elicited robust antibody responses and provided complete protection against lethal doses of BoNT/A, BoNT/B, and BoNT/E. Our findings highlight EBA's potential as a stable and effective broad-spectrum vaccine against BoNT. Moreover, our technology offers a versatile platform for developing multivalent, stable vaccines targeting various biological threats by substituting the BoNT domain(s) with neutralizing epitopes from other life-threatening pathogens, thereby enhancing public health preparedness and biodefense strategies.

Efficacy of botulinum neurotoxin A in persistent idiopathic dentoalveolar pain: a case series.

OBJECTIVES: Persistent idiopathic dentoalveolar pain (PIDP) is a challenging clinical entity associated with both physical and emotional consequences. Currently, the management is symptom-based and includes both topical and/or systemic treatments. More recently, botulinum neurotoxin-A (BONT-A) has been suggested as a treatment option. MATERIALS AND METHODS: We present a case series of 9 patients (5 female) with mean age 56 ± 15 diagnosed with PIDP. All patients reported prior experience with systemic drugs without a sufficient pain-relieving effect. BONT-A (BOTOX, Allergan) 100 U diluted with saline solution was used and the dose ranged from 20U to 50U distributed in 3 sites (intraoral and/or extraoral) per session. Patients underwent further injections (50U) monthly if pain severity measured using a Numerical Rating Scale (NRS 0-10) was still > 3 for 3 months. Pain severity and characteristics were recorded at baseline (T0), after 1 month (T1), 2 months (T2) and 3 months (T3). RESULTS: Mean pain intensity at baseline was NRS 6 (4-10). Latency before analgesic effect was at least 5-10 days after injection. Minor adverse effects were sickness and muscular hypotonia. Pain significantly reduced to NRS 4 (0-8) at T1, to NRS 2 (0-8) at T2 and to NRS 2 (NRS 0-8) at T3. Patients' functional variables (discomfort while chewing, talking, swallowing) were also recorded. CONCLUSIONS: BONT-A is widely used and although the exact mechanism of action remains unclear, it can be used effectively in reducing pain for a variety of conditions including PIDP. CLINICAL RELEVANCE: Our results suggest that BONT-A seems to be an alternative therapeutic approach for patients with PIDP.

Do Diagnostic Nerve Blocks Affect the Starting Dose of Botulinum Neurotoxin Type A for Spasticity? A Case-Control Study.

One of the aims of diagnostic nerve blocks is to identify the overactive muscles that lead to a specific spasticity pattern. However, to date, there is no evidence on how nerve blocks may affect botulinum neurotoxin-A (BoNT-A) dose in patients with spasticity. This case-control study aims to assess the role of diagnostic nerve block in defining BoNT-A starting dose at first treatment. Patients with upper and lower limb spasticity treated for the first time with BoNT-A were retrospectively divided into two groups: Group 1 (n = 43) was evaluated with clinical assessment and diagnostic nerve block; Group 2 (n = 56) underwent clinical assessment only. Group 1 was injected with higher BoNT-A doses in some muscles (i.e., flexor digitorum profundus, soleus), and received a higher BoNT-A cumulative dose with a larger number of injected muscles for some spasticity patterns (i.e., "clenched fist", "flexed fingers", "adducted thigh"). Diagnostic nerve block may help the clinician to optimize and personalize the BoNT-A dose since the first BoNT-A treatment.

Botulinum Neurotoxin Type A in paediatric non-neurogenic therapy resistant overactive bladder: a cohort study.

INTRODUCTION AND OBJECTIVE: Intradetrusor Botulinum Neurotoxin Type A (BoNT-A) is an increasingly applied treatment modality for overactive bladder (OAB) in children with refractory urinary incontinence. Despite that, evidence is sparse, and the potential not fully understood. The aim of this study was to evaluate the effectiveness and safety of intradetrusor injection in children with refractory functional OAB and urinary incontinence. Furthermore, we aimed to identify predictors of efficacy and side effects to BoNT-A treatment. MATERIALS AND METHODS: We conducted a cohort study of children with OAB and urinary incontinence who received intradetrusor injection of BoNT-A in the period 01.01.2016 to 31.12.2020 at our centre. All patients were refractory to standard urotherapy, anticholinergics, mirabegron and the combination of these treatments. Patients with neurogenic bladder were excluded. Primary endpoint was the reduction on the frequency of urinary incontinence episodes from baseline. Secondary endpoints included urodynamic parameters and uroflowmetry characteristics as well as side effects. RESULTS: Forty-three children (mean age at first treatment 10.7 ± 1.8, 30 males) were included. After first treatment, a reduction of ≥ 50% in incontinence episodes was seen in 58% of patients with daytime urinary incontinence (DUI) and 47% of patients with nocturnal enuresis (NE). Adverse events, mainly urinary tract infections (UTI), were reported by 16% of patients after first treatment. Our analysis identified normal cystometric compliance as a significant predictor of treatment effect We estimated the mean duration of effect to be approximately 7 months. CONCLUSIONS: Intradetrusor BoNT-A injection appears to be a safe and effective option in treating refractory urinary incontinent children with overactive bladder. We identified cystometric compliance as a predictor of response. Most children necessitate repeated treatments. Further prospective and controlled studies are necessary in order to fully identify predictors and potential of treatment.

Multimodal therapy and use of adjunctive therapies to BoNT-A in spasticity management: defining terminology to help enhance spasticity treatment.

Spasticity management should be provided within the context of a comprehensive person-centered rehabilitation program. Furthermore, active goal setting for specific spasticity interventions is also important, with a well-established "more is better" approach. It is critical to consider adjunctive therapy and multimodal approaches if patients are not attaining their treatment goals. Often used interchangeably, there may be confusion between the terms adjunctive and multimodal therapy. Yet it is imperative to understand the differences between these approaches to achieve treatment goals in spasticity management. Addition of a secondary pharmacologic or non-pharmacologic treatment to optimize the efficacy of the initial modality, such as adding electrical stimulation or casting to BoNT-A, is considered an adjunctive therapy. Adjunctive therapy is time-specific and requires the added therapy be initiated within a specific period to enhance the primary treatment; usually within 2 weeks. Multimodal therapy is an integrated, patient-centric program of pharmacologic and non-pharmacologic strategies utilized in a concurrent/integrated or sequential manner to enhance the overall treatment effect across a variety of spasticity-associated impairments (e.g., neural and non-neural components). Moreover, within a multimodal approach, adjunctive therapy can be used to help enhance the treatment effect of one specific modality. The objectives of this paper are to clarify the differences between adjunctive and multimodal therapies, provide a brief evidence-based review of such approaches, and highlight clinical insights on selecting multimodal and adjunctive therapies in spasticity management.

Association analysis of ADRB3:rs4994 with urodynamic outcome, six months after a single intra-detrusor injection of botulinum toxin, in women with overactive bladder.

BACKGROUND: Intra-detrusor injection of botulinum neurotoxin type A (BoNT/A) is recommended as a possible treatment for patients with overactive bladder (OAB) in whom first-line therapies have failed. The c.190T > C (rs4994) polymorphism in the gene encoding the beta-3 adrenergic receptor (ADRB3) has been suggested to be associated with predisposition to OAB or with response to OAB treatment via a cholinergic muscarinic receptor antagonist. This prospective study aimed to use a urodynamic parameter-based assessment of response, six months after a single intra-detrusor injection of BoNT/A in female OAB patients, to elucidate possible association with the ADRB3 polymorphism. METHODS: The study group consisted of 138 consecutive, Polish, adult, female OAB patients. Urodynamic parameters were recorded before injection of BoNT/A and at six months after administration. ADRB3:rs4994 variants were identified by the sequencing of genomic DNA extracted from buccal swabs. RESULTS: Apart from baseline, and relative, increase in Maximum Cystometric Capacity (MCC) six months after BoNT/A injection, no significant differences were found in urodynamic parameters between reference TT homozygotes and women with at least one C allele. CONCLUSIONS: Our results do not exclude that ADRB3:rs4994 variants are associated with a positive urodynamic test-based response to intra-detrusor injection of BoNT/A in females with OAB.

Potency Evaluations of Recombinant Botulinum Neurotoxin A1 Mutants Designed to Reduce Toxicity.

Recombinant mutant holotoxin BoNTs (rBoNTs) are being evaluated as possible vaccines against botulism. Previously, several rBoNTs containing 2-3 amino acid mutations in the light chain (LC) showed significant decreases in toxicity (2.5-million-fold-12.5-million-fold) versus wild-type BoNT/A1, leading to their current exclusion from the Federal Select Agent list. In this study, we added four additional mutations in the receptor-binding domain, translocation domain, and enzymatic cleft to further decrease toxicity, creating 7M rBoNT/A1. Due to poor expression in E. coli, 7M rBoNT/A1 was produced in an endogenous C. botulinum expression system. This protein had higher residual toxicity (LD50: 280 ng/mouse) than previously reported for the catalytically inactive rBoNT/A1 containing only three of the mutations (>10 µg/mouse). To investigate this discrepancy, several additional rBoNT/A1 constructs containing individual sets of amino acid substitutions from 7M rBoNT/A1 and related mutations were also endogenously produced. Similarly to endogenously produced 7M rBoNT/A1, all of the endogenously produced mutants had ~100-1000-fold greater toxicity than what was reported for their original heterologous host counterparts. A combination of mutations in multiple functional domains resulted in a greater but not multiplicative reduction in toxicity. This report demonstrates the impact of production systems on residual toxicity of genetically inactivated rBoNTs.

New approach to generating of human monoclonal antibodies specific to the proteolytic domain of botulinum neurotoxin A.

Introduction: Botulinum neurotoxins (BoNTs) cause botulism and are the most potent natural toxins known. Immunotherapy with neutralizing monoclonal antibodies (MAbs) is considered to be the most effective immediate response to BoNT exposure. Hybridoma technology remains the preferred method for producing MAbs with naturally paired immunoglobulin genes and with preserved innate functions of immune cells. The affinity-matured human antibody repertoire may be ideal as a source for antibody therapeutics against BoNTs. In an effort to develop novel BoNT type A (BoNT/A) immunotherapeutics, sorted by flow cytometry plasmablasts and activated memory B cells from a donor repeatedly injected with BoNT/A for aesthetic botulinum therapy could be used due to obtain hybridomas producing native antibodies. Methods: Plasmablasts and activated memory B-cells were isolated from whole blood collected 7 days after BoNT/A injection and sorted by flow cytometry. The sorted cells were then electrofused with the K6H6/B5 cell line, resulting in a producer of native human monoclonal antibodies (huMAbs). The 3 antibodies obtained were then purified by affinity chromatography, analyzed for binding by Western blot assay and neutralization by FRET assay. Results: We have succeeded in creating 3 hybridomas that secrete huMAbs specific to native BoNT/A and the proteolytic domain (LC) of BoNT/A. The 1B9 antibody also directly inhibited BoNT/A catalytic activity in vitro. Conclusion: The use activated plasmablasts and memory B-cells isolated at the peak of the immune response (at day 7 of immunogenesis) that have not yet completed the terminal stage of differentiation but have undergone somatic hypermutation for hybridization allows us to obtain specific huMAbs even when the immune response of the donor is weak (with low levels of specific antibodies and specific B-cells in blood). A BoNT/A LC-specific antibody is capable of effectively inhibiting BoNT/A by mechanisms not previously associated with antibodies that neutralize BoNT. Antibodies specific to BoNT LC can be valuable components of a mixture of antibodies against BoNT exposure.

Tirbanibulin (KX2-391) analog KX2-361 inhibits botulinum neurotoxin serotype A mediated SNAP-25 cleavage in pre- and post-intoxication models in cells.

Botulinum neurotoxins (BoNT) inhibit neuroexocytosis, leading to the potentially lethal disease botulism. BoNT serotype A is responsible for most human botulism cases, and there are no approved therapeutics to treat already intoxicated patients. A growing body of research has demonstrated that BoNT/A can escape into the central nervous system, and therefore, identification of BoNT/A inhibitors that can penetrate BBB and neutralize the toxin within intoxicated neurons would be important. We previously identified an FDA-approved, orally bioavailable compound, KX2-391 (Tirbanibulin) that inhibits BoNT/A in motor neuron assays. Recently, a structural analog of KX2-391, KX2-361, has been shown to exhibit good oral bioavailability and cross BBB with high efficiency in mouse experiments. Therefore, in this work, we evaluated the inhibitory effects of KX2-361 against BoNT/A. Toward this goal, we first evaluated the compound for its effects on cell viability in PC12 cells, via MTT assay, and in mouse embryonic stem cell (mESC)-derived motor neurons, with imaging-based assays. Following, we tested KX2-361 in mESC-derived motor neurons intoxicated with BoNT/A holotoxin, and the compound exhibited activity against the toxin in both pre- and post-intoxication conditions. Excitingly, KX2-361 also inhibited BoNT/A enzymatic component (light chain; LC) in PC12 cells transfected with BoNT/A LC. Furthermore, our molecular docking analyses suggested that KX2-361 can directly bind to BoNT/A LC. Medicinal chemistry approaches to develop structural analogs of KX2-361 to increase its efficacy against BoNT/A may provide a critical lead compound with BBB penetration capacity for drug development efforts against BoNT/A intoxication.

Delphi Analysis: Optimizing Anatomy Teaching and Ultrasound Training for Botulinum Neurotoxin Type A Injection in Spasticity and Dystonia.

Our objective was to provide expert consensus on best practices for anatomy teaching and training on ultrasound-guided botulinum neurotoxin type A (BoNT-A) injection for specialists involved in treating spasticity and dystonia. Nine experts (three neurologists; six physical medicine and rehabilitation physicians) participated in a three-round modified Delphi process. Over three rounds, experts reached consensus on 15 of 16 statements describing best practices for anatomy and BoNT-A injection training. They unanimously agreed that knowledge of the target audience, including their needs and current competency, is crucial when designing training programs. Experts also agreed that alignment between instructors is essential to ensure consistency of approach over time and between regions, and that training programs should be simple, adaptable, and "hands-on" to enhance engagement and learning. Consensus was also reached for several other key areas of training program development. The best-practice principles identified by expert consensus could aid in the development of effective, standardized programs for anatomy teaching and BoNT-A injection training for the purposes of treating spasticity and dystonia. This will enhance the exchange of knowledge, skills, and educational approaches between global experts, allowing more specialists to treat important movement disorders and ultimately improving patient outcomes.

Does blepharospasm effect biometric parameters and intraocular lens power calculations?

PURPOSE: To investigate the effect of botulinum toxin-A (BTX-A) treatment on corneal topography, ocular biometry and keratometry in patients with benign essential blepharospasm (BEB) and hemifacial spasm (HFS). METHODS: This study comprised 66 eyes of 33 patients with BEB and 5 eyes of 5 patients with HFS who underwent BTX-A injections consecutively. Refractive error values, tear break-up time (TBUT), corneal topography [corneal power of flat axis (K1) and steep axis (K2), mean corneal power (Km), corneal astigmatism (K2-K1)] and ocular optical biometry [axial length (AL), anterior chamber depth (ACD)] were recorded before BTX-A treatment and 1 month after BTX-A treatment. The researchers calculated the expected emmetropic intraocular lens power (emm-IOL) using the SRK-T, Holladay, Hoffer-Q and Haigis formulas at each examination. RESULTS: K1 (43.48 ± 2.02 vs. 43.57 ± 2.08, p = 0.036), Km (43.91 ± 1.99 vs. 43.99 ± 2.06, p = 0.024) and ACD (3.22 (2.77-3.76) vs. 3.41 (2.99-4.02), p < 0.001) values were found to be significantly higher. The expected emm-IOL according to the SRK-T (21.04 ± 1.6 vs. 20.93 ± 1.6, p = 0.048), Holladay (21.05 ± 1.6 vs. 20.91 ± 1.62, p = 0.037) and Hoffer-Q (21.08 ± 1.65 vs. 20.94 ± 1.68, p = 0.038) decreased significantly. The expected emm-IOL according to the Haigis formula slightly decreased, but it was not significant (p = 0.386). Additionally, TBUT was found to be significantly lower (p < 0.001) after BTX-A injection. Other parameters were not statistically significant (p > 0.05). CONCLUSIONS: Our study is the first in the literature to compare optic biometry data and intraocular lens power calculation formulas before and after BTX-A injection in eyes with BEB and HFS. BTX-A injection could play an important role in changing the keratometric and ACD values. It should be considered that IOL power calculations that might be unpredictable due to blepharospasm, so repeated measurements and especially measurements after releasing the spasm with BTX-A injections, are necessary in BEB and HFS.

The analgesic effects of botulinum neurotoxin by modulating pain-related receptors; A literature review.

Botulinum neurotoxins (BoNTs), produced by Clostridium botulinum, have been used for the treatment of various central and peripheral neurological conditions. Recent studies have suggested that BoNTs may also have a beneficial effect on pain conditions. It has been hypothesized that one of the mechanisms underlying BoNTs' analgesic effects is the inhibition of pain-related receptors' transmission to the neuronal cell membrane. BoNT application disrupts the integration of synaptic vesicles with the cellular membrane, which is responsible for transporting various receptors, including pain receptors such as TRP channels, calcium channels, sodium channels, purinergic receptors, neurokinin-1 receptors, and glutamate receptors. BoNT also modulates the opioidergic system and the GABAergic system, both of which are involved in the pain process. Understanding the cellular and molecular mechanisms underlying these effects can provide valuable insights for the development of novel therapeutic approaches for pain management. This review aims to summarize the experimental evidence of the analgesic functions of BoNTs and discuss the cellular and molecular mechanisms by which they can act on pain conditions by inhibiting the transmission of pain-related receptors.

Territories of Nerve Endings of the Medial Plantar Nerve within the Abductor Hallucis Muscle: Clinical Implications for Potential Pain Management.

This study aimed to elucidate the intramuscular distribution pattern of the medial plantar nerve and determine its motor nerve ending territories within the abductor hallucis muscle using modified Sihler's staining and external anatomical landmarks. The study included 40 specimens of the abductor hallucis muscle (13 men and seven women) from formalin-fixed (ten cadavers) and fresh cadavers (ten cadavers), with a mean age of 77.6 years. The entry point of the medial plantar nerve into the muscle was examined, followed by Sihler's staining to analyze the intramuscular distribution pattern and motor nerve ending location within the abductor hallucis muscle. Ultrasound- and palpation-guided injections were performed to verify the applicability of motor nerve ending location-based injections. The areas with the highest concentrations of nerve entry points and nerve endings were identified in the central portion of the muscle. Ultrasound- and palpation-guided injections were safely positioned near the densest nerve ending region of the muscle. These detailed anatomical data and injection methods would be beneficial for proceeding with safe and effective injection treatments using various analgesic agents to alleviate abductor hallucis muscle-associated pain disorders.

Surgical management of chronic sixth cranial nerve palsy: case report and literature review.

Background: Esotropia resulting from sixth cranial nerve palsy can substantially impact an individual's visual acuity and overall quality of life. If the condition does not resolve in 6-10 months, surgical intervention may be necessary. Various muscle surgeries may be considered, with vertical rectus muscle transposition emerging as the primary option for treatment of complete palsy. However, this technique carries the risk of anterior segment ischemia and post-surgery deviations. Herein, we present a successful treatment of chronic complete sixth nerve palsy using a modified Nishida procedure, without splitting or tenotomy, and an adjunct botulinum toxin A (BTA) injection in the ipsilateral medial rectus muscle. Case Presentation: A 59-year-old woman with a history of traumatic sixth nerve palsy had previously undergone horizontal muscle strabismus surgeries. Following multiple left medial rectus recessions, lateral rectus resection, and BTA injections, esotropia persisted. The worsening of her condition led to emotional distress and impaired social interaction. Initial examination revealed marked esotropia and limited left eye abduction. Magnetic resonance imaging (SIGNA MR750w, GE Healthcare, Waukesha, WI, USA) of the left eye revealed a contracted medial rectus muscle and substantial atrophy of the left lateral rectus muscle. A modified Nishida procedure was performed with an injection of 3 units of BTA into the ipsilateral medial rectus muscle, resulting in improved ocular alignment and stable findings after nine postoperative months. Furthermore, we supported our successful outcome with a summary of similar reported cases of sixth nerve palsy managed using the modified Nishida procedure with or without adjunctive procedures. Conclusions: Following the modified Nishida procedure, the patient experienced a reduction in diplopia, improved ocular alignment and stability, and an increased binocular diplopia-free field. This case underscores the importance of an individualized approach to complex strabismus cases and highlights the modified Nishida procedure as a valuable tool in such circumstances. In the future, strabismus management will focus on refining personalized treatment and exploring innovative techniques for complex cases. Our success in using a combination of Nishida procedure and BTA injection should be further investigated in large-scale studies.

Clinical implications of genetic polymorphisms in blepharospasm.

The possible genetic variants associated with blepharospasm (BSP) and facial dystonia have been investigated. Although genetic variants associated with BSP have been extensively studied, the contribution of single-nucleotide polymorphisms towards this condition remains poorly understood. In addition, the etiology of BSP remains to be fully elucidated. Therefore, the present study aimed to assess the role of polymorphisms in the torsin 1A (TOR1A), dopamine receptor D (DRD)2 and DRD5 genes in South Korean patients with BSP. Furthermore, the role of genetic variants of these three aforementioned genes was investigated. A prospective case-control study was established, where 56 patients with BSP and 115 healthy controls were recruited at the Department of Ophthalmology of CHA Bundang Medical Center (Seongnam, South Korea) using single nucleotide polymorphisms analysis by real-time PCR. The TOR1A rs1182CC/DRD5 rs6283TC genotype combination was found to be associated with decreased BSP risk [adjusted odds ratio (AOR), 0.288; P=0.013]. DRD5 rs6283 was observed to be associated with the periocular type of BSP in the co-dominant (for the TC genotype; AOR, 0.370; P=0.029) and dominant models (AOR, 0.406; P=0.029). The recessive model of TOR1A rs1801968 (AOR, 0.245; P=0.030), and the recessive (AOR, 0.245; P=0.029) and over-dominant models (AOR, 2.437; P=0.019) of DRD2 rs1800497 were found to be associated with superior responses to botulinum neurotoxin A (BoNT) treatment. By contrast, dominant (AOR, 0.205; P=0.034) and additive (AOR, 0.227; P=0.030) models of DRD5 rs6283 were associated with poor responses to BoNT treatment. To conclude, these results suggested that DRD2 rs1800497 can confer genetic susceptibility to BSP responses to BoNT treatment, whereas the TOR1A rs1182CC/DRD5 rs6283TC genotype combination appeared to contribute to the association with BoNT efficacy in BSP.

Anatomical considerations of medial eye wrinkles: Guidelines for botulinum neurotoxin injections.

Crow's feet lines in the lateral canthal region are a common concern among aging patients, initially appearing as dynamic wrinkles during facial expressions and becoming more pronounced with age. Botulinum neurotoxin temporarily paralyzes muscles by inhibiting acetylcholine release, smoothing wrinkles and enhancing skin's youthful appearance. Effective treatment requires tailored approaches considering individual anatomy and muscle activity. Recent cadaveric studies identified the tear trough muscle, emphasizing its role in infraorbital support and aging. Clinically, patients often present medial eye wrinkles after BoNT treatment for crow's feet, prompting exploration of underlying mechanisms and management strategies. Three cases demonstrated that medial BoNT injections in the orbicularis oculi muscle significantly improve medial eye wrinkles and tear trough appearance. The study underscores the importance of understanding muscle hyperactivity and anatomical variations for precise treatment. Enhanced injection techniques targeting specific areas can achieve better outcomes and minimize complications, particularly in culturally sensitive regions where facial expressions are valued. This research highlights the necessity for comprehensive anatomical knowledge and patient-specific treatment strategies to address medial eye wrinkles effectively.