Botulinum Neurotoxin A Injection Research Articles

Synergistic Therapy for Graves’ Ophthalmopathy-Associated Eyelid Retraction: Steroid, 5-FU, and Botulinum Neurotoxin a Combination

Background: Graves’ ophthalmopathy (GO) is characterized by upper eyelid retraction (UER), the most prevalent clinical sign. We aimed to assess the clinical efficacy of a multimodal combination of steroids, 5-fluorouracil (5-FU), and botulinum neurotoxin A (BoNT-A) injections in managing UER with GO and analyze the clinical factors in relation to the injection response. Methods: A total of 37 eyes from 23 patients were enrolled for UER with GO. At the endocrinology clinic, the patients were referred to the ophthalmology clinic after taking antithyroid medication for an average of 5.76 months (13 patients), while 10 patients were initially diagnosed with GO and referred to the endocrinology clinic for management of the thyroid hormone function. They performed an orbital computed tomography (CT) scan and measured the cross-sectional area of the orbit, orbital fat, and each extra ocular muscle (EOM) except for the inferior oblique muscle 4 mm behind the eyeball. Each of the EOMs and orbital fat were calculated as a ratio to the total orbit area. A total of 0.1 cc of triamcinolone (40 mg/mL), dexamethasone (5 mg/mL), 5-FU, and BoNT-A (2.5 units) was injected transconjunctivally. Medical records were examined and photographs were utilized to assess MRD1, inferior palpebral fissure (IPF), and lid lag during down gaze before and after the injection. The patients were divided into two groups: responders (more than 1 mm decrease in MRD1 after injection) and non-responders. During the follow-up period (11.0 ± 11.6 months), any potential adverse effects were monitored. Results: CAS decreased from 3.0 ± 0.8 to 1.4 ± 0.5 after the injection, and MRD1 decreased from 5.0 ± 0.9 mm to 4.5 ± 1.3 mm. Sixty percent of the patients were responders. Before and after the injection, the difference between IPF and MRD1 in responders was 0.60 ± 1.10 mm and 0.90 ± 0.90 mm, respectively, whereas, in non-responders, it was −0.57 ± 0.88 mm and −0.15 ± 0.75 mm, respectively. In the responders, pre-injection IPF and FT4 were significantly higher (p < 0.05). Responders had a larger EOM cross-sectional area (153.5 ± 18.0 mm2), including a larger lateral rectus muscle cross-sectional area (37.6 ± 9.7 mm2) than non-responders (132.0 ± 27.9 mm2; 29.1 ± 8.1 mm2). In responders, the treatment effect on IPF and MRD1 remained consistent at 1.2 ± 3.4 mm and 1.2 ± 1.6 mm, respectively, during the latest follow-up assessment. Conclusions: The combination injection of corticosteroids, 5-FU, and BoNT-A would be effective, especially, in patients with hyperthyroidism and an elongated IPF. Additionally, an increase in EOM cross-sectional area on CT, up to 150 mm2, may serve as an additional positive indicator for the use of multimodal injections in UER with GO.

Role of BoNT-A in patient with post COVID-19 spasticity, assessed by H-reflex

Background. COVID-19 is a pandemic disease due to viral infection. It spread throughout the world, and the association of COVID-19 with neuroendocrine system is a well-known fact especially while the connection between the endocrine and immune system neuroinflammation play a crucial role in pathophysiology. Therapeutic indication of Botulinum-neurotoxin-A (BoNT-A) is used in the treatment of focal post-stroke spasticity (PSS) and in re-habilitation which is regarded as a safe and effective type of treatment. Objective. To assess spasticity after COVID-19 infection. Methods. Thirty patients diagnosed as post-COVID-19 stroke spasticity were enrolled, their age ranged from (30-60 years). They had focal spasticity of lower extremities. BoNT-A was given in day 0 and 4 weeks later, in the gastrocnemius and soleus muscle. H-reflex was recorded from soleus muscles at 1st presentation and 4 weeks after injection of BoNT-A. Muscle power was assessed by Medical Research Council scale (MRC) and MAS. Results. The amplitude and latency of H-reflex record from soleus muscles and the H/M ratio showed a statistically significant difference between pre- and post-therapy with BoNT-A injection in cases with post COVID-19 spasticity. There was a significant increase in MRC scale but, MAS scale showed a significant reduction after injection of BoNT-A. Conclusion. Post COVID spasticity is a well-known complication after COVID-19 infection, there was clinical improvement in PSS post BoNT-A injections, which was assessed clinically by MAS and MRC scale, neurophysiological the H-reflex was correlated negatively regarding latency, while there was no correlation regarding H-reflex amplitude or Hmax/Mmax ratio and MAS.

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

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). 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. 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 3months 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. 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.

Predicting non-response to intraglandular botulinum neurotoxin A injections for drooling in children with neurodevelopmental disabilities.

To develop robust multivariable prediction models for non-response to (1) submandibular botulinum neurotoxin A (BoNT-A) injections and (2) concurrent submandibular and parotid (four-gland) injections, to guide treatment decisions for drooling in children with neurodevelopmental disabilities, including cerebral palsy. This was a retrospective cohort study including 262 children (155 males/107 females, median age 7 years 11 months [IQR 5 years 1 month], range 4 years 0 months - 17 years 11 months) receiving submandibular injections and 74 children (52 males/22 females, median age 7 years 7 months [IQR 4 years 3 months], range 4 years 9 months - 18 years 8 months) receiving four-gland injections. Multivariable logistic regression analyses were used to estimate associations between candidate predictors and non-response 8 weeks after injection. Ninety-six children (37%) were non-responders to submandibular injections, for which developmental age was the strongest predictor (adjusted odds ratio [aOR] 2.13; 95% confidence interval [CI] 1.02-4.45 for developmental age <4 years or 4-6 years with IQ <70). Other characteristics that showed a trend towards an increased risk of non-response were diagnosis, sex, and head position. Thirty-four children (46%) were non-responders to four-gland injections, for which tongue protrusion (aOR 3.10; 95% CI 1.14-8.43) seemed most predictive, whereas multiple preceding submandibular injections (aOR 0.34; 95% CI 0.10-1.16) showed a trend towards being protective. Predictors were, however, unstable across different definitions of non-response and both models (i.e. submandibular and four-gland) had insufficient discriminative ability. Potential predictors of non-response to BoNT-A injections were identified. Nevertheless, the developed prediction models seemed inadequate for guidance of treatment decisions.

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

IntroductionChronic 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. MethodsA 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. ResultsA 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. ConclusionsHeadache 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.

Intravesical injections of botulinum neurotoxin A to treat overactive bladder and/or detrusor overactivity related to multiple sclerosis: 5-Year continuation rate and specific risk factors for discontinuation—A study from the neuro-urology committee of the French Association of Urology

Background: While intravesical injections of botulinum neurotoxin A (BoNT-A) are currently recommended for patients experiencing refractory neurogenic overactive bladder and/or detrusor overactivity (OAB/DO), it is unclear how much this therapy is effective and sustainable in the long-term in patients with multiple sclerosis (MS). Objectives: To assess the mid-term continuation rate of BoNT-A injections to treat neurogenic OAB/DO in MS patients and to investigate MS-specific risk factors for discontinuation. Methods: This retrospective study involved 11 French university hospital centers. All MS patients who received BoNT-A to treat neurogenic OAB/DO between 2008 and 2013 and were subsequently followed up for at least 5 years were eligible. Results: Of the 196 MS patients included, 159 (81.1%) were still under BoNT-A 5 years after the first injection. The combination of the Expanded Disability Status Scale (EDSS < 6 or ⩾ 6) and of the MS type (relapsing–remitting vs progressive) predicted the risk of discontinuation. This risk was 5.5% for patients with no risk factor, whereas patients presenting with one or two risk factors were 3.3 and 5.7 times more likely to discontinue, respectively. Conclusion: BoNT-A is a satisfying mid-term neurogenic OAB/DO therapy for most MS patients. Combining EDSS and MS type could help predict BoNT-A discontinuation.

Examining the role of intrinsic and reflexive contributions to ankle joint hyper-resistance treated with botulinum toxin-A

BackgroundSpasticity, i.e. stretch hyperreflexia, increases joint resistance similar to symptoms like hypertonia and contractures. Botulinum neurotoxin-A (BoNT-A) injections are a widely used intervention to reduce spasticity. BoNT-A effects on spasticity are poorly understood, because clinical measures, e.g. modified Ashworth scale (MAS), cannot differentiate between the symptoms affecting joint resistance. This paper distinguishes the contributions of the reflexive and intrinsic pathways to ankle joint hyper-resistance for participants treated with BoNT-A injections. We hypothesized that the overall joint resistance and reflexive contribution decrease 6 weeks after injection, while returning close to baseline after 12 weeks.MethodsNine participants with spasticity after spinal cord injury or after stroke were evaluated across three sessions: 0, 6 and 12 weeks after BoNT-A injection in the calf muscles. Evaluation included clinical measures (MAS, Tardieu Scale) and motorized instrumented assessment using the instrumented spasticity test (SPAT) and parallel-cascade (PC) system identification. Assessments included measures for: (1) overall resistance from MAS and fast velocity SPAT; (2) reflexive resistance contribution from Tardieu Scale, difference between fast and slow velocity SPAT and PC reflexive gain; and (3) intrinsic resistance contribution from slow velocity SPAT and PC intrinsic stiffness/damping.ResultsIndividually, the hypothesized BoNT-A effect, the combination of a reduced resistance (week 6) and return towards baseline (week 12), was observed in the MAS (5 participants), fast velocity SPAT (2 participants), Tardieu Scale (2 participants), SPAT (1 participant) and reflexive gain (4 participants). On group-level, the hypothesis was only confirmed for the MAS, which showed a significant resistance reduction at week 6. All instrumented measures were strongly correlated when quantifying the same resistance contribution.ConclusionAt group-level, the expected joint resistance reduction due to BoNT-A injections was only observed in the MAS (overall resistance). This observed reduction could not be attributed to an unambiguous group-level reduction of the reflexive resistance contribution, as no instrumented measure confirmed the hypothesis. Validity of the instrumented measures was supported through a strong association between different assessment methods. Therefore, further quantification of the individual contributions to joint resistance changes using instrumented measures across a large sample size are essential to understand the heterogeneous response to BoNT-A injections.

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.

Clinical features of cervical dystonia patients classified by the COL-CAP concept and treated with ultrasound-guided botulinum neurotoxin.

<p>Cervical dys&shy;tonia (CD) is the most common form of focal dystonias, where the identification of the involved muscles, the determination of optimal botulinum neurotoxin A (BoNT-A) dose per muscle injection, and precise tar&shy;ge&shy;ting may be challenging. The aim of the current study is to compare local centre data with international data, enabling the iden&shy;tification of population and me&shy;tho&shy;do&shy;&shy;lo&shy;gical factors behind the differences, there&shy;by further improvement of the care of Hun&shy;ga&shy;rian patients with CD.</p>. <p>The data of all consecutive CD patients, who were injected with BoNT-A at the botulinum neurotoxin outpatient clinic at the Department of Neurology, University of Szeged between 11 August and 21 Sep&shy;tember 2021, were retrospectively col&shy;lected and analysed in a cross-sectional manner. The frequency of the involved muscles, determined by the application of the collum-caput (COL-CAP) concept, and the parameters for the BoNT-A formulations, injected via ultrasound (US)-guidance, were calculated and compared with available international data.</p>. <p>In the current study, 58 patients (19 males and 39 females) were involved with mean age of 58.4 (&plusmn; SD 13.6, range 24-81) years. The most common subtype was torticaput (29.3%). Tremor affected 24.1% of patients. The most injected muscles were trapezius (56.9% of all cases), followed by the levator scapulae (51.7%), splenius capitis (48.3%), sternocleidomastoid (32.8%), and semispinalis capitis (22.4%). The injected mean doses per patient were 117 &plusmn; SD 38.5 (range: 50-180) units for onaBoNT-A, 118 &plusmn; SD 29.8 (range: 80-180) units for incoBoNT-A, and 405 &plusmn; SD 162 (range: 100-750 units) for aboBoNT-A.</p>. <p>Although there were several similarities between the results of the current and the multicentre studies, all were carried out using the COL-CAP concept and US-guided BoNT-A injections, authors should pay attention to better distinction of torti-forms and the more frequent injection of especially the obliquus capitis inferior, mainly in cases with no-no tremor.</p>.

Botulinum neurotoxin-A in a patient with post-stroke spasticity: a neurophysiological study.

Post-stroke spasticity (PSS) is a disorder of the sensory-motor control, leading to upper motor neuron lesions manifesting either as intermittent or sustained involuntary activation of muscles. Botulinum neurotoxin-A (BoNT-A) is mostly utilized in a variety of therapeutic indications, and it is effective and safe in the management of focal PSS in the rehabilitation scenario. The study aimed to evaluate the effect of BoNT-A administration on H-reflex of upper and lower limbs following PSS. In addition, the investigation of the association among the degree of spasticity (assessed by the Modified Ashworth Scale [MAS]) and motor neuron pool excitability (assessed by analysing H-reflex excitability) was done. Fifty patients with a stroke of either sex aged 30 to 60 years presented with either upper or lower limb focal spasticity were studied. BoNT-A was given on two occasions to the gastrocnemius, soleus, biceps brachii muscles and flexor carpi radialis (FCR). H-reflex was documented from the FCR and soleus muscles at baseline and 3-4 weeks post BoNT-A injection. Medical Research Council scale and MAS were used to assess the PSS and muscle strength. H-reflex latency and amplitude, H/M ratio recorded from FCR and soleus muscles were significantly different between pre- and post-management. The MRC scale was significantly increased whereas the MAS was significantly reduced post BoNT-A injection. BoNT-A causes obvious improvement in PSS clinically as assessed by MAS and MRC scale as well as neurophysiologically by H-reflex. A negative correlation between H-reflex latency but not the amplitude or H max /M max ratio and MAS was observed.

A Comprehensive Ultrasound Evaluation Approach of Lower Facial Structure Before Masseter Muscle Botulinum Toxin Injection.

Masseter reduction by botulinum neurotoxin A (BoNT-A) injection is a popular procedure in East Asia. Inappropriate injection can result in various complications. The aim of this study was to develop an approach for comprehensively evaluating the lower facial structure based on the shape of the mandible angle, the thickness of the masseter, and the thickness of subcutaneous fat. Clinical profiles and standard ultrasound images were collected from patients seeking masseter BoNT-A injections. Lower facial structures were evaluated based on 3 aspects: mandible, masseter, and subcutaneous fat and skin. The mandibular angle was classified as extroverted, straight, or introverted. The starting point of the middle part of the masseter was recorded. The thickness of the deep inferior tendon, the superficial and deep belly of the superficial part of the masseter, and their contractility were measured. Overall thickness and the thickness of subcutaneous fat and skin were also measured. Eighty-four masseters from 42 patients were included. Straight mandibular angles were the most common type of angle (48.81%), followed by introverted (26.19%) and extroverted angles (25.00%). The middle part of the masseter starts from 2.33 [0.36] cm (mean [standard deviation]) above the mandible edge, which is above the usual injection points. The superficial belly was thicker than the deep belly in both static and clenching states (P = .048, P = .001) and had greater contractility. The average overall thickness was 1.87 [0.29] cm. Comprehensive evaluation of the lower facial contour and structure based on ultrasound examination could be a reliable and replicable assessment approach.

IncobotulinumtoxinA Injection for Treating Children with Idiopathic Toe Walking: A Retrospective Efficacy and Safety Study.

There is no gold-standard treatment for idiopathic toe walking (ITW). Some previous evidence suggested that botulinum neurotoxin-A injection might improve ITW. This is a single-center retrospective study on children with ITW treated with incobotulinumtoxinA injection in the gastrocnemius medialis/lateralis muscles. We screened the charts of 97 ITW children treated with incobotulinumtoxinA (January 2019-December 2021), and the data of 28 of them, who satisfied the inclusion/exclusion criteria, were analyzed. The maximal passive ankle dorsiflexion (knee extended) was assessed at three time points, i.e., immediately before incobotulinumtoxinA injection (T0), after incobotulinumtoxinA injection during the timeframe of its effect (T1), and at follow-up, when the effect was expected to disappear (T2). The maximal passive ankle dorsiflexion was improved by incobotulinumtoxinA injection, and the effect lasted up to 6 months in some children. No adverse effects were reported to incobotulinumtoxinA injections. The treatment with incobotulinumtoxinA might improve the maximal passive ankle dorsiflexion and is safe and well-tolerated in ITW with a longer-than-expected effect in comparison to cerebral palsy. These results may offer ground to future randomized controlled trials and studies assessing the effect of BoNT-A in combination with other non-invasive approaches and exercise programs in children with ITW.

Experiences of patients with poststroke spasticity throughout a botulinum toxin treatment cycle: Results from a prospective ethnographic study.

This study was conducted to capture the experience of patients with poststroke spasticity (PSS) throughout one botulinum neurotoxin A (BoNT-A) treatment cycle. The REBOT study (NCT03995524) was a prospective, observational ethnographic study conducted in France, Italy, the UK, and the USA. It combined a mixed-method ethnography (including semi-structured qualitative interviews within a week of a BoNT-A injection) with completion of a longitudinal quantitative patient-reported outcome questionnaire and sharing of video and images, both reported weekly over a 12–14-week period throughout the BoNT-A treatment cycle. The study recruited 30 adult patients with PSS who were receiving BoNT-A treatment. The most commonly used BoNT-A product was onabotulinumtoxinA (Botox®), which was administered to 21 patients (70%), whereas two patients (6.7%) received abobotulinumtoxinA (Dysport®) and seven patients (23.3%) did not specify the BoNT-A medication that they received. Patients reported a high, continuous burden of PSS, with spasms, sleeping difficulties, stiffness, and pain being the most commonly reported symptoms. In line with an observed waning effect of BoNT-A injections, spasticity symptoms initially were improved at Weeks 4–6 after injection but reemerged after 9–11 weeks. Treatment satisfaction levels decreased over the BoNT-A treatment cycle, as reflected by the worsening of symptoms and the need to self-medicate and consult a physician. The psychological impact of PSS was high. Patients acknowledged the benefits of BoNT-A treatment but wished for more individualized treatment plans with flexible dosing and injection intervals. Additionally, only 10% of patients reported that they had a trusting relationship with their physician and believed that their needs were considered by those managing their PSS. To our knowledge, this was the first ethnographic study in patients with PSS who were treated with BoNT-A. This ethnographic approach to patient surveys complements traditional research methods and allows improved identification of patients' unmet needs by capturing their weekly experience of treatment. The findings of this study confirm previous observations of the diminishing effectiveness of BoNT-A injections between treatment sessions, highlighting the need for agents with a longer duration of action and/or a more flexible treatment pattern that allows for more frequent injections.

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

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). 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, 3weeks after BTX-A treatment and 2months after BTX-A treatment. 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 3weeks and 2months 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. 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.

Painful Legs and Moving Toes

Painful Legs and Moving Toes syndrome (PLMT) is a rare neurological movement disorder characterized by involuntary and irregular movements of one or more toes, often together, with moderate to severe diffuse pain at the foot and leg. It can appear on one or both sides and in the upper limbs as well as lower limbs. The etiology of PLMT is still unclear; therefore, the main symptoms of PLMT, including pain in limbs as well as involuntary movements of toes, can be treated only symptomatically, and the outcomes are often unsatisfactory. Central or peripheral nerve injuries have been assumed to be the possible causes of irregular involuntary movements, often accompanied by chronic pain; however, its etiology is unknown in most cases. The management of PLMT is very difficult because of its rare prevalence and obscure pathogenesis, and there have been no clear guidelines for the treatment of PLMT. Oral medications (e.g., GABAergic agents, benzodiazepines, antiepileptics, antidepressants, atypical antipsychotics, beta-blockers, corticosteroids, cannabis, calcitonin, and analgesics) and several therapeutic interventions (e.g., local botulinum neurotoxin-A injection, spinal cord stimulation, anesthetic, and surgical interventions) have been recommended, based on individual experiences from several cases. Its etiology, pathogenesis, and effective treatments should be further discussed.

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.

Plasma Metabolomic Changes in Children with Cerebral Palsy Exposed to Botulinum Neurotoxin.

The long-term effect of botulinum neurotoxin A (BoNT-A) on children with cerebral palsy (CP) is unclear, and how the dynamic changes of metabolites impact the duration of effect remains unknown. To tackle this, we collected 120 plasma samples from 91 children with spastic CP for analysis, with 30 samples in each time point: prior to injection and 1, 3, and 6 months after injection. A total of 354 metabolites were identified across all the time points, 39 of which exhibited significant changes (with tentative IDs) (p values <0.05, VIP > 1). Principal component analysis and partial least-squares discriminant analysis disclosed a clear separation between different groups (p values <0.05). Network analysis revealed the coordinated changes of functional metabolites. Pathway analysis highlighted the metabolic pathways associated with energy consumption and glycine, serine, and threonine metabolism and cysteine and methionine metabolism. Collectively, our results identified the significant dynamic changes of plasma metabolite after BoNT-A injections on children with CP. Metabolic pathways associated with energy expenditure might provide a new perspective for the effect of BoNT-A in children with CP. Glycine, serine, and threonine metabolism and cysteine and methionine metabolism might be related to the duration of effect of BoNT-A.

Changes in Cortical Activity in Stroke Survivors Undergoing Botulinum Neurotoxin Therapy for Treatment of Focal Spasticity.

Background: Botulinum NeuroToxin-A (BoNT-A) relieves muscle spasticity and increases range of motion necessary for stroke rehabilitation. Determining the effects of BoNT-A therapy on brain neuroplasticity could help physicians customize its use and predict its outcome.Objective: The purpose of this study was to investigate the effects of Botulinum Toxin-A therapy for treatment of focal spasticity on brain activation and functional connectivity.Design: We used functional Magnetic Resonance Imaging (fMRI) to track changes in blood oxygen-level dependent (BOLD) activation and functional connectivity associated with BoNT-A therapy in nine chronic stroke participants, and eight age-matched controls. Scans were acquired before BoNT-A injections (W0) and 6 weeks after the injections (W6). The task fMRI scan consisted of a block design of alternating mass finger flexion and extension. The voxel-level changes in BOLD activation, and pairwise changes in functional connectivity were analyzed for BoNT-A treatment (stroke W0 vs. W6).Results: BoNT-A injection therapy resulted in significant increases in brain activation in the contralesional premotor cortex, cingulate gyrus, thalamus, superior cerebellum, and in the ipsilesional sensory integration area. Lastly, cerebellar connectivity correlated with the Fugl-Meyer assessment of motor impairment before injection, while premotor connectivity correlated with the Fugl-Meyer score after injection.Conclusion: BoNT-A therapy for treatment of focal spasticity resulted in increased brain activation in areas associated with motor control, and cerebellar connectivity correlated with motor impairment before injection. These results suggest that neuroplastic effects might take place in response to improvements in focal spasticity.

Effect of muscle selection for botulinum neurotoxin treatment on spasticity in patients with post-stroke elbow flexor muscle over-activity: an observational prospective study

Purpose/Aim To investigate the effect of muscle selection for botulinum neurotoxin A (BoNT-A) treatment on spasticity in patients with post-stroke elbow flexor muscle over-activity. Materials and Methods Chronic stroke patients with a deforming spastic paresis in the upper limb (elbow flexion with forearm pronation) who were injected BoNT-A into at least one of elbow flexor muscles (brachialis, brachioradialis, and biceps brachii) were included in this prospective observational study. The main outcome measure was spasticity angle by Tardieu Scale recorded at pre-treatment and week 4 after treatment. Results Three muscle selection groups with sufficient sample size for statistical analysis were able to be created; brachialis (n = 14), biceps brachii (n = 21), and brachialis plus brachioradialis (n = 11). Although there was a significant improvement in spasticity angle within all groups over time (p < 0.05), the change in spasticity angle was not different between the groups (p > 0.05 for each pairwise comparison). However, the magnitude of the change in spasticity angle was larger in the groups in which brachialis was preferred. Conclusions In stroke patients with a spontaneous spastic posture of elbow flexion and forearm pronation, targeting brachialis for BoNT-A injection seems more effective in reducing the severity of spasticity. Clinical trial registration no NCT04036981

Effects of ultrasound-assisted botulinum neurotoxin-A injection in patients with bruxism and masseter hypertrophy.

Objectives This study aims to explore effects of ultrasound-assisted injection of the botulinum neurotoxin-A (BoNT-A) on muscle thickness (MT) in patients with masseter hypertrophy. Patients and methods Between December 2018 and December 2019, a total of 20 patients (3 males, 17 females; mean age: 28±6.9 years; range, 18 to 42 years) with bruxism who underwent BoNT-A injections were reviewed retrospectively. The patients were treated using individualized injection dosages and sites. Assessment methods included length between the tragus and the angle of the mouth, maximal bite force, and MT of the masseter muscle. Follow-up data were collected from the hospital electronic database. Results There were 26 masseter muscles with masseter hypertrophy in 20 patients. There was a significant difference in ultrasonographic measurements of the relaxed and contracted masseter muscles between the baseline and two weeks, one month and three months after the treatment (p<0.05). In the ultrasonographic measurement of the relaxed masseter muscle, post-treatment third month values significantly differed from the second week values. The differences in the measurement of the line between the tragus and the angle of the mouth between the baseline and two weeks, one month and three months after the treatment were statistically significant (p<0.05). In the maximal bite force measurements, no significant difference was observed between the baseline and post-intervention measurements (p>0.05). Conclusion The MT decreases after a single dose of BoNT-A injection in patients with masseter muscle hypertrophy and ultrasonography is a convenient imaging modality for BoNT-A injection to the masseter.