Tamoxifen Alters TGF-ß1/Smad Signaling in Vocal Fold Injury.

OBJECTIVES: Effective treatments for vocal fold fibrosis remain elusive. Tamoxifen (TAM) is a selective estrogen receptor modulator and was recently reported to have antifibrotic actions. We hypothesized that TAM inhibits vocal fold fibrosis via altered transforming growth factor beta 1 (TGF-ß1) signaling. Both in vitro and in vivo approaches were employed to address this hypothesis. METHODS: In vitro, vocal fold fibroblasts were treated with TAM (10-8 or 10-9 M) ± TGF-ß1 (10 ng/ml) to quantify cell proliferation. The effects of TAM on genes related to fibrosis were quantified via quantitative real-time polymerase chain reaction. In vivo, rat vocal folds were unilaterally injured, and TAM was administered by oral gavage from pre-injury day 5 to post-injury day 7. The rats were randomized into two groups: 0 mg/kg/day (sham) and 50 mg/kg/day (TAM). Histological changes were examined on day 56 to assess tissue architecture. RESULTS: TAM (10-8 M) did not affect Smad3, Smad7, Acta2, or genes related to extracellular matrix metabolism. TAM (10-8 or 10-9 M) + TGF-ß1, however, significantly increased Smad7 and Has3 expression and decreased Col1a1 and Acta2 expression compared to TGF-ß1 alone. In vivo, TAM significantly increased lamina propria area, hyaluronic acid concentration, and reduced collagen deposition compared to sham treatment. CONCLUSIONS: TAM has antifibrotic potential via the regulation of TGF-ß1/Smad signaling in vocal fold injury. These findings provide foundational data to develop innovative therapeutic options for vocal fold fibrosis. LEVEL OF EVIDENCE: NA Laryngoscope, 133:2248-2254, 2023.

Long-term outcomes of basic fibroblast growth factor treatments in patients with vocal fold scarring, aged vocal fold, and sulcus vocalis.

OBJECTIVE: Fibrotic changes in the vocal fold mucosa have been observed in patients with vocal fold scarring, aged vocal fold, and sulcus vocalis, which often lead to severe voice disorders. Previous research suggests that the basic fibroblast growth factor (b FGF) improves variations in vocal fold properties [1,2]. Although clinical studies on b FGF treatments have been conducted [3,4,5], these studies only demonstrated the efficacy of this drug over a short period. The present study is the first to investigate the long-term efficacy of b FGF treatment. METHODS: b FGF injections were performed in six patients from January of 2016 to December of 2017 at our institution. Patient follow-up continued for at least two years after the last injection. Three patients had vocal fold scarring, two had aged vocal fold atrophy, and one patient had sulcus vocalis. Each vocal fold was injected with 10 µg of b FGF four times. Voice and stroboscopic examinations were performed after surgery (at one month, three months, six months, one year, two years). Fundamental frequency, maximum phonation time (MPT), mean flow rate (MFR), amplitude perturbation quotient (APQ), pitch perturbation quotient (PPQ), and noise-to-harmonic ratio (NHR), and voice handicap index-10 (VHI-10) were examined and compared statistically between the pretreatment time and at each posttreatment time point. RESULTS: The speaking F0 had an obvious decreasing tendency, with significant differences suggesting the increase in volume in the vocal folds. Aerodynamic parameters also showed small improvements. The most remarkable improvement was observed in the acoustic parameters, indicating that the treatment could improve the vocal fold to make vibrations symmetrically and regularly for a long period. Achievement of symmetry and regularity on vocal fold vibrations suggested the property changes had happened in the vocal folds. Consequently, the score of VHI-10 had improved, indicating high patient satisfaction with this treatment. CONCLUSION: b FGF injections could be a reliable treatment option for diseases that deteriorate the property of vocal fold.

Vocal fold botulinum toxin injection for refractory paradoxical vocal fold motion disorder.

OBJECTIVE: Demonstrate efficacy of vocal fold botulinum toxin injection for treatment of refractory paradoxical vocal fold motion disorder (PVFMD). METHODS: A retrospective review was completed of patients diagnosed with PVFMD who underwent vocal fold botulinum toxin injection for dyspnea symptoms that persisted despite laryngeal control therapy, medical management, and biofeedback therapy. Outcomes measured included overall improvement and resolution of dyspnea symptoms, number of botulinum toxin injections and dose range, change in dyspnea severity index (DSI) scores, and adverse effects of injection therapy. RESULTS: Thirteen patients (9 female/4 male) underwent vocal fold botulinum toxin injection for refractory PVFMD. The average dose was 2.55 units per vocal fold (range 1.75-5.5 units). The average number of injections was 3.85 (range 1-12 injections). Eleven of 13 (84.6%) patients experienced improvement in dyspnea symptoms, with two of 11 (18.2%) having complete resolution of symptoms. There was a statistically significant improvement in DSI scores because the mean preinjection DSI was 30.43 and improved to 17.43 postinjection (P = 0.017). Temporary breathy voice quality was experienced by all patients with no other adverse side effects. CONCLUSION: Vocal fold botulinum toxin injection is a safe and effective treatment option for PVFMD and should be considered in patients with refractory dyspnea symptoms following appropriate medical therapy and respiratory retraining protocols. LEVEL OF EVIDENCE: 4 Laryngoscope, 129:808-811, 2019.

Paradoxical Vocal Cord Motion in a Pair of Twin Preterm Infants.

BACKGROUND: Intractable obstructive apneas requiring multiple intubations are rare in newborns. CASE CHARACTERISTICS: We report a pair of twins born at 29 weeks gestation who had severe obstructive apneas due to Paradoxical Vocal Cord Motion (PVCM). OUTCOME: The symptoms resolved promptly with ipratropium nebulization. Follow-up at 12 months of age revealed normal development. MESSAGE: PVCM should be considered in the differential diagnosis of intractable obstructive apneas in very low birth weight preterm infants.

Subcutaneous Neurotrophin 4 Infusion Using Osmotic Pumps or Direct Muscular Injection Enhances Aging Rat Laryngeal Muscles.

Laryngeal dysfunction in the elderly is a major cause of disability, from voice disorders to dysphagia and loss of airway protective reflexes. Few, if any, therapies exist that target age-related laryngeal muscle dysfunction. Neurotrophins are involved in muscle innervation and differentiation of neuromuscular junctions (NMJs). It is thought that neurotrophins enhance neuromuscular transmission by increasing neurotransmitter release. The neuromuscular junctions (NMJs) become smaller and less abundant in aging rat laryngeal muscles, with evidence of functional denervation. We explored the effects of NTF4 for future clinical use as a therapeutic to improve function in aging human laryngeal muscles. Here, we provide the detailed protocol for systemic application and direct injection of NTF4 to investigate the ability of aging rat laryngeal muscle to remodel in response to NTF4 application. In this method, rats either received NTF4 either systemically via osmotic pump or by direct injection through the vocal folds. Laryngeal muscles were then dissected and used for histological examination of morphology and age-related denervation.

Primidone Therapy for Essential Vocal Tremor.

IMPORTANCE: Essential vocal tremor is difficult to treat. An effective pharmacologic treatment could allow patients to avoid or decrease the frequency or dosage of botulinum neurotoxin injections. OBJECTIVE: To evaluate the efficacy of primidone in the treatment of essential vocal tremor. DESIGN, SETTING, AND PARTICIPANTS: Medical records of all patients with a primary or secondary diagnosis of laryngeal spasm or essential tremor treated with primidone between June 1, 2012, and March 21, 2014, at a tertiary care medical center were reviewed. Data analysis occurred in April 2014. MAIN OUTCOMES AND MEASURES: Duration of therapy, improvement of symptoms, and whether the patient subsequently initiated botulinum neurotoxin therapy. RESULTS: All 30 patients were female (mean [SD] age, 71.9 [11.8] years). Mean (SD) therapy duration was 5.25 (7.22) months. Nine patients (30%) had other vocal conditions (4 had coexisting spasmodic dysphonia, 4 had laryngopharyngeal reflux disease, and 1 had muscle tension dysphonia). Twelve (40%) had previously undergone treatment. Fourteen of 26 patients (54%) reported an improvement in their vocal symptoms, and 16 of 29 (55%) did not discontinue primidone therapy. Twenty-two of 30 patients (73%) experienced adverse effects. Therapy was discontinued by 11 of 21 patients (52%) who experienced adverse effects and 2 of 8 patients (25%) who did not report adverse effects (P = .24) (1 patient who had adverse effects was missing data on discontinuation of therapy). Sixteen patients (53%) subsequently initiated botulinum toxin therapy, including 5 of 14 patients (36%) who reported clinical improvement with primidone therapy and 7 of 12 patients (58%) who did not report improvement (P = .43). CONCLUSIONS AND RELEVANCE: Primidone therapy was an effective pharmacologic treatment for essential vocal tremor in 14 of 26 patients in this case series, providing an alternative to botulinum neurotoxin therapy.

Office-based laryngeal injection of botulinum toxin for paradoxical vocal fold motion in a child.

We describe the case of a 13-year-old girl with paradoxical vocal fold motion (PVFM) who failed to improve with repeated medical treatment, speech therapy and psychotherapy, but was successfully treated with botulinum toxin A (BTX-A) injection to the vocal folds. For delivering the BTX-A we used a channeled fiber-optic laryngoscope under local anesthesia, in an office setting. The patient remained asymptomatic of PVFM for 5 months, was successfully treated again with the same method, and had no important side effects.

Dexamethasone Controlled Release on TGF-ß1 Treated Vocal Fold Fibroblasts.

OBJECTIVE: Corticosteroids may be beneficial in treating vocal fold scarring. Current drug delivery methods do not permit controlled corticosteroid release. Here we investigate the effects of poly-lactic-co-glycolic acid (PLGA) microparticles loaded with the corticosteroid dexamethasone in reducing collagen synthesis and inflammation in vocal fold fibroblasts treated with and without TGF-ß1. STUDY DESIGN: Experimental, in vitro study. METHODS: PLGA microparticles of differing molecular weight and terminating moieties were synthesized using a hydrogel template method. The release of dexamethasone was characterized from these microparticles over 4 days. Based on the release studies, ester-terminated low molecular weight PLGA microparticles were loaded with dexamethasone and applied to TGF-ß1 treated vocal fold fibroblasts for 4 days. Quantitative polymerase chain reaction (qPCR) and enzyme-linked immunosorbent assays (ELISAs) were used to assess the effects of released dexamethasone on collagen synthesis and inflammatory mediators. RESULTS: COL3A1 and COL1A2 were significantly down-regulated after exposure to ester-terminated low molecular weight PLGA microparticles loaded with dexamethasone. The loaded microparticles also reduced interleukin-6 synthesis. CONCLUSION: These data show promise in using a PLGA microparticle-based delivery system to control dexamethasone release over 4 days. Our findings lay the groundwork for developing more effective treatments for vocal fold scarring.

Abnormal vocal cord movement treated with botulinum toxin in patients with asthma resistant to optimised management.

BACKGROUND AND OBJECTIVE: Abnormal vocal cord movement may coexist with asthma and cause additional upper/middle airway obstruction. The condition may be a form of muscular dystonia that could contribute to asthma resistant to optimised treatments. Botulinum toxin causes temporary paralysis of muscle and may be an effective local treatment that improves asthma control. METHODS: In an observational study, we evaluated the benefits of unilateral vocal cord injection with botulinum toxin in 11 patients (total 24 injections). Subjects had asthma resistant to optimised treatment and abnormal vocal cord movement. Responses after botulinum toxin treatment were assessed using asthma control test (ACT) scores, vocal cord narrowing quantified by computerised tomography (CT) of the larynx and spirometry. Side-effects were recorded. RESULTS: ACT scores improved overall (9.1 ± 2.4 before and 13.5 ± 4.5 after treatment; difference 4.4 ± 4.2; P < 0.001). There was also an improvement in airway size on CT larynx (time below lower limit of normal at baseline 39.4 ± 37.63% and improved to 17.6 ± 25.6% after injection; P = 0.032). Spirometry was not altered. One patient experienced an asthma exacerbation but overall side-effects were moderate, chiefly dysphonia and dysphagia. CONCLUSIONS: Although a placebo effect cannot be ruled out, local injection of botulinum toxin may be an effective treatment for intractable asthma associated with abnormal vocal cord movement. Further mechanistic studies and a double-blind randomised controlled trial of botulinum toxin treatment are merited.

Periodic botulinum toxin injections for paradoxical vocal fold motion in a child with cerebral palsy: a case study.

We describe an unusual case of paradoxical vocal fold motion in a child with cerebral palsy. Clinically, the child presented with mild stridor, which worsened over months, eventually requiring emergency intubation. After an unsuccessful trial of medical management, microlaryngoscopy revealed abnormal adduction of the vocal folds during inspiration. This was successfully treated with periodic type A botulinum toxin injections to the vocal folds, sparing the child from tracheostomy.