Voice Disorders Associated With the Use of Inhaled Corticosteroids.

OBJECTIVE: Inhaled corticosteroids (ICS) have been demonstrated to be associated with voice changes. The goal was to determine the strength of the association between ICS use and a diagnosis of dysphonia made by an otolaryngologist and to determine whether inhaler particle type or medication type influenced this risk. STUDY DESIGN: A case-control study from 2018 to 2020. SETTING: Urban academic medical system. METHODS: Adult patients with dysphonia diagnosed by an otolaryngologist, and control patients matched on age, gender, race, and health status, were included. Exposure to ICS was assessed, and the odds ratio (OR) of the association of ICS with dysphonia was calculated. RESULTS: A total of 6551 cases and 6551 matched controls were included. We found that ICS use was significantly associated with dysphonia (OR: 5.11, 95% confidence interval: 4.23-6.17, p < .001). Subset analyses demonstrated no significant differences between inhaler particle types or specific active medications. CONCLUSION: This study emphasizes the importance of identifying ICS use in the evaluation and treatment of patients with dysphonia.

Iron Pill-Induced Chemical Laryngitis.

OBJECTIVE: To discuss the presentation and management of pill-induced chemical laryngitis by illustrating a rare case. METHODS: We report a unique case of a patient with iron pill-induced laryngitis. RESULTS: A 71-year-old male presented for evaluation of dysphonia. Five weeks prior, the patient had reportedly aspirated an iron pill. The pill was lodged in his throat for several hours before being coughed up, soft but still intact. Since that event, the patient noted complete voice loss and in clinic was found to have a very breathy and asthenic voice. Stroboscopy revealed aperiodicity with severe false fold compression and significant ulceration of the infraglottic region associated with thick exudate. Vocal folds were mobile but atrophic, with overlying crusted secretions. A sensory deficit was suspected based on scope tolerance. The patient was treated with nebulized ciprodex and humidified air with some improvement in mucosal crusting but had persistent glottic insufficiency and dysphonia, prompting bilateral hyaluronic acid injection. CONCLUSIONS: Pill-induced laryngitis is an extremely rare phenomenon. While typically associated with bisphosphonates, this condition should be considered in any patient presenting with dysphonia and history of aspiration of a pill, including iron supplements. Regardless of the inciting medication, pill-induced laryngitis may be treated with humidified air, nebulized steroids, and antibiotics. Injection augmentation of the vocal folds may be made considered when glottic insufficiency and weak cough contribute to the presentation.

Laryngeal Botulinum Toxin Injection: Can It Be a Cause of Obstructive Sleep Apnea as an Adverse Effect?

Spasmodic dysphonia is a chronic voice disorder that is characterized by involuntary spasms of the laryngeal muscles during speech production. Botulinum toxin injection into to the laryngeal muscles is the most common and effective treatment of choice for symptoms of spasmodic dysphonia. We present a 44-year-old man with adductor spasmodic dysphonia who was diagnosed as having upper airway obstruction in a polysomnographic examination during sleep after a botulinum toxin injection.

Chemotherapy-related dysphonia: Similar and differentiating features of six cases.

Dysphonia has been reported with anti-angiogenic chemotherapy agents. Dysphonia in patients with cancer receiving chemotherapy tends to be overlooked in clinical practice since it is non-life-threatening. However, it reduces quality of life. Although inhibition of vascular endothelial growth factor receptor is the reported mechanism of dysphonia, it has not been elucidated. We report 6 cases of patients with dysphonia suspected to be due to panitumumab and nivolumab that have not been reported previously. Peripheral edema, a factor in dysphonia, can be seen with aflibercept, bevacizumab, panitumumab, and nivolumab. Therefore, chemotherapy drugs with peripheral edema may be related to dysphonia.

[Drug-induced dysphonia]. / Lekarstvenno-indutsirovannaya disfoniya.

Drug-induced dysphonia is a non-life-threatening adverse drug reaction, however, this complication can significantly worsen the quality of life of patients, especially those in voice-speaking professions. The aim of the work was to search for information about the prevalence, etiology, pathogenesis, and features of treatment and prevention of drug-induced dysphonia. In the case of some drugs, the true prevalence may be higher than described in the literature, due to the fact that dysphonia is in most cases mild, reversible and, in comparison with other undesirable drug reactions, rarely attracts the attention of both the patient and practitioners.

Bevacizumab-induced dysphonia: A case report with brief review of literature.

INTRODUCTION: Anti-angiogenic treatment in adjunct with chemotherapy is widely used for the treatment of various cancers. These agents inhibit vascular endothelial growth factor (VEGF) signaling thereby inhibiting tumor proliferation and invasion. Dysphonia, or voice changes, has been documented, but is an underreported side effect of anti-angiogenic agents. We report a case of intermittent dysphonia in a patient with metastatic, platinum-refractory ovarian cancer treated with bevacizumab. CASE REPORT: A 48-year-old female with high grade mixed type ovarian adenocarcinoma and concurrent left sided breast cancer was transitioned to palliative therapy with gemcitabine-bevacizumab for her ovarian cancer. At a follow-up visit after three cycles of the new therapy, the patient complained of intermittent changes in her voice, describing periods of hoarseness or softness in her voice after the chemotherapy-sometimes to the point that her voice was inaudible. Management and outcome: A new pelvic thrombus was discovered upon assessment of the patient's disease. Bevacizumab was held and she was referred to ear, nose, and throat evaluation for dysphonia. Laryngoscopic examination showed normal vocal cord, with normal movements and no lesion or necrosis. During subsequent follow-up, the patient reported improvement in her voice with no additional dysphonia. DISCUSSION: Vocal adverse effects of anti-VEGF agents have been documented in landmark trials and case reports; however, clinicians are often unaware of this rare side effect. Although VEGF-induced dysphonia may be rare and may not impede the patient's quality of life in some cases, it is critical to acknowledge and not underestimate this adverse effect.

Disfonía como efecto secundario dosis dependiente del tratamiento con duloxetina / Dysphonia as side-effect dose-dependent during treatment with duloxetine

La duloxetina es un antidepresivo inhibidor de la recaptación de serotonina y noradrenalina (IRSN) utilizado para el tratamiento de la depresión mayor, así como el dolor neuropático. La dosis recomendada para el dolor neuropático es de 60 mg una vez al día

Duloxetine is a serotonin-norepinephrine reuptake inhibitor (SNRI) is indicated for the management of major depressive disorder and neuropathic pain. The dose recommended for neuropathic pain is 60 mg once a day

[Laryngeal dystonia: novel forms of therapeutic administration of botulinum toxin by direct routes]. / Distonia laringea: nuevas formas de administracion terapeutica de toxina botulinica por via directa.

AIM: To describe our experience in the treatment of laryngeal dystonia (in abduction and adduction), with special emphasis given to the technical aspects (approach procedure, dosage and type of botulinum toxin type A used), as well as treatment response and possible side effects. PATIENTS AND METHODS: We conducted a cross-sectional descriptive study of a sample of patients with laryngeal dystonia treated by means of transoral administration of onabotulinumtoxinA or incobotulinumtoxinA over a period of 10 years (2007-2017). Data collected include demographic and clinical variables, treatment response (based on a self-rating scale), the duration of treatment and the appearance of side effects. SAMPLE SIZE: 15 patients (11 women; mean age: 44.06 years) with laryngeal dystonia (mean time since onset of 40 months; 12 patients with dystonia in adduction) and 174 administrations (92% incobotulinumtoxinA; average dosage of 5 U in each vocal cord). The procedure took an average of 11.7 minutes to perform. Response was good in 31% of the procedures and very good in 57.5%. Side effects were recorded in 14.4% of the procedures, although always mild and transitory, with a predominance of dysphagia and dysphonia. CONCLUSION: In our experience, transoral administration of botulinum toxin type A to treat laryngeal dystonia has proved to be a simple, quick, effective and safe technique.

TITLE: Distonia laringea: nuevas formas de administracion terapeutica de toxina botulinica por via directa.Objetivo. Describir nuestra experiencia en el tratamiento de la distonia laringea (en abduccion y aduccion), destacando los aspectos tecnicos (procedimiento de abordaje, dosis y tipo de toxina botulinica de tipo A utilizada), asi como la respuesta al tratamiento y los posibles efectos adversos. Pacientes y metodos. Estudio descriptivo transversal de una muestra de pacientes con distonia laringea tratados mediante administracion transoral de onabotulinumtoxina o incobotulinumtoxina A durante un periodo de 10 años (2007-2017). Se recogen las variables demograficas y clinicas, la respuesta al tratamiento (a partir de una escala de autoevaluacion), la duracion de este y la aparicion de efectos adversos. Resultados. Tamaño muestral: 15 pacientes (11 mujeres; edad media: 44,06 años) con distonia laringea (tiempo medio de evolucion de 40 meses; 12 pacientes con distonia en aduccion) y 174 administraciones (92% incobotulinumtoxina A; dosis media de 5 U en cada cuerda vocal). La duracion media del procedimiento fue de 11,7 minutos. La respuesta fue notable en el 31% de los procedimientos y alta en el 57,5%. Se registraron efectos adversos en el 14,4% de los procedimientos, siempre de caracter leve y transitorio, con predominio de la disfagia y la disfonia. Conclusion. En nuestra experiencia, la administracion transoral de toxina botulinica de tipo A como tratamiento de la distonia laringea ha demostrado ser una tecnica sencilla, rapida, eficaz y segura.

Avelumab for metastatic or locally advanced previously treated solid tumours (JAVELIN Solid Tumor): a phase 1a, multicohort, dose-escalation trial.

BACKGROUND: Avelumab (MSB0010718C) is a human IgG1 monoclonal antibody that binds to PD-L1, inhibiting its binding to PD-1, which inactivates T cells. We aimed to establish the safety and pharmacokinetics of avelumab in patients with solid tumours while assessing biological correlatives for future development. METHODS: This open-label, single-centre, phase 1a, dose-escalation trial (part of the JAVELIN Solid Tumor trial) assessed four doses of avelumab (1 mg/kg, 3 mg/kg, 10 mg/kg, and 20 mg/kg), with dose-level cohort expansions to provide additional safety, pharmacokinetics, and target occupancy data. This study used a standard 3 + 3 cohort design and assigned patients sequentially at trial entry according to the 3 + 3 dose-escalation algorithm and depending on the number of dose-limiting toxicities during the first 3-week assessment period (the primary endpoint). Patient eligibility criteria included age 18 years or older, Eastern Cooperative Oncology Group performance status 0-1, metastatic or locally advanced previously treated solid tumours, and adequate end-organ function. Avelumab was given as a 1-h intravenous infusion every 2 weeks. Patients in the dose-limiting toxicity analysis set were assessed for the primary endpoint of dose-limiting toxicity, and all patients enrolled in the dose-escalation part were assessed for the secondary endpoints of safety (treatment-emergent and treatment-related adverse events according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0), pharmacokinetic and pharmacodynamic profiles (immunological effects), best overall response by Response Evaluation Criteria, and antidrug antibody formation. The population for the pharmacokinetic analysis included a subset of patients with rich pharmacokinetic samples from two selected disease-specific expansion cohorts at the same study site who had serum samples obtained at multiple early timepoints. This trial is registered with ClinicalTrials.gov, number NCT01772004. Patient recruitment to the dose-escalation part reported here is closed. FINDINGS: Between Jan 31, 2013, and Oct 8, 2014, 53 patients were enrolled (four patients at 1 mg/kg, 13 at 3 mg/kg, 15 at 10 mg/kg, and 21 at 20 mg/kg). 18 patients were analysed in the dose-limiting toxicity analysis set: three at dose level 1 (1 mg/kg), three at dose level 2 (3 mg/kg), six at dose level 3 (10 mg/kg), and six at dose level 4 (20 mg/kg). Only one dose-limiting toxicity occurred, at the 20 mg/kg dose, and thus the maximum tolerated dose was not reached. In all 53 enrolled patients (the safety analysis set), common treatment-related adverse events (occurring in >10% of patients) included fatigue (21 patients [40%]), influenza-like symptoms (11 [21%]), fever (8 [15%]), and chills (6 [11%]). Grade 3-4 treatment-related adverse events occurred in nine (17%) of 53 patients, with autoimmune disorder (n=3), increased blood creatine phosphokinase (n=2), and increased aspartate aminotransferase (n=2) each occurring in more than one patient (autoimmune disorder in two patients at 10 mg/kg and one patient at 20 mg/kg, increased blood creatine phosphokinase in two patients at 20 mg/kg, and increased aspartate aminotransferase in one patient at 1 mg/kg, and one patient at 10 mg/kg). Six (11%) of 53 patients had a serious treatment-related adverse event: autoimmune disorder (two [13%]), lower abdominal pain (one [7%]), fatigue (one [7%]), and influenza-like illness (one [7%]) in three patients treated at 10 mg/kg dose level, and autoimmune disorder (one [5%]), increased amylase (one [5%]), myositis (one [5%]), and dysphonia (one [5%]) in three patients who received the 20 mg/kg dose. We recorded some evidence of clinical activity in various solid tumours, with partial confirmed or unconfirmed responses in four (8%) of 53 patients; 30 (57%) additional patients had stable disease. Pharmacokinetic analysis (n=86) showed a dose-proportional exposure between doses of 3 mg/kg and 20 mg/kg and a half-life of 95-99 h (3·9-4·1 days) at the 10 mg/kg and 20 mg/kg doses. Target occupancy was greater than 90% at doses of 3 mg/kg and 10 mg/kg. Antidrug antibodies were detected in two (4%) of 53 patients. No substantial differences were found in absolute lymphocyte count or multiple immune cell subsets, including those expressing PD-L1, after treatment with avelumab. 31 (58%) of 53 patients in the overall safety population died; no deaths were related to treatment on study. INTERPRETATION: Avelumab has an acceptable toxicity profile up to 20 mg/kg and the maximum tolerated dose was not reached. Based on pharmacokinetics, target occupancy, and immunological analysis, we chose 10 mg/kg every 2 weeks as the dose for further development and phase 3 trials are ongoing. FUNDING: National Cancer Institute and Merck KGaA.

Inhaled Corticosteroids and Voice Problems. What Is New?

BACKGROUND: Voice problems are the most common and most annoying local side effect of inhaled corticosteroids (ICS), affecting not only patients' treatment compliance but also their quality of life. The literature is very poor regarding prevalence, mechanism, prevention, and management of voice problems attributed to ICS use and especially for the new ICS, ciclesonide. Prevalence of dysphonia seems to be less common with the use of ciclesonide and beclomethasone dipropionate. METHOD: We conducted a bibliography review based on recently published data, including data from the recently introduced ICS, ciclesonide, which are lacking in previous reviews. RESULTS: Very little improvement, based on limited number of new papers published during previous years without any direct comparison between available ICS, has been made in our understanding of ICS local side effects. CONCLUSION: Our understanding concerning basic information of ICS effects on voice still remains poor, and further investigation is needed to have a better understanding on epidemiology, predisposing factors, mechanisms, prevention, and treatment of voice problems attributed to ICS.

Therapy-resistant symptoms in Parkinson's disease.

In recent years, the management of Parkinson's disease (PD) has come a long way, leading to an increase in therapeutic options that now include oral and transdermal drug delivery, infusion as well as surgical treatments. Nonetheless, in the evolution of this complex neurodegenerative disorder, several symptoms remain refractory to dopaminergic therapy. It is our aim to review the literature to date and to bring them into focus, as well as emphasizing on pathophysiological mechanisms, profile of risk factors in their development, and therapeutic options. We will focus on freezing of gait, camptocormia, dysphagia and dysphonia, as well as cognitive impairment and dementia because they represent the far end of therapy-resistant symptoms, encompassing poor health-related quality of life and often a more reserved prognosis with either a rapid evolution of the disease, and/or merely a more severe clinical picture. Pathophysiological mechanisms and brain neurotransmitter abnormalities behind these symptoms seem to overlap to some extent, and a better understanding of these correlations is desirable. We believe that further research is paramount to expand our knowledge of the dopamine-resistant symptoms and, consequently, to develop specific therapeutic strategies.

[Saxitoxins and tetrodotokxins as a new biological weapon]. / Saksytoksyny i tetrodotoksyny jako nowa bron biologiczna.

Saxitoxins (STX) and tetrodotoxins (TTX) are a group of chemical compounds produced by certain species of marine algae and fish. Lethal dose for a human is about 0.5-2.0 mg when the toxin enters the body via food, and 0.05 mg of poisoning at the time of injection. In the case of aerosol the lethal dose for human being is 5 mg/min/m(3). STX and TTX poisoning cause mostly symptoms from the nervous system in the form of: paresthesia around the lips, tongue, gums, distal segments of the limbs, headache, dysphonia, astigmatism, floating feeling, muscle weakness, paralysis of cranial and peripheral nerves. There is no specific antidote for STX and TTX. It is recommended supportive treatment.

Dysphonia associated with the use of inhaled corticosteroids.

PURPOSE OF REVIEW: This article discusses the relationship between inhaled corticosteroids and dysphonia, with discussion of the therapeutic use of inhaled steroids in laryngeal disease and a review of negative laryngeal effects of this class of medication in patients with reactive airway disease. RECENT FINDINGS: Although prescribed for their anti-inflammatory effects (predominantly for pulmonary disease and less often for laryngeal conditions), corticosteroid inhalers can cause laryngeal inflammation. This may relate to chemical irritation from the inhaler itself as well as fungal inflammation related to opportunistic candidiasis that may accompany inhaler use. Patients who suffer from dysphonia because of inhaler use may improve if switched to another inhaler. Studies suggest that ciclesonide metered-dose inhaler may have less oropharyngeal deposition and therefore be associated with reduced oropharyngeal candidiasis and dysphonia compared with other inhaled corticosteroids. SUMMARY: Corticosteroid inhalers are a common cause of dysphonia and their use should be investigated in any patient with laryngeal complaints.

Axitinib for the treatment of metastatic renal cell carcinoma: recommendations for therapy management to optimize outcomes.

Axitinib is a novel, oral, multitargeted tyrosine kinase inhibitor, which inhibits vascular endothelial growth factor receptors 1, 2, and 3 at subnanomolar concentrations in vitro. In the phase III clinical trial in patients with metastatic renal cell carcinoma, axitinib showed a high objective response rate, and significantly prolonged progression-free survival compared with sorafenib. Thus, it is the first drug that has proven the concept of sequencing tyrosine kinase inhibitors in second-line treatment in a phase III prospective randomized trial. Although generally well tolerated and associated with a low incidence of grade 3 or 4 toxicities, axitinib shows a distinct pattern of adverse events that require monitoring and management. The most common adverse events observed with axitinib include diarrhea, hypertension, fatigue, nausea, and vomiting. This article summarizes the most important adverse events observed and proposes recommendations for their monitoring, prevention, and treatment. The recommendations are based on the existing literature and discussion by an expert group of international physicians and nurses specialized in oncologic treatment of metastatic renal cell carcinoma, which gathered in July 2011 in London, UK. Proactive assessment and management of adverse events during axitinib therapy can minimize treatment interruptions and ensure optimal effect of treatment.

Safety of botulinum toxin for dysphagia in oculopharyngeal muscular dystrophy.

INTRODUCTION: Despite multiple studies reporting marked benefit of botulinum toxin (BTX) for treatment of cricopharyngeal dysphagia, little is known about its safety for this indication. We examined the safety of cricopharyngeal BTX for dysphagia in oculopharyngeal muscular dystrophy (OPMD). METHODS: We reviewed records of patients with OPMD who received cricopharyngeal BTX. RESULTS: Twenty-four patients underwent 66 procedures. Overall adverse event frequency was 44%. The most common adverse events were dysphonia (24%) and worsened dysphagia (14%). Logistic regression demonstrated that dose was a significant predictor of worsened dysphagia (P = 0.036) and of the composite event of dysphonia or worsened dysphagia (P = 0.009). There was a nonsignificant trend for dose as a predictor of dysphonia (P = 0.073). 59% of procedures were associated with symptomatic improvement. CONCLUSIONS: While BTX appears to be beneficial for treatment of dysphagia in OPMD, caution is warranted when injecting the cricopharyngeus muscle due to dose-related risk of dysphonia or worsened dysphagia.

Dysphonia induced by anti-angiogenic compounds.

The number of studies reporting the benefit of angiogenesis inhibition is steadily increasing. Anti-angiogenic drugs, used as monotherapy or in association with chemotherapy, have been shown to benefit patients with several different malignancies. Despite the benefits of these therapies, however, each drug has different side effects. This review is specifically focused on analyzing the frequency of one of the complications the most frequently overlooked by physicians, dysphonia. Perhaps this side effect is overlooked because it is not life-threatening, but dysphonia may nevertheless affect quality of life considerably. We reviewed 88 studies concerning treatment with anti-angiogenics (bevacizumab, aflibercept, sunitinib, sorafenib, pazopanib, axitinib and regorafenib) presently approved for clinical use, to review the incidence of dysphonia or voice changes in phase I, II and III closed clinical studies reported in ClinicalTrials.gov until March 2013. We found that almost all studies reported certain degree of dysphonia in the trial arms associated with anti-angiogenic treatment. We discuss these findings in light of the fact that it is not an uncommon side effect in patients exposed to these kinds of drugs. Particularly for treatments with axitinib, aflibercept and regorafenib, the angiogenesis inhibition possibly plays a role by altering the larynx in some way and modifying vocal fold vibrations, leading to dysphonia.

Posterior pharyngeal candidiasis in the absence of clinically overt oral involvement: a cross-sectional study.

PURPOSE: Although oropharyngeal candidiasis is associated with inhaled corticosteroid (ICS) usage, there is sparse data on the prevalence of posterior pharyngeal candidiasis in those without any detectable oral candidiasis on clinical examination. We systematically investigated the relationship between oral candidiasis on clinical examination and the presence of posterior pharyngeal candidiasis at bronchoscopy. METHODS: We conducted a cross-sectional study on a convenience sample of 100 patients undergoing bronchoscopy at our institution. Patients were assessed for symptoms of and risk factors for candida infection and had an examination of their oropharynx for evidence of candidiasis before bronchoscopy. They subsequently had a detailed assessment for posterior candidiasis at bronchoscopy. We performed a posteriori subgroup analysis, which focused solely on those patients on ICS maintenance therapy. RESULTS: Median age was 54.7 (27-84) years, and 55 patients were male; 47 % of patients were on ICS, and 20 % of this cohort received recent oral corticosteroids. Twenty-eight percent of this convenience sample had posterior pharyngeal candidiasis; however, only 10.7 % (3/28) of these patients had clinically detectable oral candidiasis on clinical examination before bronchoscopy. Factors that were independently associated with the presence of pharyngeal candidiasis at bronchoscopy were OR (95 % CI) ICS usage 6.9 (2.5-19.2), particularly fluticasone usage 6.8 (2.62-17.9) and the presence of dysphonia 3.2 (1.3-8.0). In the subgroup analysis of ICS usage, posterior pharyngeal candidiasis was correlated with the presence of dysphonia but was not independently associated with fluticasone or budesonide dosage. CONCLUSIONS: This study demonstrates that posterior pharyngeal candidiasis in the absence of clinically overt oral candidiasis is frequent amongst ICS users. A history of ICS use, particularly fluticasone usage, as well as the presence of dysphonia are associated with posterior pharyngeal candidiasis at bronchoscopy, even in the absence of clinically overt oral involvement.

Practical considerations for dysphonia caused by inhaled corticosteroids.

Inhaled corticosteroid (ICS) therapy has become standard in the treatment of asthma. A common local adverse effect of ICS therapy is dysphonia, which has been reported to affect 5% to 58% of patients. Although causes of dysphonia associated with ICS therapy have been underinvestigated, it may result from deposition of an active ICS in the oropharynx during administration, which then causes myopathy or a mucosal effect in the laryngopharynx. Use of ICS should be considered during any evaluation of dysphonia. We recommend using the lowest effective dosage of ICS, administering medication with a spacer, gargling, rinsing the mouth and washing the face after inhalation, and washing the spacer. If dysphonia develops despite these interventions, ICS use should be suspended until symptoms resolve, provided that asthma control is not compromised.