Botulinum toxin injection into the intrinsic laryngeal muscles to treat spasmodic dysphonia: A multicenter, placebo-controlled, randomized, double-blinded, parallel-group comparison/open-label clinical trial.

BACKGROUND AND PURPOSE: Botulinum toxin (BT) injection into the laryngeal muscles has been a standard treatment for spasmodic dysphonia (SD). However, few high-quality clinical studies have appeared, and BT is used off-label in most countries. METHODS: We performed a multicenter, placebo-controlled, randomized, double-blinded, parallel-group comparison/open-label clinical trial to obtain approval for BT (Botox) therapy in Japan. Twenty-four patients (22 with adductor SD and two with abductor SD) were enrolled. The primary end point was the change in the number of aberrant morae (phonemes) at 4 weeks after drug injection. The secondary end points included the change in the number of aberrant morae, GRBAS scale, Voice Handicap Index (VHI), and visual analog scale (VAS) over the entire study period. RESULTS: In the adductor SD group, the number of aberrant morae at 4 weeks after injection was reduced by 7.0 ± 2.30 (mean ± SE) in the BT group and 0.2 ± 0.46 in the placebo group (p = 0.0148). The improvement persisted for 12 weeks following BT injections. The strain element in GRBAS scale significantly reduced at 2 weeks after BT treatment. The VHI and VAS scores as subjective parameters also improved. In the abductor SD group, one patient responded to treatment. Adverse events included breathy hoarseness (77.3%) and aspiration when drinking (40.9%) but were mild and resolved in 4 weeks. CONCLUSIONS: Botulinum toxin injection was safe and efficacious for the treatment of SD. Based on these results, BT injection therapy was approved as an SD treatment in Japan.

Clinical Significance of Surgical Intervention to Restore Swallowing Function for Sustained Severe Dysphagia.

Owing to rapid population aging, patients with dysphagia are significantly increasing in society. Dysphagia treatment is aimed at the restoration of the swallowing function and the prevention of recurrent aspiration-induced pulmonary infection. However, despite intensive rehabilitation, oral food intake remains inadequate in many patients with severe dysphagia, which results in the deterioration of patients' quality of life and joy of living. Surgical intervention may serve as a useful therapeutic strategy to restore swallowing function in these patients. The study included 25 patients (mean, 70.4 years; male/female ratio, 20:5) with chronic dysphagia. Dysphagia was associated with cerebrovascular diseases in sixteen patients; with age-induced physiological deterioration in five patients; and with miscellaneous etiologies in four cases. Cricopharyngeal and infrahyoid myotomies were performed in all patients. Laryngeal elevation and the medialization of the paralyzed vocal fold were performed in 15 and 3 patients, respectively. The Food Intake Level Scale (FILS) and videoendoscopic examination score (VEES) were used to evaluate swallowing function. The FILS showed a restoration of oral food intake alone in 72% of patients, and 64% of patients maintained this improvement at their last follow-up visit. We observed significantly improved VEES scores postoperatively. However, patients with cognitive impairment or advanced age showed poor outcomes. In conclusion, surgical intervention may be an effective therapeutic option to restore swallowing function in cases of sustained severe dysphagia; however, surgical indications require careful consideration.

Botulinum Toxin Therapy for Spasmodic Dysphonia in Japan: The History and an Update.

Spasmodic dysphonia (SD) is a rare neurological disorder that impairs phonatory function by triggering involuntary and intermittent contractions of the intrinsic laryngeal muscles. SD is classified into three types: adductor SD (AdSD), abductor SD (AbSD), and mixed SD. Of these, AdSD accounts for 90-95% of disease; younger females are predominantly affected. Botulinum toxin injection into the laryngeal muscles is safe, minimally invasive, and very effective. Here, we review the history of clinical research for SD conducted in Japan. The first use of botulinum toxin injection therapy to treat SD in Japan was by Kobayashi et al. in 1989. The group developed an objective mora (syllable) method to evaluate SD severity. Recently, we conducted a placebo-controlled, randomized, double-blinded clinical trial of botulinum toxin therapy for AdSD and an open-label trial for AbSD to obtain the approval of such therapy by the Japanese medical insurance system. The mora method revealed significant voice improvement and the evidence was of high quality. Additionally, a clinical trial of type 2 thyroplasty using titanium bridges confirmed the efficacy and safety of such therapy. These studies broadened the SD treatment options and have significantly benefited patients.

Laryngeal malignant peripheral nerve sheath tumor mixed with high- and low-grade malignancies.

Malignant peripheral nerve sheath tumors (MPNSTs), as defined by immunohistochemical evaluation, are identified along a spectrum ranging from atypical neurofibroma to high-grade MPNST because these tumors are similar in terms of cell shape and tissue components on hematoxylin-eosin (HE) staining. The patient was a 57-year-old male referred to our hospital, with a recurrent red tumor at the anterior commissure of the larynx and submucosal swelling of the right vocal fold. A surgical specimen from a right horizontal partial laryngectomy was evaluated immunohistochemically. A high-grade MPNST lesion was included in the submucosal white tumor, whereas a low-grade MPNST lesion was encountered around the high-grade MPNST lesion. This tumor may involve different malignancies even when it is small. Although intra-tumor heterogeneity in cancers has been reported recently, careful immunohistochemical examination can be important and beneficial for eradicating the tumor while preserving vocal function.

Botulinum Toxin Therapy: A Series of Clinical Studies on Patients with Spasmodic Dysphonia in Japan.

Spasmodic dysphonia (SD) is a rare voice disorder caused by involuntary and intermittent spasms of the laryngeal muscles. Both diagnosis and treatment have been controversial. Therefore, a series of clinical studies has recently been conducted in Japan. A nationwide epidemiological survey revealed that adductor SD predominated (90-95% of all cases; 3.5-7.0/100,000), principally among young women in their 20s and 30s. To facilitate early diagnosis, we created diagnostic criteria for SD and a severity grading system. The diagnostic criteria include the principal and accompanying symptoms, clinical findings during phonation, the treatment response, and the differential diagnoses. The severity grade is determined using a combination of subjective and objective assessments. Botulinum toxin (BT) injection is the treatment of choice; however, there have been few high-quality clinical studies and BT has been used off-label. We conducted a placebo-controlled, randomized, double-blinded clinical trial of BT therapy; this was effective and safe. BT treatment is now funded by the Japanese medical insurance scheme. Studies thus far have facilitated early diagnosis and appropriate therapy; they have fostered patient awareness of SD.

Post-treatment clinical course following botulinum toxin injection therapy for adductor spasmodic dysphonia: Analysis of data from a placebo-controlled, randomized, double-blinded clinical trial in Japan.

OBJECTIVE: Botulinum toxin (BT) therapy is a first-line treatment for spasmodic dysphonia (SD). However, a detailed chronological course and clinical factors that affect the therapeutic effect have been vague. In this study, we analyzed the data from our placebo-controlled, randomized, double-blinded parallel-group comparison/open-label clinical trial of BT (Botox) to clarify these. METHODS: A total of 22 patients with abductor SD (ADSD) were enrolled. The female-to-male ratio was 20:2 with a mean age of 40.0 ± 10.3 years and a median duration of symptoms of 7.5 years. The therapeutic effect was evaluated based on the change in the number of aberrant morae (phonemes), GRBAS scale, Voice Handicap Index (VHI), and Visual Analogue Scale (VAS). RESULTS: The change in the number of aberrant morae peaked at 2 weeks and lasted for 12 weeks in the BT group with significance (P < .01) compared to the placebo group. Objective improvement (number of aberrant morae and [S] element in GRBAS) preceded subjective improvement (VHI and VAS). The change in number of aberrant morae and VHI showed a significant correlation (P < .01). The changes in the number of aberrant morae, VHI, and VAS in younger subjects were greater than in older subjects. Patients who presented with post-treatment breathy hoarseness or dysphagia showed better therapeutic effects. CONCLUSIONS: BT therapy was effective for ADSD based on both objective and subjective assessments. Improvements in subjective parameters were delayed compared to objective measures due to post-treatment breathy hoarseness. However, this adverse event was believed to reflect the treatment effect. LEVEL OF EVIDENCE: 1b.

The prevalence and clinical features of spasmodic dysphonia: A review of epidemiological surveys conducted in Japan.

OBJECTIVES: Spasmodic dysphonia (SD) is a rare disease and its epidemiological status is unclear. This review aimed to explore the current prevalence and clinical features of SD in Japan. METHODS: We reviewed Japanese surveys of SD and compared them to surveys reported from other countries. We focused on SD prevalence, clinical features (SD type, sex and age), and treatment modalities. RESULTS: The SD prevalence in Japan was 3.5-7.0/100,000, similar to that in Rochester (NY, USA) and Iceland. Adductor SD predominated (90-95%) and females were four-fold more likely to be affected than males. Mean age at onset was approximately 30 years in Japan. Several years elapsed from onset to diagnosis. The most frequent treatment was botulinum toxin injection, and surgical intervention, particularly type 2 thyroplasty is becoming more popular. CONCLUSIONS: Our review demonstrated some differences of clinical features of SD in Japan compared with other countries, such as a greater female predominance and younger age of onset. Many physicians and patients may be unfamiliar with the clinical features of SD leading to delayed of diagnosis. Therefore, we proposed diagnostic criteria to facilitate early diagnosis and an appropriate choice of treatment modalities.

Apnea hypopnea indices categorized by REM/NREM sleep and sleep positions in 100 children with adenotonsillectomy for obstructive sleep apnea disease.

OBJECTIVES: In pediatric obstructive sleep apnea (OSA), the relationship between rapid eye movement sleep and upper airway collapse, and between sleep position and airway dimensions are well known. However, the interrelations between these factors and the obstructive apnea hypopnea index (O-AHI) have not been thoroughly investigated. METHODS: A retrospective study including 100 children who underwent adenotonsillectomy between March 2010 and July 2017. Total O-AHI was divided into four subcategories by sleep stage and position. RESULTS: Preoperatively 14 of 47 mild cases of OSA (1 ≤ total O-AHI) and 17 of 18 moderate (5 ≤ total O-AHI) had time showing severe apnea (10 ≤ subcategorized O-AHI). Twenty-two of 24 severe cases (10 ≤ total O-AHI) exhibited very severe apnea (30 ≤ subcategorized O-AHI). All 11 very severe cases (30 ≤ total O-AHI) experienced more than 50 apnea events per hour in at least one of the O-AHI subcategories. After surgery, 23 of 70 cases classified as completely resolved (total O-AHI < 1) still had mild apnea in the O-AHI subcategories, and six of 13 cases who continued to experience apnea events had moderate-to-severe apnea. Seventeen cases worsened in the O-AHI subcategories, and total O-AHI deteriorated in two cases of the 17. The amount of REM sleep and use of the supine position increased significantly postoperatively in the quartile groups with the lowest baseline values (p < 0.0001). CONCLUSIONS: When an unexpected AHI value is encountered, the O-AHI subcategories may be informative regarding the indications for surgery and evaluating the efficacy thereof.