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.

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.

Ginger Orally Disintegrating Tablets to Improve Swallowing in Older People.

We previously prepared and pharmaceutically evaluated ginger orally disintegrating (OD) tablets, optimized the base formulation, and carried out a clinical trial in healthy adults in their 20 s and 50s to measure their effect on salivary substance P (SP) level and improved swallowing function. In this study, we conducted clinical trials using the ginger OD tablets in older people to clinically evaluate the improvements in swallowing function resulting from the functional components of the tablet. The ginger OD tablets were prepared by mixing the excipients with the same amount of mannitol and sucrose to a concentration of 1% ginger. Eighteen healthy older adult volunteers aged 63 to 90 were included in the swallowing function test. Saliva was collected before and 15 min after administration of the placebo and ginger OD tablets. Swallowing endoscopy was performed by an otolaryngologist before administration and 15 min after administration of the ginger OD tablets. A scoring method was used to evaluate the endoscopic swallowing. Fifteen minutes after taking the ginger OD tablets, the salivary SP amount was significantly higher than prior to ingestion or after taking the placebo (p<0.05). Among 10 subjects, one scored 1-3 using the four evaluation criteria. Overall, no aspiration occurred and a significant improvement in the swallowing function score was observed (p<0.05) after taking the ginger OD tablets. Our findings showed that the ginger OD tablets increased the salivary SP amount and improved swallowing function in older people with appreciably reduced swallowing function.

Quantitative evaluation of age-related alteration of swallowing function: Videofluoroscopic and manometric studies.

OBJECTIVE: Swallowing function progressively deteriorates with advancing age, leading to high morbidity and mortality in the elderly population. To establish strategies for treatment of age-related swallowing disorders, the mechanisms of such disorders must be quantitatively clarified. The purpose of this paper was to elucidate the swallowing function of healthy elderly individuals by comparison with that of young adults by videofluorographic and manometric examinations. METHODS: The subjects were 70 healthy volunteers with no history of diseases affecting swallowing function. They were classified into three groups according to age: the young adult group (21-32 years of age, n=8), early elderly group (60-69 years of age, n=39), and late elderly group (70-83 years of age, n=23). Their swallowing functions were quantitatively evaluated by videofluorographic and manometric studies. RESULTS: Videofluorographic examination showed no significant differences in the moving distances of the hyoid bone and larynx in the pharyngeal swallowing phase between the young and elderly groups. The pharyngeal transit time (PTT) of the bolus in the elderly group was longer and the percentage of laryngeal elevation (%LE) was lower than those in the young group. Manometric examination revealed higher hypopharyngeal swallowing pressure in the elderly groups. The traveling velocity of the swallowing pressure in the upper esophageal sphincter (UES) region and the UES relaxation time decreased with aging. Reduction of the UES pressure during the pharyngeal swallowing phase was insufficient in 15.4% of the early elderly group and 30.4% of the late elderly group. Additionally, the UES zone was broadened in 20.5% of the early elderly group and 26.1% of the late elderly group. CONCLUSION: Videofluorographic and manometric examinations quantitatively demonstrated that the swallowing reflex was delayed and UES opening was impaired by aging. UES dysfunction may develop secondary by increased tonicity and decreased elasticity of the cricopharyngeal muscle. Stimulation of oropharyngeal sensory function and exercising the laryngeal levator muscles may be effective for age-related swallowing disorders.

Evaluation of "Open Essence" odor-identification test card by application to healthy volunteers.

OBJECTIVE: In the United States and European countries, the University of Pennsylvania Smell Identification Test (UPSIT), the Quick Smell Identification Test (Q-SIT), a shorter version of the UPSIT, and "Sniffin' Sticks" are widely used for testing olfaction. The odor stick identification test for Japanese (OSIT-J) has been manufactured in Japan. This was followed by the development of "Open Essence," consisting of cards that make use of sealed odorants. This study examined the usefulness of Open Essence in young volunteers with normal olfaction. METHOD: The participants were 176 medical students in their clinical clerkships at the Department of Otolaryngology, Kochi Medical School Hospital. There were 111 males and 65 females, with a median age of 24 years (range 22-42 years). The olfactory function of all participants was confirmed as normal by screening with T&T olfactometry. Before beginning Open Essence, the subjects were asked to answer a questionnaire on their olfaction and habits. RESULTS: Females had significantly better smell identification than males. Of the 12 odorants, "perfume" and "cooking gas" were difficult to identify, because perfume involves different imagery and the compounds that give the smell of gas are readily volatilized. In contrast, all participants recognized "curry" and "menthol," probably because they are received as both somatosensory stimuli and smell. CONCLUSIONS: These results suggest that, with improvement, Open Essence might be used for testing olfaction in Japanese subjects.

[New scoring proposed for endoscopic swallowing evaluation and clinical significance].

Dysphagia is becoming a critical medical and social issue with aging population. Appropriate treatment requires that swallowing be assessed objectively. The simple, clinic-based scoring we developed for flexible endoscopic evaluation of swallowing (FEES) uses four parameters--(1) the salivary pooling degree at the vallecula and piriform sinuses, (2) the glottal closure reflex induced by touching the epiglottis or arytenoid with the endoscope, (3) swallowing reflex initiation assessed by "white-out" timing, and (4) pharyngeal clearance after blue-dyed water is swallowed-categorized as 0 for normal, 1 for mildly impaired, 2 for moderate, or 3 for severe. Scores given by experienced otolaryngologists expert in treating dysphagic subjects correlated significantly with those of nonexpert otolaryngologists and speech-language-hearing therapists. Pharyngeal clearance evaluated by videofluorography correlated with FEES clearance scores, as did aspiration severity with total scores statistically significantly. Feeding procedures related significantly to total scores for the four parameters, indicating its usefulness in deciding oral food intake. Our new scoring is thus simple and reliable in evaluating dysphagia severity and features, and potentially clinically advantageous.

A totally implanted intra-arterial chemotherapy system for advanced maxillary sinus carcinoma.

CONCLUSION: Both reservoir systems for intra-arterial cisplatin and intravenous sodium thiosulfate infusions are low- invasive, safe and effective procedures for treatment of advanced maxillary sinus carcinoma. OBJECTIVES: To use our reservoir system for intra-arterial high-dose cisplatin infusion therapy in patients with advanced maxillary sinus carcinoma. MATERIALS AND METHODS: Eight patients with advanced maxillary sinus carcinomas underwent treatment utilizing intra-arterial cisplatin (CDDP) infusion and radiation therapy followed by planned surgical resection. For intra-arterial infusion of high-dose cisplatin, both intra-arterial and intravenous reservoir systems were used. RESULTS: CDDP was infused 4-6 times (mean 5.1) and the total dose of CDDP was between 690 and 910 mg (mean 771 mg). The response rate was 100 with 50% CR and 50% PR and all patients underwent medial maxillectomy. Only 1 T(4) patient had local recurrence and 1 other patient had bilateral neck metastasis.