Rapid and long-lasting efficacy of high-dose ambroxol therapy for neuronopathic Gaucher disease: A case report and literature review.

Gaucher disease (GD) is a lysosomal storage disorder caused by a deficiency in the GBA1-encoded enzyme, ß-glucocerebrosidase. Enzyme replacement therapy is ineffective for neuronopathic Gaucher disease (nGD). High-dose ambroxol has been administered as an alternative treatment for a group of patients with nGD. However, little is known about the clinical indication and the long-term outcome of patients after ambroxol therapy. We herein report a case of a female patient who presented with a progressive disease of GD type 2 from 11 months of age and had the pathogenic variants of p.L483P (formerly defined as p.L444P) and p.R502H (p.R463H) in GBA1. A combined treatment of imiglucerase with ambroxol started improving the patient's motor activity in 1 week, while it kept the long-lasting effect of preventing the deteriorating phenotype for 30 months. A literature review identified 40 patients with nGD, who had received high-dose ambroxol therapy. More than 65% of these patients favorably responded to the molecular chaperone therapy, irrespective of p.L483P homozygous, heterozygous or the other genotypes. These results highlight the long-lasting effect of ambroxol-based chaperone therapy for patients with an expanding spectrum of mutations in GBA1.

Social anxiety disorder in adolescents who stutter: A risk for school refusal.

BACKGROUND: Stuttering is a childhood-onset fluency disorder. Part of the counseling for middle and high school students with persistent stuttering is related to school refusal. Anxiety disorders are known to contribute to school refusal. However, it is not known whether social anxiety disorder (SAD) is a factor in school refusal among adolescents who stutter. METHODS: In our first study, we examined the relationship between school refusal and SAD in 84 middle and high school students who stutter; 26% of the 84 students were in the school refusal group and the remaining 74% were in the school attendance group. The second study examined whether SAD was associated with 10 factors related to speech and stuttering frequency using the Japanese version of the Liebowitz Social Anxiety Scale for Children and Adolescents to determine the presence of SAD. Of the 84 students in the first study, 40 participated in the second study. RESULTS: The school refusal group of adolescents who stutter had significantly higher rates of SAD than the school attendance group. Fifty percent of adolescents who stutter met the criteria for SAD. Moreover, adolescents who stutter with SAD had significantly higher scores on the items "When speaking in public, do you experience tremors in your limbs?" and "After you stutter, do you have negative thoughts about yourself?" than the adolescents who stutter without SAD. CONCLUSIONS: When examining adolescents who stutter, checking for comorbid SAD may lead to better support. Moreover, noticing their repetitive negative thinking, nervousness, and trembling during speech may help to resolve SAD.

Type I Thyroplasty Is Safe in Patients Undergoing Antithrombotic Therapy.

INTRODUCTION: Type I thyroplasty is one of the most useful surgeries for unilateral vocal fold paralysis. The study objective was to determine whether type I thyroplasty is safe and perioperative antithrombotic management is acceptable in patients undergoing antithrombotic therapy. METHODS: This is a single-hospital retrospective cohort study. The records of 204 patients who underwent type I thyroplasty at a Japanese university hospital, between 2008 and July 2018 were reviewed. We compared the prothrombin time international normalized ratio, prothrombin time, operative time, intraoperative blood loss, and intra- and postoperative complications between patients who did and did not receive antithrombotic therapy. RESULTS: Of 204 patients, 51 (25%) received antithrombotic therapy (antithrombotic group). The remaining 153 patients were assigned to the control group. There were no significant differences in operative time, intraoperative blood loss, or intraoperative complications between the two groups. Sixteen (31%) patients in the antithrombotic group had a hemorrhage or hematoma in the vocal fold mucosa postoperatively, no patient had airway obstruction necessitating tracheostomy, and all patients recovered with follow-up observation only. There were no cases of intraoperative or postoperative complications, such as ischemic heart disease, ischemic stroke, or deep vein thrombosis. CONCLUSION: Type I thyroplasty with careful pre- and postoperative management is safe in patients undergoing antithrombotic therapy.

Long-term effectiveness, safety, and quality of life outcomes following endoscopic posterior nasal neurectomy with submucosal turbinectomy for the treatment of intractable severe chronic rhinitis.

OBJECTIVE: In recent decades, posterior nasal neurectomy (PNN) with submucosal inferior turbinectomy (ST) has been increasingly used for the treatment of intractable severe rhinitis; however, to the best of our knowledge, there have been few studies regarding its long-term therapeutic effects or its influence on patient quality of life (QOL). Therefore, this study examined the long-term therapeutic effects in patients who underwent PNN with ST, as well as their QOL and medication use after surgery. METHODS: This retrospective cohort study initially included 16 consecutive patients who underwent PNN with ST from January 2010 to December 2011. Ten of the 16 patients participated in a paper-based survey questionnaire between June 2018 and November 2018; the responses of these 10 patients were used for analysis in this study. To clarify the effects of surgical treatment on symptoms, QOL, and medication status, data recorded before and 3 months after surgery were compared with data recorded at 8 years after surgery using the Japan Rhinoconjunctivitis Quality of Life Questionnaire No. 1 and Classification of the Severity of Allergic Rhinitis Symptoms I and II. RESULTS: Nasal symptoms including runny nose and nasal congestion, medication score, respective total symptoms medication scores (i.e., combined average total symptoms score and medication score), and the scores of troubles with daily life and total QOL were significantly improved at 3 months and 8 years after surgery, compared with before surgery; scores were not significantly worsened at 8 years after surgery, compared with 3 months after surgery. In addition, there were no adverse events requiring treatment after surgery. CONCLUSION: Our findings suggest that PNN with ST is effective and safe for long-term treatment of severe chronic rhinitis symptoms, as well as reduction of medication use and improvement of QOL.

Awareness of stuttering in Japanese children aged 3-7 years.

BACKGROUND: Boey et al. (2009) devised a questionnaire for measuring children's awareness of stuttering and showed that even very young children were often aware of their stuttering. There has been no replication of studies using Boey et al.'s parent-reported questionnaire. The aim of this study was to test whether using Boey et al.'s seven questions, developed for a Dutch speaking population could be effective for measuring the awareness of stuttering in Japanese children. METHODS: Participants were 54 children who stutter (CWS) aged 3-7 years. Parents answered seven questions about their child's awareness of stuttering according to the questions developed Boey et al. RESULTS: Parental-reported observations of the child responses citing at least one awareness incident were 76%. The percentage of stuttering children with awareness of their own speech difficulties, according to chronological age, were as follows: 70% at age 3 years; 67% at age 4 years; 75% at age 5 years; 81% at age 6 years; and 90% at age 7 years. CONCLUSIONS: We found that even at age 3 years, many CWS were already aware of their stuttering. The similarity of the data with the seminal study by Boey et al. suggests that the question-based assessment is reproducible even in a country with a different spoken language. The seven questions in Boey et al. are useful for evaluating whether children's awareness of stuttering could contribute to a clinical decision as well as stuttering severity.

Tracheoesophageal diversion improves oral uptake of food: a retrospective study.

PURPOSE: Tracheoesophageal diversion (TED) is an effective therapeutic procedure for intractable aspiration. In this study, we performed TED in cases of intractable aspiration and/or repetitive pneumonia, investigated the main route of nutritional uptake after the procedure, and evaluated the swallowing method using videofluoroscopy. We also evaluated the validity of TED for treating intractable aspiration. METHODS: We retrospectively reviewed 44 patients (30 male and 14 female patients; median age, 55 years; range 15-85 years) who underwent TED for the treatment of intractable aspiration between January 2008 and December 2017. We examined the route of nutritional uptake before and after the operation and performed videofluoroscopy to detect the swallowing method after the operation. RESULTS: The percentage of patients with oral intake increased from 21% (9/44) before TED to 56% (25/44) within 1 month after TED (p < 0.01); this percentage included patients with poor preoperative swallowing function. Overall, 60% patients who were able to communicate and mobilize using a wheelchair as well as 92% patients who were able to communicate and mobilize in the supine position were able to consume food orally. We subsequently performed videofluoroscopy in 24 of the 25 patients with oral intake and assessed the passage route of the contrast agent, which was found to move through the laryngeal route in 54% of these patients. CONCLUSION: TED may be suitable for the treatment of intractable aspiration and can improve oral intake, particularly in patients with good mobility and communication ability.

Altered neural synchronization to pure tone stimulation in patients with mesial temporal lobe epilepsy: An MEG study.

OBJECTIVE: Our previous study of monaural auditory evoked magnetic fields (AEFs) demonstrated that hippocampal sclerosis significantly modulated auditory processing in patients with mesial temporal lobe epilepsy (mTLE). However, the small sample size (n = 17) and focus on the M100 response were insufficient to elucidate the lateralization of the epileptic focus. Therefore, we increased the number of patients with mTLE (n = 39) to examine whether neural synchronization induced by monaural pure tone stimulation provides useful diagnostic information about epileptic foci in patients with unilateral mTLE. METHODS: Twenty-five patients with left mTLE, 14 patients with right mTLE, and 32 healthy controls (HCs) were recruited. Auditory stimuli of 500-Hz tone burst were monaurally presented to subjects. The AEF data were analyzed with source estimation of M100 responses in bilateral auditory cortices (ACs). Neural synchronization within ACs and between ACs was evaluated with phase-locking factor (PLF) and phase-locking value (PLV), respectively. Linear discriminant analysis was performed for diagnosis and lateralization of epileptic focus. RESULTS: The M100 amplitude revealed that patients with right mTLE exhibited smaller M100 amplitude than patients with left mTLE and HCs. Interestingly, PLF was able to differentiate the groups with mTLE, with decreased PLFs in the alpha band observed in patients with right mTLE compared with those (PLFs) in patients with left mTLE. Right hemispheric predominance was confirmed in both HCs and patients with left mTLE while patients with right mTLE showed a lack of right hemispheric predominance. Functional connectivity between bilateral ACs (PLV) was reduced in both patients with right and left mTLE compared with that of HCs. The accuracy of diagnosis and lateralization was 80%-90%. CONCLUSION: Auditory cortex subnormal function was more pronounced in patients with right mTLE compared with that in patients with left mTLE as well as HCs. Monaural AEFs can be used to reveal the pathophysiology of mTLE. Overall, our results indicate that altered neural synchronization may provide useful information about possible functional deterioration in patients with unilateral mTLE.

A case of multiple system atrophy-parkinsonian type with stuttering- and palilalia-like dysfluencies and putaminal atrophy.

Both developmental and acquired stuttering are related to the function of the basal ganglia-thalamocortical loop, which includes the putamen. Here, we present a case of stuttering- and palilalia-like dysfluencies that manifested as an early symptom of multiple system atrophy-parkinsonian type (MSA-P) and bilateral atrophy of the putamen. The patient was a 72-year-old man with no history of developmental stuttering who presented with a stutter for consultation with our otorhinolaryngology department. The patient was diagnosed with MSA-P based on parkinsonism, autonomic dysfunction, and bilateral putaminal atrophy revealed by T2-weighted magnetic resonance imaging. Treatment with levodopa improved both the motor functional deficits related to MSA-P and stuttering-like dysfluencies while reading; however, the palilalia-like dysfluencies were much less responsive to levodopa therapy. The patient died of aspiration pneumonia two years after his first consultation at our hospital. In conclusion, adult-onset stuttering- and palilalia-like dysfluencies warrant careful examination of the basal ganglia-thalamocortical loop, and especially the putamen, using neuroimaging techniques. Acquired stuttering may be related to deficits in dopaminergic function.

Kinematic evaluation of penetration and aspiration in laryngeal elevating and descending periods.

OBJECTIVES: It is important to evaluate swallowing movements by dividing them into periods of laryngeal closure and release. The purpose of this study was to evaluate penetration-aspiration (PA) according to human pathophysiology and to identify the factors for predicting PA. STUDY DESIGN: Case-control study. METHODS: Eighty-one patients with complaints of dysphagia caused by various etiologies were enrolled in this study. Videofluoroscopic swallowing studies were conducted, and the spatial and temporal factors were analyzed by computer-assisted motion analysis. RESULTS: The initiation of laryngeal vestibule closure in the laryngeal elevating period and its duration in the laryngeal descending period were significant factors for evaluating PA. CONCLUSION: A knowledge of the delay of laryngeal vestibule closure in the laryngeal elevating period and its short duration in the laryngeal descending period could make it easier to evaluate the risk of PA. LEVEL OF EVIDENCE: 3b. Laryngoscope, 128:806-811, 2018.

Videoendoscopy worsens swallowing function: a videofluoroscopic study. A randomized controlled trial.

Aspiration pneumonia is a cause of mortality in the elderly. Evaluating swallowing function is important. Videofluoroscopy and flexible endoscopic evaluation of swallowing are comparable; however, observing all swallowing dynamics is impossible using the latter approach. We examined the significance of flexible endoscopic evaluation of swallowing using videofluoroscopy. Thirty-seven patients with dysphagia [70.0 ± 8.9 (range 49-84) years] were included. In random order, patients underwent videofluoroscopy with 10 cc contrast material, once without, and once with an endoscope inserted. Laryngeal elevation delay time, Penetration-Aspiration Scale score, and Pharyngeal Residue Severity Rating Scale score were evaluated. Laryngeal elevation delay time without or with endoscope insertion was similar (0.35 ± 0.16 s vs. 0.36 ± 0.16 s, P = 0.29). The Penetration-Aspiration Scale (3.59 ± 2.71 vs. 4.41 ± 2.85; P < 0.001) and Pharyngeal Residue Severity Rating Scale (0.97 ± 0.93 vs. 1.46 ± 1.10; P < 0.001) scores differed significantly. The cases that showed no aspiration without endoscope insertion showed greater aspiration with endoscope insertion, and the cases that did not show aspiration with an endoscope inserted also showed no aspiration without an endoscope. Flexible endoscopic insertion resulted in more severe aspiration and residue than non-insertion, as assessed using videofluoroscopy.

Abnormal auditory synchronization in stuttering: A magnetoencephalographic study.

In a previous magnetoencephalographic study, we showed both functional and structural reorganization of the right auditory cortex and impaired left auditory cortex function in people who stutter (PWS). In the present work, we reevaluated the same dataset to further investigate how the right and left auditory cortices interact to compensate for stuttering. We evaluated bilateral N100m latencies as well as indices of local and inter-hemispheric phase synchronization of the auditory cortices. The left N100m latency was significantly prolonged relative to the right N100m latency in PWS, while healthy control participants did not show any inter-hemispheric differences in latency. A phase-locking factor (PLF) analysis, which indicates the degree of local phase synchronization, demonstrated enhanced alpha-band synchrony in the right auditory area of PWS. A phase-locking value (PLV) analysis of inter-hemispheric synchronization demonstrated significant elevations in the beta band between the right and left auditory cortices in PWS. In addition, right PLF and PLVs were positively correlated with stuttering frequency in PWS. Taken together, our data suggest that increased right hemispheric local phase synchronization and increased inter-hemispheric phase synchronization are electrophysiological correlates of a compensatory mechanism for impaired left auditory processing in PWS.

Spatiotemporal signatures of an abnormal auditory system in stuttering.

People who stutter (PWS) can reduce their stuttering rates under masking noise and altered auditory feedback; such a response can be attributed to altered auditory input, which suggests that abnormal speech processing in PWS results from abnormal processing of auditory input. However, the details of this abnormal processing of basic auditory information remain unclear. In order to characterize such abnormalities, we examined the functional and structural changes in the auditory cortices of PWS by using a 306-channel magnetoencephalography system to assess auditory sensory gating (P50m suppression) and tonotopic organization. Additionally, we employed voxel-based morphometry to compare cortical gray matter (GM) volumes on structural MR images. PWS exhibited impaired left auditory sensory gating. The tonotopic organization in the right hemisphere of PWS is expanded compared with that of the controls. Furthermore, PWS showed a significant increase in the GM volume of the right superior temporal gyrus, consistent with the right tonotopic expansion. Accordingly, we suggest that PWS have impaired left auditory sensory gating during basic auditory input processing and that some error signals in the auditory cortex could result in abnormal speech processing. Functional and structural reorganization of the right auditory cortex appears to be a compensatory mechanism for impaired left auditory cortex function in PWS.