[Research progress in targeted delivery of inner ear using nanocarriers].

Various inner ear diseases such as sensorineural deafness and Meniere's disease bring about problems such as speech communication disorders and decreased work efficiency, which seriously affect the life quality of patients. Due to the special anatomical structure and blood-labyrinth barrier in the inner ear, the current drug administration methods are often unable to achieve satisfactory results. Nanocarriers are the forefront and hot spot of nanotechnology research. In recent years, a lot of research progress has been made in the field of targeted delivery of the inner ear, which is expected to be eventually applied to the treatment of clinical diseases of the inner ear. This review focuses on the advantages, main research achievements and limitations of various nanocarriers in the targeted delivery of the inner ear, hoping to provide new ideas for related research.

Low-sodium diet with adequate water intake improved the clinical efficacy in Ménière's disease.

BACKGROUND: Ménière's disease (MD) is a common idiopathic inner ear disorder in otorhinolaryngology characterized by recurrent episodes of vertigo, fluctuating sensorineural hearing loss, tinnitus and ear fullness. OBJECTIVE: To study the effects of low-sodium diet with adequate water intake on the clinical efficacy in MD. METHODS: Fifty patients diagnosed with stage-3 unilateral MD were randomly divided into control group(n = 25) and experimental group(n = 25). The control group was given routine medication therapy, and the experimental group was restricted to an sodium intake of 1500 mg/d and a water intake of 35 ml/kg/d based in addition to the routine medication therapy. The two groups were assessed using pure tone audiometry, electrocochleography, Tinnitus Handicap Inventory (THI), and Dizziness Handicap Inventory (DHI). RESULTS: The pure tone audiometry and electrocochleography showed better improvements after treatment in the experimental group than the control group (p < 0.05). The THI improved values in the experimental group were significantly higher than the control group (p < 0.001). The DHI improved values in the experimental group were significantly higher than the control group (p = 0.004). CONCLUSIONS AND SIGNIFICANCE: Low-sodium diet with adequate water intake improved the hearing and alleviated vertigo and tinnitus in MD patients.

Enhancing the therapeutic potential of intravenous glycerol for Meniere's disease: Robust results from an extensive patient cohort.

INTRODUCTION: Meniere's disease (MD) is an idiopatic condition characterized by recurrent attacks of vertigo, hearing loss, tinnitus, and aural fullness, affecting quality of life. Intravenous glycerol has shown potential as a therapeutic option. This study evaluates its efficacy in a larger patient cohort. MATERIALS AND METHODS: Retrospective study with 168 patients having unilateral MD unresponsive to dietary restrictions. Intravenous 10 % glycerol with 0.9 % sodium chloride was administered for six months. Audio-vestibular assessments and questionnaires were used. RESULTS: Significant improvements in vertigo control observed. 7.1 % achieved complete control, and 58.3 % had substantial control. Quality of life measures improved, and audiometry thresholds remained unchanged. No major adverse events reported. DISCUSSION: Intravenous glycerol effectively controlled vertigo and improved MD patients' quality of life. Limitations include lack of a control group and a relatively short-term follow-up. Future prospects include randomized controlled trials and optimization of treatment protocols. CONCLUSION: Intravenous glycerol shows promise as a therapeutic option for MD, with notable improvements in vertigo control and quality of life. Further research is needed for validation and optimization.

Efficacy and preservation of hearing with low-dose gentamicin in unilateral meniere's disease: A clinical symptomatology-based study.

PURPOSE: Meniere's disease (MD), a disorder of the inner ear, presents numerous therapeutic challenges, and intratympanic (IT) gentamicin has been proposed for intractable cases. However, controversy regarding dosage and method persists. The purpose of this study was to assess the efficacy and safety of low-dose IT gentamicin on vertigo attacks in MD using a clinical symptomatology-based method, wherein administration was repeated only if vertigo attacks recurred, with a 2-week interval between injections. MATERIALS AND METHODS: This study included 88 patients with unilateral intractable MD. All patients received one to five IT injections with 0.5 ml of 10 mg of gentamicin (80 mg/2 ml) with an interval of 2 weeks between injections. Vertigo attacks were evaluated before and after therapy and categorized into classes A-F according to the 2015 Equilibrium Committee criteria. Audiovestibular assessments, including Pure Tone Audiometry and Vestibulo-Ocular Reflex evaluations, were performed. RESULTS: Before treatment, patients had an average of 4.4 vertigo attacks/month; after treatment, this average decreased to 0.52. The majority of patients (57 %) reached Class A or B vertigo control with five or fewer gentamicin injections. VOR gain was slightly affected on the healthy side and significantly reduced on the affected side. No hearing deterioration was found in any of the treated patients. CONCLUSIONS: Low-dose IT gentamicin administration based on clinical symptomatology can produce a satisfactory control of vertigo attacks after treatment. This protocol primarily affected the vestibular function, as demonstrated by the significant reduction in VOR gain on the affected side, while avoiding cochlear damage. The lack of adverse events and preservation of hearing underscore the safety and efficacy of this method. These findings have significant clinical implications, suggesting that a low-dose, clinical symptomatology-based gentamicin treatment regimen could be an effective and safe strategy for managing unilateral Meniere's disease in a larger population.

Placebo effect in randomized controlled trials for Meniere's disease: A meta-analysis.

PURPOSE: Meniere's Disease is a condition known for its recurrent vertigo, fluctuating sensorineural hearing loss, aural fullness, and tinnitus. Previous studies have demonstrated significant influence of placebo treatments. Our objective was to quantify the magnitude of the placebo effect in randomized controlled trials for Meniere's Disease. MATERIALS AND METHODS: A systematic review was performed by searching PubMed, SCOPUS, CINAHL, and Cochrane databases from inception through September 27, 2022. Data extraction, quality rating, and risk of bias assessment were performed by two independent reviewers. A meta-analysis of mean differences with 95 % confidence interval, weighted summary proportions, and proportion differences were calculated using random and fixed effects models. RESULTS: A total of 15 studies (N = 892) were included in the review. Significant improvement was seen in the functional level scores of the pooled placebo groups, with a mean difference of -0.6 points, (95%CI: -1.2 to -0.1). There was no difference in pure tone audiometry, speech discrimination score, or vertigo frequency at 1 and 3 months for the placebo group. Patient-reported vertigo episodes were improved in 52.5 % (95%CI: 39.2 to 65.5) of the placebo group and was significantly less than the pooled experimental group (90.1 %, 95%CI: 39.2 to 65.5, p < 0.001). CONCLUSIONS: The placebo effect in Meniere's Disease trials is associated with some symptomatic improvement in subjective outcomes, such as patient reported vertigo episodes. However, the clinical significance is questionable across other outcomes measures, especially when analyzing objective data. The extent and strength of the placebo effect continues to be a hurdle in the search for better treatment options.

Associations Among Medical Therapy, SelfAdministered Exercise, and Characteristics of Ménière's Disease.

BACKGROUND: The aim of the current study was to explore the associations among different therapeutic procedures, self-administered exercise, and characteristics of Ménière's disease. METHODS: The study used a retrospective design and included 539 people with Ménière's disease who were focusing on self-administered exercise. The mean age and history of Ménière's disease among these participants were 61.9 years and 15.6 years, respectively. Of the participants, 79.5% were female. The data were collected by an electronic questionnaire that focused on symptoms of Ménière's disease, exercise and training habits, balance problems, impacts of the complaints, quality of life, medical treatment, physiotherapy, and psychotherapy. RESULTS: Of the participants, 79.3% used medical treatment. Betahistine (56.8%) was the most popular followed by periodical anti-emetic use (41.0%) and diuretics (22.4%). Of the participants 70% were doing some self-administered training. The frequency of training depended on age, severity of balance problems, vestibular drop attacks, and gait problems. The type of training depended on age, quality of life, vestibular drop attacks, and gait problems. No association was found between vertigo and frequency/type of balance training. CONCLUSION: The use or effect of therapeutic procedures for Ménière's disease patients was not related to symptoms experienced. Most participants with Ménière's disease used training programs that aimed to alleviate their condition, especially balance-, gait-, and vestibular drop attack-associated problems. Patient support organizations should be working to help characterize the types of balance disorders people are dealing with in order to individually tailor a rehabilitation program to the patient's needs.

Efficacy of Intratympanic OTO-104 for the Treatment of Ménière's Disease: The Outcome of Three Randomized, Double-Blind, Placebo-Controlled Studies.

OBJECTIVE: To determine the efficacy of intratympanic OTO-104 for the treatment of Ménière's disease. STUDY DESIGNS: Three randomized, double-blind, placebo-controlled, multicenter studies of OTO-104 in patients with Ménière's disease. SETTING: The United States and throughout Europe. PATIENTS: Individuals with Ménière's disease aged 18 to 85 years. INTERVENTIONS: All three studies were conducted according to a similar protocol, whereby after a 1-month lead-in period, eligible patients received a single intratympanic injection of either 12 mg OTO-104 (otic formulation of dexamethasone in thermosensitive poloxamer) or placebo (1:1) and were observed for 3 months. MAIN OUTCOME MEASURES: The primary efficacy endpoint was measured by the number of definitive vertigo days (DVDs) at month 3. Secondary objective was OTO-104 safety and tolerability including adverse events, audiometry, tympanometry, and otoscopic examinations. RESULTS: Although OTO-104 demonstrated numerically greater reductions in DVD compared with placebo across all three studies, statistical significance versus placebo (primary efficacy endpoint) was only achieved in one study, the AVERTS-2 study (n = 174, p = 0.029). Secondary vertigo efficacy endpoints were statistically significant at month 3 in that study including vertigo severity, the effect of vertigo on daily activity (days at home sick or bedridden), and vertigo frequency. In the AVERTS-1 study, which did not meet the primary endpoint, a subgroup analysis of the 115 patients (69.7% of study population) who did not previously receive intratympanic steroid injections demonstrated that OTO-104 patients had significantly lower mean DVD at month 3 than patients receiving placebo (1.9 for OTO-104 versus 3.0 for placebo; p = 0.045). Importantly, a significant placebo response was observed across studies in Ménière's disease patients. OTO-104 and the intratympanic injection procedure were well tolerated. CONCLUSIONS: In all three high-quality, randomized, double-blind, placebo-controlled, multicenter studies, a single intratympanic injection of 12 mg OTO-104 demonstrated numerically greater reductions in vertigo versus placebo in patients with Ménière's disease, but statistical separation from placebo was demonstrated in only one of the studies. OTO-104 was safe and well tolerated.(Otonomy, Inc. funded; NCT02717442, NCT02612337, NCT03664674).

Betahistine Prescribing Practices in England: An Analysis of Prescribing and National Spending Pre- and Post-BEMED Trial.

OBJECTIVE: Betahistine has not been proven to be superior to placebo in the BEMED study, a multicenter, double-blind, randomized, placebo controlled trial. Our study aimed to establish the prescribing practices of clinicians in England in relation to betahistine and to assess if there has been any change in prescribing practices since the publication of the BEMED trial. STUDY DESIGN: Retrospective study and clinician survey. PATIENTS: All patients who were prescribed betahistine from primary care. MAIN OUTCOME MEASURE: Total quantity of betahistine prescribed and total actual cost. RESULTS: The average total monthly quantity prescribed was 11,143,253 tablets (range, 10,056,516-12,276,423). Prescribing did not decrease from the period before (January 2014-February 2016) to after (February 2016-February 2021) the publication of the BEMED trial, with the average monthly prescribing before publication being 11,294,848 tablets (range, 10,280,942- 12,276,423) and the average monthly prescribing after publication being 11,081,123 tablets (range, 10,056,516-11,915,707). The average actual monthly cost increased from the period before publication to after publication from a sum of £279,264.82 to a sum of £428,846.22. Most (90.5%) of the survey respondents prescribed betahistine for Menière's disease. Less than half (38.09%) prescribed betahistine for indications other than Menière's disease. Only 45.24% of the clinicians were aware of the results of the BEMED trial. CONCLUSIONS: Knowledge of the BEMED trial among otology and neurotology subspecialists is lacking. The results of the BEMED have made no difference to prescribing practice, and in fact, the cost of the medication to the health bill has increased.

Evaluation of changes in endolymphatic hydrops volume after medical treatments for Meniere's disease using 3D magnetic resonance imaging.

OBJECTIVE: To elucidate the relationship between vertigo and EH volume after medical treatment, we investigated changes in endolymphatic hydrops (EH) volume using inner ear magnetic resonance imaging (ieMRI) in relation to clinical results for vertigo and hearing after administration of the anti-vertiginous medications betahistine, adenosine triphosphate (ATP), isosorbide (ISO), and saireito (SAI) for Meniere's disease (MD). METHODS: We retrospectively enrolled 202 consecutive patients diagnosed with unilateral MD from 2015 to 2021 and assigned them to four groups: Group I (G-I), symptomatic oral medication with betahistine only (CONT); Group II (G-II), inner ear vasoactive oral medication (ATP); Group III (G-III), osmotic diuretic oral medication (ISO); and Group IV (G-IV), kampo oral medication (SAI). In total, 172 patients completed the planned one-year-follow-up, which included the assessment of vertigo frequency, hearing improvement, and changes in EH using ieMRI (G-I, n=40; G-II, n=42; G-III, n=44; G-IV, n=46). We constructed 3D MRI images semi-automatically and fused the 3D images of the total fluid space (TFS) of the inner ear and endolymphatic space (ELS). After fusing the images, we calculated the volume ratios of the TFS and ELS (ELS ratios). RESULTS: One year after treatment, vertigo was controlled with zero episodes per month in 57.5% (23/40) of patients in G-I, 78.6% (33/42) in G-II, 81.8% (36/44) in G-III, and 82.6% (38/46) in G-IV (statistical significance: G-I 10 dB in 5.0% (2/40) of patients in G-I, 16.7% (7/42) in G-II, 18.2% (8/44) in G-III, and 21.7% (10/46) in G-IV (statistical significance: G-I=G-II=G-III=G-IV). ELS ratios were significantly reduced after treatment only in the vestibule for G-II, G-III, and G-IV when compared with G-I. Especially among patients with complete control of vertigo after treatment, ELS ratios were significantly reduced after treatment in the vestibule and total inner ear for G-II; in the cochlea, vestibule, and total inner ear for G-III; and in the cochlea, vestibule, and total inner ear for G-IV compared with G-I. However, there were no significant findings in the relationship between hearing results and changes in ELS ratios. CONCLUSION: These results indicate that daily administration of anti-vertiginous medications including ATP, ISO, and SAI could be an effective treatment option for patients with MD at an early stage before it becomes intractable. Treatments to reduce EH might offer better control of vertigo rather than improve hearing.

Intratympanic gentamicin for Ménière's disease.

BACKGROUND: Ménière's disease is a condition that causes recurrent episodes of vertigo, associated with hearing loss and tinnitus. Aminoglycosides are sometimes administered directly into the middle ear to treat this condition. The aim of this treatment is to partially or completely destroy the balance function of the affected ear. The efficacy of this intervention in preventing vertigo attacks, and their associated symptoms, is currently unclear. OBJECTIVES: To evaluate the benefits and harms of intratympanic aminoglycosides versus placebo or no treatment in people with Ménière's disease. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 14 September 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs in adults with a diagnosis of Ménière's disease comparing intratympanic aminoglycosides with either placebo or no treatment. We excluded studies with follow-up of less than three months, or with a cross-over design (unless data from the first phase of the study could be identified).  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were: 1) improvement in vertigo (assessed as a dichotomous outcome - improved or not improved), 2) change in vertigo (assessed as a continuous outcome, with a score on a numerical scale) and 3) serious adverse events. Our secondary outcomes were: 4) disease-specific health-related quality of life, 5) change in hearing, 6) change in tinnitus and 7) other adverse effects. We considered outcomes reported at three time points: 3 to < 6 months, 6 to ≤ 12 months and > 12 months. We used GRADE to assess the certainty of evidence for each outcome.  MAIN RESULTS: We included five RCTs with a total of 137 participants. All studies compared the use of gentamicin to either placebo or no treatment. Due to the very small numbers of participants in these trials, and concerns over the conduct and reporting of some studies, we considered all the evidence in this review to be very low-certainty.  Improvement in vertigo This outcome was assessed by only two studies, and they used different time periods for reporting. Improvement in vertigo was reported by more participants who received gentamicin at both 6 to ≤ 12 months (16/16 participants who received gentamicin, compared to 0/16 participants with no intervention; risk ratio (RR) 33.00, 95% confidence interval (CI) 2.15 to 507; 1 study; 32 participants; very low-certainty evidence) and at > 12 months follow-up (12/12 participants receiving gentamicin, compared to 6/10 participants receiving placebo; RR 1.63, 95% CI 0.98 to 2.69; 1 study; 22 participants; very low-certainty evidence). However, we were unable to conduct any meta-analysis for this outcome, the certainty of the evidence was very low and we cannot draw any meaningful conclusions from the results.  Change in vertigo Again, two studies assessed this outcome, but used different methods of measuring vertigo and assessed the outcome at different time points. We were therefore unable to carry out any meta-analysis or draw any meaningful conclusions from the results. Global scores of vertigo were lower for those who received gentamicin at both 6 to ≤ 12 months (mean difference (MD) -1 point, 95% CI -1.68 to -0.32; 1 study; 26 participants; very low-certainty evidence; four-point scale; minimally clinically important difference presumed to be one point) and at > 12 months (MD -1.8 points, 95% CI -2.49 to -1.11; 1 study; 26 participants; very low-certainty evidence). Vertigo frequency was also lower at > 12 months for those who received gentamicin (0 attacks per year in participants receiving gentamicin compared to 11 attacks per year for those receiving placebo; 1 study; 22 participants; very low-certainty evidence).  Serious adverse events None of the included studies provided information on the total number of participants who experienced a serious adverse event. It is unclear whether this is because no adverse events occurred, or because they were not assessed or reported.  AUTHORS' CONCLUSIONS: The evidence for the use of intratympanic gentamicin in the treatment of Ménière's disease is very uncertain. This is primarily due to the fact that there are few published RCTs in this area, and all the studies we identified enrolled a very small number of participants. As the studies assessed different outcomes, using different methods, and reported at different time points, we were not able to pool the results to obtain more reliable estimates of the efficacy of this treatment. More people may report an improvement in vertigo following gentamicin treatment, and scores of vertigo symptoms may also improve. However, the limitations of the evidence mean that we cannot be sure of these effects. Although there is the potential for intratympanic gentamicin to cause harm (for example, hearing loss) we did not find any information about the risks of treatment in this review.  Consensus on the appropriate outcomes to measure in studies of Ménière's disease is needed (i.e. a core outcome set) in order to guide future studies in this area and enable meta-analysis of the results. This must include appropriate consideration of the potential harms of treatment, as well as the benefits.

Intratympanic corticosteroids for Ménière's disease.

BACKGROUND: Ménière's disease is a condition that causes recurrent episodes of vertigo, associated with hearing loss and tinnitus. Corticosteroids are sometimes administered directly into the middle ear to treat this condition (through the tympanic membrane). The underlying cause of Ménière's disease is unknown, as is the way in which this treatment may work. The efficacy of this intervention in preventing vertigo attacks, and their associated symptoms, is currently unclear. OBJECTIVES: To evaluate the benefits and harms of intratympanic corticosteroids versus placebo or no treatment in people with Ménière's disease. SEARCH METHODS: The Cochrane ENT Information Specialist searched the Cochrane ENT Register; Central Register of Controlled Trials (CENTRAL); Ovid MEDLINE; Ovid Embase; Web of Science; ClinicalTrials.gov; ICTRP and additional sources for published and unpublished trials. The date of the search was 14 September 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs in adults with a diagnosis of Ménière's disease comparing intratympanic corticosteroids with either placebo or no treatment. We excluded studies with follow-up of less than three months, or with a cross-over design (unless data from the first phase of the study could be identified).  DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were: 1) improvement in vertigo (assessed as a dichotomous outcome - improved or not improved), 2) change in vertigo (assessed as a continuous outcome, with a score on a numerical scale) and 3) serious adverse events. Our secondary outcomes were: 4) disease-specific health-related quality of life, 5) change in hearing, 6) change in tinnitus and 7) other adverse effects (including tympanic membrane perforation). We considered outcomes reported at three time points: 3 to < 6 months, 6 to ≤ 12 months and > 12 months. We used GRADE to assess the certainty of evidence for each outcome.  MAIN RESULTS: We included 10 studies with a total of 952 participants. All studies used the corticosteroid dexamethasone, with doses ranging from approximately 2 mg to 12 mg.  Improvement in vertigo Intratympanic corticosteroids may make little or no difference to the number of people who report an improvement in their vertigo at 6 to ≤ 12 months follow-up (intratympanic corticosteroids 96.8%, placebo 96.6%, risk ratio (RR) 1.00, 95% confidence interval (CI) 0.92 to 1.10; 2 studies; 60 participants; low-certainty evidence) or at more than 12 months follow-up (intratympanic corticosteroids 100%, placebo 96.3%; RR 1.03, 95% CI 0.87 to 1.23; 2 studies; 58 participants; low-certainty evidence). However, we note the large improvement in the placebo group for these trials, which causes challenges in interpreting these results.  Change in vertigo Assessed with a global score One study (44 participants) assessed the change in vertigo at 3 to < 6 months using a global score, which considered the frequency, duration and severity of vertigo. This is a single, small study and the certainty of the evidence was very low. We are unable to draw meaningful conclusions from the numerical results. Assessed by frequency of vertigo Three studies (304 participants) assessed the change in frequency of vertigo episodes at 3 to < 6 months. Intratympanic corticosteroids may slightly reduce the frequency of vertigo episodes. The proportion of days affected by vertigo was 0.05 lower (absolute difference -5%) in those receiving intratympanic corticosteroids (95% CI -0.07 to -0.02; 3 studies; 472 participants; low-certainty evidence). This is equivalent to a difference of approximately 1.5 days fewer per month affected by vertigo in the corticosteroid group (with the control group having vertigo on approximately 2.5 to 3.5 days per month at the end of follow-up, and those receiving corticosteroids having vertigo on approximately 1 to 2 days per month). However, this result should be interpreted with caution - we are aware of unpublished data at this time point in which corticosteroids failed to show a benefit over placebo. One study also assessed the change in frequency of vertigo at 6 to ≤ 12 months and > 12 months follow-up. However, this is a single, small study and the certainty of the evidence was very low. Therefore, we are unable to draw meaningful conclusions from the numerical results. Serious adverse events Four studies reported this outcome. There may be little or no effect on the occurrence of serious adverse events with intratympanic corticosteroids, but the evidence is very uncertain (intratympanic corticosteroids 3.0%, placebo 4.4%; RR 0.64, 95% CI 0.22 to 1.85; 4 studies; 500 participants; very low-certainty evidence). AUTHORS' CONCLUSIONS: The evidence for intratympanic corticosteroids in the treatment of Ménière's disease is uncertain. There are relatively few published RCTs, which all consider the same type of corticosteroid (dexamethasone). We also have concerns about publication bias in this area, with the identification of two large RCTs that remain unpublished. The evidence comparing intratympanic corticosteroids to placebo or no treatment is therefore all low- or very low-certainty. This means that we have very low confidence that the effects reported are accurate estimates of the true effect of these interventions. Consensus on the appropriate outcomes to measure in studies of Ménière's disease is needed (i.e. a core outcome set) in order to guide future studies in this area, and enable meta-analysis of the results. This must include appropriate consideration of the potential harms of treatment, as well as the benefits. Finally, we would also highlight the responsibility that trialists have to ensure results are available, regardless of the outcome of their study.

Low Dose Betahistine in Combination With Selegiline Increases Cochlear Blood Flow in Guinea Pigs.

OBJECTIVE: Betahistine is frequently used in the pharmacotherapy for Menière's Disease (MD). Little is known about its mode of action and prescribed dosages vary. While betahistine had an increasing effect on cochlear microcirculation in earlier studies, low dose betahistine of 0.01 mg/kg bw or less was not able to effect this. Selegiline inhibits monoaminooxidase B and therefore potentially the breakdown of betahistine. The goal of this study was to examine whether the addition of selegiline to low dose betahistine leads to increased cochlear blood flow. METHODS: Twelve Dunkin-Hartley guinea pigs were anesthetized, the cochlea was exposed and a window opened to the stria vascularis. Blood plasma was visualized by injecting fluoresceinisothiocyanate-dextrane and vessel diameter and erythrocyte velocity were evaluated over 20 minutes. One group received low dose betahistine (0.01 mg/kg bw) and selegiline (1 mg/kg bw) i.v. while the other group received only selegiline (1 mg/kg bw) and saline (0.9% NaCl) as placebo i.v. RESULTS: Cochlear microcirculation increased significantly (P < .001) in guinea pigs treated with low dose betahistine combined with selegiline by up to 58.3 ± 38.7% above baseline over a period of up to 11 minutes. In one guinea pig, the increase was 104.6%. Treatment with Selegiline alone did not affect microcirculation significantly. CONCLUSIONS: Low dose betahistine increased cochlear microcirculation significantly when combined with selegiline. This should be investigated in further studies regarding dose-effect relation in comparison to betahistine alone. Side effects, in particular regarding circulation, should be considered carefully in view of the clinical applicability of a combination therapy in patients with MD.

The role of serum osmolality in Meniere's disease with acute sensorineural hearing loss.

OBJECTIVE: This study investigated the role of serum osmolality in Meniere's disease (MD) patients with acute sensorineural hearing loss (SNHL). DESIGN: Retrospective study. STUDY SAMPLES: Twenty definite MD patients with acute unilateral SNHL were treated with an osmotic diuretic (Isosorbide, 100 mL daily) and assigned to Group A. Another 20 age- and sex-matched definite MD patients with acute SNHL were not given Isosorbide and assigned to Group B. Both groups underwent audiometry and blood examination for serum osmolality before and after treatment. RESULTS: Group A revealed a significant increase in serum osmolality after treatment. The optimal cut-off values for increased serum osmolality in Group A were +1.5 mOSM/L for predicting hearing improvement at frequencies of 250-1000 Hz, and +2.5 mOSM/L at 2000-4000 Hz. Comparing increased levels of serum osmolality (> +2.0 vs. ≤ +2.0 mOSM/L), Isosorbide dosing at 3.0 L vs. 1.0 L, significantly differed in the odds ratio (OR). Isosorbide at a total dosage of 3.0 L thus improves the hearing threshold by >10 dB at frequencies of 250-2000 Hz. CONCLUSION: The Isosorbide at a total dosage of 3.0 L may increase serum osmolality by > +2.0 mOSM/L, and improve the hearing threshold for hydropic ears at least >10 dB at low- and mid-frequencies.

Oral splint therapy in patients with Menière's disease and temporomandibular disorder: a long-term, controlled study.

PURPOSE: To assess the effect of oral splint therapy on audio-vestibular symptoms in patients with Menière's disease (MD) and temporomandibular disorder (TMD). METHODS: Retrospective case-control study. Treatment group: 37 patients with MD and TMD who received gnatological treatment. CONTROL GROUP: 26 patients with MD and TMD who had never received gnatological treatment. The number of vertigo spells in 6 months (primary endpoint), pure-tone audiometry average (PTA), MD stage, functional level, Dizziness handicap Index (DHI), Tinnitus handicap Index (THI) and Aural Fullness Scale (AFS) were compared at baseline and after 24 months according to groups. Analysis of Covariance was used to determine the treatment effect. RESULTS: Groups were comparable for demographic, clinical data, baseline PTAs and the number of vertigo spells. Analysis of covariance showed a significant effect of gnathological treatment on number of vertigo spells ([Formula: see text] = 0.258, p < 0.001), PTA ([Formula: see text] = 0.201, p < 0.001), MD stage ([Formula: see text] = 0.224, p < 0.001), functional level ([Formula: see text] = 0.424, p < 0.001), DHI ([Formula: see text] = 0.421, p < 0.001), THI ([Formula: see text] = 0.183, p < 0.001), but not for AFS ([Formula: see text] = 0.005, p = 0.582). The treatment group showed vertigo control of class A in 86.5% and class B in 13.5% of patients. In the control group, vertigo control was of class A in 19.2% of patients and class B in 11.5%, class C in 30.8%, class D in 11.5%, class E in 19.2% and class F in 7.7%. Classes of vertigo control differed significantly (X2 test, p < 0.001). CONCLUSIONS: Oral splint therapy could represent a viable treatment in patients with TMD and uncontrolled MD disease. The effects are maintained at least after 2 years.

Treatment of Meniere's disease by Multi-session Dexamethasone Injections.

BACKGROUND: Meniere's Disease (MD) is a complex and multifactorial inner ear problem characterized by episodic vertigo, unilateral sensori-neural hearing loss and tinnitus or fullness in the ear due to Endolymphatic hydrops. There are multiple treatment options available for this disease; from which cortisone therapy can be given in different routes and in different doses. OBJECTIVES: is to identify the successfulness of treatment of MD by multi-session intra-tympanic dexamethasone injection compared to the single-session method. METHOD: Interventional prospective study of study 70 cases of definite MD treated by 4 sessions of intra-tympanic injection weekly and compared to a control group of 66 cases of age matched patients with definite MD treated by the traditional single intra-tympanic injection. Patients In the study and the control group were observed for 6 months after the treatment for the development of any vertiginous attacks. RESULTS: only 3 patients in the study group and 30 patients in the control group failed to respond to treatment and developed vertigo in the period of 6 months after treatment. The difference between the success rate in the two groups was statistically highly significant. CONCLUSION: multi-session Intra-tympanic dexamethasone injection is superior to the single injection in control of vertigo in patients with definite MD.

[Consensus on intratympanic drug delivery for Menière's disease].

Objective:Intratympanic（IT） drug delivery receives attention due to its effectivity in treatment for Menière's disease（MD）. Due to the release of the consensuses and new evidence on IT drug delivery for MD have been published, the review with a view to supplementing the details of IT treatment of MD is indispensable. Methods:The literatures on IT injection for MD treatment over the last two decades are retrieved, International consensus（ICON） on treatment of Menière's disease（2018）, Clinical Practice Guideline（2020） and European Position statement on Diagnosis and Treatment of Menière's disease（2018） are taken into account for reference, and follow advice from experts from Europe, USA and China. Results:Experts agree on the following: ①The effectiveness of IT methylprednisolone（ITM） on vertigo control seems to be somewhat better than that of IT dexamethasone（ITD）, and ITM can restore hearing in some cases. ②Due to the ototoxicity of aminoglycosides, the application of intratympanic gentamicin（ITG） in MD patients with good hearing is conservative. However, some studies suggest that ITG with low doses has no significant effect on hearing, which needs to be further proved by clinical studies with high levels of evidence. ③Currently, generally accepted treatment endpoint of ITG is no vertigo attack in a 12-month period or a vestibular loss in objective tests in the affected ear. Conclusion:More studies with high level of evidence are needed to evaluate the drug type, efficacy, and therapeutic endpoint of IT therapy for MD.

Consensus on intratympanic drug delivery for Menière's disease.

PURPOSE: Intratympanic (IT) drug delivery receives attention due to its effectivity in treatment for Menière's disease (MD). Due to the release of the consensuses and new evidence on IT drug delivery for MD have been published, the review with a view to supplementing the details of IT treatment of MD is indispensable. METHODS: The literatures on IT injection for MD treatment over the last two decades are retrieved, International consensus (ICON) on treatment of Menière's disease (2018), Clinical Practice Guideline (2020) and European Position statement on Diagnosis and Treatment of Meniere's Disease (2018) are taken into account for reference, and follow advice from experts from Europe, USA and China. RESULTS: Experts agree on the following: (1) The effectiveness of IT methylprednisolone (ITM) on vertigo control seems to be somewhat better than that of IT dexamethasone (ITD), and ITM can restore hearing in some cases. (2) Due to the ototoxicity of aminoglycosides, the application of intratympanic gentamicin (ITG) in MD patients with good hearing is conservative. However, some studies suggest that ITG with low doses has no significant effect on hearing, which needs to be further proved by clinical studies with high levels of evidence. (3) Currently, generally accepted treatment endpoint of ITG is no vertigo attack in a 12-month period or a vestibular loss in objective tests in the affected ear. CONCLUSION: More studies with high level of evidence are needed to evaluate the drug type, efficacy, and therapeutic endpoint of IT therapy for MD.

Duration of symptom control following intratympanic dexamethasone injections in Meniere's disease.

PURPOSE: Intratympanic (IT) injections of corticosteroids have emerged as a non-ablative alternative to gentamicin in the management of refractory Meniere's disease. However, currently, the duration of the symptom control achieved via intratympanic corticosteroids is under reported. METHODS: We retrospectively reviewed the notes of all patients who underwent IT injections of dexamethasone for the treatment of definite Meniere's disease at a single tertiary referral university centre over a 6-year period. We included demographic information, the number of procedures patients required, duration of symptom-control achieved (time interval between repeat IT injections), and the presence of co-morbidities, with a focus on the presence of autoimmune disease. RESULTS: We identified 27 patients who underwent a total of 42 procedures; 23/27 (85.2%) patients demonstrated clinical response with a median period of symptom control of 14.5 months (range 1-64, IQR 10.25). The median longest asymptomatic period per patient was 19 months (range 11-64, IQR: 18). Interestingly, all patients with autoimmune disease (7/27) demonstrated a clinical response; autoimmune disease was found to be a statistically significant predictor of response to treatment (p = 0.002). In patients who received repeated treatment following disease relapse, there was no difference in duration of symptom-control achieved. CONCLUSIONS: IT steroids can provide an effective alternative to gentamicin ablation. Symptom control is achieved for a median of 14.5 months, and treatment can be repeated with no loss of efficacy. Those patients who have an underlying autoimmune co-morbidity are more likely to demonstrate a clinical response to therapy, which may provide insight into the underlying pathophysiology of Meniere's disease.

A Perspective for Ménière's Disease: In Silico Investigations of Dexamethasone as a Direct Modulator of AQP2.

Ménière's disease is a chronic illness characterized by intermittent episodes of vertigo associated with fluctuating sensorineural hearing loss, tinnitus and aural pressure. This pathology strongly correlates with a dilatation of the fluid compartment of the endolymph, so-called hydrops. Dexamethasone is one of the therapeutic approaches recommended when conventional antivertigo treatments have failed. Several mechanisms of actions have been hypothesized for the mode of action of dexamethasone, such as the anti-inflammatory effect or as a regulator of inner ear water homeostasis. However, none of them have been experimentally confirmed so far. Aquaporins (AQPs) are transmembrane water channels and are hence central in the regulation of transcellular water fluxes. In the present study, we investigated the hypothesis that dexamethasone could impact water fluxes in the inner ear by targeting AQP2. We addressed this question through molecular dynamics simulations approaches and managed to demonstrate a direct interaction between AQP2 and dexamethasone and its significant impact on the channel water permeability. Through compartmentalization of sodium and potassium ions, a significant effect of Na+ upon AQP2 water permeability was highlighted as well. The molecular mechanisms involved in dexamethasone binding and in its regulatory action upon AQP2 function are described.