Lymphatic Vessels in the Inner Ear of Patients With Meniere Disease: A Novel Pathological Finding.

Background: Meniere disease, characterized by intermittent episodes of vertigo, fluctuating sensorineural hearing loss, tinnitus, and aural pressure, is a common cause of vertigo in humans. The pathogenesis of Meniere disease remains unknown. The current study aimed to describe a novel pathological change discovered in the inner ears of patients with Meniere disease who underwent labyrinthectomy. Methods: This retrospective case-control study was conducted with 21 patients with MD who underwent labyrinthectomy. A total of 15 patients diagnosed with acoustic neuroma or glomus jugular tumor were review over the same period of time as control. The clinical information of the patients and the pathological features of the membrane are described. Results: The new pathological tissue was a morbid membrane structure sealing the round window, characterized by the formation of lymphatic capillaries. Histochemical and immunofluorescent staining was positive for D2-40, LYVE-1, podoplanin, and PROX1, which are the classical markers of the lymphatic vessels. Transmission electron microscopy revealed that the lymph capillaries lacked a typical basement membrane and that their ends were blind, composed of a single layer of endothelial cells with valval connection structures between adjacent capillary epithelial cells. Conclusion: This is the first report of lymphatic vessels in the human inner ear, and this pathological structure is a completely new discovery. The lymphatic vessels may develop due to inflammation or decompensation of pressure in the inner ear, suggesting that the inner ear can reactively form lymphatic vessels in some inflammation and fluid flow-dependent pathological conditions. The current findings help in improving our understanding of the pathogenesis of Meniere disease.

Ménière's disease and allergy: Epidemiology, pathogenesis, and therapy.

The etiology of Ménière's disease (MD) remains controversial. Allergies are potential extrinsic factors that, in conjunction with underlying intrinsic factors, may cause MD. The link between allergies and MD was first described in 1923. For nearly a century, studies have demonstrated a possible link between allergies and MD, even though a causal relationship has not been definitively determined. Previous reviews have mainly focused on clinical epidemiology studies of patients. In this review, we shed light on the association between allergies and MD not only in terms of its epidemiology, but also from an immunology, pathophysiology, and immunotherapy perspective in both patients and animal models. Patients with MD tend to have a high risk of comorbid allergies or an allergy history, showing positive allergy immunology characteristics. Other MD-related diseases, such as migraine, may also interact with allergies. Allergy mediators such as IgE may worsen the symptoms of MD. Deposits of IgE in the vestibular end organs indicate the ability of the inner ear to participate in immune reactions. Allergic challenges can induce vertigo in animals and humans. Anti-allergy therapy plays a positive role in patients with MD and animal models of endolymphatic hydrops.

Triple Semicircular Canal Plugging versus Labyrinthectomy for Meniere Disease: A Retrospective Study.

OBJECTIVES: The study goals were to compare the long-term efficacy of semicircular canal plugging (SCP) with labyrinthectomy in the treatment of advanced Meniere's disease (MD). STUDY DESIGN: A retrospective study. SETTING: Single tertiary medical center. METHODS: A total of 116 MD patients (TSCP group of 90; labyrinthectomy group of 26) with complete medical documents in Shandong Provincial ENT Hospital, from March 2017 to March 2019 were retrospectively analyzed, including a battery of auditory and vestibular function tests, recovery time from imbalance and function level scores (FLS). RESULTS: The total control rate of vertigo in the TSCP group was 96.7% (87/90). The rate of hearing loss was 23.3% (21/90). The control rate of vertigo in the labyrinthectomy group was 100% (26/26). All patients lost their auditory function after labyrinthectomy with a 100% hearing loss rate. There was no significant difference in the vertigo control rate between the two groups (P > 0.05). The hearing loss rate in the TSCP group was significantly lower than that in the labyrinthectomy group (P < 0.00). The median time recovered from imbalance was 15 days in TSCP group and 21 days in labyrinthectomy group, which is significantly different (P < 0.05). There was no significant difference in the FLS between the two groups (P > 0.05). CONCLUSIONS: Compared to labyrinthectomy, TSCP can preserve hearing at a high probability; meanwhile, otolith organ function preservation benefits patients from faster vestibular compensation. LEVEL OF EVIDENCE: 3 Laryngoscope, 133:3178-3184, 2023.

Serum/glucocorticoid-inducible kinase 1 deficiency induces NLRP3 inflammasome activation and autoinflammation of macrophages in a murine endolymphatic hydrops model.

Ménière's disease, a multifactorial disorder of the inner ear, is characterized by severe vertigo episodes and hearing loss. Although the role of immune responses in Ménière's disease has been proposed, the precise mechanisms remain undefined. Here, we show that downregulation of serum/glucocorticoid-inducible kinase 1 is associated with activation of NLRP3 inflammasome in vestibular-resident macrophage-like cells from Ménière's disease patients. Serum/glucocorticoid-inducible kinase 1 depletion markedly enhances IL-1ß production which leads to the damage of inner ear hair cells and vestibular nerve. Mechanistically, serum/glucocorticoid-inducible kinase 1 binds to the PYD domain of NLRP3 and phosphorylates it at Serine 5, thereby interfering inflammasome assembly. Sgk-/- mice show aggravated audiovestibular symptoms and enhanced inflammasome activation in lipopolysaccharide-induced endolymphatic hydrops model, which is ameliorated by blocking NLRP3. Pharmacological inhibition of serum/glucocorticoid-inducible kinase 1 increases the disease severity in vivo. Our studies demonstrate that serum/glucocorticoid-inducible kinase 1 functions as a physiologic inhibitor of NLRP3 inflammasome activation and maintains inner ear immune homeostasis, reciprocally participating in models of Ménière's disease pathogenesis.

Efficacy of Resection of Lateral Wall of Endolymphatic Sac for Treatment of Meniere's Disease.

Background: To explore the long-term efficacy and safety of resection of the lateral wall of the endolymphatic sac for the treatment of intractable Meniere's disease (MD) as an alternative surgical procedure for treating this disorder. Methods: Data from 73 patients who were referred to our hospital and diagnosed with unilateral MD between January 2015 and June 2019 were retrospectively analyzed in this study. Seventy-three patients who had frequent vertigo even after receiving standardized conservative treatment for at least half a year underwent resection of the lateral wall of the endolymphatic sac. Vertigo control and auditory function were assessed. Pure tone audiometry, caloric test, and vestibular evoked myogenic potential were performed to evaluate audiological and vestibular functions. The post-operative follow-up duration was more than 2 years. Results: Among the 73 patients (male 34 cases, female 39 cases; age 20-69 years, average 51.4), vertigo was controlled effectively for 66 cases (90.4%) after 2 years of follow-up; 45 cases (61.6%) were completely controlled, and 21 cases (28.8%) were substantially controlled in this study. The patients of 16.4% had hearing loss with more than 10 dB change based on the four-tone average (0.5, 1, 2 and 3 kHz). No patient had a facial nerve weakness, cerebrospinal fluid leakage, or other complications. Conclusion: Resection of the lateral wall of the endolymphatic sac, which can effectively control vertiginous symptoms in intractable MD patients, represents an effective and safe therapy for this disease. Resection of the lateral wall of the endolymphatic sac is expected to be used as an alternative treatment for MD.

Bidirectional Transport of IgE by CD23 in the Inner Ear of Patients with Meniere's Disease.

Meniere's disease (MD) is a disorder of the inner ear characterized by episodes of spontaneous vertigo, fluctuating hearing loss, and tinnitus. Recent studies have demonstrated that IgE may play a role in the pathogenesis of MD. Patients with MD (n = 103), acoustic neuroma (n = 5), and healthy subjects (n = 72) were recruited into the study. Serum from the participants was analyzed for IgE and type 2-related cytokines. IgE and CD23 expression levels in vestibular end organs of patients, C57BL/6 mice, or mouse HEI-OC1 cells were analyzed. Finally, the role of CD23 in IgE transcytosis was assessed using HEI-OC1 cells. Serum IgE was elevated in patients with MD and positively correlated with clinical symptoms. IL-4, IL-5, IL-10, IL-13, and CD23 levels were increased in patients with MD compared with the control group. In the transcytosis assay, mouse IgE was found to be bidirectionally transported across the HEI-OC1 cell monolayer. Additionally, CD23 downregulation using a small interfering RNA approach significantly reduced the efficiency of IgE transcytosis, suggesting that IgE is transported by CD23. Furthermore, exposure to IL-4 increased CD23 expression and enhanced IgE transcytosis in the HEI-OC1 cells and primary vestibular end organs. Our study indicated that IgE may play a role in the pathophysiology of MD. In addition, CD23-mediated IgE transcytosis in the hair cells may play a critical role in initiating inflammation in the inner ear. Thus, reducing the level of IgE may be a potentially effective approach for MD treatment.

Protective effect of anakinra on audiovestibular function in a murine model of endolymphatic hydrops.

Introduction: Ménière's disease (MD), a common disease in the inner ear, is characterized by an increase in endolymph in the cochlear duct and vestibular labyrinth. The pathophysiology of the condition appears to be the immune response. Studies have shown that basal levels of the IL-1ß increased in some MD patients. Methods: Here, we used a murine model of endolymphatic hydrops (EH) to study the effect of anakinra on auditory and vestibular function. Mice were intraperitoneal injected with anakinra or saline before LPS by postauricular injection. Weight and disease severity were measured, histologic changes in auditory were assessed, and inflammation state was evaluated. Results: We found that anakinra therapy reduced LPS-induced EH, alleviated LPS-induced hearing loss and vestibular dysfunction, and inhibited the expression of the inflammatory cytokines and macrophage infiltration in the cochlea of mice. We further demonstrated that anakinra ameliorated the disorganization and degeneration of myelin sheath, and reduced the neuron damage in cochlea of EH mice. Discussion: Consequently, anakinra contributes to a promising therapeutic approach to MD, by restricting EH, alleviating auditory and vestibular function, inhibiting inflammation of the inner ear and protecting the cochlear nerve. Further investigations are needed to assess the potential therapeutic benefits of anakinra in patients with MD.

Neuroprotective Effect of Brimonidine against Facial Nerve Crush Injury in Rats via Suppressing GFAP/PAF Activation and Neuroinflammation.

OBJECTIVE: This study aimed to investigate the potential neuroprotective action of brimonidine against facial nerve crush injury in rats and the possible underlying mechanisms. METHODS: Sixty Wistar adult rats were randomly and equally divided into 3 groups: 40 rats underwent unilateral facial nerve crush injury and were administered with either saline (intraperitoneal, n = 20) or brimonidine 1 mg/kg/day (intraperitoneal, n = 20) for 5 consecutive days. Functional and electromyographic recovery was recorded postoperatively. The facial nucleus of 5 mice in each group was analyzed for mRNA expression levels of GFAP, PAF, NT-4, P75NTR, NF-κB, TNF-α, IL-6, and α2-ARs by qRT-PCR. RESULTS: Brimonidine promoted the recovery of vibrissae movement, eyelid closure, and electrophysiological function in a rat model of nerve crush injury. Hematoxylin and eosin staining and electron microscopy showed significant recovery of Schwann cells and axons in the brimonidine group. Brimonidine attenuated the crush-induced upregulation in GFAP and PAF mRNA (p < 0.05), as well as enhanced the mRNA levels of NT-4 and P75NTR (p < 0.05), while decreased the expression of NF-κB, TNF-α and IL-6 (p < 0.05). CONCLUSIONS: Brimonidine could promote the recovery of facial nerve crush injury in rats via suppressing of GFAP/PAF activation and neuroinflammation and increasing neurotrophic factors. Brimonidine may be apromising candidate agent for the treatment of facial nerve injury.

Long-term efficacy of triple semicircular canal plugging in the treatment of patients with ipsilateral delayed endolymphatic hydrops.

This study aims to explore the long-term efficacy of triple semicircular canal plugging (TSCP) in the treatment of intractable ipsilateral delayed endolymphatic hydrops (DEH), so as to provide an alternative therapy for this disease. Forty-eight patients diagnosed with ipsilateral DEH referred to vertigo clinic of our hospital between Dec. 2010 and Dec. 2017, were included in this study for retrospective analysis. All patients were followed up for 2 years. Vertigo control and auditory functions were measured and analyzed. Pure tone audiometry, caloric test, and vestibular evoked myogenic potential (VEMP) were performed in two-year follow-up. Forty-five patients who accepted intratympanic gentamicin (26.7 mg/mL) twice given one week apart were selected as a control group. The total control rate of vertigo in TSCP group was 97.9% (47/48) in the two-year follow-up, with complete control rate of 83.3% (40/48) and substantial control rate of 14.6% (7/48). The rate of hearing loss was 22.9% (11/48). The total control rate of vertigo in intratympanic gentamicin group was 80.0% (36/45), with complete control rate of 57.8% (26/45) and substantial control rate of 22.2% (10/45), and the rate of hearing loss was 20.0% (9/45). The vertigo control rate of TSCP was significantly higher than that of intratympanic gentamicin (χ2 = 6.01, p < 0.05). There was no significant difference of hearing loss rate between two groups. (χ2 = 0.12, p > 0.05). TSCP, which can reduce vertiginous symptoms in patients with intractable ipsilateral DEH, represents an effective therapy for this disorder.

Dexamethasone protects the hearing of Meniere's disease patients after triple semicircular canal plugging.

Background: TSCP has shown its efficacy in vertigo control for intractable Meniere's disease. However, hearing impairment remains a problem and hampered the application of the surgery.Aims/objectives: To investigate the effect of dexamethasone on the hearing of Meniere's disease patients after TSCP to determine whether inflammation is involved in this processMaterial and methods: Meniere's disease patients who received TSCP surgeries were treated with or without dexamethasone postoperatively. All patients' hearing function were evaluated during a follow up of 2 years after surgery and compared between the two groups.Results: Hearing worsening and word recognition score loss were milder in the dexamethasone group than in the non-dexamethasone group. The rates of profound hearing worsening and word recognition score loss remained significantly lower in the dexamethasone group than in the non-dexamethasone group even 2 years after surgery.Conclusions: Dexamethasone protects the hearing of Meniere's patients after TSCP. Inflammation may be involved in the mechanism by which TSCP causes hearing impairment in these patients.Significance: This finding suggests that steroids should be used routinely after TSCP for hearing preservation, and operative precedures need to be modified to minimize inflammation in the inner ear.

Long-term outcomes of triple semicircular canal plugging for the treatment of intractable Meniere's disease: A single center experience of 361 cases.

INTRODUCTION: Meniere's disease is a common chronic inner ear disease. Because the definitive pathogenesis is still unknown, there is currently no cure for this disorder. Semicircular canal plugging (SCP), first used to treat patients with intractable benign paroxysmal positional vertigo, has since been applied to patients with intractable peripheral vertigo. This study was aimed to explore the long-term efficacy of triple semicircular canal plugging (TSCP) in the treatment of intractable Meniere's disease (MD) so as to provide a new method in the framework of treatment with MD. METHODS: Three hundred and sixty-one unilateral MD patients, who were treated with TSCP in our hospital between Dec. 2010 and Sep. 2016, were recruited in this study for retrospective analysis. Vertigo control and auditory function were monitored during a period of two-year follow-up. Seventy three patients who were subjected to intratympanic gentamicin were selected as a control group. Pure tone audiometry, caloric test, vestibular evoked myogenic potential (VEMP) were performed in two-year follow-up. RESULTS: The total control rate of vertigo in TSCP group was 97.8% (353/361) in the two-year follow-up, with complete control rate of 80.3% (290/361) and substantial control rate of 17.5% (63/361). The rate of hearing loss was 26.3% (95/361). The total control rate of vertigo in intratympanic gentamicin group was 83.6% (61/73), with complete control rate of 63.0% (46/73) and substantial control rate of 20.5% (15/73). The rate of hearing loss was 24.7% (18/73). The vertigo control rate of TSCP was significantly higher than that of chemical labyrinthectomy(χ2 = 24.798, p <  0.05). There was no significant difference of hearing loss rate between two groups. (χ2 = 0.087, p >  0.05). CONCLUSION: Triple semicircular canal plugging (TSCP), which can reduce vertiginous symptoms in patients with intractable Meniere's disease (MD), represents an effective therapy for this disorder. It might become a new important method in the framework of treatment with MD.

Solute carrier family 4 member 1 might participate in the pathogenesis of Meniere's disease in a murine endolymphatic hydrop model.

Background: To date, the pathogenesis of Meniere's disease (MD) remains unclear. Previous research found that the SLC4A1 gene significantly down-regulated. Aims: This study sought to understand the effect of SLC4A1 on the pathogenesis of MD. ELH C57 mice models were induced by intraperitoneal injection of AVP. Material and methods: The mRNA expression levels of SLC4A1, SLC4A10 and SLC26A4 were monitored by real-time quantitative PCR, the protein expression levels of SLC4A1 were monitored by immunoblotting and immunofluorescence before and after the ELH. DIDS is an inhibitor of SLC4A1. The expression levels of SLC4A1 were also monitored in the AVP + DIDS group. Results: We successfully established the model of ELH after applied AVP. The results of HE staining showed displacement of Reissner's membrane with bulge to scala vestibule in ears of the AVP group. Cochlea/ELS SLC4A1 protein and SLC4A1, SLC4A10, SLC26A4 mRNA expressions were reduced significantly in C57 mice of the AVP group. The SLC4A1 protein expression levels and SLC4A1, SLC4A10, SLC26A4 mRNA expression levels declined more obvious in the cochlea and ELS in C57 mice of the AVP + DIDS group. Conclusions and significance: SLC4A1 was a protective factor in the pathogenesis of MD, but the mechanisms were unknown.

Meclofenamic Acid Reduces Reactive Oxygen Species Accumulation and Apoptosis, Inhibits Excessive Autophagy, and Protects Hair Cell-Like HEI-OC1 Cells From Cisplatin-Induced Damage.

Hearing loss is the most common sensory disorder in humans, and a significant number of cases is due to the ototoxicity of drugs such as cisplatin that cause hair cell (HC) damage. Thus, there is great interest in finding agents and mechanisms that protect HCs from ototoxic drug damage. It has been proposed that epigenetic modifications are related to inner ear development and play a significant role in HC protection and HC regeneration; however, whether the m6A modification and the ethyl ester form of meclofenamic acid (MA2), which is a highly selective inhibitor of FTO (fatmass and obesity-associated enzyme, one of the primary human demethylases), can affect the process of HC apoptosis induced by ototoxic drugs remains largely unexplored. In this study, we took advantage of the HEI-OC1 cell line, which is a cochlear HC-like cell line, to investigate the role of epigenetic modifications in cisplatin-induced cell death. We found that cisplatin injury caused reactive oxygen species accumulation and increased apoptosis in HEI-OC1 cells, and the cisplatin injury was reduced by co-treatment with MA2 compared to the cisplatin-only group. Further investigation showed that MA2 attenuated cisplatin-induced oxidative stress and apoptosis in HEI-OC1 cells. We next found that the cisplatin-induced upregulation of autophagy was significantly inhibited after MA2 treatment, indicating that MA2 inhibited the cisplatin-induced excessive autophagy. Our findings show that MA2 has a protective effect and improves the viability of HEI-OC1 cells after cisplatin treatment, and they provide new insights into potential therapeutic targets for the amelioration of cisplatin-induced ototoxicity.

Adaptive robust fault tolerant control design for a class of nonlinear uncertain MIMO systems with quantization.

In this paper, we investigate the adaptive control problem for a class of nonlinear uncertain MIMO systems with actuator faults and quantization effects. Under some mild conditions, an adaptive robust fault-tolerant control is developed to compensate the affects of uncertainties, actuator failures and errors caused by quantization, and a range of the parameters for these quantizers is established. Furthermore, a Lyapunov-like approach is adopted to demonstrate that the ultimately uniformly bounded output tracking error is guaranteed by the controller, and the signals of the closed-loop system are ensured to be bounded, even in the presence of at most m-q actuators stuck or outage. Finally, numerical simulations are provided to verify and illustrate the effectiveness of the proposed adaptive schemes.

Allicin protects auditory hair cells and spiral ganglion neurons from cisplatin - Induced apoptosis.

Cisplatin is a broad-spectrum anticancer drug that is commonly used in the clinic. Ototoxicity is one of the major side effects of this drug, which caused irreversible sensorineural hearing loss. Allicin, the main biologically active compound derived from garlic, has been shown to exert various anti-apoptotic and anti-oxidative activities in vitro and in vivo studies. We took advantage of C57 mice intraperitoneally injected with cisplatin alone or with cisplatin and allicin combined, to investigate whether allicin plays a protective role in vivo against cisplatin ototoxicity. The result showed that C57 mice in cisplatin group exhibited increased shift in auditory brainstem response, whereas the auditory fuction of mice in allicin + cisplatin group was protected in most frequencies, which was accordance with observed damages of outer hair cells (OHCs) and spiral ganglion neurons (SGNs) in the cochlea. Allicin markedly protected SGN mitochondria from damage and releasing cytochrome c, and significantly reduced pro-apoptosis factor expressions activated by cisplatin, including Bax, cleaved-caspase-9, cleaved-caspase-3and p53. Furthermore, allicin reduced the level of Malondialdehyde (MDA), but increased the level of superoxide dismutase (SOD). All data suggested that allicin could prevent hearing loss induced by cisplatin effectively, of which allicin protected SGNs from apoptosis via mitochondrial pathway while protected OHCs and supporting cells (SCs) from apoptosis through p53 pathway.

PARP-1-modulated AIF translocation is involved in streptomycin-induced cochlear hair cell death.

Conclusion SM-induced dose- and location-dependent cochlear hair cell death in vitro. AIF might be translocated from mitochondria to nucleus and cytoplasm within SM-treated hair cells. The translocation of AIF might be modulated by PARP-1. Objective Streptomycin (SM), one of the widely used aminoglycoside nowadays, is still causing significant permanent sensorineural hearing loss owing to sensory hair cell death. This study was designed to investigate the role of apoptosis-inducing factor (AIF), an important mitochondrial cell death regulator, in SM ototoxicity within neonatal rat cochleae and HEI-OC1 cells. Methods The viability of HEI-OC1 cells was quantified by MTT assay. AIF, PARP-1, and myosin VIIa distributions were achieved by immunofluorescence. mRNA and protein expression of AIF and PARP-1 were examined by q-PCR and Western-blot. Results The hair cell loss was concomitant with the SM concentration variation, and aggravated from apical to basal turn. AIF was detected in nuclear region and AIF mRNA was up-regulated after SM incubation. Besides, AIF protein expression in mitochondria was decreased, whereas in cytosol it was increased. PARP-1 mRNA and protein were also up-regulated. 3-AB could attenuate the cell death and reverse the changes of AIF distribution by blocking PARP-1.