Ménière's Disease Pathophysiology: Endolymphatic Sac Immunohistochemical Study of Aquaporin‐2, V2R Vasopressin Receptor, NKCC2, and TRPV4

Abstract

Objectives Endolymphatic sac (ELS) pathophysiology in Ménière's disease (MD) remains poorly understood. We identified from the literature a group of proteins expressed on the ELS and involved in endolymph volume regulation: aquaporin-2 (AQP2), vasopressin receptor V2R, sodium potassium chloride cotransporter 2 (NKCC2), and transient receptor potential cation channel V4 (TRPV4). Our objective was to determine whether their ELS expression was altered in MD, to better understand the pathophysiology of endolymphatic hydrops. Study Design Prospective case-control study. Setting Tertiary care center. Subjects Twenty-four patients with definite MD undergoing endolymphatic duct blockage surgery were recruited, as well as 23 controls with no history of MD undergoing surgery for vestibular schwannoma (VS). Methods ELS biopsies and blood samples for plasma arginine vasopressin (AVP) were obtained. Immunohistochemistry for AQP2, V2R, NKCC2, and TRPV4 was performed. Slides were scanned digitally for highly sensitive pixel density analysis by specialized software (VIS; Visiopharm). Results Global scores generated by the software represent total and relative protein expression density of 3 staining intensity levels, exclusively on ELS epithelium. AQP2 expression density was significantly elevated in MD compared to VS ( P = .003). There was no significant difference in plasma AVP, V2R, NKCC2, and TRPV4 expression. Conclusion This original study evaluates simultaneous in situ expression of AQP2, V2R, NKCC2, and TRPV4 on the human ELS in MD, with a control group. Our results show only AQP2 upregulation on the ELS of patients with MD. We suggest a constitutively increased expression of AQP2 in MD, independent of its regulatory axis (AVP-V2R). Acquired regulator sequence mutations could support this model.

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

“…Nordström et al found that 40% of human endolymphatic sac epithelial cells express Na + -K + -ATPase, indicating that they have considerable secretory ability ( 12 ). Immunohistochemical and ultrastructural studies showed that the endolymphatic sac of MD patients had excessive secretion of glycoprotein ( 13 , 14 ), and the overexpression of aquaporin-2 in the endolymphatic sac epithelium was also involved in the formation of endolymphatic hydrops ( 15 ), suggesting that the endolymphatic sac secretion exceeded absorption, increasing the inner ear pressure. Li et al used micro-computed tomography and high-resolution synchrotron phase contrast non-invasive imaging techniques to image and analyze the structures of the utricular duct and utricular-endolymphatic valve (or Bast's valve) of the human temporal bone specimens, suggesting that there is a two-way exchange of endolymphatic fluid involving the utricle, semicircular canal, and endolymphatic duct.…”

Dynamics in Endolymphatic Hydrops & Symptoms in Meniere's Disease After Endolymphatic Duct Blockage, Preliminary Results

“…The increased hydrops was detected in 3 patients, 2 of which exhibited concomitant symptomatic worsening, suggesting that EDB does not always work to improve EH in MD. As a high degree of interindividual variability exists in the etiology of MD (11,39), it was speculated that two etiologically distinct inner ear pathologies (hypersecretion and malabsorption of endolymph) may exist in the sacs of different patients with MD and thus not all MD patients will benefit from EDB.…”

“…This simply highlights the complexity of this disease and reveals the ongoing needs for further study in optimal treatment options for MD. An immunohistochemical and ultrastructural investigation of the human endolymphatic sac in MD revealed both the secretion of glycoproteins and the possible existence of hypersecretions of endolymph in the sac (8)(9)(10), and an increased expression of aquaporin-2 in the endolymphatic sac epithelium of patients with MD was proposed to be involved in the pathophysiology of EH (11), which may support the assumption that an increased secretion outweighs a decreased absorption resulting in increased pressure in the inner ear (12). According to this hypothesis, a novel surgical sac technique, endolymphatic duct blockage (EDB), was proposed for the treatment of MD and shown be effective for the control of symptoms of MD, without any noticeable cochlear and vestibular damage (12).…”

Identification of Potential Meniere's Disease Targets in the Adult Stria Vascularis

“…Of these genes, evidence of decreased expression in MD has been noted for Atp13a5, Cacna2d1, and Ank2 (23) while Cav1 expression has been shown to be increased in patients with MD (23,31). While it has been suggested that TRPV4 expression may be decreased in human endolymphatic sac tissue from MD patients (82), a subsequent case-control replication study examining TRPV4 expression failed to demonstrate an association between TRPV4 expression and MD (83). Expression of TRPV4 in the cochlea in patients with MD has not been compared to unaffected human patients.…”