High-salt intake exacerbates endolymphatic hydrops and alters aldosterone regulation in a Ménière's disease animal model.

There are some kinds of sicknesses provoked by inadequate adaptation to physical and/or psychogenic stress in daily life. Delayed endolymphatic hydrops (DEH) is an inner ear disease like Ménière's disease (MD) characterized by episodic vertigo in the setting of preexisting unilateral deafness that especially occurs in civilized people with a stressful lifestyle. Its otopathologic finding was demonstrated to be inner ear endolymphatic hydrops through a temporal bone study in 1976, as in the case with MD in 1938. To elucidate the relationship between stress and the inner ear, we examined the plasma antidiuretic stress hormone vasopressin (pAVP) and its type 2 receptor (V2R) expression in the endolymphatic sac in patients with DEH. A prospective molecular biological study. Between 1998 and 2007, we enrolled 20 patients with ipsilateral DEH to examine their pAVP during remission from vertigo attacks. Plasma vasopressin was also examined in 87 patients with unilateral MD and 30 control patients with chronic otitis media. Using the real-time polymerase chain reaction method with tissue samples obtained during surgery, we examined V2R mRNA expression in the endolymphatic sac in 6 patients with ipsilateral DEH, 9 patients with unilateral MD, and 6 control patients with acoustic neuroma. Plasma vasopressin (1.5 times versus controls; unpaired t test, p = 0.140) and V2R mRNA expression in the endolymphatic sac (35.8 times versus controls; unpaired t test, p = 0.002) were higher in patients with DEH compared with those with acoustic neuroma. There were no significant differences in pAVP or V2R expression in the endolymphatic sac between DEH and MD. Patients with DEH showed a significantly negative correlation between pAVP and V2R (Pearson test, r = -0.92, p = 0.009) as in those with MD (Pearson test, r = -0.68, p = 0.043). Civilized people are frequently exposed to stress in their daily life, and pAVP can easily become elevated at any time. Therefore, a negative feedback system between pAVP and V2R in the endolymphatic sac may function for inner ear fluid homeostasis against stress-induced increases in pAVP. For the pathogenesis of endolymphatic hydrops resulting in vertigo attacks in patients with DEH as well as MD, pAVP may represent a matter of consequence, but V2R overexpression in the endolymphatic sac could be much more essential as a basis for these diseases.

Meniere's disease, although idiopathic by definition, has been ascribed to a variety of causes, which more recently include autoimmune factors. Interest in the role of allergy in Meniere's disease has also increased. Studies from this institution and elsewhere provide evidence that allergy and immunologic factors play a role in Meniere's disease in at least some patients. The symptoms of Meniere's disease are thought to be produced by a sudden influx of fluid into the endolymphatic sac, producing a rupture of Reissner's membrane in the cochlea. The endolymphatic sac is capable of trapping antigen and generating its own immune response. It has a highly vascular subepithelial space containing numerous fenestrated blood vessels that are peripheral and "leaky." At least three mechanisms by which allergy may play a role in the production of fluid in the endolymphatic sac are described: the endolymphatic sac itself might be a "target organ" of mediator released from systemic inhalant or food reactions; deposition of circulating immune complex may produce inflammation and interfere with the sac's filtering capability; and a predisposing viral infection in childhood that produces a mild impairment of endolymphatic sac function may interact with allergies in adulthood and cause the endolymphatic sac to decompensate, resulting in endolymphatic hydrops. The endolymphatic sac is the seat of immune reactivity in the inner ear. Repeated inflammatory reactions can produce sac dysfunction and eventual production of Meniere's disease.

Allergic and immunologic aspects of Meniere's disease

Understanding Fluctuating Hearing Loss

The pathophysiology of the endolymphatic sac (ES) in Meniere's disease was studied by scanning electron microscopy and staining of immunoglobulins in the intradural portion of the ES. The peroxidase-antiperoxidase method by means of paraffin sections was used for staining of immunoglobulins. First, subjects without hearing impairment and malformation of the temporal bone, ranging from a 7-month-old fetus to an 80-year-old adult, were investigated. All subjects, including fetuses, showed well-arranged epithelial cells by scanning electron microscopy. The epithelial cells in the proximal portion of the intradural ES were oval, showing a tendency of transitional change to be flat as they drew near the distal portion of the ES. The epithelial cells consisted mostly of light cells, but sporadic dark cells were seen. Regarding the immunoglobulins. IgG was slightly positive in the epithelial and subepithelial layers. All 15 patients with Meniere's disease showed various types of degeneration of the epithelial cells though to varying degrees. However, these findings were also seen in cases of cochlear deafness. On the other hand, the ES of acoustic tumors, with retrocochlear or neural deafness revealed a normal finding, as found in healthy subjects. Inner ear deafness experimentally produced in animals by Kanamycin sulfate (KM) injection showed degeneration of the epithelial cells of the ES similar to that found in human cochlear deafness. IgG of the ES in Meniere's disease showed moderately evident deposits compared to normal subjects. However, this was also found not only in inner ear deafness other than Meniere's disease, but also in animal deafness experimentally produced by KM injection. It is very interesting to note that moderate endolymphatic hydrops was found in animals one year after Preyer's reflex had disappeared. It is postulated that endolymphatic hydrops develop because of impairment of endolymphatic fluid resorption at the rugose portion and stenosis of the lumen in the same portion, due to degeneration of the epithelial cells. From the above results, it is argued that degenerated epithelial cells and immunoglobulins of the ES in Meniere's disease may arise from the sequelae of cochlear deafness. It is also hypothesized that endolymphatic hydrops--at least in the terminal stage of Meniere's disease--may be consistent with the same pathophysiological conditions as in animal experiments.

Ménière's disease (MD) is an idiopathic inner ear disorder characterized by recurrent episodes of episodic rotational vertigo, fluctuating hearing loss, tinnitus, and a feeling of ear stuffiness. Endolymphatic sac (ES)-related surgery is used primarily in patients with MD who have failed to respond to pharmacologic therapy. Endolymphatic duct blockage (EDB) is a new procedure for the treatment of MD, and related clinical studies are still scarce. This study aims to investigate the dynamic changes in endolymphatic hydrops (EH) and the long-term surgical outcomes in MD patients undergoing EDB, and to evaluate the impact of different types of ES on the surgical efficacy. A retrospective analysis was conducted on 33 patients with refractory MD who underwent EDB. Based on the morphology of their endolymphatic sacs, patients were divided into a normal-type group (n=14) and an atrophic-type group (n=19). The frequency of vertigo symptoms, hearing, vestibular function, and the dynamic changes of gadolinium-enhanced MRI of the inner ear were compared were compared before and after surgery between the 2 groups. Compared with the atrophic-type group, the patients in the normal-type group had a higher rate of complete vertigo control, better cochlear and vestibular function, and a lower endolymph to vestibule volume ratio (all P<0.05). In addition, 7 patients in the normal-type group were found to have reversal of EH, while no reversal of EH was detected in the atrophic-type group after surgery. The response to EDB treatment varies between normal and atrophic MD patients, suggesting that the 2 pathological types of endolymphatic sacs may have different underlying mechanisms of disease.

Schuknecht (1985) classified delayed endolymphatic hydrops (DEH) into three types, ipsilateral, contralateral and bilateral. The concept of DEH has been generally accepted; however, there is a problem that contralateral DEH might be unilateral Meniere's disease, accidentally appearing in on the ear opposite to that with severe deafness. In this paper the characteristics of contralateral DEH are compared with ipsilateral DEH and unilateral Meniere's disease.In the past 9 years 20 patients with DEH, 10 ipsilateral and 10 contralateral, were selected from among all the patients who had visited our clinic in the same period for a retrospective investigation of unilateral and bilateral severe deafness. Patients with unilateral Meniere's disease in the ear opposite to that with early onset of severe deafness, were included in the contralateral DEH. Three cases with contralateral DEH had no vertigo or dizziness with fluctuating hearing loss. Four patients with contralateral DEH had episodic vertigo; sensorineural hearing loss, which was of sudden onset in three, appeared from one to 10 years before the fluctuating hearing loss. Thus, in seven patients with contralateral DEH, cochlear disorders were the only symptom of DEH or preceded the onset of DEH. This tendency is different from the nature of the onset of Meniere's disease. In six of the nine patients with contralateral DEH (66%), endolymphatic hydrops was detected by the glycerol test, the ECochG and/or the furosemide VOR. Because not all patients were tested with all three examinations, the percentage of those with endolymphatic hydrops was lower than in those with Meniere's disease in our clinic (90%). In the four patients, who were tested with all three examinations, however, endolymphatic hydrops were demonstrated, There-fore we concluded that the number of findings pointing to endolymphatic hydrops in contralateral DEH was not very different from that in Meniere's disease.These results suggest that the characteristics of contralateral DEH may be different from those of Meniere's disease although both diseases have the same pathogenesis : endolymphatic hydrops.

Is Endolymphatic Sac Surgery Beneficial For Meniere's Disease?

To investigate the isosorbide-induced dehydration effect on the endolymphatic space by intratympanic administration of isosorbide. Isosorbide, an osmotic diuretic, is used orally as a typical conservative therapy for Menière's disease (MD) in Japan. The dehydration effect occurs 6 hours after isosorbide ingestion. Intratympanic administration of isosorbide resolves endolymphatic hydrops faster than oral ingestion. In addition, the dehydration effect has never been shown directly. Therefore, we investigated the dehydration effect of intratympanic administration of isosorbide on endolymphatic hydrops using optical coherence tomography. We used eight Hartley guinea pigs, divided into normal and hydrops groups. In the hydrops group, the animals underwent endolymphatic sac obliteration to create endolymphatic hydrops. We obtained midmodiolar section images of the cochleae using optical coherence tomography. Then, 50 to 70% isosorbide was sequentially administered intratympanically for 5 minutes, and the apical turn of the cochlea was observed. The relative midmodiolar cross-sectional area of the scala media was calculated for quantitative assessment of the endolymphatic space. In the normal group, 50% isosorbide had a slight but significant dehydration effect on the scala media; at 55 to 70%, Reissner's membrane became flat. In the hydrops group, 50% isosorbide slightly reduced endolymphatic hydrops; 65% flattened Reissner's membrane, and 70% slightly concaved it toward the basilar membrane. The results suggest that we could select the concentration of isosorbide according to the stage or severity of MD and relief from acute attack. Intratympanic administration of isosorbide may be a promising treatment for patients with MD.

Meniere's disease is an inner ear disorder without a known cause. Endolymphatic hydrops is a swelling of the endolymph spaces that has been observed consistently on post-mortem histology in patients with a history of Meniere's disease but can occur in asymptomatic individuals and in association with other diseases. Since its discovery, Meniere's disease has been a disorder managed primarily by otolaryngologists. Surgical treatments, therefore, have accompanied attempts at medical management. Inspired by patients' sensations of ear fullness and later by the histologic findings of hydrops, surgeons began manipulating the membranous labyrinth to relieve episodes of vertigo while attempting to preserve hearing. This review highlights this history of manipulation of the membranous labyrinth. These procedures indicate a rich history of innovation that parallels developments in otologic surgery. The studies involving patients are uniformly retrospective, with some procedures performed first in animal models of endolymphatic hydrops. Many approaches were endorsed by eminent otologic surgeons. Surgeries on the endolymphatic sac are performed by some surgeons today; however, procedures on the membranous labyrinth resulted in similar symptomatic relief through a minimally invasive technique, in many cases performed using only local anesthetic. Episodic vertigo in patients with Meniere's disease is a distressing symptom, yet spontaneous remissions are common. The reports of procedures on the membranous labyrinth reviewed here consistently indicated fewer vertigo episodes. Variable degrees of hearing loss were common following these procedures, and many were abandoned. Additional innovative surgeries are inevitable, but we must understand better the relationships among endolymphatic hydrops, Meniere's disease pathophysiology, and patient symptoms.

We used light microscopy and computerized graphic reconstruction techniques to examine the endolymphatic duct and sac in 20 pairs of bones from patients with Menière's disease and 21 bones from controls. The diameters of the endolymphatic duct and the proximal portion of the vestibular aqueduct were significantly smaller in Menière's disease ears than in controls. Graphic reconstructions showed the Menière's sacs to be smaller and to have fewer tubular epithelial structures in the intraosseous portion than in the control ears. The median volume of the sac in the Menière's disease side was substantially lower than in the contralateral ear. The width of the external aperture of the vestibular aqueduct was significantly smaller in Menière's disease ears than in controls. These findings indicate that the size not only of the vestibular aqueduct but also of the sac is reduced in Menière's disease. The results may suggest that the endolymphatic sac is pathologically changed in Menière's disease and that a reduced resorptive capacity of a small endolymphatic sac could result in endolymphatic hydrops.

Meniere's disease is peculiar to humans and is characterised by episodic vertigo, fluctuating hearing loss and tinnitus, and attacks of the affliction occurring under conditions of stress. Its pathology was first revealed to be inner ear hydrops through temporal bone studies in 1938. Although subsequently proposed as a disorder of water metabolism in the inner ear, its pathogenesis remains unsolved. The present study aimed to assess the link between the inner ear pathology in Meniere's disease and vasopressin, an anti-diuretic stress hormone with a potential role in inner ear fluid homeostasis. Blood samples were obtained from Meniere's disease patients in the morning, before any surgical treatment, to examine plasma vasopressin (pAVP) levels, and then from inner ear tissue during surgical treatment, to examine vasopressin type-2 receptor (V2R) in the endolymphatic sac. pAVP and the relative V2R mRNA expression in the endolymphatic sac were examined using a real-time polymerase chain reaction. Relative cAMP activity in the endolymphatic sac was also examined using tissue culture and cAMP assay. Both pAVP (1.6-fold versus controls; P = 0.048) and inner ear V2R mRNA expression (41.5-fold versus controls; P = 0.022) were significantly higher in Meniere's patients. cAMP activity was basally up-regulated (2.1-fold versus controls) and cAMP sensitivity to vasopressin application was largely elevated (4.9-fold versus controls) in Meniere's patients. We conclude that, in the pathogenesis of inner ear hydrops, resulting in Meniere's attacks, elevation of pAVP levels (probably as a result of stress) may present as a matter of consequence, but susceptibility of the V2R-overexpressed and cAMP-hypersensitized inner ear to pAVP elevation might be essential as the basis of this disease. Further experimental and clinical studies are needed to better clarify the relationship between Meniere's disease and stress.

Meniere's disease, characterised by episodic vertigo, fluctuating hearing loss and tinnitus, can occur under conditions of stress. Its pathology was first revealed to be inner ear hydrops through temporal bone studies in 1938. Although its pathogenesis has been proposed to be a disorder of water transport in the inner ear, subsequently, it remains unsolved, until now. A recent study revealed that both plasma stress hormone, vasopressin (pAVP) and its receptor, V2 (V2R) expression in the inner ear endolymphatic sac were significantly higher in Meniere's patients. In the present study, to link V2R-related molecules and inner ear hydrops, we examined V2R-linked water channel molecule, aquaporin-2 (AQP2) expression and translocation in human endolymphatic sac. AQP2 mRNA expression in the endolymphatic sac was significantly higher in Meniere's patients by using real-time polymerase chain reaction, as further confirmed by western blotting. AQP2-like immunoreactivity (-LIR) was translocated from luminal to basolateral side with endosomal trapping in the endolymphatic sac at the time of AVP exposure in human endolymphatic sac tissue culture. The similar AQP2-LIR translocation was also demonstrated by forskolin and blocked by vasopressin/V2R specific antagonist, OPC31260 and protein kinase A (PKA) specific antagonists, H-89 and KT-5720. We concluded that in the pathogenesis of inner ear hydrops resulting in Meniere's attacks, pAVP elevation as a result of stress and subsequent V2R-cAMP-PKA-AQP2 activation and endosomal trapping of AQP2 in the endolymphatic sac, might be important as a basis of this disease. Further experimental and clinical studies are needed to better clarify the neuroscientific relationship between stress and Meniere's disease.

Meniere's disease is characterized by episodic vertigo, fluctuating hearing loss, aural fullness and tinnitus. Endolymphatic hydrops, found on post-mortem examination, is the histologic hallmark. Recent research suggests that endolymphatic hydrops results from cytochemical perturbations of unknown etiology that lead to disturbance of the normal endolymphatic fluid homeostasis. This consequent hydropic state or the associated cytochemical perturbations appears to create a neurotoxic environment that ultimately leads to spiral ganglion cell death likely via the apoptotic mechanism. This review highlights some of the recent advances in the understanding of the pathophysiology of endolymphatic hydrops and progressive cochleovestibular deterioration, with emphasis placed on its potential therapeutic implications. Recent evidence supports that endolymphatic hydrops is possibly an epiphenomenon, and is preceded by perturbation of the normal ionic transport regulatory mechanisms. Furthermore, chronic cochleovestibular deterioration appears to be the result of an excitotoxic response to chronic hydrops. A recently described animal model, the Phex mouse, carrying a mutation in the Phex Hyp-Duk gene, provides a novel insight to genetically regulated postnatal endolymphatic hydrops and a useful tool to expand our understanding. Despite encouraging recent advances, there are considerable challenges that remain in the development of targeted therapeutic interventions that may offer new avenues of neuroprotection in known cases of Meniere's disease. These advances will hopefully provide pharmacotherapeutic interventions aimed at preventing progressive cochleovestibular dysfunction.

Delayed endolymphatic hydrops (DEH), a disease entity that can be differentiated from Meniere's disease, typically develops in patients who have experienced a profound, long-term hearing loss in one ear. This condition was first reported by Kamei et al. ('71), who indicated that it occurred in about 20% of patients who had had unilateral profound deafness since early childhood (UPDC), and it appeared at various stages of adulthood, during or after puberty. Wolfson and Leiberman ('75) and Nadol et al. ('75) reported other types of unilateral profound deafness causing this condition that were due to viral and bacterial labyrinthitis, head trauma, or sudden deafness. Schuknecht ('78) defined DEH and classified it into two types: the ipsilateral type, in which vestibular symptoms identical to the vestibular symptoms of Meniere's disease develop in a previously deafened ear, and the contralateral type, in which a fluctuating hearing loss and/or vestibular symptoms develop in the hearing ear. The underlying pathophysiologic mechanism for the development of DEH has been explained as progressive endolymphatic hydrops in the inner ear due to delayed atrophy or fibrous obliteration of the endolymphatic resorption system, resulting from a previous inner-ear injury. In the ipsilateral type, episodic vertigo is not usually accompanied by fluctuating hearing levels and tinnitus because the hearing loss is profound. The period between the onset of pre-existent deafness in one ear and the onset of DEH ranges from several months to 74 years. The cause of the pre-existent deafness is UPDC in more than half of the cases of both types of DEH. Almost all kinds of other degenerative disorders of the inner ear are mostly due to inflammation (viral and bacterial) and trauma (physical and acoustic). The ipsilateral type of DEH is more frequently seen than the contralateral type. The onset age of the contralateral type is higher, in general, than that of the ipsilateral type. Medical treatment may be effective for both types of DEH. Complete relief from episodic recurrent vertigo may be expected in 65% of cases within 5 years after the onset of vertigo and in 90% of cases within 10 years. Labyrinthectomy or vestibular nerve section in the deaf ear is curative in the ipsilateral type, but no satisfactory surgical therapy is available for the contralateral type of the disease. The audiological definition of DEH by Schuknecht seems, however, to be somewhat arbitrary, as the patients' symptoms form a continuous spectrum with other Meniere's syndrome cases, occurring in association with less-marked degrees of sensorineural hearing loss. The existence of the contralateral type of DEH due to UPDC, which often shows typical symptoms of Meniere's disease, seems to suggest that Meniere's disease may occur as a delayed sequela of subclinical damage of the inner ear, especially damage sustained in childhood.