Development and Characteristics of Hearing Loss With the Progression of Endolymphatic Hydrops

Abstract

Objectives

This study aims to explore how patients’ hearing loss developed with the progression of endolymphatic hydrops and the characteristics of hearing loss at different stages.

Materials and Methods

We collected 73 patients with definite or possible unilateral Meniere’s disease or sudden hearing loss who underwent magnetic resonance imaging after intravenous contrast agent injection. There were 25 cases of isolated cochlear hydrops, 24 cases of isolated vestibular hydrops, and 24 cases of cochlear and vestibular hydrops. Primary outcome analyses included their evaluation of endolymphatic hydrops and hearing thresholds at low and high frequencies.

Results

The overall hearing threshold of patients with vestibular and cochlear hydrops was significantly higher than that of patients with isolated cochlear hydrops and patients with isolated vestibular hydrops. There was a significant correlation between low-frequency hearing loss and cochlear hydrops, and the low-frequency hearing threshold was proportional to the grade of cochlear hydrops. At low frequency, the hearing threshold of patients with isolated vestibular hydrops was lower than that of patients with isolated cochlear hydrops and patients with both cochlear and vestibular hydrops. The audiogram configurations of patients with isolated cochlear hydrops consist largely of flat type and up-sloping type. The audiogram configurations of patients with isolated vestibular hydrops and patients with both cochlear and vestibular hydrops are mainly flat type and down-sloping type.

Conclusions

Patients present with low-frequency hearing loss in the early stage of endolymphatic hydrops. When the hydrops involves the whole cochlea and vestibule, the patients’ hearing is impaired at both low and high frequencies.

Keywords

endolymphatic hydrops magnetic resonance imaging hearing loss

Introduction

As early as 1983, C. S. Hallpike observed endolymphatic hydrops (EH) in temporal bone pathological specimens of Meniere’s disease (MD) patients.¹ In 2007, a team from Nagoya University reported for the first time the visualization of EH in MD patients using magnetic resonance imaging (MRI).² In this study, researchers observed gadolinium in parts of the perilymph after intratympanic injection of diluted gadolinium. Then, around the theme of endolymphatic hydrops, contrast agent injection methods, new magnetic resonance imaging techniques, and different evaluation methods continue to develop. Patients with Meniere’s disease, sudden hearing loss, vestibular schwannoma, and other diseases have been confirmed to have endolymphatic hydrops, even in healthy individuals.^3,4,5 Recently, many studies have shown that patients’ hearing loss is related to endolymphatic hydrops. Some scholars have proposed that there is a significant correlation between hearing loss and the extent of cochlear and vestibular endolymphatic hydrops, and the hearing threshold is proportional to the grade of endolymphatic hydrops.⁶ Endolymphatic hydrops and hearing loss progress even with pharmacotherapy and intratympanic steroid therapy.^7,8

This study aimed to explore how patients’ hearing loss developed with the progression of endolymphatic hydrops and the characteristics of hearing loss at different stages.

Methods

Patients

Excluding patients who had previously been treated with tympanic injection, this study collected 73 patients with definite or probably unilateral MD or unilateral sudden hearing loss (25 with isolated cochlear hydrops, 24 with isolated vestibular hydrops, and 24 with cochlear and vestibular hydrops). From January 2020 to June 2021, they underwent MRI scans after intravenous injection of gadolinium contrast agent at Fudan University Eye, Ear, Nose, and Throat Hospital, including 30 men and 43 women with an average age of 53.0 years. The patients' basic information, such as age, sex, and affected side, is listed in Table 1. A diagnosis for MD was based on criteria put forth by the 2015 Guidelines.⁹ Definite MD: (A) Two or more spontaneous episodes of vertigo, each lasting 20 minutes to 12 hours. (B) Audiometrically documented low- to medium-frequency sensorineural hearing loss in one ear, defining the affected ear on at least one occasion before, during or after one of the episodes of vertigo. (C) Fluctuating aural symptoms (hearing, tinnitus, or fullness) in the affected ear. (D) Not better accounted for by another vestibular diagnosis. Probable MD: (A) Two or more episodes of vertigo or dizziness, each lasting 20 minutes to 24 hours. (B) Fluctuating aural symptoms (hearing, tinnitus, or fullness) in the affected ear. (C) Not better accounted for by another vestibular diagnosis. The diagnostic criteria for sudden hearing loss were referred from the AAO-HNS (American Academy of Otolaryngology-Head and Neck Surgery) guidelines: A rapid-onset subjective sensation of sensorineural hearing loss (not less than 30 decibels), affecting at least 3 consecutive frequencies within a 72-hour window.¹⁰ This study was approved by the Medical Ethics Committee of the Eye, Ear, Nose, and Throat Hospital affiliated to Fudan University, and we obtained informed consent from all patients.

Table 1.

Demographics.

	Vestibular Hydrops (24)	Cochlear Hydrops (25)	Cochlear and Vestibular Hydrops (24)
Sex	Female, 12	Female, 18	Female, 13
Sex	Male, 12	Male, 7	Male, 11
Age	Range (34–69)	Range (22–71)	Range (30–70)
Age	Mean, 54.0	Mean, 49.4	Mean, 55.9
Affected side	Right, 8	Right, 13	Right, 10
Affected side	Left, 16	Left, 12	Left, 14

Pure-Tone Audiometry

Pure-tone audiometry thresholds were measured at all conventional frequencies (125–8000 Hz) using a GSI 61 audiometer (Grason Stadler). According to the frequency distribution of hearing loss, it was divided into low-frequency (125 Hz–1000 Hz) hearing loss and high-frequency (2000 Hz–8000 Hz) hearing loss. Audiogram configurations were classified as up-sloping (hearing loss affecting 125,250 Hz more), flat (less than 20 dB difference between the highest and lowest threshold), down-sloping (hearing loss affecting 4000, 8000 Hz more), and profound (thresholds of 90 dB or more in each test frequency) hearing loss.¹¹

Image Acquisition

All enrolled patients accepted MRI scans 4 hours later after the intravenous injection of gadolinium. To obtain satisfactory images, we used a double dose (.4 mL/kg body weight) of gadolinium (Magnevist, Bayer Health Care, Beijing, China). Both the ethics committee and the patients accepted this proposal. A 3.0 T MRI scanner (Magnetom Verio, Siemens Healthineers, Erlangen, Germany) and an 8-channel array coil were used for T2 SPACE (Sampling Perfection with Application-Optimized Contrasts by using different flip angle Evolutions) and 3D-real IR (3-dimensional inversion recovery sequence with real reconstruction) sequence scanning. The parameters of the T2 SPACE sequence included slice thickness (.6 mm), repletion time (1000 ms), echo time (132 ms), flip angle (120°), matrix(384 × 384), field of view (200 × 100 mm²), and scan time (2 minutes and 44 seconds). The parameters of the 3D-real IR sequence included slice thickness (.6 mm), repetition time (6000 ms), echo time (181 ms), inversion time (1850 ms), flip angles (180°), matrix size (768 × 768), field of view (160 × 160 mm²), and scan time (15 minutes and 20 seconds).

Evaluation of Endolymphatic Hydrops

In this study, JUSHA workstation (Nanjing JUSHA Commercial & Trading Co., LTD.) was used for maximum intensity projection and multifaceted reconstruction of the collected three-dimensional images. After intravenous injection of gadolinium, gadolinium passed through the blood–perilymph barrier into the perilymphatic space. Thus, the perilymphatic space showed high signal and the endolymphatic space showed low signal.¹² For the evaluation of cochlear and vestibular EH, we referred to the criteria of Nakashima (Table 2).¹³ Two imaging investigators independently evaluated the images of each subject. Figures 1 –3 showed the images of patients with isolated cochlear hydrops, isolated vestibular hydrops, and cochlear and vestibular hydrops, respectively.

Table 2.

Evaluation of Endolymphatic Hydrops.

Hydrops Evaluation	Vestibule (Area Ratio)	Cochlea
None	≤ 33.3%	No displacement of Reissner’s membrane
Mild	> 33.3%, ≤ 50%	Displacement of Reissner’s membrane Area of cochlear duct ≤ area of the scala vestibuli
Significant	> 50%	Area of the cochlear duct exceeds the area of the scala vestibuli

Figure 1.

A patient with isolated cochlear hydrops (mild endolymphatic hydrops) on the right side.

Figure 2.

The left and right images showed the cochlea and vestibule of a patient with left isolated vestibular hydrops (significant endolymphatic hydrops).

Figure 3.

The left and right images showed the cochlea and vestibule of a patient with left cochlear and vestibular hydrops (significant cochlear and vestibular endolymphatic hydrops).

Statistical Analysis

We used SPSS (v.26; IBM, Armonk, NY) to analyze the statistical data. The chi-square test was used to compare the degree of endolymphatic hydrops. The Kruskal–Wallis test and one-way ANOVA were applied to compare the hearing loss of each group. The Spearman test was applied to explore the correlation between cochlear hydrops and low-frequency hearing loss. Fisher’s exact test was used to compare the distribution of audiogram configurations among 3 groups. P-value < .05 was considered statistically significant.

Results

There were no significant differences in age and sex among the 3 groups. EH evaluation results of each group were as follows: cochlear and vestibular hydrops group (13 cases of mild cochlear hydrops, 11 cases of significant cochlear hydrops, 4 cases of mild vestibular hydrops, and 20 cases of significant vestibular hydrops), isolated cochlear hydrops group (21 cases of mild cochlear hydrops and 4 cases of significant cochlear hydrops) and isolated vestibular hydrops group (9 cases of mild vestibular hydrops and 15 cases of significant vestibular hydrops). There was significant difference in the degree of cochlear hydrops between the cochlear and vestibular hydrops group and the isolated cochlear hydrops group (P = .024). The average value and range of hearing thresholds were listed in Table 3. The results showed that the overall average hearing loss was statistically different among the 3 groups. P-values are listed in Table 4. As shown in Table 3 and Table 4, the overall hearing threshold of patients with vestibular and cochlear hydrops was significantly higher than that of patients with isolated cochlear hydrops (P = .008) and patients with isolated vestibular hydrops (P = .008). There was no statistical difference between the cochlear hydrops group and the vestibular hydrops group. At low frequency, the hearing threshold of patients with isolated vestibular hydrops was lower than that of patients with isolated cochlear hydrops (P = .045) and patients with both cochlear and vestibular hydrops (P = .001) (Figure 4). The hearing threshold of patients with isolated cochlear hydrops was lower than that of patients with cochlear and vestibular hydrops with no significant difference. At high frequency, the hearing threshold of patients with isolated cochlear hydrops was lower than that of patients with cochlear and vestibular hydrops (P = .003). No significant difference was seen between the other 2 groups (Figure 4). There was a significant correlation between low-frequency hearing loss and cochlear hydrops (P = .003), and low-frequency hearing threshold was proportional to the grade of cochlear hydrops.

Table 3.

Average Value and Range of Hearing Thresholds.

	Vestibular Hydrops	Cochlear Hydrops	Cochlear and Vestibular Hydrops
Overall	39.6(20.0–70.0)	39.7(12.0–71.0)	53.2(26.0–93.0)
Low-frequency	34.8(15.0–70.0)	44.5(15.0–73.6)	52.1(25.0–90.0)
High-frequency	49.4(23.3–75)	39.4(11.7–80.0)	58.1(25.0–100)

Table 4.

The P-Value of each 2 Groups.

	Overall	Low-Frequency	High-Frequency
Cochlear and vestibular hydrops–cochlear hydrops	.008	.138	.003
Cochlear and vestibular hydrops–vestibular hydrops	.008	.001	.080
Cochlear hydrops–vestibular hydrops	.991	.045	.064

Figure 4.

The distribution of hearing thresholds at low frequency and high frequency among 3 groups.

Of the patients with cochlear and vestibular hydrops, 12% (3/24) showed an up-sloping audiogram configuration, 29.2% (7/24) showed a flat audiogram configuration, and 58.3% (14/24) had a down-sloping audiogram configuration. Of the patients with isolated cochlear hydrops, 52% (13/25) showed an up-sloping audiogram configuration, 20% (5/25) showed a flat audiogram configuration, and 28% (7/25) had a down-sloping audiogram configuration. Of the patients with isolated vestibular hydrops, 4.2% (1/24) showed an up-sloping audiogram configuration, 8.3% (3/24) showed a flat audiogram configuration, and 87.5% (21/24) had a down-sloping audiogram configuration. No one had a profound hearing loss. The patient with the most severe hearing loss had cochlear and vestibular hydrops, and the hearing threshold at each frequency was 85, 95, 90, 90, 100, 95, 105, respectively. The distribution of audiogram configurations was significantly different among the 3 groups (P < .001).

Discussion

At present, there have been many studies on the relationship between EH and hearing loss. This paper focused on the hearing loss in 3 different stages of EH, which had not been explored in previous studies and was the innovation of this paper. In this study, we included patients with isolated cochlear hydrops, isolated vestibular hydrops, and both cochlear and vestibular hydrops to compare the differences in hearing loss among these 3 groups. Our objective was to reveal how patients' hearing loss developed with the progression of EH and the characteristics of hearing loss at different stages. Our results showed that the overall hearing loss of patients with cochlear and vestibular hydrops was worse than that of patients with isolated cochlear hydrops and patients with isolated vestibular hydrops. Moreover, the degree of cochlear hydrops in the cochlear and vestibular hydrops group was significantly higher than that of the isolated cochlear hydrops group. Among the patients enrolled in this study, the patient with the most severe hearing loss was in the cochlear and vestibular hydrops group. A previous study indicated that EH began at the apical turn of the cochlear and subsequently extended to the cochlear aqueduct and vestibular apparatus.¹⁴ EH usually involved the inferior segment of the labyrinth, mainly in the cochlea and saccule.¹⁵ As the disease progressed, the degree of EH gradually increased. Even after medical treatments, hearing loss and EH will develop longitudinally with the deterioration of inner ear function.⁷

At low frequency, the hearing threshold of patients with isolated cochlear hydrops and patients with both cochlear and vestibular hydrops was higher than that of patients with isolated vestibular hydrops. There was a significant correlation between low-frequency hearing loss and cochlear hydrops. In 2017, some researchers created an endolymphatic hydrops model by injecting small volumes of artificial endolymph to explore frequency hearing loss.¹⁶ Based on this model, they measured low-frequency hearing loss using the Auditory Nerve Overlapped Waveform (ANOW) technique. The ANOW originated from the response of the auditory nerve fibers that innervated the cochlear apex.¹⁷ The cochlear apex was one of the most dilatable areas of the inner ear, which may result from the gradation of the width and hardness of the basilar membrane.¹⁸ And this gradation made cochlear apex more prone to accumulation of endolymphatic fluid than other parts of the cochlea.¹⁶ Our results showed that low-frequency hearing loss was predominant in patients with isolated cochlear hydrops. We think that isolated cochlear hydrops may be the early stage of the disease. EH developed from the apical turn of the cochlea and initially affected the apical turn of the cochlea, which caused the distension of cochlear apex and impairment of low-frequency hearing. Our results also showed that the low-frequency hearing threshold was proportional to the grade of cochlear hydrops, which was consistent with the previous results. The audiograms of patients with isolated cochlear hydrops consisted largely of up-sloping pattern and flat pattern, which was consistent with the outcomes of Jose E. Alonso.¹⁹

In our study, the characteristics of hearing loss in patients with isolated vestibular hydrops and patients with cochlear and vestibular hydrops were different from those in patients with isolated cochlear hydrops. These patients had hearing loss at both low and high frequencies, with more severe hearing loss at high frequency. And their audiograms consisted mainly of flat pattern and down-sloping pattern. The previous study indicated that there were multiple gradients in the gene expression profile from the base of the cochlea to the apex.^20,21 These gene expression gradients may be related to low- and high-frequency hearing loss. Carmen Martín-Sierra et al. found the expression profile of PKCB II and demonstrated the PRKCB gene was associated with low-frequency hearing.²² In their study, PKCB II was strongly expressed in 2 types of cochlear supporting cells in the apical turn of the cochlea, followed by the cells in the middle and basal turn and, finally, vestibular hair cells. The gradient in gene expression demonstrated that hearing loss varied with the progression of EH. When the apical turn of the cochlea was involved in the early stage, the patients mainly presented with low-frequency hearing loss. And with the development of the disease, the later involvement of the middle and basal turn of the cochlea and vestibule led to the gradual impairment of high-frequency hearing. The viewpoint of Michael Hoa et al. that disease not only affected low-frequency hearing but was also accompanied by corresponding changes in high-frequency hearing was consistent with ours.²³

There are also limitations in this study. This study was retrospective, so we did not follow patients' disease progression in real time and obtain the corresponding imaging data. The sample size of these patients included in our study was small, and a larger sample size is needed in the future to prove our point of view.

Conclusions

Endolymphatic hydrops mainly involves the apical turn of the cochlea in the early stage of the disease, affecting low-frequency hearing. There is a significant correlation between low-frequency hearing loss and cochlear hydrops, and low-frequency hearing threshold is proportional to the grade of cochlear hydrops. In the stage of isolated cochlear hydrops, patients’ audiograms consist largely of flat type and up-sloping type. With the development of hydrops, hydrops involves the whole cochlea and vestibule, which not only affects low-frequency hearing but also high-frequency hearing. The audiograms of patients with isolated vestibular hydrops and patients with cochlear and vestibular hydrops are mainly flat type and down-sloping type.

Footnotes

Declaration of Conflicting Interests

The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This study was supported by the Shanghai Municipal Science and Technology Commission Biomedicine Division Western Medicine Guidance Project under Grant [19411965700].

ORCID iDs

Yue Niu

Yan Sha

References

Hallpike

Cairns

. Observations on the pathology of Ménière's Syndrome: (Section of Otology). Proc R Soc Med. 1938;31(11):1317-1336.

Nakashima

Naganawa

Sugiura

, et al. Visualization of endolymphatic hydrops in patients with Meniere's disease. Laryngoscope. 2007;117(3):415-420.

Inui

Sakamoto

Ito

Kitahara

. Magnetic resonance-based volumetric measurement of the endolymphatic space in patients with Meniere's disease and other endolymphatic hydrops-related diseases. Auris Nasus Larynx. 2019;46(4):493-497.

Karch-Georges

Veillon

Vuong

, et al. MRI of endolymphatic hydrops in patients with vestibular schwannomas: a case-controlled study using non-enhanced T2-weighted images at 3 Teslas. Eur Arch Otorhinolaryngol. 2019;276(6):1591-1599.

Ito

Kitahara

Inui

, et al. Endolymphatic space size in patients with Meniere's disease and healthy controls. Acta Otolaryngol. 2016;136(9):879-882.

Zhang

Hui

Zhang

, et al. The correlation between endolymphatic hydrops and clinical features of meniere disease. Laryngoscope. 2021;131(1):E144-E150.

Fukushima

Kitahara

Oya

, et al. Longitudinal up-regulation of endolymphatic hydrops in patients with Meniere's disease during medical treatment. Laryngoscope Investig Otolaryngol. 2017;2(6):344-350.

Morita

Nakamaru

Fujiwara

, et al. The short- and long-term outcome of intratympanic steroid therapy as a salvage treatment for acute low-tone sensorineural hearing loss without episodes of vertigo. Audiol Neurootol. 2016;21(3):132-140.

Lopez-Escamez

Carey

Chung

, et al. Diagnostic criteria for Menière's disease. J Vestib Res. 2015;25(1):1-7.

10.

Chandrasekhar

Tsai Do

Schwartz

, et al. Clinical practice guideline: sudden hearing loss (Update). Otolaryngol Head Neck Surg. 2019;161(1_suppl):S1-S45.

11.

Alimoglu

Inci

Edizer

Ozdilek

Aslan

. Efficacy comparison of oral steroid, intratympanic steroid, hyperbaric oxygen and oral steroid + hyperbaric oxygen treatments in idiopathic sudden sensorineural hearing loss cases. Eur Arch Otorhinolaryngol. 2011;268(12):1735-1741.

12.

Bernaerts

De Foer

. Imaging of Ménière disease. Neuroimaging Clin N Am. 2019;29(1):19-28.

13.

Nakashima

Naganawa

Pyykko

, et al. Grading of endolymphatic hydrops using magnetic resonance imaging. Acta Otolaryngol Suppl. 2009;129(560):5-8.

14.

Thai-Van

Bounaix

Fraysse

. Menière’s disease pathophysiology and treatment. Drugs. 2001;61(8):1089-1102.

15.

Kimura

. Experimental pathogenesis of hydrops. Arch Otorhinolaryngol. 1976;212(4):263-275.

16.

Lichtenhan

Lee

Dubaybo

Wenrich

Wilson

. The auditory nerve overlapped waveform (ANOW) detects small endolymphatic manipulations that may go undetected by conventional measurements. Front Neurosci. 2017;11:405.

17.

Lichtenhan

Hartsock

Gill

Guinan

Jr Salt

. The auditory nerve overlapped waveform (ANOW) originates in the cochlear apex. J Assoc Res Otolaryngol. 2014;15(3):395-411.

18.

Kimura

Schuknecht

. Membranous Hydrops in the Inner Ear of the Guinea Pig after Obliteration of the Endolymphatic Sac. Pract. ORL. 1965;27(6):343-354.

19.

Alonso

Ishiyama

Fujiwara

RJT

Pham

Ledbetter

Ishiyama

. Cochlear Meniere’s: A distinct clinical entity with isolated cochlear hydrops on high-resolution MRI Front Surg. 2021;8:680260.

20.

Frucht

Uduman

Kleinstein

Santos-Sacchi

Navaratnam

. Gene expression gradients along the tonotopic axis of the chicken auditory epithelium. J Assoc Res Otolaryngol. 2011;12(4):423-435.

21.

Yoshimura

Takumi

Nishio

Suzuki

Iwasa

Usami

. Deafness gene expression patterns in the mouse cochlea found by microarray analysis. PLoS One. 2014;9(3):e92547.

22.

Martín-Sierra

Requena

Frejo

, et al. A novel missense variant in PRKCB segregates low-frequency hearing loss in an autosomal dominant family with Meniere's disease. Hum Mol Genet. 2016;25(16):3407-3415.

23.

Hoa

Friedman

Fisher

Derebery

. Prognostic implications of and audiometric evidence for hearing fluctuation in Meniere's disease. Laryngoscope. 2015;125(suppl 12):S1-S12.