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\begin{document}

\title{The etiologies of hearing loss in Meniere's disease:Impairment of
internal auditory canal barrier}



\author[1]{Weidong Zhang}%
\author[1]{Jiapei Xie}%
\author[2]{Songbai Li}%
\author[2]{Bo Zhang}%
\affil[1]{Henan Provincial People's Hospital}%
\affil[2]{The First Hospital of China Medical University}%


\vspace{-1em}



  
  \date{May 24, 2024}


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\selectlanguage{english}
\begin{abstract}
\textbf{Objective}: The aim of this investigation was to explore the
potential correlation between signal intensity ratio (SIR) at internal
auditory canal (IAC) bottom and hearing impairment in MD, thereby
providing a foundation for further comprehension of the underlying
mechanisms contributing to hearing loss. \textbf{Design}: Fifty patients
diagnosed with unilateral definited MD were enrolled in the study.
3D-FLAIR MRI was conducted four hours after intravenous administration
of gadobutrol to determine the SIR of bilateral IAC bottom. The
difference of SIR of IAC bottom was assessed between affected and
unaffected sides, followed by an analysis of its correlation with low-,
middle-, and high-tone hearing thresholds. Additionally, correlation
analysis was conducted between the degree of EH in vestibular and
cochlea and the SIR on the affected side. \textbf{Results:} The degree
of EH in MD can be clearly visualized through 3D-FLAIR MRI. The SIR on
the affected side was significantly higher than that on the unaffected
side (P=0.000). Furthermore, a positive correlation was observed between
the SIR at the affected and low (r=0.692, P=0.000), middle (r=0.615,
P=0.000) and high-tone (r=0.440, P=0.001); the SIR showed no significant
correlation with cochlear (r=0.315, P=0.088) or vestibular hydrops
(r=0.215, P=0.244). \textbf{Conclusion}: 3D-FLAIR MRI can observe the
degree of EH in MD; impairment of the internal auditory barrier may be
one of the factors of hearing loss in MD.%
\end{abstract}%



\sloppy


\textbf{Introduction}

Meniere's disease (MD) is a multifaceted disorder of the inner ear,
characterized by fluctuating sensorineural hearing loss, episodic
vertigo, tinnitus and aural fullness \textsuperscript{1}. It is commonly
regarded as a midlife disorder, with an average onset age of 40 to 50
years and an incidence rate of about 513/100,000\textsuperscript{2}. Its
etiology and pathogenesis remain unknown and may be associated with
autoimmune, genetic, neurophysiological, cellular, and molecular
mechanisms. Currently, endolymphatic hydrops(EH) is generally considered
its pathological hallmark\textsuperscript{3}.

According to the 2015 diagnostic criteria, all patients with definited
MD exhibit varying degrees of hearing loss\textsuperscript{4}. A wealth
of clinical data has demonstrated that low-frequency hearing declines in
the early stages of MD, while middle- and high-frequency hearing
gradually deteriorate as the condition progresses\textsuperscript{5}.
The sound is transmitted to the cochlea via the auditory pathway, where
it causes eardrum vibration and activates auditory receptors in the
cochlea. These receptors convert acoustic vibrations into nerve impulses
that travel along the auditory nerve to reach the brain's auditory
center. Disruption of any aspect within this process may result in
hearing loss. The bipolar cells located in the spiral ganglion serve as
the primary neurons for auditory conduction. Their peripheral processes
are distributed among inner ear hair cells, while their central
processes form the cochlear nerve responsible for transmitting auditory
signals to the brain. Research has demonstrated a strong correlation
between EH and degeneration of spiral ganglion cells within the
cochlea\textsuperscript{6}; Megerian et al. discovered a significant
reduction in the maximum diameter of the auditory nerve in mice with
EH\textsuperscript{7}. We hypothesize that EH plays a significant role
in the development of hearing loss in patients with MD. However, it
remains unclear whether other factors contribute to this condition and
further investigation is warranted.

With the continuous advancement of magnetic resonance technology in
recent years, visualization of EH has gradually become feasible and is
now being applied in clinical practice. Intravenous administration of
contrast agents enables simultaneous imaging of bilateral inner ear
structures while also reflecting blood-labyrinth barrier permeability
through signal intensity ratio of cochlear basal tur\textsuperscript{8}.
Therefore, the signal intensity ratio can serve as a reliable indicator
for permeability estimation and barrier integrity assessment at specific
locations.

The internal auditory canal (IAC) is a crucial component of the inner
ear, characterized by intricate anatomical architecture. It houses vital
blood vessels (labyrinthine artery) and nerves (facial nerve,
vestibulocochlear nerve). In patients with non-sudden sensorineural
hearing loss, Three-dimensional fluid-attenuated inversion recovery
(3D-FLAIR) MRI scanning after intravenous injection of gadolinium
contrast agent reveals higher signal intensity in the IAC bottom on the
affected side compared to the normal side\textsuperscript{9}; this may
be related to the patient's hearing loss. We hypothesize that a
potential obstruction exists at the IAC bottom, and its destruction may
result in hearing impairment.

All patients diagnosed with definited MD exhibit hearing loss. Our
hypothesis suggests that the IAC bottom may be compromised in these
individuals, yet no research has specifically examined the signal
intensity of this region and its correlation to hearing loss; The
objective of this investigation was to examine whether the signal
intensity of the IAC bottom alters in MD patients following intravenous
administration of gadolinium contrast agent, and to investigate its
correlation with hearing loss.

\textbf{Materials and Methods}

\textbf{The patient}

This study was observational study(cross-sectional study). According to
the diagnostic criteria established by the American Academy of
Otolaryngology, Head and Neck Surgery in 2015\textsuperscript{4}, a
total of 50 patients with unilateral definited MD at the Department of
Otolaryngology in the First Hospital of China Medical University from
November 2020 to December 2021 were included. There were 21 male and 29
female patients, aged between 28 to 74 years old, with an average age of
56 years old. Among them, there were 31 cases of left ear and 19 cases
of right ear. All patients underwent physical examination and medical
history collection by professional otologists. They all presented with
varying degrees of hearing loss in the affected ear, persistent tinnitus
and intermittent vertigo.

None of the patients had a history of gadolinium contrast allergy,
neurogenic deafness or otitis media, or ear surgery. This study was
approved by the Medical Ethics Committee of our Hospital (2018-298-2),
and all patients provided informed consent for MRI enhancement.

\textbf{MRI image scanning}

All patients received a double dose (0.2ml/kg) of gadobutrol
intravenously (Bayer Pharmaceuticals, specifications: 7.5ml/ tube,
1.0mol/L), 3D-FLAIR sequence scan was performed after a 4-hour delay
using a 3T MR Scanner (GE signa pioneer 3.0T) and matching 21-channel
head coil.

Before the contrast agent is injected, whole-brain T2 FLAIR scan (TE
95ms, TR 9000ms, Slice Thickness 5mm, FOV 24*0.9, TI 2468ms, Matrix Size
256*256, Echo Train Length 22, Acceleration Factor 1, Scan Time 1 min
and 57 sec), inner ear scanning 3D FIESTA C Shim (TE 95ms, TR 6.6ms,
Acceleration Factor 2, TI 3.1ms, Matrix Size 256*256, FOV 18*1, Slice
Thickness 0.8mm, Scan Time 3 min and 37 sec) were performed. After an
injection of gadolinium, 3D-FLAIR sequence scan (TE 189ms, TR 9000ms,
Acceleration Factor 4, TI 2134ms, Slice Thickness 1mm, FOV 22*0.8,
Matrix Size 320*320, Echo Train Length 180, Scan Time 10 min and 52 sec)
was performed.

\textbf{Image analysis}

The routine sequence is utilized for the purpose of excluding neoplastic
lesions of the brain and inner ear, as well as malformations of the
inner ear. According to Kim's method of measuring signal
intensity\textsuperscript{9}, we selected a 4 mm2 region of interest
located at the optimal display position of the bilateral inner auditory
canal bottom, we conducted three measurements and calculated the average
value. A 50mm2 region of interest (ROI) was selected from the bilateral
cerebellar white matter at the same level (\textbf{Figure1a} ). The
signal intensity ratio between the average signal intensity at the IAC
bottom on the affected side and unaffected side were calculated. The
signal intensity ratio served as an indicator of the extent of
enhancement at the IAC bottom, while our previous measurements were
utilized to evaluate the degree of cochlear and vestibular
hydrops\textsuperscript{8, 10}. The images of all patients were assessed
in a double-blind manner by two experienced imaging diagnostic
physicians with 30 years of expertise, and the mean value of their
measurements was calculated.

\textbf{Statistical Analysis}

SPSS 22.0 software was used for data analysis, and data conforming to
normal distribution were expressed as mean \selectlanguage{ngerman}± standard deviation. Paired
sample T test was used to analyze the difference in the signal intensity
of the IAC between the affected and unaffected sides. Pearson
correlation was utilized to examine the association between low, middle,
and high tone hearing thresholds, cochlear and vestibular hydrops, as
well as signal intensity of the IAC on the affected side. A statistical
difference was observed when P\textless{}0.05.

\textbf{Results}

No other abnormal lesions were detected in the brain or inner ear. The
images of all patients were clear, and structures such as the cochlea,
vestibule, semicircular canal, and IAC could be distinctly identified.
In all cases, there was enhancement of the perilymphatic space with a
clear demarcation between endolymph and perilymph; furthermore, varying
degrees of EH were observed in each patient (\textbf{Figure1b} ). The
signal intensity at the IAC bottom is illustrated in \textbf{Figure 2} .
The low, middle, and high tone were 57.72±16.10 dB, 56.16±19.87 dB,
66.20±17.56 dB, respectively. Cochlear and vestibular hydrops were
0.39±0.20 and 0.44±0.17, respectively. The signal intensity ratios of
the affected and unaffected internal auditory channels were 4.72±0.70
and 3.76±0.80, respectively.

The signal intensity ratio of the IAC on the affected side exhibited a
statistically significant increase compared to that on the unaffected
side (\textbf{Figure3} ). The Pearson correlation analysis revealed a
significant positive correlation between the hearing threshold of low,
middle and high tones and the signal intensity ratio of the IAC bottom
(\textbf{Table 1} ). The scatter diagram depicting this relationship is
presented in \textbf{Figure 4} . The signal intensity of the IAC bottom
did not show a significant correlation with cochlear and vestibular
hydrops (\textbf{Table 1} ).

\textbf{Discussion}

According to the 2015 diagnostic criteria, hearing loss is a necessary
component for definitive clinical diagnosis of MD, highlighting its
pivotal role in the pathogenesis of this condition. However, the
underlying mechanisms leading to hearing loss remain poorly understood.
After intravenous administration of gadolinium, the 3D-FLAIR sequence
offers distinct advantages in visualizing EH and plays a pivotal role in
diagnosing MD\textsuperscript{11, 12}. In this study, a 3D-FLAIR scan
was conducted four hours after double-dose gadobutrol injection,
revealing varying degrees of EH among all patients. However, our study
also revealed a statistically significant enhancement in signal
intensity at the IAC bottom on the affected side of the patient compared
to the unaffected side. This suggests that the contrast agent permeates
more deeply into IAC bottom of the affected than the unaffected side,
potentially due to compromised barrier integrity on the affected side.
So, does it affect hearing? Therefore, further investigation is
necessary to determine its impact on hearing.

In this study, we further investigated the correlation between the
signal intensity ratio of the IAC and hearing levels. Our analysis
revealed a significant correlation between signal intensity at the IAC
bottom and low, middle, and high-tone hearing loss. The IAC contains
vital anatomical structures such as nerves and blood vessels, whose
integrity is crucial for optimal hearing function. Disruption of the IAC
barrier can result in nerve damage, leading to hearing loss; the
severity of hearing loss is directly proportional to the extent of
damage to the IAC barrier. Similar to our study, in patients with
neurogenic deafness, the signal intensity at the IAC bottom was observed
to be higher on the affected side than on the unaffected
side\textsuperscript{9}, which is believed to be associated with hearing
loss on the affected side; Labyrinthitis is a prominent etiology of
sensorineural hearing loss\textsuperscript{13}, and certain
investigations have demonstrated that patients with labyrinthitis
exhibit conspicuous enhancement of the labyrinth and IAC bottom on
enhanced MRI, implying an association with hearing
impairment\textsuperscript{14, 15}. Therefore, we hypothesize that a
barrier exists at the IAC bottom, and its disruption results in hearing
impairment in the affected ear.

Studies indicate that EH can result in significant loss of spiral
ganglion cells located at the cochlea apex, and this loss is closely
associated with the severity of EH\textsuperscript{6}; Other studies
have demonstrated a consistent pattern of spiral ganglion cell loss
progressing from the cochlear apex to the base, which aligns with the
progression of EH\textsuperscript{16}; Currently, numerous studies have
demonstrated a positive correlation between the degree of EH and hearing
loss in patients diagnosed with MD\textsuperscript{10, 17, 18}.
Therefore, it is our belief that EH may serve as a contributing factor
to hearing loss among individuals afflicted with this condition.

We observed a positive correlation between the signal intensity of the
inner auditory canal bottom and hearing loss on the affected side in
patients with MD. However, there was no significant correlation found
between this signal intensity and the degree of cochlear and vestibular
hydrops. Therefore, we hypothesize that the changes in signal intensity
at the affected side's IAC bottom are not directly associated with EH,
but rather caused by destruction of the barrier within the canal. In
conclusion, it is postulated that the disruption of the IAC barrier in
MD patients may contribute to hearing impairment. The destruction of
this barrier can potentially harm the auditory nerve traversing through
it, ultimately leading to hearing loss.

\textbf{Limitation}

Our study has several limitations.

1. Because EH cannot be detected pathologically in vivo, the presence of
EH cannot be confirmed through pathological means in this study.
Therefore, animal experiments are necessary to further validate our
hypothesis.

2. Our study was limited by the absence of a healthy control group, and
previous research has indicated that unilateral MD may progress to
bilateral involvement over time\textsuperscript{19}. Although no EH or
hearing loss were detected in the unaffected side of our patients, it is
possible that some microscopic structures have undergone changes, which
could potentially impact the precision of our findings.

\textbf{Conclusion}

Intravenous administration of a double dose of gadobutrol is a viable
method for assessing EH in MD. The disruption of the internal auditory
barrier may be one contributing factor to hearing loss in MD.

\textbf{References}

1. Pyykko I, Nakashima T, Yoshida T, et al. \emph{Meniere's disease: a
reappraisal supported by a variable latency of symptoms and the MRI
visualisation of endolymphatic hydrops.} BMJ Open, 2013.\textbf{3}
(2):1-10.

2. Havia M, Kentala E, Pyykkö I, et al. \emph{Prevalence of Menière's
Disease in General Population of Southern Finland.} Otolaryngol Head
Neck surg, 2005. \textbf{133} (5):762-768.

3. Hallpike CS, Cairns H. \emph{Observations on the pathology of
Menie`re's syndrome.} Proc R Soc Med, 1938. \textbf{31} (11):
1317--1336.

4. Lopez-Escamez JA, Carey J, Chung WH, et al. \emph{Diagnostic criteria
for Meniere's disease.} J Vestib Res, 2015. \textbf{25} (1):1-7.

5. Belinchon A, Perez-Garrigues H, Tenias JM, et al. \emph{Hearing
assessment in Meniere's disease.} Laryngoscope, 2011.\textbf{121}
(3):622-6.

6. Bixenstine PJ, Maniglia MP, Vasanji A, et al. \emph{Spiral ganglion
degeneration patterns in endolymphatic hydrops.} Laryngoscope,
2008.\textbf{118} (7):1217-23.

7. Megerian CA. \emph{Diameter of the cochlear nerve in endolymphatic
hydrops: implications for the etiology of hearing loss in Meniere's
disease.} Laryngoscope, 2005. \textbf{115} (9):1525-35.

8. Zhang W, Xie J, Hui L, et al. \emph{The Correlation Between
Endolymphatic Hydrops and blood-labyrinth barrier Permeability of
Meniere Disease.} Ann Otol Rhinol Laryngol, 2021.\textbf{130}
(6):578-584.

9. Kim TY, Park DW, Lee YJ, et al. \emph{Comparison of Inner Ear
Contrast Enhancement among Patients with Unilateral Inner Ear Symptoms
in MR Images Obtained 10 Minutes and 4 Hours after Gadolinium
Injection.} AJNR Am J Neuroradiol, 2015. \textbf{36} (12):2367-72.

10. Zhang W, Hui L, Zhang B, et al. \emph{The Correlation Between
Endolymphatic Hydrops and Clinical Features of Meniere
Disease.}Laryngoscope, 2020. \textbf{131} (1):1-7.

11. Xie J, Zhang W, Zhu J, et al. \emph{Differential Diagnosis of
Endolymphatic Hydrops Between ''Probable'' and ''Definite'' Meniere's
Disease via Magnetic Resonance Imaging.} Otolaryngol Head Neck Surg,
2021. \textbf{165} (5):696-700.

12. Xie J, Zhang W, Zhu J, et al. \emph{Comparison of inner ear MRI
enhancement in patients with Meniere's disease after intravenous
injection of gadobutrol, gadoterate meglumine, or gadodiamide.} Eur J
Radiol, 2021. \textbf{139} :109682.

13. Huang BY, Zdanski C, Castillo M. \emph{Pediatric sensorineural
hearing loss, part 2: syndromic and acquired causes.} AJNR Am J
Neuroradiol, 2012. \textbf{33} (3):399-406.

14. Hwang M, Zuccoli G. \emph{Rapidly Destructive Autoimmune
Labyrinthitis Associated With Ulcerative Colitis.} Pediatr Neurol,
2015.\textbf{53} (4):375-6.

15. Benson JC, Carlson ML, Lane JI. \emph{MRI of the Internal Auditory
Canal, Labyrinth, and Middle Ear: How We Do It.} Radiology,
2020.\textbf{297} (2):252-265.

16. Semaan MT, Zheng QY, Han F, et al. \emph{Characterization of
Neuronal Cell Death in the Spiral Ganglia of a Mouse Model of
Endolymphatic Hydrops.} Otol Neurotol, 2013. \textbf{34} (3):559-569.

17. Shi S, Guo P, Li W, et al. \emph{Clinical Features and Endolymphatic
Hydrops in Patients With MRI Evidence of Hydrops.} Ann Otol Rhinol
Laryngol, 2019. \textbf{128} (4):286-292.

18. Yang S, Zhu H, Zhu B, et al. \selectlanguage{english}\emph{Correlations Between the Degree
of Endolymphatic Hydrops and Symptoms and Audiological Test Results in
Patients With Menière's Disease.} Otology \& Neurotology,
2018.\textbf{39} (3):351-356.

19. Huppert D, Strupp M, Brandt T. \emph{Long-term course of Meniere's
disease revisited.} Acta Otolaryngol, 2010. \textbf{130} (6):644-51.

\textbf{Figure1 a} : The optimal layer was shown at the bilateral
internal auditory canal bottom on 3D-FLAIR image. A
4mm\textsuperscript{2} ROI was drawn on the bilateral internal auditory
canal bottom and a 50mm\textsuperscript{2} ROI was drawn on the
cerebellar hemisphere of the corresponding layer.

\textbf{b} : Endolymphatic hydrops in patients with Meniere's disease on
the right side. Arrow: cochlear hydrops; Triangle: vestibular hydrops.

\textbf{Figure2} : Endolymphatic hydrops in patients with Meniere's
disease on the right side. Thick arrow: affected side (signal intensity
ratio: 5.18); Thin arrow: unaffected side (signal intensity ratio: 2.7).

\textbf{Figure3} : The signal intensity ratio at the auditory canal
bottom on the affected side was significantly higher than that on the
unaffected side (P=0.000).

\textbf{Figure4:} Correlation of signal intensity ratio of internal
auditory canal and low, middle and high tone hearing thresholds in
patients with Meniere's disease.\selectlanguage{english}
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