Clinical Imaging 39 (2015) 26–31
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Delayed intravenous contrast-enhanced 3D FLAIR MRI in Meniere’s disease: correlation of quantitative measures of endolymphatic hydrops with hearing☆,☆☆ Ali R. Sepahdari a,⁎, Gail Ishiyama c, Nopawan Vorasubin b, Kevin A. Peng b, Michael Linetsky a, Akira Ishiyama b a b c
Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA USA Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA USA Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA USA
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Article history: Received 12 February 2014 Received in revised form 14 August 2014 Accepted 9 September 2014 Keywords: Inner ear Meniere's disease Endolymphatic hydrops 3D FLAIR
a b s t r a c t Objective: Using three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging (3D-FLAIR MRI), our goal was to correlate quantifiable measures of endolymphatic hydrops (EH) with auditory function in the setting of Meniere’s disease (MD). Materials and methods: Forty-one ears were analyzed in 21 subjects (12 ears with MD, 29 without MD). Vestibular endolymphatic space size measurements obtained with two different techniques were referenced against clinical data. Results: EH was better evaluated on 3D maximum intensity projections (MIPs) than on two-dimensional (2D) images. Using MIPs, quantitative assessments EH correlated with severity of hearing impairment. Conclusion: 3D MIPs were superior to 2D images for evaluating EH in the setting of MD. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Meniere’s disease (MD) is an incompletely understood syndrome which presents with the classical tetrad of sensorineural hearing loss (SNHL), tinnitus, vertigo, and aural fullness [1]. Postmortem histopathological studies demonstrate a ballooning of the endolymphatic system, endolymphatic hydrops (EH), that remains the gold standard to confirm the diagnosis of MD. The availability of an imaging modality that enables the clinician to quantify the degree of EH and vestibular endolymphatic space (VES) size would be invaluable as an adjunctive diagnostic tool. Additionally, the ability to correlate VES size and EH with clinical parameters in MD and other inner ear disorders is critical to advance our understanding of otological diseases. In general, neither computed tomography (CT) nor conventional magnetic resonance imaging (MRI) is able to distinguish endolymph from perilymph in the inner ear, and EH, the primary pathologic alteration in MD, is therefore impossible to detect by conventional imaging. CT and MRI are important to rule out other causes of hearing loss and can be used to assess for anatomy that may be associated with EH. Prior studies focused on measuring the caliber of the vestibular aqueduct, operating on the hypothesis that narrowing of the aqueduct produces hydrops through impaired longitudinal flow of endolymph ☆ This work has not been previously presented. ☆☆ We have no extramural funding to report. ⁎ Corresponding author. 757 Westwood Blvd, Suite 1621D, Los Angeles, CA 90095. Tel.: +1 310 267 6708; fax: +1 310 267 3635. E-mail address: [email protected] (A.R. Sepahdari). http://dx.doi.org/10.1016/j.clinimag.2014.09.014 0899-7071/© 2015 Elsevier Inc. All rights reserved.
[2–4]. These findings have not gained widespread clinical use, and this pathological mechanism has been challenged [5]. MRI with contrast-enhanced fluid-attenuated inversion recovery (FLAIR) imaging has been explored as an imaging technique to distinguish the perilymphatic and endolymphatic compartments, including studies using intratympanic injections of gadolinium-based contrast agent (GBCA) and studies that imaged patients at a 4-h delay after intravenous GBCA injection [6–17]. Both of these techniques result in an accumulation of dilute contrast agent in the perilymph, which appears bright by FLAIR imaging due its sensitivity to T1 shortening. The membranous labyrinth, which is impermeable to contrast due to the presence of tight junctions, appears as a signal void on these images, allowing for evaluation of an increase in VES size, i.e., EH. Though the prior studies provide support for the potential use of contrast-enhanced FLAIR MRI to detect EH, they have not validated criteria for determining hydrops with a robust quantitative analysis. Furthermore, none of these studies have assessed for a quantitative relationship between EH and clinical function, which would further validate the results. The purposes of our study were to (a) establish quantitative criteria for EH using delayed intravenous contrast-enhanced 3D-FLAIR MRI, specifically comparing the results 3D image analysis with conventional two-dimensional (2D) images; (b) validate the quantitative criteria for diagnosing EH by establishing a qualitative analysis that is reproducible and that correlates with the quantitative criteria; and (c) assess for and confirm the relationship between EH and auditory function in the setting of MD.
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2. Methods 2.1. Subjects The American Academy of Otolaryngology-Head and Neck Surgery criteria for definite MD were used to establish the diagnosis of MD [1]. With Institutional Review Board approval, a waiver of Health Insurance Portability and Accountability Act authorization, and a waiver of informed consent, a prospectively created database of patients imaged with delayed intravenous contrast-enhanced 3D-FLAIR MRI was reviewed. A total of 27 consecutive patients were imaged from November 2012 through March 2013 and were followed clinically. One patient was lost to follow-up and not included in the study. Clinical diagnoses in the remaining 26 patients revealed 11 patients with MD (9 unilateral, 2 bilateral), 4 patients with delayed EH, and 11 patients with sudden SNHL (9 unilateral, 2 bilateral). Subjects with delayed EH were excluded from analysis, given that the pathophysiology may differ from MD. The symptomatic ear in one patient was excluded from analysis because of previous endolymphatic sac shunt surgery. The final analysis group consisted of 41 ears in 22 subjects, 11 men and 11 women, with average age of 55years (range: 27–75). 2.2. Imaging technique All patients were imaged on a 3-T scanner using a 16-channel head and neck coil (Skyra; Siemens Healthcare, Erlangen, Germany) at 4 h postadministration of 0.2 mmol/kg gadodiamide intravenous contrast (Magnevist; Bayer HealthCare). Patients with abnormal renal function were excluded from imaging per institutional policy. Imaging consisted of three sequences: (a) “Cisternographic” 3D turbo spin echo T2 (T2 SPACE: sampling perfection with application-optimized contrasts by using different flip angle evolutions), (b) variable flip angle 3D turbo spin echo T2-weighted FLAIR (SPACE FLAIR), and (c) heavily T2weighted (hT2w)-3D-FLAIR. All sequences were acquired in the axial plane along the infraorbitomeatal line. The T2 SPACE sequence was acquired with the following parameters: slice thickness: 1 mm, repetition time (TR)/echo time (TE): 1430/ 265 ms, number of averages: 2, echo train length: 98, flip angle: 140, matrix: 320×320, and field of view (FOV): 200×200 mm. The SPACE FLAIR sequence was acquired with the following parameters: slice thickness: 0.8 mm, TR/TE: 6000/338 ms, inversion time: 2100 ms, number of averages: 2, echo train length: 215, flip angle: 120 (variable), matrix: 256×256, FOV: 184×184 mm, acquisition time: 4 min and 31 s. The hT2w 3D-FLAIR sequence was acquired with the following parameters: slice thickness: 0.8 mm, TR/TE: 9000/534 ms, inversion time: 2350 ms, number of averages: 2, echo train length, 144, flip angle: 120, matrix: 320×260, FOV: 200×167 mm, acquisition time: 6 min and 45 s. 2.3. Image analysis The cisternographic T2-weighted images and the 3D-FLAIR images were reviewed side by side. Bright signal in the labyrinth on the cisternographic T2-weighted images represented both perilymphatic and endolymphatic fluid. Bright signal on the 3D-FLAIR represented only perilymphatic fluid. Internal dark signal within the labyrinth on 3DFLAIR represented only endolymphatic fluid (Fig. 1). The hT2w-3DFLAIR images demonstrated superior differentiation between endolymph and perilymph and were used for further analysis. The isotropic hT2w-3DFLAIR images were reformatted in the plane of the lateral semicircular canal (LSC) to maintain intersubject consistency in measurements. The images were made anonymous, transferred to an Osirix workstation (Osirix v5.1.1, Geneva, Switzerland), and assessed quantitatively by a subspecialty certified neuroradiologist, who was blinded to the clinical data, using 2D images. The images were first assessed using a previously described technique [8]: the axial image through the vestibule at the level of the LSC was identified. A freehand region of interest
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(ROI) was drawn around the VES, and ROI area was recorded. A second freehand ROI was drawn around the entire vestibule, which included both the vestibular perilymph (bright signal) and the vestibular endolymph (dark signal). The VES/vestibule ratio was then calculated (Fig. 2). One month later, the same observer performed similar measurements using 3D maximum intensity projection (MIP) reconstructions. The hT2w-3D-FLAIR images were reconstructed as a single 3D MIP image, viewed from below, oriented to demonstrate both vestibules without overlap from the cochlea or semicircular canals. The VES was consistently seen as a dumbbell-shaped signal void, or as two small signal voids, in the center of the vestibule on these images. The VES/vestibule ratio was calculated using the same measurement parameters as those used for the source images. 2.4. Statistical analysis Using the American Academy of Otolaryngology-Head and Neck Surgery criteria for definite MD, the VES/vestibule ratios corresponding to MD were segregated from those corresponding to non-MD. An unpaired Student’s t test was used to assess for statistical differences between the VES/vestibule ratio in MD vs. non-MD. The unpaired Student’s t test was conducted for the 2D MRI data and the 3D MRI data separately. Descriptive statistics of mean and standard deviation were obtained for the 2D and 3D measurements. The quantitative 3D data and 2D data were compared to each other using Pearson correlation and using Bland–Altman method comparison. The proportion of MD ears that showed evidence of hydrops was determined for the 2D data and the 3D data separately. Qualitative analysis was performed to validate the quantitative assessment of VES/vestibule ratio. The MIP images were reviewed by the original observer and by a second subspecialty-certified neuroradiologist. Each neuroradiologist evaluated the MIP images independently, blinded to the clinical diagnoses, and evaluated the images as EH or not EH based on whether the VES appeared to occupy more than 45% of the vestibule (2 standard deviations above the mean of the non-MD ears). Fisher’s Exact Test was used to determine whether the qualitative interpretations of each observer matched the clinical diagnoses. Interobserver agreement was tested using Cohen’s kappa. Six months after this initial analysis, both observers also independently evaluated the 2D images through the level of the LSC in each ear and made a determination of whether an ear was involved by significant hydrops based on criteria described by Nakashima et al. [8]. As with the 3D data, Fisher’s Exact Test was used to determine whether the qualitative interpretations of each observer matched the clinical diagnoses. Interobserver agreement was tested using Cohen’s kappa. VES/vestibule ratio was also compared with audiogram results, obtained within 1 to 2 months of the MRI used for the study. The audiogram pure tone average (PTA) and word recognition score (WRS) were correlated with the VES/vestibule ratio in subjects with MD using Spearman rank order correlation. Pb.05 was used to determine statistical significance for all statistical tests. 3. Results The VES/vestibule ratio was significantly higher in MD ears compared with non-MD ears using both 2D image measurement (P=.003) and 3D MIP measurements (Pb .0001). However, there was greater overlap between MD and non-MD ears using the 2D source image measurements, with overlapping 95% confidence intervals (CIs) (Fig. 3). There was no overlap of the 95% CIs when using the 3D MIP data, despite a broad distribution of values in the EH group. Table 1 summarizes these results. Pearson correlation showed a strong relationship between the 3D and 2D quantitative data (Pb.0001). Bland–Altman method comparison showed a bias of 0.1 between 3D and 2D quantitative data, with a standard deviation of 0.16. Review of the Bland–Altman plot shows greatest variation between 3D and 2D measurements among
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Fig. 1. Normal inner ear MRI. (A) Axial cisternographic T2 through the level of the LSC shows normal hyperintense fluid signal in the labyrinth. (B) Axial 3D-FLAIR source image shows low signal in the vestibular endolymphatic structures and bright signal throughout the perilymphatic spaces, including the LSC, cochlea, and posterior semicircular canal. (C) 3D-FLAIR source image, slightly inferior to (B), shows normal perilymph in the anterior and inferior portion of the vestibule. (D) 3D MIP reconstruction shows small size of the endolymphatic structures relative to the vestibule.
subjects with VES/vestibule ratios in the 0.4–0.6 range (Fig. 3), which is especially relevant in discriminating between mild hydrops and a normal ear.
Using 3D data, 67% (8/12) of MD ears showed hydrops. Fisher’s Exact Test showed that qualitative assessments by both observers were significantly related to clinical diagnoses (Pb.002 for both observers).
Fig. 2. Quantitative assessment of vestibular endolymphatic structure size, using 2D source images and 3D MIPs, in a normal ear (A, B) and an ear involved by MD (C, D). (A) 2D source image freehand ROIs drawn around the vestibule and vestibular endolymph on the axial image through the level of the LSC. The endolymph/vestibule ratio is calculated. (B) 3D MIP method: a 3D MIP is created from the source images, and viewed from below, oriented to eliminate overlap between the cochlea, vestibule, and semicircular canals. Measurements are obtained as in (A). (C and D) Hydrops, which is visible on gross inspection.
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Fig. 4. A plot of PTA hearing loss in decibels (dB) against VES/vestibule ratio in MD ears, based on 3D MIP, shows a moderate correlation between hearing loss and VES enlargement.
Fig. 3. Quantitative assessment of vestibular endolymphatic structures (VES). (A) Mean and 95% CIs for VES/vestibule ratio using 2D measurements through the LSC show apparent dilation of the VES in affected ears with MD compared to asymptomatic (asx) ears in MD patients, symptomatic (sx) ears and asymptomatic ears in sudden SNHL patients, and all non-MD ears in aggregate. However, note the overlapping 95% CIs. (B) Measurements based on 3D MIP show greater differences between MD ears and non-MD ears, with no overlap in the 95% CIs. (C) Bland–Altman plot of difference vs. average for 2D and 3D measurements of each ear reveals a relatively wide variation in quantitative measurements for subjects with VES/vestibule ratios near 0.4, which is close to the cutoff between normal and abnormal. This suggests that the increased variability in 2D measurements may affect the clinical performance of the test.
Table 1 Comparison between 2D and 3D quantitative assessments of VES size
EH ear VES/vestibule ratio (mean±S.D.) Non-EH ears VES/vestibule ratio (mean±S.D.)
2D quantitative
3D MIP quantitative
0.62±0.24 0.44±0.13
0.59±0.29 0.32±0.06
Furthermore, the qualitative reads closely matched the quantitative data, with an impression of hydrops in the same eight MD ears and impression of no hydrops in the same four MD ears for both observers. When using 3D MIPs, the subjective interpretations of the two observers were 91% concordant overall, with κ=0.76 (95% CI: 0.53–0.98). Using 2D data, 50% (6/12) of the MD ears showed hydrops, as determined by VES/vestibule ratio more than 2 standard deviations above the mean of the non-MD group. Fisher’s Exact Test did not show a significant relationship between qualitative interpretations of hydrops and a clinical diagnosis of MD. The qualitative reads showed only 68% concordance between observers, with κ=0.31 (95% CI: 0.01–0.61). In 12 MD ears, the VES/vestibule ratio based on 3D MIP images showed a significant, strong positive correlation with PTA (Spearman ρ=0.89, P=.0003)with greater degrees of EH as assessed by VES/ vestibule ratio associated with more severe hearing loss (Fig. 4). There was also a significant, moderate correlation between VES/vestibule ratio and WRS in MD (Spearman ρ=0.67, P=.02). In contrast, there was no significant relationship between 2D source image VES/vestibule ratio and PTA (Spearman ρ=0.42, P=.17) or WRS (ρ=0.49, P=.11). In 12 sudden SNHL ears, there was no significant relationship between VES/ vestibule ratio and hearing loss using either 2D or 3D measurements. Vestibular endolymph and perilymph were easily distinguished on multiple sequential slices in all cases. The ability to distinguish endolymph from perilymph and bone was most apparent at the level of the LSC, and VES dilation was sometimes seen on 2D images through this level (Fig. 2). At other levels, closer to the edges of the bony labyrinth, endolymph was difficult to distinguish from that of bone, given their similarly low signal. Despite optimal contrast between endolymph and perilymph at the level of the LSC, VES enlargement was not always seen at this level on 2D images in subjects with clinical MD and abnormal 3D MIP images (Fig. 5), demonstrating the superior imaging characteristics of MIP projections for the analysis of VES/vestibule ratio and EH. 4. Discussion This study demonstrated the consistent and reproducible ability to differentiate the perilymphatic and endolymphatic compartments using delayed intravenous contrast-enhanced 3D-FLAIR MRI. This methodology is preferred over intratympanic injection of GBCA due to potential complications of infection, persistent tympanic membrane perforation, and pain. 3D MIP imaging allowed for less overlap in appearance between MD and non-MD ears, with better ability to detect EH as evidenced by increased VES/vestibule ratio. Quantitative assessments of EH were replicated by qualitative assessments that were reproducible by a second neuroradiologist. The degree of VES dilation, assessed by the VES/vestibule ratio using 3D MIP-based measurements, was strongly statistically positively correlated with poorer auditory function, assessed by PTA and WRS, in the symptomatic ears of MD
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Fig. 5. EH in a 66-year-old man with MD demonstrated with MIP but not with source images. (A) 2D source image through the level of the LSC shows apparently normal size of the vestibular endolymphatic structures (VES), which appear as a signal void surrounded by adequate bright perilymph (arrow). (B) 3D MIP image shows relative enlargement of the VES, with effacement of the surrounding perilymph. Compare to normal ears shown in Figs. 1 and 2.
patients, but not in other ears. 2D images through the LSC were not as effective as 3D MIPs in evaluating hydrops. Despite statistically significant differences between MD ears and non-MD ears using 2D data, the results could not be reproduced by qualitative analysis, the interpretations were not reproducible between observers, and there was no relationship between quantitative VES/vestibule ratio and tests of auditory function. Although the 3D data and the 2D data were strongly correlated, this was due largely to the fact that the data were widely distributed. The poor clinical performance of the 2D images compared to 3D images was likely related to the degree of variability within the range of values that discriminates mild hydrops from a normal ear, as demonstrated by Bland–Altman method comparison. The use of MRI to distinguish endolymph from perilymph was first reported in multiple studies from Naganawa et al. [12,14–16,18]. Our results provide needed confirmation of those initial reports with detailed clinical parameters. Naganawa et al. and others [6] have used various quantitative, semiquantitative, and qualitative techniques for identifying hydrops in the vestibule based primarily on source image evaluation [6,8,10]. However, the methods used in these prior studies were not validated through analysis with a control group and have not been tested for reproducibility. Using image analysis based on 3D MIP, we present data demonstrating superior ability to distinguish EH from non-EH as compared to a 2D source image-based technique. The 3D MIP-based method we used offered certain advantages over 2D image-based methods. One advantage of 3D MIPs is the ability to evaluate the VES/vestibule for hydrops in the anterior/inferior vestibule, a region that has a known predilection for involvement in MD [19]. This anatomic region is not assessed on source images through the level of the LSC and, in general, is difficult to assess on source images because of difficulty distinguishing endolymph from bone. Orienting the MIP such that both vestibules could be seen without overlap from the cochlea or semicircular canals on either side resulted in a consistent appearance of the vestibule. We also noted that source images are also susceptible to variability based on the imaging plane used, a factor that was corrected for in this study by performing careful axial reformations in all cases. Notably, this factor was not corrected for in previous studies. Imaging the membranous labyrinth during attacks and between attacks could deepen our understanding of the pathophysiology of otopathologies, leading to new therapeutic strategies and/or imaging markers to monitor disease status and effectiveness of treatment. Further investigations of delayed intravenous contrast-enhanced 3D-FLAIR MRI would benefit from simultaneous pursuit of two objectives: continued improvement in image quality and investigation of the relationship between imaging and clinical course. A significant minority (4/12) of the MD ears in our study did not show enlargement of the VES, consistent with the findings of Seo et al.
[6]. However, in all MD patients with EH in our study, there was significant hearing loss. It is important to note that the correlation between MD and histopathologically confirmed EH was made on postmortem temporal bone studies [5]. Prior to the development of MRI to assess for EH, the inner ear was inaccessible during the lifetime, and conventional techniques of pathological study including delineation of anatomical structures were not possible. Therefore, human temporal bone (HTB) studies were, by necessity, postmortem examinations, and thus the majority of HTB specimens were obtained from late stage MD. It is possible that dilation of the endolymphatic space only occurs some time after developing symptoms and, therefore, possible that some subjects in our study had normal findings due to being imaged early in their disease course. It is also possible that histological data are skewed toward more severe disease in HTB donations. The strong correlation between anatomic hydrops and impaired auditory function in our population with clinical MD would be consistent with the hypothesis of a lack of EH in mildly symptomatic MD. A third potential explanation is that hydrops is a fluctuating abnormality. There was an apparent reversal of EH in one patient followed serially after successful diuretic treatment, supporting this theory. Lastly, in patients with a clinical diagnosis of MD, the absence of apparent EH may reflect our inability to consistently visualize the cochlear duct. Of note, EH can be seen in only the cochlear region on postmortem HTB studies [20]. Alternatively, the apparent absence of EH in some cases may reflect a flaw in the histological gold standard or a flaw in the clinical criteria for a diagnosis of MD. There were several limitations to this study. Firstly, the control group of non-MD ears is imperfect, given that the 11 patients with a history of sudden sensorineural hearing loss may have other confounding inner ear pathology. Future studies on healthy subjects with no otopathology would be the ideal control group. It is unlikely that this limitation affected the data, given that postmortem HTB studies do not demonstrate hydrops as a feature of sudden SNHL, which formed much of the non-MD control group [21]. The quantitative values for VES/vestibule ratio clustered tightly around the mean in all non-MD inner ears, including the asymptomatic side in MD, symptomatic side in sudden SNHL, and asymptomatic side in sudden SNHL, which also argues against a significant confounding factor in the control group. Secondly, the spatial resolution of our MR technique did not permit consistent evaluation of other components of the membranous labyrinth outside of the vestibule, in particular the cochlear duct. This may limit the sensitivity of MRI-based imaging for cochlear hydrops. Although other investigators have stated an ability to evaluate cochlear hydrops using techniques similar to ours, we note that the scala vestibuli compartment of the inner ear is only one or two voxels in thickness using their imaging techniques [6,8,14] and that their results have relied on qualitative interpretations by single observers, without
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use of normal control groups, making it difficult to validate their data. Finally, hydrops has been demonstrated in a small percentage of patients who did not have MD during lifetime [5]; however, it is important to note that many of these patients had moderate to severe hearing loss and some may have had cochlear MD. 5. Conclusion The sensitivity of the study for EH in patients with MD, the reproducibility of the results by both qualitative analysis and a second blinded neuroradiologist, and the relationship between quantitative EH and auditory function argue that the VES/vestibule ratio as determined by 3D MIP imaging is robust and accurate. The ability to image EH at varied points in the clinical course of MD and to evaluate for EH in other otological conditions such as fluctuating hearing without vertigo will allow researchers to further develop an understanding of the pathogenesis of otopathologies. References [1] Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Menière's disease. American Academy of Otolaryngology–Head and Neck Foundation, Inc. Otolaryngol Head Neck Surg 1995;113:181–5. [2] Krombach GA, Boom M, Martino E, Schmitz-Rode T, Westhofen M, Prescher A, et al. Computed tomography of the inner ear: size of anatomical structures in the normal temporal bone and in the temporal bone of patients with Menière’s disease. Eur Radiol 2005;15:1505–13. [3] Schmalbrock P, Dailiana T, Chakeres DW, Oehler MC, Welling DB, Williams PM, et al. Submillimeter-resolution MR of the endolymphatic sac in healthy subjects and patients with Menière disease. AJNR Am J Neuroradiol 1996;17:1707–16. [4] Valvassori GE, Dobben GD. Multidirectional and computerized tomography of the vestibular aqueduct in Meniere's disease. Ann Otol Rhinol Laryngol 1984;93:547–50. [5] Merchant SN, Adams JC, Nadol JB. Pathophysiology of Meniere's syndrome: are symptoms caused by endolymphatic hydrops? Otol Neurotol 2005;26:74–81. [6] Seo YJ, Kim J, Choi JY, Lee W-S. Auris nasus larynx. Auris Nasus Larynx 2013;40:25–30. [7] Pyykko I, Nakashima T, Yoshida T, Zou J, Naganawa S. Meniere's disease: a reappraisal supported by a variable latency of symptoms and the MRI visualisation of endolymphatic hydrops. BMJ Open 2013;3 [e001555–5].
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Clinical Imaging journal homepage: http://www.clinicalimaging.org
Delayed intravenous contrast-enhanced 3D FLAIR MRI in Meniere’s disease: correlation of quantitative measures of endolymphatic hydrops with hearing☆,☆☆ Ali R. Sepahdari a,⁎, Gail Ishiyama c, Nopawan Vorasubin b, Kevin A. Peng b, Michael Linetsky a, Akira Ishiyama b a b c
Department of Radiological Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA USA Department of Head and Neck Surgery, David Geffen School of Medicine at UCLA, Los Angeles, CA USA Department of Neurology, David Geffen School of Medicine at UCLA, Los Angeles, CA USA
a r t i c l e
i n f o
Article history: Received 12 February 2014 Received in revised form 14 August 2014 Accepted 9 September 2014 Keywords: Inner ear Meniere's disease Endolymphatic hydrops 3D FLAIR
a b s t r a c t Objective: Using three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging (3D-FLAIR MRI), our goal was to correlate quantifiable measures of endolymphatic hydrops (EH) with auditory function in the setting of Meniere’s disease (MD). Materials and methods: Forty-one ears were analyzed in 21 subjects (12 ears with MD, 29 without MD). Vestibular endolymphatic space size measurements obtained with two different techniques were referenced against clinical data. Results: EH was better evaluated on 3D maximum intensity projections (MIPs) than on two-dimensional (2D) images. Using MIPs, quantitative assessments EH correlated with severity of hearing impairment. Conclusion: 3D MIPs were superior to 2D images for evaluating EH in the setting of MD. © 2015 Elsevier Inc. All rights reserved.
1. Introduction Meniere’s disease (MD) is an incompletely understood syndrome which presents with the classical tetrad of sensorineural hearing loss (SNHL), tinnitus, vertigo, and aural fullness [1]. Postmortem histopathological studies demonstrate a ballooning of the endolymphatic system, endolymphatic hydrops (EH), that remains the gold standard to confirm the diagnosis of MD. The availability of an imaging modality that enables the clinician to quantify the degree of EH and vestibular endolymphatic space (VES) size would be invaluable as an adjunctive diagnostic tool. Additionally, the ability to correlate VES size and EH with clinical parameters in MD and other inner ear disorders is critical to advance our understanding of otological diseases. In general, neither computed tomography (CT) nor conventional magnetic resonance imaging (MRI) is able to distinguish endolymph from perilymph in the inner ear, and EH, the primary pathologic alteration in MD, is therefore impossible to detect by conventional imaging. CT and MRI are important to rule out other causes of hearing loss and can be used to assess for anatomy that may be associated with EH. Prior studies focused on measuring the caliber of the vestibular aqueduct, operating on the hypothesis that narrowing of the aqueduct produces hydrops through impaired longitudinal flow of endolymph ☆ This work has not been previously presented. ☆☆ We have no extramural funding to report. ⁎ Corresponding author. 757 Westwood Blvd, Suite 1621D, Los Angeles, CA 90095. Tel.: +1 310 267 6708; fax: +1 310 267 3635. E-mail address: [email protected] (A.R. Sepahdari). http://dx.doi.org/10.1016/j.clinimag.2014.09.014 0899-7071/© 2015 Elsevier Inc. All rights reserved.
[2–4]. These findings have not gained widespread clinical use, and this pathological mechanism has been challenged [5]. MRI with contrast-enhanced fluid-attenuated inversion recovery (FLAIR) imaging has been explored as an imaging technique to distinguish the perilymphatic and endolymphatic compartments, including studies using intratympanic injections of gadolinium-based contrast agent (GBCA) and studies that imaged patients at a 4-h delay after intravenous GBCA injection [6–17]. Both of these techniques result in an accumulation of dilute contrast agent in the perilymph, which appears bright by FLAIR imaging due its sensitivity to T1 shortening. The membranous labyrinth, which is impermeable to contrast due to the presence of tight junctions, appears as a signal void on these images, allowing for evaluation of an increase in VES size, i.e., EH. Though the prior studies provide support for the potential use of contrast-enhanced FLAIR MRI to detect EH, they have not validated criteria for determining hydrops with a robust quantitative analysis. Furthermore, none of these studies have assessed for a quantitative relationship between EH and clinical function, which would further validate the results. The purposes of our study were to (a) establish quantitative criteria for EH using delayed intravenous contrast-enhanced 3D-FLAIR MRI, specifically comparing the results 3D image analysis with conventional two-dimensional (2D) images; (b) validate the quantitative criteria for diagnosing EH by establishing a qualitative analysis that is reproducible and that correlates with the quantitative criteria; and (c) assess for and confirm the relationship between EH and auditory function in the setting of MD.
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2. Methods 2.1. Subjects The American Academy of Otolaryngology-Head and Neck Surgery criteria for definite MD were used to establish the diagnosis of MD [1]. With Institutional Review Board approval, a waiver of Health Insurance Portability and Accountability Act authorization, and a waiver of informed consent, a prospectively created database of patients imaged with delayed intravenous contrast-enhanced 3D-FLAIR MRI was reviewed. A total of 27 consecutive patients were imaged from November 2012 through March 2013 and were followed clinically. One patient was lost to follow-up and not included in the study. Clinical diagnoses in the remaining 26 patients revealed 11 patients with MD (9 unilateral, 2 bilateral), 4 patients with delayed EH, and 11 patients with sudden SNHL (9 unilateral, 2 bilateral). Subjects with delayed EH were excluded from analysis, given that the pathophysiology may differ from MD. The symptomatic ear in one patient was excluded from analysis because of previous endolymphatic sac shunt surgery. The final analysis group consisted of 41 ears in 22 subjects, 11 men and 11 women, with average age of 55years (range: 27–75). 2.2. Imaging technique All patients were imaged on a 3-T scanner using a 16-channel head and neck coil (Skyra; Siemens Healthcare, Erlangen, Germany) at 4 h postadministration of 0.2 mmol/kg gadodiamide intravenous contrast (Magnevist; Bayer HealthCare). Patients with abnormal renal function were excluded from imaging per institutional policy. Imaging consisted of three sequences: (a) “Cisternographic” 3D turbo spin echo T2 (T2 SPACE: sampling perfection with application-optimized contrasts by using different flip angle evolutions), (b) variable flip angle 3D turbo spin echo T2-weighted FLAIR (SPACE FLAIR), and (c) heavily T2weighted (hT2w)-3D-FLAIR. All sequences were acquired in the axial plane along the infraorbitomeatal line. The T2 SPACE sequence was acquired with the following parameters: slice thickness: 1 mm, repetition time (TR)/echo time (TE): 1430/ 265 ms, number of averages: 2, echo train length: 98, flip angle: 140, matrix: 320×320, and field of view (FOV): 200×200 mm. The SPACE FLAIR sequence was acquired with the following parameters: slice thickness: 0.8 mm, TR/TE: 6000/338 ms, inversion time: 2100 ms, number of averages: 2, echo train length: 215, flip angle: 120 (variable), matrix: 256×256, FOV: 184×184 mm, acquisition time: 4 min and 31 s. The hT2w 3D-FLAIR sequence was acquired with the following parameters: slice thickness: 0.8 mm, TR/TE: 9000/534 ms, inversion time: 2350 ms, number of averages: 2, echo train length, 144, flip angle: 120, matrix: 320×260, FOV: 200×167 mm, acquisition time: 6 min and 45 s. 2.3. Image analysis The cisternographic T2-weighted images and the 3D-FLAIR images were reviewed side by side. Bright signal in the labyrinth on the cisternographic T2-weighted images represented both perilymphatic and endolymphatic fluid. Bright signal on the 3D-FLAIR represented only perilymphatic fluid. Internal dark signal within the labyrinth on 3DFLAIR represented only endolymphatic fluid (Fig. 1). The hT2w-3DFLAIR images demonstrated superior differentiation between endolymph and perilymph and were used for further analysis. The isotropic hT2w-3DFLAIR images were reformatted in the plane of the lateral semicircular canal (LSC) to maintain intersubject consistency in measurements. The images were made anonymous, transferred to an Osirix workstation (Osirix v5.1.1, Geneva, Switzerland), and assessed quantitatively by a subspecialty certified neuroradiologist, who was blinded to the clinical data, using 2D images. The images were first assessed using a previously described technique [8]: the axial image through the vestibule at the level of the LSC was identified. A freehand region of interest
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(ROI) was drawn around the VES, and ROI area was recorded. A second freehand ROI was drawn around the entire vestibule, which included both the vestibular perilymph (bright signal) and the vestibular endolymph (dark signal). The VES/vestibule ratio was then calculated (Fig. 2). One month later, the same observer performed similar measurements using 3D maximum intensity projection (MIP) reconstructions. The hT2w-3D-FLAIR images were reconstructed as a single 3D MIP image, viewed from below, oriented to demonstrate both vestibules without overlap from the cochlea or semicircular canals. The VES was consistently seen as a dumbbell-shaped signal void, or as two small signal voids, in the center of the vestibule on these images. The VES/vestibule ratio was calculated using the same measurement parameters as those used for the source images. 2.4. Statistical analysis Using the American Academy of Otolaryngology-Head and Neck Surgery criteria for definite MD, the VES/vestibule ratios corresponding to MD were segregated from those corresponding to non-MD. An unpaired Student’s t test was used to assess for statistical differences between the VES/vestibule ratio in MD vs. non-MD. The unpaired Student’s t test was conducted for the 2D MRI data and the 3D MRI data separately. Descriptive statistics of mean and standard deviation were obtained for the 2D and 3D measurements. The quantitative 3D data and 2D data were compared to each other using Pearson correlation and using Bland–Altman method comparison. The proportion of MD ears that showed evidence of hydrops was determined for the 2D data and the 3D data separately. Qualitative analysis was performed to validate the quantitative assessment of VES/vestibule ratio. The MIP images were reviewed by the original observer and by a second subspecialty-certified neuroradiologist. Each neuroradiologist evaluated the MIP images independently, blinded to the clinical diagnoses, and evaluated the images as EH or not EH based on whether the VES appeared to occupy more than 45% of the vestibule (2 standard deviations above the mean of the non-MD ears). Fisher’s Exact Test was used to determine whether the qualitative interpretations of each observer matched the clinical diagnoses. Interobserver agreement was tested using Cohen’s kappa. Six months after this initial analysis, both observers also independently evaluated the 2D images through the level of the LSC in each ear and made a determination of whether an ear was involved by significant hydrops based on criteria described by Nakashima et al. [8]. As with the 3D data, Fisher’s Exact Test was used to determine whether the qualitative interpretations of each observer matched the clinical diagnoses. Interobserver agreement was tested using Cohen’s kappa. VES/vestibule ratio was also compared with audiogram results, obtained within 1 to 2 months of the MRI used for the study. The audiogram pure tone average (PTA) and word recognition score (WRS) were correlated with the VES/vestibule ratio in subjects with MD using Spearman rank order correlation. Pb.05 was used to determine statistical significance for all statistical tests. 3. Results The VES/vestibule ratio was significantly higher in MD ears compared with non-MD ears using both 2D image measurement (P=.003) and 3D MIP measurements (Pb .0001). However, there was greater overlap between MD and non-MD ears using the 2D source image measurements, with overlapping 95% confidence intervals (CIs) (Fig. 3). There was no overlap of the 95% CIs when using the 3D MIP data, despite a broad distribution of values in the EH group. Table 1 summarizes these results. Pearson correlation showed a strong relationship between the 3D and 2D quantitative data (Pb.0001). Bland–Altman method comparison showed a bias of 0.1 between 3D and 2D quantitative data, with a standard deviation of 0.16. Review of the Bland–Altman plot shows greatest variation between 3D and 2D measurements among
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Fig. 1. Normal inner ear MRI. (A) Axial cisternographic T2 through the level of the LSC shows normal hyperintense fluid signal in the labyrinth. (B) Axial 3D-FLAIR source image shows low signal in the vestibular endolymphatic structures and bright signal throughout the perilymphatic spaces, including the LSC, cochlea, and posterior semicircular canal. (C) 3D-FLAIR source image, slightly inferior to (B), shows normal perilymph in the anterior and inferior portion of the vestibule. (D) 3D MIP reconstruction shows small size of the endolymphatic structures relative to the vestibule.
subjects with VES/vestibule ratios in the 0.4–0.6 range (Fig. 3), which is especially relevant in discriminating between mild hydrops and a normal ear.
Using 3D data, 67% (8/12) of MD ears showed hydrops. Fisher’s Exact Test showed that qualitative assessments by both observers were significantly related to clinical diagnoses (Pb.002 for both observers).
Fig. 2. Quantitative assessment of vestibular endolymphatic structure size, using 2D source images and 3D MIPs, in a normal ear (A, B) and an ear involved by MD (C, D). (A) 2D source image freehand ROIs drawn around the vestibule and vestibular endolymph on the axial image through the level of the LSC. The endolymph/vestibule ratio is calculated. (B) 3D MIP method: a 3D MIP is created from the source images, and viewed from below, oriented to eliminate overlap between the cochlea, vestibule, and semicircular canals. Measurements are obtained as in (A). (C and D) Hydrops, which is visible on gross inspection.
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Fig. 4. A plot of PTA hearing loss in decibels (dB) against VES/vestibule ratio in MD ears, based on 3D MIP, shows a moderate correlation between hearing loss and VES enlargement.
Fig. 3. Quantitative assessment of vestibular endolymphatic structures (VES). (A) Mean and 95% CIs for VES/vestibule ratio using 2D measurements through the LSC show apparent dilation of the VES in affected ears with MD compared to asymptomatic (asx) ears in MD patients, symptomatic (sx) ears and asymptomatic ears in sudden SNHL patients, and all non-MD ears in aggregate. However, note the overlapping 95% CIs. (B) Measurements based on 3D MIP show greater differences between MD ears and non-MD ears, with no overlap in the 95% CIs. (C) Bland–Altman plot of difference vs. average for 2D and 3D measurements of each ear reveals a relatively wide variation in quantitative measurements for subjects with VES/vestibule ratios near 0.4, which is close to the cutoff between normal and abnormal. This suggests that the increased variability in 2D measurements may affect the clinical performance of the test.
Table 1 Comparison between 2D and 3D quantitative assessments of VES size
EH ear VES/vestibule ratio (mean±S.D.) Non-EH ears VES/vestibule ratio (mean±S.D.)
2D quantitative
3D MIP quantitative
0.62±0.24 0.44±0.13
0.59±0.29 0.32±0.06
Furthermore, the qualitative reads closely matched the quantitative data, with an impression of hydrops in the same eight MD ears and impression of no hydrops in the same four MD ears for both observers. When using 3D MIPs, the subjective interpretations of the two observers were 91% concordant overall, with κ=0.76 (95% CI: 0.53–0.98). Using 2D data, 50% (6/12) of the MD ears showed hydrops, as determined by VES/vestibule ratio more than 2 standard deviations above the mean of the non-MD group. Fisher’s Exact Test did not show a significant relationship between qualitative interpretations of hydrops and a clinical diagnosis of MD. The qualitative reads showed only 68% concordance between observers, with κ=0.31 (95% CI: 0.01–0.61). In 12 MD ears, the VES/vestibule ratio based on 3D MIP images showed a significant, strong positive correlation with PTA (Spearman ρ=0.89, P=.0003)with greater degrees of EH as assessed by VES/ vestibule ratio associated with more severe hearing loss (Fig. 4). There was also a significant, moderate correlation between VES/vestibule ratio and WRS in MD (Spearman ρ=0.67, P=.02). In contrast, there was no significant relationship between 2D source image VES/vestibule ratio and PTA (Spearman ρ=0.42, P=.17) or WRS (ρ=0.49, P=.11). In 12 sudden SNHL ears, there was no significant relationship between VES/ vestibule ratio and hearing loss using either 2D or 3D measurements. Vestibular endolymph and perilymph were easily distinguished on multiple sequential slices in all cases. The ability to distinguish endolymph from perilymph and bone was most apparent at the level of the LSC, and VES dilation was sometimes seen on 2D images through this level (Fig. 2). At other levels, closer to the edges of the bony labyrinth, endolymph was difficult to distinguish from that of bone, given their similarly low signal. Despite optimal contrast between endolymph and perilymph at the level of the LSC, VES enlargement was not always seen at this level on 2D images in subjects with clinical MD and abnormal 3D MIP images (Fig. 5), demonstrating the superior imaging characteristics of MIP projections for the analysis of VES/vestibule ratio and EH. 4. Discussion This study demonstrated the consistent and reproducible ability to differentiate the perilymphatic and endolymphatic compartments using delayed intravenous contrast-enhanced 3D-FLAIR MRI. This methodology is preferred over intratympanic injection of GBCA due to potential complications of infection, persistent tympanic membrane perforation, and pain. 3D MIP imaging allowed for less overlap in appearance between MD and non-MD ears, with better ability to detect EH as evidenced by increased VES/vestibule ratio. Quantitative assessments of EH were replicated by qualitative assessments that were reproducible by a second neuroradiologist. The degree of VES dilation, assessed by the VES/vestibule ratio using 3D MIP-based measurements, was strongly statistically positively correlated with poorer auditory function, assessed by PTA and WRS, in the symptomatic ears of MD
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Fig. 5. EH in a 66-year-old man with MD demonstrated with MIP but not with source images. (A) 2D source image through the level of the LSC shows apparently normal size of the vestibular endolymphatic structures (VES), which appear as a signal void surrounded by adequate bright perilymph (arrow). (B) 3D MIP image shows relative enlargement of the VES, with effacement of the surrounding perilymph. Compare to normal ears shown in Figs. 1 and 2.
patients, but not in other ears. 2D images through the LSC were not as effective as 3D MIPs in evaluating hydrops. Despite statistically significant differences between MD ears and non-MD ears using 2D data, the results could not be reproduced by qualitative analysis, the interpretations were not reproducible between observers, and there was no relationship between quantitative VES/vestibule ratio and tests of auditory function. Although the 3D data and the 2D data were strongly correlated, this was due largely to the fact that the data were widely distributed. The poor clinical performance of the 2D images compared to 3D images was likely related to the degree of variability within the range of values that discriminates mild hydrops from a normal ear, as demonstrated by Bland–Altman method comparison. The use of MRI to distinguish endolymph from perilymph was first reported in multiple studies from Naganawa et al. [12,14–16,18]. Our results provide needed confirmation of those initial reports with detailed clinical parameters. Naganawa et al. and others [6] have used various quantitative, semiquantitative, and qualitative techniques for identifying hydrops in the vestibule based primarily on source image evaluation [6,8,10]. However, the methods used in these prior studies were not validated through analysis with a control group and have not been tested for reproducibility. Using image analysis based on 3D MIP, we present data demonstrating superior ability to distinguish EH from non-EH as compared to a 2D source image-based technique. The 3D MIP-based method we used offered certain advantages over 2D image-based methods. One advantage of 3D MIPs is the ability to evaluate the VES/vestibule for hydrops in the anterior/inferior vestibule, a region that has a known predilection for involvement in MD [19]. This anatomic region is not assessed on source images through the level of the LSC and, in general, is difficult to assess on source images because of difficulty distinguishing endolymph from bone. Orienting the MIP such that both vestibules could be seen without overlap from the cochlea or semicircular canals on either side resulted in a consistent appearance of the vestibule. We also noted that source images are also susceptible to variability based on the imaging plane used, a factor that was corrected for in this study by performing careful axial reformations in all cases. Notably, this factor was not corrected for in previous studies. Imaging the membranous labyrinth during attacks and between attacks could deepen our understanding of the pathophysiology of otopathologies, leading to new therapeutic strategies and/or imaging markers to monitor disease status and effectiveness of treatment. Further investigations of delayed intravenous contrast-enhanced 3D-FLAIR MRI would benefit from simultaneous pursuit of two objectives: continued improvement in image quality and investigation of the relationship between imaging and clinical course. A significant minority (4/12) of the MD ears in our study did not show enlargement of the VES, consistent with the findings of Seo et al.
[6]. However, in all MD patients with EH in our study, there was significant hearing loss. It is important to note that the correlation between MD and histopathologically confirmed EH was made on postmortem temporal bone studies [5]. Prior to the development of MRI to assess for EH, the inner ear was inaccessible during the lifetime, and conventional techniques of pathological study including delineation of anatomical structures were not possible. Therefore, human temporal bone (HTB) studies were, by necessity, postmortem examinations, and thus the majority of HTB specimens were obtained from late stage MD. It is possible that dilation of the endolymphatic space only occurs some time after developing symptoms and, therefore, possible that some subjects in our study had normal findings due to being imaged early in their disease course. It is also possible that histological data are skewed toward more severe disease in HTB donations. The strong correlation between anatomic hydrops and impaired auditory function in our population with clinical MD would be consistent with the hypothesis of a lack of EH in mildly symptomatic MD. A third potential explanation is that hydrops is a fluctuating abnormality. There was an apparent reversal of EH in one patient followed serially after successful diuretic treatment, supporting this theory. Lastly, in patients with a clinical diagnosis of MD, the absence of apparent EH may reflect our inability to consistently visualize the cochlear duct. Of note, EH can be seen in only the cochlear region on postmortem HTB studies [20]. Alternatively, the apparent absence of EH in some cases may reflect a flaw in the histological gold standard or a flaw in the clinical criteria for a diagnosis of MD. There were several limitations to this study. Firstly, the control group of non-MD ears is imperfect, given that the 11 patients with a history of sudden sensorineural hearing loss may have other confounding inner ear pathology. Future studies on healthy subjects with no otopathology would be the ideal control group. It is unlikely that this limitation affected the data, given that postmortem HTB studies do not demonstrate hydrops as a feature of sudden SNHL, which formed much of the non-MD control group [21]. The quantitative values for VES/vestibule ratio clustered tightly around the mean in all non-MD inner ears, including the asymptomatic side in MD, symptomatic side in sudden SNHL, and asymptomatic side in sudden SNHL, which also argues against a significant confounding factor in the control group. Secondly, the spatial resolution of our MR technique did not permit consistent evaluation of other components of the membranous labyrinth outside of the vestibule, in particular the cochlear duct. This may limit the sensitivity of MRI-based imaging for cochlear hydrops. Although other investigators have stated an ability to evaluate cochlear hydrops using techniques similar to ours, we note that the scala vestibuli compartment of the inner ear is only one or two voxels in thickness using their imaging techniques [6,8,14] and that their results have relied on qualitative interpretations by single observers, without
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use of normal control groups, making it difficult to validate their data. Finally, hydrops has been demonstrated in a small percentage of patients who did not have MD during lifetime [5]; however, it is important to note that many of these patients had moderate to severe hearing loss and some may have had cochlear MD. 5. Conclusion The sensitivity of the study for EH in patients with MD, the reproducibility of the results by both qualitative analysis and a second blinded neuroradiologist, and the relationship between quantitative EH and auditory function argue that the VES/vestibule ratio as determined by 3D MIP imaging is robust and accurate. The ability to image EH at varied points in the clinical course of MD and to evaluate for EH in other otological conditions such as fluctuating hearing without vertigo will allow researchers to further develop an understanding of the pathogenesis of otopathologies. References [1] Committee on Hearing and Equilibrium guidelines for the diagnosis and evaluation of therapy in Menière's disease. American Academy of Otolaryngology–Head and Neck Foundation, Inc. Otolaryngol Head Neck Surg 1995;113:181–5. [2] Krombach GA, Boom M, Martino E, Schmitz-Rode T, Westhofen M, Prescher A, et al. Computed tomography of the inner ear: size of anatomical structures in the normal temporal bone and in the temporal bone of patients with Menière’s disease. Eur Radiol 2005;15:1505–13. [3] Schmalbrock P, Dailiana T, Chakeres DW, Oehler MC, Welling DB, Williams PM, et al. Submillimeter-resolution MR of the endolymphatic sac in healthy subjects and patients with Menière disease. AJNR Am J Neuroradiol 1996;17:1707–16. [4] Valvassori GE, Dobben GD. Multidirectional and computerized tomography of the vestibular aqueduct in Meniere's disease. Ann Otol Rhinol Laryngol 1984;93:547–50. [5] Merchant SN, Adams JC, Nadol JB. Pathophysiology of Meniere's syndrome: are symptoms caused by endolymphatic hydrops? Otol Neurotol 2005;26:74–81. [6] Seo YJ, Kim J, Choi JY, Lee W-S. Auris nasus larynx. Auris Nasus Larynx 2013;40:25–30. [7] Pyykko I, Nakashima T, Yoshida T, Zou J, Naganawa S. Meniere's disease: a reappraisal supported by a variable latency of symptoms and the MRI visualisation of endolymphatic hydrops. BMJ Open 2013;3 [e001555–5].
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