The clinical features and image characteristics of Meniere's disease patients with endolymphatic hydrops confirmed by enhanced magnetic resonance imaging

Highlights • 3D-real IR MRI can provide a better assessment of EH in MD patients.• Including EH in the diagnostic criteria can increase the MD diagnosis rate.• The EH degree or distribution may be related to the degree of hearing loss.


Introduction
Meniere's Disease (MD) is an idiopathic inner ear disease whose cause is still unclear, named after the French physician Prosper Meniere first proposed in 1861. Hallpike and Cairns 1 reported that the major pathological change of the disease was Endolymphatic Hydrops (EH) of the membranous labyrinth in 1938. This finding had been confirmed by many scholars. The clinical symptoms of MD are recurrent rotating vertigo with fluctuating hearing loss, tinnitus, and ear fullness. At present, the diagnosis of MD mainly depends on a range of clinical symptoms but lacks objective imaging evidence. In 2007, Nakashima et al. 2 applied transtympanic gadolinium contrast MRI technology to see EH in the cochlea or (and) vestibule of MD patients. This was the first time that the inner ear gadolinium imaging technology had been applied to the MD patients to observe EH.
The clinical manifestations of MD are often atypical, and vestibular migraine, psychogenic vertigo, benign paroxysmal positional vertigo, etc. can also be manifested as vertigo symptoms similar to MD, 3 which indirectly increases the difficulty of the diagnosis of MD. Although EH is the recognized pathological basis of MD, in addition to MD, traumatic diseases of the inner ear, sudden deafness, low-frequency sensorineural hearing loss, recurrent peripheral vestibular disease, 4 semicircular canal dysplasia, 5 semicircular canal fissure syndrome, and vestibular aqueduct syndrome 6 can also be manifested as EH. Therefore, the diagnosis of MD needs to combine clinical manifestations and imaging characteristics at the same time.
In this study, we further analyzed and summarized the clinical features and image characteristics of MD patients with EH confirmed by MRI in order to provide some clinical and imaging evidence for the accurate diagnosis of MD.

Patients
From July 2018 to September 2020, 252 MD patients (208 unilateral cases and 44 bilateral cases, totaling 296 affected ears) who underwent MR scans via intravenous gadolinium injection of the inner ear at our hospital were enrolled in this study, including 113 men and 139 women, with an average age of 48.75 years (11---79 years). The clinical features such as age, gender, affected side, disease course, hearing loss and other symptoms such as vertigo, tinnitus and ear fullness

Endolymphatic hydrops evaluation
The gadolinium flows into the perilymphatic space of the inner ear through the blood-labyrinth circulatory system, which makes the perilymphatic space appear as obvious high signal on the MRI. Meanwhile, due to the existence of the barrier between endolymph and perilymph, the gadolinium contrast agent cannot enter the endolymphatic space, so the endolymphatic space shows obviously low signal on the MRI. This imaging principle can be used to distinguish endolymph from perilymph, and then to determine whether there is EH. In this research, we applied the method reported by Nakashima et al. 8 for the EH grading (Table 3). Based on the double-blind principle and the grading method displayed on Table 3, two radiologists with eleven and thirteen years of working experience respectively in the diagnosis of inner ear diseases independently browsed and evaluated the images. If there were differences of result, the final outcome depended on the consensus reached by both sides.

Statistical analyses
The IBM SPSS (Version 22; IBM, Armonk, New York) was used to handle all data. The independent sample t-test and the 2-test were used for comparison between groups. And p < 0.05 was considered statistically significant.

MRI results
The 252 patients enrolled in our group all obtained good images of the inner ears via MR scans with intravenous gadolinium injection. Different degrees of EH were shown in the vestibule or different turns of the cochlea in the affected ears of all MD patients, and Fig. 1

Clinical features
In the affected ears of 252 patients, the presence of EH was confirmed by enhanced MR scan. Among all patients, 113 were males and 139 were females, with an average age of 48.75 years (11---79 years). All patients showed dizziness and other ear symptoms. 115 cases (45.6%) had symptoms in the left ear, 93 cases (36.9%) had symptoms in the right ear, and 44 cases (17.5%) had symptoms in both ears. The specific clinical features were classified as follows: 1) Causes and accompanying symptoms: Among the 252 patients, the onset of vertigo had no obvious connec-

Correlation between EH and clinical features
The age, age of first onset, and course of disease of 208 patients with unilateral EH and 44 patients with bilateral between the unilateral patients and the bilateral patients were not statistically significant ( Table 5). The average hearing thresholds of the MD patients with different levels of EH in the vestibule and cochlea had statistically significant differences (all p < 0.001), and the EH levels of the vestibule and cochlea were correlated with the degree of hearing loss (Table 6).

Discussion
According to the latest statistical studies such as Bruderer et al., 9 the incidence of MD in recent years was about 13.1 per 100,000. Although more and more studies on MD were published in recent years, there is still no clear conclusion about its etiology. With the wide application of gadolinium contrast technology, EH was increasingly found in the inner ear of MD patients. 2,10 Meanwhile, in the animal experiments, membrane labyrinth swelling characterized by EH was considered to be the key pathological change of MD. 11 Therefore, the presence or absence of EH had gradually become an important indicator for assisting the diagnosis of MD. However, in addition to MD, many other inner ear diseases can also be manifested as EH. Besides, due to the diverse clinical manifestations of MD, it is easy to be confused with other vertigo diseases such as migraine. Therefore, this study selected 252 patients whose clinical symptoms at least met probable MD and confirmed the presence of EH by inner ear MRI, and further analyzed their clinical features and imaging characteristics.
Our study showed that the occurrence of MD was not significantly related to gender. For the reports that the proportion of women in the diagnosis of MD was significantly higher than that of men, we speculated that this may be due to the misdiagnosis of migraine patients. The majority of MD groups were middle-aged and elderly, indicating that we should be cautious about the diagnosis of MD in minors and young people. Among the 252 MD patients, the onset of vertigo was mostly unrelated to changes in body position, and most of them had no obvious cause. Some patients experienced the onset of vertigo during sleep. Besides, 226 patients (89.7%) had nausea and vomiting during the onset of vertigo. Maybe we can consider antiemetic drugs for preventive treatment before the onset of the disease. 60 patients had the apprehensive symptoms such as fear of light, fear of cold, and fear of sound during the onset of the disease. Vestibular migraine was easily confused with MD. 12 About 30% of patients with vestibular migraine had no headache symptoms when the onset of the disease, and the dizziness could last for several seconds or even days. 13 Some studies believed that MD and vestibular migraine can exist at the same time, and vestibular migraine may be a factor that exacerbates the development of MD. But in patients with vestibular migraine, EH generally did not exist. 14 Therefore, inner ear MRI can effectively distinguish the two.
Vertigo-related fluctuating low-medium frequency hearing loss, tinnitus, and ear fullness are characteristic manifestations of MD. The hearing examination showed that 252 patients all had low-medium frequency hearing loss. Moreover, 243 patients (96.4%) had symptoms of tinnitus and/or ear fullness. It can be seen that ear symptoms are an important factor in the diagnosis of MD, but the manifestations of tinnitus and ear fullness are diverse, so the diagnosis of MD cannot be completely dependent on the patient's self-reported ear symptoms. Meanwhile, our research showed that the duration and frequency of vertigo in different patients were not the same. Besides, our study found that in some MD patients, the onset of vertigo had a certain hereditary nature. This was consistent with the report of Requena et al. 15 Relatives (father or mother) of 22 patients (8.7%) had a positive history of vertigo. In 8 patients, their mothers, and grandmothers both had a positive history of vertigo. This suggested that MD may have a certain degree of maternal inheritance. Regarding the hereditary characteristics of MD, further research is needed in the future.
The MRI results showed that compared with patients with unilateral EH, the symptoms of the first affected ear of patients with bilateral EH were more serious. There were no significant differences in the age, age of first onset, and course of disease between unilateral EH patients and bilateral EH patients. In addition, we found that the degree of EH was significantly positively correlated with the degree of hearing loss. The more severe the vestibular and cochlear EH, the more severe the hearing loss.

Conclusions
3D-real IR MRI with intravenous gadolinium injection can provide a better assessment of EH in MD patients. The clinical features of MD patients with EH confirmed by enhanced MRI did not fully meet the existing diagnostic criteria for definite MD. Including the diagnosis of EH in the diagnostic criteria of MD can increase the diagnosis rate of MD. Besides, the degree and distribution of EH may be related to the degree of hearing loss.

Funding
This work was supported by the Shanghai Municipal Science and Technology Commission Biomedicine Division Western Medicine Guidance Project (grant n o 19411965700).

Ethics approval
The medical ethics committee of the EENT Hospital of Fudan University had approved this research (2020056).