Meniere's disease (MD), a chronic inner ear disorder, causes fluctuating vestibular and auditory symptoms and exhibits a highly variable disease course among patients (1, 2). Most severely affected are the 10–50% of patients (3–5) in whom the disease progresses to bilateral MD, often years to decades after its initial (unilateral) manifestation. Due to bilateral vestibulopathy, patients with bilateral MD experience chronic debilitating vestibular symptoms, such as oscillopsia and imbalance, and a broad range of cognitive and emotional impairment (6). Moreover, bilateral MD often leads to severe to profound hearing loss with unserviceable speech discrimination (7, 8). A biomarker for future bilateral disease would allow clinicians to identify those patients, to preemptively counsel them about the expected disease course, and to personalize therapy regimens in clinically meaningful ways.

In this study, radiological evidence for endolymphatic sac (ES) hypoplasia (9, 10), i.e., the suspected etiopathology in approximately 30% of MD patients, with the designated endotype “MD-hp” (11), was used to prognosticate disease laterality. In a recent human temporal bone study, either of two pathologies of the ES, i.e., degeneration or developmental hypoplasia, was consistently found in cases with clinical MD (9). These ES pathologies (“endotypes”) can be linked to the pathogenesis of endolymphatic hydrops, a histopathologic and radiologic marker of MD (9, 12). The subtype of ES pathology correlates with the course of the vestibular aqueduct, which–in contrast to the ES epithelium–can be visualized in clinical imaging (10). In MD, the course of the vestibular aqueduct can therefore be used as a radiologic surrogate marker for the underlying subtype of cellular ES pathology (10). Using this marker, it has been shown in clinical patients that the pathologic endotypes are associated with differing clinical phenotypes (11). In MD-hp patients, one or both inner ears may exhibit ES hypoplasia. However, to date, it is not clear whether ES hypoplasia critically predisposes to MD. Here, we hypothesized that progression to bilateral MD only occurs in patients with bilateral ES hypoplasia (cohort MD_uni-hp_bi) but not in those with unilateral ES hypoplasia (cohort MD_uni-hp_uni).

MD-hp patients statistically have a 25% risk for developing bilateral disease, which is 5-fold higher than other MD patients (11). Thus, providing MD-hp patients with a personalized prognosis, instead of a mere statistical one-in-four chance for bilateral disease progression, would advance the clinical management of this patient group, which is at highest risk for a severe disease course, in a clinically relevant manner.

MD-hp patients are distinguished by a developmentally rudimentary, i.e., hypoplastic, ES (Figure 1b′), which has been initially described in sporadic MD cases (19–22) and was more recently demonstrated as a consistent finding in about 30% of pathology cases with a clinical MD diagnosis (9)—now designated as the MD-hp patient group (11). Pathophysiologically, the absence of normal ion transport mechanisms in the hypoplastic ES epithelium is believed to be the key pathology that causes disturbances of the inner ear fluids and, ultimately, endolymphatic hydrops and clinical symptoms (9, 23). ES hypoplasia is consistently associated with a hypoplastic bony VA, which can be radiologically visualized and was established as a clinical surrogate marker (ATVA) for the presence of ES hypoplasia (10).

This present preliminary and previous (11) data suggest that the radiological ATVA marker has absolute positive and negative predictive power for making this personalized prognosis. If ultimately validated by long-term prospective studies, this would allow clinicians (i) to counsel patients about aspects of their future disease course, in particular about the long-term impacts on hearing and balance functions; (ii) to make better decisions on whether ablative therapies, such as intratympanic gentamicin or vestibular neurectomy, can be considered; and potentially also (iii) to screen family members and children from MD-hp patients for their risk of developing uni- or bilateral MD. Furthermore, the ATVA marker enables to define clinically more homogenous subgroups of MD patients for future (genomic) studies.

In bilateral MD, non-ablative treatments, such as intratympanic steroids, should be preferred over ablative treatments, which should be avoided (16). Using the ATVA marker, progression to bilaterality can be anticipated in MD-hp_bi patients and virtually excluded in MD-hp_uni patients. Therefore, this clinical tool may allow to obviate iatrogenic bilateral vestibular loss and/or hearing loss due to ablative treatments in MD-hp_bi patients. On the other hand, in MD-hp_uni patients with an infinitesimal risk for bilateral progression, ablative treatments, such as intratympanic gentamicin administration, may be liberally used.

ES surgery is commonly considered as a non-ablative treatment of MD (16). It should be noted, however, that in MD-hp patients, the ES is hypoplastic and anteriorly displaced. These anatomical abnormalities impede the surgical approach of the ES via the commonly used transmastoid route; furthermore, the hypoplastic ES occasionally does not exit the temporal bone at all. Of note, the surgical non-visualization rate of the ES during ES surgery corresponds to the percentage of MD-hp patients among all MD patients (11, 24). Although there is lacking evidence for a beneficial effect of ES surgery (25), this “non-ablative” surgical treatment–if considered–may therefore be particularly avoided in MD-hp patients.

Notably, among other proposed markers for predicting bilateral MD (2, 18), cervical vestibular-evoked myogenic potential (cVEMP) metrics were retrospectively found to be altered, with high specificity and sensitivity, in clinically yet unaffected contralateral ears 24–288 months before clinical symptoms manifested (26, 27). The actual time course of these cVEMP changes and their earliest appearance during the presymptomatic phase remain to be investigated. The present radiological (ATVA) marker may potentially identify inner ears at risk even before any MD-associated functional changes occur, i.e., in early childhood, when the temporal bone anatomy is matured. However, its validity for predicting MD in asymptomatic individuals with ES hypoplasia needs to be investigated.

Regarding the potential clinical use of the ATVA marker, the following points should further be considered: (i) the time interval from initial MD diagnosis to bilateral affection is highly variable among patients (4, 5, 11, 28, 29) and cannot be predicted with the ATVA marker; (ii) the measurement of an α_exit of <120° in the contralateral ear does not with absolute certainty exclude progression to bilateral disease, since a different MD-causing process can affect this ear (i.e., another MD endotype) (9, 11), although this remains hypothetical; and (iii) the determination of the ATVA on both sides in Gd-MRI (3D IR sequence) data requires systemic (i.v.) delivery of the Gd-contrast agent.

In conclusion, ongoing observations will determine whether the promising preliminary data hold up and whether both study cohorts remain “true to prediction,” thus ultimately validating the ATVA marker as a prognostic tool for bilateral disease progression in MD-hp patients.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Ethikkommission Zürich, KEK-ZH-Nr. 2016-01619/2019-01006. The patients/participants provided their written informed consent to participate in this study.

The study was concepted and designed by DB and AE. Acquisition and analysis of data were performed by DB, BS, JD, and AE. DB and AE drafted the manuscript. All authors critically reviewed and revised the manuscript.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.