Endotype-Phenotype Patterns in Meniere's Disease Based on Gadolinium-Enhanced MRI of the Vestibular Aqueduct

Abstract

Two histopathological subtypes of Meniere's disease (MD) were recently described in a human post-mortem pathology study. The first subtype demonstrated a degenerating distal endolymphatic sac (ES) in the affected inner ear (subtype MD-dg); the second subtype (MD-hp) demonstrated an ES that was developmentally hypoplastic. The two subtypes were associated with different clinical disease features (phenotypes), suggesting that distinct endotype-phenotype patterns exist among MD patients. Therefore, clinical endotyping based on ES pathology may reveal clinically meaningful MD patient subgroups. Here, we retrospectively determined the ES pathologies of clinical MD patients (n = 72) who underwent intravenous delayed gadolinium-enhanced inner ear magnetic resonance imaging using previously established indirect radiographic markers for both ES pathologies. Phenotypic subgroup differences were evidenced; for example, the MD-dg group presented a higher average of vertigo attacks (ratio of vertigo patterns daily/weekly/other vs. monthly, MD-dg: 6.87: 1; MD-hp: 1.43: 1; p = 0.048) and more severely reduced vestibular function upon caloric testing (average caloric asymmetry ratio, MD-dg: 30.2% ± 30.4%; MD-hp: 13.5% ± 15.2%; p = 0.009), while the MD-hp group presented a predominantly male sex ratio (MD-hp: 0.06:1 [f/m]; MD-dg: 1.2:1 [f/m]; p = 0.0004), higher frequencies of bilateral clinical affection (MD-hp: 29.4%; MD-dg: 5.5%; p = 0.015), a positive family history for hearing loss/vertigo/MD (MD-hp: 41.2%; MD-dg: 15.7%; p = 0.028), and radiographic signs of concomitant temporal bone abnormalities, i.e., semicircular canal dehiscence (MD-hp: 29.4%; MD-dg: 3.6%; p = 0.007). In conclusion, this new endotyping approach may potentially improve the diagnosis, prognosis and clinical decision-making for individual MD patients.

Keywords: degeneration; endolymphatic sac; hypoplasia; patient subgroups; phenotype.

Figure 1

Study flowchart. MD was definitively diagnosed per the guidelines from the Committee on Hearing and Equilibrium of the American Academy of Otolaryngology-Head and Neck Surgery for the Definition of Meniere's Disease from 1995 (9). VA bending angles and clinical chart reviews were assessed in a blinded manner (see text for details). ^*according to Merchant and Nadol (10). (Gd-MRI, gadolinium-enhanced magnetic resonance imaging; ES, endolymphatic sac; MD, Meniere's disease; VA, vestibular aqueduct).

Figure 2

CT vs. Gd-MRI correlation for α_exit. Angles were measured from HRCT and Gd-MRI data from the same 16 MD patients.

Figure 3

Gd-MRI VA morphology in representative MD cases with degenerative (A,B) and hypoplastic (C,D) ES pathology. Maximum intensity projections of axial plane images (A,C), and 3D reconstructions (postero-superior view) of the labyrinthine fluid spaces with the VA shown in magenta (B,D). Arrowheads in (A,C) indicate the VA in the opercular region. Insets in (A,C) show angle measurements of the VA's angular trajectory as described previously (7) (sSCC, superior semicircular canal; hSCC, lateral semicircular canal; pSCC, posterior semicircular canal). Scale bars, 10 mm.

Figure 4

Clinical differences between and within the two MD endotypes. Data from (A–F,H) are also shown in Table 2, data from (G) and (I) were not part of the initial null hypotheses. Bilat, bilateral; contralat, contralateral; EH, endolymphatic hydrops; ipsilat, ipsilateral; MD, Meniere's disease; post, posterior; SCC, semicircular canal; sup, superior; unilat, unilateral; VA, vestibular aqueduct.