BACKGROUND AND PURPOSE:Although the otic capsule is fully formed at birth, the vestibular aqueduct (VA) continues to mature postnatally. Failure of this maturation-VA hypoplasia-identifies a subgroup of patients with Menière disease and can be detected on CT by measuring the angular trajectory of the VA (ATVA). However, the age at which the ATVA stabilizes and hypoplasia can be reliably diagnosed remains unclear. We, therefore, defined the normal timeline of ATVA development to establish age-specific CT norms for distinguishing physiologic VA development from fetal/hypoplastic arrest. MATERIALS AND METHODS:We retrospectively reviewed temporal bone and head CTs in 159 children (318 ears) 0-16 years of age without an otologic abnormality. Two head and neck radiologists measured the ATVA and retrolabyrinthine bone (RL) thickness-previously established surrogates of VA hypoplasia-on axial reformatted images. Interreader reliability was assessed by the intraclass correlation coefficient. We modeled the ATVA versus age by using generalized additive mixed models. First-derivative analysis of the age spline identified when ATVA change plateaued. Eighty percent and 95% prediction intervals determined the ages at which the ATVA reliably fell below clinical thresholds (140°, 130°, 120°). RESULTS:Interreader agreement was excellent (intraclass correlation coefficient = 0.92 ATVA; 0.88, RL thickness). The mean ATVA declined from 135° (SD, 7.5°) in infants to 98° (SD, 6.0°) in adolescents. At the 80% prediction interval, the ATVA upper limit fell below 140° by ∼1.8 years; 130° by ∼3.1 years; and 120° by ∼10.4 years. The 95% interval excluded ATVA ≥140° by ∼3.0 years and ≥130° by ∼10.3 years, but not >120° before 16 years of age. No ears older than 8 years of age fell in the fetal category (≥140°), and none older than 12 years of age fell in the intermediate category (121°-139°). First-derivative analysis showed that ATVA change plateaued at ∼5.0 years. RL thickness of ≥1.2 mm universally corresponded to a mature ATVA (≤120°). CONCLUSIONS:ATVA transitions from a fetal (≥140°) to mature (≤120°) trajectory across the first decade, stabilizing by ∼5 years. ATVA >120° before ∼10 years reflects normal development; after ∼12 years, it indicates adult-persistent hypoplasia. RL thickness of ≥1.2 mm serves as a practical surrogate for mature VA orientation. These benchmarks empower radiologists to differentiate normal maturation from Menière disease associated VA hypoplasia, enabling early risk-stratification and management.

Hearing and balance disorders are among the most prevalent sensory impairments globally, yet their cellular and molecular basis remains poorly understood. This gap stems from the inaccessibility of the inner ear, which is encased in the temporal bone (TB)—the hardest bone in the body—and cannot be biopsied in living patients. Conventional histopathology workflows, particularly the century-old celloidin method, are time-consuming, labor-intensive, and incompatible with modern molecular analyses. We aimed to develop a faster, more versatile histology workflow for human TBs that preserves both morphology and molecular integrity. We developed a reversible polymethyl methacrylate (rPMMA) embedding protocol for formalin-fixed, calcified TBs using low-temperature resin infiltration (−40 to +4 °C). Precision near-serial sections (10–50 µm) were generated via femtosecond laser microtomy or precision diamond wire sawing. Deacrylation was performed to restore tissue accessibility for histological staining, multiplex immunofluorescence, whole-genome sequencing, and in situ RNA detection (RNAscope™). Compared to the celloidin workflow, our method reduced processing time and costs by over 90

Importance:Meniere disease (MD) is a heterogenous disorder whose underlying etiologies remain poorly understood. A subtype of MD characterized by endolymphatic sac (ES) underdevelopment (ES hypoplasia), frequent bilateral disease, and male predominance-termed MD-hp-has emerged as a promising model for genetic investigation. Objective:To test whether the PHEX gene underlies the association of XLH with MD-hp. Design, Setting, and Participants:This prospective, cross-sectional, study was conducted at tertiary academic centers in the US (Boston, Massachusetts) and Switzerland (Zurich) from January 2021 to August 2024. Participants aged 18 years and older with XLH were recruited. Data were analyzed from October 2024 to August 2025. Exposure:Diagnosis of XLH. Main Outcomes and Measures:The primary outcome was co-occurrence of XLH and MD-hp as compared with population prevalences. MD-hp assessment included pure-tone audiometry and speech-intelligibility testing, vestibular function testing via caloric and video head-impulse testing, symptom history indicating definite MD criteria, high-resolution computed tomography assessment of ES hypoplasia (angular trajectory of the vestibular aqueduct ≥140°), delayed 3-dimensional fluid-attenuated inversion recovery magnetic resonance imaging for detection of endolymphatic hydrops, and PHEX pathway gene sequencing. Results:Given population prevalences of XLH (approximately 0.005%), MD (approximately 0.2%), and MD-hp (approximately 30% of MD), random co-occurrence would be approximately 1 in 33 million. In this cohort of 33 patients (10 male; mean [SD] age, 53.1 [13.0] years and 23 female; mean [SD] age, 46.2 [17.6] years), 6 (18.2%) met bilateral MD-hp criteria (approximately 1 in 5.5 patients)-a more than 6 million-fold enrichment. All 6 case patients were hemizygous males (including 2 males with fluctuating-progressive sensorineural hearing loss but no vertigo). Two additional hemizygous males younger than 40 years displayed bilateral ES hypoplasia without clinical MD, and 2 males with mosaic or hypomorphic PHEX variants showed normal ES anatomy and no audiovestibular symptoms. No female carriers met MD-hp criteria; instead, 5 females exhibited mild to moderate, low- to mid-frequency sensorineural hearing loss without vertigo, and 2 females had isolated conductive hearing loss. Conclusions and Relevance:These findings support an inner ear-specific PHEX gene-dosage threshold model for MD-hp penetrance; complete loss of function in hemizygous males leads to bilateral ES hypoplasia and MD, whereas mosaic or partial-loss variants in males-and heterozygosity in females-permit residual PHEX activity, resulting in milder or absent audiovestibular phenotypes. This genotype-endotype-phenotype linkage (complete PHEX loss, ES hypoplasia, and MD) enables early risk stratification and personalized surveillance and paves the way for targeted therapies in patients with XLH.

Ménière’s disease presents with endolymphatic hydrops and disproportionately poor word-recognition compared to other forms of sensorineural hearing loss, yet the underlying patterns of cochlear degeneration are not well defined. This study aimed to characterize cochlear pathology in Ménières, compare it to age-matched controls and clinically unaffected contralateral ears, and evaluate how hydrops severity and clinical endotypes relate to tissue degeneration. We analyzed 97 human cochleas, including 43 Ménière’s ears, 10 contralateral (clinically unaffected) ears, and 44 age-matched controls. Quantitative histopathology assessed survival of hair cells, spiral ganglion cells, auditory-nerve peripheral axons, stria vascularis, and spiral ligament fibrocytes, along with the degree of endolymphatic hydrops. We also examined the effects of disease duration and endolymphatic sac phenotype (hypoplastic vs degenerative). Ménière’s ears displayed consistent cochlear hydrops and more severe saccular hydrops. They showed roughly half the normal complement of cochlear hair cells but only 25

BACKGROUND AND PURPOSE:As the endolymphatic (ES) undergoes normal postnatal maturation, the surrounding vestibular aqueduct (VA) undergoes a corresponding change in morphology, quantified by its angular trajectory (ATVA). In adult temporal bones with Meniere's disease (MD), a fetal orientation ATVA (≥140°) indicates underlying ES hypoplasia and defines the so called hypoplastic disease endotype (MD-hp). However, ES hypoplasia has also been described histologically in other inner ear syndromes and congenital conditions, independent of MD. We aimed to investigate whether ATVA ≥140° occurs in mature temporal bones beyond its established association with the MD-hp endotype. MATERIALS AND METHODS:Retrospective retrieval of CT scans performed on patients over age 12 years at Massachusetts Eye and Ear between January 2016 and December 2024 was conducted, with search terms encompassing diseases previously described to be associated with temporal bone anomalies. CT studies that did not allow adequate assessment of the VA were excluded. Two neuroradiologists blinded to clinical information independently performed ATVA measurements, with consensus interpretation rendered for disagreements in ATVA categories (adult, intermediate, or fetal orientation). RESULTS:103 patients with congenital temporal bone anomalies were identified. 98 patients (190 ears) met inclusion criteria. Fetal VA orientation (ATVA ≥140°) was identified in 8 ears from 6 patients. Intermediate VA orientation (ATVA 121°-139°) was identified in 19 ears from 15 patients. Among 8 patients with branchio-oto-renal (BOR) syndrome, 2 patients had bilateral fetal orientation ATVA and 2 patients had mixed fetal/intermediate orientation ATVA. Among 11 patients with trisomy 21, 5 demonstrated unilateral abnormal ATVA. Higher than 120° ATVA values were also observed in CHARGE syndrome, Apert syndrome, and Chiari I malformation. Review of clinical records did not show a diagnosis of MD within our cohort. CONCLUSIONS:Fetal and intermediate ATVA orientations were observed in several congenital temporal bone anomalies without documented MD. These findings further support that abnormal ATVA reflects altered VA/ES developmental morphology and is not exclusive to the MD-hp endotype. Accordingly, fetal orientation ATVA should be interpreted within the broader clinical and radiologic context, particularly in the presence of additional congenital abnormalities.

Meniere's disease (MD), a degenerative inner ear disorder, is characterized by debilitating episodic vertigo and hearing fluctuations, progressing to permanent sensory impairment. The prevailing dogma attributes these symptoms to abnormal inner ear fluid buildup-endolymphatic hydrops (EH)-with pressure rise and repetitive microtrauma to sensory epithelia. However, this pressure-based mechanism lacks direct experimental evidence and fails to explain key clinical aspects. To revisit EH, we performed 3D reconstructive, machine-learning-enhanced histological analyses and immunohistochemistry on postmortem human inner ear specimens. Contrary to the classic pressure-based theory, EH-affected epithelia showed neither increased spacing between neighboring cells nor morphological evidence of ruptures; instead, they exhibited a 4-7-fold increase in epithelial cell number (hyperplasia) in Reissner's and saccular membranes, present in both early and advanced EH. Quantification of hyperplastic epithelial surface area and immunolocalization of fluid homeostasis-associated proteins suggest this hyperplasia may compensate for cell loss in the endolymphatic sac, a key MD site. These findings challenge the view of EH as purely a pressure phenomenon, revealing epithelial expansion consistent with a coordinated compensatory response to preserve fluid homeostasis and function. This paradigm shift introduces dual beneficial and detrimental roles for EH, suggesting new therapies that promote tissue repair while preventing maladaptive remodeling.

Prosper Meniere made his immortal contribution to the field of otology in 1861. At that time, all manner of “fits” were lumped together under the diagnosis of “apoplectiform cerebral congestion”—too much blood in the brain. His genius was to identify a specific subset of this heterogeneous pool whose cardinal symptoms, tinnitus, fluctuating progressive deafness, and episodic vertigo, were due to dysfunction of the inner ear. Seventy-seven years later, in 1938, Hallpike and Cairns in England and Yamakawa in Japan identified cochleosaccular endolymphatic hydrops (EH) as the histopathologic correlate of Meniere’s disease (MD). Over the 85 years since then, many theories to explain the symptoms of MD have come and gone. A consensus has slowly emerged that patients with this condition have a failure of inner ear homeostasis. The cause(s) of this homeostatic failure and the mechanism(s) by which this failure leads to fluctuating progressive sensorineural hearing loss and episodic vertigo has remained elusive. In the last few years, new techniques and findings in temporal bone histopathology and in vivo temporal bone imaging have yielded breakthroughs in this field. We are now recapitulating Meniere’s approach by taking the heterogeneous population of patients with MD and segregating them into specific subtypes based upon clinical phenotype. Salient clinical features include vestibular aqueduct and endolymphatic sac morphology, age at symptom onset, sex, and incidence of bilateral involvement. Furthermore, new imaging modalities enable unequivocal diagnosis of EH, transitioning MD from a “clinical” diagnosis to one based upon specific objective criteria. These breakthroughs have opened the door to genetic analyses, consideration of comorbid clinical disorders, especially migraine, and potential new treatments, and demand that we revisit all the various treatments that have been considered previously. They also demand new and more stringent criteria for any publication about this condition. In this paper we will review these new findings, discuss their immediate implications for clinical practice, and consider some of the most pressing research questions for near- and long-term address.

Sensorineural hearing loss (SNHL) is a hallmark symptom in patients with neurofibromatosis type 2-associated schwannomatosis (NF2-SWN), a genetic condition caused by mutations in the Neurofibromin II gene that encodes the tumor suppressor protein Moesin-Ezrin-Radixin-Like Protein (Merlin; also known as schwannomin). These mutations lead to the development of various tumors, including schwannomas, ependymomas and meningiomas along the vestibular nerve and the cerebellopontine angle. Original theories attributed SNHL in NF2-SWN to the mechanical compression of the vestibulocochlear nerve from the tumor itself, in addition to secretion of toxic tumor byproducts. However, the observation that SNHL can progress independently of tumor size and growth dynamics challenges this view and reveals a critical gap in our understanding of its underlying etiology. To better define cochlear changes associated with hearing loss in NF2-SWN, immunohistochemical cell type markers were used on archival postmortem temporal bone samples from both NF2-SWN patients and healthy controls and quantified the number and cellular density of neural (TUJ1), glial (SOX10), and immune cells (IBA1) within apical, middle, and basal turns of the cochlea. Our findings demonstrated a significant loss of spiral ganglion neurons, a slight increase of Schwann cells, and marked activation of cochlear macrophages in NF2-SWN cases. These findings indicate the contribution of cochlear macrophage-mediated inflammation and Schwann cell dysregulation in the pathophysiology of SNHL in NF2-SWN.

OBJECTIVE:To investigate whether one of the two recently described MD endotypes-defined by either endolymphatic sac degeneration (MD-dg patients) or hypoplasia (MD-hp patients)-is associated with an increased likelihood of undergoing CI. STUDY DESIGN:Retrospective multicenter cross-sectional study. SETTING:Five tertiary referral centers. PATIENTS:CI cohort: 115 adult MD patients with a history of uni- or bilateral CI. Non-CI cohort: 72 MD patients with no CI history. All included patients matched current diagnostic criteria for definite MD. INTERVENTION:Cochlear implantation. MAIN OUTCOME MEASURES:Endotype distribution (MD-dg versus MD-hp) between the CI cohort and the non-CI cohort. The endotype was determined using high-resolution CT data based on the angular trajectory of the vestibular aqueduct, following established protocols. Secondary outcomes included disease laterality, age at MD diagnosis, duration of MD, and pre-CI hearing thresholds. RESULTS:The CI cohort included significantly more MD-hp patients than the non-CI cohort (72% versus 24%, p < 0.0001). The odds ratio of CI for an MD-hp patient relative to an MD-dg patient was 8.4 (95% confidence interval, 4.3-16.1). Pre-CI audiometric data showed no significant differences in hearing thresholds between endotypes, neither in the implanted nor in the non-implanted ear. CONCLUSIONS:The MD-hp endotype, frequently associated with bilateral disease and early-age disease onset, is strongly linked to a higher likelihood of CI. Endotyping of MD patients based on endolymphatic sac pathology can effectively stratify their risk of severe hearing loss, guiding personalized audiological follow-up and clinical decisions regarding potential CI.

BACKGROUND/OBJECTIVES:Electrocochleography (ECochG) is a promising tool to monitor preservation of cochlear structures and function during cochlear implant (CI) surgery. However, the interpretation of ECochG signal changes during insertion of the CI electrode array remains controversial. This study investigates the influence of the degree and localization of cochlear trauma on ECochG signal changes using a mouse model. METHODS:C57BL/6J-Crl1 mice underwent intracochlear ECochG recordings during the insertion of a platinum-iridium electrode. RESULTS:In case of grade 1 and 2 cochlear trauma, as determined by post-mortem histological analysis, we found that a reduction in intracochlear cochlear microphonic (CM) amplitude correlates more significantly with the location of the trauma than with its severity. The more basally a trauma is located, the larger the CM amplitude drop. Furthermore, the results revealed that grade 1 or 2 trauma was detectable through ECochG before more severe trauma developed. CONCLUSIONS:These findings suggest that intracochlear ECochG can serve as a reliable intraoperative tool for detecting early and possibly reversible cochlear trauma, preventing more severe damage and aiding hearing preservation. The results emphasize the need for a nuanced interpretation of CM signal drops, considering trauma location and cochlear structure integrity at the site of trauma and apical to it.

The human cochlea is encased within the otic capsule, the densest bone in the body, posing significant challenges for anatomical imaging of cochlear structures. Because of difficult access and the fragility of cochlear structures, our understanding of intracochlear anatomy has historically relied on postmortem histology. We thus have a limited understanding of human cochlear anatomy in its native, unfixed state. Clinical diagnostics for hearing loss, such as audiometry and otoacoustic emissions, offer functional assessments but fail to elucidate the often diverse underlying structural pathologies with any degree of precision. To address the critical need for assessing the human cochlear anatomy and associated pathologies without the risk of traumatizing cochlear structures, we imaged fresh cochleae (N = 23, 15 males, 8 females) in situ soon after death through the intact round window membrane with Optical Coherence Tomography (OCT) without inserting instruments inside or opening the cochlea. Micron-resolution OCT cross-sectional images of the human intracochlear structures were acquired and compared with corresponding histology systematically to aid in the identification of fine structural features and possible pathologies. With OCT imaging, we observed varied anatomy of the organ of Corti, and developed a cochlear “integrity” rating system to differentiate healthy-appearing cochleae from various pathological states. These results demonstrate the capability of OCT to non-traumatically visualize cochlear integrity, highlighting its potential as a diagnostic tool. This work shows promise in translating the ability to determine the likelihood of existing or lack of hair cells and supporting cells in live patients, which would enable appropriate targeted treatments.

Objective:Semicircular canal dehiscence (SCD) and vestibular aqueduct (VA) hypoplasia are developmental anomalies associated with distinct inner ear syndromes-SCD syndrome and Meniere's disease (MD). Our previous work found frequent SCD in MD patients with VA hypoplasia, suggesting a shared developmental origin. To further explore this association, we adopted a reciprocal approach by assessing VA hypoplasia prevalence in patients diagnosed with SCD.Study Design:Retrospective cohort study.Setting:Tertiary referral center.Patients:A total of 219 ears from 173 patients (mean age 53.5 years, standard deviation 16.6 years; 54.3% females) were evaluated for suspected SCD, confirmed by temporal bone computed tomography (CT).Interventions:Radiological analysis of temporal bone CT scans using the angular trajectory of the vestibular aqueduct (ATVA) marker; review of clinical records for diagnosis of MD.Main Outcome Measures:Prevalence of VA hypoplasia among SCD patients; association of radiological findings with clinical diagnosis of MD.Results:VA hypoplasia was identified in 4 of 173 patients (2.3%), representing a 46-fold increase compared with the estimated 0.05% prevalence of MD patients with VA hypoplasia in the general population. These cases showed an atypical SCD localization in the posterior limb of the superior semicircular canal. All 4 patients were diagnosed with MD ipsilateral to the SCD/VA hypoplasia.Conclusions:SCD and VA hypoplasia are associated in a distinct patient group, suggesting a shared developmental etiology. These patients may be predisposed to an early overlap of SCD syndrome and MD, with their clinical course eventually dominated by the progressive nature of MD.

BACKGROUND AND PURPOSE:Menière disease (MD) manifests in 2 major endotypes: one with a hypoplastic, underdeveloped endolymphatic sac (MD-hp) and the other with a normally developed sac that degenerates over time (MD-dg). Determining the specific endotype in patients is important for predicting disease progression, tailoring patient counseling, and optimizing treatment strategies. Endotype diagnosis involves measuring an angular trajectory of the vestibular aqueduct (ATVA), with an ATVA ≥140° indicative of MD-hp and an ATVA ≤120° of MD-dg. However, assessing the ATVA can be challenging. This study aimed to explore the link between ATVA and the thickness of the retrolabyrinthine bone as an alternative diagnostic measure that could provide differentiation between MD endotypes using CT and MR imaging. MATERIALS AND METHODS:Retrospective review of CT temporal bone imaging from 32 adult patients with definite MD (60 ears) and 33 age-matched controls without MD or other inner ear symptoms (61 ears) was performed. The ATVA and retrolabyrinthine bone thickness were measured using uniform methodology on standardized axial CT images. Comparative analyses were performed to determine the correlation between ATVA and retrolabyrinthine bone thickness. Additionally, from a separate cohort of 11 patients (22 ears), CT and MR examinations of the temporal bone were retrospectively reviewed for retrolabyrinthine bone thickness measurements, to verify the correlation across the 2 modalities. RESULTS:The average retrolabyrinthine bone thickness was statistically significantly different between MD endotypes, being a mean of 0.8 (SD, 0.3) mm in patients with MD-hp (ATVA ≥140°) and 2.0 (SD, 0.9) mm in patients with MD-dg (ATVA ≤120°), with a consistent pattern of thin retrolabyrinthine bone in MD-hp and variable thickness in MD-dg. Receiver operating characteristic curve analysis within the MD cohort revealed that a retrolabyrinthine bone thickness ≥1.2 mm effectively rules out MD-hp. Excellent interrater reliability was noted for the retrolabyrinthine measurement, and there was near-perfect correlation between CT and MR measurements. CONCLUSIONS:Retrolabyrinthine bone thickness proved to be a useful and straightforward alternative marker for distinguishing MD endotypes, being particularly useful for excluding MD-hp. Including information on retrolabyrinthine bone thickness should be considered a routine part of reporting in the context of MD imaging.

Pathology repositories worldwide store millions of celloidin-processed human brain and temporal bone (TB) sections vital for studying central nervous system diseases and sensory organs. However, accessing these sections for modern molecular-pathological research, like immunohistochemistry, is hindered by the challenge of removing celloidin without damaging tissue. In this study, we explored the use of polyethylene glycols (PEGs), a class of non-hazardous, ethylene glycol oligomers, combined with an improved section mounting technique, to gently and effectively dissolve celloidin from sections archived for up to 40 years. Optimizing our protocol involved exploring celloidin dissolution kinetics in PEGs of varying molecular weights and terminations, as well as different temperatures. Low molecular weight PEGs, particularly PEG 200, were the most efficient celloidin solvent. Nuclear magnetic resonance (NMR) spectroscopy of celloidin-PEG 200 dissolution products revealed no chemical alterations, suggesting pure solvation without chemical modification. Because the solvation of celloidin in PEG was inhibited by proteins, we further developed a protein-free mounting protocol allowing complete celloidin removal in 30 to 60 minutes by immersing in PEG 200. In summary, our approach overcomes major methodological hurdles, rendering decades-old archival celloidin sections viable for immunohistochemical and other molecular biological techniques, while enhancing safety and workflow efficiency.

Introduction Meniere’s disease (MD) has been recently associated with either of two histopathologies of the endolymphatic sac (ES), i.e. ES degeneration or ES hypoplasia. These ES pathologies (“endotypes”) can be diagnosed using clinical imaging data. This presentation will give an overview on the therapeutic and prognostic implications of diagnosing endotypes in MD.

Beim Morbus Menière (MM) findet sich histopathologisch stets eine von zwei pathologischen Veränderungen des Saccus endolymphaticus (SE), nämlich eine Degeneration oder eine Hypoplasie des SE. Diese pathologischen Veränderungen («Endotypen») können mittels klinischer Bildgebung diagnostiziert werden. Mit den hier präsentierten Arbeiten soll die therapeutische und prognostische Bedeutung der Diagnose von Endotypen beim MM aufgezeigt werden.

*Department of Otorhinolaryngology, Head and Neck Surgery, Ruhr University Bochum, St. Elisabeth Hospital Bochum; †International Graduate School of Neuroscience (IGSN), Ruhr-University Bochum, Bochum, Germany; ‡Department of Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Antwerp, Belgium; §Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital Zurich, and University of Zurich, Zurich, Switzerland; ||Institute of Neuroradiology, Ruhr University Bochum, St. Josef Hospital Bochum; ¶Department of Neurology, Ruhr University Bochum, St. Josef Hospital Bochum, Bochum, Germany; **Department of Otolaryngology, Harvard Medical School, Boston, Massachusetts, USA; and ††Otopathology Laboratory, Department of Otolaryngology, Massachusetts Eye and Ear Infirmary, MA, USA