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Cisplatin chemotherapy causes permanent hearing loss in 40–80% of treated patients. It is unclear whether the cochlea has unique sensitivity to cisplatin or is exposed to higher levels of the drug. Here we use inductively coupled plasma mass spectrometry (ICP-MS) to examine cisplatin pharmacokinetics in the cochleae of mice and humans. In most organs cisplatin is detected within one hour after injection, and is eliminated over the following days to weeks. In contrast, the cochlea retains cisplatin for months to years after treatment in both mice and humans. Using laser ablation coupled to ICP-MS, we map cisplatin distribution within the human cochlea. Cisplatin accumulation is consistently high in the stria vascularis, the region of the cochlea that maintains the ionic composition of endolymph. Our results demonstrate long-term retention of cisplatin in the human cochlea, and they point to the stria vascularis as an important therapeutic target for preventing cisplatin ototoxicity. Permanent hearing loss occurs in many cancer patients treated with cisplatin. In this study, the authors examine cisplatin pharmacokinetics in the cochleae of mice and humans showing that cisplatin is retained for months to years after treatment.

Objectives To compare the performance and optimal combination of MRI descriptors used for the diagnosis of Ménière’s disease (MD) between a real-IR sequence with “zero-point” endolymph (ZPE), and an optimised real-IR sequence with negative signal endolymph (NSE). Materials and methods This retrospective single-centre cross-sectional study evaluated delayed post-gadolinium ZPE and NSE real-IR MRI in consecutive patients with Ménièriform symptoms (8/2020–10/2023). Two observers assessed 14 MRI descriptors. “Definite MD” (2015 criteria) and “all MD” ears (wider clinical criteria) were compared to controls. Cohen’s kappa and risk ratios (RR) were evaluated for each descriptor. Forward stepwise logistic regression established which combination of descriptors best predicted MD. Results The study included 132 patients (57 men; mean age 57.7 ± 13.6), with 87 “all MD” (56 “definite”) and 39 control ears. The NSE sequence demonstrated increased perilymph SNR, and improved both diagnostic performance and reliability for 9/14 descriptors. However, ZPE demonstrated superior diagnostic performance for the best descriptor of “saccule absent, large as or confluent with the utricle” (RR 6.571, ZPE; 6.300, NSE) and that of “asymmetric perilymphatic enhancement” (RR 3.628, ZPE; 2.903, NSE). Both sequences combined these two descriptors in the optimal predictive model for “definite MD”, with “grade 2 cochlear hydrops” also significant for NSE. ZPE and NSE descriptor combinations both correctly classified 95.8% of ears. The ZPE descriptor combination performed better for “all MD” (ZPE, AUC-ROC 0.914; NSE, AUC-ROC 0.893). Conclusion Parameter optimisation with NSE Real-IR influenced the optimal selection of MRI descriptors but did not improve their diagnostic performance in definite MD. Key Points Question Delayed post-gadolinium ZPE (FLAIR) and NSE (REAL-IR) sequences are widely applied for diagnosing MD, but their relative benefits remain unclear . Findings Optimised NSE sequences improve perilymphatic depiction and influence the selection of the optimal MRI descriptors, but do not improve diagnostic performance . Clinical relevance Radiologists may continue to apply either ZPE or NSE sequences since they offer similar diagnostic abilities, but the choice of the sequence will influence which MRI features should be evaluated to support the diagnosis of MD .

Meniere's disease (MD) is a disorder of the inner ear that causes vertigo attacks, fluctuating hearing loss, tinnitus and aural fullness. The aetiology of MD is multifactorial. A characteristic sign of MD is endolymphatic hydrops (EH), a disorder in which excessive endolymph accumulates in the inner ear and causes damage to the ganglion cells. In most patients, the clinical symptoms of MD present after considerable accumulation of endolymph has occurred. However, some patients develop symptoms in the early stages of EH. The reason for the variability in the symptomatology is unknown and the relationship between EH and the clinical symptoms of MD requires further study. The diagnosis of MD is based on clinical symptoms but can be complemented with functional inner ear tests, including audiometry, vestibular-evoked myogenic potential testing, caloric testing, electrocochleography or head impulse tests. MRI has been optimized to directly visualize EH in the cochlea, vestibule and semicircular canals, and its use is shifting from the research setting to the clinic. The management of MD is mainly aimed at the relief of acute attacks of vertigo and the prevention of recurrent attacks. Therapeutic options are based on empirical evidence and include the management of risk factors and a conservative approach as the first line of treatment. When medical treatment is unable to suppress vertigo attacks, intratympanic gentamicin therapy or endolymphatic sac decompression surgery is usually considered. This Primer covers the pathophysiology, symptomatology, diagnosis, management, quality of life and prevention of MD. Meniere's disease is a disorder of the inner ear that causes vertigo attacks, fluctuating hearing loss, tinnitus and aural fullness. In this Primer, Nakashima et al . give an overview of the complex aetiology, classification systems, diagnostic tools and management strategies.

Menière’s disease, clinically characterized by fluctuating, recurrent, and invalidating vertigo, hearing loss, and tinnitus, is linked to an increase in endolymph volume, the so-called endolymphatic hydrops. Since dysregulation of water transport could account for the generation of this hydrops, we investigated the role of aquaporin 3 (AQP3) in water transport into endolymph, the K-rich, hyperosmotic fluid that bathes the apical ciliated membrane of sensory cells, and we studied the regulatory effect of dexamethasone upon AQP3 expression and water fluxes. The different AQP subtypes were identified in inner ear by RT-PCR. AQP3 was localized in human utricle and mouse inner ear by immunohistochemistry and confocal microscopy. Unidirectional transepithelial water fluxes were studied by means of 3 H 2 O transport in murine EC5v vestibular cells cultured on filters, treated or not with dexamethasone (10 −7  M). The stimulatory effect of dexamethasone upon AQP3 expression was assessed in EC5v cells and in vivo in mice. AQP3 was unambiguously detected in human utricle and was highly expressed in both endolymph secretory structures of the mouse inner ear, and EC5v cells. We demonstrated that water reabsorption, from the apical (endolymphatic) to the basolateral (perilymphatic) compartments, was stimulated by dexamethasone in EC5v cells. This was accompanied by a glucocorticoid-dependent increase in AQP3 expression at both messenger RNA (mRNA) and protein level, presumably through glucocorticoid receptor-mediated AQP3 transcriptional activation. We show that glucocorticoids enhance AQP3 expression in human inner ear and stimulate endolymphatic water reabsorption. These findings should encourage further clinical trials evaluating glucocorticoids efficacy in Menière’s disease.

The endolymphatic sac is a small sac-shaped organ at the end of the membranous labyrinth of the inner ear. The endolymphatic sac absorbs the endolymph, in which the ion balance is crucial for inner ear homeostasis. Of the three sections of the endolymphatic sac, the intermediate portion is the center of endolymph absorption, particularly sodium transport, and is thought to be regulated by aldosterone. Disorders of the endolymphatic sac may cause an excess of endolymph (endolymphatic hydrops), a histological observation in Meniere’s disease. A low-salt diet is an effective treatment for Meniere’s disease, and is based on the assumption that the absorption of endolymph in the endolymphatic sac abates endolymphatic hydrops through a physiological increase in aldosterone level. However, the molecular basis of endolymph absorption in each portion of the endolymphatic sac is largely unknown because of difficulties in gene expression analysis, resulting from its small size and intricate structure. The present study combined reverse transcription-quantitative polymerase chain reaction and laser capture microdissection techniques to analyze the difference of gene expression of the aldosterone-controlled epithelial Na+ channel, thiazide-sensitive Na+-Cl− cotransporter, and Na+, K+-ATPase genes in the three individual portions of the endolymphatic sac in a rat model. A low-salt diet increased the expression of aldosterone-controlled ion transporters, particularly in the intermediate portion of the endolymphatic sac. Our findings will contribute to the understanding of the physiological function of the endolymphatic sac and the pathophysiology of Meniere’s disease.

Background Non-contrast FLAIR revealed increased signal within the inner ear in patients with vestibular schwannoma, which is generally assumed to occur in the perilymph; however, the majority of previous studies did not differentiate between the endolymph and perilymph. Therefore, endolymph signal changes have not yet been investigated in detail. The purpose of the present study was three-fold: (1) to assess perilymph signal changes in patients with vestibular schwannoma on heavily T2-weighted (T2W) 3D FLAIR, also termed positive perilymphatic images (PPI), (2) to evaluate signal and morphological changes in the endolymph on PPI, and (3) to establish whether vertigo correlates with the signal intensity ratios (SIR) of the vestibular perilymph or vestibular endolymphatic hydrops. Methods Forty-two patients with unilateral vestibular schwannoma were retrospectively recruited. We semi-quantitatively and qualitatively evaluated the perilymph signal intensity on the affected and unaffected sides. We also quantitatively examined the signal intensity of the vestibular perilymph and assessed the relationship between vertigo and the SIR of the vestibular perilymph on the affected side. We semi-quantitatively or qualitatively evaluated the endolymph, and investigated whether vestibular hydrops correlated with vertigo. Results The perilymph on the affected side showed abnormal signal more frequently (signal intensity grade: overall mean 1.45 vs. 0.02; comparison of signal intensity: overall mean 36 vs. 0 cases) and in more parts (the entire inner ear vs. the basal turn of the cochlea and vestibule) than that on the unaffected side. No significant difference was observed in the SIR of the vestibular perilymph with and without vertigo (5.54 vs. 5.51, p  = 0.18). The endolymph of the vestibule and semicircular canals showed the following characteristic features: no visualization (n = 4), signal change (n = 1), or vestibular hydrops (n = 10). A correlation was not observed between vestibular hydrops and vertigo ( p  = 1.000). Conclusions PPI may provide useful information on signal and morphological changes in the endolymph of patients with vestibular schwannoma. Further research is warranted to clarify the relationship between vertigo and the MR features of the inner ear.

Endothermy underpins the ecological dominance of mammals and birds in diverse environmental settings 1 , 2 . However, it is unclear when this crucial feature emerged during mammalian evolutionary history, as most of the fossil evidence is ambiguous 3 – 17 . Here we show that this key evolutionary transition can be investigated using the morphology of the endolymph-filled semicircular ducts of the inner ear, which monitor head rotations and are essential for motor coordination, navigation and spatial awareness 18 – 22 . Increased body temperatures during the ectotherm–endotherm transition of mammal ancestors would decrease endolymph viscosity, negatively affecting semicircular duct biomechanics 23 , 24 , while simultaneously increasing behavioural activity 25 , 26 probably required improved performance 27 . Morphological changes to the membranous ducts and enclosing bony canals would have been necessary to maintain optimal functionality during this transition. To track these morphofunctional changes in 56 extinct synapsid species, we developed the thermo-motility index, a proxy based on bony canal morphology. The results suggest that endothermy evolved abruptly during the Late Triassic period in Mammaliamorpha, correlated with a sharp increase in body temperature (5–9 °C) and an expansion of aerobic and anaerobic capacities. Contrary to previous suggestions 3 – 14 , all stem mammaliamorphs were most probably ectotherms. Endothermy, as a crucial physiological characteristic, joins other distinctive mammalian features that arose during this period of climatic instability 28 . The functional morphology of the fluid-filled semicircular ducts of the inner ear is adapted to body temperature and behavioural activity and can be used to investigate the evolution of endothermy.

Intravenous contrast agent-enhanced magnetic resonance imaging of the endolymphatic space (ELS) of the inner ear permits direct, in-vivo, non-invasive visualization of labyrinthine structures and thus verification of endolymphatic hydrops (ELH). However, current volumetric assessment approaches lack normalization. The aim of this study was to develop a probabilistic atlas of the inner ear’s bony labyrinth as a first step towards an automated and reproducible volume-based quantification of the ELS. The study included three different datasets: a source dataset (D1) to build the probabilistic atlas and two testing sets (D2, D3). D1 included 24 right-handed patients (12 females; mean age 51.5 ± 3.9 years) and D2 5 patients (3 female; mean age 48.8 ± 5.01 years) with vestibular migraine without ELH or any measurable vestibular deficits. D3 consisted of five patients (one female; mean age 46 ± 5.2 years) suffering from unilateral Menière’s disease and ELH. Data processing comprised three steps: preprocessing using an affine and deformable fusion registration pipeline, computation of an atlas for the left and right inner ear using a label-assisted approach, and validation of the atlas based on localizing and segmenting previously unseen ears. The three-dimensional probabilistic atlas of the inner ear’s bony labyrinth consisted of the internal acoustic meatus and inner ears (including cochlea, otoliths, and semicircular canals) for both sides separately. The analyses showed a high level of agreement between the atlas-based segmentation and the manual gold standard with an overlap of 89% for the right ear and 86% for the left ear (measured by dice scores). This probabilistic in vivo atlas of the human inner ear’s bony labyrinth and thus of the inner ear’s total fluid space for both ears represents a necessary step towards a normalized, easily reproducible and reliable volumetric quantification of the perilymphatic and endolymphatic space in view of MR volumetric assessment of ELH. The proposed atlas lays the groundwork for state-of-the-art approaches (e.g., deep learning) and will be provided to the scientific community.

Balance is achieved and maintained by a balance system called a labyrinth that is composed of three semicircular canals and the otolith organs that sense linear gravity and acceleration. Within each semicircular canal, there is a gelatinous structure called the cupula, which is deformed under the influence of the surrounding endolymph. One of the balance disorders is benign paroxysmal positional vertigo, and one of the pathological conditions that have been identified as possible causes of this syndrome is canalithiasis—disturbance of the endolymph flow and cupular displacement caused by the free-moving otoconia particles within the lumen of the canal. Analysis of phenomena occurring within the semicircular canal can help to explain some balance-related disorders and the response of the vestibular system to external perturbations under various pathological conditions. Numerical simulations allow a study of the influence of a wide range of factors, without the need to perform experiments and clinical examinations. In case of canalithiasis, an accurate explanation and tracking of the motion of otoconia particles in vivo is obviously nearly impossible. In this study, a numerical model was developed to predict the motion of otoconia particles within the semicircular canal and the effect of the endolymph flow and particles on the deformation of the cupula.

Cochlear endolymph, an extracellular solution containing 150 mM K + , exhibits a positive potential of +80 mV. This is called the endocochlear potential (EP) and is essential for audition. The mechanism responsible for formation of the EP has been an enigma for the half century since its first measurement. A key element is the stria vascularis, which displays a characteristic tissue structure and expresses multiple ion-transport apparatus. The stria comprises two epithelial layers: a layer of marginal cells and one composed of intermediate and basal cells. Between the two layers lies an extracellular space termed the intrastrial space (IS), which is thus surrounded by the apical membranes of intermediate cells and the basolateral membranes of marginal cells. The fluid in the IS exhibits a low concentration of K + and a positive potential similar to the EP. We have demonstrated that the IS is electrically isolated from the neighboring extracellular fluids, perilymph, and endolymph, which allows the IS to sustain its positive potential. This IS potential is generated by K + diffusion across the apical membranes of intermediate cells, where inwardly rectifying Kir4.1 channels are localized. The low K + concentration in the IS, which is mandatory for the large K + -diffusion potential, is maintained by Na + ,K + -ATPases and Na + ,K + ,2Cl − -cotransporters expressed at the basolateral membranes of marginal cells. An additional K + -diffusion potential formed by KCNQ1/KCNE1-K + channels at the apical membranes of marginal cells also contributes to the EP. Therefore, the EP depends on an electrically isolated space and two K + -diffusion potentials in the stria vascularis.