The importance of bone density and anatomical structure in superior semicircular canal dehiscence.

OBJECTIVE: This study investigates the importance of bone density, surface area, and diameter of anatomical structures of the superior semicircular canal (SSC), lateral semicircular canal (LSC), posterior semicircular canal (PSC), utricle, and saccule in patients diagnosed with superior semicircular canal dehiscence (SSCD). MATERIALS AND METHODS: The bone density, surface area, and diameter of SSC, LSC, PSC, utricle, and saccule were measured and compared between the SSCD group and control group. Fifteen ears in the SSCD group and 60 ears in the control group were evaluated. Additionally, within the SSCD group, the dehiscent and healthy sides were evaluated independently. RESULTS: SSC's bone density was significantly lower in the SSCD group compared to the control group (p = 0.008). No significant differences were found in surface area and diameter between the groups (p > 0.05). While most of the anatomical structures showed no significant difference in bone density between dehiscent and healthy ears (p > 0.05), SSC bone density was significantly lower in affected ears (p = 0.000) in SSCD group. CONCLUSION: Based on the data obtained in this study, bone density and anatomical structure may be useful in patients diagnosed with SSCD.

Characteristic findings in the human fetus vestibule: A human temporal bone study.

OBJECTIVE: The "collapse," a highly flexed, dented, or caved membrane between the endo- and peri-lymph of the saccule and utricle in adults, is considered as a morphological aspect of Ménière's syndrome. Likewise, when mesh-like tissues in the perilymphatic space are damaged or lost, the endothelium loses mechanical support and causes nerve irritation. However, these morphologies were not examined in fetuses. METHODS: By using histological sections from 25 human fetuses (crown-rump length[CRL] 82-372 mm; approximately 12-40 weeks), morphologies of the perilymphatic-endolymphatic border membrane and the mesh-like tissue around the endothelium were examined. RESULTS: The highly flexed or caved membrane between the endo- and peri-lymphatic spaces was usually seen in the growing saccule and utricle of fetuses, especially at junctions between the utricle and ampulla at midterm. Likewise, the perilymphatic space around the saccule, utricle and semicircular ducts often lost the mesh-like tissues. The residual mesh-like tissue supported the veins, especially in the semicircular canal. CONCLUSION: Within a cartilaginous or bony room showing a limited growth in size but containing increased perilymph, the growing endothelium appeared to become wavy. Owing to a difference in growth rates between the utricle and semicircular duct, the dentation tended to be more frequently seen at junctions than at free margins of the utricle. The difference in site and gestational age suggested that the deformity was not "pathological" but occurred due to unbalanced growth of the border membrane. Nevertheless, the possibility that the deformed membrane in fetuses was an artifact caused by delayed fixation is not deniable.

Correlation between magnetic resonance imaging classification of endolymphatic hydrops and clinical manifestations and audiovestibular test results in patients with definite Ménière's disease.

OBJECTIVES: The purpose was to evaluate magnetic resonance imaging (MRI) classification of endolymphatic hydrops with clinical features, audiological and vestibular tests in patients with definite unilateral Ménière's disease (MD). METHODS: Thirty-eight patients were enrolled in this study. The severity of the main clinical symptoms, audiovestibular tests, and MRI, performed 4 hours after intravenous injection of gadobutrol to visualize inner ear compartments, were evaluated. Endolymphatic space dilatation was assessed using Barath and Bernaerts grading systems, and the correlation between the grade of the hydrops and clinical features was evaluated. RESULTS: Using the Barath system, cochlear hydrops was visualized in 81.6% of affected ears, while vestibular was 63.2%. Sensitivity increased to 94.7% using Bernaerts' modification. Vestibular hydrops involving the utricle was present only among patients with cochlear and saccular endolymphatic space dilatation. There was a significant relationship between the hearing level and the vestibular hydrops degree in the Bernaerts scale. The grade of the hydrops correlated neither with the duration of MD nor with the severity of main clinical symptoms. Our study proved MRI to be a sensitive diagnostic tool in MD. The endolymphatic hydrops' grade correlates with the hearing level, which confirms endolymphatic space dilatation's role in hearing loss. CONCLUSIONS: In our study, two similar MRI grading systems were used; however, several differences were found compared to one another. The Bernaerts scale was more sensitive than the Barath scale, and several relationships between the radiological and clinical data were found. Therefore, several MRI evaluating scales and correlating them with the clinical features are needed. The increased perilymphatic enhancement of the cochlea and an extra low-grade vestibular hydrops distinguished in the Bernaerts scale may increase MD diagnosis sensitivity. Magnetic resonance findings in MD support the clinical diagnosis and may help to understand MD pathophysiology better. This study adds to the knowledge and diagnostics in MD for healthcare to improve patients' treatment.

3D-reconstructions of Bast's Valve and Membranous Labyrinth: Insights for Vestibular Implantation and Meniere's Disease.

HYPOTHESIS/BACKGROUND: Bast's valve is a poorly understood inner ear structure located at the junction between pars superior and inferior in the membranous labyrinth. Anatomically precise three-dimensional reconstructions (3D-reconstructions) of Bast's valve can help illuminate the morphology of the valve, and point toward its role in normal physiology and pathological states such as endolymphatic hydrops. This is of particular relevance to the development of a vestibular implant, a device intended to rehabilitate deficits in the vestibular system. METHODS: Six postmortem human temporal bones from healthy donors were scanned using a micro-computed tomography (microCT) scanner. The microCT data allowed 3D-reconstructions of the membranous labyrinth, with a particular focus on Bast's valve, vestibule, and cochlear duct. RESULTS: The microCT images of Bast's valve showed a rigid lip containing a core of soft tissue, opposing the thin membranous wall of the utricle. The maximum recorded length and width of the rigid lip were 440.4 µm and 88 µm, respectively. The 3D-reconstructions illustrated the slit-like opening of Bast's valve into the utricle, the twisting course of the basal turn of the cochlear duct, and the spatial orientation of utricle and saccule with respect to the stapes footplate. CONCLUSIONS: The present study provided a novel anatomical perspective on the microscopic structure of Bast's valve. The interplay between endolymphatic hydrops and Bast's valve is an ongoing area of research, but defining this anatomy in 3D will play a key role in furthering our understanding of the disease process. Implications for vestibular implantation are explored through the various 3D-reconstructions.

An in vitro model to assess the peripheral vestibulotoxicity of aromatic solvents.

Epidemiological and experimental studies indicate that a number of aromatic solvents widely used in the industry can affect hearing and balance following chronic exposure. Animal studies demonstrated that long-term exposure to aromatic solvents directly damages the auditory receptor within the inner ear: the cochlea. However, no information is available on their effect on the vestibular receptor, which shares many structural features with the cochlea and is also localized in inner ear. The aim of this study was to use an in vitro approach to assess and compare the vestibular toxicity of different aromatic solvents (toluene, ethylbenzene, styrene and ortho-, meta-, para-xylene), all of which have well known cochleotoxic properties. We used a three-dimensional culture model of rat utricles ("cysts") with preserved functional sensory and secretory epithelia, and containing a potassium-rich (K+) endolymph-like fluid for this study. Variations in K+ concentrations in this model were considered as biomarkers of toxicity of the substances tested. After 72 h exposure, o-xylene, ethylbenzene and styrene decreased the K+ concentration by 78 %, 37 % and 28 %, respectively. O- xylene and styrene both caused histopathological alterations in secretory and sensory epithelial areas after 72 h exposure, whereas no anomalies were observed in ethylbenzene-exposed samples. These in vitro results suggest that some widely used aromatic solvents might have vestibulotoxic properties (o-xylene, styrene and ethylbenzene), whereas others may not (p-xylene, m-xylene, toluene). Our results also indicate that variations in endolymphatic K+ concentration may be a more sensitive marker of vestibular toxicity than histopathological events. Finally, this study suggests that cochleotoxic solvents might not be necessarily vestibulotoxic, and vice versa.

Dynamic patterns of YAP1 expression and cellular localization in the developing and injured utricle.

The Hippo signaling pathway is a key regulator of tissue development and regeneration. Activation of the Hippo pathway leads to nuclear translocation of the YAP1 transcriptional coactivator, resulting in changes in gene expression and cell cycle entry. Recent studies have demonstrated the nuclear translocation of YAP1 during the development of the sensory organs of the inner ear, but the possible role of YAP1 in sensory regeneration of the inner ear is unclear. The present study characterized the cellular localization of YAP1 in the utricles of mice and chicks, both under normal conditions and after HC injury. During neonatal development, YAP1 expression was observed in the cytoplasm of supporting cells, and was transiently expressed in the cytoplasm of some differentiating hair cells. We also observed temporary nuclear translocation of YAP1 in supporting cells of the mouse utricle after short periods in organotypic culture. However, little or no nuclear translocation of YAP1 was observed in the utricles of neonatal or mature mice after ototoxic injury. In contrast, substantial YAP1 nuclear translocation was observed in the chicken utricle after streptomycin treatment in vitro and in vivo. Together, these data suggest that differences in YAP1 signaling may partially account for the differing regenerative abilities of the avian vs. mammalian inner ear.

Simultaneous gentamicin-mediated damage and Atoh1 overexpression promotes hair cell regeneration in the neonatal mouse utricle.

Loss of hair cells from vestibular epithelium results in balance dysfunction. The current therapeutic regimen for vestibular diseases is limited. Upon injury or Atoh1 overexpression, hair cell replacement occurs rapidly in the mammalian utricle, suggesting a promising approach to induce vestibular hair cell regeneration. In this study, we applied simultaneous gentamicin-mediated hair cell ablation and Atoh1 overexpression to induce neonatal utricular hair cell formation in vitro. We confirmed that type I hair cells were the primary targets of gentamicin. Furthermore, injury and Atoh1 overexpression promoted hair cell regeneration in a timely and efficient manner through robust viral transfection. Hair cells regenerated with type II characteristics in the striola and type I/II characteristics in non-sensory regions. Rare EdU+/myosin7a+ cells in sensory regions and robust EdU+/myosin7a+ signals in ectopic regions indicate that transdifferentiation of supporting cells in situ, and mitosis and differentiation of non-sensory epithelial cells in ectopic regions, are sources of regenerative hair cells. Distinct regeneration patterns in in situ and ectopic regions suggested robust plasticity of vestibular non-sensory epithelium, generating more developed hair cell subtypes and thus providing a promising stem cell-like source of hair cells. These findings suggest that simultaneously causing injury and overexpressing Atoh1 promotes hair cell regeneration efficacy and maturity, thus expanding the understanding of ectopic plasticity in neonatal vestibular organs.

Knockdown of Foxg1 in Sox9+ supporting cells increases the trans-differentiation of supporting cells into hair cells in the neonatal mouse utricle.

Foxg1 plays important roles in regeneration of hair cell (HC) in the cochlea of neonatal mouse. Here, we used Sox9-CreER to knock down Foxg1 in supporting cells (SCs) in the utricle in order to investigate the role of Foxg1 in HC regeneration in the utricle. We found Sox9 an ideal marker of utricle SCs and bred Sox9CreER/+Foxg1loxp/loxp mice to conditionally knock down Foxg1 in utricular SCs. Conditional knockdown (cKD) of Foxg1 in SCs at postnatal day one (P01) led to increased number of HCs at P08. These regenerated HCs had normal characteristics, and could survive to at least P30. Lineage tracing showed that a significant portion of newly regenerated HCs originated from SCs in Foxg1 cKD mice compared to the mice subjected to the same treatment, which suggested SCs trans-differentiate into HCs in the Foxg1 cKD mouse utricle. After neomycin treatment in vitro, more HCs were observed in Foxg1 cKD mice utricle compared to the control group. Together, these results suggest that Foxg1 cKD in utricular SCs may promote HC regeneration by inducing trans-differentiation of SCs. This research therefore provides theoretical basis for the effects of Foxg1 in trans-differentiation of SCs and regeneration of HCs in the mouse utricle.

MRI utricle diameter asymmetry is significantly greater in dogs with idiopathic vestibular syndrome compared with unaffected dogs.

Idiopathic vestibular syndrome (IVS) is the most common cause of acute unilateral peripheral vestibular dysfunction in older dogs. The purpose of this retrospective, cross-sectional study was to characterize morphological changes in the utricle of dogs affected by IVS, using MRI. To evaluate differences between affected and unaffected utricles, the ratio of the largest to the smallest utricle diameter was obtained, as measured on transverse T2-weighted images, and defined as the utricle asymmetricity ratio (UAR). Out of 137 patients diagnosed with IVS after excluding other vestibular diseases by MRI, 101 were eligible for inclusion. Additionally, 31 older dogs with no signs of vestibular disorders or other intracranial diseases were included as a control group. The disease group was divided into two subgroups in which the direction of head tilt and nystagmus symptoms versus the decreased utricle diameters were consistent or inconsistent. The medians of UARs of the IVS and control groups were 0.83 (range 0.37-1.00) and 0.98 (0.70-1.00), respectively. The medians of the UARs of the consistent and inconsistent IVS subgroups were 0.82 (0.37-0.99) and 0.90 (0.74-1.00), respectively. The UAR of the IVS group was significantly decreased than that of the control group and UAR of the consistent sub-group was significantly decreased than that of the inconsistent sub-group (P < .01). In conclusion, significant asymmetry of utricle diameter was identified in dogs with IVS versus unaffected dogs. We propose that canine IVS may possibly be correlated with structural atrophy of the vestibular system.

Styrene alters potassium endolymphatic concentration in a model of cultured utricle explants.

Despite well-documented neurotoxic and ototoxic properties, styrene remains commonly used in industry. Its effects on the cochlea have been extensively studied in animals, and epidemiological and animal evidence indicates an impact on balance. However, its influence on the peripheral vestibular receptor has yet to be investigated. Here, we assessed the vestibulotoxicity of styrene using an in vitro model, consisting of three-dimensional cultured newborn rat utricles filled with a high­potassium (K+) endolymph-like fluid, called "cysts". K+ entry in the cyst ("influx") and its exit ("efflux") are controlled by secretory cells and hair cells, respectively. The vestibular epithelium's functionality is thus linked to K+ concentration, measured using a microelectrode. Known inhibitors of K+ efflux and influx validated the model. Cysts were subsequently exposed to styrene (0.25; 0.5; 0.75 and 1 mM) for 2 h or 72 h. The decrease in K+ concentration measured after both exposure durations was dose-dependent, and significant from 0.75 mM styrene. Vacuoles were visible in the cytoplasm of epithelial cells from 0.5 mM after 2 h and from 0.25 mM after 72 h. The results presented here are the first evidence that styrene may deregulate K+ homeostasis in the endolymphatic space, thereby altering the functionality of the vestibular receptor.

Transient Vertigo with Horizontal Nystagmus to Loud Noise and Pressure: Utricular Hydrops or Vestibular Atelectasis?

We present an unusual case of a patient with a positive Tullio phenomenon, brief Valsalva-induced transient horizontal nystagmus, reduced left caloric response, and bilateral vestibulo-ocular reflex loss. This study discusses the pathophysiology and differential diagnosis concerning the suspected pathology for the phenomenon of utricular hydrops or vestibular atelectasis and presents a literature review.

cVEMP correlated with imbalance in a mouse model of vestibular disorder.

BACKGROUND: Cervical vestibular evoked myogenic potential (cVEMP) testing is a strong tool that enables objective determination of balance functions in humans. However, it remains unknown whether cVEMP correctly expresses vestibular disorder in mice. OBJECTIVE: In this study, correlations of cVEMP with scores for balance-related behavior tests including rotarod, beam, and air-righting reflex tests were determined in ICR mice with vestibular disorder induced by 3,3'-iminodipropiontrile (IDPN) as a mouse model of vestibular disorder. METHODS: Male ICR mice at 4 weeks of age were orally administered IDPN in saline (28 mmol/kg body weight) once. Rotarod, beam crossing, and air-righting reflex tests were performed before and 3-4 days after oral exposure one time to IDPN to determine balance functions. The saccule and utricles were labeled with fluorescein phalloidin. cVEMP measurements were performed for mice in the control and IDPN groups. Finally, the correlations between the scores of behavior tests and the amplitude or latency of cVEMP were determined with Spearman's rank correlation coefficient. Two-tailed Student's t test and Welch's t test were used to determine a significant difference between the two groups. A difference with p < 0.05 was considered to indicate statistical significance. RESULTS: After oral administration of IDPN at 28 mmol/kg, scores of the rotarod, beam, and air-righting reflex tests in the IDPN group were significantly lower than those in the control group. The numbers of hair cells in the saccule, utricle, and cupula were decreased in the IDPN group. cVEMP in the IDPN group was significantly decreased in amplitude and increased in latency compared to those in the control group. cVEMP amplitude had significant correlations with the numbers of hair cells as well as scores for all of the behavior tests in mice. CONCLUSIONS: This study demonstrated impaired cVEMP and correlations of cVEMP with imbalance determined by behavior tests in a mouse model of vestibular disorder.

MRI of endolymphatic hydrops in patients with vestibular schwannomas: a case-controlled study using non-enhanced T2-weighted images at 3 Teslas.

OBJECTIVE: Vestibular schwannomas (VS) may present with similar symptoms endolymphatic hydrops. Association between hydrops and internal auditory canal VS has been described by Naganawa et al. (Neuroradiology 53:1009-1015, 2011), but has never been confirmed since. The aim of this work was to study the prevalence of a saccular dilation on a T2-weighted sequence at 3 T MRI in VS compared to a control group. MATERIALS AND METHODS: All patients presenting with typical VS between May 2009 and July 2018 were included (n = 183) and compared to a control group (n = 53). All underwent a high-resolution T2-weighted 3D sequence (FIESTA-C). The height and width of the saccule were measured on a coronal plane by two radiologists. RESULTS: The saccule was dilated on the side of the schwannoma in 28% of the cases (p = 2.81 × 10- 5), with 15.7% of bilateral dilation. Saccular dilation was correlated to sensorineural hearing loss (OR 3.26, p = 0.02). There was also a significant correlation between saccular hydrops on the normal contralateral side of patients with VS and vertigo (p = 0.049), and between saccular hydrops on the side of the tumour and tinnitus (p = 0.006). CONCLUSION: A third (29%) of VS are associated with a saccular dilation on the side of the tumour, which is an MR sign of endolymphatic hydrops (bilateral in 15.7% of the cases) and it appears related to sensorineural hearing loss and tinnitus, as well as vertigo if a contralateral dilation is present. This opens new therapeutic potentialities with the use of anti-vertiginous drugs, which could have a beneficial effect on the clinical symptoms.

The Biomechanics of Lesion Formation in Endolymphatic Hydrops: Single and Double Hit Mechanisms.

BACKGROUND: The vestibular membranes of the cochlea and saccule are subject to two simultaneous constraints as they deform in endolymphatic hydrops. Boundary tethers impose a bulge-type constraint during pressure-induced transverse membrane displacement, while inherent elasticity imposes a stretch-type constraint during stress-induced longitudinal membrane distention. OBJECTIVE: The aim of this study is to reconcile the effect of these dual constraints on membrane deformation. It is hypothesized that it is the interaction of these constraints that determines whether a stable membrane configuration can be achieved or progression to endolymphatic hydrops will occur. METHODS: Reissner's membrane was modeled as a flat elastic ribbon that was bound along its lateral edges and subject to trans-mural pressure. The bulge and stretch constraints on membrane deformation were formulated mathematically. A graphic solution of the constraint functions was used to examine the nature of the interaction and determine how pressure and elasticity influence the hydropic process. RESULTS: The graphic analysis shows how bulge and stretch phenomena interact to achieve an equilibrium point that satisfies both physical requirements. Nominal values of pressure and elasticity are projected to result in a stable membrane equilibrium in the precritical zone with the modest isolated increases in either parameter alone compatible with stability. However, a sufficiently large increase in either pressure or elasticity alone can constitute a single hit mechanism to exceed the critical point and destabilize the membrane. Moreover, simultaneous modest increases in both pressure and elasticity, neither of which would be sufficient in its own right, can be additive and constitute a double hit mechanism to destabilize the membranes as well. Finally, extreme values of pressure and elasticity that fail to intersect imply that no solution is feasible and that the affected membranes will fail immediately. CONCLUSIONS: Sufficiently large increases in either endolymphatic pressure or membrane elasticity alone can destabilize the membranes and constitute single hit mechanisms for inducing hydrops. Combined moderate increases in both trans-mural pressure and membrane elasticity can also destabilize the membranes and constitute a double hit mechanism for hydrops induction.

Degeneration of saccular hair cells caused by MITF gene mutation.

BACKGROUND: Waardenburg syndrome (WS) is the consequence of an inherited autosomal dominant mutation which causes the early degeneration of intermediate cells of cochlear stria vascularis (SV) and profound hearing loss. Patients with WS may also experience primary vestibular symptoms. Most of the current WS studies did not discuss the relationship between WS and abnormal vestibular function. Our study found that a spontaneous mutant pig showed profound hearing loss and depigmentation. MITF-M, a common gene mutation causes type WS which affect the development of the intermediate cell of SV, was then identified for animal modeling. RESULTS: In this study, the degeneration of vestibular hair cells was found in pigs with MITF-M. The morphology of hair cells in vestibular organs of pigs was examined using electron microscopy from embryonic day E70 to postnatal two weeks. Significant hair cell loss in the mutant saccule was found in this study through E95 to P14. Conversely, there was no hair cell loss in either utricle or semi-circular canals. CONCLUSIONS: Our study suggested that MITF-M gene mutation only affects hair cells of the saccule, but has no effect on other vestibular organs. The study also indicated that the survival of cochlear and saccular hair cells was dependent on the potassium release from the cochlear SV, but hair cells of the utricle and semi-circular canals were independent on SV.

Characterization of the Transcriptome of Hair Cell Regeneration in the Neonatal Mouse Utricle.

BACKGROUND/AIMS: Hearing and balance deficits are mainly caused by loss of sensory inner ear hair cells. The key signals that control hair cell regeneration are of great interest. However, the molecular events by which the cellular signals mediate hair cell regeneration in the mouse utricle are largely unknown. METHODS: In the present study, we investigated gene expression changes and related molecular pathways using RNA-seq and qRT-PCR in the newborn mouse utricle in response to neomycin-induced damage. RESULTS: There were 302 and 624 genes that were found to be up-regulated and down-regulated in neomycin-treated samples. GO and KEGG pathway analyses of these genes revealed many deregulated cellular components, molecular functions, biological processes and signaling pathways that may be related to hair cell development. More importantly, the differentially expressed genes included 9 transcription factors from the zf-C2H2 family, and eight of them were consistently down-regulated during hair cell damage and subsequent regeneration. CONCLUSION: Our results provide a valuable source for future studies and highlighted some promising genes, pathways or processes that may be useful for therapeutic applications.

Saccular measurements in routine MRI can predict hydrops in Menière's disease.

Most patients with suspicion of hydrops do not have access to MRI with 3D reconstruction of the endolymphatic space. Our main objective was to show that measurements of the saccule on a non-enhanced 3D-T2 MRI could show hydrops and help diagnose Menière disease. We conducted a prospective study from 2015 to 2016 to compare consecutive patients consulting for Menière's disease to a control group (patients with unilateral non-hydrops disorders and contralateral healthy ears). They all received full auditory and vestibular testing. They also underwent a 3-Tesla 3D-T2 MRI using CISS sequence (0.4 mm thick slices), which were blindly evaluated by two independent neuroradiologists. The saccular height and width were measured in a coronal plane and Menière's disease patients' symptomatic ears were compared to asymptomatic and control ears. 36 patients with definite Menière's disease and 36 control patients were studied, including 42 symptomatic Menière, 30 asymptomatic Menière and 72 control ears. Saccular measurements were significantly different between symptomatic Menière ears compared to healthy ears (1.59 vs 1.32 mm, p < 0.001 for height; 1.13 vs 0.90 mm, p < 0.001 for width). Symptomatic and asymptomatic Menière ears' measurements were not significantly different (p = 0.307 and p = 0.109). Using ROC curve, we found cut-off values for saccular height 1.51 mm, Se = 63%, Sp = 95% and width 1.05 mm, Se = 41%, Sp = 95%. Routine 3D-T2 MRI, which patients must undergo for differential diagnosis, could help diagnose hydrops with high specificity using saccular measurements.

Dose-dependent cochlear and vestibular toxicity of trans-tympanic cisplatin in the rat.

In vivo studies are needed to study cisplatin ototoxicity and to evaluate candidate protective treatments. Rats and mice are the preferred species for toxicological and pharmacological pre-clinical research, but systemic administration of cisplatin causes high morbidity in these species. We hypothesized that trans-tympanic administration of cisplatin would provide a good model for studying its auditory and vestibular toxicity in the rat. Cisplatin was administered by the trans-tympanic route in one ear (50µl, 0.5-2mg/ml) of rats of both sexes and two different strains. Cochlear toxicity was corroborated by histological means. Vestibular toxicity was demonstrated by behavioral and histological analysis. Cisplatin concentrations were assessed in inner ear after trans-tympanic and i.v. administration. In all experiments, no lethality and only scant body weight loss were recorded. Cisplatin caused dose-dependent cochlear toxicity, as demonstrated by hair cell counts in the apical and middle turns of the cochlea, and vestibular toxicity, as demonstrated by behavioral analysis and hair cell counts in utricles. High concentrations of cisplatin were found in the inner ear after trans-tympanic administration. In comparison, i.v. administration resulted in lower inner ear concentrations. We conclude that trans-tympanic administration provides an easy, reproducible and safe model to study the cochlear and vestibular toxicity of cisplatin in the rat. This route of exposure may be useful to address particular questions on cisplatin induced ototoxicity and to test candidate protective treatments.

Saccular Impairment in Alzheimer's Disease Is Associated with Driving Difficulty.

BACKGROUND/AIMS: Patients with Alzheimer's disease (AD) experience increased rates of vestibular loss. Recent studies suggest that saccular impairment in mild cognitive impairment (MCI) and AD patients is associated with impaired spatial cognitive function. However, the impact of saccular impairment on everyday behaviors that rely on spatial cognitive function is unknown. METHODS: We recruited 60 patients (21 MCI and 39 AD) from an interdisciplinary Memory Clinic. Saccular function was measured, and a visuospatial questionnaire was administered to assess whether participants experienced impairments in terms of driving difficulty, losing objects, falls, and fear of falling. RESULTS: In multiple logistic regression analyses, MCI and AD patients with bilateral saccular impairment had a significant, greater than 12-fold odds of driving difficulty (OR 12.1, 95% CI 1.2, 117.7) compared to MCI and AD patients with normal saccular function, and the association appears to be mediated by spatial cognition as measured by the Money Road Map Test. CONCLUSION: This study suggests a novel link between saccular impairment and driving difficulty in MCI and AD patients and demonstrates that driving difficulty may be a real-world manifestation of impaired spatial cognition associated with saccular impairment.

Deterioration of Vestibular Cells in Labyrinthitis.

OBJECTIVE: To quantitatively assess the effect of serous labyrinthitis, suppurative labyrinthitis, and labyrinthitis ossificans on vestibular hair cells, dark cells, and transitional cells. METHODS: We examined human temporal bone specimens with serous labyrinthitis, suppurative labyrinthitis, and labyrinthitis ossificans, then compared them with age-matched control groups without labyrinthitis. We evaluated the density of type I and II vestibular hair cells, dark cells, and transitional cells in the peripheral sensorial organs. RESULTS: The mean density of type I vestibular hair cells in the maculae of the saccule significantly differed between the serous labyrinthitis group and its control group. The loss of type I and II vestibular hair cells in all of the peripheral sensorial organs was significantly higher in the suppurative labyrinthitis group than in its control group. The mean density of dark cells in the lateral and posterior semicircular canals was significantly lower in the suppurative labyrinthitis group than in its control group. The mean density of type I and II vestibular hair cells, dark cells, and transitional cells was significantly lower in the labyrinthitis ossificans group than in its control group. CONCLUSION: The loss of vestibular hair cells and degenerative changes in dark cells and transitional cells could affect vestibular function in patients with labyrinthitis.