Search Results (22)

Introduction: The important factor in applying substances for inner ear therapy is the atraumatic execution, as well as effective concentration uniformly distributed in all regions of the cochlea within a reasonable time frame. This study investigates whether an additional cochlear opening (“second-hole technique”) can improve fluid distribution and reduce intracochlear pressure during dye delivery into the cochlear models and human petrous bone. Material and Methods: Three experimental setups were used: an uncoiled scala tympani model, a full-scale 3D-printed cochlear model, and a human petrous bone. In all cases, 1% methylene blue-stained saline was infused using a cochlear catheter (MED-EL, Innsbruck, Austria) through the round window. Intracochlear pressure was measured via fiberoptic pressure sensors inserted through a burr hole (artificial cochlear models) or at the lateral semicircular canal (human petrous bone). A second hole was made on the helicotrema in the inner ear models or at the oval window of the human petrous bone to examine the effect of a second hole on intracochlear pressure and fluid distribution. Dye distribution and intracochlear pressure were measured in 3D artificial models at two flow rates (0.2 and 0.4 mL/h). The intracochlear pressure were measured in the human petrous bone at a fixed rate (0.4 mL/h). Results: The use of a second hole significantly improved dye distribution in 3D models at both flow rates (p < 0.05) and led to earlier saturation-level distribution. Intracochlear pressure remained significantly lower and more stable in models with a second hole (p < 0.05). In human petrous bones, pressure fluctuation was reduced by the second hole, though pressure still increased over time. Conclusions: Using a second-hole technique leads to a faster, uniform level of dye distribution throughout the cochlear models, as well as a lower intracochlear pressure, which can be assumed to be an essential factor for hearing preservation during dye application. Full article

Vestibular atelectasis (VA) is a rare clinical entity characterized by a collapse of the endolymphatic space resulting in vestibular loss with the possible onset of positional and/or sound/pressure-induced vertigo. It could be idiopathic or secondary to other inner-ear diseases including Meniere’s disease (MD). A collapse of the membranous labyrinth involving the semicircular canals (SCs) and the utricle represents its distinctive histopathological feature. While specific radiological patterns consistent with VA have been described on contrast-enhanced MRI with delayed acquisitions, an impairment of the blood–labyrinthine barrier (BLB) could be detected in several disorders leading to vestibular loss. We conducted a narrative review of the literature on VA focusing on the putative pathomechanisms accounting for positional and sound/pressure-induced nystagmus despite unilateral vestibular loss (UVL) in this condition, providing two novel cases of VA. Both patients presented with a clinical picture consistent with unilateral MD that rapidly turned into progressive UVL and positional and/or sound/pressure-induced vertigo. In both cases, the posterior SC was initially impaired at the video-head impulse test (vHIT) and both cervical and ocular VEMPs were initially reduced. Progressively, they developed unsteadiness with paretic spontaneous nystagmus, an impairment also for the lateral and anterior SCs, caloric hypo/areflexia and VEMPs areflexia. They both exhibited ipsilesional nystagmus to sound/pressure stimuli and in one case a persistent geotropic direction-changing positional nystagmus consistent with a “light cupula” mechanism involving the lateral SC of the affected side. A collapse of the membranous labyrinthine walls resulting in contact between the vestibular sensors and the stapes footplate could explain the onset of nystagmus to loud sounds and/or pressure changes despite no responses to high- and low-frequency inputs as detected by caloric irrigations, vHIT and VEMPs. On the other hand, the onset of positional nystagmus despite UVL could be explained with the theory of the “floating labyrinth”. Both patients received contrast-enhanced brain MRI with delayed acquisition exhibiting increased contrast uptake in the pars superior of the labyrinth, suggesting an impairment of the BLB likely resulting in secondary VA. A small intralabyrinthine schwannoma was detected in one case. VA should always be considered in case of positional and/or sound/pressure-induced vertigo despite UVL. Full article

The inner ear and/or lateral line are responsible for hearing and balance of vertebrate. The otic sensory hair cells (HCs) employ cilium organelles, namely stereocilia and/or kinocilia, to mediate mechanical stimuli to electrical signal transition. Tektins (Tekts) are known as the cilium microtubule stabilizer and inner-space filler, and four Tekt(1-4)-encoding genes are identified in zebrafish HCs, but the subcellular location of Tekts in HCs remains unknown. In the present study, we first found that tekt3 is expressed in the inner ear and lateral line neuromast. Antibody staining revealed that Tekt3 is present in neuromast and utricular HCs. It is absent in the saccule, the authentic hearing end-organ of zebrafish and the crista of semi-circular canals. Furthermore, Tekt3 were enriched at the apical side of neuromast and utricular HCs, mainly in the cytosol. Similar subcellular distribution of Tekt3 was also evident in the outer HCs of mature mouse cochlea, which are not directly linked to the hearing sense. However, only neuromast HCs exerted morphological defect of kinocilia in tekt3 mutant. The disrupted or distorted HC kinocilia of mutant neuromast ultimately resulted in slower vital dye intake, delayed HC regeneration after neomycin treatment, and reduced startle response to vibration stimulation. All functional defects of tekt3 mutant were largely rescued by wild-type tekt3 mRNA. Our study thus suggests that zebrafish Tekt3 maintains the integrity and function of neuromast kinocilia to against surrounding and persistent low-frequency noises, perhaps via the intracellular distribution of Tekt3. Nevertheless, TEKT3/Tekt3 could be used to clarify HC sub-types in both zebrafish and mice, to highlight the non-hearing HCs. Full article

Novel therapeutic delivery systems and delivery methods to the inner ear are necessary to treat hearing loss and inner ear disorders. However, numerous barriers exist to therapeutic delivery into the bone-encased and immune-privileged environment of the inner ear and cochlea, which makes treating inner ear disorders challenging. Nanoparticles (NPs) are a type of therapeutic delivery system that can be engineered for multiple purposes, and posterior semicircular canal (PSCC) infusion is a method to directly deposit them into the cochlea. We sought to assess PSCC infusion of gold NPs into the cochlea, including the NPs’ distribution and effect on cochlear mechanics. We performed optical coherence tomography (OCT) imaging to monitor PSCC infusion of gold NPs into the cochlear chambers. OCT imaging demonstrated that the infusion specifically targeted the perilymphatic spaces within the cochlea. We assessed cochlear mechanics by using OCT vibrometry to measure sound-evoked movements of the basilar membrane. We found no changes in cochlear mechanics between measurements at baseline, after the PSCC canalostomy, immediately after the infusion, and 1 h after the infusion of gold NPs (p > 0.05, paired t-test). These findings validate the PSCC infusion approach for perfusing the cochlear perilymphatic space with a nanoparticle delivery system. Thus, PSCC infusion of nanoparticles is a feasible therapeutic delivery technique for treating inner ear disorders while preserving residual cochlear function. Full article

Background: Alternative splicing is essential for the physiological and pathological development of the inner ear. Disruptions in this process can result in both syndromic and non-syndromic forms of hearing loss. DHX38, a DEAH box RNA helicase, is integral to pre-mRNA splicing regulation and plays critical roles in development, cell differentiation, and stem cell maintenance. However, its specific role in inner ear development remains undefined. Here, we utilized a dhx38 knockout zebrafish model to monitor the ear morphology and elucidate a crucial role for DHX38 in the development of the zebrafish inner ear. Methods: Bright-field morphological analysis and in situ hybridization were performed to observe ear morphology changes. Immunofluorescence and semi-quantitative RT-PCR were employed to test apoptotic cells and abnormal splicing. Results: The dhx38^-/- mutant zebrafish showed significant inner ear impairments, including decrescent otocysts, absent semicircular canal protrusion, and smaller otoliths. These structural abnormalities were accompanied by substantial DNA damage and p53-dependent apoptosis within the inner ear cells. Alternative splicing analysis showed that genes related to DNA damage repair and inner ear morphogenesis are abnormal in dhx38 knockout mutants. In summary, we suggest that dhx38 promotes cell survival during the inner ear development of zebrafish by ensuring the correct splicing of genes related to DNA damage repair. Full article

Conductive hearing loss caused by external or middle ear problems prevents the transmission of sound waves from the external auditory canal to the cochlea, and it is a common condition, especially in pediatric patients aged 1–5 years. The most common etiological factors are otitis media and cerumen during childhood. In some patients, external and middle ear functions and structures may be normal bilaterally despite the air-bone gap on the audiogram. This condition, which is often a missed diagnosis in children, is defined as a pseudo-conductive hearing loss (PCHL) caused by third window syndromes (TWSs) such as semicircular canal dehiscence, inner ear malformations with third window effect, and perilymphatic fistula. In this review of the literature, the authors emphasize the pitfalls of pediatric audio-vestibular evaluation on TWSs as well as the key aspects of this evaluation for the differential diagnosis of PCHL brought on by TWSs. This literature review will provide audiologists and otologists with early diagnostic guidance for TWSs in pediatric patients. Full article

Posterior semicircular canal dehiscence (PSCD) has been demonstrated to result in a third mobile window mechanism (TMWM) in the inner ear similar to superior semicircular canal dehiscence (SSCD). Typical clinical and instrumental features of TMWM, including low-frequency conductive hearing loss (CHL), autophony, pulsatile tinnitus, sound/pressure-induced vertigo and enhanced vestibular-evoked myogenic potentials, have been widely described in cases with PSCD. Nevertheless, video-head impulse test (vHIT) results have been poorly investigated. Here, we present six patients with PSCD presenting with a clinical scenario consistent with a TMWM and an impaired vestibulo-ocular reflex (VOR) for the affected canal on vHIT. In two cases, an additional dehiscence between the facial nerve and the horizontal semicircular canal (HSC) was detected, leading to a concurrent VOR impairment for the HSC. While in SSCD, a VOR gain reduction could be ascribed to a spontaneous “auto-plugging” process due to a dural prolapse into the canal, the same pathomechanism is difficult to conceive in PSCD due to a different anatomical position, making a dural herniation less likely. Alternative putative pathomechanisms are discussed, including an endolymphatic flow dissipation during head impulses as already hypothesized in SSCD. The association of symptoms/signs consistent with TMWM and a reduced VOR gain for the posterior canal might address the diagnosis toward PSCD. Full article

Background: Constructive interference in steady state (CISS) is a gradient echo magnetic resonance imaging (MRI) pulse sequence that provides excellent contrast between cerebrospinal fluid and adjacent structures but is prone to banding artifacts due to magnetic field inhomogeneities. We aimed to characterize artifacts in the inner ear and eye. Methods: In 30 patients (60 ears/eyes) undergoing CISS sequence MRI, nine low-signal intensity regions were identified in the inner ear and compared to temporal bone histopathology. The number and angle of bands across the eye were examined. Results: In the cochlea, all ears had regions of low signal corresponding to anatomy (modiolus (all), spiral lamina (n = 59, 98.3%), and interscalar septa (n = 50, 83.3%)). In the labyrinth, the lateral semicircular canal crista (n = 42, 70%) and utricular macula (n = 47, 78.3%) were seen. Areas of low signal in the vestibule seen in all ears may represent the walls of the membranous utricle. Zero to three banding artifacts were seen in both eyes (right: 96.7%, mean 1.5; left: 93.3%, mean 1.3). Conclusion: Low signal regions in the inner ear on CISS sequences are common and have consistent patterns; most in the inner ear represent anatomy, appearing blurred due to partial volume averaging. Banding artifacts in the eye are more variable. Full article

Objective: The transmastoid plugging of a superior semicircular canal is considered a safe and effective technique for the management of superior semicircular canal dehiscence (SSCD). The aim of this meta-analysis is to assess the postoperative hearing outcomes after the transmastoid plugging of the superior semicircular canal. Search method and data sources: A systematic database search was performed on the following databases until 30 January 2023: MEDLINE, Embase, Cochrane Library, Web of Science, CINAHL, ICTRP, and clinicaltrials.gov. A systematic literature review and meta-analysis of the pooled data were conducted. We also included a consecutive case series with SCDS for those who underwent transmastoid plugging treatment at our clinic. Results: We identified 643 citations and examined 358 full abstracts and 88 full manuscripts. A total of 16 studies were eligible for the systematic review and 11 studies for the meta-analysis. Furthermore, 159 ears (152 patients) were included. The postoperative mean air conduction threshold remained unchanged (mean difference, 2.89 dB; 95% CI: −0.05, 5.84 dB, p = 0.58), while the mean bone conduction threshold was significantly worse (mean difference, −3.53 dB; 95% CI, −6.1, −0.95 dB, p = 0.9). Conclusion: The transmastoid plugging technique for superior semicircular canal dehiscence syndrome, although minimally worsening the inner ear threshold, is a safe procedure in terms of hearing preservation and satisfactory symptom relief. Full article

Background: In vertebrates, the development of the inner ear is a delicate process, whereas its relating molecular pathways are still poorly understood. LMO4, an LIM domain-only transcriptional regulator, is drawing an increasing amount of interest for its multiple roles regarding human embryonic development and the modulation of ototoxic side effects of cisplatin including cochlear apoptosis and hearing loss. The aim of the present study is to further explore the role of lmo4a in zebrafish inner ear development and thus explore its functional role. Methods: The Spatial Transcript Omics DataBase was referred to in order to evaluate the expression of lmo4a during the first 24 h of zebrafish development. In situ hybridization was applied to validate and extend the expression profile of lmo4a to 3 days post-fertilization. The morpholino (MO) knockdown and CRISPR/Cas9 knockout (KO) of lmo4a was applied. Morphological analyses of otic vesical, hair cells, statoacoustic ganglion and semicircular canals were conducted. The swimming pattern of lmo4a KO and MO zebrafish was tracked. In situ hybridization was further applied to verify the expression of genes of the related pathways. Rescue of the phenotype was attempted by blockage of the bmp pathway via heat shock and injection of Dorsomorphin. Results: lmo4a is constitutively expressed in the otic placode and otic vesicle during the early stages of zebrafish development. Knockdown and knockout of lmo4a both induced smaller otocysts, less hair cells, immature statoacoustic ganglion and malformed semicircular canals. Abnormal swimming patterns could be observed in both lmo4a MO and KO zebrafish. eya1 in preplacodal ectoderm patterning was downregulated. bmp2 and bmp4 expressions were found to be upregulated and extended in lmo4a morphants, and blockage of the Bmp pathway partially rescued the vestibular defects. Conclusions: We concluded that lmo4a holds a regulative effect on the Bmp pathway and is required for the normal development of zebrafish inner ear. Our study pointed out the conservatism of LMO4 in inner ear development between mammals and zebrafish as well as shed more light on the molecular mechanisms behind it. Further research is needed to distinguish the relationships between lmo4 and the Bmp pathway, which may lead to diagnostic and therapeutic approaches towards human inner ear malformation. Full article

Vertigo due to vestibular dysfunction is rare in children. The elucidation of its etiology will improve clinical management and the quality of life of patients. Genes for vestibular dysfunction were previously identified in patients with both hearing loss and vertigo. This study aimed to identify rare, coding variants in children with peripheral vertigo but no hearing loss, and in patients with potentially overlapping phenotypes, namely, Meniere’s disease or idiopathic scoliosis. Rare variants were selected from the exome sequence data of 5 American children with vertigo, 226 Spanish patients with Meniere’s disease, and 38 European–American probands with scoliosis. In children with vertigo, 17 variants were found in 15 genes involved in migraine, musculoskeletal phenotypes, and vestibular development. Three genes, OTOP1, HMX3, and LAMA2, have knockout mouse models for vestibular dysfunction. Moreover, HMX3 and LAMA2 were expressed in human vestibular tissues. Rare variants within ECM1, OTOP1, and OTOP2 were each identified in three adult patients with Meniere’s disease. Additionally, an OTOP1 variant was identified in 11 adolescents with lateral semicircular canal asymmetry, 10 of whom have scoliosis. We hypothesize that peripheral vestibular dysfunction in children may be due to multiple rare variants within genes that are involved in the inner ear structure, migraine, and musculoskeletal disease. Full article

Background: Fundamental knowledge of the anatomy and physiology of the inner ear is necessary to understand otologic diseases and therapeutic strategies. Aim: Evaluate the inter- and intraindividual variability of the modiolar position in relation to vestibular landmarks and cranial morphology on computed tomography scans (CT scan). Methods: Thirty CT scans of normal temporal bones (25 adults, 5 children) were analyzed after multiplanar reconstruction (MPR). The measurements for each ear included the angle of each semicircular canal (SCC) made by a line passing through the chosen plane and a line passing between the apex and the ampulla of the SCC studied and the angle of the modiolus in the transverse and sagittal planes. Results: Intraindividual asymmetries with a moderate to good right/left correlation were observed for the lateral SCC in the transverse plane, posterior SCC in the frontal plane, and the superior SCC in the sagittal plane and for the modiolus in the transverse plane. Conclusions: An anatomical variability in the cochlea, independent of other surrounding anatomical elements, seems to exist, but the SCCs seem to remain symmetrical. Significance: The orientation of the modiolus is an important knowledge to acquire during presurgical planning prior to transmodiolar auditory nerve implantation. Full article

The causes of vestibular dysfunction include the loss of hair cells (HCs), synapses beneath the HCs, and nerve fibers. 7, 8–dihydroxyflavone (DHF) mimics the physiological functions of brain-derived neurotrophic factor. We investigated the effects of the orally-administered DHF in the guinea pig crista ampullaris after gentamicin (GM)-induced injury. Twenty animals treated with GM received daily administration of DHF or saline for 14 or 28 days (DHF (+) or DHF (−) group; N = 5, each). At 14 days after GM treatment, almost all of the HCs had disappeared in both groups. At 28 days, the HCs number in DHF (+) and DHF (−) groups was 74% and 49%, respectively, compared to GM-untreated control. In the ampullary nerves, neurofilament 200 positive rate in the DHF (+) group was 91% at 28 days, which was significantly higher than 42% in DHF (−). On day 28, the synaptic connections observed between C–terminal–binding protein 2-positive and postsynaptic density protein-95-positive puncta were restored, and caloric response was significantly improved in DHF (+) group (canal paresis: 57.4% in DHF (+) and 100% in DHF (−)). Taken together, the oral administration of DHF may be a novel therapeutic approach for treating vestibular dysfunction in humans. Full article

Inner ear gene therapy using adeno-associated viral vectors (AAVs) in neonatal mice can alleviate hearing loss in mouse models of deafness. However, efficient and safe transgene delivery to the adult mouse cochlea is critical for the effectiveness of AAV-mediated therapy. Here, we examined three gene delivery approaches including posterior semicircular canal (PSCC) canalostomy, round window membrane (RWM) injection, and tubing-RWM+PSCC (t-RP) in adult mice. Transduction rates and survival rates of cochlear hair cells were analyzed, hearing function was recorded, AAV distribution in the sagittal brain sections was evaluated, and cochlear histopathologic images were appraised. We found that an injection volume of 1 μL AAV through the PSCC is safe and highly efficient and does not impair hearing function in adult mice, but local injection allows AAV vectors to spread slightly into the brain. We then tested five AAV serotypes (PHP.eB, IE, Anc80L65, AAV2, and PHP.s) in parallel and observed the most robust eGFP expression in inner hair cells, outer hair cells, and spiral ganglion neurons throughout the cochlea after AAV-Anc80L65 injection. Thus, PSCC-injected Anc80L65 provides a foundation for gene therapy in the adult cochlea and will facilitate the development of inner ear gene therapy. Full article

Herpes zoster oticus (HZO) is characterized by otalgia and erythematous vesicles in the auricle or external auditory canal. Ramsay Hunt syndrome (RHS) can be diagnosed when facial nerve palsy is accompanied by these symptoms of HZO, and in this case, audio-vestibular symptoms such as hearing loss or dizziness often develop. Recently, 3D-fluid-attenuated inversion recovery sequence (3D-FLAIR) magnetic resonance imaging (MRI) has been introduced in order to evaluate the inner ear structure pathology. The purpose of this study was to investigate the audio-vestibular characteristics in correlation with temporal bone MRI findings in HZO patients. From September 2018 to June 2022, 18 patients with HZO participated in the study. Thirteen patients (77%) showed high-signal intensity in the inner ear structures in 4 h post-contrast 3D-FLAIR images. In a bithermal caloric test, the lateral semicircular canal showed high signal intensity in 4 h post-contrast 3D-FLAIR images in 75% of patients with abnormal canal paresis. While the cochlea showed high signal intensity in 4 h post-contrast 3D-FLAIR images in 75% of patients with hearing loss, the vestibulo-cochlear nerve showed enhancement in post-contrast T1-weighted images in only 33% of patients with hearing loss. The present study demonstrates that audio-vestibular deficits are well-correlated with increased signal intensity of the inner ear endorgans in 4 h post contrast 3D-FLAIR MRI. Full article