The spatial distribution of otosclerosis: a quantitative study using design-based stereology

Conclusions: Age-dependent microdamage (MDx) accumulates excessively in human perilabyrinthine bone, where the bone turnover is almost absent. This may have pathological implications for bone-specific disorders such as otosclerosis. The role of MDx accumulation is discussed from an osteodynamic perspective. Objectives: Bone remodelling is highly inhibited within the otic capsule compared with the rest of the skeleton. Consequently excessive accumulation of age-dependent capsular MDx is expected. This study describes the prevalence, size and topographical distribution of MDx in the human otic capsule. Methods: A total of 241 undecalcified human temporal bones were examined. Bulk staining and the cutting-grinding technique were used to separate in vivo MDx from microcrack artefacts induced post mortem by the milling procedure. Quantitative data were obtained by fluorescence microscopy by counting and measuring and by the use of stereology. Results: Microcracks accumulated continuously and extensively in the human otic capsule throughout life. Both the number and total length of MDx were higher close to the inner ear space as compared with the capsular periphery. The mean length of the MDx remained constant with age. There was no statistically significant sex difference.

Introduction: Otosclerosis is a bone disorder affecting the labyrinthine capsule that leads to conductive and occasionally sensorineural hearing loss. The etiology of otosclerosis remains unknown; factors such as infection, hormones, inflammation, genetics, and autoimmunity have been discussed. Treatment consists primarily of surgical stapes replacement and cochlear implantation. High-resolution computed tomography is routinely used to visualize bone pathology. In the present study, we used synchrotron radiation phase-contrast imaging (SR-PCI) to examine otosclerosis plaques in a temporal bone for the first time. The primary aim was to study their three-dimensional (3D) outline, vascular interrelationships, and connections to the middle ear. Methods: A donated ear from a patient with otosclerosis who had undergone partial stapedectomy with the insertion of a stapes wire prosthesis was investigated using SR-PCI and compared with a control ear. Otosclerotic lesions were 3D rendered using the composite with shading technique. Scalar opacity and color mapping were adjusted to display volume properties with the removal of bones to enhance surfaces. Vascular bone channels were segmented, and the communications between lesions and the middle ear were established. Results: Fenestral, cochlear, meatal, and vestibular lesions were outlined three-dimensionally. Vascular bone channels were found to be frequently connected to the middle ear mucosa, perilabyrinthine air spaces, and facial nerve vessels. Round window lesions partly embedded the cochlear aqueduct which was pathologically narrowed, while the inferior cochlear vein was significantly dilated in its proximal part. Conclusion: Otosclerotic/otospongiotic lesions were imaged for the first time using SR-PCI and 3D rendering. The presence of shunts and abnormal vascular connections to the labyrinth appeared to result in hyper-vascularization, overloading the venous system, and leading to sensorineural hearing loss. We speculate about possible local treatments to alleviate the impact of such critical lesions on the labyrinthine microcirculation.

Otosclerosis is a complex bone dystrophy of the human otic capsule leading to conductive and sensorineural hearing loss. Since otosclerosis may, at least in part, be considered as an autoimmune-inflammatory disease, disturbed balance of TNF-alpha and osteoprotegerin (OPG) expression has been implicated in the pathological bone remodeling. It has been supposed that active otosclerosis is characterized by decreased or missing local OPG production with invariable OPG sensitivity of the otosclerotic foci. Ankylotic stapes footplates (n = 41) removed by stapedectomy were processed to histological examination, OPG-specific RT-PCR, tissue culturing and alkaline-phosphatase (AP) activity assessment, respectively. OPG concentration of serum specimens (n = 41) was measured by ELISA. Cortical bone fragments harvested from the external ear canal were used as negative controls of otosclerosis. Among 41 ankylotic stapes footplates, 22 active and 19 inactive otosclerosis cases were histologically diagnosed. OPG expression was significantly lower (p < 0.001) in active otosclerosis compared to inactive cases. Osteoclast cultures originated from active otosclerotic foci showed a considerable susceptibility against external OPG dosage, which resulted in a significant decrease of AP activity (p < 0.001). In contrast, OPG serum levels were in the normal range (5-100 ng/ml) indicating a non-systemic bone resorption. In conclusion, secondary decreased local OPG production might play an important role in the pathogenesis of otosclerotic bone remodeling disorder. As to previous and current results, decreased OPG sensitivity of lesion-forming cells should be excluded. These observations may indicate the potential role of recombinant OPG treatment in early stages of otosclerosis.

It has been suggested that Paget's disease of bone and otosclerosis may share a myxoviral etiology. However, the association between virus infection and pathologic bone remodeling is still controversial. The aim of this study was to estimate the spatial distribution of pagetic bone remodeling around the inner ear space and to compare it with that of otosclerosis in a contemporary context of temporal bone dynamics. From the temporal bone collection of Massachusetts Eye and Ear Infirmary, 15 of 29 temporal bones with Paget's disease were selected to obtain an independent sample. All volume distributions were obtained along the normal axis of capsular bone remodeling activity by the use of vector-based stereology. Pagetic bone remodeling was distributed centrifugally around the inner ear space at the individual and the general level. This pattern is similar to the normal distribution of perilabyrinthine bone remodeling but entirely different from the spatial location of otosclerosis, which are focal and centripetally distributed around the inner ear space. In Paget's disease, the antiresorptive barrier around the inner ear space becomes gradually overruled as pagetic bone resorption invades the otic capsule from the outside. However, in otosclerosis, this barrier has somehow failed locally inside the otic capsule. Although virus infections potentially may trigger osteoclastic activity additional pathogenetic factors are needed to explain the organ-specific nature and spatial properties of otosclerosis.

Conclusion: The external layer of the otic capsule arises from periosteal osteoblasts, which produce large numbers of Volkmann's canals as well as lamellar bone. The main plaque of otosclerosis is a histologic replica of the external layer and seems to arise from similar cells in the periosteum and to follow a defined invasive course into the footplate of the stapes, the basal coil of the cochlea and the saccule. Objectives: To determine by histologic study of the developing otic capsule and temporal bones with otosclerosis the site, tissue of origin, and pathways of growth of the disease. Methods: Step sections of 60 celloidin-embedded temporal bones from fetuses and 24 from patients aged between 1 and 52 years were examined in the study of the development of the otic capsule. Step sections of 65 temporal bones each with 2 or more deposits of otosclerosis were surveyed to obtain data on the site, tissue of origin, and pathways of its growth. Results: The otic capsule differs from other bones in that the formation of the ultimate lamellar bone tissue is accompanied by very numerous intercommunicating channels. In the middle (cartilage origin) layer these are chondro-osseous canals and Volkmann's canals (like Haversian canals, but multidirectional). In the external (periosteal origin) layer these are Volkmann's canals only. In all, 63 of the 65 temporal bones with otosclerosis that were studied showed a prominent posterior otic capsule plaque. Evidence that this is derived from the periosteum of the external canal is as follows. (a) The otosclerotic tissue of the plaque – like all otosclerotic tissue – is composed of Volkmann's canals and lamellar bone only, as does external layer tissue. (b) All posterior plaques have an edge at the periosteum bordering the processus cochleariformis and tensor tympani muscle. The presumed invasive edge of the plaque on the opposite (cochlear) side shows a variable level of its front. (c) The tissue on the cochlear side of the plaque has a darkly stained appearance with large numbers of osteoblasts and poorly differentiated Volkmann's canals, suggesting that this is an invasive front. The otosclerosis becomes progressively better differentiated away from the darkly stained zone, indicating increasing maturation, which is greatest in the suggested origin of the plaque at the processus/tensor tympani muscle region because this would be the oldest region of the plaque. The pathway of the growth indicated by this study suggests a possible time sequence in the symptomatology of otosclerosis as it moves first to stapes footplate and then through the spiral ligament of cochlea to the saccule. An anterior plaque was seen in 42 of the 65 temporal bones with multiple sites of otosclerosis examined. These showed features similar to those listed above for the posterior plaque, with a base on the periosteum bordering the canal for the internal carotid artery, dark zonation at the invasive front near the cochlea, and increasing differentiation towards the base.

ABSTRACTContemporary imaging techniques, particularly micro–computed tomography, enable detailed visualization and analysis of pathological changes in skeletal remains. This study examines the right temporal bone of a male individual from the Early Bronze Age Mierzanowice culture (2200–2000 bc), discovered in southeastern Poland. Macroscopic analysis revealed significant unilateral enlargement of the right petrous part and mastoid process. The aim of our study was to identify the underlying condition using high‐resolution micro–computed tomography imaging. Scanning with a Nanotom 180 N device (30‐μm‐slice thickness) revealed substantial structural destruction of the otic capsule, consistent with a diagnosis of otosclerosis. The mastoid process was notably widened, with a clearly visible Koerner's septum. Comparative analysis with a nonpathological reference bone and the absence of systemic skeletal changes helped to rule out differential diagnoses such as osteogenesis imperfecta, otosyphilis, and Paget's disease. Micro–computed tomography provided exceptional insight into the internal architecture of the temporal bone, revealing detailed features associated with otosclerosis, including a hypodense focus in the region of the fissula ante fenestram and the “double ring sign” of the cochlea. These findings underscore the diagnostic power of micro–computed tomography in paleopathology and its potential to uncover subtle yet significant ancient diseases.

Otosclerosis (OTSC) is a complex bone disorder of the otic capsule, which causes conductive hearing impairment in human adults. The dysregulation of the signaling axis mediated by the receptor activator of nuclear factor-kappa-B (RANK), RANK ligand (RANKL), and osteoprotegerin has been widely attributed to the context of metabolic bone disorders. While genetic associations and epigenetic alterations in the TNFSF11 gene (RANKL) have been well-linked to metabolic bone diseases of the skeleton, particularly osteoporosis, they have never been addressed in OTSC. This study aimed to assess whether the genetic association of rs1021188 polymorphism in the upstream of TNFSF11 and the DNA methylation changes in its promoter CpG-region reveal the susceptibility of OTSC. Peripheral blood DNA samples were collected from unrelated Tunisian-North African subjects for genotyping (109 cases and 120 controls) and for DNA methylation analysis (40 cases and 40 controls). The gender-stratified analysis showed that the TNFSF11 rs1021188 C/T was associated with OTSC in men (p = 0.023), but not in women (p = 0.458). Individuals with CC genotype were more susceptible to OTSC, suggesting an increased risk to disease development. Using publicly available data, the rs1021188 was within a cluster grouping the subpopulations with African ethnicity. Moreover, 26 loci in the TNFSF11 gene were in linkage disequilibrium with rs1021188, revealing relative similarities between different populations. Significant differences in both DNA methylation and unmethylation status were detected with 4.53- and 4.83-fold decreases in the global DNA methylation levels in female and male OTSC groups, respectively. These changes could contribute to an increased risk of OTSC development. Bioinformatic analyses indicated that each of the rs1021188 variations and the DNA methylation changes in the promoter CpG-sites within TNFSF11 may play an important role in its transcription regulation. To our knowledge, this is the first study that investigates an independent effect of the rs1021188 polymorphism and DNA hypomethylation of TNFSF11 promoter in OTSC. Genetic and epigenetic changes in the regulatory regions of TNFSF11 could offer new molecular insights into the understanding of the complexity of OTSC.

The viability and spatial distribution of osteocytes in the human labyrinthine capsule: A quantitative study using vector-based stereology

Background Otosclerosis is a common ear disease that causes fixation of the stapes and conductive hearing impairment. However, the pathogenesis of otosclerosis is still unknown. Otosclerosis could be associated with the unique bony environment found in the otic capsule. Normal bone remodelling is almost completely absent around the inner ear after birth allowing degenerative changes and dead osteocytes to accumulate. High levels of inner ear anti resorptive osteoprotegerin (OPG) is most likely responsible for this capsular configuration. Studies have demonstrated how osteocyte lifespan variation creates occasional clusters of dead osteocytes, so-called cellular voids, at otosclerotic predilection sites in the human otic capsule. These cellular voids have been suggested as possible starting points of otosclerosis. Aim To describe the cellular viability in otosclerotic lesions and compare it to that of cellular voids. Materials and Methods The study was based on unbiased stereological quantifications in undecalcified human temporal bones with otosclerosis. Results Osteocyte viability was found to vary within the otosclerotic lesions. Furthermore, the results presented here illustrate that inactive otosclerotic lesions consist of mainly dead interstitial bone, much like cellular voids. Conclusions and significance Focal degeneration in the otic capsule may play an important role in the pathogenesis of otosclerosis.

The article presents a brief review of the literature on the anatomy and physiology of the round window (RW) niche, the causes of occlusion, the diagnosis of this pathology, the features of auditory disorders and tactics when it is detected in patients with otosclerosis (OS). A clinical case of diagnosis and effective surgical treatment for obliteration of RW in a patient with advanced OS, which occurred in 2019 in 0.7% of cases, is described. Removal of RW niche obliteration was carried out with a curette and microcresis by smoothing the canopy over RW until partial visualization of the secondary membrane. It was this stage of the operation that made it possible to restore the normal hydrodynamics of the inner ear fluids and contributed to a functional result. Thus, the diagnosis of RW obliteration in patients with OS is difficult, but possible when using computed tomography of the temporal bones and assessing the mobility of the RW membrane or analyzing changes in hearing at the end of the operation, if it is performed under local anesthesia. The simultaneous performance of stapedoplasty and the removal of bone obliteration of RW makes it possible to safely achieve functional rehabilitation in patients with OS.