Cochlear degeneration in leigh disease: histopathologic features

OBJECTIVE: To describe pathologic findings from temporal bones acquired from an infant with Leigh disease. STUDY DESIGN: Retrospective case review. MATERIALS AND METHODS: Temporal bones were taken at autopsy from an 8-month-old infant with Leigh disease. The right temporal bone was studied by microdissection. The middle ear was examined and the inner ear sensory organs dissected for study by light microscopy. The left temporal bone was embedded in celloidin, and sections were cut for microscopic examination. RESULTS: Middle ear structures were normal bilaterally. There was, however, evidence of otitis media in both middle ears, which was more severe on the left side. Inner and outer hair cell loss, patchy degeneration of organ of Corti, and loss of nerve fibers in the osseous spiral lamina were found in the basal and middle turns of both cochleas. Basophilic deposits in the stria vascularis were observed in the apical portion of the left cochlea. CONCLUSIONS: Inner ear sensorineural degeneration may occur in Leigh disease. Possible cochlear dysfunction caused by the degenerative changes needs to be considered in the hearing assessment of patients with Leigh disease.     

Temporal bone histopathology of noise-induced hearing loss

To examine the relationship between hearing and changes in the inner ear, we investigated human temporal bone specimens from 2 patients with noise-induced hearing loss and prepared audio-cytocochleograms as described by Schuknecht et al. Patient 1 was a 50-year-old male who died of thyroid cancer and had worked at a printing house for 38 years. Patient 2 was a 58-year old male who died of maxillary sinus cancer and had worked in construction for 22 years. A pure-tone audiogram showed high-tone sensorineural hearing loss with c5-dip-type hearing disorder in both ears in Patient 1, and a high-tone abrupt form of sensorineural hearing loss in Patient 2. Pathological examination of the temporal bone revealed degeneration and disappearance of the organ of Corti at the basal turn and disappearance of cochlear neurons in both patients. Audio-cytocochleograms revealed hearing disorder consistent with the changes in the inner ear in both patients. Marked degeneration and disappearance of the organ of Corti and stria vascularis were present in patient 1. It is generally known that disorders of the organ of Corti for a long period is involved in the etiology of noise-induced hearing loss. This degeneration of the organ of Corti is produced at a basilar membrane with the maximum amplitude related to exposure to noise according to a physical and mechanical factors. Moreover, animal experiments have shown that exposure to noise decrease cochlear blood flow. In Patient 1 both the organ of Corti and the stria vascularis exhibited degeneration, suggesting that not only physical and mechanical factors but a cochlear circulatory disorder related to exposure to noise was involved in the etiology of the pathological changes in the temporal bone related to noise-induced hearing loss.     

Electron microscopic temporal bone histopathology in experimental pneumococcal meningitis.

Bacterial meningitis is one of the most common causes of acquired profound sensorineural deafness in children. Measurement of hearing and examination of the cochlea is limited in patients suffering from acute meningitis. A rabbit model of pneumococcal meningitis was developed to identify the temporal bone histopathologic changes that occur in meningogenic labyrinthitis caused by Streptococcus pneumoniae. Light microscopy was previously performed on temporal bones from acutely meningitic rabbits with profound hearing loss as determined electrophysiologically. Extensive inflammation of the cochlea with endolymphatic hydrops was observed. The organ of Corti, however, showed preserved architecture in the majority of these animals. In order to further investigate these findings, a protocol was used to create meningitic rabbits with hearing loss ranging from early high-frequency loss to profound deafness. The temporal bones from 7 rabbits were examined by transmission electron microscopy. In cases of mild hearing loss, partial degeneration of the inner row of outer hair cells, as well as edema of efferent cochlear nerve endings and marginal cells of the stria vascularis, was seen. With increasing degrees of hearing loss, the remainder of the organ of Corti and intermediate cells of the stria showed ultrastructural abnormalities. Spiral ganglion cells and basal cells of the stria vascularis remained intact in all subjects. This study provides unique information regarding the histology and pathophysiology of meningogenic deafness. The clinical implications of these findings are discussed, with an emphasis on potentially reversible changes and therapeutic intervention.     

耳蜗图的绘制及应用进展

位于耳蜗基底膜上的Corti器是接受声振动刺激的初级感受器，作为Corti器中的感觉细胞，毛细胞的损害将引起不同程度及频率范围的听力损失。对耳蜗毛细胞在基底膜不同部位的丢失情况进行定量分析是内耳组织病理学研究中最常用的手段，将全耳蜗毛细胞损害的定量定位分析结果与听功能相结合将有益于对疾病机制的探索和对治疗方法的评价。目前对全耳蜗毛细胞定位定量分析常采用耳蜗图来表示，但在听力学研究中耳蜗图的绘制方法并不完全相同，尚缺乏统一的绘制标准及原则，使得各个实验结果之间缺乏可比性。为更精准地对全耳蜗毛细胞的损伤情况进行定位定量分析，需要统一耳蜗图的绘制方法及原则。本文就目前文献报导中常用的耳蜗图绘制方法及绘制原则进行了综述。     

Histological and electrophysiological study of cryosurgery of the cochlea of guinea pigs

For studies on cochlear function after inner ear trauma, cryosurgery gives reproductive morphological changes that may help the understanding and the correlation of hair cell loss with cochlear physiology. In all cases of partial destruction of the organ of Corti we noticed a completely reversible limitation of hearing, whereas when injuring the organ of Corti in the whole cochlea a restriction of function persisted. We could never induce complete deafness.     

Temporal bone histopathologic abnormalities associated with mitochondrial mutation T7511C

OBJECTIVES: We previously reported a mitochondrial T7511C mutation in the tRNA gene in a Japanese family with nonsyndromic hearing loss (HL). However, the temporal bone histopathology associated with T7511C has not been reported. The aim of the present study is to report histopathologic findings of a temporal bone from a patient in the Japanese family with this mutation. STUDY DESIGN: Single case study. METHODS: A temporal bone was obtained from the right ear of a male subject with progressive HL from 5 years of age and who died at 60 years of age from cerebral infarction. The bone was embedded, sectioned, and stained with hematoxylin-eosin for light microscopic study. Graphic reconstruction of the cochlea was performed using the method described by Schuknecht to determine loss of the stria vascularis and neurosensory elements including hair cells and spiral ganglion neurons. RESULTS: The most significant histopathologic finding was severe loss of spiral ganglion cells in all turns of the cochlea. Severe loss of neuronal filaments in Rosenthal's canal was also observed. The organ of Corti showed scattered loss of inner and outer hair cells in the basal turn. Partial atrophy of the stria vascularis was observed in all turns of the cochlea. CONCLUSION: Our results suggest that severe loss of spiral ganglion cells was the main cause of sensorineural HL associated with the T7511C mutation.     

Survival of Partially Differentiated Mouse Embryonic Stem Cells in the Scala Media of the Guinea Pig Cochlea

The low regenerative capacity of the hair cells of the mammalian inner ear is a major obstacle for functional recovery following sensorineural hearing loss. A potential treatment is to replace damaged tissue by transplantation of stem cells. To test this approach, undifferentiated and partially differentiated mouse embryonic stem (ES) cells were delivered into the scala media of the deafened guinea pig cochlea. Transplanted cells survived in the scala media for a postoperative period of at least nine weeks, evidenced by histochemical and direct fluorescent detection of enhanced green fluorescent protein (EGFP). Transplanted cells were discovered near the spiral ligament and stria vascularis in the endolymph fluid of the scala media. In some cases, cells were observed close to the damaged organ of Corti structure. There was no evidence of significant immunological rejection of the implanted ES cells despite the absence of immunosuppression. Our surgical approach allowed efficient delivery of ES cells to the scala media while preserving the delicate structures of the cochlea. This is the first report of the survival of partially differentiated ES cells in the scala media of the mammalian cochlea, and it provides support for the potential of cell-based therapies for sensorineural hearing impairment.     

Otoacoustic emissions in an adult with severe hearing loss

The present study describes the unexpected finding of evoked otoacoustic emissions (EOAEs) from the left ear of a subject with severe-to-profound bilateral sensorineural hearing loss. No EOAEs could be measured from the right ear. To ensure that the EOAEs were not artifacts, two different instrumentation systems were used and both provided similar results. It is suggested that the subject may have a group of surviving outer hair cells in some regions of her left cochlea with corresponding inner hair cell or neural damage.     

An electrophysiologic study of experimental perilymphatic fistula

This study was undertaken to elucidate the mechanism that causes sensorineural hearing loss in clinical cases with perilymphatic fistula. Perilymph was experimentally aspirated through the round window membrane in 17 guinea pigs. The extent of cochlear damage was examined electrophysiologically as well as histopathologically. Immediately after aspiration, several types of changes in summating potential (SP) were observed. Two animals without a polarity change of the SP showed only slight threshold changes in both cochlear microphonic and action potentials, and no specific histopathologic changes in the cochlea. Reversed polarity of the SP was observed in three animals, of which one showed a high-amplitude negative SP followed by rapidly progressive hearing loss. Bulging of Reissner's membrane was confirmed histopathologically in this case. The SP disappeared in the remaining 12 animals. In animals with profound electrophysiologic changes, bulging or rupture of Reissner's membrane and damaged hair cells were observed. These findings suggest that an abrupt change in perilymphatic pressure produces morphologic changes in the membranous labyrinth, causing changes in the vibration function of the cochlear partition and in the function of the organ of Corti. Abrupt pressure imbalance may be a causative factor of sensorineural hearing loss in the case of perilymphatic fistula.     

Cytotoxic changes in hair cells secondary to pneumococcal middle-ear infection

To determine whether the bacterial toxins associated with otitis media could induce morphologic changes in the organ of Corti, we inoculated the middle-ear cavities of healthy guinea pigs with either Streptococcus pneumoniae or sterile saline and then examined the organ of Corti histologically at 1, 2, and 3 weeks postinoculation. We found that the outer hair cells (OHCs) in the infected ears underwent several changes that were dependent on both the length of time following inoculation and also the position of the OHCs in the cochlea. At 2 weeks postinoculation, 7.0 to 20% of the OHC nuclei from the infected animals became very swollen, with the most significant swelling occurring in the basal turn. At 3 weeks postinoculation, 2.5 to 3.5% of the OHCs were missing in the infected animals, with the most significant loss occurring in the basal and middle turns. These results suggest that bacterial otitis media can produce cytotoxic changes in the cochlea. These changes may be a clinically significant factor in the temporary and permanent sensorineural hearing loss that has been associated with bacterial otitis media.     

The cochlear amplifier: augmentation of the traveling wave within the inner ear

PURPOSE OF REVIEW: There have been many recent advancements in our understanding of cochlear function within the past ten years. In particular, several mechanisms that underlie the sensitivity and sharpness of mammalian tuning have been discovered. This review focuses on these issues. RECENT FINDINGS: The cochlear amplifier is essentially a positive feedback loop within the cochlea that amplifies the traveling wave. Thus, vibrations within the organ of Corti are sensed and then force is generated in synchrony to increase the vibrations. Mechanisms that generate force within the cochlea include outer hair cell electromotility and stereociliary active bundle movements. These processes can be modulated by the intracellular ionic composition, the lipid constituents of the outer hair cell plasma membrane, and the structure of the outer hair cell cytoskeleton. SUMMARY: A thorough understanding of the cochlear amplifier has tremendous implications to improve human hearing. Sensorineural hearing loss is a common clinical problem and a common site of initial pathology is the outer hair cell. Loss of outer hair cells causes loss of the cochlear amplifier, resulting in progressive sensorineural hearing loss.     

A review of cis-platinum ototoxicity

A review of the ototoxic effects of cis-diamminedichloroplatinum (II) (cis-platinum) is presented. Cis-platinum impairs auditory function by preferentially destroying the outer hair cells of the organ of Corti in the basal turn of the cochlea. Hair cell loss in the vestibular labyrinth has also been observed. Auditory sequelae include tinnitus and/or hearing loss, both of which are usually reversible. The incidence of tinnitus in clinical studies is about 7%. Hearing loss is noted in about 69% of patients, usually in the 4,000-8,000 Hz range, although speech frequencies (1,000-4,000 Hz) may occasionally become involved. The hearing losses range from 15-65 dB, and only 7% of all patients complain of difficulty in understanding speech. A direct dose effect relationship does not appear to exist for either tinnitus or hearing loss. The onset of hearing loss, however, appears to be related to cumulative levels of the drug. Vestibular dysfunction has also been shown to be a side effect of therapy. Case management strategies are discussed.     

Genetic and pharmacological intervention for treatment/prevention of hearing loss

Twenty years ago it was first demonstrated that birds could regenerate their cochlear hair cells following noise damage or aminoglycoside treatment. An understanding of how this structural and functional regeneration occurred might lead to the development of therapies for treatment of sensorineural hearing loss in humans. Recent experiments have demonstrated that noise exposure and aminoglycoside treatment lead to apoptosis of the hair cells. In birds, this programmed cell death induces the adjacent supporting cells to undergo regeneration to replace the lost hair cells. Although hair cells in the mammalian cochlea undergo apoptosis in response to noise damage and ototoxic drug treatment, the supporting cells do not possess the ability to undergo regeneration. However, current experiments on genetic manipulation, gene therapy, and stem cell transplantation suggest that regeneration in the mammalian cochlea may eventually be possible and may 1 day provide a therapeutic tool for hearing loss in humans. LEARNING OUTCOMES: The reader should be able to: (1) Describe the anatomy of the avian and mammalian cochlea, identify the individual cell types in the organ of Corti, and distinguish major features that participate in hearing function, (2) Demonstrate a knowledge of how sound damage and aminoglycoside poisoning induce apoptosis of hair cells in the cochlea, (3) Define how hair cell loss in the avian cochlea leads to regeneration of new hair cells and distinguish this from the mammalian cochlea where there is no regeneration following damage, and (4) Interpret the potential for new approaches, such as genetic manipulation, gene therapy and stem cell transplantation, could provide a therapeutic approach to hair cell loss in the mammalian cochlea.     

Inner ear pathology in the mucopolysaccharidosis VII mouse

Mucopolysaccharidosis type VII (MPS VII, Sly syndrome) is caused by dysfunction of the acid hydrolase beta-D-glucuronidase. The defect results in the accumulation of incompletely degraded glycosaminoglycans within lysosomes of a wide array of cell types. MPS VII is associated with mixed (conductive and sensorineural) hearing loss, vision defects, shortened stature, mental retardation and decreased lifespan. Whether the sensorineural component of hearing loss in MPS VII involves degeneration of cochlear sensory cells is not yet clear. The MPS VII mouse resembles its human counterpart in all major aspects, and has been the focus of extensive research seeking to correct MPS VII and other lysosomal storage diseases. The value of potential treatments for this hearing loss can be determined only if cochlear pathology in this model is well characterized. We examined threshold sensitivity, frequency tuning, hair cell density and the appearance of the cochlea and vestibular organs in MPS VII mice ranging from 1.0 to 7.5 months of age. At all ages, lysosomal storage is pronounced within cells of spiral limbus, spiral prominence, spiral ligament and glial cells, but not within organ of Corti, stria vascularis, or neurons. Within the vestibular maculae and cristae, both hair cells and supporting cells also show lysosomal storage. Although hearing thresholds are never normal, reduction in the sharpness of frequency tuning is not apparent until 2.5 months of age, suggesting that the sensorineural component of hearing loss begins in adulthood. No evidence was found for cell loss within the organ of Corti, or any other structure, however. Our results suggest that sensorineural hearing loss in the MPS VII mouse is not caused by degeneration, but may arise from alterations in mass and stiffness of cochlear structures or impaired sensory cell function. They also indicate a possible vestibular component in MPS VII.     

KHRI-3 monoclonal antibody-induced damage to the inner ear: antibody staining of nascent scars

Intracochlear infusion of the KHRI-3 monoclonal antibody results in in vivo binding to guinea pig inner ear supporting cells, loss of hair cells and hearing loss. To further characterize the basis for KHRI-3-induced hearing loss, antibody was produced in a bioreactor in serum-free medium, affinity purified, and compared to conventionally prepared antibody by infusion into the scala tympani using mini-osmotic pumps. In vivo antibody binding was observed in 10 of 11 guinea pigs. A previously unreported pattern of KHRI-3 antibody binding to cells involved in scar formation was noted in five guinea pigs. All but one of the KHRI-3-infused animals demonstrated a hearing loss of > 10 dB in the treated ear. In five of 11 animals the threshold shift was 30 dB or more, and all had hair cell losses. In one guinea pig infused with 2 mg/ml of antibody, the organ of Corti was absent in the basal turn of the infused ear. This ear had a 45-50 dB threshold shift but, curiously, no detectable antibody binding in the residual organ of Corti. Organ of Corti tissue was fragile in antibody-infused ears. Breaks within the outer hair cell region occurred in 5/11 infused ears. The contralateral ears were normal except for one noise-exposed animal that demonstrated hair cell loss in the uninfused ear. Three animals were exposed to 6 kHz noise (108 dB) for 30 min on day 7. Antibody access to the organ of Corti may be increased in animals exposed to noise, since the strongest in vivo binding was observed in noise-exposed animals. Loss of integrity of the organ of Corti seems to be the primary mechanism of inner ear damage by KHRI-3 antibody. The binding of KHRI-3 antibody in new scars suggests a role of the antigen in scar formation. Antibodies with binding properties similar to KHRI-3 have been detected in 51% of patients diagnosed with autoimmune sensorineural hearing loss; thus, it seems likely that such autoantibodies also may have pathologic effects resulting in hearing loss in humans.     

Strategies to regenerate hair cells: identification of progenitors and critical genes

Deafness commonly results from a lesion of the sensory cells and/or of the neurons of the auditory part of the inner ear. There are currently no treatments designed to halt or reverse the progression of hearing loss. A key goal in developing therapy for sensorineural deafness is the identification of strategies to replace lost hair cells. In amphibians and birds, a spontaneous post-injury regeneration of all inner ear sensory hair cells occurs. In contrast, in the mammalian cochlea, hair cells are only produced during embryogenesis. Many studies have been carried out in order to demonstrate the persistence of endogenous progenitors. The present review is first focused on the occurrence of spontaneous supernumerary hair cells and on nestin positive precursors found in the organ of Corti. A second approach to regenerating hair cells would be to find genes essential for their differentiation. This review will also focus on critical genes for embryonic hair cell formation such as the cell cycle related proteins, the Atoh1 gene and the Notch signaling pathway. Understanding mechanisms that underlie hair cell production is an essential prerequisite to defining therapeutic strategies to regenerate hair cells in the mature inner ear.     

Direct Evidence of Nitric Oxide Production in the Guinea Pig Organ of Corti

Production of nitric oxide (NO) in the organ of Corti of the guinea pig was investigated using the new fluorescence indicator 4,5-diaminofluorescein diacetate for direct detection of NO. The organ of Corti, lateral wall of the cochlea and isolated outer and inner hair cells were examined to locate NO production sites. The fluorescence intensities were augmented by stimulation with L-arginine or glutamate, and significantly increased after inoculation with lipopolysaccharide. This is the first direct evidence of NO production in the cochlea. NO may play an important role in the physiology of the organ of Corti and may also be involved in hearing disorders.     

Direct evidence of nitric oxide production in the guinea pig organ of Corti.

Production of nitric oxide (NO) in the organ of Corti of the guinea pig was investigated using the new fluorescence indicator 4,5-diaminofluorescein diacetate for direct detection of NO. The organ of Corti, lateral wall of the cochlea and isolated outer and inner hair cells were examined to locate NO production sites. The fluorescence intensities were augmented by stimulation with L-arginine or glutamate, and significantly increased after inoculation with lipopolysaccharide. This is the first direct evidence of NO production in the cochlea. NO may play an important role in the physiology of the organ of Corti and may also be involved in hearing disorders.     

Bilaterally Preserved Otoacoustic Emissions in Four Children with Profound Idiopathic Unilateral Sensorineural Hearing Loss

Severe to profound unilateral sensorineural hearing loss of the left ear was discovered by screening in four healthy children without any family history of hearing loss. Three of the children were four years old and one child was seven years old at the time of discovery. The PTA0.5–2 was 66–75 dB HL for three of the children and one child was without any hearing reactions on the affected ear. The hearing of the right ear was normal in all four cases. The hearing thresholds have been stable during an observation period of 3–12 years. No certain auditory-evoked brainstem responses were recorded with stimulation of the affected ear. Electronystagmography was normal in all cases and magnetic resonance imaging gave no explanation of the hearing loss. Repeated recordings of the transiently evoked otoacoustic emissions (TEOAE) have shown clear bilateral responses using different instrumentation systems. Recently the hearing levels were unchanged and the TEOAE responses of the affected ears were 6.7–19.9 dB SPL (waveform reproducibility: 88–98 per cent) recorded on the ILO88 OAE Analyser (stimulus: 82.2–83.4 dB peak). The collected results suggest that the children suffer from a similar disorder with a unilateral affection of the cochlea, involving the inner hair cells and/or the first neuron. The TEOAE recordings indicate substantially preserved outer hair cell function independent of the profound hearing loss.     

Cochlear damage and increased threshold in alpha-difluoromethylornithine (DFMO) treated guinea pigs

Alpha-difluoromethylornithine (DFMO) inhibits polyamine synthesis and is used as an antineoplastic and antiparasitic drug. In early human trials DFMO unexpectedly caused a sensorineural hearing loss. In the current study DFMO was administered to guinea pigs to investigate its effects on organ of Corti histology and on auditory thresholds. Histologic examination revealed that DFMO caused greatest damage in the hook and first turn. Damage in the second and third turns was minimal. Animals treated for 12 weeks with DFMO differed significantly (P less than 0.05) from controls in the hook and first turn in that: 1) DFMO caused a loss of hair cells in all rows. Loss of inner hair cells was greater than that of outer hair cells. 2) The remaining outer hair cells were shorter and contained a greater number of Hensen bodies. 3) The Deiters' cell bodies were longer and this increased length was associated with the decreased length of the corresponding outer hair cells. Brainstem audiometry showed that DFMO produced a hearing loss and the magnitude of this loss increased over twelve weeks of DFMO administration.