Calpain inhibitor alleviates permanent hearing loss induced by intense noise by preventing disruption of gap junction-mediated intercellular communication in the cochlear spiral ligament.

Our previous studies demonstrated that intense noise-induced hearing loss might be at least in part due to an oxidative stress-induced decrease in the level of gap junction-composing protein connexins in the spiral ligament (SL) of the cochlear lateral wall structures in mice. Further, an in vivo exposure of mice to intense noise activates calpain in the cochlear SL. Based on these studies, we sought to determine whether a calpain inhibitor would prevent an intense noise exposure from causing hearing loss, disruption of gap junction-mediated intercellular communication (GJIC) in the SL. An exposure of mice to intense noise (8-Hz octave band noise, 110-dB sound pressure level, 1h) produced permanent hearing loss and cochlear hair cell death. The results of an ex vivo assay using gap-fluorescence recovery after photobleaching of dissected lateral wall structures revealed that the intense noise disrupted GJIC in the cochlear SL at day-7 post exposure. A prior intracochlear injection of the calpain inhibitor PD150606 significantly abolished this noise-induced hearing loss on days 5 and 7 post exposure. Similarly, PD150606 prevented noise-induced hair cell death and the GJIC disruption on day-7 post exposure. The intense noise temporarily enhanced the gene expression of calpain subtypes Capn1 and Capn2 immediately after exposure. Taken together, our data suggest that calpain inhibitor alleviated the noise-induced hearing loss, at least in part, by preventing disruption of GJIC in the cochlear SL. It possible that calpain inhibitors would be useful as a candidate of therapeutic drugs for sudden sensorineural hearing loss.

Histopathology of the human inner ear in Alström's syndrome.

Alström's syndrome is an autosomal recessive syndromic genetic disorder caused by mutations in the ALMS1 gene. Sensorineural hearing loss occurs in greater than 85% of patients. Histopathology of the inner ear abnormalities in the human has not previously been fully described. Histopathology of the inner ear in Alström's syndrome is presented in 2 genetically confirmed cases. The predominant histopathologic correlates of the sensorineural loss were degeneration of the organ of Corti, both inner and outer hair cells, degeneration of spiral ganglion cells, and atrophy of the stria vascularis and spiral ligament.

Lysine-specific demethylase 1 inhibitors protect cochlear spiral ganglion neurons against cisplatin-induced damage.

Cisplatin is a widely used chemotherapeutic drug, but one of its side effects is ototoxicity. Epigenetic-related drugs, such as lysine-specific demethylase 1 (LSD1) inhibitors, have been reported to protect against cisplatin-induced hair cell loss by preventing demethylation of histone H3K4 (H3K4me2). However, the protective effect of LSD1 inhibitors in spiral ganglion neurons (SGNs) remains unclear. To investigate whether LSD1 inhibitors exert similar protective effects on SGNs, we treated mouse cochlear explant cultures with LSD1 inhibitors (2PCPA, S2101, or CBB1007) together with cisplatin. Low concentrations of cisplatin damaged SGNs much more than high concentrations, and blocking the demethylation of H3K4me2 with LSD1 inhibitors prevented the SGNs from injury. Reactive oxygen species are also involved in the injury process, and LSD1 inhibitors protected SGNs by increasing the expression level of the antioxidant gene Slc7a11 and decreasing the level of the pro-oxidant gene lactoperoxidase (Lpo). Our findings show that LSD1 inhibitors prevent cisplatin-induced SGN loss by regulating the demethylation of H3K4 and preventing increases of reactive oxygen species levels, which might provide a potential therapeutic strategy for cisplatin-induced hearing loss.

Disruption of ion-trafficking system in the cochlear spiral ligament prior to permanent hearing loss induced by exposure to intense noise: possible involvement of 4-hydroxy-2-nonenal as a mediator of oxidative stress.

Noise-induced hearing loss is at least in part due to disruption of endocochlear potential, which is maintained by various K(+) transport apparatuses including Na(+), K(+)-ATPase and gap junction-mediated intercellular communication in the lateral wall structures. In this study, we examined the changes in the ion-trafficking-related proteins in the spiral ligament fibrocytes (SLFs) following in vivo acoustic overstimulation or in vitro exposure of cultured SLFs to 4-hydroxy-2-nonenal, which is a mediator of oxidative stress. Connexin (Cx)26 and Cx30 were ubiquitously expressed throughout the spiral ligament, whereas Na(+), K(+)-ATPase α1 was predominantly detected in the stria vascularis and spiral prominence (type 2 SLFs). One-hour exposure of mice to 8 kHz octave band noise at a 110 dB sound pressure level produced an immediate and prolonged decrease in the Cx26 expression level and in Na+, K(+)-ATPase activity, as well as a delayed decrease in Cx30 expression in the SLFs. The noise-induced hearing loss and decrease in the Cx26 protein level and Na(+), K(+)-ATPase activity were abolished by a systemic treatment with a free radical-scavenging agent, 4-hydroxy-2,2,6,6-tetramethylpiperidine 1-oxyl, or with a nitric oxide synthase inhibitor, N(ω)-nitro-L-arginine methyl ester hydrochloride. In vitro exposure of SLFs in primary culture to 4-hydroxy-2-nonenal produced a decrease in the protein levels of Cx26 and Na(+), K(+)-ATPase α1, as well as Na(+), K(+)-ATPase activity, and also resulted in dysfunction of the intercellular communication between the SLFs. Taken together, our data suggest that disruption of the ion-trafficking system in the cochlear SLFs is caused by the decrease in Cxs level and Na(+), K(+)-ATPase activity, and at least in part involved in permanent hearing loss induced by intense noise. Oxidative stress-mediated products might contribute to the decrease in Cxs content and Na(+), K(+)-ATPase activity in the cochlear lateral wall structures.

Idiopathic sudden sensorineural hearing loss: vascular or viral?

OBJECTIVE: To demonstrate that sudden sensorineural hearing loss is possibly of viral origin rather than vascular. STUDY DESIGN: The histopathologic morphology in 7 temporal bones with known vascular impairment due to surgical interventions was compared with that of 11 bones with a history of idiopathic sudden sensorineural hearing loss (ISSNHL). Attention was paid to the spiral ligament, stria vascularis, organ of Corti hair cells, tectorial membrane, ganglion cell population, and degree of perilymph fibrosis and the auditory nerve. SETTING: A temporal bone laboratory that has been in operation for more than 50 years and includes a database consisting of clinical and histopathological information that facilitates quantitative and qualitative analysis. SUBJECTS: Eight hundred forty-nine individuals who pledged their temporal bones for scientific study, of which 18 were selected for this study by means of the database criteria of sudden sensorineural hearing loss and postmiddle fossa and retro sigmoid sinus tumor removal or vestibular nerve section. RESULTS: Sudden sensorineural hearing loss bones exhibited no perilymph fibrosis compared with 6 of 7 vascular cases with fibrosis (P ≤ .001), exhibited less loss of ganglion cells (P ≤ .026), exhibited greater survival of spiral ligament (P ≤ .029), and averaged twice the survival of hair cells and more widespread tectorial membrane abnormalities. CONCLUSION: Analysis of human temporal bones from patients with a sudden sensorineural hearing loss does not support a vascular insufficiency but is more suggestive of a viral etiology.

Systemic dexamethasone for the prevention of cisplatin-induced ototoxicity.

Ototoxicity is a common side effect of cisplatin chemotherapy. This study was undertaken to determine the potential protective effects of a systemic administration of dexamethasone against cisplatin-induced ototoxicity. A prospective controlled trial conducted in an animal model. The setting was Animal care research facilities of the Montreal Children's Hospital Research Institute. An experimental guinea pig model was used. The animals were divided as follows: group 1 (n = 10): 12 mg/kg intraperitoneal (IP) cisplatin, group 2 (n = 14): 15 mg/kg/day dexamethasone IP for 2 days followed by cisplatin 12 mg/kg IP, group 3 (n = 14): 10 mg/kg/day dexamethasone IP for 2 days, on day 3, they received cisplatin 12 mg/kg IP followed by 20 mg/kg/day dexamethasone for 2 days and group 4 (n = 5): 10 ml of saline IP twice a day for 3 days. Auditory brainstem response (ABR) threshold shifts were measured at four frequencies (8, 16, 20 and 25 kHz) for groups 1, 2 and 3. Histological changes in the organ of Corti, the stria vascularis, the spiral ligament and the spiral ganglion neurons as well as scanning electron microscopy for outer hair cells were completed. Immunohistochemistry for tumour necrosis factor-alpha (TNF-α) was performed. ABR threshold shifts were similar in all groups. Histological and scanning electron findings demonstrate that dexamethasone has greater protective effect on the stria vascularis. Systemic dexamethasone administration in a guinea pig model did not provide significant protection against cisplatin-induced ototoxicity. Dexamethasone may be useful in future applications as a complementary treatment.

Inner ear changes in mucopolysaccharidosis type I/Hurler syndrome.

OBJECTIVE: Mucopolysaccharidosis type I/Hurler syndrome is an autosomal recessive disease caused by a deficiency of α-L-iduronidase activity. Recurrent middle ear infections and hearing loss are common complications in Hurler syndrome. Although sensorineural and conductive components occur, the mechanism of sensorineural hearing loss has not been determined. The purpose of this study is to evaluate the quantitative inner ear histopathology of the temporal bones of patients with Hurler syndrome. PATIENTS: Eleven temporal bones from 6 patients with Hurler syndrome were examined. Age-matched healthy control samples consisted of 14 temporal bones from 7 cases. MAIN OUTCOME MEASURES: Temporal bones were serially sectioned in the horizontal plane and stained with hematoxylin and eosin. The number of spiral ganglion cells, loss of cochlear hair cells, area of stria vascularis, and cell density of spiral ligament were evaluated using light microscopy. RESULTS: There was no significant difference between Hurler syndrome and healthy controls in the number of spiral ganglion cells, area of stria vascularis, or cell density of spiral ligament. The number of cochlear hair cells in Hurler syndrome was significantly decreased compared with healthy controls. CONCLUSION: Auditory pathophysiology in the central nerve system in Hurler syndrome remains unknown; however, decreased cochlear hair cells may be one of the important factors for the sensorineural component of hearing loss.

Apoptosis of the fibrocytes type 1 in the spiral ligament and blood labyrinth barrier disturbance cause hearing impairment in murine cerebral malaria.

BACKGROUND: Experimental murine malaria has been shown to result in significant hearing impairment. Microscopic evaluation of the temporal bones of these animals has revealed regular morphology of the cochlea duct. Furthermore, the known vascular pathologic changes being associated with malaria could not be found. Immunohistochemistry for ICAM1 showed a strong marking in the stria vascularis, indicating a disturbance of the endocochlear potential. The aim of this study was to evaluate the role of apoptosis and the disturbance of the blood labyrinth barrier in the murine malaria associated hearing impairment. METHODS: The temporal bones of seven mice with cerebral malaria-four with hearing impairment, three without hearing impairment-were evaluated with immunohistochemistry for cleaved caspase 3 to detect apoptosis and connexin 26, a gap junction protein being a cornerstone in the endocochlear potassium recirculation. Furthermore five animals with cerebral malaria were treated with Evans blue prior to sacrification to detect disturbances of the blood labyrinth barrier. RESULTS: Cleaved caspase 3 could clearly be detected by immunohistochemistry in the fibrocytes of the spiral ligament, more intensively in animals with hearing impairment, less intensively in those without. Apoptosis signal was equally distributed in the spiral ligament as was the connexin 26 gap junction protein. The Evans blue testing revealed a strong signal in the malaria animals and no signal in the healthy control animals. CONCLUSION: Malfunction of the fibrocytes type 1 in the spiral ligament and disruption of the blood labyrinth barrier, resulting in a breakdown of the endocochlear potential, are major causes for hearing impairment in murine cerebral malaria.

Late-phase recovery in the cochlear lateral wall following severe degeneration by acute energy failure.

We previously reported a model of acute cochlear energy failure using a mitochondrial toxin, 3-nitropropionic acid (3-NP), to study mechanisms of inner ear disorders such as inner ear ischemia. In this model, the main cause of hearing loss is apoptosis of fibrocytes in the cochlear lateral wall. Here, we analyzed the time course of structural and hearing level changes in the cochlea from the acute phase to the chronic phase up to 2 months after surgery. Hearing levels as determined by auditory brainstem response (ABR) thresholds exceeded the maximum acoustic output (>87 dBSPL) of the system at all frequencies 1 day after 3-NP treatment. Histology showed nearly complete loss of fibrocytes 2 weeks after 3-NP treatment. However, after 2 months, ABR showed significant recovery at low frequency (8 kHz) in four of five rats treated with 3-NP. ABR thresholds at 20 kHz occasionally showed some recovery. At 40 kHz, recovery of ABR thresholds was not observed. Histology of 3-NP-treated rats revealed partial recovery of the lateral wall and the regenerated fibrocytes in the spiral ligament expressed Na/K-ATPase in the cochlear basal turn 2 months after 3-NP treatment. These results indicate that ABR recovery is caused by regeneration of the cochlear lateral wall. Our findings demonstrate the recoverable capacity of the cochlear lateral wall that leads to functional recovery after severe damage.

Pou3f4 deficiency causes defects in otic fibrocytes and stria vascularis by different mechanisms.

DFN3, the most prevalent X-linked hearing loss, is caused by mutations in the POU3F4 gene. Previous studies in Pou3f4 knockout mice suggest that defective otic fibrocytes in the spiral ligament of the cochlear lateral wall may underlie the hearing loss in DFN3. To better understand the pathological mechanisms of the DFN3 hearing loss, we analyzed inner ears of Pou3f4-deficient mice during development. Our results indicate that compartmentalization of the spiral ligament mesenchyme setting up boundaries for specific otic fibrocytes occurs normally in Pou3f4-deficient cochlea. However, differentiation of the compartmentalized mesenchyme into specific otic fibrocytes was blocked in the absence of Pou3f4 function. In addition, we found that stria vascularis in the cochlear lateral wall was also affected in Pou3f4-deficient cochlea. Unlike the otic fibrocytes, differentiation of stria vascularis was completed in the absence of Pou3f4 function, yet expression of Kir4.1 channels in the strial intermediate cells, essential for the sound transduction, was lost afterwards. These results suggest that Pou3f4 deficiency causes defects in both otic fibrocytes and stria vascularis at different developmental stages and by different pathological mechanisms, which may account for the progressive nature of DFN3 hearing loss.

Factors associated with incomplete insertion of electrodes in cochlear implant surgery: a histopathologic study.

OBJECTIVES: Atraumatic and complete insertion of the electrode array is a stated objective of cochlear implant surgery. However, it is known that obstructions within the cochlea such as new bone formation, cochlear otosclerosis, temporal bone fracture, and cochlear anomalies may limit the depth of insertion of the electrode array. In addition, even among patients without obvious clinical or radiographic indicators of obstruction, incomplete insertion may occur. The current study is a histopathologic evaluation of possible sources of resistance to insertion of the electrode array using the temporal bone collection of the Massachusetts Eye and Ear Infirmary. METHODS: Forty temporal bones from patients who in life had undergone cochlear implantation were evaluated. Temporal bones were removed at autopsy and fixed and prepared for histologic study by standard techniques. Specimens were then serially sectioned and reconstructed by 2-dimensional methods. Two electrode metrics were determined for each bone: the inserted length (IL: the distance measured from the cochleostomy site to the apical tip of the electrode) and the active electrode length (AEL: the distance between the most basal and most apical electrodes on the electrode array). The ratio of these two metrics (IL/AEL) was used to split the temporal bones into two groups: those with incomplete insertion (n = 27, IL/AEL <1.0) and those with complete insertion (n = 13, IL/AEL ≥ 1.0). Seven possible histopathologic indicators of resistance to insertion of the electrode due to contact with the basilar membrane, osseous spiral lamina and/or spiral ligament were evaluated by analysis of serial sections from the temporal bones along the course of the electrode tracks. RESULTS: Obvious obstruction by abnormal intracochlear bone or soft tissue accounted for only 6 (22%) of the 27 partial insertions. Of the remaining 21 bones with incomplete insertions and 13 bones with complete insertions, dissection of the spiral ligament to the lateral cochlear wall was the only histopathologic indicator of insertion resistance identified with significantly higher frequency in the partial-insertion bones than in the complete-insertion bones (p = 0.003). An observed trend for the percentage of complete insertions to decrease with the number of times the electrode penetrated the basilar membrane did not reach significance. In the bones without an obvious obstruction, the most frequently observed indicator of insertion resistance was dissection of the spiral ligament (with no contact of the lateral cochlear wall) identified in 67% (14/21) of partial-insertion bones and in 92% (12/13) of complete-insertion bones. CONCLUSION: These results are consistent with the view that (1) electrode contact with cochlear structures resulting in observable trauma to the basilar membrane, osseous spiral lamina and/or spiral ligament does not necessarily impact the likelihood of complete insertion of the electrode array and (2) once contact trauma to the spiral ligament reaches the point of dissection to the cochlear wall, the likelihood of incomplete insertion increases dramatically.

Cochlear otosclerosis adjacent to round window and oval window: a histopathological temporal bone study.

HYPOTHESIS: The purpose of this histopathological study is to examine temporal bones of patients with cochlear otosclerosis adjacent to the round window or adjacent to the oval window as compared with healthy controls. BACKGROUND: It is unclear if the extent and site of otosclerosis affects the extent of damage to cochlear structures and hearing loss. METHODS: Twelve temporal bones from 10 patients with cochlear otosclerosis adjacent to the round window, 11 temporal bones from 8 patients with cochlear otosclerosis adjacent to the oval window, and 12 bones of healthy age-matched controls were selected for study. We calculated the number of spiral ganglion cells, changes in cochlear structures, the extent and site of cochlear otosclerosis, and audiometric data. RESULTS: The loss of spiral ganglion cells and the absence of outer hair cells in patients with cochlear otosclerosis adjacent to the round window were significantly higher than those in patients with cochlear otosclerosis adjacent to the oval window and healthy controls. The area of the spiral ligament in patients with cochlear otosclerosis adjacent to the oval window was significantly smaller than that in healthy controls. However, no significant difference was found in the spiral ligament of patients with cochlear otosclerosis adjacent to the round window and healthy controls. There was no significant difference between patients with cochlear otosclerosis and age-matched controls in audiometric data. CONCLUSION: Cochlear otosclerosis adjacent to the round window caused significantly more damage to spiral ganglion cells and outer hair cells than cochlear otosclerosis adjacent to the oval window without loss of spiral ligament.

Noise exposure alters cyclooxygenase 1 (COX-1) and 5-lipoxygenase (5-LO) expression in the guinea pig cochlea.

CONCLUSION: Changes in the metabolism of arachidonic acid (AA) might be part of a noise-induced compensatory mechanism with regional specificity. OBJECTIVES: The released imbalance of prostaglandins and leukotrienes, both AA metabolites, might result in altered blood flow regulation in the inner ear and probably contributes to noise-induced hearing loss. The aim of this study was to gain further information about noise-dependent changes in AA metabolism in the mammalian cochlea. METHODS: In this prospective animal study, 10 male guinea pigs were exposed to tone bursts for 1 h at 70 dB sound pressure level (SPL) (n = 5) or 90 dB SPL (n = 5). Five animals were used as controls. Alterations in cyclooxygenase 1 (COX-1) and 5-lipoxygenase (5-LO) expression were determined by quantitative immunohistochemical analysis in 11 cochlear regions. RESULTS: COX-1 expression was decreased after both 70 dB SPL and 90 dB SPL exposure in most cell types of the organ of Corti and increased in the nerve fibers of the osseous spiral lamina. 5-LO was lowered after 90 dB SPL exposure, preferentially in the third cochlear turn in the organ of Corti, in the first and second turn in spiral ganglion cells, and in all turns in the stria vascularis.

Visualization and contractile activity of cochlear pericytes in the capillaries of the spiral ligament.

Pericytes, mural cells located on microvessels, are considered to play an important role in the formation of the vasculature and the regulation of local blood flow in some organs. Little is known about the physiology of cochlear pericytes. In order to investigate the function of cochlear pericytes, we developed a method to visualize cochlear pericytes using diaminofluorescein-2 diacetate (DAF-2DA) and intravital fluorescence microscopy. This method can permit the study of the effect of vasoactive agents on pericytes under the in vivo and normal physiological condition. The specificity of the labeling method was verified by the immunofluorescence labeling of pericyte maker proteins such as desmin, neural proteoglycan (NG2), and thymocyte differentiation antigen 1 (Thy-1). Superfused K(+) and Ca(2+) to the cochlear lateral wall resulted in localized constriction of capillaries at pericyte locations both in vivo and in vitro, while there was no obvious change in cochlear capillary diameters with application of the adrenergic neurotransmitter noradrenaline. The method could be an effective way to visualize cochlear pericytes and microvessels and study lateral wall vascular physiology. Moreover, we demonstrate for the first time that cochlear pericytes have contractility, which may be important for regulation of cochlear blood flow.

A mouse model for degeneration of the spiral ligament.

Previous studies have indicated the importance of the spiral ligament (SL) in the pathogenesis of sensorineural hearing loss. The aim of this study was to establish a mouse model for SL degeneration as the basis for the development of new strategies for SL regeneration. We injected 3-nitropropionic acid (3-NP), an inhibitor of succinate dehydrogenase, at various concentrations into the posterior semicircular canal of adult C57BL/6 mice. Saline-injected animals were used as controls. Auditory function was monitored by measurements of auditory brain stem responses (ABRs). On postoperative day 14, cochlear specimens were obtained after the measurement of the endocochlear potential (EP). Animals that were injected with 5 or 10 mM 3-NP showed a massive elevation of ABR thresholds along with extensive degeneration of the cochleae. Cochleae injected with 1 mM 3-NP exhibited selective degeneration of the SL fibrocytes but alterations in EP levels and ABR thresholds were not of sufficient magnitude to allow for testing functional recovery after therapeutic interventions. Animals injected with 3 mM 3-NP showed a reduction of around 50% in the EP along with a significant loss of SL fibrocytes, although degeneration of spiral ganglion neurons and hair cells was still present in certain regions. These findings indicate that cochleae injected with 3 mM 3-NP may be useful in investigations designed to test the feasibility of new therapeutic manipulations for functional SL regeneration.

Anatomy of the middle-turn cochleostomy.

OBJECTIVE: Middle-turn cochleostomies are occasionally used for cochlear implant electrode placement in patients with labyrinthitis ossificans. This study evaluates the anatomic characteristics of the middle-turn cochleostomy and its suitability for placement of implant electrodes. METHODS: Ten cadaveric human temporal bones were dissected using a facial recess approach. A middle-turn cochleostomy was drilled 2 mm anterior to the oval window and just inferior to the cochleariform process. The preparations were then stained with osmium tetroxide and microdissections were performed. The location of the cochleostomy on the cochlear spiral and its path through the various cochlear compartments were evaluated in all 10 specimens. A Cochlear Corporation depth gauge was inserted in five of the specimens and insertion trauma, number of contact rings, and depth of insertion were recorded. RESULTS: Eight of the 10 cochleostomies were placed at approximately 360 degrees on the cochlear spiral, near the transition between the basal and middle turns. In one case, the cochleostomy was found to enter the cochlear apex and in another it entered scala vestibuli of the proximal basal turn. The cochleostomy entered scala media in six bones and scala vestibuli in four specimens. A depth gauge was inserted in five specimens. The number of contacts placed within the cochlear lumen ranged from four to nine. There was evidence of insertional trauma to the lateral wall of the cochlear duct, basilar membrane, and Reissner's membrane, but no evidence of fractures to the osseous spiral lamina or modiolus. CONCLUSION: This study demonstrates that electrodes inserted via a middle-turn cochleostomy are likely to enter scala vestibuli and have access to the middle- and apical-cochlear turns. It is also possible that the electrode could be directed into the descending portion of the basal turn depending on cochleostomy orientation. Middle-turn cochleostomy seems to be a viable alternative for electrode placement when preservation of residual hearing is not a concern.

Generalized arteriosclerosis and changes of the cochlea in young adults.

HYPOTHESIS: To disclose the histopathologic findings of the cochlea in young adults with generalized arteriosclerosis. BACKGROUND: It is well known that arteriosclerosis begins and progresses during childhood. Although the relationship between arteriosclerosis and auditory function in elderly people was examined in many reports, the histopathologic effect of arteriosclerosis on the cochlea in young adults has not been studied. METHODS: This study involved quantitative analysis, including the number of spiral ganglion cells, the loss of cochlear outer hair cells, and the areas of stria vascularis and spiral ligament. It included 10 temporal bones from 6 subjects with generalized arteriosclerosis and 10 age-matched normal control temporal bones from 7 subjects. RESULTS: The mean number of spiral ganglion cells in the cochlea with generalized arteriosclerosis was significantly lower than that in normal controls in the basal turn. The mean loss of outer hair cells in the cochlea with generalized arteriosclerosis was significantly greater than that of normal controls in the basal and apical turns. The stria vascularis and spiral ligament were severely atrophic, with generalized arteriosclerosis in the basal turn. There was no significant difference in the thickness of the spiral modiolar artery between generalized arteriosclerosis and normal controls. CONCLUSION: Degeneration of the cochlea, especially in the basal turn, was already apparent in young adults with generalized arteriosclerosis.