Histopathology of the Clarion cochlear implant electrode positioner in a human subject.

A Silastic electrode positioner was introduced by the Advanced Bionics Corporation in 1999 and it was designed to achieve a perimodiolar position of the stimulating electrode. The positioner was voluntarily recalled in the United States in July 2002 due to an apparent higher risk of bacterial meningitis in patients in whom the electrode positioner had been placed. A detailed histopathologic study of the positioner in the human has not previously been published. The histopathologic findings in a 74-year-old woman who underwent bilateral cochlear implantation using the positioner are presented. Findings include a large track caused by the combined electrode and its positioner with considerable disruption of the basilar membrane and osseous spiral lamina. Although there was a fibrous sheath around the electrode and positioner at the cochleostomy in both ears, this fibrous sheath did not extend deeply into the cochlea except at the apical end of the electrode beyond the positioner. This resulted in a large fluid space around and between the positioner and electrode within the cochlea and presumably in fluid continuity with the cerebrospinal fluid space. Possible clinical implications are discussed.

Mutations in a novel cochlear gene cause DFNA9, a human nonsyndromic deafness with vestibular dysfunction.

DFNA9 is an autosomal dominant, nonsyndromic, progressive sensorineural hearing loss with vestibular pathology. Here we report three missense mutations in human COCH (previously described as Coch5b2), a novel cochlear gene, in three unrelated kindreds with DFNA9. All three residues mutated in DFNA9 are conserved in mouse and chicken Coch, and are found in a region containing four conserved cysteines with homology to a domain in factor C, a lipopolysaccharide-binding coagulation factor in Limulus polyphemus. COCH message, found at high levels in human cochlear and vestibular organs, occurs in the chicken inner ear in the regions of the auditory and vestibular nerve fibres, the neural and abneural limbs adjacent to the cochlear sensory epithelium and the stroma of the crista ampullaris of the vestibular labyrinth. These areas correspond to human inner ear structures which show histopathological findings of acidophilic ground substance in DFNA9 patients.

Three-dimensional quantification of fibrosis and ossification after cochlear implantation via virtual re-sectioning: Potential implications for residual hearing.

Hearing preservation may be achieved initially in the majority of patients after cochlear implantation, however, a significant proportion of these patients experience delayed hearing loss months or years later. A prior histological report in a case of delayed hearing loss suggested a potential cochlear mechanical origin of this hearing loss due to tissue fibrosis, and older case series highlight the frequent findings of post-implantation fibrosis and neoosteogenesis though without a focus on the impact on residual hearing. Here we present the largest series (N = 20) of 3-dimensionally reconstructed cochleae based on digitally scanned histologic sections from patients who were implanted during their lifetime. All patients were implanted with multichannel electrodes via a cochleostomy or an extended round window insertion. A quantified analysis of intracochlear tissue formation was carried out via virtual re-sectioning orthogonal to the cochlear spiral. Intracochlear tissue formation was present in every case. On average 33% (SD 14%) of the total cochlear volume was occupied by new tissue formation, consisting of 26% (SD 12%) fibrous and 7% (SD 6%) bony tissue. The round window was completely covered by fibro-osseous tissue in 85% of cases and was associated with an obstruction of the cochlear aqueduct in 100%. The basal part of the basilar membrane was at least partially abutted by the electrode or new tissue formation in every case, while the apical region, corresponding with a characteristic frequency of < 500 Hz, appeared normal in 89%. This quantitative analysis shows that after cochlear implantation via extended round window or cochleostomy, intracochlear fibrosis and neoossification are present in all cases at anatomical locations that could impact normal inner ear mechanics.

A study of postmortem autolysis in the human organ of Corti.

Forty-six human temporal bones from 24 individuals were removed at autopsy and prepared for electron microscopy. The adequacy of histologic preservation was evaluated by light and electron microscopy. Characteristic autolytic changes included vacuolization of afferent neurons and neural poles of inner and outer hair cells, lysis of limiting membranes of hair and supporting cells, swelling of endoplasmic reticulum, and dissolution of mitochondrial cristae. The rate of autolysis varied significantly within cellular components of the inner ear. The neural poles of hair cells demonstrated more rapid autolysis than apical poles and nerve terminals showed more autolysis than myelinated nerve fibers. Postmortem time and the cause of death affected the adequacy of histologic preservation. Fixation in patients dying of pneumonia, hypoxia, head injury, or malignancy tended to be poor, whereas the fixation achieved in patients dying of cardiac disease with postmortem time of under 140 minutes was generally good.

Dense innervation of Deiters' and Hensen's cells persists after chronic deefferentation of guinea pig cochleas.

Innervation of Deiters' and Hensen's cells has been described in the organ of Corti of several mammalian species and has been suggested to arise from the olivocochlear (OC) efferent system (Wright and Preston [1976] Acta Otolaryngol. 82:41-47). In the present study, antineurofilament immunostaining was used to reveal these outer supporting cell fibers (OSCFs) in the normal guinea pig. In control ears, OSCFs were absent in the basal half of the cochlea but increased in number steadily toward the apex, peaking at values of over 1,200 fibers/mm. These values indicate a far more profuse innervation of supporting cells than has been described previously, suggesting that most OSCFs were not stained in previous immunohistochemical studies. Chronic cochlear deefferentation was used to test whether OSCFs are part of the OC system. The OC bundle was transected unilaterally, and the animals were allowed to survive for 4-8 weeks. Completeness of deefferentation was assessed by using acetylcholinesterase staining of the brainstem and measurement of the density of OC fascicles in the cochlea. By using these metrics, unilateral deefferentation was nearly complete in three animals. In successfully deefferented cases, the OSCF innervation density was not statistically different from control values. We conclude that the vast majority of OSCFs are not of OC origin. We speculate that they may be branches of type II afferent fibers to outer hair cells and that a smaller population of OSCFs with different morphology and immunoreactivity may arise from the OC system.

Invasive external otitis. Report of 21 cases and review of the literature.

We report 21 cases of invasive external otitis and review 130 cases from the English literature. Invasive external otitis is the term that most appropriately describes the locally invasive Pseudomonas infections that begins in the external ear canal, breaches the epithelial barrier and results in signs of local subcutaneous tissue invasion. Nineteen patients were diabetic. FIfteen of these 19 had preexistent, long-standing diabetes (average 15.8 years) and 10 had microvascular disease. Studies of the skin of the temporal bone in two patients provided evidence of diabetic microangiopathy of the dermal capillaries. Pseudomonas aeruginosa was isolated from the involved area in all cases. All patients without neurologic deficits survived, compared with six of nine with deficits of the central nervous system. All 13 patients in whom initial therapy was successful received a combination of an aminoglycoside and a semisynthetic penicillin, whereas all six episodes of recurrent disease occurred when only one antibiotic was used. The overall mortality was 15 percent (three of 20 in whom the long-term outcome is known). We propose that diabetic microangiopathy of the skin of the temporal bone results in poor local perfusion and creates an environment well suited for invasion by Pseudomonas aeruginosa. There is a good correlation between the extent of disease clinically and prognosis. Effective treatment requires early diagnosis and combination therapy with an aminoglycoside and a semisynthetic penicillin.

The impact of dexamethasone on hearing loss in experimental pneumococcal meningitis.

Bacterial meningitis, particularly that resulting from Streptococcus pneumoniae, is a common cause of acquired profound sensorineural deafness in children. The pathogenesis of meningogenic hearing loss has been investigated in an experimental rabbit model. In this study significant deafness was documented within the first 15 hours of infection. Initiation of antibiotic therapy at this time diminished the severity of hearing loss in most animals. The addition of dexamethasone to antibiotic therapy prevented the development of profound deafness. These results suggest this model will be useful in developing antiinflammatory strategies to improve the outcome of bacterial meningitis.

Carcinoid tumor of the middle ear.

A primary tumor of the middle ear with histologic, histochemical, and ultrastructural features of a neuroendocrine neoplasm is described. This neoplasm superficially resembles the so-called adenomatous tumor of the middle ear, and potential relationships and differences between these tumors are discussed. Although the histogenesis of the carcinoid tumor of the middle ear is not well understood, it most likely originates from pre-existing neuroendocrine cells or a primitive precursor cell. This neoplasm should be considered in the differential diagnosis when biologically low-grade tumors with prominent acinar or trabecular architectures are encountered in the middle ear. Since the carcinoid tumor of the middle ear is presumably of foregut derivation, stains for argyrophilic granules and electron-microscopic identification of neurosecretory granules are important diagnostic aids.

Comparative anatomy of the cochlea and auditory nerve in mammals.

The numbers and structure of hair cells; afferent, efferent, and reciprocal synapses as seen at the base of hair cells; innervation patterns of first order cochlear neurons; and number and morphology of spiral ganglion cells will be discussed and compared in the guinea pig, rat, cat, monkey and man. Despite many similarities both in the organ of Corti and the spiral ganglion in these species, there are a number of differences which may have important physiologic implications. In the organ of Corti, the major differences among species are the length and width of the basilar membrane, the number of inner and outer hair cells, and the length of hairs on both inner and outer hair cells. Significant differences in the innervation pattern of the inner hair cell among these species include the number of afferent nerve terminals per inner hair cell, the degree of branching of afferent fibers, and the number of synapses per afferent nerve terminal. Among outer hair cells, the number of afferent nerve terminals per outer hair cell, presence or absence of a pre-synaptic body, presence or absence of reciprocal synapses, the number of efferent terminals per outer hair cell, and the presence of dendodendritic synapses in outer spiral bundles may be differences important physiologically. In the spiral ganglion, there are significant differences in the number of spiral ganglion cells, the number of cochlear nerve fibers, the percentage of spiral ganglion cells which are myelinated, and the presence of synapses on spiral ganglion cells.

Degeneration of cochlear neurons as seen in the spiral ganglion of man.

A light and electron microscopic study of the spiral ganglion cells of a normal individual, a patient with Meniere's syndrome, and a patient with long-standing unilateral profound deafness was done to evaluate patterns of neural degeneration in the human inner ear. Parametric data for the normal spiral ganglion are presented and compared with the pathologic ganglia. In the ear with Meniere's syndrome, the nuclear area and axonic diameter of spiral ganglion cells were significantly smaller than in the contralateral and the normal ear. This was interpreted as evidence of neuronal degeneration in Meniere's syndrome. In the spiral ganglion of the long-standing deaf ear, there appeared to be selective preservation of large cells with no dendritic processes, contrary to the pattern of degeneration seen in the spiral ganglion of the animal.

Supranuclear efferent synapses on outer hair cells and Deiters' cells in the human organ of Corti.

Synaptophysin immunoreactivity and transmission electron microscopy have demonstrated vesiculated nerve endings synapsing on the supranuclear zone of outer hair cells and also of Deiters' cells in the human organ of Corti. These fibers seem similar to supranuclear fibers, apparently derived from the olivocochlear efferent system, which have been described in the animal. However, these endings were found throughout the cochlea in the human whereas in the animal such fibers were limited to the apical cochlea. Although such fibers have been demonstrated among supporting cells by immunohistochemical techniques, this is the first demonstration by transmission electron microscopy of morphology consistent with a chemical synapse between such fibers and Deiters' cells. Although the role of such fibers is unknown, neurophysiologic evidence suggests that they may modify the micromechanics of the outer hair cell. The function of neural innervation of Deiters' cells is speculative.

Patterns of innervation of outer hair cells in a chimpanzee: I. Afferent and reciprocal synapses.

Three varieties of synaptic specialization, afferent, efferent, and reciprocal, have been demonstrated at the base of outer hair cells of one chimpanzee. The purpose of the present study was to investigate the innervation density of afferent and reciprocal synapses in the three rows and three turns of the organ of Corti. The data presented is based on light and electron microscopy from one aged chimpanzee using serial section electron microscopy. Afferent fibers make contact with outer hair cells as either terminal swellings or en passant contacts. In addition to membrane specialization, presynaptic bodles were present at the majority of afferent synapses. The mean innervation density of afferent endings was highest in the middle turn. Reciprocal endings were found on 74% of all outer hair cells. The average number of reciprocal endings increased from the base to apex and, except in the apical turn, from the first to third row of outer hair cells. On the basis of morphological criteria, endings with a reciprocal synapses were more similar to afferent than to efferent endings.

Patterns of innervation of outer hair cells in a chimpanzee: II. Efferent endings.

A morphometric analysis of the efferent innervation of the outer hair cells in the organ of Corti of one chimpanzee was performed. There was a wide variability in the size of efferent endings which ranged from approximately 0.1 to 4.5 microns 3 in volume. Based on the size distribution of endings, a volume of 1.0 microns 3 was chosen to divide efferent endings into two groups, 'large' and 'small'. The incidence of large efferent fibers decreased from base to apex and from the first to third row of each turn, whereas the incidence of small efferents increased from base to apex and from the first to third row in each turn. This data was interpreted to suggest that at least two types of efferent endings may exist at the base of outer hair cells of the organ of Corti in the chimpanzee.

Postnatal maturation of human spiral ganglion cells: light and electron microscopic observations.

The presence of two types of ganglion cells, based on cell size and other morphologic parameters, is well established in the adult mammalian and human spiral ganglion. On the other hand, there is little data concerning cell morphology in the neonatal spiral ganglion. The present study was undertaken to evaluate the differences in the morphometry and distribution of cell types in the spiral ganglion of the human neonate as compared to the adult. A total of five human temporal bones from two neonates and three infants were included in this study. Light microscopic analysis of all specimens was performed, and electron microscopic evaluation of a 14 day old neonatal spiral ganglion was accomplished. The segmental density of spiral ganglion cells was higher in the neonate than in the adult. The prevalence of type II spiral ganglion cells was higher in the neonate than has been reported in the adult, particularly in the middle and apical turns where type II cells constituted 24% and 26% of all ganglion cells, respectively. The prevalence of type II ganglion cells decreased with age, particularly in the middle and apical turns. In the neonate, the maximal cross sectional area of type I neurons increased from the base to the apex and seemed to increase with age especially in the basal turn. The present study strongly supports a clear differentiation of type I and type II ganglion cells in the human neonate and that the prevalence of type II cells is greater in the neonate than the adult. This finding is discussed with reference to postnatal development of the spiral ganglion.

Morphologic evidence for innervation of Deiters' and Hensen's cells in the guinea pig.

The presence of nerve fibers and terminals among Deiters' and Hensen's cells of the organ of Corti of the adult guinea pig is demonstrated using immunostaining for synaptophysin and neurofilaments, acetylcholinesterase histochemistry, and transmission electron microscopy. These nerve terminals appeared to form chemical synapses with Deiters' and Hensen's cells. Nerve fibers and synapses were more common in the apical as compared to the basal cochlea. The terminals were often present on basal appendages of Hensen's cells, which were rich in mitochondria and often contained a Golgi apparatus and dense core vesicles. Electron microscopy and immunostaining for neurofilaments showed that most Hensen's cells in the apical cochlea received innervation. Few of the nerve fibers and terminals were positive for acetylcholinesterase, which suggests that they were not collaterals of cholinergic olivocochlear fibers. The density of these fibers, as shown by immunohistochemistry for neurofilaments, was far greater than previous reports of GABA-ergic fibers, which suggests that they were not GABA-ergic olivocochlear fibers. The role of such fibers and synapses with supporting cells of the outer hair cell area is unknown. Determination of the origins and functions of these fibers will provide new insights into cochlear structure and function.

Patterns of degeneration in the human cochlear nerve.

The patterns of neural degeneration of the spiral ganglion were studied in 12 human pathologic specimens and 2 normal neonatal specimens. Morphometric analysis of spiral ganglion cells included the maximum cross-sectional areas of both large (type 1) and small (type II) spiral ganglion cells. The organ of Corti in segments corresponding to the spiral ganglion, was evaluated for the presence or absence of inner (IHC) and outer (OHC) hair cells and supporting cells. The relationship between degeneration of spiral ganglion cells and degeneration in the organ of Corti, the age, sex, duration of deafness, cochlear location and delay between death and fixation was evaluated statistically. Both primary and secondary degeneration of the spiral ganglion were more severe in the basal than apical half of the cochlea. Degeneration of the spiral ganglion was most severe when both IHCs and OHCs were absent in the organ of Corti. No survival advantage was identified for type II ganglion cells as has been previously reported. That is, there was no correlation between the degree of degeneration of the spiral ganglion and the prevalence of type II ganglion cells. In fact, there was more severe degeneration of type II cells when the corresponding organ of Corti was severely degenerated. These findings in the human were compared with animal models of degeneration of the spiral ganglion, and the implications for cochlear implantation were discussed.

Prevalence and ultrastructural morphology of axosomatic synapses on spiral ganglion cells in humans of different ages.

Axosomatic synapses were found on human spiral ganglion cells (HSGCs). Ultrastructural characterization and calculation of the prevalence of these synapses were performed by electron microscopic semi-serial sections of both type I and type II HSGCs, in specimens from subjects of ages 1 day, 14 days, 21 years and 51 years. Synapses on type I HSGCs were extremely rare. In contrast, axosomatic synapses were present on approximately 50% of type II HSGCs of a young adult. This prevalence seemed to vary by age. Thus, no synapses were found in a 1-day old neonate, few in a 14-day old, and on approximately 15% of the type II SGCs from a 51-year old specimen. The origin of the nerve fibers synapsing on the type II HSGCs could not be determined. In view of the fact that some of the fibers projected from the intraganglionic spiral bundle, which is known to contain olivocochlear efferents, these fibers may represent an efferent pathway to the spiral ganglion. However, since there was morphological evidence of more than one type of nerve fiber synapsing on type II HSGCs, other neural origins must be considered. Although the physiological function of these synapses is unknown, they may mediate pre-synaptic neural modulation of the type II HSGCs at the level of the spiral ganglion.

Pattern of degeneration of the spiral ganglion cell and its processes in the C57BL/6J mouse.

Although degeneration of spiral ganglion cells has been described as a histopathologic correlate of hearing loss both in animals and humans, the pattern and sequence of this degeneration remain controversial. Degeneration of hair cells and of spiral ganglion cells and their dendritic processes was evaluated in the C57BL/6J mouse, in which there is a genetically determined progressive sensorineural loss starting in the high frequencies that is similar to the pattern commonly seen in the human. Auditory function was evaluated by brainstem evoked responses, and degeneration of hair cells, ganglion cells and their dendrites was evaluated histologically at 3, 8, 12 and 18 months of age. Progressive loss of auditory sensitivity was correlated with the loss of outer and inner hair cells and spiral ganglion cells and their dendritic processes. In addition, dendritic counts were consistently lower at a distal location in the osseous spiral lamina (i.e. near the organ of Corti) than at a proximal location (i.e. near the spiral ganglion), and the difference between the number of distal dendrites and the number of proximal dendrites tended to be greater with advancing age. These observations suggest an age-related progressive retrograde degeneration of spiral ganglion cells. Thus, in degenerating cochleas, some remaining spiral ganglion cells may have no distal dendritic processes near the organ of Corti. This may have implications for successful stimulation of the cochlear neuron in cochlear implantation.

Morphologic evidence for three cell types in the human spiral ganglion.

Although two types of spiral ganglion cells (large type I and smaller type II) have classically been described by anatomic studies in both animal and human spiral ganglion, there is physiologic and morphologic evidence for subtypes of the large type I ganglion cell. In addition, in the animal and human, a variety of morphologic differences based on cytoplasmic content, myelinization, immunostaining and morphometric analysis have suggested more than one variety of type I ganglion cell. Light and electron microscopic serial sections of the spiral ganglion in two human specimens in the basal, middle and upper middle turns were pooled for morphometric analysis of the cell area, nuclear area and axon diameter. Analysis of variance, bivariate scatter plots and multivariate cluster analysis provided evidence for 3 types of ganglion cells in the human spiral ganglion: large, intermediate and small, varying from each other significantly on the basis of cell area. It was suggested, based on the morphologic findings and prevalence of the cell types, that the large and intermediate cells were subtypes of the classic type I spiral ganglion cell, whereas the small ganglion cell was consistent with the classically described type II ganglion cell.

Serial section reconstruction of the neural poles of hair cells in the human organ of Corti. I. Inner hair cells.

Study of the anatomy of the cochlea, and in particular the morphology of synaptic relationships between hair cells and cochlear neurons, is essential for elucidation of the mechanisms of transduction of mechanical acoustic signals into electrical neural events. Because considerable gaps remain in our understanding of the microscopic anatomy of these synapses, particularly in the human, a reconstruction of neural pole of inner hair cells of the human organ of Corti was performed. The data are based on 526 serial sections from the basal turn (10 mm region) and 356 serial sections from the middle turn (26 mm region). This provided complete data on 3 and partial data on 5 inner hair cells. Afferent terminals on inner hair cells were variable in size, ranging 1 to 20 micrometers in diameter. Branching of large fibers to produce multiple terminals innervating from 1 to 3 inner hair cells was common. Each inner hair cell received approximately 6 to 8 different nerve terminals. In addition, each terminal possessed a variable number of synaptic contacts. Junctional membrane specialization consisted of synapses, desmosomes, coated vesicles and arrays of microtubules and membrane cisternae. Specialization at synapses consisted of asymmetrical membrane thickening. At inner hair cells the postsynaptic membrane was thicker than the presynaptic membrane. Eighty-three percent of synapses had presynaptic bodies. Vesiculated efferent terminals synapsed on afferent fibers at the base of inner hair cells, but never directly on the inner hair cell. These anatomical data demonstrate distinct differences between the human and animal inner ear, which are important in the interpretation of neurophysiological data in animals and the formulation of hypotheses that involve assumptions crossing species.