Vestibular histopathology of the human temporal bone. What can we learn?

Histologic sections of the human temporal bone display snapshots of the entire lifetime integrated into the moment the bone enters fixative. The bulk of the literature on vestibular histopathology is anecdotal and descriptive in nature, rather than quantitative. This is because the means of describing and measuring patients' vestibular symptoms are poorly developed, and the complex geometry of the vestibular labyrinth complicates efforts to study it in serial histologic sections. Histopathologic findings in the common peripheral vestibulopathies, including Meniere's syndrome, benign paroxysmal positional vertigo, viral labyrinthitis, vestibular neuronitis, and ototoxicity, have all been described. A new quantitative method for assessment of vestibular otopathology using Nomarski optics has recently been reported. It has been successfully applied to create a normative database of age-related changes in the vestibular hair cell populations which, in turn, has been used to study the effects of aminoglycoside ototoxicity and Meniere's syndrome. These data provide the first meaningful opportunity to make structure-function correlations between vestibular function testing and temporal bone pathology in humans. Wider clinical application of vestibular function testing and postmortem temporal bone donation should be promoted by all investigators interested in accumulating the resources necessary to gain a deeper understanding of the human vestibular system in health and disease.

Decreasing hair cell counts in aging humans.

Deterioration of balance with advancing age is a well-known fact of life. Some investigators have reported a 50% prevalence of dizziness in the elderly. Clinically, progressive dysequilibrium of aging presents as gradually worsening balance due to age-related decline in function of the peripheral vestibular system, central nervous system, vision, and musculoskeletal system. Vestibular function testing has shown clear evidence of age-related changes in peripheral and central sites. Histopathologic changes in the vestibular sensory organs include progressive hair cell degeneration, otoconial degeneration in the otolith organs, and decreasing number of Scarpa's ganglion neurons. Recently, a new quantitative method of assessing vestibular otopathology has been described, utilizing Nomarski differential interference contrast microscopy. This technique has been applied to 67 human temporal bones of individuals from birth to age 100 to create a normative database of total, type I, and type II hair cell counts as a function of age. Results show a highly significant continuous decrease in all counts from birth to age 100, best fit by a linear regression model. Type I hair cell counts in all three semicircular canal cristae decrease at a similar rate, significantly faster than the degeneration observed in type I hair cells of the maculae. Type II hair cell counts decline at the same rate for all 5 sensory epithelia. These normative data provide the basis for comparisons to hair cell counts made in temporal bones from subjects with known vestibular disorders. They also provide a basis for drawing correlations between vestibular function testing and vestibular otopathology.

Transferrin microheterogeneity in human perilymph.

OBJECTIVES/HYPOTHESIS: Assay for beta2-(asialo-) transferrin has been advocated for use in diagnosis of cerebrospinal fluid (CSF) leak or perilymphatic fistula based on the fact that it is present in these fluids but not in serum. Quantitation of the sensitivity of transferrin assays has not been reported previously. The present study was undertaken to quantify the sensitivity of a microelectrophoretic assay of beta2-transferrin and assess its potential applicability to clinical diagnosis of perilymphatic fistula. STUDY DESIGN: The initial part of the study was a prospective bench biochemistry assessment of assay sensitivity and reliability. Subsequent application of the assay was a blinded prospective clinical trial. METHODS: Transferrin is a ubiquitous monomeric glycoprotein consisting of 679 amino acids, two iron-binding sites, and two N-linked complex glycan chains. The N-glycan chains branch in variable degree, carrying from zero to eight sialic acid residues. This variation in sialylation has been termed "microheterogeneity." When both iron-binding sites are saturated, the microheterogeneity of sialic acid content results in isoelectric points ranging from pH 5 to pH 6. Thus these nine transferrin variants can be distinguished by isoelectric focusing. Samples of transferrin solution or body fluids (serum, CSF, and perilymph) were incubated in iron-loading buffer to saturate both iron-binding sites and then subjected to isoelectric focusing (IEF). The separated proteins were immunoprecipitated in the IEF gel and silver stained for visualization. Serial dilutions of pure transferrin solution were used to determine assay sensitivity. Neuraminidase was used to digest sialic acid side chains from pure transferrin in solution, and the reaction product was used as a reference standard for comparison to assay of unknown fluids. Patient inner ear fluid samples obtained during stapedectomy or cochlear implantation were used to assess clinical applicability of the assay. RESULTS: This microelectrophoretic technique, using only 0.3 microL of iron-loaded sample, was able to consistently detect less than 250 pg of transferrin in solution and separate the different sialylation variants based on their isoelectric points. Assay of patient serum samples clearly demonstrated transferrin microheterogeneity. Assay of CSF consistently showed the predicted beta2-(asialo-) transferrin band. Assay of inner ear fluid samples also demonstrated transferrin microheterogeneity. However, no inner ear fluid samples had detectable levels of beta2-transferrin. Presumably, perilymph sample dilution during iron loading and by admixture with serum, local anesthetic, or middle ear secretions lowered the beta2-transferrin concentration below the detection limen of the assay. CONCLUSIONS: Microelectrophoretic assay of iron-loaded transferrin can detect as little as 250 pg of protein and can identify microheterogeneity in serum, CSF, and perilymph. However, dilutional effects of sample handling and preparation can lower the beta2-transferrin concentration of inner ear fluid samples below the detection limen of the assay. Thus, depending on the relative amounts of serum and perilymph (or CSF) in a mixed sample, electrophoretic separation of transferrin variants may not be diagnostic.

Intratympanic gentamicin for treatment of intractable Meniere's disease: a preliminary report.

Topical administration of aminoglycoside antibiotics in the middle ear can achieve "chemical labyrinthectomy" in patients with intractable Meniere's disease. Herein we report our results of intratympanic gentamicin therapy in 21 patients using two different dosing protocols, twice weekly and twice daily (b.i.d.). Both hearing and vertigo outcome were evaluated. Complete control of episodic vertigo was achieved initially in 20 of 21 patients (95.2%). However, 6 of 20 responders (30%) developed relapsing symptoms within 12 months. Retreatment was successful in 75% of these patients. Overall, hearing was preserved or improved in 62% of cases, worse in 24%, and not yet tested in 14%. When the cumulative dose of gentamicin was < or = 4 injections in the first week, only 1 of 14 (7.1%) lost hearing. Intratympanic gentamicin offers better risk/benefit outcome than other invasive therapies for intractable Meniere's disease.

Clinical application of an implantable bone conduction hearing device.

For some patients, the transcutaneous bone-conduction implant offers a viable alternative to conventional amplification. However, this option should be employed only after considering the relative advantages and disadvantages of conventional medical management and, when feasible, the fitting of air-conduction amplification. The cases presented here illustrate some important factors to consider in the selection and fitting of bone-implant candidates.

Anti-heat shock protein 70 antibodies in Meniere's disease.

OBJECTIVES: To determine the prevalence of anti-heat shock protein 70 (anti-HSP70) antibodies in patients with Meniere's disease and healthy subjects and to probe the relationship between antibody status and clinical features of Meniere's disease. STUDY DESIGN: Prospective cohort study of consecutive consenting patients with Meniere's disease. METHODS: Serum samples were obtained prospectively from 134 patients with Meniere's disease and 124 blood donors. Serial samples were taken at 3-month intervals in 38 of 134 patients with Meniere's disease. Demographic data and clinical characterization of vestibular and auditory status were acquired with each sample. Serum was assayed for anti-HSP70 antibodies by Western blot using bovine renal extract, recombinant bovine HSP70, and recombinant human HSP70 antigens. RESULTS: Immunoreactivity against bovine renal extract HSP70 was found in 38% of patients with Meniere's disease, compared with 25% of blood donors (P < .04). Reactivity with recombinant antigens was not significantly different between patients with Meniere's disease and healthy control subjects. Patients with Meniere's disease who reacted with all three antigens were more likely to have simultaneously active hearing and balance symptoms (P = .03). Neither univariate nor multivariate statistical analysis established any other association between serological findings and clinical features of Meniere's disease. Tests performed on serial samples of patients with Meniere's disease also showed no association of positive or negative test results with changes in clinical course. CONCLUSIONS: Because of the high prevalence of antiHSP70 antibodies in healthy subjects and the very limited association of anti-HSP70 antibody status with clinical features or course of Meniere's disease, we conclude that, at present, the detection of anti-HSP70 antibodies by Western blotting offers little clinically useful information in Meniere's disease.

Nucleus 22 cochlear implantation results in postmeningitic deafness.

Cochlear implant surgery was performed on 13 patients with postmeningitic deafness (seven adults, six children). Two adults and two children (30.8%) had severe labyrinthitis ossificans requiring radical "drill-out." Five of 13 (38.5%) had some bone growth requiring partial drill-out, and four of 13 (30.8%) had normal insertion with no drill-out. Hearing results for patients with no bone growth were similar to nonmeningitic patients; three of four (75%) had open-set speech recognition. Performance of patients with total drill-out was poor; "auditory only" performance was limited to detection and pattern perception of speech, and no patients had open-set speech recognition. Results for patients with partial drill-out were similar to results in patients with no bone growth. Labyrinthitis ossificans not only presents surgical challenges to cochlear implantation but may also adversely affect hearing outcome.

Recognition of a dominant epitope in bovine heat-shock protein 70 in inner ear disease.

OBJECTIVE: To investigate the specificity of antibodies to heat-shock protein 70 (HSP70) in patients with idiopathic, progressive, bilateral sensorineural hearing loss (IPBSNHL) and Meniere disease. STUDY DESIGN: Test immunoreactivity of patients' sera using recombinant human (rh) and bovine (rb) HSP70, as well as segments representing different regions of bovine HSP70 as antigen. METHODS: Sera were tested by Western blotting. RESULTS: Of 52 patients with IPB-SNHL, 40 sera reacted only with rbHSP70; 12 reacted with both rbHSP70 and rhHSP70. Sera from 13 patients with IPBSNHL and from 8 with Meniere disease were tested on the panel of bovine HSP70 segments. Eleven and 7 samples, respectively, reacted with amino acid segment 427-461 from the carboxy (C)-terminal region of the molecule. CONCLUSION: In IPBSNHL and Meniere disease, antibodies are directed primarily against an epitope(s) within the C-terminal region of HSP70 where diversity in sequence among different species, including possible pathogens, is greatest. These findings may provide clues to the pathogenesis or specific serodiagnosis (or both) of diseases of the inner ear.

Efficacy of tympanomastoid surgery for control of infection in active chronic otitis media.

The efficacy of surgery in controlling infection in 272 tympanomastoidectomy procedures for chronic otitis media (COM) was assessed by means of a four-point rating scale that incorporated both symptoms and signs, such as the presence or absence of otorrhea and granulation tissue. Of the 272 procedures, 170 were performed for COM with cholesteatoma and 102 were for active COM with granulation tissue but no cholesteatoma. Forty-seven percent were primary procedures, and 53% were revisions. Minimum follow-up was 12 months for all cases, with a mean of 30 months. Adequate control of infection occurred in 248 (91%) of the 272 cases. Of the 24 cases (9%) that developed persistent infection, 10 were controlled with a combination of oral and topical antibiotics and/or delayed skin grafting in the office. Thus overall satisfactory control of infection was achieved in 258 of 272 cases (95%). The outcome was influenced by the diagnostic category of COM: COM with cholesteatoma did significantly better than COM with granulation tissue (P = 0.02). The outcome was not influenced by the following variables: primary versus revision surgery, canal wall-up versus canal wall-down surgery, and extent of disease. The results suggest that active COM with granulation tissue may be more difficult to control than COM with cholesteatoma.

Revision stapedectomy: intraoperative findings, results, and review of the literature.

Seventy-four revision stapedectomies performed consecutively over 10 years (1986 to 1995) were reviewed retrospectively. The most common intraoperative findings were incus erosion, prosthesis displacement, and oval window closure. Incus erosion was more frequently associated with multiple revisions. The postoperative results were reported using the conventional method (postoperative air minus preoperative bone) as well as the guidelines recently published by the American Academy of Otolaryngology--Head and Neck Surgery (postoperative air minus postoperative bone), with success rates of postoperative air-bone gap closure to within 10 dB after revision surgery of 51.6% and 45.6%, respectively. Patients with persistent conductive hearing loss (large residual air-bone gaps) after primary stapedectomy had poorer postrevision hearing results. Sensorineural hearing loss (defined as a drop in bone pure-tone average of more than 10 dB) occurred in four cases (5.4%). The number of revision surgeries, variations in operative techniques using laser or drill, and the ossicle to which the prosthesis was attached did not statistically affect the postoperative air-bone gaps. These results were compared with previously published data.

Serum antibodies to heat shock protein 70 in sensorineural hearing loss.

OBJECTIVE: To identify the 68-kd target of antibody in serum samples from patients with idiopathic, progressive, bilateral sensorineural hearing loss. DESIGN: To purify target protein from renal extracts using gel filtration, ion-exchange chromatography, and polyacrylamide gel electrophoresis and to transfer to nitrocellulose membranes. The purified protein was digested with trypsin, and peptide fragments were separated by high-pressure liquid chromatography. RESULTS: One fraction obtained by high-performance liquid chromatography contained a peptide of 2776 molecular weight. The sequence of a stretch of 22 amino acids within this peptide was identical to that of amino acids 424 through 445 of heat shock protein 70 (HSP70). On Western blotting, monoclonal antibody directed against HSP70 (but capable of recognizing both constitutive HSP70 [HSC70] and stress-inducible HSP70) reacted with the purified 68-kd protein. We compared the reactivity of serum samples from six patients with idiopathic, progressive, bilateral sensorineural hearing loss, as well as monoclonal antibody to HSC70, and monoclonal antibody to HSP70 with renal extract. The pattern obtained suggested that patient antibodies are preferentially directed at HSP70. CONCLUSION: The target of antibody in serum samples from patients with idiopathic, progressive, bilateral sensorineural hearing loss is HSP70.

The National Temporal Bone, Hearing, and Balance Pathology Resource Registry.

The National Temporal Bone, Hearing, and Balance Pathology Resource Registry has been established with funding provided by the National Institute on Deafness and Other Communication Disorders of the National Institutes of Health. The registry is meant to serve as a national resource for researchers and the public to stimulate and facilitate human otopathologic research. It will maintain a computerized database of currently active and inactive temporal bone and auditory brain-stem collections throughout the United States. In addition, it will encourage human temporal bone research by disseminating pertinent information, developing and fostering temporal bone professional educational activities, implementing a national temporal bone acquisition network, and encouraging investigative collaborations in the study of the human temporal bone and brain structures. It will also identify otopathologic collections at risk of being discarded or lost and will develop mechanisms and strategies to conserve them.

Perilymph fistula pathophysiology.

A great deal of the controversy associated with perilymph fistula is due to the lack of a sensitive, specific way of detecting and thus diagnosing one. The existing subjective, clinical observations need to be replaced with an objective, scientific methodology having higher specificity and sensitivity for the detection of perilymph fistula. Three detection methods presently under development are presented here. One uses a miniendoscope to observe the middle ear. This procedure is less traumatic than inspection with tympanotomy. Thus it is less likely to create artifacts that can be mistaken for a fistula leakage. The "yes-no" observation decision is to be replaced with a graded quantitative measure. The second method concentrates on detected leakage from inner to middle ear. beta 2-Transferrin, a unique endogenous substance found in perilymph and cerebrospinal fluid, can be detected with one- or two-dimensional gel electrophoresis and immunoblotting. The third method is a system identification fistula test. It measures a change in a physiologic response that is caused by the presence of the fistula. Classic biophysical models of the vestibular end organs can be used to predict the dynamics of responses to systems identification stimuli.

Significance of auditory brain stem response and gadolinium-enhanced magnetic resonance imaging for idiopathic sudden sensorineural hearing loss.

Previous studies tried to correlate prognosis and response to oral corticosteroids in patients with idiopathic sudden sensorineural hearing loss to such factors as the age of the patient, presence of vertigo, shape of the audiogram, or severity of the hearing loss. However, temporal bone histopathologic evidence shows that idiopathic sudden sensorineural hearing loss may be caused by cochleitis or cochlear nerve neuritis. Herein we report results of a retrospective study of 96 consecutive patients with idiopathic sudden sensorineural hearing loss who were evaluated with auditory brain stem responses and gadolinium-enhanced magnetic resonance imaging. Results of the auditory brain stem response and magnetic resonance imaging were correlated with hearing outcome. Follow-up was available for 65 patients: 14 with abnormal and 51 with normal auditory brain stem responses. The overall rate of hearing recovery or improvement was 65% in the normal auditory brain stem response group compared with 43% in the abnormal auditory brain stem response group (p = 0.07). Among the 38 patients treated with a tapering course of oral corticosteroids, the recovery or improvement rate was 83% for those with normal auditory brain stem responses and 56% for those with abnormal auditory brain stem responses (p < 0.05). Of the 27 patients who did not receive steroid therapy, the improvement rate was 41% in those with normal auditory brain stem responses and 20% in those with abnormal auditory brain stem responses (p = 0.09). Magnetic resonance imaging with gadolinium was obtained on all 14 patients with abnormal auditory brain stem responses but on none with normal auditory brain stem responses.(ABSTRACT TRUNCATED AT 250 WORDS)

Videolaryngoscopy in the office--a critical evaluation.

In view of the growing popularity of office videolaryngoscopy, surprisingly little objective data exist as to its influence on clinical practice. We reviewed 150 consecutive laryngeal recordings in an attempt to determine what effect videolaryngoscopy has had on our practice and the patient care provided.

Toronto Facial Grading System: interobserver reliability.

The Toronto Facial Grading System (TFGS) is an observer scale for rating facial nerve dysfunction. The TFGS scores aspects of resting symmetry, symmetry of voluntary movement, and synkinesis for each division of the face (subscores) and then provides calculated total scores and an overall composite score of facial function. The developers of the scale have validated its sensitivity for identifying small changes in facial dysfunction and the independence of the different components measured. Herein we report our results in a study of interobserver reliability using the TFGS. Twenty-five patients from the Massachusetts Eye and Ear Infirmary Facial Nerve Center with varying degrees of facial paresis, paralysis, and synkinesis were videotaped, and the video recordings were scored by 5 independent observers using the TFGS. Intraclass correlation coefficients (kappa) and 95% confidence intervals were calculated for subscores and for each total and composite score. Intraclass correlation coefficients ranged from 0.59 to 0.85, all considered substantial to near-perfect agreement between observers. We believe the TFGS is superior to other scales by virtue of its sensitivity, comprehensiveness, ease of use, and interobserver reliability. The TFGS presently appears to be the best option in those situations in which accurate and precise documentation of facial function is required.

Malformation and degeneration in the inner ear of mos transgenic mice.

Transgenic mice carrying the mos proto-oncogene linked to a retroviral transcriptional control sequence display behavioral abnormalities including circling, hyperactivity, head tilt, and bobbing. Axonal degeneration, neuronal chromatolysis, spongiform encephalopathy, gliosis, and inflammatory infiltrates are reportedly found in the central nervous systems of all mutants with the behavioral traits. Hearing was tested by means of broadband free-field rarefaction clicks with auditory brain stem response recorded between vertex and mouth electrodes. No detectable auditory response was elicited in transgenic animals, in contrast to five distinct positive peaks observed in littermate control animals. Light microscopic survey of temporal bone histopathology in mutants revealed extensive degeneration of the organ of Corti with loss of hair cells in all cochlear turns and loss of supporting cells and atrophy of spiral ganglion cells. The spiral limbus was deformed, with replacement of the usual convexity of the superior surface by a flattened trough configuration. Hair cells of the vestibular end organs appeared normal. Pathologic alteration in levels of mos transgene RNA appears to have a direct effect on the structural integrity of the inner ear.

Bovine temporal bones as a source of inner ear antigen.

Modern immunologic techniques of immunostaining, immunoblotting, and creation of monoclonal antibodies are gaining wide application in studies of development, function, and pathology of the ear. These techniques require a source of inner ear tissue for production of antigen extract. Human tissue is not readily available, and other mammalian species common in auditory research are small in size. Bovine temporal bones are readily available, and the membranous portions of the inner ear are abundant and easily accessible. Herein we report our technique for acquisition and dissection of bovine temporal bones and preparation and preservation of inner ear antigen.

High jugular bulb: implications for posterior fossa neurotologic and cranial base surgery.

The suboccipital-retrosigmoid approach to the internal auditory canal and cerebellopontine angle is being used with increasing frequency for neurotologic surgery, including vestibular nerve section and resection of acoustic neuroma. It offers wide exposure of the cerebellopontine angle and the cranial nerve VII-VIII complex as it courses from the brain stem to the temporal bone. Exposure of the internal auditory canal can be achieved by removing its posterior bony wall. Safe utilization of this approach requires familiarity with the variable position of structures within the petrous bone, including the lateral venous sinus and jugular bulb. We report here a case in which bleeding resulted from injury to a high jugular bulb during surgical exposure of the internal auditory canal via the suboccipital route and discuss the regional anatomy of the jugular bulb based on study of 378 consecutive temporal bone specimens from the collection of the Massachusetts Eye and Ear Infirmary. High jugular bulb was defined as encroachment of the dome of the bulb within 2 mm of the floor of the internal auditory canal. Forty-six percent of scoreable specimens met this criterion. However, when donors less than 6 years of age were excluded, a high jugular bulb was identified in 63% of specimens. Relevance to neurotologic surgery of the posterior fossa is presented.

Meniere's syndrome and endolymphatic hydrops. Double-blind temporal bone study.

A systematic double-blind assessment of case histories and histopathologic findings in temporal bones in the collection at the Massachusetts Eye and Ear Infirmary was performed to test the hypothesis that clinical Meniere's syndrome is associated with endolymphatic hydrops demonstrated histopathologically at death. Thirteen of 13 cases of clinical Meniere's syndrome were found to have endolymphatic hydrops not attributable to other causes. However, some patients with idiopathic endolymphatic hydrops did not exhibit clinical Meniere's syndrome as revealed in their medical records. These results challenge the dogma that endolymphatic hydrops per se generates the symptoms of Meniere's syndrome.