Joni K. Doherty

Meniere's disease: prevalence of contralateral ear involvement.

Objective: Determine the prevalence and time interval for conversion from unilateral to bilateral involvement in Menieres disease and cochlear hydrops. Study Design and Setting: Retrospective chart review in a tertiary otologic referral center. Patients: 232 patients diagnosed with Menieres Disease (n = 186) or cochlear hydrops (n = 46) between 1959 and 2001, who visited the clinic over a five-year period between 1997-2001 and have at least 2 audiograms more than 12 months apart. Main Outcome Measures: Prevalence of cochlear hydrops relative to Menieres Disease, rate of progression from unilateral to bilateral involvement; interval between unilateral onset of symptoms and bilateral involvement; and rate of progression from cochlear hydrops to Menieres disease. Results: Initial diagnosis was Menieres disease in 71% and cochlear hydrops in 29% of all 950 hydropic patients presenting between 1997 and 2001. In the study sample, Menieres disease was bilateral at presentation in 11%; an additional 12% (14% of unilaterals) became bilateral during the follow-up period. At presentation, 6.5% of cochlear hydrops patients were bilateral, with another 26% becoming bilateral. Conversion from cochlear hydrops to Menieres disease occurred in 33% and some of these are included among the bilateral. The average time interval for conversion from unilateral to bilateral Menieres was 7.6 years (SD = 7.0 years). Conclusion: Most otologists are aware of the potential for contralateral ear involvement and conversion from cochlear hydrops to Menieres disease after diagnosis. These changes are significant, require long-term follow-up for detection, and may necessitate further treatment. Patients should be counseled regarding this potential when interventions are considered, especially with respect to ablative treatments.

Autologous Fat Grafting for the Refractory Patulous Eustachian Tube

The patulous eustachian tube (pET) presents a challenging management problem. Patients with the pET disorder are disturbed to the point of mental illness by their symptoms of aural fullness and autophony, especially the echo of their own voice. Thus far, described treatment methods are often temporary or ineffective. Here, we describe a minimally invasive method for the treatment of pET that involves cauterization with autologous fat graft plugging of the ET at its nasopharyngeal orifice, in conjunction with myringotomy and ventilation tube placement. This procedure has been successful for the treatment of refractory pET in 2 patients at the House Ear Clinic with at least 1-year follow-up and we propose that it may accomplish relief of symptoms by permanent stenosis of the ET.

Concordance of bilateral vestibular schwannoma growth and hearing changes in neurofibromatosis 2: neurofibromatosis 2 natural history consortium.

Objective: To examine the relationship between the amount of change in size and associated hearing in bilateral vestibular schwannomas (VSs) in persons with neurofibromatosis 2 (NF2). Study Design: Annual magnetic resonance imaging and audiological examinations were conducted on NF2 patients. Subjects: Fifty-two patients enrolled in the NF2 Natural History Consortium in whom both VSs were untreated. Magnetic resonance imaging and hearing exams were available for at least 2 time points 1 year apart. The 32 males and 20 females had a mean age at diagnosis of 26 years (SD = 18). In 19 (37%) subjects, the NF2 germline mutation could not be identified in the blood (mosaic). Outcome Measures: Greatest diameter change in tumor size for each of the 2 tumors from first to second evaluation was determined. Differences in amounts of change between the 2 sides and in hearing (4-frequency pure-tone average) were evaluated using multivariate analysis of variance. Results: Overall, the VSs demonstrated significant average growth (p < 0.001), and hearing worsened significantly (p < 0.001) over 1 year. The amount of change in the bigger tumors was not associated with the amount of change in the smaller tumors within each patient. Vestibular schwannoma size changes were not associated with the corresponding hearing changes (Kendalls &tgr;, p = not significant [n.s.]). Conclusion: A significant 1-year change in VS size and hearing occurred in NF2 patients. Clinically, tumor change or hearing deterioration on one VS cannot be used to predict changes in the other VS. This suggests that, although NF2 is a Mendelian disease, the germline genotype-phenotype relationship may resemble that of complex disorders.

ErbB and Nrg: potential molecular targets for vestibular schwannoma pharmacotherapy.

Objective: Identify molecular targets for development of tumor-specific pharmacotherapeutics aimed at treating vestibular schwannomas (VSs). Activated epidermal growth factor receptor B (ErbB) 2 and ErbB3 are abundantly expressed in VS. ErbB2 signaling is essential for Schwann cell differentiation, survival, and proliferation. VS arise after loss of functional merlin, a putative tumor suppressor. Merlin internalizes ErbB2 receptors in rodent Schwann cells.Unregulated ErbB signaling may contribute to VS tumorigenesis. Study Design: Molecular analyses, retrospective clinical correlation. Setting: Tertiary referral center. Patients: Thirty-eight specimens from patients operated for sporadic (n = 21) and neurofibromatosis (NF) 2-related (n = 17) VS. Intervention(s): VS analyses via real-time polymerase chain reaction, immunohistochemistry, and correlation with patient clinical data. Main Outcome Measure(s): ErbB signaling molecule expression, tumor size, age, and NF2 status. Results: VS upregulated epidermal growth factor (EGF) receptor in 68% (62% sporadic and 75% NF2-associated VS) and ErbB2 in 84% (76% sporadic and 94% NF2-related VS). ErbB3 was upregulated in 34%, and ErbB4 is downregulated in NF2-related VS. Of EGF receptor (EGFR) ligands, EGF was upregulated in all NF2-related VS, but none of the sporadic VS (p < 0.01), and transforming growth factor &agr; and &bgr;-cellulin showed upregulation in 67% of NF2-related VS but not sporadic VS (p = 0.02 and p = 0.01, respectively). Neuregulin (Nrg) was upregulated in 86% of sporadic VS versus 19% of NF2-related VS (p < 0.01). EGFR expression levels correlated directly with VS tumor size and inversely with patient age, whereas Nrg expression correlated directly with age (p = 0.0005). EGF expression predicts NF2 status, whereas Nrg predicts non-NF2 status (p < 0.01). Conclusion: These findings implicate the ErbB pathway in VS growth and as potential molecular targets for VS pharmacotherapy.

Round window versus cochleostomy technique in cochlear implantation: histologic findings.

Hypothesis Cochleostomy or round window enlargement techniques for cochlear implant electrode insertion result in more abnormal tissue formation in the basal cochlea and are more apt to produce endolymphatic hydrops than round window electrode insertion. Methods Twelve temporal bones from implanted patients were examined under light microscopy and reconstructed with 3-dimensional reconstruction software to determine cochlear damage and volume of neo-ossification and fibrosis after electrode insertion. Amount of new tissue was compared between 3 groups of bones: insertion through the round window (RW), after enlarging the RW (RWE) and cochleostomy (Cochl). The probable role of the electrode was evaluated in each case with hydrops. Results More initial damage occurred in the Cochl and RWE groups than in the RW group, and the difference was significant between RWE and RW in cochlear segment I (p < 0.026). The volume of new bone in Segment I differed significantly between groups (p < 0.012) and was greater in the RWE group than in either the Cochl or RW groups (post hoc p’s < 0.035 and 0.019, respectively). Hydrops was seen in 5 cases, all in the Cochl and RWE groups. Blockage of the duct was because of new tissue formation in 4 of the 5 hydrops cases. Conclusion With the electrodes in this series, implantation through the RW minimized initial intracochlear trauma and subsequent new tissue formation, whereas the RW extension technique used at the time of these implantations produced the greatest damage. Future studies may clarify whether today’s techniques and electrodes will produce these same patterns of damage.

Spiral ligament and stria vascularis changes in cochlear otosclerosis: effect on hearing level.

Objective: To investigate the effect of changes within the spiral ligament and stria vascularis on hearing in cochlear otosclerosis, we examined spiral ligament hyalinization, stria vascularis atrophy, and sensory hearing loss in cochlear otosclerosis and described changes in ion transport molecule expression. Study Design: Retrospective. Setting: Tertiary referral center. Patients: Thirty-two cochleae from 24 temporal bone donors with histologic evidence of cochlear otosclerosis, including spiral ligament hyalinization. Intervention: Audiography. Main Outcome Measures: Measurements of spiral ligament width, stria vascularis, and bone-conduction thresholds were compared by the amount of hyalinization. Expression of the ion transport molecules Na,K-ATPase, connexin 26, and carbonic anhydrase II were assessed by immunohistochemical techniques. Results: Hyalinization most often involved the posterior basal turn (88%) and the posterior middle turn (27%). Spiral ligament hyalinization correlated significantly with stria vascularis atrophy in the posterior middle turn of the cochlea (ρ = −0.63, p < 0.01). There was a trend toward a significant association in the posterior basal turn (ρ = −0.31, p < 0.08). Bone-conduction thresholds at 2,000 and 4,000 Hz were significantly associated with the amount of stria vascularis atrophy (ρ = −0.44, −0.40, p < 0.05). In addition, we observed decreased immunostaining for both carbonic anhydrase II with Type I fibrocytes and Na,K-ATPase with stria vascularis and Type II and Type IV fibrocytes of the spiral ligament in cochlear otosclerosis sections compared with normal cochlea. Na,K-ATPase staining within the stria vascularis was further decreased in the presence of spiral ligament hyalinization. No significant differences were seen with connexin 26 immunostaining. However, immunostaining results were somewhat inconsistent. Conclusion: These data suggest that spiral ligament structure and function are essential for stria vascularis survival. In addition, dampened expression of ion transport molecules within the spiral ligament and stria vascularis may disrupt potassium ion recycling, resulting in loss of endocochlear potential and sensory hearing loss.

Distribution of Nonvestibular Cranial Nerve Schwannomas in Neurofibromatosis 2

Objective: To describe the prevalence and location of cranial nerve schwannomas, other than bilateral vestibular schwannoma, in patients with neurofibromatosis 2 (NF2). The NF2 Natural History Consortium prospectively gathered cranial magnetic resonance imaging for 83 patients across 3 annual evaluations. The time between the first and last evaluation was approximately 3 years. Results: Forty-two patients (51%) had nonvestibular cranial nerve schwannomas (NVSs). Of these, 25 (60%) also had cranial meningiomas. Twenty-one of those without NVS (25% of 83) had at least 1 meningioma. The average size of the NVS was 0.4 cm3. Overall, there was no significant change in NVS size from Year 1 to Year 3 or from Year 1 to Year 2. The most common locations of the NVS were occulomotor and trigeminal. A family history of NF2 did not predict NVS location or growth. Conclusion: Nonvestibular cranial nerve schwannoma usually affect cranial nerves III and V, as was the case in our NF2 sample. Fortunately, neuropathies associated with these tumors are rare. In contrast, lower cranial nerve schwannomas, although also rare, are associated with swallowing difficulty, aspiration, and other sequelae.

Egf and bfgf Promote Invasion That Is Modulated by Pi3/akt Kinase and Erk in Vestibular Schwannoma

Objectives: Vestibular schwannomas (VSs) are slow-growing benign tumors but, on rare occasion, can invade adjacent cranial nerves, causing significant morbidity, especially in association with neurofibromatosis 2 (NF2). We aimed to determine the role of the growth factors EGF, bFGF, and the hormone, Epo, in promoting such invasive behavior in VS, as well as their mechanisms of action. Methods: Immunohistochemical staining showed expression of EGFR, bFGF, Epo, EpoR in archived VS tissue. Western blots and immunofluorescence showed expression of EGFR, EpoR and FGF in HEI-193, an immortalized cell line derived from human NF2-related VS. Matrigel invasion assays were used to study the effect of Epo, FGF and bFGF on invasive behavior in HEI-193. Western blotting showed levels of phospho-Akt and phospho-Erk in HEI-193 upon addition of growth factors plus PI3K or MEK inhibitors. Quantitative RT-PCR was performed to determine the expression of MMP2 and MMP9 after treatment with growth factors. Results: EGFR, bFGF, Epo and EpoR were expressed in VS tissue and HEI193. Addition of EGF and bFGF increased cellular invasion by 10 and 3.5-fold, respectively. Epo had minimal effect on invasion. Results indicated that Erk is involved in bFGF but not EGF-induced invasion, while Akt is involved in both pathways. EGF treatment moderately induced MMP9, but is unlikely to account for the observed invasion. Conclusion: Activation of EGFR and FGFR may promote invasive behavior in VS through ERK and Akt signaling pathways. Further investigation will be necessary to elucidate their potential as useful targets in the treatment of VS.

CPA melanoma: diagnosis and management.

Melanoma rarely invades the cerebellopontine angle (CPA) and can evade accurate diagnosis, which may alter management decisions. Diagnosis may be facilitated via careful history, magnetic resonance imaging (MRI) findings, and cerebrospinal fluid (CSF) analysis. Study Design: Retrospective case review. Setting: Tertiary referral center. Patients: Thirteen internal auditory canal/CPA lesions in eight patients who presented with CPA syndrome and who had a pathological diagnosis consistent with malignant melanoma. There were four bilateral and four unilateral lesions. Six of eight patients had a history of melanoma. One was apparently primary CPA lesion, whereas all others were metastatic. Intervention(s): T1- and T2-weighted precontrast and postcontrast gadolinium-enhanced MRI were obtained, including fat suppression and fluid-attenuated inversion recovery sequence images in two patients; lumbar puncture with CSF centrifugation and cytological analysis confirmed the diagnosis in two patients. Translabyrinthine craniotomy was performed for tumor extirpation in five patients. Main Outcome Measure(s): Symptoms at presentation, MRI findings, presence of malignant cells in CSF, tumor progression, intraoperative findings, response to treatment, time interval from initial diagnosis of melanoma elsewhere, and survival. Results: Seven of eight patients had history and/or MRI findings suggestive of malignancy in the internal auditory canal and/or CPA, and diagnosis was confirmed via CSF analysis in two patients. In one patient, diagnosis was made at surgery. Conclusion: Internal auditory canal melanoma portends a grim prognosis, can occur up to 17 years after initial melanoma diagnosis/treatment, and can be detected with appropriate MRI sequences, especially enhanced fluid-attenuated inversion recovery images. In disseminated cases, diagnosis can be confirmed with lumbar puncture demonstrating malignant cells. Management includes tumor resection when melanoma seems to be solitary and malignant cells are not present in CSF. Intrathecal chemotherapy and radiation are recommended for dissemination, although the survival rate is still poor.

Comparative case series of exostoses and osteomas of the internal auditory canal.

Exostoses and osteomas are benign bony lesions of the auditory canal. Although common in the external auditory canal, they are rare and difficult to distinguish in the internal auditory canal (IAC). In this literature review and case presentation, we define radiologic and histologic criteria to differentiate exostoses from osteomas of the IAC. Two patients with exostoses and 1 patient with an osteoma of the IAC are described here. Patient 1 presented with disabling vertigo and was found to have bilateral exostoses with nerve impingement on the right. After removal of the right-sided exostoses via retrosigmoid craniotomy, the patient had complete resolution of her symptoms over 1 year. Patient 2 presented with bilateral pulsatile tinnitus and vertigo and was found to have bilateral IAC exostoses. Patient 3 presented with hearing loss and tinnitus, and a unilateral IAC osteoma was ultimately discovered. Because of the mild nature of their symptoms, patients 2 and 3 were managed without surgery. We show that IAC osteomas can be differentiated from exostoses by radiographic evidence of bone marrow in high-resolution computed tomography scans, or by the presence of fibrovascular channels on histologic analysis. Management of these rare entities is customized on the basis of patient symptoms.