Improvement in Patient-reported Hearing After Treatment With Bevacizumab in People With Neurofibromatosis Type 2.

OBJECTIVE: Assess patient-reported outcomes (PRO) for hearing and tinnitus relative to clinical hearing assessment in people with neurofibromatosis 2 (NF2) associated hearing loss. STUDY DESIGN: Prospective, open label, phase-II clinical trial with PRO administered pre-, post-, and after treatment. SETTING: Three tertiary referral centers. PATIENTS: Fourteen patients with NF2, median age of 30 years (range, 14-79 yr) and progressive hearing loss (median baseline word recognition score, 60%; range, 13-82%). Half of these patients achieved objective hearing response (word recognition score improved beyond the 95% critical difference versus baseline). INTERVENTION: Bevacizumab 7.5 mg/kg was administered every 3 weeks for 48 weeks, followed by surveillance for 24 weeks off-drug. MAIN OUTCOME MEASURES: Speech, spatial, and qualities of hearing scale (SSQ) and tinnitus reaction questionnaire (TRQ) to assess hearing difficulties in life situations and tinnitus related distress. RESULTS: Patient-reported speech understanding and auditory quality improved with bevacizumab treatment and were significantly correlated with word recognition scores, but not pure tone threshold average. There was no change in spatial perception after treatment. Reduction in tinnitus distress after treatment with bevacizumab did not reach statistical significance. CONCLUSION: Participants had reductions in hearing difficulty during treatment with bevacizumab, suggesting that patients subjectively experience hearing-related benefit mirroring clinical hearing assessments. We suspect the lack of significant reduction in tinnitus distress is related to small sample size and low intensity of distress in our sample. These data highlight the usefulness of PRO measures to assess benefits of treatment in the setting of NF2-associated hearing loss.

Efficacy and Biomarker Study of Bevacizumab for Hearing Loss Resulting From Neurofibromatosis Type 2-Associated Vestibular Schwannomas.

PURPOSE: Neurofibromatosis type 2 (NF2) is a tumor predisposition syndrome characterized by bilateral vestibular schwannomas (VSs) resulting in deafness and brainstem compression. This study evaluated efficacy and biomarkers of bevacizumab activity for NF2-associated progressive and symptomatic VSs. PATIENTS AND METHODS: Bevacizumab 7.5 mg/kg was administered every 3 weeks for 46 weeks, followed by 24 weeks of surveillance after treatment with the drug. The primary end point was hearing response defined by word recognition score (WRS). Secondary end points included toxicity, tolerability, imaging response using volumetric magnetic resonance imaging analysis, durability of response, and imaging and blood biomarkers. RESULTS: Fourteen patients (estimated to yield > 90% power to detect an alternative response rate of 50% at alpha level of 0.05) with NF2, with a median age of 30 years (range, 14 to 79 years) and progressive hearing loss in the target ear (median baseline WRS, 60%; range 13% to 82%), were enrolled. The primary end point, confirmed hearing response (improvement maintained ≥ 3 months), occurred in five (36%) of 14 patients (95% CI, 13% to 65%; P < .001). Eight (57%) of 14 patients had transient hearing improvement above the 95% CI for WRS. No patients experienced hearing decline. Radiographic response was seen in six (43%) of 14 target VSs. Three grade 3 adverse events, hypertension (n = 2) and immune-mediated thrombocytopenic purpura (n = 1), were possibly related to bevacizumab. Bevacizumab treatment was associated with decreased free vascular endothelial growth factor (not bound to bevacizumab) and increased placental growth factor in plasma. Hearing responses were inversely associated with baseline plasma hepatocyte growth factor (P = .019). Imaging responses were associated with high baseline tumor vessel permeability and elevated blood levels of vascular endothelial growth factor D and stromal cell-derived factor 1α (P = .037 and .025, respectively). CONCLUSION: Bevacizumab treatment resulted in durable hearing response in 36% of patients with NF2 and confirmed progressive VS-associated hearing loss. Imaging and plasma biomarkers showed promising associations with response that should be validated in larger studies.

Hearing and facial function outcomes for neurofibromatosis 2 clinical trials.

OBJECTIVES: Vestibular schwannomas are the hallmark of neurofibromatosis 2 (NF2), occurring in >95% of patients. These tumors develop on the vestibulocochlear nerve and are associated with significant morbidity due to hearing loss, tinnitus, imbalance, facial weakness, and risk of early mortality from brainstem compression. Although hearing loss and facial weakness have been identified as important functional outcomes for patients with NF2, there is a lack of consensus regarding appropriate endpoints in clinical trials. METHODS: The functional outcomes group reviewed existing endpoints for hearing and facial function and developed consensus recommendations for response evaluation in NF2 clinical trials. RESULTS: For hearing endpoints, the functional group endorsed the use of maximum word recognition score as a primary endpoint, with the 95% critical difference as primary hearing outcomes. The group recommended use of the scaled measurement of improvement in lip excursion (SMILE) system for studies of facial function. CONCLUSIONS: These recommendations are intended to provide researchers with a common set of endpoints for use in clinical trials of patients with NF2. The use of common endpoints should improve the quality of clinical trials and foster comparison among studies for hearing loss and facial weakness.

Audiology in the sudden hearing loss clinical trial.

OBJECTIVE: To report the pretreatment and posttreatment population characteristics and the overall stability of the audiologic outcomes found during the Sudden Hearing Loss Clinical Trial (ClinicalTrials.gov: Identifier NCT00097448). STUDY DESIGN: Multicenter, prospective randomized noninferiority trial of oral versus intratympanic (IT) steroid treatment of sudden sensorineural hearing loss (SSNHL). SETTING: Fifteen academically based otology practices. PATIENTS: Two hundred fifty patients with unilateral SSNHL presenting within 14 days of onset with 50 dBHL or greater pure tone average hearing threshold in the affected ear. INTERVENTION: Either 60 mg/d oral prednisone for 14 days with a 5-day taper (121 patients) or 4 IT doses for 14 days of 40 mg/ml methylprednisolone (129 patients). MAIN OUTCOME MEASURE: Primary end point was change in hearing [dB PTA] at 2 months after treatment. Noninferiority was defined as less than 10 dB difference in hearing outcome between treatments. In this article, pretreatment and posttreatment hearing findings will be reported in detail. RESULTS: A general (and stable) effect of treatment and a specific effect of greater improvement at low frequencies were found in both treatment groups. CONCLUSION: Hearing improvements are stable, and a significantly greater improvement occurs with lower frequency after either oral or IT steroid treatment of SSNHL.

Bevacizumab for progressive vestibular schwannoma in neurofibromatosis type 2: a retrospective review of 31 patients.

OBJECTIVE: Early studies suggest that bevacizumab treatment can result in tumor shrinkage and hearing improvement for some patients with neurofibromatosis type 2 (NF2). The aim of this study was to report extended follow-up in a larger cohort of similarly treated patients. STUDY DESIGN: Retrospective study. SETTING: Tertiary referral center PATIENTS: Thirty-one consecutive NF2 patients who received bevacizumab for progressive vestibular schwannomas. MAIN OUTCOME MEASURE: Hearing improvement, defined as an improvement in word recognition score above the 95% critical difference compared with baseline, and radiographic response, defined as a 20% or greater decrease in tumor volume compared with baseline. RESULTS: The median age was 26 years (range, 12-73 yr). The median volumetric tumor growth rate before treatment was 64% per year. At the time of analysis, the median duration of treatment was 14 months (range, 6-41 mo) with a total of 47 patient-years of follow-up. A hearing response occurred in 57% (13/23) of evaluable patients and a radiographic response in 55% (17/31) of target vestibular schwannomas. The median time to response was 3 months for both end points. The only clinical or radiographic feature at baseline that correlated with change in tumor volume at 3 months was the mean apparent diffusion coefficient value, a radiologic marker of edema (p = 0.036). Ninety percent of patients had stable or improved hearing after 1 year of treatment and 61% at 3 years; 88% of patients had stable or decreased tumor size after 1 year of treatment and 54% at 3 years. Overall, treatment was well tolerated. CONCLUSION: Bevacizumab treatment was followed by hearing improvement and tumor shrinkage in more than 50% of progressive vestibular schwannomas in NF2 patients. Stable or improved hearing was retained in the majority of patients.

Improvement in word recognition score with level is associated with hearing aid ownership among patients with hearing loss.

Market surveys consistently show that only 22% of those with hearing loss own hearing aids. This is often ascribed to cosmetics, but is it possible that patients apply a different auditory criterion than do audiologists and manufacturers? We tabulated hearing aid ownership in a survey of 1000 consecutive patients. We separated hearing loss cases, with one cohort in which word recognition in quiet could improve with gain (vs. 40 dB HL) and another without such improvement but nonetheless with audiometric thresholds within the manufacturer's fitting ranges. Overall, we found that exactly 22% of hearing loss patients in this sample owned hearing aids; the same finding has been reported in many previous, well-accepted surveys. However, while all patients in the two cohorts experienced difficulty in noise, patients in the cohort without word recognition improvement were found to own hearing aids at a rate of 0.3%, while those patients whose word recognition could increase with level were found to own hearing aids at a rate of 50%. Results also coherently fit a logistic model where shift of the word recognition performance curve by level corresponded to the likelihood of ownership. In addition to the common attribution of low hearing aid usage to patient denial, cosmetic issues, price, or social stigma, these results provide one alternative explanation based on measurable improvement in word recognition performance.

Erlotinib for progressive vestibular schwannoma in neurofibromatosis 2 patients.

OBJECTIVE: In vitro treatment of Nf2-deficient cells with epidermal growth factor receptor (EGFR) inhibitors can reduce cellular proliferation. We sought to determine the activity of erlotinib for progressive vestibular schwannoma (VS) associated with neurofibromatosis 2 (NF2). STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Eleven NF2 patients with progressive VS who were poor candidates for standard therapy. INTERVENTION: Erlotinib 150 mg daily. MAIN OUTCOME MEASURES: A radiographic response was defined as >or= 20% decrease in tumor volume compared with baseline. A hearing response was defined as a statistically significant increase in word recognition score (WRS) compared with baseline; a minor hearing response was defined as a 10 dB improvement in pure-tone average with stable WRS. RESULTS: : Before treatment, the median and mean annual volumetric growth rate for 11 index VS were 26% and 46%, respectively. Among 10 evaluable patients, the median time-to-tumor progression was 9.2 months. Three patients with stable disease experienced maximum tumor shrinkage of 4%, 13%, and 14%. Nine patients underwent audiologic evaluations. One experienced a transient hearing response, 2 experienced minor hearing responses, 3 remained stable, and 2 developed progressive hearing loss. The median time-to-progressive hearing loss was 9.2 months and to either tumor growth or progressive hearing loss was 7.1 months. Adverse treatment effects included mild-to-moderate rash, diarrhea, and hair thinning, with 2 episodes of grade 3 toxicity. CONCLUSION: Erlotinib treatment was not associated with radiographic or hearing responses in NF2 patients with progressive VS. Because a subset of patients experienced prolonged stable disease, time-to-progression may be more appropriate than radiographic or hearing response for anti-EGFR agents in NF2-associated VS.

Hearing improvement after bevacizumab in patients with neurofibromatosis type 2.

BACKGROUND: Profound hearing loss is a serious complication of neurofibromatosis type 2, a genetic condition associated with bilateral vestibular schwannomas, benign tumors that arise from the eighth cranial nerve. There is no medical treatment for such tumors. METHODS: We determined the expression pattern of vascular endothelial growth factor (VEGF) and three of its receptors, VEGFR-2, neuropilin-1, and neuropilin-2, in paraffin-embedded samples from 21 vestibular schwannomas associated with neurofibromatosis type 2 and from 22 sporadic schwannomas. Ten consecutive patients with neurofibromatosis type 2 and progressive vestibular schwannomas who were not candidates for standard treatment were treated with bevacizumab, an anti-VEGF monoclonal antibody. An imaging response was defined as a decrease of at least 20% in tumor volume, as compared with baseline. A hearing response was defined as a significant increase in the word-recognition score, as compared with baseline. RESULTS: VEGF was expressed in 100% of vestibular schwannomas and VEGFR-2 in 32% of tumor vessels on immunohistochemical analysis. Before treatment, the median annual volumetric growth rate for 10 index tumors was 62%. After bevacizumab treatment in the 10 patients, tumors shrank in 9 patients, and 6 patients had an imaging response, which was maintained in 4 patients during 11 to 16 months of follow-up. The median best response to treatment was a volumetric reduction of 26%. Three patients were not eligible for a hearing response; of the remaining seven patients, four had a hearing response, two had stable hearing, and one had progressive hearing loss. There were 21 adverse events of grade 1 or 2. CONCLUSIONS: VEGF blockade with bevacizumab improved hearing in some, but not all, patients with neurofibromatosis type 2 and was associated with a reduction in the volume of most growing vestibular schwannomas.

Suggested response criteria for phase II antitumor drug studies for neurofibromatosis type 2 related vestibular schwannoma.

Neurofibromatosis type 2 (NF2) is a tumor suppressor gene syndrome characterized by multiple schwannomas, especially vestibular schwannomas (VS), and meningiomas. Anticancer drug trials are now being explored, but there are no standardized endpoints in NF2. We review the challenges of NF2 clinical trials and suggest possible response criteria for use in initial phase II studies. We suggest two main response criteria in such trials. Objective radiographic response is defined as a durable 20% or greater reduction in VS volume based on post-contrast T1-weighted MRI images collected with 3 mm or finer cuts through the internal auditory canal. Hearing response is defined as a statistically significant improvement in word recognition scores using 50-word recorded lists in audiology. A possible composite endpoint incorporating both radiographic response and hearing response is outlined. We emphasize pitfalls in response assessment and suggest guidelines to minimize misinterpretations of response. We also identify research goals in NF2 to facilitate future trial conduct, such as identifying the expectations for time to tumor progression and time to measurable hearing loss in untreated NF2-related VS, and the relation of both endpoints to patient prognostic factors (such as age, baseline tumor volume, and measures of disease severity). These data would facilitate future use of endpoints based on stability of tumor size and hearing, which might be more appropriate for testing certain drugs. We encourage adoption of standardized endpoints early in the development of phase II trials for this population to facilitate comparison of results across trials of different agents.

Hearing aids and cochlear damage: the case against fitting the pure tone audiogram.

Herein we propose a different approach to hearing aids, an approach that flows logically from the pathophysiology of cochlear disorders. This approach challenges some central tenets of the industry by 1) suggesting that many, if not most, cases would be better served by flat, undistorted gain across all frequencies rather than by "fitting" gain to the audiogram; and 2) suggesting that most of the improvements in hearing aid technology are targeted at reducing patient complaints as opposed to increasing measurable word recognition performance. We recommend that it is better to accommodate the damaged cochlea in these cases than to attempt to reverse-engineer the audiometric test results.

Clinical implications of a damaged cochlea: pure tone thresholds vs information-carrying capacity.

The pure tone audiogram is an accurate measure of auditory threshold as a function of stimulus frequency. However, it does not provide the complete picture in patients with sensorineural hearing loss (SNHL) because it is not a direct measure of damage to the cochlear epithelium or of the associated limits on information-carrying capacity that restrict word recognition. Diagnostic use of the audiogram leads to the error of viewing SNHL as "dB of hearing loss," which may seem reversible by gain. Cochlear disorders, on the other hand, often give rise to abnormal thresholds because regions are damaged and may best be thought of more in terms of intractable sensory limitations, comparable to vision loss in retinal disease. We argue that word recognition testing at low vs high presentation levels provides a quantification of the cochlea's information-carrying capacity and is a useful predictor of word recognition limits with hearing aids.

Twenty years of audiology in a patient with Norrie disease.

OBJECTIVE: To describe disease progression and treatment outcomes over a 20-year period (ages 5-25) in a young man with Norrie disease (occuloacousticocerebral dysplasia), ND; OMIM #310600. Affected individuals are born blind and develop progressive sensory loss with onset in adolescence. This disease is X-linked and has been associated with mutations of the NDP gene (Xp11.4). METHODS: The patient was followed using repeated audiograms, as well as reports of educational progress and hearing aid use. The specific mutation was found by molecular analysis. RESULTS: The patient demonstrated progressive sensory loss with good preservation of word recognition. The loss was initially high frequency and asymmetric in adolescence and became more severe, more symmetric and affected practically all frequencies by the end of childhood. Educational progress was affected by the cognitive effects of the syndrome, and hearing aid use was very effective. CONCLUSIONS: A bilateral progressive sensory loss with good preservation of word recognition was documented in detail. The residual word recognition supported good use of hearing aids in this case.

Audiologic and radiographic response of NF2-related vestibular schwannoma to erlotinib therapy.

BACKGROUND: A 48-year-old man presented to a neurologist with complaints of bilateral hearing loss and tinnitus. The patient was a member of a large family affected by neurofibromatosis type 2 and first noted hearing loss 10 years before presentation. INVESTIGATIONS: Medical and neurological examination, MRI scan of the brain and spinal cord, pure-tone audiometry, NU-6 monosyllabic word test with phoneme scoring, City University of New York topic-related sentences test, noise/voice test of minimal auditory capability battery. DIAGNOSIS: Progressive neurofibromatosis-type-2-related vestibular schwannomas. MANAGEMENT: Annual cranial MRI and audiology, surgical resection of right vestibular schwannoma, high-power behind-the-ear hearing aid, erlotinib therapy for progressive left vestibular schwannoma.

Incidence of responses at the lower audiometric limits.

PURPOSE: To put forward a symbol extension, consisting of an upward arrow added to current symbols, to denote that a patient continued to respond at the audiometric limit (i.e., -10 dB HL). Also, to present survey data to characterize the incidence of these responses. METHOD: A retrospective survey of 2,821 sequential audiometric evaluations was performed. Responses at the audiometric limits were counted, along with the stimulus conditions (i.e., transducer, frequency, and masking) and the age of the patient. RESULTS: A total of 307 instances of responses at the lower audiometric limits were seen in 173 of these cases (6.13%), with the majority by bone conduction. CONCLUSIONS: The overall rate of responses at the audiometric limits was low, as expected. However, these responses were primarily seen in the age group from 4 to 15 years, and at least one such response occurred in 26% of cases in that age range.

Using audiometric thresholds and word recognition in a treatment study.

OBJECTIVES: First, to examine a possible limit on significant results imposed by a progressive floor effect for hearing threshold improvement in a treatment study. This floor effect for hearing recovery suggests that if inclusion criteria are not set sufficiently high, the superiority of a treatment group may not be detectable. Second, to examine the outcomes when using two different types of criteria for significant change in a subject's word recognition score. METHODS: Several single-number criteria (e.g., 15 percentage points) are compared with the 95% (p=0.05) criteria from the binomial critical difference table for monosyllables. Critical differences for binomial variables change depending on whether the starting value lies in the middle (near 50% correct) or at either extreme of the range of scores (0 or 100%). Different judgments of significant word recognition improvement (or decrease) using binomial versus single-value criteria are presented. DATA SOURCE: A recent treatment study of sudden sensorineural hearing loss (n=318) is used to illustrate these effects. CONCLUSION: First, there is a progressive floor effect of presenting severity that co-varies with the outcome measure hearing threshold recovery. In some designs, this may act to constrain the ability to detect a significant difference. Second, in the example data set, the use of single-value criteria for significant within-subject change in word recognition (e.g., 15 percentage points) introduced a miscategorization error rate of approximately 9% when compared with the result of the binomial 95% critical difference table.

Audiologic features of Norrie disease.

OBJECTIVES: Norrie disease is an X-linked recessive disorder in which patients are born blind and develop sensory hearing loss in adolescence. The hearing loss associated with Norrie disease has been shown in a genetically altered knockout mouse to involve dysfunction of the stria vascularis; most other structures are preserved until the later stages of the disease. The objective of this study was to characterize the audiologic phenotype of Norrie disease for comparison with the pathophysiologic mechanism. METHODS: The design combined two series of clinical audiologic evaluations, with special attention to speech intelligibility. RESULTS: The audiologic results for 12 affected individuals and 10 carriers show that patients with Norrie disease retain high speech intelligibility scores even when the threshold loss is severe. CONCLUSIONS: The cochlear mechanism-- failure of the stria vascularis-- accounts for some of the higher values in the wide distribution of speech scores in cases with similar pure tone audiograms.

Oral steroid treatment of sudden sensorineural hearing loss: a ten year retrospective analysis.

OBJECTIVE: To describe ten years of experience with Sudden Sensorineural Hearing Loss and compare the outcomes with and without treatment with oral corticosteroids. STUDY DESIGN: Retrospective review of medical records. SETTING: Large specialty hospital, Department of Otolaryngology. PATIENTS: Patients presenting with sudden onset (72 hours) unilateral sensorineural hearing loss, with no evidence of Ménière's Disease, acoustic injury, retrocochlear disease, and other specifiable disorders. INTERVENTIONS: The majority of patients received a standard course of oral corticosteroids (Prednisone 60 mg and taper). A smaller group declined treatment. MAIN OUTCOME MEASURES: Recovery of hearing sensitivity was measured using standard audiometry and reported as change in Pure Tone Average. Word recognition scores were also analyzed. RESULTS: When severe-to-profound cases are analyzed, a significant improvement (p <.01) in Pure Tone Average is seen in cases treated with steroids versus those untreated. When milder cases are included, a statistical floor effect prevents differentiation of these groups. Word recognition scores were significantly improved (p <.05) in the treated group. CONCLUSIONS: Application of steroid medication significantly improves the recovery outcomes in cases of Severe Sudden Sensorineural Hearing Loss.

Vascular defects and sensorineural deafness in a mouse model of Norrie disease.

Norrie disease is an X-linked recessive syndrome of blindness, deafness, and mental retardation. A knock-out mouse model with an Ndp gene disruption was studied. We examined the hearing phenotype, including audiological, histological, and vascular evaluations. As is seen in humans, the mice had progressive hearing loss leading to profound deafness. The primary lesion was localized to the stria vascularis, which houses the main vasculature of the cochlea. Fluorescent dyes showed an abnormal vasculature in this region and eventual loss of two-thirds of the vessels. We propose that one of the principal functions of norrin in the ear is to regulate the interaction of the cochlea with its vasculature.