Jean-Pierre Lavieille

Introduction Although a broadband acoustic click is physically the shortest duration sound we can hear, its peripheral neural representation is not as short because of cochlear filtering. The traveling wave imposes frequency-dependent delays to the sound waveform so that in response to a click, apical nerve fibers, coding for low frequencies, are excited several milliseconds after basal fibers, coding for high frequencies. Nevertheless, a click sounds like a click and these across-fiber delays are not perceived. This suggests that they may be compensated by the central auditory system, rendering our perception consistent with the external world. This explanation is difficult to evaluate in normal-hearing listeners because the contributions of peripheral and central auditory processing cannot easily be disentangled. Here, we test this hypothesis in cochlear implant listeners for whom cochlear mechanics is bypassed. Method Eight cochlear implant users ranked in perceived duration 12 electrical chirps of various physical durations and spanning the cochlea in the apex-to-base or base-to-apex direction (Exp. 1). Late-latency cortical potentials were also recorded in response to a subset of these chirps (Exp. 2). Results We show that an electrical chirp spanning the cochlea from base-to-apex is perceived as shorter than the same chirp spanning the cochlea in the opposite direction despite having the same physical duration. Cortical potentials also provide neural correlates of this asymmetry in perception. Conclusion These results demonstrate that the central auditory system processes frequency sweeps differently depending on the direction of the frequency change and that this processing difference is not simply the result of peripheral filtering.

Presbycusis, or age-related hearing loss (ARHL), is a major public health issue. About half the phenotypic variance has been attributed to genetic factors. Here, we assessed the contribution to presbycusis of ultrarare pathogenic variants, considered indicative of Mendelian forms. We focused on severe presbycusis without environmental or comorbidity risk factors and studied multiplex family age-related hearing loss (mARHL) and simplex/sporadic age-related hearing loss (sARHL) cases and controls with normal hearing by whole-exome sequencing. Ultrarare variants (allele frequency [AF] < 0.0001) of 35 genes responsible for autosomal dominant early-onset forms of deafness, predicted to be pathogenic, were detected in 25.7% of mARHL and 22.7% of sARHL cases vs. 7.5% of controls (P = 0.001); half were previously unknown (AF < 0.000002). MYO6, MYO7A, PTPRQ, and TECTA variants were present in 8.9% of ARHL cases but less than 1% of controls. Evidence for a causal role of variants in presbycusis was provided by pathogenicity prediction programs, documented haploinsufficiency, three-dimensional structure/function analyses, cell biology experiments, and reported early effects. We also established Tmc1^N321I/+ mice, carrying the TMC1:p.(Asn327Ile) variant detected in an mARHL case, as a mouse model for a monogenic form of presbycusis. Deafness gene variants can thus result in a continuum of auditory phenotypes. Our findings demonstrate that the genetics of presbycusis is shaped by not only well-studied polygenic risk factors of small effect size revealed by common variants but also, ultrarare variants likely resulting in monogenic forms, thereby paving the way for treatment with emerging inner ear gene therapy. Significance Presbycusis, or age-related hearing loss, is a major public health issue and the principal potentially modifiable risk factor for dementia. It is caused by environmental factors and largely uncharacterized genetic factors. We compared DNA sequences across genomic coding regions between familial or sporadic cases of severe presbycusis and controls with normal hearing. The frequency of ultrarare predicted pathogenic variants in genes known to cause dominant early-onset forms of deafness was significantly higher in both familial and sporadic cases than in controls. Pathogenicity of many of these variants was established with complementary analyses. Ultrarare variants have a large effect size and are known to cause monogenic disorders. These findings open up possibilities for curing these forms of presbycusis by gene therapy.

Purpose To provide more data on the clinical presentation and natural evolution of facial nerve schwannomas and to provide guidance for therapeutic decision making. Methods A retrospective case review of eighty patients diagnosed with a facial nerve schwannoma between 1990 and 2018 in ten tertiary referral centers in Europe was performed. Patients’ demographics, symptomatology, audiometry, anatomical site (segments involved), size and whenever possible volume measurement were registered. Results At presentation, transient or persistent facial palsy was the most common symptom, followed by hearing loss. The schwannoma involved more than one segment in the majority of the patients with the geniculate ganglion being most commonly involved. Initial treatment consisted of a wait and scan approach in 67.5%, surgery in 30% and radiation therapy in 2.5% of the patients. Tympanic segment schwannomas caused mainly conductive hearing loss and were more prone to develop facial palsy at follow-up. Internal auditory canal or cerebellopontine angle schwannomas presented with significantly more sensorineural hearing loss. Conclusions Although modern imaging has improved diagnosis of this tumor, choosing the best treatment modality remains a real challenge. Based on the literature review and current findings, more insights into the clinical course and the management of facial nerve schwannomas are provided.

BACKGROUND AND PURPOSE: Recurrent middle ear cholesteatomas are commonly preoperatively assessed using MR imaging (non-EPI-DWI) and CT. Both modalities are used with the aim of distinguishing scar tissue from cholesteatoma and determining the extent of bone erosions. Inflammation and scar tissue associated with the lesions might hamper a proper delineation of the corresponding extensions on CT images. Using surgical findings as the criterion standard, we assessed the recurrent middle ear cholesteatoma extent using either uncoregistered or fused CT–MR imaging datasets and determined the corresponding accuracy and repeatability. MATERIALS AND METHODS: Twenty consecutive patients with suspected recurrent middle ear cholesteatoma and preoperative CT–MR imaging datasets were prospectively included. A double-blind assessment and coregistration of the recurrent middle ear cholesteatoma extent and manual delineation of 18 presumed recurrent middle ear cholesteatomas were performed by 2 radiologists and compared with the criterion standard. “Reliability score” was defined to qualify radiologists9 confidence. For each volume, segmentation repeatability was assessed on the basis of intraclass correlation coefficient and overlap indices. RESULTS: For the whole set of patients, recurrent middle ear cholesteatoma was further supported by surgical results. Two lesions were excluded from the analysis, given that MR imaging did not show a restricted diffusion. Lesions were accurately localized using the fused datasets, whereas significantly fewer lesions (85%) were correctly localized using uncoregistered images. Reliability scores were larger for fused datasets. Segmentation repeatability showed an almost perfect intraclass correlation coefficient regarding volumes, while overlaps were significantly lower in uncoregistered (52%) compared with fused (60%, P < .001) datasets. CONCLUSIONS: The use of coregistered CT–MR images significantly improved the assessment of recurrent middle ear cholesteatoma with a greater accuracy and better reliability and repeatability.

Background: ¹⁸F‐FDOPA PET/CT was proved to be a highly sensitive imaging method for detecting head and neck paraganglioma (HNPGL). The primary aim of the study was to evaluate the relationship between tumor characteristics and the SDHx‐mutational status in a large series of patients with HNPGL evaluated by ¹⁸F‐FDOPA PET/CT.Methods: A total of 104 patients with HNPGL (65 sporadic/39 SDHx‐mutated) were included.Results: In comparison to SDHB/SDC/SDHx‐negative cases, patients with SDHD were younger at diagnosis and had a higher rate of multifocal, vagal, and carotid paraganglioma. In patients with SDHD, vagal paraganglia represented the primary site of tumor origin. Multicentric involvement of the vagus nerve alone or in association with other locations was found to be a typical feature of SDHD cases compared to other cases (odds ratio = 59.4).Conclusion: The present study shows that tumor multifocality within the vagus nerve is a phenotypic marker of SDHD mutation. This information is essential in the choice of the therapeutic strategy.