Autosomal Recessive Non-Syndromic Deafness: Is AAV Gene Therapy a Real Chance?

The etiology of sensorineural hearing loss is heavily influenced by genetic mutations, with approximately 80% of cases attributed to genetic causes and only 20% to environmental factors. Over 100 non-syndromic deafness genes have been identified in humans thus far. In non-syndromic sensorineural hearing impairment, around 75-85% of cases follow an autosomal recessive inheritance pattern. In recent years, groundbreaking advancements in molecular gene therapy for inner-ear disorders have shown promising results. Experimental studies have demonstrated improvements in hearing following a single local injection of adeno-associated virus-derived vectors carrying an additional normal gene or using ribozymes to modify the genome. These pioneering approaches have opened new possibilities for potential therapeutic interventions. Following the PRISMA criteria, we summarized the AAV gene therapy experiments showing hearing improvement in the preclinical phases of development in different animal models of DFNB deafness and the AAV gene therapy programs currently in clinical phases targeting autosomal recessive non syndromic hearing loss. A total of 17 preclinical studies and 3 clinical studies were found and listed. Despite the hurdles, there have been significant breakthroughs in the path of HL gene therapy, holding great potential for providing patients with novel and effective treatment.

Intraoperative Measurement of Insertion Speed in Cochlear Implant Surgery: A Preliminary Experience with Cochlear SmartNav.

OBJECTIVES: The objectives were to present the real-time estimated values of cochlear implant (CI) electrode insertion speed (IS) during intraoperative sessions using the Cochlear Nucleus SmartNav System to assess whether this measure affected CI outcomes and to determine whether real-time feedback assists expert surgeons in achieving slow insertion. METHODS: The IS was measured in 52 consecutive patients (65 implanted ears) using the CI632 electrode. The IS values were analyzed in relation to procedure repetition over time, NRT ratio, and CI audiological outcomes. RESULTS: The average IS was 0.64 mm/s (SD = 0.24); minimum and maximum values were 0.23 and 1.24 mm/s, respectively. The IS significantly decreased with each array insertion by the operator (p = 0.006), and the mean decreased by 24% between the first and last third of procedures; however, this reduction fell within the error range of SmartNav for IS (+/-0.48 mm/s). No correlation was found between IS and the NRT ratio (p = 0.51), pure-tone audiometry (PTA) at CI activation (p = 0.506), and PTA (p = 0.94) or word recognition score (p = 0.231) at last evaluation. CONCLUSIONS: The estimated IS reported by SmartNav did not result in a clinically significant reduction in insertion speed or an improvement in CI hearing outcomes. Real-time feedback of IS could potentially be used for training, but its effectiveness requires confirmation through additional studies and more accurate tools. Implementation of IS assessment in clinical practice will enable comparisons between measurement techniques and between manual and robot-assisted insertions. This will help define the optimal IS range to achieve better cochlear implant (CI) outcomes.

Intratympanic Gels for Inner Ear Disorders: A Scoping Review of Clinical Trials.

OBJECTIVE: Intratympanic injections are a safe, well tolerated procedure routinely performed by ENT's specialists. Intratympanic injections of gels have the potential to deliver therapeutics into the cochlea through the round window membrane prolonging the release of drugs in the inner ear compartment. Aim of the present review is to summarize clinical trials testing pharmacological treatments for inner ear pathologies through intratympanic gel formulations. DATA SOURCES: Online databases (Google scholar and PubMed) and registers (Clinicaltrials.gov and Euclinicaltrial) were used to identify clinical trials performed between 1990 and 2022. REVIEW METHODS: PRISMA criteria have been followed. Clinical trials testing gel formulations administered through local intratympanic injections and targeting inner ear disorders were included. All the reports were identified by the authors working in pairs sequentially selecting only studies respecting the inclusion criteria. RESULTS: A total of 45 clinical studies have been noticed; the gels for intratympanic injection are in the form of poloxamers or hyaluronic acid combinations; the trials found target different kind of inner ear disorders: acquired-stable SNHL, tinnitus, acute sudden SNHL, Meniere disease, cisplatin induced ototoxicity and hearing preservation in patients undergoing cochlear implant surgery. CONCLUSION: Few studies listed do not provide the specific kind of gel formulation used but only report the intratympanic delivery vehicle as "gel" or "thermogel". Multiple clinical studies have been targeting several forms of inner ear disorders by injecting different compounds through poloxamer and hyaluronic acid formulations. Larger and more advanced clinical stages are necessary to confirm the efficacy of these chemical compounds.

Bilateral simultaneous cochlear implants in children: Best timing of surgery and long-term auditory outcomes.

PURPOSE: Evaluate the hearing outcomes of bilateral deaf children implanted simultaneously and define the most appropriate timing for surgery. MATERIALS AND METHODS: Audiological CI results were retrieved in both the short-term and long-term period and compared by stratifying the patients into different subcohorts according to their age at surgery. Additional data collected were age at implant activation, etiology and timing of onset of deafness, presence of psychomotor delay. RESULTS: fifty-six bilaterally implanted children were included. The short-term outcomes differed significantly when comparing groups of different ages at implantation: younger patients achieved better aided pure tone audiometry results. Considering long-term follow-up, a significant correlation was identified between an early age at implantation and the hearing outcome at ages 2 to 5 years. Perceptive levels were better at 4 years of age in the younger group. No significant differences were found between children implanted at before 12 months and between 12 and 16 months of age. CONCLUSIONS: The results of the analyzed follow-up data support the hypothesis that children implanted at before 24 months are expected to have better hearing performances. Nevertheless, these results are referred to a widely heterogeneous group of patients and the duration of auditory deprivation should be considered.

Cochlear implantation after head and neck radiotherapy: A multicentric study and systematic review.

OBJECTIVE: The objective of this study is to assess whether cochlear implantation is feasible in patients treated with radiotherapy of the temporal bone (for diseased other than vestibular schwannoma), in terms of surgical management and auditory outcome. METHODS: A systematic review of the literature was performed, screening PubMed, Embase, and Scopus databases, according to PRISMA criteria, retrieving 12 articles. Moreover, 9 cases coming from a multicentric study involving Padova and Pisa University Hospitals, were added, for a total of 62 cases of irradiated patients receiving cochlear implantation. RESULTS: In our multicentric study we included a total of 9 patients, 6 males, and 3 females (mean age at first cochlear implantation was 53.89 years ± 21.07), while from the literature we considered 53 cases (mean age at first cochlear implantation 48.78 years ± 12.41). We considered for both groups a set of preoperative imaging abnormalities, intraoperative complications and possible postoperative complications. In our cohort, the preoperative pure tone average (PTA) in the implanted ear was 105.6 dB, and the postoperative one was 34.6 dB. In the literature the preoperative PTA was 111.5 dB (when reported), and the postoperative one 52.8 dB. CONCLUSION: Both our experience and the literature suggest that cochlear implantation in an irradiated ear is feasible with a good auditory outcome. Surgical difficulties and fitting challenges can be easily managed by professionals aware of these findings, making these patients good candidates to this rehabilitative option.

Hearing Aid in Vestibular-Schwannoma-Related Hearing Loss: A Review.

(1) Background: Several types of hearing aids are available for the rehabilitation of vestibular-schwannoma (VS)-related hearing loss. There is a lack of recently published papers regarding this theme. The aim of the present work is to organize current knowledge. (2) Methods: A review of the literature regarding the topics "vestibular schwannoma", "hearing loss", and "hearing aid" was performed. Nineteen studies were thus considered. (3) Results: Conventional hearing aids, contralateral routing of signal (CROS) aids, bone anchored hearing aids (BAHA), and others are available options for hearing rehabilitation in VS patients. The speech discrimination score (SDS) is considered the best measure to assess candidacy for rehabilitation with hearing aids. The best hearing rehabilitative conditions in VS patients when using conventional hearing aid devices are a mild-moderate hearing loss degree with good word recognition (more than 50% SDS). CROS-Aid and BAHA are reported to be beneficial. CROS-Aid expands on the area of receiving hearing. BAHA aids use direct bone-conduction stimulation. Unfortunately, there are no available studies focused specifically on VS patients that compare CROS and BAHA technologies. (4) Conclusions: Hearing aids, CROS, and BAHA are viable options for rehabilitating hearing impairment in VS, but require an accurate case-by-case audiological evaluation for rehabilitating hearing impairment in VS. Further studies are needed to prove if what is currently known about similar hearing illnesses can be confirmed, particularly in the case of VS.

Early cochlear implantation in prelingual profound hearing loss in Italy, analyzed by means of a social media survey.

Objective: To assess newborn hearing screening (NHS) impact on timing of cochlear implant (CI) surgery of patients with prelingual bilateral profound hearing impairment (BPHI), in order to evaluate whether the NHS ultimately serves the needs of the target population in Italy. Methods: An online questionnaire was created to survey subjects affected by prelingual BPHL born between 1990 and 2018. Questions focused on age at BPHI diagnosis, first and second CI surgery (if performed), and the region in which the surgery was performed. The survey was distributed to potential participants via social media communities used by hearing impaired people or their family members for sharing advice and offering support. Responses were analyzed using descriptive statistics. Results: Among the 318 respondents who completed the questionnaire, 276 (87%) reported having chosen CI surgery, 2/3 of them bilaterally. In the vast majority (97%) of cases the CI is used on a daily basis. Most of the people residing in the center (65%) and southern Italy (71%) had to move from their region of residence to perform the surgery. Late CI surgery was associated with failure to perform NHS (p = 0.007), birth before 2011 (p = 0.009), definitive diagnosis of BPHI after 6 months of life (p = 0.002), and progressive hearing impairment (p < 0.001). Conclusion: The worldwide scientific approval of the NHS as the current best opportunity for early diagnosis and CI treatment for prelingual BPHI is confirmed by what patients and families reported via the online questionnaire used for this study. In recent years, early bilateral cochlear implantation has become increasingly available in Italy, but late diagnosis, progressive hearing loss, failure to perform the NHS and lack of follow-up are still open questions. A large proportion of families had to move from the region of residence to have their child undergo CI surgery, revealing inequalities in terms of geographical disparities. Social media has proved to be a valuable, fast and inexpensive tool for gathering information on the effectiveness of health prevention programs, involving a large sample of individuals in a short amount of time.

Epidemiologic, Imaging, and Clinical Issues in Bezold's Abscess: A Systematic Review.

Bezold's abscess is a deep neck abscess related to otomastoiditis. Due to the insidious clinical presentation, diagnosis can be extremely challenging, leading to delays in treatment and possible life-threatening complications. The literature currently provides a fragmented picture, presenting only single or small number of cases. The present study aims at examining our experience and the literature findings (based on PRISMA criteria) of 97 patients with Bezold's abscess, summarizing their epidemiology, pathogenesis, clinical presentation, imaging findings, and treatments. Bezold's abscess is found at any age, with overt male prevalence among adults. The clinical presentation, as well as the causative pathogens, are strikingly heterogeneous. Otomastoiditis and cholesteatoma are major risk factors. A clinical history of otitis is commonly reported (43%). CT and MRI are the main diagnostic tools, proving the erosion of the mastoid tip in 53% of patients and the presence of a concomitant cholesteatoma in 40%. Intracranial vascular (24%) or infectious (9%) complications have also been reported. Diagnosis might be easily achieved when imaging (CT) is properly applied. MRI has a limited diagnostic role, but it might be crucial whenever intracranial complications or the coexistence of cholesteatoma are suspected, helping to develop proper treatment (prompt antibiotic therapy and surgery).

Cochlear implant in vestibular schwannomas: long-term outcomes and critical analysis of indications.

PURPOSE: To describe our institutional experience in cochlear implantation after vestibular schwannoma (VS) resection, and compare the audiological outcomes between sporadic and neurofibromatosis type 2 (NF2) VS sub-cohorts of patients, and in relation to preoperative contralateral hearing. METHODS: Seventeen patients (8 sporadic and 9 NF2-associated VSs) who had undergone VS resection and cochlear implant (CI) were analyzed retrospectively. Audiological outcomes at 24 months were correlated with preoperative clinical variables. The results according to VS type (sporadic vs. NF2-associated) and contralateral hearing (impaired vs. normal) were compared. RESULTS: Fourteen CIs were actively used by the patients (77.8%). Twenty-four months after CI activation, the median postoperative PTA (pure tone average) was 45.6 dB nHL and a measurable WRS (Word Recognition Score) was achieved by 44.4% of patients (median WRS = 40%). The median postoperative PTA in the implanted ear resulted better in the group with an impaired contralateral hearing (36.3 dB nHL vs. 78.8 dB nHL, p = 0.019). Good preoperative contralateral hearing status (A-B classes of AAO-HNS) was a negative prognostic factor for CI performance on open-set discrimination (OR = 28.0, 95% CI 2.07-379.25, p = 0.012). CONCLUSIONS: CI is a viable rehabilitative option for patients with sporadic or NF2-associated VS. A good contralateral hearing adversely affects CI outcome and should be taken into consideration for patients' selection and rehabilitation programs.

Pediatric Hearing Loss Management in the COVID-19 Era: Possible Consequences and Resources for the Next Future.

Pediatric hearing loss early diagnosis and treatment have been limited by the current restrictions due to the coronavirus disease 2019 pandemic. The difficulty in accessing the multiple facilities required for the rehabilitative process is influencing the timing of each step of the process. Auditory hearing screening programs, etiological characterization, surgical timing, and speech therapies have all been limited in the past year. The current conditions have forced us to adopt different strategies to overcome the necessary social distancing prescriptions. Although their efficacy should be proved over time, some of these resources will be probably useful even in a nonpandemic future.

Bezold's abscess secondary to os tympanicum cholesteatoma in Goldenhar syndrome.

OBJECTIVES: The diagnosis of Bezold's abscess can be challenging especially when craniofacial malformations imply facial and cervical morphological asymmetries. In addition, craniofacial malformations might predispose to the occurrence and atypical diffusion pathways of suppurative processes originating from abnormally developed temporal bone structures. METHODS: A 30-year-old female presented with a left laterocervical swelling, worsening over time. The female was affected by Goldenhar syndrome. CT and MRI were performed. RESULTS: CT revealed a dysmorphic os tympanicum and a deep cervical abscess in continuity with its cavity. Drainage of the cervical abscess was performed but a subsequent brain MRI detected a large cholesteatoma that was removed with left lateral petrosectomy. CONCLUSIONS: Radiology has a crucial role in the diagnosis and planning of the treatment of Bezold's abscesses, particularly in syndromic patients. MRI, in this case, helped in diagnosing the presence of the cholesteatoma and consequently appropriately approach the surgical removal.

Cochlear implantation in adults with auditory deprivation: What do we know about it?

INTRODUCTION: In the ENT community, auditory deprivation is frequently considered as a negative prognostic factor for a good hearing outcome of cochlear implantation (CI), even if a growing literature suggests that this is not completely true. The purpose of this study is to evaluate the results of CI in patients with hearing deprivation, to compare them to results from non-deprived patients and then estimate how time of deprivation impacts on CI outcome and how a bilateral deprivation can affect the outcome compared to a unilateral deprivation. METHODS: Seventy-eight adults with severe to profound post-verbal hearing loss, with and without auditory deprivation history, received CI; audiological results obtained at 3-6-12-24 months follow up post CI were analyzed. RESULTS: No differences were founded between patients with unilateral deprivation and patients with no deprivation. Patients with bilateral deprivation seem to have a worse hearing outcome compared to that of those patients with unilateral deprivation or no deprivation at all. Long time deprivation (>15 years) seems to have a negative influence on the hearing outcome but results with CI remain excellent. CONCLUSIONS: Auditory deprivation should not be considered a contraindication to CI. The duration of auditory deprivation in the implanted ear seems to be a negative prognostic factor only for ears deprived from more of 15 years.

Cochlear implant outcomes in the elderly: a uni- and multivariate analyses of prognostic factors.

PURPOSE: To assess preoperative features that could predict the audiological outcome after cochlear implantation in the elderly, in terms of pure tone audiometry, speech audiometry, and speech perception performance. METHODS: All available records of patients with cochlear implants aged 65 or more at the time of their implantation at our Institution were reviewed (50 patients, mean age 70.76 ± 4.03 years), recording preoperative clinical features. Pure tone audiometry, speech audiometry, and speech perception performance 1 year after cochlear implant activation and fitting were used as outcome measures. RESULTS: No statistically significant association emerged between clinical features and pure tone audiometry. On univariate analysis, progressive sensorineural hearing loss of unknown origin was associated with a better outcome in terms of speech audiometry and speech perception performance (p = 0.035 and p = 0.033, respectively). On multivariate analysis, progressive sensorineural hearing loss retained its independent prognostic significance in terms of speech perception performance (p = 0.042). The discriminatory power of a two-variable panel (age and etiology of hearing loss) featured an AUC (ROC) of 0.738 (an acceptable discriminatory power according to the Hosmer-Lemeshow scale). CONCLUSIONS: A progressive sensorineural hearing loss of unknown origin was associated with a better outcome in terms of speech perception in the elderly in our case study. Further features that can predict audiological outcome achievable with cochlear implants in the elderly are desirable to perform adequate counselling and rehabilitation programs.

Epidemiologic, Imaging, Audiologic, Clinical, Surgical, and Prognostic Issues in Common Cavity Deformity: A Narrative Review.

IMPORTANCE: Common cavity deformity is a rare congenital inner ear malformation associated with profound hearing loss and attributed to an early developmental arrest of the cochlear-vestibular structures. This narrative review highlights the need to identify reliable indicators of hearing rehabilitation outcome. OBSERVATIONS: Despite its relatively simple definition, common cavity deformity varies widely in morphologic features, presence of cochlear nerve fibers and remnants of Corti organ, and outcome after cochlear or brainstem implant. CONCLUSIONS AND RELEVANCE: Cochlear implant has been shown to be a valid option for common cavity deformity, but its outcome remains variable and poor. Identification of specific neuroradiologic, audiologic, and neurophysiologic prognostic features; tailoring of the surgical approach; and standardization of outcome measures are needed to optimize the management of common cavity deformity and hearing rehabilitation after implant.

Rhinencephalon changes in tuberous sclerosis complex.

PURPOSE: Despite complex olfactory bulb embryogenesis, its development abnormalities in tuberous sclerosis complex (TSC) have been poorly investigated. METHODS: Brain MRIs of 110 TSC patients (mean age 11.5 years; age range 0.5-38 years; 52 female; 26 TSC1, 68 TSC2, 8 without mutation identified in TSC1 or TSC2, 8 not tested) were retrospectively evaluated. Signal and morphological abnormalities consistent with olfactory bulb hypo/aplasia or with olfactory bulb hamartomas were recorded. Cortical tuber number was visually assessed and a neurological severity score was obtained. Patients with and without rhinencephalon abnormalities were compared using appropriate parametric and non-parametric tests. RESULTS: Eight of110 (7.2%) TSC patients presented rhinencephalon MRI changes encompassing olfactory bulb bilateral aplasia (2/110), bilateral hypoplasia (2/110), unilateral hypoplasia (1/110), unilateral hamartoma (2/110), and bilateral hamartomas (1/110); olfactory bulb hypo/aplasia always displayed ipsilateral olfactory sulcus hypoplasia, while no TSC patient harboring rhinencephalon hamartomas had concomitant forebrain sulcation abnormalities. None of the patients showed overt olfactory deficits or hypogonadism, though young age and poor compliance hampered a proper evaluation in most cases. TSC patients with rhinencephalon changes had more cortical tubers (47 ± 29.1 vs 26.2 ± 19.6; p = 0.006) but did not differ for clinical severity (p = 0.45) compared to the other patients of the sample. CONCLUSIONS: Olfactory bulb and/or forebrain changes are not rare among TSC subjects. Future studies investigating clinical consequences in older subjects (anosmia, gonadic development etc.) will define whether rhinencephalon changes are simply an imaging feature among the constellation of TSC-related brain changes or a feature to be searched for possible implications in the management of TSC subjects.

Salivary glands abnormalities in oculo-auriculo-vertebral spectrum.

BACKGROUND: Feeding and swallowing impairment are present in up to 80% of oculo-auriculo-vertebral spectrum (OAVS) patients. Salivary gland abnormalities have been reported in OAVS patients but their rate, features, and relationship with phenotype severity have yet to be defined. MATERIAL AND METHODS: Parotid and submandibular salivary gland hypo/aplasia was evaluated on head MRI of 25 OAVS patients (16 with severe phenotype, Goldenhar syndrome) and 11 controls. RESULTS: All controls disclosed normal salivary glands. Abnormal parotid glands were found exclusively ipsilateral to facial microsomia in 21/25 OAVS patients (84%, aplasia in six patients) and showed no association with phenotype severity (14/16 patients with Goldenhar phenotype vs 7/9 patients with milder phenotype, p = 0.6). Submandibular salivary gland hypoplasia was detected in six OAVS patients, all with concomitant ipsilateral severe involvement of the parotid gland (p < 0.001). Submandibular salivary gland hypoplasia was associated to Goldenhar phenotype (p < 0.05). Parotid gland abnormalities were associated with ipsilateral fifth (p < 0.001) and seventh cranial nerve (p = 0.001) abnormalities. No association was found between parotid gland anomaly and ipsilateral internal carotid artery, inner ear, brain, eye, or spine abnormalities (p > 0.6). CONCLUSIONS: Salivary gland abnormalities are strikingly common in OAVS. Their detection might help the management of OAVS-associated swallowing and feeding impairment.

Facial asymmetry quantitative evaluation in oculoauriculovertebral spectrum.

OBJECTIVES: Facial asymmetries in oculoauriculovertebral spectrum (OAVS) patients might require surgical corrections that are mostly based on qualitative approach and surgeon's experience. The present study aimed to develop a quantitative 3D CT imaging-based procedure suitable for maxillo-facial surgery planning in OAVS patients. MATERIALS AND METHODS: Thirteen OAVS patients (mean age 3.5 ± 4.0 years; range 0.2-14.2, 6 females) and 13 controls (mean age 7.1 ± 5.3 years; range 0.6-15.7, 5 females) who underwent head CT examination were retrospectively enrolled. Eight bilateral anatomical facial landmarks were defined on 3D CT images (porion, orbitale, most anterior point of frontozygomatic suture, most superior point of temporozygomatic suture, most posterior-lateral point of the maxilla, gonion, condylion, mental foramen) and distance from orthogonal planes (in millimeters) was used to evaluate the asymmetry on each axis and to calculate a global asymmetry index of each anatomical landmark. Mean asymmetry values and relative confidence intervals were obtained from the control group. RESULTS: OAVS patients showed 2.5 ± 1.8 landmarks above the confidence interval while considering the global asymmetry values; 12 patients (92%) showed at least one pathologically asymmetric landmark. Considering each axis, the mean number of pathologically asymmetric landmarks increased to 5.5 ± 2.6 (p = 0.002) and all patients presented at least one significant landmark asymmetry. CONCLUSIONS: Modern CT-based 3D reconstructions allow accurate assessment of facial bone asymmetries in patients affected by OAVS. The evaluation as a global score and in different orthogonal axes provides precise quantitative data suitable for maxillo-facial surgical planning. CLINICAL RELEVANCE: CT-based 3D reconstruction might allow a quantitative approach for planning and following-up maxillo-facial surgery in OAVS patients.