Exploration of the relationship between cumulative exposure to tobramycin and ototoxicity in patients with cystic fibrosis.

BACKGROUND: Aminoglycosides (AGs), such as tobramycin, are essential antibiotics in the management of pulmonary infections in patients with cystic fibrosis (CF). They induce ototoxicity without the relationship being clearly described in the literature. Our aim is to propose a mathematical and statistical model describing the relationship between the estimated cumulative exposure (Area Under the Curve, AUC) to tobramycin and ototoxicity with audiogram interpretation in young patients with CF. METHODS: Cumulative AUCs were estimated for each course of tobramycin, for the 106 individuals with CF (between 4 and 22 years of age) enrolled in this retrospective study (35 who had received IV tobramycin, 71 controls). Mean hearing loss was calculated for each audiogram and a statistical model was developed to predict hearing loss. RESULTS: The model confirms a significant relationship between cumulative tobramycin exposure and changes in hearing acuity: Meanhearingloss=2.7+(3×10-5)×AUC_tobramycin+individual_susceptibility However, the ototoxic effect is not clinically perceptible (mean hearing loss: 3.8 dB). The impact of AUC on hearing loss is minor in these subjects who received a limited number of courses of tobramycin (median: 5 courses). CONCLUSION: A significant relationship between cumulative exposure to tobramycin and ototoxicity was demonstrated. Individual treatment susceptibility should not be overlooked. As ototoxicity is not clinically perceptible in the study subjects, hearing tests should be continued during adulthood to provide individualized medical guidance and to obtain a lifetime analysis of the relationship between exposure and hearing loss.

Functional Reorganization of the Central Auditory System in Children with Single-Sided Deafness: A Protocol Using fNIRS.

In children, single-sided deafness (SSD) affects the development of linguistic and social skills and can impede educational progress. These difficulties may relate to cortical changes that occur following SSD, such as reduced inter-hemispheric functional asymmetry and maladaptive brain plasticity. To investigate these neuronal changes and their evolution in children, a non-invasive technique is required that is little affected by motion artifacts. Here, we present a research protocol that uses functional near-infrared spectroscopy (fNIRS) to evaluate the reorganization of cortical auditory asymmetry in children with SSD; it also examines how the cortical changes relate to auditory and language skills. The protocol is designed for children whose SSD has not been treated, because hearing restoration can alter both brain reorganization and behavioral performance. We propose a single-center, cross-sectional study that includes 30 children with SSD (congenital or acquired moderate-to-profound deafness) and 30 children with normal hearing (NH), all aged 5-16 years. The children undergo fNIRS during monaural and binaural stimulation, and the pattern of cortical activity is analyzed using measures of the peak amplitude and area under the curve for both oxy- and deoxyhemoglobin. These cortical measures can be compared between the two groups of children, and analyses can be run to determine whether they relate to binaural hearing (speech-in-noise and sound localization), speech perception and production, and quality of life (QoL). The results could be of relevance for developing individualized rehabilitation programs for SSD, which could reduce patients' difficulties and prevent long-term neurofunctional and clinical consequences.

Quality of life of children treated for unilateral hearing loss: a systematic review and meta-analysis.

OBJECTIVE: To evaluate the treatments' consequences for unilateral hearing loss in children. DESIGN: Systematic review and meta-analysis (CRD42018109417). The MEDLINE, CENTRAL, ISRCTN and ClinicalTrials databases were searched between September 2018 and May 2019. Articles were screened and data were collected independently by two authors following the Cochrane and Preferred Reporting Items for Systematic review and Meta-Analysis guidelines. The risk of bias was evaluated using the Cochrane tool, the Newcastle-Ottawa Scale, the National Institute of Health, USA tool and considering the risk of confounding. In the studies with the lowest risk of bias, a meta-analysis was conducted. INTERVENTIONS: Validated hearing rehabilitation devices. PATIENTS: 6-15 years old children with moderate to profound unilateral hearing loss. MAIN OUTCOME MEASURES: The primary study outcome was children's quality of life. Academic performances were studied as an additional outcome. RESULTS: 731 unique articles were identified from the primary search. Of these, 18 articles met the Population, Intervention, Control, Outcomes and Study design selection criteria. In the eight studies with the lowest risk of bias, two meta-analysis were conducted. There was not enough data on academic results to conduct a meta-analysis. In 73 children included in a fixed effect meta-analysis (two studies), no effect of treatment could be shown (g=-0.20, p=0.39). In 61 children included in a random-effect meta-analysis (six studies), a strong positive effect of hearing treatment on quality of life was demonstrated (g=1.32, p<0.05). CONCLUSIONS: The treatment of unilateral hearing loss seems to improve children's quality of life. Further research is needed to identify the most effective treatment and its corresponding indications.

Nontuberculous lymphadenitis in children: What management strategy?

OBJECTIVES: Nontuberculous mycobacterial (NTM) lymphadenitis is a rare disease of children under 5 years. Its treatment is not standardized, even a "wait-and-see" approach is shown to be effective in the literature. Here, we discuss the diagnostic and therapeutic strategies employed in our departments. METHODS: Records of pediatric patients treated for NTM cervical lymphadenitis from 2010 to 2015 in our tertiary center were retrospectively reviewed. Patients underwent cervical echotomography and/or CT scan. Every patient but one had microbiological explorations (NTM polymerase chain reaction [PCR] and culture) on fine needle aspiration of pus and/or adenitis biopsy. Differential diagnoses (tuberculosis, cat scratch disease) were excluded with serologies, chest X-Ray, and PCR on adenitis samples. Patients were classified as "proven diagnosis" (NTM detected), "highly probable" (suggestive clinical and anatomopathological aspect) or "possible" infection (suggestive adenitis alone). Treatments, follow-up and adverse events were reviewed. RESULTS: Thirty-one patients were treated for NTM, median age 2.40 years (Interquartile Range IQR = [1.85-3.16]). Twenty-nine patients (96.77%) had an isolated cervico-facial localization. Median follow-up was 8.00 months (IQR = [4.20-13.43]). We found 17 "proven diagnosis" (58.62%), 5 "highly probable" (17.24%) and 7 "possible" infections (24.14%). "Proven" infections were due to: Mycobacterium avium (n = 12, 66.67%) and M. intracellulare (n = 5, 27.78%). All 29 patients received antibiotics, which were effective for 10 (34.48%, group 1); 10 underwent surgical excision for a poor outcome with antibiotics (34.48%, group 2); spontaneous or surgical drainage occurred in 9 on antibiotics (31.03%, group 3). The median times to resolution for group 1, 2 and 3 were respectively 6.33 months, 6.22 months and 9.53 months. Antibiotics treatment was mostly clarithromycin (n = 27, 93.10%) and/or rifampicin (n = 19, 65.52%); 18 patients (62.07%) received both. Median antibiotics duration was 6.23 months (IQR = [5.17-7.46]), with good compliance (79.31%). The observed adverse effects were 3 (13.04%) isolated transient transaminase elevations, 1 case (4.35%) of minor creatinine elevation, and 1 case (4.35%) of transient diarrhea. Surgical drainage caused 1 transient marginal mandibular nerve palsy, resolutive after 1 month. CONCLUSION: Antibiotics in NTM adenitis lead to resolution in 7 months, with good tolerance and compliance. The efficacy of "wait-and-see" attitude in the literature make excision surgery a second line treatment.

Impaired functional responses in follicular lymphoma CD8+TIM-3+ T lymphocytes following TCR engagement.

Upregulation of T cell immunoglobulin-3 (TIM-3) has been associated with negative regulation of the immune response in chronic infection and cancer, including lymphoma. Here, we investigated the possible correlation between TIM-3 expression by ex vivo cytotoxic T cells (CTL) from follicular lymphoma (FL) biopsies and their functional unresponsiveness that could limit the favorable impact of CTL on disease progression. We report a high percentage of CD8+TIM-3+T cells in lymph nodes of FL patients. When compared to their CD8+TIM-3- counterparts, CD8+TIM-3+ T cells exhibited defective cytokine production following TCR engagement. Furthermore, CD8+TIM-3+ T cells display ex vivo markers of lytic granule release and remain unresponsive to further TCR-induced activation of the lytic machinery. Although confocal microscopy showed that TIM-3 expression on CD8+ T cells correlated with minor alterations of immunological synapse, a selective reduction of ERK signaling in CD8+TIM-3+T cells was observed by phospho-flow analysis. Finally, short relapse-free survival despite rituximab(R)-chemotherapy was observed in patients with high content of TIM-3+ cells and a poor infiltrate of granzyme B+ T cells in FL lymph nodes. Together, our data indicate that, besides selective TCR early signaling defects, TIM-3 expression correlates with unresponsiveness of ex vivo CD8+ T cells in FL. They show that scores based on the combination of exhaustion and cytolytic markers in FL microenvironment might be instrumental to identify patients at early risk of relapses following R-chemotherapy.

Decisive criteria between stapedotomy and cochlear implantation in patients with far advanced otosclerosis.

OBJECTIVES: To describe the hearing outcomes in patients with far-advanced otosclerosis and to identify the best initial approach based on preoperative word recognition scores (WRS), pure tone averages (PTA), and radiological classification. STUDY DESIGN: Retrospective case review. SETTING: Academic neurotology tertiary referral center. PATIENTS: All patients (n = 58) with preoperative air conduction PTA less than 85 dB (HL), disyllabic WRS less than or equal to 50% at 60 dB (HL) with well-fitted hearing aids, and evidence of otosclerosis on CT scan, treated in our department over the past 20 years. INTERVENTIONS: Stapedotomy, cochlear implantation, or both. MAIN OUTCOME MEASURES: Postoperative WRS after a minimum of 12 months' follow-up, percentage of patients with WRS greater than 50%. Reliability of air and bone conduction PTAs and WRS in predicting failure of stapedotomy. RESULTS: Fifty-eight patients were divided into three groups: group I, primary stapedotomy (n = 32); group II, primary cochlear implantation (n = 9); and group III, secondary cochlear implantation (with a previous history of stapedotomy) (n = 25). The mean postoperative WRS were 50.6% (± 34), 75% (± 17), and 72% (± 20), respectively. Sixty percent of patients in the stapedotomy group had a postoperative WRS greater than 50% requiring no further treatment, compared to 85% for cochlear implant recipients. No specific predictive factors for stapedotomy outcome could be identified. Surgical difficulties during cochlear implantation were significantly higher in patients with advanced radiological stage. CONCLUSION: Although cochlear implantation gives better overall results, stapedotomy with hearing aids can still be very effective in the management of patients with far-advanced otosclerosis. It should therefore be proposed as a first-line treatment.

Spontaneous tegmen defect and semicircular canal dehiscence: same etiopathogenic entity?

OBJECTIVES: To describe the clinical and radiologic features of associated spontaneous tegmen defects (STDs) with semicircular canal dehiscences (SCCDs) and to postulate a novel etiopathogenic hypothesis of these pathologic conditions. METHODS: Medical records of all patients with surgically confirmed STD between 2001 and May 2010 were reviewed. We excluded all secondary tegmen defects. Clinical, audiological, and radiologic data were analyzed. RESULTS: Twenty-three patients matched the inclusion criteria. Semicircular canal dehiscence was associated to STD in 13 patients. Of these patients, 12 (95%) had protruding superior semicircular canals in the middle cranial fossa versus only 3 (30%) of 10 patients for the nondehiscent cases. Twenty-two patients complained of hearing loss. Cerebrospinal fluid leak was found in 13 patients. Four patients had history of meningitis. Vestibular symptoms were present in 8 patients. CONCLUSION: This is the largest series of reported coexistence of STD and SCCD in the literature. Protrusion of the superior semicircular canal in the middle cranial fossa is probably an additional factor underlying STD and SCCD etiopathogeny. Semicircular canal dehiscence should always be looked for when STD is present.

Revision stapes surgery: the "lateralized piston syndrome".

OBJECTIVE: The need for revision stapes surgery has many causes, and among these, we describe a particular displacement of the piston: the "lateralized piston syndrome". The goal of this study is to define criteria and surgical management of this syndrome. STUDY DESIGN: Retrospective study over 13 years. SETTING: Tertiary reference center. PATIENTS: A review of 1,289 consecutive stapes operations revealed 119 revisions (9%) from which 22 cases (18.5%) could be classified under the lateralized piston syndrome. INTERVENTION: Revision stapedotomy. MAIN OUTCOME MEASURES: Medical files, preoperative and postoperative audiograms, computed tomographic scans, and operative reports. RESULTS: The 22 cases presented as a delayed conductive hearing loss in 95.5% of cases. Preoperative computed tomographic scans showed a lateralized piston out of the stapedotomy in 81% of cases and touching the tympanic membrane in 54.5% of cases. Revisions revealed a lateral displacement of the piston out of the entire oval window in 86% of cases, with closure of the stapedotomy in all cases and incus necrosis in 77% of cases. Conventional pistons were fitted in 12 cases. In case of a significantly eroded incus, total prostheses (TORPs) in 6 cases and offset pistons in 4 cases were placed. Air-bone gap (ABG) was closed to within 20 dB in 82% of cases. Air-conduction puretone audiometry improvement was 17.2 dB (standard deviation [SD], 19.2), with a mean postoperative ABG of 16.2 dB (SD, 12.7). Only 1 ear, operated with TORP, had a sensorineural deterioration of 20 dB. With offset pistons, ABG was closed to within 20 dB in 100% of cases with a mean postoperative ABG of 8.8 dB (SD, 7.2). CONCLUSION: The lateralized piston syndrome was found in 18.5% of stapes surgery revisions. Surgical management was effective in correcting the conductive hearing loss. In the event of significant eroded incus, we observed better results with offset pistons than with TORPs.

Reliability of high-resolution CT scan in diagnosis of otosclerosis.

OBJECTIVE: To assess the reliability of high-resolution computed tomographic scan (HRCT scan) for the diagnosis of otosclerosis and to determine its usefulness to predict hearing deterioration and surgical difficulties. STUDY DESIGN: Prospective study. SETTING: Tertiary reference center. PATIENTS: Two hundred nine ears (200 patients) presenting progressive conductive hearing loss with normal tympanic membrane, abnormal stapedial reflex, and scheduled for stapes surgery. The mean age was 47.3 years. INTERVENTION: All patients underwent HRCT scan before surgery (slice thickness of 0.6 to 1 mm). Stapedotomy was performed in 99% of cases. MAIN OUTCOME MEASURES: High-resolution computed tomographic scan results were categorized as positive, doubtful, or negative. We classified a CT scan as positive for otosclerosis when a hypodense focus was seen around the otic capsule. Preoperative and postoperative air- and bone-conduction thresholds were collected. RESULTS: Of 209 HRCT scans, 84.2% were classified positive, 8.6% doubtful, and 7.2% negative. In all patients with positive CT scan, otosclerosis was confirmed in surgery. Among 15 negative cases, we found 4 minor malformations and 1 fracture of the stapes. Footplate incidents (mobilized, floating, or fractured footplate; 5.3%) occurred significantly more frequently when an HRCT scan was negative or doubtful (p = 0.05). Mean preoperative air-bone gap was 27.7 dB (standard deviation, 10). Mean postoperative air-bone gap was within 10 dB in 65% and within 20 dB in 92% of cases. Greater than 10 dB deterioration of bone-conduction thresholds occurred in 2% of cases. Mean preoperative and postoperative bone-conduction thresholds were significantly lower in cases of round window obliteration, pericochlear, or internal auditory canal hypodensities (p < 0.005 and p < 0.0001, respectively). CONCLUSION: In our series, the sensitivity of HRCT scan to otosclerosis was 95.1%. Hypodense otosclerotic foci were mostly localized at the anterior part of footplate. Negative or doubtful cases were associated with the highest incidence of stapes footplate complications. Foci involving otic capsule, internal auditory canal, or round window led to a significantly higher risk of sensorineural hearing loss.

Screening to detect permanent childhood hearing impairment in neonates transferred from the newborn nursery.

OBJECTIVES: The focus of this report is hearing screening of newborns transferred from the regular nursery to a specialized area. The purpose of the study undertaken was: (1) to determine whether screening coverage in this population was achieved; (2) to establish whether the linkage between neonatal screening and the diagnostic follow-up was carried out correctly; (3) to better determine the incidence of permanent childhood hearing impairment (PCHI) in this at-risk population. METHODS: Six population centres averaging 12,000 births annually participated (Bordeaux, Lille, Paris, Marseille, Toulouse and Lyon). Automated auditory brainstem response (AABR) (Natus ALGO 3i) screening was performed in two stages: i.e. infants with initial "positive" results were screened a second time using the same technique. Of the 117,103 babies born during the study period, 4972 neonates were "transferred" and comprised the population for this report (4.2% of the total births). RESULTS AND DISCUSSION: Screening results for 4972 "transferred" neonates were compared with those of non-transferred neonates (N=112,131). Screening coverage of eligible infants was significantly lower (75.4%) in "transferred" neonates (3750 infants screened) compared to 97.5% coverage of non-transferred neonates (109,349 infants screened). The rate of positive results after the first stage AABR was higher in the "transferred" population (11.1%) than in the non-transferred population (6.5%). Of the 415 "transferred" newborns with initial positive screens, 91.3% were rechecked as stipulated in the project protocol. The second pre-discharge AABR ascertained that in half of the cases auditory function had normalized in the day. Of the 183 "transferred" infants whose result remained suspect at the conclusion of both stages of the neonatal screen (4.9% of the tested population), only 70.5% returned to the audiology centre for diagnostic follow-up. The incidence of bilateral PCHI was markedly higher (4/1000) in "transferred" infants than in the non-transferred population (1.08/1000). CONCLUSIONS: The difficulty of obtaining universal screening coverage in "transferred" infants was, unfortunately, verified in this prospective, multicentre study. Further, the diversity of our "transferred" population was not much greater than that revealed by careful analysis of published hearing screening studies in neonatal intensive care unit (NICU) infants. The influence of risk factors and their more or less complex combinations is apparent.

Very far-advanced otosclerosis: stapedotomy or cochlear implantation.

CONCLUSION: Every patient with severe or profound hearing loss must have a temporal bone high-resolution computed tomography (CT) scan. Stapedotomy is a simple, safe and low-cost procedure compared with cochlear implantation and can provide very good results. This can justify our decision to propose stapedotomy at the initial treatment in patients with very far-advanced otosclerosis. In cases of hearing failure after stapes surgery, cochlear implantation is an option. OBJECTIVE: This study aimed to find the best first intention treatment of very far-advanced otosclerosis. MATERIALS AND METHODS: This was a retrospective study and included 14 patients with non-measurable preoperative bone and air conduction thresholds and otosclerosis on temporal bone high-resolution CT scan. Stapes surgery followed by a well fitted hearing aid was the initial treatment in 11 patients and cochlear implantation in 7 patients, including 4 patients who had poor results after stapedotomy. Objective and subjective audiometric results were studied and compared between stapedotomy and cochlear implantation groups. RESULTS: Objective and subjective results were statistically better in the cochlear implant group than in the stapedotomy group. However, four patients in the stapedotomy group had comparable results to the patients with cochlear implants.

OPA1 R445H mutation in optic atrophy associated with sensorineural deafness.

The heterozygous R445H mutation in OPA1 was found in five patients with optic atrophy and deafness. Audiometry suggested that the sensorineural deafness resulted from auditory neuropathy. Skin fibroblasts showed hyperfragmentation of the mitochondrial network, decreased mitochondrial membrane potential, and adenosine triphosphate synthesis defect. In addition, OPA1 was found to be widely expressed in the sensory and neural cochlear cells of the guinea pig. Thus, optic atrophy and deafness may be related to energy defects due to a fragmented mitochondrial network.

Binaurality in middle ear implant recipients using contralateral digital hearing AIDS.

OBJECTIVE: For some patients, conventional hearing aids might have disadvantages that clearly limit the benefit of using them. The middle ear implant, Vibrant Soundbridge hearing prosthesis offers an approach to help such patients. Our study's objective was to identify the binaurality in a well-fitted digital hearing aid worn in the contralateral ear in recipients experienced with use of the Vibrant Soundbridge middle ear implant device. STUDY DESIGN: In a prospective study, warble-tone thresholds and stereophony were evaluated for the following conditions: (1) binaural unaided-with the middle ear implant inactive and the behind-the-ear hearing aid removed; (2) middle ear implant alone-middle ear implant active, behind-the-ear hearing aid removed; (3) middle ear implant plus behind-the-ear omnidirectional-middle ear implant active, behind-the-ear active; and (4) behind-the-ear omnidirectional alone-middle ear implant inactive, behind-the-ear omnidirectional active. Behind-the-ear omnidirectional and behind-the-ear is defined as the behind-the-ear active in the omnidirectional or directional response, respectively. Behind-the-ear is a contralateral digital hearing aid to the middle ear implant. Benefits such as improved sound detection, speech perception in quiet and in noise, and sound quality were investigated. The evaluation of subjective hearing benefit was based on the Abbreviated Profile of Hearing Aid Benefit (APHAB) test. Paired t tests (subject) were used to analyze the differences between mean thresholds for the different test conditions. SETTING: Tertiary referral center. PATIENTS: Eight adults (aged 45-68 yr) had undergone implantation with a single Vibrant Soundbridge at least 12 months before starting the study. These eight subjects presented no contraindication for contralateral hearing aid use. Patients were fitted 5 weeks before testing with a Siemens Signia digital behind-the-ear hearing aid in the side contralateral to the Vibrant Soundbridge. RESULTS: Five weeks after use of the contralateral hearing aid together with the middle ear implant, mean differences in warble-tone thresholds between Conditions 2 and 3 and between Conditions 3 and 4 were both statistically significant. The mean differences in speech reception thresholds were in line with the mean differences in average warble-tone thresholds. The mean speech reception threshold for the middle ear implant plus behind-the-ear omnidirectional condition was slightly worse (3 dB) than that for the middle ear implant alone condition; however, this difference was not statistically significant. Whereas speech reception threshold difference between Condition 1 and Condition 4 was not statistically significant (60 dB and 61 dB, respectively). The mean difference for the 0-degree azimuth alone was statistically significant (p < 0.05) for the conditions middle ear implant alone and middle ear implant plus behind-the-ear omnidirectional. The middle ear implant alone appears to give good sensitivity at 2 kHz for any direction. Increasing scores indicate greater percentages of problems. Percentages of problems were on average lower for the middle ear implant when used with the contralateral digital hearing aid based on the global score. CONCLUSION: The use of a middle ear implant Vibrant Soundbridge together with a contralateral digital hearing aid improved functional gain and speech perception thresholds in quiet, especially for the sound coming from the front of the patient. The use of a middle ear implant together with a contralateral digital hearing did not significantly improve hearing in noise.

Speech perception and speech intelligibility in children after cochlear implantation.

OBJECTIVE: This study aimed to evaluate the long-term speech perception and speech intelligibility of congenitally and prelingually deaf children after cochlear implantation. It was a longitudinal study following 63 congenitally or prelingually deaf children up to 5 years after implantation. They each received a nucleus multichannel cochlear implant before they were 10 years old. METHODS: Perception is evaluated using the Test for the Evaluation of Voice Perception and Production (TEPP) and concerns closed- and open-set word and sentence perception without lip-reading. The intelligibility is classified according to the Speech Intelligibility Rating (SIR). The evaluations have been made every 3 months for 1 year, then at 18 months, 2 years, 3 years and 5 years after the cochlear implantation. RESULTS: After 5 years of implantation, the median percentage of closed-words speech perception (CSW) is 95.5%-93.67% for closed-sentence speech perception (CSS) and 76.3% for open-sentence speech perception (OSS); the median Speech Intelligibility Rating is 3.83. CONCLUSIONS: Congenitally and prelingually deaf children who receive cochlear implant before the age of 10 years develop speech perception and speech intelligibility abilities. The closed-set perception progresses quickly and seems to reaching a plateau at 5 years post implantation. The improvement of open-sentence perception is not significant until the first year post implantation. The speech intelligibility improves regularly the five first year post implantation.

Music perception in adult cochlear implant recipients.

OBJECTIVE: To evaluate musical perception in adult cochlear implant (CI) recipients, i.e. perceptual accuracy for pitch, timbre, rhythmic patterns and song identification. MATERIAL AND METHODS: Twenty-nine adult patients were included in this transverse single-center study. Evaluative measures included tests assessing ability to discriminate pitch, rhythm and timbre and to identify nursery songs with and without verbal cues. Performance scores were correlated with duration of deafness, duration of implantation, speech discrimination and musical perception skills. RESULTS: A total of 38% of patients reported that they did not enjoy listening to music with their device and 86% presented lower scores of listening habits after implantation. We found positive correlations between musical background and pitch identification and identification of nursery songs played by piano. We also found positive correlations between speech discrimination and rhythm, timbre and identification of nursery songs with verbal cues. CONCLUSION: Trends in the patterns of correlation between speech and music perception suggest that music patterns are differentially accessible to CI users. New processing strategies may improve this.