Towards Clinical Application of Neurotrophic Factors to the Auditory Nerve; Assessment of Safety and Efficacy by a Systematic Review of Neurotrophic Treatments in Humans.

Animal studies have evidenced protection of the auditory nerve by exogenous neurotrophic factors. In order to assess clinical applicability of neurotrophic treatment of the auditory nerve, the safety and efficacy of neurotrophic therapies in various human disorders were systematically reviewed. Outcomes of our literature search included disorder, neurotrophic factor, administration route, therapeutic outcome, and adverse event. From 2103 articles retrieved, 20 randomized controlled trials including 3974 patients were selected. Amyotrophic lateral sclerosis (53%) was the most frequently reported indication for neurotrophic therapy followed by diabetic polyneuropathy (28%). Ciliary neurotrophic factor (50%), nerve growth factor (24%) and insulin-like growth factor (21%) were most often used. Injection site reaction was a frequently occurring adverse event (61%) followed by asthenia (24%) and gastrointestinal disturbances (20%). Eighteen out of 20 trials deemed neurotrophic therapy to be safe, and six out of 17 studies concluded the neurotrophic therapy to be effective. Positive outcomes were generally small or contradicted by other studies. Most non-neurodegenerative diseases treated by targeted deliveries of neurotrophic factors were considered safe and effective. Hence, since local delivery to the cochlea is feasible, translation from animal studies to human trials in treating auditory nerve degeneration seems promising.

Comparison Between Simulated and Actual Unilateral Hearing in Sequentially Implanted Cochlear Implant Users, a Cohort Study.

Introduction: Previous studies have proven the effectiveness of bilateral cochlear implantation compared to unilateral cochlear implantation. In many of these studies the unilateral hearing situation was simulated by switching off one of the cochlear implants in bilateral cochlear implant users. In the current study we assess the accuracy of this test method. Does simulated unilateral hearing (switching off one cochlear implant) result in the same outcomes as real life unilateral hearing with one cochlear implant and a non-implanted contralateral ear? Study design: We assessed the outcomes of one arm of a multicenter randomized controlled trial. Methods: In the original trial, 38 postlingually deafened adults were randomly allocated to either simultaneous bilateral cochlear implantation or sequential bilateral cochlear implantation. In the current study we used the data of the sequentially implanted group (n = 19). The primary outcome was speech perception-in-noise from straight ahead. Secondary outcomes were speech perception-in-silence, speech intelligibility-in-noise from spatially separated sources and localization capabilities. A within-subjects design was used to compare the results of hearing with one cochlear implant and a non-implanted contralateral ear (1- and 2-year follow-up) with the results of switching off one cochlear implant after sequential bilateral implantation (3-year follow-up). Results: We found no significant differences on any of the objective outcomes after 1-, 2-, or 3-year follow-up. Conclusion: This study shows that simulating unilateral hearing by switching off one cochlear implant seems a reliable method to compare unilateral and bilateral hearing in bilaterally implanted patients. Clinical Trial Registration: Dutch Trial Register NTR1722.

No Difference in Behavioral and Self-Reported Outcomes for Simultaneous and Sequential Bilateral Cochlear Implantation: Evidence From a Multicenter Randomized Controlled Trial.

Objective: The primary aim of this study was to longitudinally compare the behavioral and self-reported outcomes of simultaneous bilateral cochlear implantation (simBiCI) and sequential BiCI (seqBiCI) in adults with severe-to-profound postlingual sensorineural hearing loss. Design: This study is a multicenter randomized controlled trial with a 4-year follow-up period after the first moment of implantation. Participants were allocated by randomization to receive bilateral cochlear implants (CIs) either, simultaneously (simBiCI group) or sequentially with an inter-implant interval of 2 years (UCI/seqBiCI group). All sequential patients where encouraged to use their hearing aid on the non-implanted ear over of the first 2 years. Patients were followed-up on an annual basis. The primary outcome was speech perception in noise coming from a source directly in front of the patient. Other behavioral outcome measures were speech intelligibility-in-noise from spatially separated sources, localization and speech perception in quiet. Self-reported outcome measures encompassed questionnaires on quality of life, quality of hearing and tinnitus. All outcome measures were analyzed longitudinally using a linear or logistic regression analysis with an autoregressive residual covariance matrix (generalized estimating equations type). Results: Nineteen participants were randomly allocated to the simBiCI group and 19 participants to the UCI/seqBiCI group. Three participants in the UCI/seqBiCI group did not proceed with their second implantation and were therefore unavailable for follow-up. Both study groups performed equally well on speech perception in noise from a source directly in front of the patient longitudinally. During all 4 years of follow-up the UCI/seqBiCI group performed significantly worse compared to the simBiCI group on spatial speech perception in noise in the best performance situation (8.70 dB [3.96 - 13.44], p < 0.001) and localization abilities (largest difference 60 degrees configuration: -44.45% [-52.15 - -36.74], p < 0.0001). Furthermore, during all years of follow-up, the UCI/seqBiCI group performed significantly worse on quality of hearing and quality of life questionnaires. The years of unilateral CI use were the reason for the inferior results in the UCI/SeqBiCI group. One year after receiving CI2, the UCI/seqBiCI group performance did not statistically differ from the performance of the simBiCI group on all these outcomes. Furthermore, no longitudinal differences were seen in tinnitus burden prevalence between groups. Finally, the complications that occurred during this trial were infection, dysfunction of CI, facial nerve palsy, tinnitus and vertigo. Conclusion: This randomized controlled trial on bilaterally severely hearing impaired participants found a significantly worse longitudinal performance of UCI/seqBiCI compared to simBiCI on multiple behavioral and self-reported outcomes regarding speech perception in noise and localization abilities. This difference is associated with the inferior performance of the UCI/seqBiCI participants during the years of unilateral CI use. After receiving the second CI however, the performance of the UCI/seqBiCI group did not significantly differ from the simBiCI group. Trial Registration: Dutch Trial Register NTR1722.

No Squelch Effect After Sequential Bilateral Cochlear Implantation in Postlingually Deafened Adults: Is There a First Ear Advantage?

OBJECTIVES: To investigate whether a squelch effect develops in postlingually deafened adults after sequential bilateral cochlear implantation. STUDY DESIGN: Prospective study as part of a randomized controlled trial on the difference between simultaneous versus sequential bilateral cochlear implantation. SETTING: Tertiary referral center. PARTICIPANTS: Sixteen postlingually deafened adults. INTERVENTION: Sequential bilateral cochlear implantation with a 2-year interimplant interval. MAIN OUTCOME MEASURE: A squelch effect was defined as a better bilateral score than unilateral score on a speech-intelligibility-in-noise test with spatially separated sources. The squelch effect was evaluated for the participants' best performing cochlear implant (CI) ear, the left CI in the condition with speech from -60 degrees azimuth and noise from +60 degrees azimuth (S-60 N+60), the right CI (N-60 S+60), CI1 and CI2. Evaluations took place 1, 2 and median 4 years after sequential implantation. RESULTS: No significant squelch effect was found, except for the right CI (N-60 S+60) after 2 years. No differences in speech perception-in-noise from straight ahead were seen between CI1 and CI2. Comparing performance of participants whose better or worse ear was implanted first did not reveal differences either. For the best performing situation, 7/16, 6/16, and 3/12 participants exhibited a squelch effect after 1, 2, and 4 years of follow-up. CONCLUSIONS: Participants who underwent sequential bilateral cochlear implantation with a 2-year interimplant interval did not develop an evident squelch effect on group level after a median follow-up of 4 years. Individual participants were able to make use of the squelch effect. The less evident squelch effect is at odds with our group of simultaneously implanted bilateral cochlear implant users. Neither a difference between CI1 and CI2, nor implanting the better or worse ear first could explain the less evident squelch effect in these patients. TRIAL REGISTRATION: Dutch Trial Register NTR1722.

Association of Behavior With Noise-Induced Hearing Loss Among Attendees of an Outdoor Music Festival: A Secondary Analysis of a Randomized Clinical Trial.

Importance: To date, factors associated with noise-induced hearing loss at music festivals have not yet been analyzed in a single comprehensive data set. In addition, little is known about the hearing loss-associated behavior of music festival attendees. Objectives: To assess which factors are associated with the occurrence of a temporary threshold shift (TTS) after music exposure and to investigate the behavior of music festival attendees. Design, Setting, and Participants: This prospective post hoc analysis gathered data from a randomized, single-blind clinical trial conducted on September 5, 2015, at an outdoor music festival in Amsterdam, the Netherlands. Adult volunteers with normal hearing were recruited via social media from August 26 through September 3, 2015. Intention to use earplugs was an exclusion criterion. Of 86 volunteers assessed, 51 were included. This post hoc analysis was performed from October 3, 2016, through February 27, 2017. Interventions: Music festival visit for 4.5 hours. Main Outcomes and Measures: The primary outcome was a TTS on a standard audiogram for the frequencies 3.0- and 4.0-kHz. Multivariable linear regression was performed to determine which factors are associated with a TTS. A questionnaire on behavior, hearing, and tinnitus was distributed to the participants before and after the festival visit. Results: A total of 51 participants were included (18 men [35%] and 33 women [65%]) with a mean (SD) age of 27 (6) years. Mean (SD) threshold change across 3.0 and 4.0 kHz was 5.4 (5.7) dB for the right ear and 4.0 (6.1) dB for the left ear. Earplug use (absolute difference in the left ear, -6.0 dB [95% CI, -8.7 to -3.2 dB]; in the right ear, -6.4 dB [95% CI, -8.8 to -4.1 dB]), quantity of alcohol use (absolute difference per unit in the left ear, 1.1 dB [95% CI, 0.5 to 1.7 dB]; in the right ear, 0.7 dB [95% CI, 0.1 to 1.4 dB]), drug use (absolute difference in the right ear, 6.0 dB [95% CI, 0.9 to 11.1 dB]), and male sex (absolute difference in the right ear, 4.1 dB [95% CI, 0.3 to 5.9 dB]) were independently associated with hearing loss, with earplug use being the most important factor. Unprotected participants reported significantly worse subjective hearing performance and tinnitus after the festival visit than did participants using earplugs (Cramer V, 0.62 [95% CI, 0.47-0.79] and 0.39 [95% CI, 0.16-0.62], respectively). In the earplug group, the perceived loudness (r = -0.72; 95% CI, -1.00 to -0.43) and appreciation (r = 0.53; 95% CI, 0.29 to 0.78) of music and speech perception (r = 0.21; 95% CI, 0.09 to 0.35) were correlated with the duration of earplug use. Conclusions and Relevance: The present study identified nonuse of earplugs, use of alcohol and drugs, and male sex as associated with a TTS at an outdoor music festival. Physicians should consider these factors to raise awareness about the combined risk of attending music festivals without using earplugs while consuming alcohol and/or drugs. The intention to use earplugs was correlated with the loudness and appreciation of music with earplugs, which may advocate for the use of personalized earplugs. Trial Registration: trialregister.nl Identifier: NTR5401.

Tinnitus after Simultaneous and Sequential Bilateral Cochlear Implantation.

IMPORTANCE: There is an ongoing global discussion on whether or not bilateral cochlear implantation should be standard care for bilateral deafness. Contrary to unilateral cochlear implantation, however, little is known about the effect of bilateral cochlear implantation on tinnitus. OBJECTIVE: To investigate tinnitus outcomes 1 year after bilateral cochlear implantation. Secondarily, to compare tinnitus outcomes between simultaneous and sequential bilateral cochlear implantation and to investigate long-term follow-up (3 years). STUDY DESIGN: This study is a secondary analysis as part of a multicenter randomized controlled trial. METHODS: Thirty-eight postlingually deafened adults were included in the original trial, in which the presence of tinnitus was not an inclusion criterion. All participants received cochlear implants (CIs) because of profound hearing loss. Nineteen participants received bilateral CIs simultaneously and 19 participants received bilateral CIs sequentially with an inter-implant interval of 2 years. The prevalence and severity of tinnitus before and after simultaneous and sequential bilateral cochlear implantation were measured preoperatively and each year after implantation with the Tinnitus Handicap Inventory (THI) and Tinnitus Questionnaire (TQ). RESULTS: The prevalence of preoperative tinnitus was 42% (16/38). One year after bilateral implantation, there was a median difference of -8 (inter-quartile range (IQR): -28 to 4) in THI score and -9 (IQR: -17 to -9) in TQ score in the participants with preoperative tinnitus. Induction of tinnitus occurred in five participants, all in the simultaneous group, in the year after bilateral implantation. Although the preoperative and also the postoperative median THI and TQ scores were higher in the simultaneous group, the median difference scores were equal in both groups. In the simultaneous group, tinnitus scores fluctuated in the 3 years after implantation. In the sequential group, four patients had an additional benefit of the second CI: a total suppression of tinnitus compared with their unilateral situation. CONCLUSION: While bilateral cochlear implantation can have a positive effect on preoperative tinnitus complaints, the induction of (temporary or permanent) tinnitus was also reported. CLINICAL TRIAL REGISTRATION: Dutch Trial Register NTR1722.

Objective and Subjective Measures of Simultaneous vs Sequential Bilateral Cochlear Implants in Adults: A Randomized Clinical Trial.

Importance: To date, no randomized clinical trial on the comparison between simultaneous and sequential bilateral cochlear implants (BiCIs) has been performed. Objective: To investigate the hearing capabilities and the self-reported benefits of simultaneous BiCIs compared with those of sequential BiCIs. Design, Setting, and Participants: A multicenter randomized clinical trial was conducted between January 12, 2010, and September 2, 2012, at 5 tertiary referral centers among 40 participants eligible for BiCIs. Main inclusion criteria were postlingual severe to profound hearing loss, age 18 to 70 years, and a maximum duration of 10 years without hearing aid use in both ears. Data analysis was conducted from May 24 to June 12, 2016. Interventions: The simultaneous BiCI group received 2 cochlear implants during 1 surgical procedure. The sequential BiCI group received 2 cochlear implants with an interval of 2 years between implants. Main Outcomes and Measures: First, the results 1 year after receiving simultaneous BiCIs were compared with the results 1 year after receiving sequential BiCIs. Second, the results of 3 years of follow-up for both groups were compared separately. The primary outcome measure was speech intelligibility in noise from straight ahead. Secondary outcome measures were speech intelligibility in noise from spatially separated sources, speech intelligibility in silence, localization capabilities, and self-reported benefits assessed with various hearing and quality of life questionnaires. Results: Nineteen participants were randomized to receive simultaneous BiCIs (11 women and 8 men; median age, 52 years [interquartile range, 36-63 years]), and another 19 participants were randomized to undergo sequential BiCIs (8 women and 11 men; median age, 54 years [interquartile range, 43-64 years]). Three patients did not receive a second cochlear implant and were unavailable for follow-up. Comparable results were found 1 year after simultaneous or sequential BiCIs for speech intelligibility in noise from straight ahead (difference, 0.9 dB [95% CI, -3.1 to 4.4 dB]) and all secondary outcome measures except for localization with a 30° angle between loudspeakers (difference, -10% [95% CI, -20.1% to 0.0%]). In the sequential BiCI group, all participants performed significantly better after the BiCIs on speech intelligibility in noise from spatially separated sources and on all localization tests, which was consistent with most of the participants' self-reported hearing capabilities. Speech intelligibility-in-noise results improved in the simultaneous BiCI group up to 3 years following the BiCIs. Conclusions and Relevance: This study shows comparable objective and subjective hearing results 1 year after receiving simultaneous BiCIs and sequential BiCIs with an interval of 2 years between implants. It also shows a significant benefit of sequential BiCIs over a unilateral cochlear implant. Until 3 years after receiving simultaneous BiCIs, speech intelligibility in noise significantly improved compared with previous years. Trial Registration: trialregister.nl Identifier: NTR1722.

Stable benefits of bilateral over unilateral cochlear implantation after two years: A randomized controlled trial.

OBJECTIVES/HYPOTHESIS: To investigate hearing capabilities and self-reported benefits of simultaneous bilateral cochlear implantation (BiCI) compared with unilateral cochlear implantation (UCI) after a 2-year follow-up and to evaluate the learning effect of cochlear implantees over time. STUDY DESIGN: Multicenter randomized controlled trial. METHODS: Thirty-eight postlingually deafened adults were included in this study and randomly allocated to either UCI or simultaneous BiCI. Our primary outcome was speech intelligibility in noise, with speech and noise coming from straight ahead (Utrecht-Sentence Test with Adaptive Randomized Roving levels). Secondary outcomes were speech intelligibility in noise with spatially separated sources, speech intelligibility in silence (Dutch phoneme test), localization capabilities and self-reported benefits assessed with different quality of hearing and quality of life (QoL) questionnaires. This article describes the results after 2 years of follow-up. RESULTS: We found comparable results for the UCI and simultaneous BiCI group, when speech and noise were both presented from straight ahead. Patients in the BiCI group performed significantly better than patients in the UCI group, when speech and noise came from different directions (P = .01). Furthermore, their localization capabilities were significantly better. These results were consistent with patients' self-reported hearing capabilities, but not with the questionnaires regarding QoL. We found no significant differences on any of the subjective and objective reported outcomes between the 1-year and 2-year follow-up. CONCLUSIONS: This study demonstrates important benefits of simultaneous BiCI compared with UCI that remain stable over time. Bilaterally implanted patients benefit significantly in difficult everyday listening situations such as when speech and noise come from different directions. Furthermore, bilaterally implanted patients are able to localize sounds, which is impossible for unilaterally implanted patients. LEVEL OF EVIDENCE: 1b Laryngoscope, 127:1161-1168, 2017.

The Effect of Earplugs in Preventing Hearing Loss From Recreational Noise Exposure: A Systematic Review.

IMPORTANCE: The prevalence of hearing loss among children and adolescents is rising dramatically, caused mainly by increased exposure to recreational noise. OBJECTIVE: To present a systematic overview of the effectiveness of wearing earplugs to music venues, such as nightclubs and concert halls, to prevent hearing loss and tinnitus directly after exposure. EVIDENCE ACQUISITION: PubMed, EMBASE, and the Cochrane Library databases were searched for articles from database inception to June 22, 2015, using the keywords music and earplugs and all synonyms. Titles, abstracts, and full text of retrieved articles were screened for eligible articles. The directness of evidence (relevance of the assessed articles) and risk of bias of eligible articles were assessed. For the included articles, the study characteristics and data on our outcomes of interest (hearing loss and tinnitus) were extracted. Data analysis occurred from June 22 to July 3, 2015. FINDINGS: Of 228 articles screened, 4 were eligible for critical appraisal. After critical appraisal, 2 studies with a high directness of evidence and low or moderate risk of bias remained for data extraction. Only 1 of these articles was a randomized clinical trial, which found significantly lower postconcert differences in thresholds and a lower proportion of threshold shifts in the group using earplugs compared with the unprotected group. In the other study, only 3 individuals wore earplugs, and no significant differences were found between the 2 groups. CONCLUSIONS AND RELEVANCE: The available evidence on the effectiveness of earplugs in preventing hearing damage directly after recreational music exposure is scarce. Only 1 well-conducted randomized clinical trial was found, which showed that wearing earplugs to concerts is effective in reducing postconcert threshold shifts. There is a need for further research on this topic to strengthen the level of evidence. Physicians should promote awareness on the risks of recreational noise and recommend the use of earplugs among their patients who visit music venues.

Effectiveness of Earplugs in Preventing Recreational Noise-Induced Hearing Loss: A Randomized Clinical Trial.

IMPORTANCE: The incidence of hearing loss has risen in past years. Attendance at music festivals and concerts may contribute to this increasing problem. OBJECTIVE: To assess the effectiveness of earplugs in preventing temporary hearing loss immediately following music exposure. DESIGN, SETTING, AND PARTICIPANTS: A randomized, single-blind clinical trial was conducted on September 5, 2015, at an outdoor music festival in Amsterdam, the Netherlands. Normal-hearing adult volunteers were recruited via social media. An exclusion criterion was the participants' intention to wear earplugs. Of the 86 volunteers assessed, 51 were included in the study. All analyses were performed on an intention-to-treat basis. INTERVENTIONS: Participants were randomly assigned to a group using earplugs or an unprotected group during a 4½-hour festival visit. MAIN OUTCOMES AND MEASURES: The primary study outcome was a temporary threshold shift (TTS) on the audiogram, primarily for frequencies at 3 and 4 kHz. Secondary study outcomes included distortion product otoacoustic emission (DPOAE) measurements and claims of tinnitus using a questionnaire and tinnitus matching experiments. RESULTS: Of 51 participants included, 25 were randomized to the earplug group and 26 to the unprotected group. Nine in each group (36% and 35%, respectively) were men, and the mean (SD) ages were 27.3 (5.6) years in the earplug group and 27.0 (6.2) years in the unprotected group. Baseline demographics were similar in both groups. The time-averaged, equivalent A-weighted sound pressure level experienced was 100 dBA during the festival. A TTS over frequencies at 3 and 4 kHz after exposure was seen in 4 of 50 ears (8%) in the earplug group compared with 22 of 52 ears (42%) in the unprotected group (P < .001). The relative risk for a TTS after exposure was 5.3 (95% CI, 2.0-14.3) for the unprotected group vs the earplug group. The number needed to treat with earplugs for preventing 1 TTS was 2.9. The DPOAE amplitudes decreased significantly more over the frequencies 2 to 8 kHz in the unprotected group: the mean (SD) decrease in magnitude was 0.6 (2.8) dB in the earplug group vs 2.2 (1.9) dB in the unprotected group (P = .04). Newly induced tinnitus following sound exposure occurred in 3 of the 25 participants (12%) in the earplug group vs 10 of 25 (40%) in the unprotected group (difference, 28%; 95% CI, 3.6%-49.0%; P = .02). CONCLUSIONS AND RELEVANCE: Earplug use is effective in preventing temporary hearing loss after loud music exposure. The present randomized clinical trial adds proof to the scarce evidence and knowledge on this topic, which is a growing global problem. TRIAL REGISTRATION: trialregister.nl Identifier: NTR5401.

Development of a Squelch Effect in Adult Patients After Simultaneous Bilateral Cochlear Implantation.

OBJECTIVES: To investigate whether a squelch effect occurs in the first 3 years after simultaneous bilateral cochlear implantation and to investigate whether this effect increases during follow-up. STUDY DESIGN: Prospective study as part of a multicenter randomized controlled trial that compares simultaneous bilateral cochlear implantation to sequential and unilateral cochlear implantation. SETTING: Tertiary referral center. PATIENTS: Nineteen postlingually deafened adults. INTERVENTION: Simultaneous bilateral cochlear implantation. MAIN OUTCOME MEASURE: The squelch effect, measured yearly with a speech-intelligibility-in-noise test with spatially separated sources. Bilateral results were compared to unilateral results in which the cochlear implant at the noise side was turned off. The squelch effect was investigated for the patients' best performing ear and for the left and right ears separately. RESULTS: In 13 individual patients, a squelch effect was present after 1 year. This number increased during follow-up years. On group level, a squelch effect was present in patients' best performing ear after 2 and 3 years (1.9 dB). A squelch effect was present in both ears after 3 years (AS: 1.7 dB, AD: 1.3 dB). CONCLUSION: Patients who underwent simultaneous bilateral cochlear implantation developed a measurable benefit from the squelch effect after 2 years in their best performing ear and after 3 years in both ears. These observations suggest that the brain learns to use interaural differences to segregate sound from noise after simultaneous bilateral cochlear implantation. The squelch effect increased over time which suggests a growth in cortical integration and differentiation of inputs from bilateral CIs due to brain plasticity. TRIAL REGISTRATION: Dutch Trial Register NTR1722. LEVEL OF EVIDENCE: 1b.