NLRP3 gene cause genetic diseases, including systemic inflammatory syndrome called cryopyrin-associated periodic syndrome (CAPS) and non-syndromic sensorineural hearing loss DFNA34. NLRP3 variants cause CAPS and DFNA34 by constitutively activating the NLRP3 inflammasome and increasing IL-1β release. Patients with CAPS show systemic inflammatory symptoms, and hearing loss is a characteristic feature. Patients with CAPS and DFNA34 show progressive bilateral sensorineural hearing loss. Hearing loss has unique characteristics that can be improved or stabilized by anti-interluekin-1 therapy, although it is usually difficult to alleviate genetic hearing loss by drugs. However, it should be noted that there is a window of opportunity to respond to treatment, and younger patients are most likely to respond. It is important to know the characteristics of CAPS and DFNA34 for early diagnosis, and mutation analysis of NLRP3 will lead to a definite diagnosis. In this review, we summarize the current understanding of the mechanisms of the NLRP3 inflammasome and characteristics of patients with CAPS and DFNA34, especially focused on auditory and vestibular findings.Inflammasomes are large multimeric protein complexes which regulate the activation of the proinflammatory cytokines interleukins-1β and−18 and inflammatory cell death called pyroptosis. NLRP1, NLRP3, NLRC4, AIM2, and pyrin can induce the formation of inflammasomes. Of these, the NLRP3 inflammasome is the most well-characterized. Recent studies revealed that variants of the  Inflammasomes are large multimeric protein complexes known for their ability to regulate the activation of the proteolytic enzyme caspase-1 . AssemblSensors of PAMPs and DAMPs in the cytosol include nucleotide-binding oligomerization domain and leucin-rich-repeat-containing receptors (NLRs), absent in melanoma-2 (AIM2)-like receptors (ALRs), and proteins that contain a tripartite motif, such as pyrin. Among these sensor proteins, some NLRs including NLRP1 (NLR family pyrin domain containing 1), NLRP3, and NLRC4 (NLR family caspase-activation and recruitment domain-containing protein 4), together with AIM2 and pyrin, can induce the formation of inflammasomes  and non-syndromic sensorineural hearing loss   , 6. The nant 34) . In thesWe obtained relevant literature published between 2012 and 2021, from PubMed and Embase, using the following medical terms: NLRP3, inflammasome for the section of NLRP3 inflammasome; CAPS, NOMID , MWS (Muckle–Wells syndrome), FCAS , hearing loss for the section of CAPS; DFNA34 for the section of DFNA34. The inclusion criteria were defined as papers from clinical series or reviews published in relevant journals with rigorous materials and methods. The exclusion criteria were defined as papers not available in full-text or papers not written in the English. Additional papers published before 2012 were identified through the references in the published literature. Full-text articles written in English language were obtained.The NLRP3 inflammasome consists of a sensor protein NLRP3, an adaptor protein known as apoptosis-associated speck-like protein containing a caspase-recruitment domain, and an effector protein caspase-1  8). NLR. NLR8). Because activation of the NLRP3 inflammasome is directly linked to the inflammatory process, it must be tightly regulated. With only a few exceptions, the activation of NLRP3 is a two-step signaling process. In the first step, it is primed, and then it is activated. Initial priming signals have at least two functions, the first of which is to upregulate the expression of the NLRP3 inflammasome components NLRP3, pro-IL-1β, and pro-IL-18. The second function is to induce post-translational modifications of NLRP3, which changes the auto-suppressed state into a non-suppressed state  15–17).–17.15–17After the initial priming step, the second step begins with the recognition of the NLRP3 activator and induction of the NLRP3 inflammasome formation. Although pattern recognition receptors are specific for one or more related PAMPs or DAMPS, NLRP3 can be activated by a wide range of unrelated stimuli . The NLRNLRP3 gene ..NLRP3 geNOMID, the most severe form of CAPS, usually occurs at birth or early childhood and is characterized by intermittent fever, urticarial rash, and persistently elevated acute-phase reactant levels with typical facial features such as frontal bossing and saddle back nose. The central nervous system (CNS) manifestations include chronic aseptic meningitis, that can lead to brain atrophy and severe intellectual disability, if untreated. Chronic polyarthritis, leading to bone deformity, is also typical . FCAS, tNLRP3 variants cause CAPS by leading to the constitutive activation of the NLRP3 inflammasome and increased IL-1β release. This is supported by in vitro studies using monocytes extracted from patients with CAPS. Monocytes from patients with CAPS only require an initial priming signal to induce IL-1β secretion, whereas wild-type control cells require a second activating signal . An. AnNLRP3g signal  27–29).–29.NLRP3g signal . It bindg signal . Canaking signal  (26). Rig signal , 31. Theg signal , 33. BHBg signal .NLRP3 variants have been reported in patients with CAPS on infevers database , and most of them affect the NOD domain of the NLRP3 protein. Some variants affect other regions of the protein, including the LRR domain. There are a few variants that cause one phenotype in some families and different phenotypes in other families. However, variants identified in patients with FCAS were not found in patients with NOMID. Thus, there is a fairly consistent genotype-phenotype correlation along the disease continuum , were conducted in five affected family members from a Dutch family with MWS. Although speech recognition scores were clearly affected in these members, they had higher speech recognition scores than patients with presbyacusis with similar levels of hearing impairment, indicating that speech recognition was well-preserved in the MWS family. The loudness growth curves of the affected family members showed steeper slopes than those of individuals with normal hearing. Both sets of findings indicate that hearing loss was primarily of cochlear origin (TECTA gene variants) and DFNA13 (COL11A2 gene), which are caused by tectorial membrane abnormalities. The mean gap detection result of the affected family members was close to that of individuals with normal hearing and was comparable to those of patients with DFNA8/12 and DFNA13. The mean DLf of the present family members was poorer than that of individuals with normal hearing, but was fairly similar to those of patients with DFNA8/12 and DFNA13. Thus, the results of loudness scaling, gap detection, and DLf of the affected family members were comparable to the results of patients with DFNA8/12 and DFNA13 with intra-cochlear conductive hearing loss, indicating that hearing loss in patients with MWS can be caused by the same pathogenesis  after the administration of gadolinium in the inner ear was performed to visualize potential inflammatory cochlear lesions . On FLAIIt should be noted that hearing loss in patients with CAPS can be improved or stabilized by inhibiting IL-1-mediated inflammation using anti-IL-1 drugs, such as anakinra and canakinumab. This is a unique characteristic of hearing loss in patients with CAPS, since it is usually difficult to treat genetic hearing loss by drugs . To dateSibley et al. presented the data of 26 patients with NOMID aged 1–42 years with a mean age of 12 years. Eighteen of the 26 patients had at least a mild hearing loss in one ear. Hearing improvement was found in 30% of the cases, and progression of hearing loss was halted in the majority of the patients by treatment with anakinra. In this study, cochlear enhancement on gadolinium-enhanced FLAIR-MRI was evaluated and scored in patients with NOMID. Higher scores were observed for ears with progressive hearing loss compared to those with stable or improved hearing, indicating that cochlear enhancement scores were predictive of further hearing loss . In a coRecently, Kim et al. evaluated the audiological response to anakinra therapy in 13 patients with CAPS, including nine patients with NOMID, two with MWS, and two with FCAS. They analyzed the audiological response in relation to the initial hearing threshold, cochlear enhancement on gadolinium-enhanced FLAIR-MRI, and inflammatory markers. Patients with initial hearing thresholds worse than 60 dB did not recover better than hearing thresholds of 60 dB, though 18-year-old male with MSW recovered from severe to moderate severe hearing loss with anakinra therapy. In contrast, patients with initial hearing thresholds better than 40 dB did not get worse than hearing thresholds of 40 dB, except for one patient with NOMID. These findings indicate that there is a time window of opportunity to respond to treatment and that initial hearing thresholds worse than 60 dB suggests poor hearing prognosis. Cochlear enhancement on FLAIR-MRI was examined in nine patients. Of these patients, cochlear enhancement was found in two patients who presented initial hearing thresholds worse than 60 dB and progression of hearing loss in spite of anakinra therapy. Thus, cochlear enhancement was associated with poor hearing prognosis. Inflammatory markers, such as C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were examined in all patients. The levels of CRP and ESR decreased immediately after anakinra therapy in most of the patients. However, sometimes the hearing deteriorated even when the inflammatory markers and systemic symptoms were well-controlled. Therefore, the dosage of anakinra required for controlling cochlear inflammation could be the highest among that required for the various tissues .Thus, anti-IL-1 therapy can mitigate hearing loss in patients with MWS and NOMID. There is a window of opportunity to respond to treatment, and the younger patients were most likely to respond to treatment, probably because persistent cochlear inflammation may damage the cochlear nerve and neuroepithelia to make hearing loss irreversible. In brief, cochlear enhancement on gadolinium-enhanced FLAIR-MRI and initial hearing thresholds worse than 60 dB may indicate poor hearing prognosis. Anakinra dosage required for controlling cochlear inflammation may be higher than that required for yielding effective results in other organs.NLRP3 related autoinflammatory hearing loss. These patients occasionally show ossification around round window and granulation tissues in scala tympani of the basal turn. Cochlear inflammation via the activation of the NLRP3 inflammasome affects cochlear tissue differently from what is caused by non-NLRP3 related autoinflammatory etiology.Audiologic performance was evaluated after CI in a patient with MWS and a patient with NOMID. Both patients had bilateral profound sensorineural hearing loss despite treatment with anakinra. The patient with MWS received CI in both ears at the age of 8 years, and the patient with NOMID received CI in the left ear at the age of 15 years. Their speech perception score, examined by the Korean version-central institute for the deaf (K-CID), reached 100% at 6 months post-CI, and was seemingly better than the CI outcomes of those with identified genetic etiology and those without identifiable genetic variants . These rDetailed vestibular function was reported in three articles on patients with MWS. In a study by Kuemmerle-Deschner et al. the vestibular function was assessed in 15 patients with MWS by videonystagmography, including observation of spontaneous and head shake nystagmus and nystagmus after caloric stimulation. None of the patients complained of vertigo. Neither spontaneous nor head-shake nystagmus was observed. Caloric stimulation showed a normal nystagmus response in all the patients . In a coNLRP3 variants  variant in the h DFNA34 , 49.Thus, two families from North American Caucasian and Korean populations were reported to have DFNA34. Surprisingly, both families have variants affecting the same amino acid, Arg918, located in the LRR domain in NLRP3. These results indicate that variants affecting Arg918 cause non-syndromic sensorineural hearing loss without inflammatory signs or symptoms in any other organ.Although the mechanism of hearing loss in CAPS and DFNA34 is still under research, some data had shed light on its etiology. Well-preserved speech recognition scores and absence of DPOAEs in patients with MWS and DFNA34, as mentioned above, are consistent with hearing loss being of cochlear origin, but not of retrocochlear etiology , 51. Cocf in patients with MWS were comparable to the results of patients with DFNA8/12 and DFNA13 with intra-cochlear conductive hearing loss, indicating that hearing loss in patients with MWS can be caused by the same pathogenesis  and JSPS KAKENHI Grant Number JP 20K09729 (HN).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer MH is currently organizing a Research Topic with the author HN.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The voice of individuals with hearing impairment has been widely described, and can be compromised in all levels of the phonatory system.To develop and validate an instrument for evaluating the voice of this population.The instrument underwent the validation steps suggested by the Scientific Advisory Committee of the Medical Outcomes Trust. The study sample consisted of seventy-eight Brazilian people with cochlear implants  and 78 individuals with normal hearing (control group), divided in groups by age range — children from 3 to 5 years; children from 6 to 10 years and adults from 18 to 46 years. The study sample participated in a voice recording of the sustained vowel /a/, connected speech and spontaneous conversation, in which three voice specialists rated using the proposed instrument. It consists of visual-analog scales of suprasegmental aspects, respiratory-phonatory coordination, resonance, phonation, additional parameters and general vocal perception.Evaluation by an expert committee and a pilot test established content validity. Reliability measures showed excellent test-retest reproducibility for the majority of the parameters. Analysis with the ROC curve showed that perceptual evaluation with the sustained vowel did not strongly differentiate individuals with cochlear implants from those with normal hearing, and the parameter “speech rate” did not differentiate the groups at all. For the connected speech and spontaneous conversation, the majority of the parameters differentiated the experimental group from the control group with an area under the curve ≥0.7. The cutoff values with maximum specificity and sensitivity were 30.5 for mild, 49.0 for moderate and 69.5 for intense deviation.The protocol for the evaluation of voice in subjects with hearing impairment, PEV-SHI, is a reliable and useful tool for assessing the particularities of the voice of individuals with hearing impairment treated with cochlear implants and can be used in research and clinical settings to standardize evaluation and facilitate information exchange among services. Voice production occurs by the integration of the respiratory, phonatory and articulatory systems,5The voice characteristics of individuals with hearing impairment can vary according to the type, severity, onset of the hearing loss, and to the treatment of choice. A list of perceptual attributes used to characterize the voice of these individuals in the last 10 years include: negative overall impression of the voice quality15Therefore, in addition to social, educational, and language limitations, hearing impairment can cause specific deviation of the communication related to speech and voice, interfering with intelligibility and crucially compromising the social integration of the individual,The studies that performed auditory-perceptual evaluation of the voice of individuals with hearing impairment used protocols and scales directed to the global population with voice problems such as the GRBAS scale For an adequate evaluation, it is important that the instrument consider all the relevant parameters to study a specific population. In addition, the scale should allow reliable discrimination between the normal voice and the voice of the target population.The ethics committee of the Brasília University — College of Health Sciences approved this study under process number 16887713.4.0000.0030. All participants, parents or legal guardians signed the informed consent.This study involved the participation of 156 individuals, seventy-eight people with cochlear implants  and their hearing peers (Control Group — CG) divided in groups by age range: 52 children from 3 to 5 years (G1), 54 children from 6 to 10 years (G2) and 50 adults from 18 to 46 years (G3). Half of the participants of each group consisted of the EG and half consisted of the CG. All participants were native speakers of the Brazilian Portuguese language. The EG included individuals with bilateral, severe to profound sensorineural hearing loss using a cochlear implant, with absence of associated disorders, attending a rehabilitation program, and who had experience of device use of at least one year. This study did not consider other criteria such as hearing loss onset, unilateral or bilateral implant, or use of contralateral hearing aid, since its purpose was to develop an instrument for the overall population with cochlear implants. The CG consisted of individuals with normal hearing. To verify normal hearing, the participants of the CG underwent pure-tone threshold audiometry. Exclusion criteria for both groups were professional voice use, stage of menopause for women, current or previous smoking, regular use of alcoholic drinks, previous laryngeal surgery and being ill with pulmonary or upper airway infection on the day of the recording session.The criteria recommended by the Scientific Advisory Committee of the Medical Outcomes TrustProtocolo de Avaliação de Voz do Deficiente Auditivo (PAV-DA), translated as Protocol for the Evaluation of Voice in Subjects with Hearing Impairment (PEV-SHI)   was deveThe establishment of content validity consisted of two steps. In the first, an expert committee consisting of speech-language pathologists and audiologists, who were not involved in in the development of the protocol, judged the initial version of the PEV-SHI for its clarity, parameters and form of evaluation. All suggestions were analyzed and a partial version was determined. In the second, two speech-language pathologists with 20 years of training performed a pilot test based on the analysis of five voice samples of each speech task of individuals with cochlear implants using the instrument. Both had participated in the expert committee. After the pilot test, final adjustments were made, determining the final version of the PEV-SHI.After the determination of the final version of the PEV-SHI, three voice specialists who had not participated in any of the previous steps of this study rated the voice samples with it. The use of an odd number of raters is important to avoid potential ties in the evaluation and this number of raters was selected based on common practice in auditory-perceptual assessment of voice.25The three raters had extensive experience in performing perceptual evaluation in normal and disordered voices, and one of them had experience working with voice disorders in individuals with cochlear implants. The raters participated in previous training sessions, with the purpose of becoming acquainted with the protocol and having the same understanding of the parameters assessed in each speech task. The ratings were performed separately by age range and speech tasks. The raters knew the age and gender of each voice sample, but not if it belonged to a participant of the EG or the CG. The raters were also unfamiliar with the patients. Each rater performed the task individually and the data was charted. If the difference between the score given by the three raters for a determined parameter was within a margin of ten points, the mean of the three scores was considered. For the parameters which the difference exceeded 10 points, consensus rating was carried out. The raters gathered in additional meetings for new analysis, discussion and rating of these parameters.The voice samples were recorded with the Sony Sound Forge 10.0 software with sampling rate of 44.100 Hz, 16 Bit, and Mono channel. The head microphone AKG C512, pre-amplifier M-audio Fast Track Pro and a notebook were used. The procedure was performed in a quiet, soundproof room with the microphone positioned at 45° with a 3 cm distance from the participant’s mouth.In order to establish reliability of the PEV-SHI, the raters repeated the auditory-perceptual evaluation of 20% of the voice samples in random order. The Interclass Correlation Coefficient (ICC) was used to verify test-retest reproducibility. The following correlation scale was adopted:Construct validity was determined in two steps. First, by comparing the scores of the EG and CG using ANOVA. In addition, analysis of efficiency, sensibility and specificity were performed using the ROC curve. The closer the AUC is to 1.0, the greater the distinction between the EG and the CG. Second, by correlating the scores of the PEV-SHI with an external clinical criterion. For this, the raters, in another occasion classified the voice samples according to the overall dysphonia Grade (G) of the GRBAS scale. This score was compared to the score of the general vocal perception of the PEV-SHI.The cutoff values were determined based on the score of the overall dysphonia Grade (G) and on the levels of specificity and sensitivity given by the ROC curve to differentiate the voice of an individual with hearing impairment from a listener using the score of the general vocal perception of the PEV-SHI for the three voice samples. In addition to the cutoff values, the severity of the vocal deviation was determined, which can range from a normal variability of the voice quality, mild deviation, moderate deviation or intense deviation.Respondent and administrative burden included a full description of any demands involving the administration of the PEV-SHI, including time, training and necessary resources.This study presents the development and validation process of the Protocol for the Evaluation of Voice in Subjects with Hearing Impairment (PEV-SHI).After analysis of all the suggestions made by the expert committee and the pilot tests, the final version of the PEV-SHI was determined. Changes from the initial version included changes in definition and order of presentation of parameters, change in terminology and unification of the parameters articulation and instability, which were previously unraveled into more parameters. The final version is clear, comprehensible and contains adequate content for the target population.The comparison of the scores between the EG and CG using ANOVA showed significant differences in most parameters. The task with least significant results was the sustained vowel, followed by the connected speech and spontaneous conversation , Table 3The efficiency of the PEV-SHI, given by the Area Under the Curve (AUC) of the ROC curve, demonstrated that the majority of the parameters is adequate to differentiate individuals with hearing impairment from individuals with normal hearing, especially for the connected speech and spontaneous conversation. Regarding the correlation between scores of the PEV-SHI with an external clinical criterion, there are significant and positive correlation between the scores of the G parameter of the GRBAS scale and the score of the general vocal perception of the PEV-SHI, indicating that as the general vocal perception increases in the VAS, it increases in the numerical scale (NS) and vice-versa. Most correlations were classified as good and excellent. This analysis was not performed for the connected speech and spontaneous conversation for G3, since there was no variability of responses in the NS .Table 6CTo determine interpretability of the PEV-SHI the ROC curve was used to set the cutoff values based on the parameter general perception of the voice quality and the parameter G from the GRBAS scale. The cutoff values in the VAS were obtained by correlation between the VAS and the NS . The maxRespondent burden refers to the recording procedure of the voice samples. In this study, the PEV-SHI was used to assess the voice of 156 individuals, divided into the EG and CG by age range. The individual had to attend the location of the recording where they received instructions to perform the three tasks. The time for the recording was about 10 min. The PEV-SHI was considered not suitable for individuals with hearing impairment who had poor language development and could not perform the speech tasks. Administrative burden included a quiet environment, recording equipment , headphones, a printed PEV-SHI, pencil and ruler. The time for analysis by the raters was about two minutes for each speech task. To complete the PEV-SHI the rater must be familiar with all of the definitions and instructions for completing the analysis with the protocol. The rater must also be experienced in the evaluation of normal and altered voices, and with speech and voice of people with cochlear implants.Auditory-perceptual evaluation of the voice quality is a key element in the clinical assessment of the voice. The use of non-specific instruments, however, may not approach some relevant characteristics of a certain population. The population with hearing impairment is an example of people with particular voice features the exceed alterations at a glottal level. An instrument that approaches all of the potential attributes of the voice is, therefore, of great importance to characterize with precision the voice of this population.The validation process was conducted in steps.In the following steps, auditory-perceptual evaluation was performed with the PEV-SHI for the extraction of the psychometric measures of reliability, efficiency, sensitivity, specificity and cutoff values.Reliability measures, extracted with the ICC based of the repetition of the auditory-perceptual evaluation of 20% of the sample showed good and excellent reliability for the majority of the parameters . The PEVThe comparison of the EG with the CG using ANOVA , Table 3In the sustained vowel, there was occurrence of AUC ≤ 0.5 for the parameters breathiness (G1), anterior resonance (G2 and G3) and breathiness  . The susThe PEV-SHI was more efficient to differentiate the population with CI from the population with normal hearing for the tasks involving speech. Even though the parameters pitch and loudness had acceptable AUC in the connected speech and spontaneous conversation for most groups , these pThe same occurs with the parameters resonance and intonation. Resonance had AUC ≥ 0.7 for two groups in the connected speech and one group in the spontaneous conversation . IndividThe sensitivity and specificity of an instrument refer to its ability to correctly detect individuals, respectively, with or without a disorder.,To determine construct validity, a simple scale for auditory-perceptual evaluation with power of discrimination of different degrees of vocal deviation using a robust parameter  and a unidimensional scale  were used.37The cutoff value is a number from which the result of a test is classified either as positive  or negative (absence of what is being tested). If the result found is smaller than the cutoff value, the result of a test is classified as negative and vice versa.The results discussed in this section show that the sustained vowel did not differentiate the voices of the individuals with cochlear implants from those with normal hearing as robustly as the connected speech and spontaneous conversation. Even so, the vowel can be used, with caution, for evaluation with the PEV-SHI, considering that this task has great importance for the global comprehension of the vocal behavior.40Some of the benefits of using the PEV-SHI for the target population over existing auditory-perceptual tools include: evaluating voice while taking into account in a single instrument all elements of the voice production Although this validation study was performed with CI users, the PEV-SHI can also be of great contribution other groups of individuals with hearing impairment, such as users of hearing aids or other implantable devices. The extraction of psychometric measures for other groups with hearing loss is recommended, since the cutoff values established in this study correspond to CI users of the studied age rage. Further studies include also the use of the PEV-SHI with individuals with hearing impairment during the stages of puberty and aging. The PEV-SHI is currently undergoing transcultural adaptation for the English language.The PEV-SHI is a reliable and useful tool for assessing the particularities of the voice of individuals with hearing impairment with cochlear implants and can be used in research to standardize evaluation and facilitate information exchange among services. It can also be used as part of the clinical assessment of patients, which should encompass all aspects of oral communication, from auditory abilities, to language development, orofacial functions and voice production. Finally, it can be useful in defining therapeutic goals, and follow up of the patient.The content of the Protocol for the Evaluation of Voice in Subjects with Hearing Impairment (PEV-SHI) is adequate for the intended target population. It has good test-retest reproducibility and is sensible and reliable for all the studied age groups, especially for the connected speech and conversational speech. The cutoff values with maximum sensibility and specificity were those found for the overall population in the conversational speech and these can be used as values of reference in the application of the PEV-SHI. The cutoff values to be considered are, therefore, from 0 to 30.5 normal variability of the voice quality, from 30.6 to 49 mild deviation, from 50 to 69.5 moderate deviation and above 69.5 intense deviation. The use of the PEV-SHI requires adequate sound capture, clinical experience and familiarity of the rater with the voice of individuals with hearing impairment.The authors declare no conflicts of interest.


Residual hearing in cochlear implant (CI) candidates requires the functional integrity of the nerve in particular regions of the cochlea. Nerve activity can be elicited as electrically evoked compound action potentials (ECAP) after cochlear implantation. We hypothesize that ECAP thresholds depend on preoperative residual hearing ability.® CI632 Slim Modiolar Electrode and who preoperatively had had residual hearing. Inclusion criteria were severe to profound hearing loss with preoperative measurable hearing in the ear to receive the implant, postlingual hearing loss, German as native language and correct placement of the electrode, inserted completely into the scala tympani. Electrically evoked compound action potential (ECAP) was recorded intraoperatively. The angular insertion was measured for each electrode contact from postoperative computed tomography to estimate the corresponding spiral ganglion frequency. Pure-tone audiometry and allocated ECAP thresholds were tested to investigate possible correlation.In a retrospective study, we analyzed 84 adult cochlear implant users who had received a Nucleusp < 0.001). Higher hearing thresholds are associated with increased ECAP thresholds.The average of hearing thresholds, tested at 0.5, 1, 2, and 4 kHz (4FPTA) was 82 ± 18 (range 47–129) dB HL. The success rate for recording ECAP thresholds was 96.9%. For all comparable pure-tone frequencies , there was significant correlation between preoperative hearing levels and intraoperative ECAP thresholds (In CI candidates with adequate residual hearing, intraoperative electrophysiological measurement records lower thresholds. This outcome may be explained by the neural survival density of the peripheral system, with less neural degeneration. The CI consists of an electrode array that is positioned directly in the cochlear and can electrically stimulate the auditory nerve. After CI surgery and initial activation, with increasing CI experience the auditory performance with CI generally improves . HoweverIn a recent study, Besides the patients’ etiology, the final positioning of the CI electrode array can also influence the postoperative hearing outcome. The excitation of a population of auditory nerve fibers by the stimulation of a single electrode is defined as “electrode–neuron interface” . E.g., amax) in subjects with unaided speech recognition correlates positively with postoperative hearing performance with a CI , which reflects neural survival rate of the peripheral system. Subjects with substantial low-frequency residual hearing can even use electric acoustic stimulation (EAS), which may increase hearing performance with a CI later on . TypicalIn recent years electrocochleography (ECoG) has gained increasing importance as a measuring tool in CIs. ECoG records the electrical potentials which are generated in the inner ear and auditory nerve after an acoustic stimulus is presented. This allows to objectively characterize the function of the peripheral auditory system and to acoustic hearing. ECoG measures can be recorded extracochlear using a recording electrode placed at the promontory, the stapes, or the tympanic membrane. Modern CI systems can also use the intracochlear electrodes as recording electrode . IntraopEven though ECoG measures can provide important information of the auditory periphery, in most CI patients responses can only be recorded reliably until 1,000 Hz , since tThe majority of today’s CI candidates – even if not regarded as EAS candidates – have preoperative hearing thresholds  within t1 between 0.2 and 0.4 ms and one positive peak P1 between 0.6 and 0.8 ms after the stimulus onset . In contrast to the acoustically evoked ECoG measures, ECAPs are evoked by an electrical stimulus. The ECAP response typically shows a biphasic morphology with one negative peak Nus onset . The ECA1 and P1 . TypicalECAP responses have already been investigated in various studies in animal models and human CI users. Animal studies have shown a relationship between ECAP responses and the number of surviving spiral ganglion cells SGCs; . The sloIn human CI recipients ECAPs are an established tool intraoperatively to monitor and verify the electrode-nerve interface and postoperatively to assist the CI fitting process. In individual cases, ECAP thresholds might be used in clinical programming to set behavioral stimulation levels; but so far studies reported only mixed results with regard to correlation of both parameters . In addiSince ECAP thresholds can be recorded in almost all CI users  and investigated their correlation with the corresponding individual, anatomical SG frequency maps. On the basis of our clinical experience, we hypothesize that subjects with low PTAs will achieve lower T-ECAPs, since there are more healthy auditory nerve fibers to respond to and the neural degeneration is less severe.2.2.1.This was a retrospective study which included adult subjects with valid pure-tone thresholds before CI implantation. Preoperative audiometric and speech measurements were acquired within the CI candidacy screening procedure. Objective T-ECAP measurements were conducted intraoperatively during CI implantation.All subjects agreed to the use of their data in this study as part of a general declaration of consent to clinical research .2.2.Participants were native German speakers and at least 18 years of age at the time of implantation. Onset of severe to profound hearing loss had to be postlingual. All subjects received a Slim Modiolar electrode CI632 . Additional inclusion criteria were: fully inserted electrodes with complete scala tympani (ST) positioning. Exclusion criteria were: tip foldover of the electrode; reimplantation or reinsertion of the electrode; abnormalities of the cochlea or of the auditory nerve; cognitive disorders which prevent undergoing audiometric assessment.The subject group consisted of 42 females and 42 males; their age at time of implantation ranged from 25 to 85 years, with a mean  of 65 ± 13 years. Of the 84 subjects, 38 received their CI on the left and 46 on the right side. Mean ± SD duration of deafness was 12 ± 13 (range: 1–59) years. Demographic data are shown in 2.3.Subjects underwent an audiological test battery during the CI assessment. The unaided pure-tone audiometric threshold for octave-spaced frequencies from 125 Hz to 8 kHz were obtained by using air-conduction headphones  and the AT 1000 audiometer  which was calibrated according to the DIN EN 60318 standard. The contralateral ear was masked appropriately. The pure-tone average threshold (4FPTA) was calculated from frequency thresholds: 0.5, 1, 2, and 4 kHz. If a pure tone was “not heard” at the maximum output level of the audiometer, the subject’s hearing loss was estimated as the maximum output level plus 10 dB.max) that was still below the patient’s loudness level of discomfort was noted (Word recognition score (WRS) for phonemically balanced monosyllabic words  under unas noted .2.4.N = 77) or round-window enlargement (N = 7). ECAP data were recorded intraoperatively after insertion and closure of the round window opening.All CI surgical procedures were performed by the same experienced surgeon according to the manufacturer’s guidelines  by the sPlain X-ray imaging was used intraoperatively to ensure that no electrodes were inserted incorrectly , and digital volume tomography (DVT) was performed within the 2 days after surgery in order to verify in detail that the intracochlear electrode positioning was correct.2.5.apical) and most basal electrode E1 . Diameter A was measured as the distance between the round window and the outer wall passing through the modiolus, while the insertion depth angles were calculated relative to the reference line drawn between the round window and the modiolus (AE) according to the manufacturer’s specifications  and the length of the outer wall (LLW) for the matching angular insertion depth according to Postoperative DVT scans were analyzed in “cochlear view”  with regmodiolus . As descThe MP describes the average proximity of the electrode contacts to the modiolus. A large MP (up to 1) corresponds to an electrode array that is placed laterally (comparable to straight electrodes), while a small MP describes an electrode array that is very close to the modiolus.2.6.In order to analyze the ECAP responses in relation to the actual cochlear place pitch, the frequency allocation for each electrode’s insertion angle was calculated.apical and θbasal were estimated by linear interpolation for each subject. For each electrode contact, the spiral ganglion frequency was determined according to the findings of The remaining 20 insertion depth angles between θ2.7.1 and P1) in a row were found; subsequent the stimulation levels decrease in 3 CU steps until a nonresponse is found. Then, the T-ECAP is estimated as the mean from the lowest recorded response and the highest recorded nonresponse  and MATLAB™ software .Post hoc analysis was performed and p values were adjusted by using the Bonferroni correction for multiple comparisons. Correlation analysis was performed by Spearman rank correlation. Statistical significance was defined as p < 0.05.Normal distribution (Shapiro–Wilk test) did not apply to all variables. Therefore, the nonparametric Friedman test and the Kruskal–Wallis test were used for comparing the equality of paired and unpaired samples, respectively. 3.3.1.χ2(6) = 269.89, p < 0.001]. Median 4FPTA was 82 dB HL .The mean preoperative hearing loss ranged from 55 dB HL (125 Hz) to 100 dB HL (8 kHz) and is illustrated in max was 35% . WRSmax and 4FPTA were significantly correlated .Mean WRS3.2.apical of 380° (SD 24.2°) was achieved, ranging from 315° to 425°. Mean insertion depth at the most basal electrode  was 9.4° . A negative correlation was found between the insertion depth angle θapical and the cochlear size with regard to diameter A .The cochlear parameters of the basal turn diameter A value  ranged from a minimum of 8 mm to a maximum of 10 mm. An average insertion depth angle θThe medial-lateral position MP ranged between 0.53 and 0.70 with a mean of 0.62 (SD 0.03). The most apical electrode E22 reached a mean SGC frequency of 749 Hz (SD 100 Hz) with a range between 615 and 1,162 Hz, while the most basal electrode E1 covered the SGC region around 16 kHz .3.3.Intraoperative T-ECAP measurements were performed in all 84 subjects at all 22 electrode contacts. In 57 out of the 1,848 electrodes tested, no valid T-ECAP could be measured. The overall success rate was 96.9%. In 61 subjects (73%) all 22 T-ECAPs could be measured. In eleven and two subjects respectively, 21 and 20 T-ECAPs were still detectable. In four subjects each, 19 and 18 T-ECAPs were measured. There was one subject with only 16 and one with only 14 valid T-ECAPs.χ2 (21) = 749.33, p < 0.001]. The pairwise comparison from post hoc analysis showed main differences among apical , medial  and basal  electrodes.The mean T-ECAP was 177 CU . The mean T-ECAP profile shows a pattern of increasing T-ECAPs from apical to medial electrodes, reaching a plateau at the medial region before thresholds increased further toward the basal region of the electrode array . T-ECAPsχ2(3) = 367.06, p < 0.001]. Post hoc comparison revealed significantly higher ECAP thresholds for electrodes within the SG octave frequency band 8 kHz compared with 1, 2 and 4 kHz. Conversely, T-ECAPs around 1 kHz were significantly lower compared with those at 2, 4 and 8 kHz.3.4.p = 0.724). Also, the insertion depth angles θapical and θbasal were not correlated with T-ECAPs at the corresponding EL22 (p = 0.539) and EL1 (p = 0.131).No correlation was found between the medial-lateral position MP and mean T-ECAP (p = 0.345).There was no correlation found between cochlear diameter A and mean T-ECAP . Additionally, r = 0.18, p < 0.001), 2 kHz , 4 kHz , and 8 kHz  with T-ECAPs at the corresponding placed electrodes. Linear regression analysis was performed for each subset.Hearing thresholds as represented by the 4FPTA and by T-ECAP were significantly correlated (max (p = 0.575). Also, there was no correlation found between cochlear diameter A and 4FPTA (p = 0.989).No correlation was found between mean T-ECAP and WRS4.The main finding of this study was that ECAP values measured intracochlearly are quantitatively correlated with preoperative hearing. Similar results were reported for acoustically measured compound action potentials measured by electrocochleography . From th4.1.Before cochlear implantation, audiometric measures are assessed in order to identify CI candidates. As Pure-tone thresholds in CI candidates for frequencies above 6 kHz are usually beyond the technical limits of the audiometer , indicating complete loss of function of the inner hair cells at and above that frequency those frequencies. Therefore, we could not measure and include frequencies beyond 8 kHz in our analysis; even though it can be expected that these basal regions are affected the most by auditory sensory loss and auditory deprivation.4.2.apical of 380 ± 24.2° is comparable to results of other studies using the Slim Modiolar electrode  of 18° compared with the 9.4° found in this study. These variations can result from various factors, e.g., different surgical approaches . The round window approach was more frequently used in this study . This success rate is even higher than the previously rate of 95.6% reported by The average T-ECAP profile of perimodiolar electrodes has been demonstrated in numerous studies. The profile typically shows increasing ECAP thresholds from the apical to the medial electrodes, where a plateau or in some cases a maximum is reached, with a slight decrease before increasing further  toward tElectrode impedance can also influence T-ECAPs. Regarding the electrodes’ intracochlear positioning, in our results the average medial-lateral position of 0.62 shows that there is an overall small distance between electrode contacts and the modiolus. Regardless of this, the physical electrode-to-modiolus distance is not correlated with ECAP thresholds, which confirms the findings of Lastly, the Slim Modiolar electrode is designed to be more effective with regard to the preservation of residual hearing. Therefore, patient recruitment might have changed over time, since more subjects with substantial amount of residual hearing nowadays receive this perimodiolar electrode array instead a straight  or shorter  electrode array.4.4.The effects of reduced ECAP responses caused by a smaller amount of surviving SGCs have been shown in animal studies . Ramekerapical) of the most apical EL22 is 380°, which corresponds to 749 Hz (SD 100 Hz) SG frequency, there are only few subjects with the most apical electrode inserted within the octave band with the 500 Hz center frequency; therefore, this frequency group was not included in the final analysis. Additionally, sufficient hearing thresholds beyond 8 kHz were not encountered in any subject; hence, we could not include higher-frequency groups in our correlation analysis with ECAP measures.Our cohort of CI users showed a similar relationship. Subjects with better preoperative hearing also had lower ECAP thresholds, meaning that a smaller amount of electrical stimulation was needed to determine the objective auditory response. We therefore take this as further evidence that T-ECAPs can reflect intracochlear neuronal health status. This correlation is evident for frequencies 1, 2, 4 and 8 kHz . Since tNonetheless, it is important to point out that around an SG frequency of 16 kHz the overall highest ECAP thresholds were found. With regard to our findings, we assume that in these basal regions the neural survival of the peripheral auditory system is particularly low. Studies that used histopathological analysis support this assumption. For example, Overall, histopathological studies show that auditory neuronal loss occurs at various stages  and is driven by age, etiology and severity of the hearing impairment.max. The arithmetic T-ECAP mean of all electrodes might be too vague, since speech recognition requires central auditory processing and T-ECAPs do not provide information about temporal processing. Other study groups who investigated in the relationship between ECAP measures and postoperative speech perception outcome with CI showed a more complex picture. Instead of just using T-ECAPs, 1-latency and refractory recovery function. In adults, they showed a significant correlation of Consonant-Nucleus-Consonant-word (CNC) lists and AzBio sentence measures in quiet with the ECAP index. Lastly, we found no correlation between intraoperative mean T-ECAP and preoperative WRS4.5.max can be a predictor of the minimum speech perception obtained with CI later on . Additionally, we have no knowledge of the individual existence of potential cochlear dead regions . If therA similar effect might occur at the electrophysiological level in ECAP measures. Due to the monopolar stimulation mode, the spatial spread generated by the electrical stimulus of one single electrode can cause excitation of neighboring SGNs . It has 5.This study in cochlear implant (CI) users with preoperative residual hearing analyzed the relationship of peripheral health status on electrically evoked action potentials with CI. In our study cohort, a significant link was found between preoperative pure-tone hearing levels and objective hearing-nerve responses at the corresponding stimulation site.This new insight adds another element in the complex relationship of the various factors that influence the subsequent outcome with a CI.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving humans were approved by Ethikkommission der Friedrich-Alexander-Universität Erlangen-Nürnberg. The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements.The study was designed by TL and UH. TL, UH, and JH collected the data. TL analyzed and interpreted the data. The manuscript was written by TL. All authors read and approved the final manuscript.


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. Vestibular schwannoma (VS), or acoustic neuroma, is a benign Schwann-cell-derived tumor that originates from the glial layer enveloping the VIII cranial nerve. VS most frequently develops from the vestibular branch of the cochlear nerve (CN) . It is mThe possible management choices depend on the tumor and on the patient’s hearing features. The therapeutic options are observation, radiotherapy, or surgery. According to size and preoperative hearing, translabyrinthine and hearing-preservation approaches  are the most frequently performed. In selected conditions, hearing preservation surgery (HPS) represents the best therapeutic choice ,4. ObserHearing loss in VS can be classified as iatrogenic and tumorigenic. Iatrogenic hearing loss is correlated with the treatment of either surgery or radiotherapy. When a hearing preservation attempt fails, surgery provides an immediate solution for hearing treatment, while in radiotherapy, hearing loss takes longer before manifesting . TumorigHearing loss is the most frequently reported symptom associated with VS. The typical form of hearing affliction caused by VS is a slowly progressive, high-frequency, unilateral, and asymmetric sensorineural hearing loss (SNHL) ,25. LessWhen hearing preservation surgery is performed with successful outcome, the quality of the preserved hearing can be similar pre-treatment conditions, or it can deteriorate to various degrees. In the case of partial hearing loss, various types of hearing rehabilitation devices can be useful. Auditory rehabilitation should be considered in these patients, especially in those who have associated contralateral hearing impairment.The available rehabilitation strategies for VS patients are conventional hearing aids, contralateral routing of signal (CROS) hearing aids, bilateral contralateral routing of signal (BiCROS) hearing aids , and bonThis paper is focused on the current knowledge about the use of hearing rehabilitation devices, such as CROS, BiCROS, and BAHA hearing aids, for both the condition of single-side deafness and hearing impairment in the VS-affected ear.PubMed, Embase, and Scopus were systematically screened from January 2012 up to July 2022 using the following free term search: “hearing aid” OR “CROS” OR “BiCROS” OR “baha” AND “vestibular schwannoma”. The literature search was independently performed by three authors . All the retrieved publications were evaluated to identify the most relevant ones. Duplications or aggregations of pre-existing data were excluded; only articles in English and Spanish were included. The reference lists of selected articles were also analyzed to identify additional studies.After a review of the available literature, 283 articles were identified. Twenty-nine studies were considered for their relevance and matched to the topic of the present narrative review. The list of analyzed studies can be found in Pure tone audiometry and speech audiometry are the gold standard exams for the assessment of hearing function and the benefit of a rehabilitation with hearing aids. The speech discrimination score (SDS), more than PTA, is a useful predictor of successful rehabilitation with hearing aids ,41. ABR There is a shortage in studies regarding the degree of VS-related hearing loss that could benefit from hearing rehabilitation, and there are no specific indications for patients affected by VS regarding this topic. It has been described that patients using any type of hearing aid device most frequently have class C−D hearing . As expected, mild−moderate hearing loss with a good word-recognition score is considered the best condition for successful rehabilitation with hearing aids, which is a frequent condition in the HPS outcome . HearingFew papers have investigated the rehabilitation of hearing loss in the less frequent intralabyrinthine schwannomas, describing poor results with different types of devices, such as conventional and CROS hearing aids . ConsideThe conventional hearing aid (air-conduction type) seems to be the most used type of device among VS hearing impaired patients . This kiA limited use of hearing aids among VS patients has been described in the literature. This finding is probably due to various factors. Among specialists, there is a general lack of knowledge regarding the available rehabilitative options. Many patients are not properly informed regarding these rehabilitation alternatives. Regular and repeated counseling is recommended to increase hearing rehabilitation after VS treatment .Another factor influencing the use of hearing aids in VS patients is a limited perception of handicap. Most patients with unilateral hearing loss become used to their condition and prefer to avoid further rehabilitations, even in the case of a high degree of hearing loss. This can be explained by the fact that hearing aids, which are visible and clearly detectable on the patient, manifest the disability, whereas single-side hearing loss can be compensated by the contralateral ear, although at the price of a disabling of any progressive hearing fatigue. Other factors affecting the use of hearing aids may include the economic cost, the difficulty of use, and the initial limited benefit provided by the current hearing rehabilitation devices .Hearing aids are considered a viable rehabilitation for those NF2 patients with serviceable hearing. These devices are mostly suggested for moderate−severe hearing loss as a temporary treatment. The type of hearing impairment of this illness, such as the retrocochlear damage, the decreased speech intelligibility, and the distortion, drive some patients to choose not to use aids . HearingDespite the presence of normal hearing function in one ear, verbal communication difficulties are quite common in unilaterally deaf patients. The unilateral deafness is characterized by two main kinds of impairment. First, the difficulty to detect sounds that come from the deaf side, due to the shadow effect of the head. As a result, the patient needs to turn the head to the sound source, to perceive sounds with the normal ear. Secondly, there is a loss of those binaural processes that usually improve the signal-to-noise ratio (SNR) and enable hearing localization ,54. BothThe authors noticed a deficit in studies regarding the use of CROS hearing aids in patients affected by VS. Introduced for the first time in 1965 from Hartford and Barry, the CROS hearing aid is a traditional recommendation for unilateral deafness rehabilitation. It consists of two devices: a microphone placed in the deaf side that routes sound to a receiver positioned in the serviceable ear. This strategy mimics binaural sound processing and expands the area of hearing. In the literature, it has been reported that non-surgical cross-hearing devices were able to enhance the sound-to-noise ratio in noisy and reverberant spaces, especially when speech signal and background noise were spatially separated . These tUnfortunately, there is a deficit in the current literature regarding studies about the use of CROS hearing aids in VS patients. Consequently, the CROS hearing aid indication can be derived only from diseases with similar clinical features. The natural history of VS as well as surgery or radiotherapy can sometimes cause profound hearing loss. All of these conditions may lead to deafness, making these patients a possible target for this kind of rehabilitation . NeverthBiCROS is like CROS, but it also rehabilitates contralateral non-VS hearing. A microphone on the deaf side provides an amplified sound to the better (but still impaired) hearing ear. It represents a useful device for SS-deaf people with a contralateral mild−moderate associated hearing loss .BAHA aids exploit transcranial bone conduction. The sound is routed to the better ear from a microphone, or a processor connected to an implant on the affected side, osseointegrated in the skull . HearingFew studies were conducted on BAHA hearing rehabilitation in patients with single-sided deafness after retrosigmoid removal of vestibular schwannoma. Boucek et al. studied the audiological results in 16 patients who accepted BAHA implantation. They found a significant improvement in sentence discrimination in the 6-week (64.0%) and 1-year (74.6%) interval at follow-up. This improvement was noticed in situations where sentences were coming from the side of the non-hearing ear, with −5 dB SNR contralateral noise .Another study evaluated the subjective hearing handicap in patients with unilateral deafness after VS surgery and the effect of the BAHA on test band. Twenty-six patients attended the BAHA testing session, and they had a median improvement in the discrimination score of 15%. However, only half of them agreed to BAHA implantation after the test .Many studies comparing CROS and BAHA technologies are available, but unfortunately none are specifically focused on VS patients. Some studies reported better speech identification with interfering noise with BAHA aids and a better acceptance from patients ,53. OtheSevere to profound single-sided deafness reduces speech perception in noisy environments, especially when the sound arrives at the affected side and noise masks the better-hearing ear. Therefore, patients suitable for CROS and BAHA devices should be evaluated using speech-in-noise tests . On the Questionnaires could also help evaluate the subjective benefit of using the devices. Lin et al. used the Abbreviated Profile of Hearing Aid Benefit (APHAB) to evaluate the effectiveness of hearing aids for speech understanding in everyday listening in patients using CROS .As for the sound source localization assessment, the Source Azimuth Identification in Noise Test (SAINT) ,53 is onVestibular-schwannoma-related hearing loss is a consequence of the natural history of the disease, or it can be the consequence of its therapy. Hearing devices are an available and useful tool for rehabilitating VS patients’ hearing loss, both in untreated cases and in cases of patients who underwent surgery or radiotherapy. The impact on the entire hearing function is strictly influenced by the contralateral ear. Hearing preservation surgery and hearing rehabilitation with a cochlear implant for deafness has achieved a prominent role when planning the therapy, especially in small tumors, whereas rehabilitation with hearing-aid devices in VS patients is frequently neglected by clinicians. Nevertheless, it should be evaluated in relation to the degree of ipsilateral hearing loss and the degree of SDS in the affected side. Despite a lack of clear indications about the choice of the specific rehabilitation, the most frequent is amplification with conventional hearing aids, when serviceable hearing is still present. CROS and BAHA systems can be a treatment option in VS-related unilateral deafness. An accurate evaluation of outcome is necessary to detect the benefit of these devices. Cochlear implantation and auditory brainstem implantation are alternative surgical strategies that can be considered when CN has or has not been preserved after tumor removal, respectively. While specific studies on hearing rehabilitation have been conducted on cochlear implants after VS resection and on ABI rehabilitation, few studies have been performed to assess the audiological benefit with hearing aids . These strategies can improve the quality of life of these patients. Any choice should be evaluated in relation to the degree of hearing loss, the state of the contralateral hearing, the patient’s personal willingness, and the feasibility of a good assessment of candidacy, as well as an evaluation of the outcome by specialized audiologists.


However,with the identification of nonreducible LaOCl moiety as an activecenter for MOC, it was demonstrated that a redox-active couple isnot a requirement to establish a high activity. In this work, we showthat Mg2+–Al3+-based mixed-metal oxide(MMO) materials are highly active and stable MOC catalysts. The synergisticinteraction between Mg2+ and Al3+ could be exploiteddue to the fact that a homogeneous distribution of the chemical elementswas achieved. This interaction was found to be crucial for the unexpectedlyhigh MOC activity, as reference MgO and γ-Al2O3 materials did not show any significant activity. OperandoRaman spectroscopy revealed that Mg2+ acted as a chlorinebuffer and subsequently as a chlorinating agent for Al3+, which was the active metal center in the methane activation step.The addition of the redox-active Eu3+ to the nonreducibleMg2+–Al3+ MMO catalyst enabled furthertuning of the catalytic performance and made the EuMg3AlMMO catalyst one of the most active MOC catalyst materials reportedso far. Combined operando Raman/luminescence spectroscopy revealedthat the chlorination behavior of Mg2+ and Eu3+ was correlated, suggesting that Mg2+ also acted as achlorinating agent for Eu3+. These results indicate thatboth redox activity and synergistic effects between Eu, Mg, and Alare required to obtain high catalytic performance. The importanceof elemental synergy and redox properties is expected to be translatableto the oxychlorination of other hydrocarbons, such as light alkanes,due to large similarities in catalytic chemistry.Methane oxychlorination(MOC) is a promising reaction for the productionof liquefied methane derivatives. Even though catalyst design is stillin its early stages, the general trend is that benchmark catalystmaterials have a redox-active site, with, e.g., Cu The methaneoxychlorination (MOC) reaction, which can be written as17Efficientconversion routes for the production of liquefied methanederivatives are pivotal for the feasibility of methane utilization.18 High conversion levels of methaneand good selectivity to the desired CH3Cl reaction productare achieved at a relatively mild temperature and pressure for benchmarkcatalysts. Even though the development of MOC catalysts is still inan early phase, a redox-active center apparently seems essential forenhanced catalytic performance in MOC chemistry. The readily reducibleelements Cu2+, Ce4+, and Pd2+ allshow great activity in the MOC reaction.20 Even for the less reducibleEu3+, the redox properties are likely to play a significantrole in the reaction mechanism.21Several reported catalyst materials showed promising catalyticbehavior in the MOC reaction.17 Interestingly, LaCl3 can even realize a chlorine atom exchange reaction between CH2Cl2 and CCl4.22 Moreover, La3+ was shown to act as a chlorine reservoirwhen combined with Eu3+ in mixed-metal oxide (MMO) catalysts,leading to higher MOC rates due to the synergy between the two elements.23With the MOC field focusing on redox-active elements, catalystcompositions based on nonreducible elements are being somewhat overlooked.However, the nonreducible LaOCl was shown to be an active catalystin the reaction, demonstrating that a stable redox-active couple isnot essential to obtain high MOC activity.2O3 inMMO catalyst materials. Stable performance for the MOC reaction wasobserved over a 100 h period, revealing that long-term stability couldbe achieved. While both Mg2+ and Al3+ have beensuccessfully applied in/as catalysts for reactions involving halogens,including olefin polymerization catalysis,31 to the best of our knowledge, this is the first record of theirapplication for MOC.Inspired by these findings, we show inthis work that very activeMOC catalysts can be obtained by the combination of nonreducible andrelatively inactive MgO and γ-Al2O3 reference materials did not show significantMOC performance, theexceptionally high activity of the Mg2+–Al3+ MMO was highly unexpected. Operando Raman spectroscopy was usedto understand the reason for the observed synergy. We found that Mg2+ acted as a chlorine buffer, providing chlorine for methaneactivation on Al3+, which would otherwise be poorly chlorinated.Considering that the MgO and γ-Al2+–Al3+ MMO showed a somewhat poor selectivity toward CH3Cl compared to the state-of-the-art. Selectivity was also not tunableby varying the HCl concentration, as is the case for redox-activecatalysts.23 To overcome this issue, we introducedvarious amounts of redox-active Eu3+ in the Mg2+–Al3+ MMO by partial substitution of Al3+ in the layered double hydroxide (LDH) precursor, without alteringthe MMO crystal structure and surface area. The introduction of theredox-active site significantly improved the catalytic performanceof the MMO materials in the MOC reaction, in terms of both activityand selectivity.Despite their very good MOC activity, Mg22.134 A round-bottom flask was filled with 50 mL of demineralized water,and the pH was adjusted to a value of 10 by the addition of a 1 Msolution of Na2CO3·10 H2O  in demineralized water. The metal chloride salts, i.e.,MgCl2·6H2O , AlCl3·6H2O , and EuCl3·xH2O ,were dissolved in 18 mL of demineralized water and loaded in a syringe.The amount of metal chloride salts was calculated to yield 1 g ofMMO per batch. Next, the metal chloride salt solution was added tothe round-bottom flask at a rate of 1 mL/min and the pH was kept between9.9 and 10.1 by adding 18 mL of 1 M Na2CO3,immediately forming white precipitates. Once the Na2CO3 solution had been added, the pH was corrected by adding a1 M solution of NaOH  in demineralized water.Next, the precipitates were aged for 20 h at 75 °C before beingfiltrated and washed 3 times with demineralized water. Finally, theLDH materials were dried at 120 °C for 3 h and finally calcinedat 450 °C in static air for 8 h to yield the MMO.The MMO catalystsstudied herein were prepared starting from layered double hydroxide(LDH) precursor materials, synthesized by the coprecipitation method.3+/Mg2+/Al3+ was calculatedto yield the following final MMO’s/Mg2AlO3.5, Mg3AlO4.5, Mg4AlO5.5, Eu0.06Mg2Al0.94O3.5, Eu0.08Mg3Al0.92O4.5, and Eu0.10Mg4Al0.90O5.5 to obtain catalyst materials with a Mg2+/Al3+ ratio of 2, 3, or 4 with a Eu3+ concentration of 2 atom%. Reference MgO, Eu0.16Mg3Al0.84O4.5, and Mg3EuO4.5 were preparedaccording to the same procedure. γ-Al2O3 , CeO2 , andMgAl2O4 were used in the catalytic tests without any pretreatment or modification.Eu/Mg3Al MMO and Eu/γ-Al2O3 were prepared by incipient wetness impregnation. The support materialwas impregnated with a europium(III) chloride hydrate  indemineralizedwater solution at room temperature under vacuum. The impregnated supportwas dried for 4 h at 80 °C under vacuum. Lastly, the dried impregnatedsolids were calcined in a static oven at 550 °C for 3 h usinga ramp rate of 5 °C/min.The ratioof Eu2.21,2 = 1.54184 Å, operatedat 40 kV. The measurements were carried out between 22 and 65°using a step size of 0.02° and a scan speed of 0.5 s, with a2 mm slit for the source. N2 adsorption isotherms weremeasured at −196 °C on a Micromeritics TriStar II Plusinstrument. Prior to all measurements, samples were dried at 300 °Cin a flow of N2 for at least 16 h. Specific surface areaswere calculated using the multipoint Brunauer–Emmett–Teller(BET) method (0.05 < p/p0 < 0.25). Pore volumes were calculated by the t-plot method; pore size distributions were obtained by the Barrett–Joyner–Halenda(BJH) analysis; the Harkins and Jura thickness model was applied forthe t-plot and BJH methods. Inductively coupled plasma-opticalemission spectroscopy (ICP-OES) was applied to determine the chemicalcomposition of the catalyst materials, using a SPECTRO CIROSCCD instrument. ICP-OES samples were prepared by dissolving the solidsin aqua regia. High-resolution transmission electron microscopy (HR-TEM)and high-angle annular dark-field scanning transmission electron microscopy(HAADF-STEM) were performed on a Talos F200× microscope equippedwith four in-column SDD Super-X detectors to perform the energy-dispersiveX-ray spectroscopy (EDS) analysis.X-ray diffraction (XRD) patterns were obtainedwith a Bruker-AXS D8 powder X-ray diffractometer in the Bragg–Brentanogeometry, using Cu KαThermodynamic calculationswere performed with HSC 9 software using the equilibrium compositionpackage from 100 to 1000 °C with a step size of 10 K. The inputsfor the reaction equations are depicted in the corresponding figures.2.39 and experimental definitions and calculationscan be found in the Supporting Information Section 1.All of the catalytictests and operando spectroscopy characterization experiments wereperformed in a lab-scale continuous-flow fixed-bed quartz reactor.Details on the experimental setup are reported elsewhere,4/HCl/O2/N2/He of2:2:1:1:14 or 2:16:1:1:0 in mL/min) was fed into the reactor. A stabilizationperiod of 15 min was applied, and then the ramp experiment of 1 °C/minwas commenced to 550 °C. For the stability tests, 250 mg of catalyst(125–425 μm sieve fraction) was loaded in a quartz reactorand heated to 450 °C under N2 with a 10 °C/minheating rate. The feed was adjusted to CH4/HCl/O2/N2:He of 2:2:1:1:14 (in mL/min), and the experiment wasperformed for 100 h. For the determination of the activity–selectivityrelation, 100 mg of catalyst (125–425 μm sieve fraction)was loaded in a quartz reactor to 350 °C under N2 witha 10 °C/min heating rate. The catalyst was subjected to CH4/HCl/O2/N2/He of 2:2:1:1:14 (in mL/min)for 45 min. The temperature was increased to 550 °C with incrementsof 10 °C with a heating rate of 5 °C/min and kept at everytemperature step for 45 min to obtain the steady-state activity. Thesubsequent chlorination–dechlorination–oxychlorinationexperiments were carried out at 500 °C. The applied CH4/HCl/O2/N2/He ratio was 0:20:0:20:0 , 2:0:1:1:16 , or2:1:1:1:14 .For the methane oxychlorination (MOC) reaction, 100mg of catalyst (125–425 μm sieve fraction) was loadedin a quartz reactor and heated to 350 °C and the desired feedmixture , 100 mg of catalyst (125–425μm sieve fraction) was loaded in a quartz reactor. Temperatureramp experiments were performed from 350 to 550 °C at a ramprate of 1 °C/min under the desired feed mixture .For the HCl oxidationreaction (4 HCl + O33.13+–Eu3+ system in the methane oxychlorination (MOC)reaction, where La3+ acted as a chlorinating agent andEu3+ as an active element, was translated to the Mg2+–Al3+ system 41 41 1C, folloaterials 1D. The materials 1E furthe2+ and Al3+, i.e., Mg2AlO3.5, Mg3AlO4.5, and Mg4AlO5.5 will be further denoted asMg2Al, Mg3Al, and Mg4Al MMOs, respectively.The Eu-MMO catalyst materials, for which Al3+ was partiallysubstituted for the reducible Eu3+, i.e., Eu0.06Mg2Al0.94O3.5, Eu0.08Mg3Al0.92O4.5, and Eu0.10Mg4Al0.90O5.5, will be further denotedin the form of EuMg2Al, EuMg3Al, and EuMg4Al MMOs, respectively. An overview of the catalyst compositionsand their corresponding physicochemical properties is provided in Accordingly,MMO and Eu-MMO catalysts were prepared by coprecipitation,and we refer to SBET) and pore volume(Vpore) of the MMO materials were quitecomparable with SBET values between 206.2and 275.0 m2/g, while the Vpore ranged between 0.50and 1.53 cm3/g. The catalyst with a Mg2+/Al3+ ratio of 3 gave the highest SBET and Vpore for both sets of MMO catalysts.In all cases, phase-pure MMO materials were synthesized, as shownby the characteristic defective MgO periclase reflections (COD 5000225),i.e., (111), (200), and (220)  analysis . Hence, we can conclude that Eu3+ is highly dispersedthroughout the material, and we can exclude the incorporation of Eu3+ into the crystal structure. Importantly, the similar physicochemicalproperties observed for the studied MMO catalysts enabled us to rationalizetheir catalytic activity mainly in terms of composition.The Brunauer–Emmett–Teller(BET) surface area (nd (220) 2A. A shi3+ ratio 2B,coinc3+ ratio 1, as a hout Eu3+ 2B. Howev3+ concentration of 2atom % was used, as a higher lanthanide concentration yielded extra-frameworkphases due to a mismatch in ionic radii and charge .34 Since extra-frameworkphases would have added another degree of complexity when trying tostudy these catalyst materials, the Eu3+ content was keptat 2 atom %, enabling a fair comparison of the Mg2+/Al3+ ratio and the effect of Eu3+.The synthesis procedure yielded the desired molar ratio forallcatalyst materials, as evidenced by inductively coupled plasma-opticalemission spectroscopy (ICP-OES) 1. A theo3.22+–Al3+ MMO catalyst materials were all very activefor the MOC reaction ,indicating that an intimate contact between Mg2+ and Al3+ is needed to obtain high methane conversion (X4CH). This observation is further strengthenedby the fact that 2 wt % of Mg/SiO2 and Mg/γ-Al2O3 did not reveal any significant activity . Accordingly, a commercial MgAl2O4 reference, where Mg and Al are intimately mixed, performed similarlyto the synthesized MMO . Nevertheless, a poor selectivity was observed forall MgxAl MMO catalysts at 480 °C(3Cl selectivity (S3ClCH) of 70% at X4CH <1% under 10% HCl was obtained for Mg3Al MMO  (S4A) after an initialinduction period. This indicates that the Mg2+–Al3+-based MMO catalysts could possess long-term stability inthe MOC reaction. The nature of this induction period can be explainedby the fact that no steady-state catalyst chlorination was reached,which is pivotal for steady-state performance . The postcharacterizationwith the XRD of the catalyst after 24 h of reaction under the sameconditions revealed that the Mg2+ in the catalyst was partiallychlorinated to MgCl2 . No Eu3+- or Al3+-based phases could be identified.After dechlorination, most of the MgCl2 has been convertedto MgO, although traces of MgCl2 appear to be present . Further analysis of the chlorinatedspent catalyst is hampered by the hygroscopic nature of the formedmetal chlorides. To get insight into the catalyst morphology and elementaldistribution in the spent catalyst, we performed a dechlorinationstep to remove any chlorides  so the catalyst could be analyzed with STEM-EDS . The elemental mapping did not show any severeagglomeration of Eu3+, Al3+, and Mg2+ after 24 h of reaction and a subsequent dechlorination step. Itmust be stated that the catalyst is altered by the dechlorinationstep and might not be representative of the catalyst under workingconditions. The addition of the Eu3+ as redox functionalitywas reflected in the fact that the EuMg3Al MMO was ableto perform the HCl oxidation reaction, i.e., 4 HCl + O2 → Cl2 + 2 H2O, where typically a redoxcouple is needed for the Mars–van Krevelen-type of reactions,47 while the Mg3Al MMO was not Cl2 during oxychlorination. The preparation of the MgxAl MMO catalysts with only 2 atom % of Eu3+ greatly improved the catalytic activity in the MOC reaction.Generally speaking, the activity is doubled over the entire testedtemperature range compared to the MMO materials  and 2 wt % of Eu/Mg3Al (X4CH = 17.2%), both preparedby impregnation, were only slightly more active compared to that ofMg3Al MMO (X4CH =14.5%) . The highest activitywas achieved for EuMg3Al MMO, possessing a methane conversionrate of 10.56 mmol·gcat–1·h–1 at 480 °C, a doubling compared to the Mg3Al MMO  and approaching FeOx–CeO2 with a methane conversionrate of roughly 15.7 mmol·gcat–1·h–1 under similar conditions.13 The functionalization of the MgxAl MMO was further evidenced by the preservationof the activity under 80% HCl, conditions under which the MgxAl MMO did not perform well. The addition ofEu3+ enhanced the methane conversion rate from 1.17 mmol·gcat–1·h–1 for Mg3Al MMO to 10.27 mmol·gcat–1·h–1 for EuMg3Al MMO, a 9-foldincrement. The selectivity could be varied by altering the HCl concentration,as the SCO is reduced for the Eu3+-MMO catalysts . To show that Al3+ was the main contributorto the (unwanted) high CO selectivity, a dual catalyst bed was made.At the top, the gas stream first contacted the active La0.50Eu0.50OCl, producing a mix of chloromethanes. Subsequently,the product mix contacted 100 mg of γ-Al2O3 before being analyzed with GC chlorination behavior of Mg2+ in MgO and Mg3Al MMO under varying reaction conditions . Any formation of AlCl3 would not be detectable with Raman due to its low boiling pointof 180 °C. The formation of bulk AlCl3 was, however,excluded as γ-Al2O3 was proven stableunder 24 h of oxychlorination conditions, as no weight loss, SBET loss, phase change, or reactor stainingwas observed (see the Supporting Information Section 2.3). The final state was reached faster in the case of MgOcompared to that of Mg3Al MMO . For Mg3Al MMO, however,the chlorine was completely removed from the catalyst, indicated bythe complete disappearance of the Mg–Cl vibration  and thus possessed lowactivity. Mg2+ was readily chlorinated by HCl and couldbe  converted from MgO to MgCl2. However, MgCl2 was not able to efficiently catalyze the MOC reaction. Thesynergy occurred when chlorine could be stored by Mg and transferredto the Mg2+–Al3+ boundary. The availablechlorine readily reacted away by Al3+ with CH4 and O2, enabling a catalytic cycle of chlorination anddechlorination when Mg2+–Al3+ can interact.In view of the nonreducibility of the two elements, we propose thatthe surface Mg–O–Al is chlorinated, which then followsa similar reaction mechanism as proposed for the nonreducible LaOCl.17In the last step, MOCconditions were applied. The MgO catalystdid not show any significant spectral change. This could be due tothe establishment of thermodynamic equilibrium between chlorinatedand dechlorinated states or due to a kinetically limited steady statebetween chlorination and dechlorination. Since product formation wasnegligible, significant dechlorination due to reaction with methanecan be excluded, suggesting that the thermodynamic equilibrium for(de)chlorination was reached. On the other hand, Mg3Al MMO evidenceda correlation between the degree of Mg2+ chlorination andcatalyst deactivation . Under10% HCl (0–60 min), the chlorination rate and dechlorinationof MgO moved to a steady state, where only partial Mg2+ chlorination was achieved. When the HCl was further increased to20% (60–120 min), an acceleration in the Mg2+ chlorinationrate was observed, coinciding with a dip in X4CH. No sign of stabilization of the Mg–ClRaman signal or the X4CH wasapparent under 20% HCl. This deactivation/Mg2+ chlorinationtrend was continued until the final HCl concentration of 80% was fed(120–300 min). Thereafter, the HCl concentration in the feedwas lowered, causing a partial and gradual dechlorination and at thesame time a partial and sudden recovery of the activity. Hence, thecatalytic performance of Mg3Al MMO was quite sensitiveto an increase in HCl concentration, caused by catalyst over chlorination.Lastly, operando Raman spectroscopy onMg3.53Al MMO catalyst, it was possible to analyzethe chlorination–dechlorination behavior of Eu3+, alongside the chlorination–dechlorination behavior of MgO.This was done by detecting the luminescence signal of Eu3+, which is quenched at elevated temperatures (>300 °C) whenEu3+ is in the chlorinated state.23 TheRaman vibration of Mg2+–Cl and the luminescencesignal of the 5D1 → 7F2 transition were plotted during the chlorination, dechlorination,and oxychlorination steps.For the EuMg2+–Cl Raman vibrationat 253 cm–1 was observable  catalysts are veryactive for the methane oxychlorination (MOC) reaction, despite thelow activity of the respective single-metal oxides MgO and γ-Al2O3. This was attributed to synergistic effectsat play between Mg2+ and Al3+ in homogeneousmixtures, such as the synthesized MMO and MgAl2O4. To explain the observed synergy, based on thermodynamic calculations,catalytic results, and operando Raman spectroscopy observations, wepropose that Mg2+ underwent chlorination under reactionconditions, acting as a chlorine buffer and chlorinating agent forAl3+, which was the active metal in the methane activationstep.In this work, we demonstratethat nonreducible, Mg4Al MMO possessed a highmethane conversionrate of 4.63 mmol·gcat–1·h–1 and good stability over a 100 h period. However,the SCO and S3ClCH could not meet the standard reported in the literature,as the SCO > 40% and the S3ClCH < 50% at X4CH ∼ 10%. Hence, the MMO was functionalized withthe redox-active Eu3+ by the partial replacement with Al3+, adding complementary Eu3+ properties to theMgxAl MMO. For the 2 atom % of Eu-MMOs,the methane conversion rate was boosted to a maximum of 10.56 mmol·gcat–1·h–1, makingthese materials one of the most active catalysts reported. The redox-activeEu3+ made the catalyst active in the HCl oxidation reaction.Furthermore, the activity was preserved under high HCl concentrationsin the feed, making the catalyst more resistant to HCl. The SCO became tunable by varying the HCl concentrationin the feed and could be suppressed by as much as 30%.The synthesized Mg3+ was needed for the activity in thereaction, the metal was also highly active in the catalytic destructionof polychlorinated C1, greatly influencing the activity–selectivityrelation. Hence, the EuMg3Al MMO was not competitive interms of selectivity to other benchmark catalysts reported in theliterature. Lastly, combined operando Raman/luminescence spectroscopyrevealed that the chlorination behavior of Mg2+ and Eu3+ was correlated, and we therefore hypothesize that Mg2+ also acted as a chlorinating agent for Eu3+.The high dispersity of Eu3+ throughout the material incombination with the chlorinating effect of Mg2+ makesthe EuMg3Al MMO exhibit even greater activity in the MOCreaction than Mg3Al. The fact that a highly active catalystmaterial could be made of nonreducible Mg2+ and Al3+ sheds new light on the importance of synergistic effectsin oxychlorination chemistry, while the addition of Eu3+ illustrates the importance of redox properties in improving theselectivity toward chlorinated methanes.Eventhough Al