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Evaluation and therapy outcome in children with auditory neuropathy spectrum disorder (ANSD)
International Journal of Pediatric Otorhinolaryngology 127 (2019) 109681
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Evaluation and therapy outcome in children with auditory neuropathy spectrum disorder (ANSD)
T
Désirée Ehrmann-Müller∗, Mario Cebulla, Kristen Rak, Matthias Scheich, Daniela Back, Rudolf Hagen, Wafaa Shehata-Dieler Department of Otorhinolaryngology, Plastic, Esthetic and Reconstructive Head and Neck Surgery, University of Wuerzburg, Josef-Schneider-Str. 11, 97080, Wuerzburg, Germany
A R T I C LE I N FO
A B S T R A C T
Keywords: Auditory neuropathy spectrum disorder Cochlear implant Hearing aids
Objectives: The aims of the present study are to: describe diagnostic findings in patients with auditory neuropathy spectrum disorder (ANSD); and demonstrate the outcomes of different therapies like hearing aids (HAs) or cochlear implantation. Methods: 32 children were diagnosed and treated at our tertiary referral center and provided with HAs or cochlear implants (CIs). All of them underwent free-field or pure-tone audiometry. Additionally, otoacoustic emissions (OAEs), impedance measurements, auditory brainstem responses (ABRs), auditory steady-state responses (ASSR), electrocochleography, and cranial magnetic resonance imaging (cMRI) were all performed. Some patients also underwent genetic evaluation. Following suitable provision pediatric audiological tests, psychological developmental diagnostic and speech and language assessments were carried out at regular intervals in all the children. Results: OAEs could initially be recorded in most of the children; 17 had no ABRs. The other eight children had a poor ABR morphology. Most of the children had typical, long-oscillating cochlear microphonics (CMs) in their ABRs, which was also observed in all of those who underwent electrocochleography. Eight children were provided with a HA and 17 received a CI. The functional gain was between 32 and 65 decibel (dB) with HAs and between 32 and 50 dB with CI. A speech discrimination level between 35 and 100% was achieved during openset monosyllabic word tests in quiet with HA or CI. With the Hochmair-Schulz-Moser (HSM) sentence test at 65 dB SPL (sound pressure level), 75% of the children with a CI achieved a speech discrimination in noise score of at least 60% at a signal to noise ratio (SNR) of 5, and four scored 80% or higher. Most of the children (72%) were full-time users of their devices. All the children with a CI used it on a regular basis. Conclusion: Only a few case reports are available in the literature regarding the long-term outcomes of ANSD therapy. The present study reveals satisfactory outcomes with respect to hearing and speech discrimination in children with CIs or HAs. The nearly permanent use of the devices reflects a subjective benefit for the children. Provision with a suitable hearing device depends on audiological results, the speech and language development of an individual child, and any accompanying disorders. Repeated audiological evaluations, interdisciplinary diagnostics, and intensive hearing and speech therapy are essential for adequate rehabilitation of this group of children.
1. Introduction Auditory neuropathy spectrum disorder (ANSD) is a particular form of sensorineural hearing loss, in which either a disruption of the synchronization of transmitting excitation along the auditory pathway (desynchrony) or a cochlear nerve deficiency (CND) is etiological for hearing loss. ANSD in children with hearing loss has a reported
prevalence of 5–10% in the literature [1–5]. In healthy babies with confirmed congenital hearing loss, 6.5% are diagnosed with ANSD [5]. ANSD is characterized by: fluctuating hearing sensitivity in pure-tone thresholds; a reduced speech-perception performance, especially in difficult hearing conditions, such as noise; and a reduction in localization capabilities [1,2,6–9]. Diagnosis and adequate therapy of this hearing impairment is
∗ Corresponding author. Department of Otorhinolaryngology, Plastic, Esthetic and Reconstructive Head and Neck Surgery, University of Wuerzburg, JosefSchneider-Str. 11, 97080, Würzburg, Germany. E-mail address: [email protected] (D. Ehrmann-Müller).
https://doi.org/10.1016/j.ijporl.2019.109681 Received 9 May 2019; Received in revised form 10 September 2019; Accepted 10 September 2019 Available online 13 September 2019 0165-5876/ © 2019 Elsevier B.V. All rights reserved.
International Journal of Pediatric Otorhinolaryngology 127 (2019) 109681
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Table 1 Presentation of all the children, with age at first examination; age at proven diagnosis; age at hearing aid (HA) or cochlear implant (CI) provision; risk factors; degree of hearing loss; and use of the device.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
First examination*
Confirmed diagnosis*
HA*
CI*
Risk factor
Affected side
Degree of hearing loss
Use of device
48 33 20 2 5 19 43 18 53 47 31 14 214 30 103 2 1 47 3 11 19 48 1 32 64
50 35 35 3 1 33 43 18 53 47 26 49 214 30 104 3 5 49 8 25 23 48 2 40 64
51 36 22 4 12 21 9 18 6 47 24 39 185 30 104 3 7 6 3 25 23 55 5 32 66 (bb)
56/119 82/95 40/50
craniofacial syndrome
both both both both both both both both both left both both both both both both both both both both both left both both right
profound severe profound severe severe profound profound profound moderate moderate to severe severe moderate moderate severe moderate profound severe profound profound severe moderate to severe moderate to severe severe profound deafness
full time full time full time full time part time full time full time full time full time nonuser full time not known not known nonuser full time full time full time full time full time full time full time full time full time nonuser full time
distant intermarriage 49/87 30/88 54/54 23/25 72/97
OTOF compound heterozygot
prematurity
58
19/19 49/53 9/9 71/162
GJB2 heterozygot prematurity prematurity prematurity prematurity Pendred syndrome toxoplasm
20/20 44/47
*age at (in months). HA = hearing aid. CI = cochlear implant.
have been able to demonstrate outcomes similar to those produced by a CI [28,29]. In other studies, the authors describe improvements limited to loudness and sound perception with HAs, but no enhancement in the processing of auditory temporal cues and, therefore, no benefits in terms of hearing and communication [6,30]. Cochlear implantation is a clear alternative therapy for most patients. However, the reported results are quite variable in children with ANSD, especially when compared to those with cochlear hearing loss. The majority of children with ANSD benefit from a CI and achieve speech understanding, language development, and communication outcomes equivalent to those of their peers with cochlear hearing loss [31,32]. Other studies have reported limited benefits of cochlear implantation [33–35] or even very poor performances [36]. In this regard, the site of the lesion, i.e., pre- or postsynaptic, or CND seem to be relevant [32,37–42]. As a result of these factors, as well as the very heterogeneous nature of ANSD, which often presents with significant accompanying disorders, decision-making about the most suitable amplification mode is often difficult. Careful evaluation is vital when counseling patients and their parents. Consequently, multidisciplinary evaluations, objective and behavioral audiological measures, and imaging of the auditory nerve and brainstem via cranial magnetic resonance imaging (cMRI) and computed tomography (CT) are required to confirm the diagnosis. Recommendations should be made on a case-by-case basis, depending on individual performance (e.g., speech discrimination in noise, language development, and spoken language skills) and the type of ANSD (desynchrony versus CND). The aims of this study are to: describe the process and results for establishing a diagnosis; and demonstrate the outcomes of different therapeutic approaches.
challenging, especially in children. Hearing loss in ANSD varies from mild to profound, and a diagnosis is quite often made late due to present otoacoustic emissions (OAEs) in newborn hearing screenings. As first reported by Starr et al., in 1996, ANSD is characterized by preserved OAEs and cochlear microphonics (CM) and absent or severely distorted auditory brainstem responses (ABRs) [6]. The regular function of outer hair cells, with detectable OAEs [10] and CMs [11] and an abnormal integrity of the function of the cochlear nerve (CN) with lost or poor ABRs [6], are currently regarded as distinct diagnostic criteria for this disorder. The outer hair cell function may also deteriorate over time [12,13]. The summating potential of inner hair cell receptors [14] provides a hint about the functional integrity of these cells, while the compound action potential [15] reveals the integrity of CN fibers. The acoustic middle ear muscle reflex is undetectable in ANSD, or only at high thresholds [16,17]. Different anatomical correlates - presynaptic (inner hair cell disorders), postsynaptic (auditory ganglion, dendrites, and axons), and central (auditory brainstem) - are known about to date. The pathophysiology is based on the loss or dysfunction of the inner hair cells and/or their synapses, with preserved outer hair cell function, abnormalities of the spiral ganglion neurons, or CND with aplasia or hypoplasia of the CN. Myelinization disorders like Charcot-Marie-Tooth syndrome and central nervous system problems such as multiple sclerosis or brainstem tumors may also cause ANSD [18]. The most common causes of the condition in children are prematurity [19], perinatal hyperbilirubinemia [20], severe newborn icterus [21], and kernicterus [22]. Hypoxia [23] mostly causes damage to the inner hair cells, and septicemia and ototoxic medications are other risk factors [4]. Forty percent of children with ANSD have an underlying genetic cause, such as syndromic conditions like Charcot-Marie-Tooth syndrome [24] or Friedreich's ataxia [25], or non-syndromic disorders like mutations in the otoferlin- or GJB2-gene [26] or the mitochondria. CND is also present in 18–33% of children with ANSD [20,27]. There are still ongoing discussions about the optimal treatment in children suffering from ANSD. Recommendations range from no amplification at all to hearing aids (HAs) or cochlear implants (CIs). Some authors describe a HA as a good hearing-rehabilitation method and
2. Materials and methods Thirty-two children (18 female, 14 male) suffering from ANSD and treated at our center between 2000 and 2016 were examined retrospectively using their charts. The first examination in our clinic was due to the presence of risk factors, failed newborn hearing screenings, 2
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3. Results
absent hearing reactions, or delayed speech and language milestones. Details of the risk factors, age at first examination and age at the fitting of HAs or CIs are set out in Table 1 in the results section. Free/soundfield or pure-tone audiometry was carried out in all the children. In addition, OAE, tympanometry, ABR, auditory steady-state responses (ASSRs), as well as transtympanic electrocochleography were also performed. ABRs with rarefaction and condensation or alternating clicks, presented at a repetition rate of 20 stimuli/s, were determined in all the children with suspected hearing loss. ASSRs in response to a narrow band chirp were analyzed in all of those examined since 2010. When identifiable responses were observed at a starting level of 80 dB nHL (normal hearing level), the intensity of the measurement stimulus was reduced in 10 dB steps until the response threshold was identified. If no responses were identified at 80 dB the stimulus intensity was increased in 10 dB steps to a maximum of 100 dB nHL. Missing or abnormal ABRs, the presence of OAEs, and a typical CM morphology in ABRs or electrocochleography were the main findings for confirming a diagnosis of ANSD. cMRI with T1 and T2 weighting with a contrast medium was used to exclude CND (true ANSD). Over the past five years, the CISS-sequence (constructive interference in steady state) was also performed to enable a detailed judgement to be made on the presence and state of the CN. The children were given a CT of the temporal bone when deciding whether to proceed to cochlear implantation. Eleven of the children underwent genetic evaluation. Seven were excluded due to CND, which was diagnosed from the cMRI scans. The details of these children have already been published elsewhere by our group [43]. The remaining 25 children were provided with HAs or CIs. The decision about whether to receive a HA or a CI depended on findings such as the degree of hearing loss, speech and language development and the general development of the child, and was taken following intensive counseling of the family. After the final fitting of the device, audiological testing, psychological developmental diagnoses and speech and language evaluations were performed at regular follow-up intervals. Age at: first examination, diagnosis, first HA fitting, and cochlear implantation was analyzed. A detailed analysis of possible risk factors for ANSD, as well as the use of a CI implant, was also performed. Post-therapeutic audiological evaluations were conducted using aided responses at five frequencies (500, 1000, 2000, 4000 and 8000 Hz) and speech discrimination tests in quiet at 65–75 dB SPL. These tests included the Freiburgers′ monosyllabic word test, the Wuerzburger monosyllabic word test, and the Goettinger or Mainzer biand monosyllabic word test. The tests were chosen according to the chronological and developmental age of the child. All the audiological tests were performed between the ages of 4 and 14 years. Speech discrimination in noise was examined using the Hochmair-Schulz-Moser (HSM) sentence test, with the speech presented at 65 dB SPL and kept constant. The noise level was varied to obtain several signal-to-noise ratios (SNRs). SNRs of +5 dB and +10 dB were used to test the children provided with a CI. All the behavioral audiological tests were conducted in a sound-treated room (IAC model 55). Audiometry was performed multiple times and varied with age and usage of device. The pure tone average (PTA) of the best aided responses, averaged over five frequencies, and the best and mostly most recent speech discrimination tests were used to evaluate the results. Data analysis was performed with Graph Pad Prism and Microsoft Office Excel. For comparison of the PTA and speech discrimination of the two groups (HA and CI) the Mann-Whitney-U-test was used. This retrospective study was approved by the responsible ethics committee (2019022002), and was conducted according to the guidelines established in the Declaration of Helsinki (Washington 2002) and the ISO 14155, Parts I and II, concerning the conduct of clinical studies involving human beings.
The first examination of the children at our clinic took place at a median age of 30 months (1–214 months). Confirmation of the diagnosis of ANSD was established at a median age of 34 months (1–214 months). Children were provided with a HA even earlier, around the age of 23 months (3–185 months). Cochlear implantation was performed at a median age of 49 months (9–82 months) (see Table 1). Most of the children had a severe to profound hearing loss (see Table 1). All of them had undergone a HA trial prior to the decision to proceed to implantation. The children with moderate hearing loss mostly continued with the HAs. In those where the loss was profound, a CI was recommended. Cochlear implantation took place either at an early age when there were no hearing reactions with HAs or later due to a lack of speech development. The children continued with HAs when they had good hearing reactions and verbal skills. The decision to proceed with cochlear implantation was sometimes difficult. That was due to fluctuating hearing sensitivity with HAs. But verbal skills and general development validated recommendations regarding the most suitable treatment. The decision for or against cochlear implantation also depended on the wishes of the parents. Fifteen of the children with ANSD on both sides were implanted bilaterally (MedEL PulsarCI 100® or concerto®), while seven children are still using two HAs. One child was provided with a MedEL Bonebridge® for single-sided ANSD due to unilateral CND that was detected later (see Table 1). Risk factors for ANSD were present in 44% of the children. The most common risk factor in this cohort was prematurity (see Table 1). Initially, OAEs were detected in 20 children, one had no OAEs and four were not tested. In some of the children, OAEs disappeared over time. The majority of the children (n = 17) had no ABRs, while eight had a poor ABR morphology, with thresholds between 70 and 100 dB. Most of the children already had long-oscillating CMs in their ABRs when these were tested with rarefaction and condensation. In earlier stages, alternating clicks were used to determine the ABRs. CMs were only observed during electrocochleography in those cases. For a typical ABR-curve, see Fig. 1. Long-oscillating CMs, with thresholds ranging from 30 to 60 dB, were detectable in all the children who underwent electrocochleography (n = 13). 3.1. Use of device Seventy-two percent of the children were full-time users of their devices (see Table 1). CIs were used on a regular basis in all the children. One child used the CI only at school, while another who did not tolerate the device suffered from bilateral aplasia of the CN, which was not discovered before implantation, and general developmental disturbance. 3.2. Results of post-therapeutic audiological evaluations Audiological evaluations with HAs/CIs were conducted in 22 children at regular intervals. The best outcome over time was used for our assessment of the results. No subjective audiometric tests were possible in three children, due to global developmental delays. Aided free-field testing was performed in 16 children, one of whom had developmental delay. The others were comparable in age, general development and accompanying disorders. The median over the five frequencies was 40–45 dB HL (hearing level) with CIs and 35–40 dB with HAs. As a consequence, no significant differences in the PTA between the CIs and HAs could be observed (p = 0,38-0,85), although the results with the latter had more variation (see Figs. 2 and 3). The aided PTA results of each child over time revealed that they improved with age and longer use of the device. Fluctuations in hearing sensitivity were reported by the parents, especially in children with HAs and prior to implantation. However, fluctuations of the pure-tone 3
International Journal of Pediatric Otorhinolaryngology 127 (2019) 109681
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Fig. 1. Typical ABR-curve with cochlear microphonics (CM) in a child with ANSD Red circle: typical CM.
Fig. 2. Median aided free-field average with cochlear implantation (the dots indicate the number of ears).
Fig. 4. Development of the pure-tone average (PTA) with CIs over time.
thresholds with CI were rarely observed. The PTA improved mostly with age and longer device use. The maps were varied during the first few months of device use, until a suitable map was found. Hardly any changes were done afterwards. Fig. 4 contains an example of the development of the PTA with a CI. Speech audiometric testing was not possible in five children because of global developmental delays and three were too young to test. Speech audiometry could not be compared before and after therapy, because either the children were often too young and did not demonstrate speech and language capabilities that could be tested prior to implantation or different speech tests were performed before and after implantation. The results of speech audiometry following therapy revealed good speech discrimination with the hearing devices (open-set speech discrimination in quiet > 50%) in 88% of the children (see Fig. 5). Eight (47%) of them had a speech discrimination score of 70% or higher. Only two children, one with HAs and the other with CIs, presented with speech discrimination in quiet of around 35% in the Freiburgers′ monosyllabic test. This could not be explained by any obvious factors, because both had satisfactory verbal communication skills. A comparison of speech discrimination tested with a CI (n = 6) or a HA (n = 6) in the Freiburgers′ monosyllabic test revealed that the former tended to produce better outcomes. This difference was not,
Fig. 3. Median aided free-field average with hearing aids (HAs; the dots indicate the number of ears).
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3.3. Communication mode Eighteen children mainly used oral language. Some of them were also able to communicate using signing. Two children only used sign language and two were unable to communicate at all due to accompanying disorders. The preferred communication mode for one child was unknown, due to the lack of follow-up. 4. Discussion ANSD is not a rare cause of hearing loss, because 5–10% of children with impaired hearing suffer from this condition [1–5]. Among the many risk factors associated with ANSD (see Introduction), prematurity was identified as the most common in this study, which corresponds to the findings in the literature [19]. 25% of the children had CND, which also confirms previous research, where CND was present in 18–33% of children with ANSD [20,27]. The present study also demonstrates the distinct diagnostic criteria for ANSD, such as: poor or no ABRs; typical CMs in ABRs and electrocochleography; and mostly present OAEs that can deteriorate over time [6,12,13]. ABR and ASSR were always done and interpreted together. With missing and abnormal ABR a desynchrony was proven. The ASSR thresholds seemed however to reflect the pure tone thresholds or CMs thresholds of the patients. These are however preliminary observations which need larger numbers of data for verification. There is an ongoing discussion about the optimal therapy in children with ANSD, because the provision of a suitable hearing device depends on audiological test results, the speech development of the children, their accompanying disorders, and the decisions made by their parents. The results of speech discrimination and language development tests vary a lot in children depending on their general development and accompanying disorders. Recommendations concerning amplification in ANSD range from no amplification to fitting of HAs or cochlear implantation. A frequency modulating system (FM-system) is only appropriate for children with mild to moderate hearing loss as a way to improve hearing in difficult conditions, e.g. noise, by improving the SNR [44]. In the present study, most of the children had severe to profound hearing loss, and so an FM-system alone was not appropriate. Some authors have demonstrated that children with ANSD have good outcomes with HAs [28,29]. Walker et al., for example, reported results with HAs in ANSD that were similar to those for children with cochlear hearing loss [28]. Furthermore, similar outcomes were obtained with HAs and CIs [29]. Other authors have described an improvement limited to sound perception with HAs, but no enhancement in the processing of auditory temporal cues and, therefore, no benefits in terms of hearing and communication [6,30]. Liu et al. reported a range from 17.5 to 57.5 dB in the four-frequency average hearing level in children with ANSD and a CI. The scores tended to be better in children implanted below the age of 24 months, but all 10 subjects who had undergone implantation showed good progress in their auditory and language capabilities [45]. In terms of our PTA results, the median over the five frequencies was 40-45dBHL (range 20-120dBHL) with CI and 35-45dBHL (range 20-70dBHL) with HAs. As a consequence, there were no significant PTA differences between CIs and HAs. The results with HAs varied more and were slightly worse than the outcomes with CIs. These differences were not, however, statistically significant, probably due to the small sample size. Overall, the hearing benefits in children with accompanying disorders were worse than in those with an isolated ANSD. Moreover, hearing tests could not be performed properly in children with multiple handicaps. Interestingly, with multiple testing, typical fluctuating hearing sensitivity for ANSD was expected, but the aided responses, whether with a CI or a HA, improved with age and the duration of use. This was also reported in children with cochlear hearing loss and CI [28]. The fluctuation in hearing sensitivity was much less than expected and was not observed in those with a CI. A systematic review by Roush demonstrated an improved PTA with
Fig. 5. Speech discrimination scores of each child in quiet at the most comfortable level (MCL) 65–75 dB.
Fig. 6. Comparison of the median with speech discrimination (SD) in quiet using the Freiburgers′ monosyllabic test; CI (cochlear implant), HA (hearing aid).
however, significant (P = 0.46), probably due to the small sample size (Fig. 6). Speech discrimination in noise was examined with the HSM sentence test at 65 dB SPL, +5 dB and +10 dB SNR, in eight children who had been provided with bilateral CIs. Seventy-five percent of them had a speech discrimination score in noise of 60% or higher at SNR 5, and four had a score of 80% or higher (see Fig. 7). At SNR 10, the results were even better (see Fig. 7). One child, who also had poor speech discrimination in quiet but did have verbal skills, had no speech discrimination at all on the left side in noise.
Fig. 7. Speech discrimination in noise using the HSM (Hochmair-Schulz-Moser) sentence test at 65 dB SPL (the dots indicate the number of patients). 5
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diagnosed in the early 2000s when cMRI with CISS was not yet performed. It thus appears that the site of the lesion (pre- or postsynaptic or CND) has an impact on the efficacy of cochlear implantation [32,37–42]. It has been reported that less than 10% of children suffering from ANSD due to CND achieve a significant speech perception capability [40,42,58]. It is important to differentiate between auditory desynchrony and a true auditory neuropathy with CND. This is because CND seen in cMRI and poor ECAPs (electrical compound action potentials) are surrogate markers of poor performance with a CI in children with ANSD [36]. There is no data currently available on the duration and regular use of CIs in children with ANSD, although the rate of regular use is reported as ranging from 63 to 96% in those with cochlear hearing loss [59,60]. With a regular device use score of 72% and above, our data on children with ANSD, especially those with a CI, correspond to that in the literature for children with cochlear hearing loss. The decision-making concerning whether to proceed to cochlear implantation, especially in very young children, is still challenging, because there may be a spontaneous improvement in or recovery from ANSD within the first two years of life as a result of neuromaturation [61,62]. Consequently, differentiation between a delay in neuromaturation and true ANSD must be achieved by repeat testing in the first year of life, especially in preterm infants. However, whether children older than 12–18 months will improve their hearing due to maturation remains unlikely [63]. Interestingly, in our study, none of the infants had a maturation delay. Generally, as many children are too young to undergo a behavioral psychophysical assessment, there is still a need to further develop preverbal measures of auditory capacity, so that objective information on hearing capabilities in the first year of life is available [64]. Additional tests to objectify auditory capacity, which may be a predictor of the benefits of acoustic amplification, for example improvements in cortical potentials, should be the focus of future research in pediatric audiology [65].
the presence of CIs in all the studies evaluated. This emphasizes that cochlear implantation is the best option for children with severe to profound hearing loss due to ANSD [35]. Several studies have reported significant improvements in speech perception with CIs, which is comparable to results in children with cochlear hearing loss [19,46–48]. In the present study, 88% of the children with either HAs or CIs achieved an open-set speech perception score in quiet of > 50%, and 47% of them had a score of 70% or higher. Consequently, satisfactory improvements in speech discrimination with a CIs or HAs were evident. On the other hand, there is no reasonable explanation for why two children with good verbal communication skills had an open-set speech discrimination score in quiet of only 35%. There were no statistically significant differences in speech discrimination levels with HAs and CIs in the Freiburgers′ monosyllabic test, possibly due to the small sample size. No speech discrimination tests in noise, e.g., HSM, were performed in the children fitted with a HA. The speech discrimination tests were conducted at different ages (four to 14 years). Humphriss et al. described an equivalent speech recognition capability in CI and HA users in a study sample of 27 subjects [49]. Alternatively, Dean et al. demonstrated that children with ANSD who do not benefit from a HA do well with cochlear implantation at a young age [50]. In the present study, cochlear implantation was recommended at an early age, but actually took place years later, or not at all, due to the wishes of the parents. Children with ANSD are implanted an average of 1.4 years later than those with cochlear hearing loss, due to fluctuating auditory performances, relatively good audiometric thresholds, and the anticipation of an improving hearing function [51]. In the study by Attias et al. [48], all the children with ANSD were implanted with a CI under the age of three and all of them performed equally well in auditory and speech recognition tests in both quiet and noise compared to children with cochlear hearing loss implanted at the same age. Questions thus arise as to: whether the benefits of a CI in ANSD depend on the age at implantation; and whether there is a certain time-window for the development of the auditory system in the children with ANSD. In the present study, observations revealed that the earlier the amplification with either HAs or CIs, the better the results. However, as already stated in the literature [34,39,52,53], hearing benefits and outcomes in speech and language development are worse in children with accompanying disorders than in those with only isolated ANSD. Several early studies have demonstrated more benefits with CIs than with HAs in children with ANSD [54–56]. These promising results possibly depend on the direct electrical stimulation and better synchronization of the neuronal structures. Improvements in CAP (categories of auditory performance) and SIR (speech intelligibility rating) have been found in children with ANSD following cochlear implantation, but this was affected by age at implantation (the younger the better) and the duration of the postoperative follow-up [57]. In terms of long-term outcomes, Breneman et al. demonstrated that 91% of 35 ANSD children with a CI had some degree of open-set word recognition and at least 80% had open-set speech perception [39]. The majority of the children with ANSD benefited from cochlear implantation and achieved speech understanding, language development and communication outcomes equivalent to their peers with cochlear hearing loss [31,32]. In the present study, 75% of the children with CIs had a speech discrimination score in noise of more than 60%, while 50% had a score of 80% and higher. These results are consistent with the studies cited above, but not with those of other authors who have reported very limited benefits of cochlear implantation in 25% of children with ANSD [33–35] or even very poor performances [36]. In their study, Teagle et al. found that half of 140 children achieved open-set speech perception, but, again, some did not benefit at all due to a lack of electricalinduced neural synchronization, CND, or other associated conditions, such as syndromes or developmental delays [34]. One of the children in our study achieved no speech discrimination on the left side. This may have been due to an undetected CND, as this was one of the children
5. Conclusion The diagnosis and treatment of ANSD, especially in children, remains a challenge. Essential for identifying the site of a lesion and determining the objective parameters for suitable implantation candidates is a careful workup with: adequate audiological testing using ABRs, OAEs and electrocochleography (and, if necessary, eBERA); radiological cMRT and CT imaging; and pediatric, neuropediatric and genetic evaluation. Cochlear implantation requires a careful preoperative assessment by audiologists and clinicians, guiding parents to realistic expectations on possible outcomes, especially in children with accompanying disorders. Furthermore, reports of speech understanding/discrimination in quiet and, particularly, noise, are needed to determine which hearing device is most suitable when it comes to achieving extended benefits from amplification. The present study demonstrates satisfactory outcomes regarding hearing and speech discrimination in children with CIs, as well as in those with HAs. The high number of full-time device users supports the benefits of amplification. There was no data available to us on speech in quiet and noise prior to the provision of a CI, and none on speech in noise with HA, meaning that a proper comparison between the devices could not be carried out. Further studies with a higher number of cases and speech in noise tests with CIs and HAs are required to identify possible differences in outcomes. An individual therapeutic concept, multidisciplinary involvement, regular assessments, and intensive hearing and speech therapy are essential in children with ANSD. Those with the condition are not routine candidates for cochlear implantation, and treatment decisions for these children should always be made on a case-by-case basis. Funding This research has not received any specific grant from funding 6
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agencies in the public, commercial or not-for-profit sectors.
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Conflicts of interest None. Acknowledgements We would like to thank Prof. Dr. Brenda Gerull from the University of Würzburg (DZHI) and Sally Ann Ross for editing our manuscript. The first author received a state doctorate scholarship (HB18EHRM) from the interdisciplinary center for clinical science “Interdisziplinäres Zentrum für Klinische Forschung (IZKF)” of the University of Würzburg. References [1] G. Rance, D.E. Beer, B. Cone-Wesson, R.K. Shepherd, R.C. Dowell, A.M. King, Clinical findings for a group of infants and young children with auditory neuropathy, Ear Hear. 20 (1999) 238–252. [2] G. Rance, Auditory neuropathy/dys-synchrony and its perceptual consequences, Trends Amplif. 9 (2005) 1–43. [3] A. Foerst, D. Beutner, R. Lang-Roth, A. Foerst, Prevalence of auditory neuropathy/ synaptopathy in profound hearing impaired children, Int. J. Pediatr. Otorhinolaryngol. 70 (8) (2006) 1415–1422. [4] I. Bielecki, A. Horbulewicz, T. Wolan, Prevalence and risk factors for Auditory Neuropathy Spectrum Disorder in a screened newborn population at risk for hearing loss, Int. J. Pediatr. Otorhinolaryngol. 76 (11) (2012) 1668–1670. [5] A. Boudewyns, F. Declau, J. van den Ende, A. Hofkens, S. Dirckx, P. Van de Heyning, Auditory neuropathy spectrum disorder (ANSD) in referrals from neonatal hearing screening at a well-baby clinic, Epub 2016/05/26, Eur. J. Pediatr. 175 (7) (2016) 993–1000, https://doi.org/10.1007/s00431-016-2735-5 PubMed PMID: 27220871. [6] A. Starr, T.W. Picton, Y. Sininger, L.J. Hood, C.I. Berlin, Auditory neuropathy, Brain 119 (1996) 741–753. [7] G. Rance, C. McKay, D. Grayden, Perceptual characterization of children with auditory neuropathy, Ear Hear. 25 (2004) 34–46. [8] G. Rance, E. Barker, M. Mok, R.C. Dowell, A. Rincon, R. Garrat, Speech perception in noise for children with auditory neuropathy/dys-synchrony type hearing loss, Ear Hear. 28 (2007) 351–360. [9] F.G. Zeng, Y.Y. Kong, J.H. Michalewski, A. Starr, Perceptual consequences of disrupted auditory nerve activity, J. Neurophysiol. 93 (2005) 3050–3063. [10] D.T. Kemp, Stimulated acoustic emission from within the human auditory system, J. Acoust. Soc. Am. 64 (1978) 1386–1391. [11] P. Dallos, M.A. Cheatham, Production of cochlear potentials by inner and outer hair cells, J. Acoust. Soc. Am. 60 (1976) 510–512. [12] A. Starr, Y. Sininger, H. Pratt, The varieties of auditory neuropathy, J. Basic Clin. Physiol. Pharmacol. 11 (2000) 215–230. [13] A. Starr, Y. Sininger, T. Nguyen, J.H. Michalewski, S. Oba, C. Abdala, Cochlear receptor (microphonic and summating potentials, otoacoustic emissions) and auditory pathway (auditory brainstem potentials) activity in auditory neuropathy, Ear Hear. 22 (2) (2001) 91–99. [14] J.D. Durrant, J. Wang, S.L. Ding, R.J. Salvi, Are inner or outer hair cells the source of summating potentials recorded from the round window, J. Acoust. Soc. Am. 104 (1998) 370–377. [15] J.J. Eggermont, Analysis of compound action potential responses to tone burts in the human and Guinea pig cochlea, J. Acoust. Soc. Am. 60 (1976) 1132–1139. [16] E. Borg, On the neuronal organization of the acoustic middle ear reflex. A physiological and anatomical study, Brain Res. 49 (1973) 101–123. [17] C.I. Berlin, L.J. Hood, T. Morlet, C.I. Berlin, Absent or elevated middle ear muscle reflexes in the presence of normal otoacoustic emissions: a univeral finding in 136 cases of auditory neuropathy/dyssynchrony, J. Am. Acad. Audiol. 16 (2005) 546–553. [18] G. Rance, A. Starr, Pathophysiological mechanisms and functional hearing consequences of auditory neuropathy, Brain 138 (2015) 3141–3158. [19] G.M. de Carvalho, Performance of chochlear implants in pediatric patients with auditory neuropathy spectrum disorder, J Int Adv Otol 12 (1) (2016) 8–15. [20] K. Rajput, M. Saeed, J. Ahmed, M. Chung, C. Munro, S. Patel, et al., Findings from aetiological investigation of Auditory Neuropathy Spectrum Disorder in children referred to cochlear implant programs, Int. J. Pediatr. Otorhinolaryngol. 116 (2019) 79–83. [21] S.B. Amin, H. Wang, N. Laroia, M. Orlando, Unbound bilirubin and auditory neuropahty spectrum disorder in late preterm and term infants with severe jaundice, J. Pediatr. 173 (2016) 84–89. [22] K. Kanga, E. Kitazumi, K. Kadama, Auditory brainstem response of kernicterus infants, Int. J. Pediatr. Otorhinolaryngol. 1 (1979) 255–264. [23] S. Sawada, N. Mori, R.J. Mount, R.V. Harrison, Differential vulnerability of inner and outer hair cell systems to chronic mild hypoxia and glutamate ototoxicity: insights into the cause of auditory neuropathy, J. Otolaryngol. 30 (2001) 106–114. [24] C.I. Berlin, L.J. Hood, P. Cecola, D.F. Jackson, P. Sazabo, Does type I afferent neuron dysfunction reveal itself through lack of efferent suppression, Hear. Res. 65 (1993) 40–50.
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[53] C.L. Budenz, K. Starr, C. Arnedt, S.A. Telian, H.A. Arts, H.K. El-Kashlan, et al., Speech and language outcomes of cochlear implantation in children with isolated neuropathy versus cochlear hearing loss, Otol. Neurotol. 34 (2013) 1615–1621. [54] E. Buss, R.F. Labadie, C.J. Brown, A.J. Gross, J.H. Grose, H.C. Pillsbury, Outcome of cochlear implantation in pediatric auditory neuropathy, Otol. Neurotol. 23 (2002) 328–332. [55] A. Peterson, J. Shallop, C.L. Driscoll, A.I. Breneman, J. Babb, R. Stoeckel, et al., Outcomes of cochlear implantation in children with auditory neuropathy, J. Am. Acad. Audiol. 14 (2003) 188–201. [56] J. Shallop, A. Peterson, G.W. Facer, L. Fabry, C.L. Driscoll, Cochlear implants in five cases of auditory neuropathy: postoperative findings and progress, The Laryngoscope 111 (2001) 555–562. [57] A. Daneshi, M. Misalehi, S.B. Hashemi, M. Ajalloueyan, M. Rajati, M.M. Ghasemi, et al., Cochlear implantation in children with auditory neuropathy spectrum disorder: a multicenter study on auditory performance and speech production outcomes, Int. J. Pediatr. Otorhinolaryngol. 108 (2018) 12–16. [58] J.W. Kutz, K.H.I.B. Lee, B. Isaacson, T.N. Booth, M.H. Sweeney, P.S. Roland, Cochlear implantation in children with cochlear nerve absence or deficiency, Otol. Neurotol. 32 (2011) 956–961. [59] K.J. Contrera, J.S. Choi, C.R. Blake, J.F. Betz, J.K. Niparko, F.R. Lin, Rates of longterm cochlear implant use in children, Epub 2014/02/13, Otol. Neurotol. 35 (3)
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Contents lists available at ScienceDirect
International Journal of Pediatric Otorhinolaryngology journal homepage: www.elsevier.com/locate/ijporl
Evaluation and therapy outcome in children with auditory neuropathy spectrum disorder (ANSD)
T
Désirée Ehrmann-Müller∗, Mario Cebulla, Kristen Rak, Matthias Scheich, Daniela Back, Rudolf Hagen, Wafaa Shehata-Dieler Department of Otorhinolaryngology, Plastic, Esthetic and Reconstructive Head and Neck Surgery, University of Wuerzburg, Josef-Schneider-Str. 11, 97080, Wuerzburg, Germany
A R T I C LE I N FO
A B S T R A C T
Keywords: Auditory neuropathy spectrum disorder Cochlear implant Hearing aids
Objectives: The aims of the present study are to: describe diagnostic findings in patients with auditory neuropathy spectrum disorder (ANSD); and demonstrate the outcomes of different therapies like hearing aids (HAs) or cochlear implantation. Methods: 32 children were diagnosed and treated at our tertiary referral center and provided with HAs or cochlear implants (CIs). All of them underwent free-field or pure-tone audiometry. Additionally, otoacoustic emissions (OAEs), impedance measurements, auditory brainstem responses (ABRs), auditory steady-state responses (ASSR), electrocochleography, and cranial magnetic resonance imaging (cMRI) were all performed. Some patients also underwent genetic evaluation. Following suitable provision pediatric audiological tests, psychological developmental diagnostic and speech and language assessments were carried out at regular intervals in all the children. Results: OAEs could initially be recorded in most of the children; 17 had no ABRs. The other eight children had a poor ABR morphology. Most of the children had typical, long-oscillating cochlear microphonics (CMs) in their ABRs, which was also observed in all of those who underwent electrocochleography. Eight children were provided with a HA and 17 received a CI. The functional gain was between 32 and 65 decibel (dB) with HAs and between 32 and 50 dB with CI. A speech discrimination level between 35 and 100% was achieved during openset monosyllabic word tests in quiet with HA or CI. With the Hochmair-Schulz-Moser (HSM) sentence test at 65 dB SPL (sound pressure level), 75% of the children with a CI achieved a speech discrimination in noise score of at least 60% at a signal to noise ratio (SNR) of 5, and four scored 80% or higher. Most of the children (72%) were full-time users of their devices. All the children with a CI used it on a regular basis. Conclusion: Only a few case reports are available in the literature regarding the long-term outcomes of ANSD therapy. The present study reveals satisfactory outcomes with respect to hearing and speech discrimination in children with CIs or HAs. The nearly permanent use of the devices reflects a subjective benefit for the children. Provision with a suitable hearing device depends on audiological results, the speech and language development of an individual child, and any accompanying disorders. Repeated audiological evaluations, interdisciplinary diagnostics, and intensive hearing and speech therapy are essential for adequate rehabilitation of this group of children.
1. Introduction Auditory neuropathy spectrum disorder (ANSD) is a particular form of sensorineural hearing loss, in which either a disruption of the synchronization of transmitting excitation along the auditory pathway (desynchrony) or a cochlear nerve deficiency (CND) is etiological for hearing loss. ANSD in children with hearing loss has a reported
prevalence of 5–10% in the literature [1–5]. In healthy babies with confirmed congenital hearing loss, 6.5% are diagnosed with ANSD [5]. ANSD is characterized by: fluctuating hearing sensitivity in pure-tone thresholds; a reduced speech-perception performance, especially in difficult hearing conditions, such as noise; and a reduction in localization capabilities [1,2,6–9]. Diagnosis and adequate therapy of this hearing impairment is
∗ Corresponding author. Department of Otorhinolaryngology, Plastic, Esthetic and Reconstructive Head and Neck Surgery, University of Wuerzburg, JosefSchneider-Str. 11, 97080, Würzburg, Germany. E-mail address: [email protected] (D. Ehrmann-Müller).
https://doi.org/10.1016/j.ijporl.2019.109681 Received 9 May 2019; Received in revised form 10 September 2019; Accepted 10 September 2019 Available online 13 September 2019 0165-5876/ © 2019 Elsevier B.V. All rights reserved.
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Table 1 Presentation of all the children, with age at first examination; age at proven diagnosis; age at hearing aid (HA) or cochlear implant (CI) provision; risk factors; degree of hearing loss; and use of the device.
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25
First examination*
Confirmed diagnosis*
HA*
CI*
Risk factor
Affected side
Degree of hearing loss
Use of device
48 33 20 2 5 19 43 18 53 47 31 14 214 30 103 2 1 47 3 11 19 48 1 32 64
50 35 35 3 1 33 43 18 53 47 26 49 214 30 104 3 5 49 8 25 23 48 2 40 64
51 36 22 4 12 21 9 18 6 47 24 39 185 30 104 3 7 6 3 25 23 55 5 32 66 (bb)
56/119 82/95 40/50
craniofacial syndrome
both both both both both both both both both left both both both both both both both both both both both left both both right
profound severe profound severe severe profound profound profound moderate moderate to severe severe moderate moderate severe moderate profound severe profound profound severe moderate to severe moderate to severe severe profound deafness
full time full time full time full time part time full time full time full time full time nonuser full time not known not known nonuser full time full time full time full time full time full time full time full time full time nonuser full time
distant intermarriage 49/87 30/88 54/54 23/25 72/97
OTOF compound heterozygot
prematurity
58
19/19 49/53 9/9 71/162
GJB2 heterozygot prematurity prematurity prematurity prematurity Pendred syndrome toxoplasm
20/20 44/47
*age at (in months). HA = hearing aid. CI = cochlear implant.
have been able to demonstrate outcomes similar to those produced by a CI [28,29]. In other studies, the authors describe improvements limited to loudness and sound perception with HAs, but no enhancement in the processing of auditory temporal cues and, therefore, no benefits in terms of hearing and communication [6,30]. Cochlear implantation is a clear alternative therapy for most patients. However, the reported results are quite variable in children with ANSD, especially when compared to those with cochlear hearing loss. The majority of children with ANSD benefit from a CI and achieve speech understanding, language development, and communication outcomes equivalent to those of their peers with cochlear hearing loss [31,32]. Other studies have reported limited benefits of cochlear implantation [33–35] or even very poor performances [36]. In this regard, the site of the lesion, i.e., pre- or postsynaptic, or CND seem to be relevant [32,37–42]. As a result of these factors, as well as the very heterogeneous nature of ANSD, which often presents with significant accompanying disorders, decision-making about the most suitable amplification mode is often difficult. Careful evaluation is vital when counseling patients and their parents. Consequently, multidisciplinary evaluations, objective and behavioral audiological measures, and imaging of the auditory nerve and brainstem via cranial magnetic resonance imaging (cMRI) and computed tomography (CT) are required to confirm the diagnosis. Recommendations should be made on a case-by-case basis, depending on individual performance (e.g., speech discrimination in noise, language development, and spoken language skills) and the type of ANSD (desynchrony versus CND). The aims of this study are to: describe the process and results for establishing a diagnosis; and demonstrate the outcomes of different therapeutic approaches.
challenging, especially in children. Hearing loss in ANSD varies from mild to profound, and a diagnosis is quite often made late due to present otoacoustic emissions (OAEs) in newborn hearing screenings. As first reported by Starr et al., in 1996, ANSD is characterized by preserved OAEs and cochlear microphonics (CM) and absent or severely distorted auditory brainstem responses (ABRs) [6]. The regular function of outer hair cells, with detectable OAEs [10] and CMs [11] and an abnormal integrity of the function of the cochlear nerve (CN) with lost or poor ABRs [6], are currently regarded as distinct diagnostic criteria for this disorder. The outer hair cell function may also deteriorate over time [12,13]. The summating potential of inner hair cell receptors [14] provides a hint about the functional integrity of these cells, while the compound action potential [15] reveals the integrity of CN fibers. The acoustic middle ear muscle reflex is undetectable in ANSD, or only at high thresholds [16,17]. Different anatomical correlates - presynaptic (inner hair cell disorders), postsynaptic (auditory ganglion, dendrites, and axons), and central (auditory brainstem) - are known about to date. The pathophysiology is based on the loss or dysfunction of the inner hair cells and/or their synapses, with preserved outer hair cell function, abnormalities of the spiral ganglion neurons, or CND with aplasia or hypoplasia of the CN. Myelinization disorders like Charcot-Marie-Tooth syndrome and central nervous system problems such as multiple sclerosis or brainstem tumors may also cause ANSD [18]. The most common causes of the condition in children are prematurity [19], perinatal hyperbilirubinemia [20], severe newborn icterus [21], and kernicterus [22]. Hypoxia [23] mostly causes damage to the inner hair cells, and septicemia and ototoxic medications are other risk factors [4]. Forty percent of children with ANSD have an underlying genetic cause, such as syndromic conditions like Charcot-Marie-Tooth syndrome [24] or Friedreich's ataxia [25], or non-syndromic disorders like mutations in the otoferlin- or GJB2-gene [26] or the mitochondria. CND is also present in 18–33% of children with ANSD [20,27]. There are still ongoing discussions about the optimal treatment in children suffering from ANSD. Recommendations range from no amplification at all to hearing aids (HAs) or cochlear implants (CIs). Some authors describe a HA as a good hearing-rehabilitation method and
2. Materials and methods Thirty-two children (18 female, 14 male) suffering from ANSD and treated at our center between 2000 and 2016 were examined retrospectively using their charts. The first examination in our clinic was due to the presence of risk factors, failed newborn hearing screenings, 2
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3. Results
absent hearing reactions, or delayed speech and language milestones. Details of the risk factors, age at first examination and age at the fitting of HAs or CIs are set out in Table 1 in the results section. Free/soundfield or pure-tone audiometry was carried out in all the children. In addition, OAE, tympanometry, ABR, auditory steady-state responses (ASSRs), as well as transtympanic electrocochleography were also performed. ABRs with rarefaction and condensation or alternating clicks, presented at a repetition rate of 20 stimuli/s, were determined in all the children with suspected hearing loss. ASSRs in response to a narrow band chirp were analyzed in all of those examined since 2010. When identifiable responses were observed at a starting level of 80 dB nHL (normal hearing level), the intensity of the measurement stimulus was reduced in 10 dB steps until the response threshold was identified. If no responses were identified at 80 dB the stimulus intensity was increased in 10 dB steps to a maximum of 100 dB nHL. Missing or abnormal ABRs, the presence of OAEs, and a typical CM morphology in ABRs or electrocochleography were the main findings for confirming a diagnosis of ANSD. cMRI with T1 and T2 weighting with a contrast medium was used to exclude CND (true ANSD). Over the past five years, the CISS-sequence (constructive interference in steady state) was also performed to enable a detailed judgement to be made on the presence and state of the CN. The children were given a CT of the temporal bone when deciding whether to proceed to cochlear implantation. Eleven of the children underwent genetic evaluation. Seven were excluded due to CND, which was diagnosed from the cMRI scans. The details of these children have already been published elsewhere by our group [43]. The remaining 25 children were provided with HAs or CIs. The decision about whether to receive a HA or a CI depended on findings such as the degree of hearing loss, speech and language development and the general development of the child, and was taken following intensive counseling of the family. After the final fitting of the device, audiological testing, psychological developmental diagnoses and speech and language evaluations were performed at regular follow-up intervals. Age at: first examination, diagnosis, first HA fitting, and cochlear implantation was analyzed. A detailed analysis of possible risk factors for ANSD, as well as the use of a CI implant, was also performed. Post-therapeutic audiological evaluations were conducted using aided responses at five frequencies (500, 1000, 2000, 4000 and 8000 Hz) and speech discrimination tests in quiet at 65–75 dB SPL. These tests included the Freiburgers′ monosyllabic word test, the Wuerzburger monosyllabic word test, and the Goettinger or Mainzer biand monosyllabic word test. The tests were chosen according to the chronological and developmental age of the child. All the audiological tests were performed between the ages of 4 and 14 years. Speech discrimination in noise was examined using the Hochmair-Schulz-Moser (HSM) sentence test, with the speech presented at 65 dB SPL and kept constant. The noise level was varied to obtain several signal-to-noise ratios (SNRs). SNRs of +5 dB and +10 dB were used to test the children provided with a CI. All the behavioral audiological tests were conducted in a sound-treated room (IAC model 55). Audiometry was performed multiple times and varied with age and usage of device. The pure tone average (PTA) of the best aided responses, averaged over five frequencies, and the best and mostly most recent speech discrimination tests were used to evaluate the results. Data analysis was performed with Graph Pad Prism and Microsoft Office Excel. For comparison of the PTA and speech discrimination of the two groups (HA and CI) the Mann-Whitney-U-test was used. This retrospective study was approved by the responsible ethics committee (2019022002), and was conducted according to the guidelines established in the Declaration of Helsinki (Washington 2002) and the ISO 14155, Parts I and II, concerning the conduct of clinical studies involving human beings.
The first examination of the children at our clinic took place at a median age of 30 months (1–214 months). Confirmation of the diagnosis of ANSD was established at a median age of 34 months (1–214 months). Children were provided with a HA even earlier, around the age of 23 months (3–185 months). Cochlear implantation was performed at a median age of 49 months (9–82 months) (see Table 1). Most of the children had a severe to profound hearing loss (see Table 1). All of them had undergone a HA trial prior to the decision to proceed to implantation. The children with moderate hearing loss mostly continued with the HAs. In those where the loss was profound, a CI was recommended. Cochlear implantation took place either at an early age when there were no hearing reactions with HAs or later due to a lack of speech development. The children continued with HAs when they had good hearing reactions and verbal skills. The decision to proceed with cochlear implantation was sometimes difficult. That was due to fluctuating hearing sensitivity with HAs. But verbal skills and general development validated recommendations regarding the most suitable treatment. The decision for or against cochlear implantation also depended on the wishes of the parents. Fifteen of the children with ANSD on both sides were implanted bilaterally (MedEL PulsarCI 100® or concerto®), while seven children are still using two HAs. One child was provided with a MedEL Bonebridge® for single-sided ANSD due to unilateral CND that was detected later (see Table 1). Risk factors for ANSD were present in 44% of the children. The most common risk factor in this cohort was prematurity (see Table 1). Initially, OAEs were detected in 20 children, one had no OAEs and four were not tested. In some of the children, OAEs disappeared over time. The majority of the children (n = 17) had no ABRs, while eight had a poor ABR morphology, with thresholds between 70 and 100 dB. Most of the children already had long-oscillating CMs in their ABRs when these were tested with rarefaction and condensation. In earlier stages, alternating clicks were used to determine the ABRs. CMs were only observed during electrocochleography in those cases. For a typical ABR-curve, see Fig. 1. Long-oscillating CMs, with thresholds ranging from 30 to 60 dB, were detectable in all the children who underwent electrocochleography (n = 13). 3.1. Use of device Seventy-two percent of the children were full-time users of their devices (see Table 1). CIs were used on a regular basis in all the children. One child used the CI only at school, while another who did not tolerate the device suffered from bilateral aplasia of the CN, which was not discovered before implantation, and general developmental disturbance. 3.2. Results of post-therapeutic audiological evaluations Audiological evaluations with HAs/CIs were conducted in 22 children at regular intervals. The best outcome over time was used for our assessment of the results. No subjective audiometric tests were possible in three children, due to global developmental delays. Aided free-field testing was performed in 16 children, one of whom had developmental delay. The others were comparable in age, general development and accompanying disorders. The median over the five frequencies was 40–45 dB HL (hearing level) with CIs and 35–40 dB with HAs. As a consequence, no significant differences in the PTA between the CIs and HAs could be observed (p = 0,38-0,85), although the results with the latter had more variation (see Figs. 2 and 3). The aided PTA results of each child over time revealed that they improved with age and longer use of the device. Fluctuations in hearing sensitivity were reported by the parents, especially in children with HAs and prior to implantation. However, fluctuations of the pure-tone 3
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Fig. 1. Typical ABR-curve with cochlear microphonics (CM) in a child with ANSD Red circle: typical CM.
Fig. 2. Median aided free-field average with cochlear implantation (the dots indicate the number of ears).
Fig. 4. Development of the pure-tone average (PTA) with CIs over time.
thresholds with CI were rarely observed. The PTA improved mostly with age and longer device use. The maps were varied during the first few months of device use, until a suitable map was found. Hardly any changes were done afterwards. Fig. 4 contains an example of the development of the PTA with a CI. Speech audiometric testing was not possible in five children because of global developmental delays and three were too young to test. Speech audiometry could not be compared before and after therapy, because either the children were often too young and did not demonstrate speech and language capabilities that could be tested prior to implantation or different speech tests were performed before and after implantation. The results of speech audiometry following therapy revealed good speech discrimination with the hearing devices (open-set speech discrimination in quiet > 50%) in 88% of the children (see Fig. 5). Eight (47%) of them had a speech discrimination score of 70% or higher. Only two children, one with HAs and the other with CIs, presented with speech discrimination in quiet of around 35% in the Freiburgers′ monosyllabic test. This could not be explained by any obvious factors, because both had satisfactory verbal communication skills. A comparison of speech discrimination tested with a CI (n = 6) or a HA (n = 6) in the Freiburgers′ monosyllabic test revealed that the former tended to produce better outcomes. This difference was not,
Fig. 3. Median aided free-field average with hearing aids (HAs; the dots indicate the number of ears).
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3.3. Communication mode Eighteen children mainly used oral language. Some of them were also able to communicate using signing. Two children only used sign language and two were unable to communicate at all due to accompanying disorders. The preferred communication mode for one child was unknown, due to the lack of follow-up. 4. Discussion ANSD is not a rare cause of hearing loss, because 5–10% of children with impaired hearing suffer from this condition [1–5]. Among the many risk factors associated with ANSD (see Introduction), prematurity was identified as the most common in this study, which corresponds to the findings in the literature [19]. 25% of the children had CND, which also confirms previous research, where CND was present in 18–33% of children with ANSD [20,27]. The present study also demonstrates the distinct diagnostic criteria for ANSD, such as: poor or no ABRs; typical CMs in ABRs and electrocochleography; and mostly present OAEs that can deteriorate over time [6,12,13]. ABR and ASSR were always done and interpreted together. With missing and abnormal ABR a desynchrony was proven. The ASSR thresholds seemed however to reflect the pure tone thresholds or CMs thresholds of the patients. These are however preliminary observations which need larger numbers of data for verification. There is an ongoing discussion about the optimal therapy in children with ANSD, because the provision of a suitable hearing device depends on audiological test results, the speech development of the children, their accompanying disorders, and the decisions made by their parents. The results of speech discrimination and language development tests vary a lot in children depending on their general development and accompanying disorders. Recommendations concerning amplification in ANSD range from no amplification to fitting of HAs or cochlear implantation. A frequency modulating system (FM-system) is only appropriate for children with mild to moderate hearing loss as a way to improve hearing in difficult conditions, e.g. noise, by improving the SNR [44]. In the present study, most of the children had severe to profound hearing loss, and so an FM-system alone was not appropriate. Some authors have demonstrated that children with ANSD have good outcomes with HAs [28,29]. Walker et al., for example, reported results with HAs in ANSD that were similar to those for children with cochlear hearing loss [28]. Furthermore, similar outcomes were obtained with HAs and CIs [29]. Other authors have described an improvement limited to sound perception with HAs, but no enhancement in the processing of auditory temporal cues and, therefore, no benefits in terms of hearing and communication [6,30]. Liu et al. reported a range from 17.5 to 57.5 dB in the four-frequency average hearing level in children with ANSD and a CI. The scores tended to be better in children implanted below the age of 24 months, but all 10 subjects who had undergone implantation showed good progress in their auditory and language capabilities [45]. In terms of our PTA results, the median over the five frequencies was 40-45dBHL (range 20-120dBHL) with CI and 35-45dBHL (range 20-70dBHL) with HAs. As a consequence, there were no significant PTA differences between CIs and HAs. The results with HAs varied more and were slightly worse than the outcomes with CIs. These differences were not, however, statistically significant, probably due to the small sample size. Overall, the hearing benefits in children with accompanying disorders were worse than in those with an isolated ANSD. Moreover, hearing tests could not be performed properly in children with multiple handicaps. Interestingly, with multiple testing, typical fluctuating hearing sensitivity for ANSD was expected, but the aided responses, whether with a CI or a HA, improved with age and the duration of use. This was also reported in children with cochlear hearing loss and CI [28]. The fluctuation in hearing sensitivity was much less than expected and was not observed in those with a CI. A systematic review by Roush demonstrated an improved PTA with
Fig. 5. Speech discrimination scores of each child in quiet at the most comfortable level (MCL) 65–75 dB.
Fig. 6. Comparison of the median with speech discrimination (SD) in quiet using the Freiburgers′ monosyllabic test; CI (cochlear implant), HA (hearing aid).
however, significant (P = 0.46), probably due to the small sample size (Fig. 6). Speech discrimination in noise was examined with the HSM sentence test at 65 dB SPL, +5 dB and +10 dB SNR, in eight children who had been provided with bilateral CIs. Seventy-five percent of them had a speech discrimination score in noise of 60% or higher at SNR 5, and four had a score of 80% or higher (see Fig. 7). At SNR 10, the results were even better (see Fig. 7). One child, who also had poor speech discrimination in quiet but did have verbal skills, had no speech discrimination at all on the left side in noise.
Fig. 7. Speech discrimination in noise using the HSM (Hochmair-Schulz-Moser) sentence test at 65 dB SPL (the dots indicate the number of patients). 5
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diagnosed in the early 2000s when cMRI with CISS was not yet performed. It thus appears that the site of the lesion (pre- or postsynaptic or CND) has an impact on the efficacy of cochlear implantation [32,37–42]. It has been reported that less than 10% of children suffering from ANSD due to CND achieve a significant speech perception capability [40,42,58]. It is important to differentiate between auditory desynchrony and a true auditory neuropathy with CND. This is because CND seen in cMRI and poor ECAPs (electrical compound action potentials) are surrogate markers of poor performance with a CI in children with ANSD [36]. There is no data currently available on the duration and regular use of CIs in children with ANSD, although the rate of regular use is reported as ranging from 63 to 96% in those with cochlear hearing loss [59,60]. With a regular device use score of 72% and above, our data on children with ANSD, especially those with a CI, correspond to that in the literature for children with cochlear hearing loss. The decision-making concerning whether to proceed to cochlear implantation, especially in very young children, is still challenging, because there may be a spontaneous improvement in or recovery from ANSD within the first two years of life as a result of neuromaturation [61,62]. Consequently, differentiation between a delay in neuromaturation and true ANSD must be achieved by repeat testing in the first year of life, especially in preterm infants. However, whether children older than 12–18 months will improve their hearing due to maturation remains unlikely [63]. Interestingly, in our study, none of the infants had a maturation delay. Generally, as many children are too young to undergo a behavioral psychophysical assessment, there is still a need to further develop preverbal measures of auditory capacity, so that objective information on hearing capabilities in the first year of life is available [64]. Additional tests to objectify auditory capacity, which may be a predictor of the benefits of acoustic amplification, for example improvements in cortical potentials, should be the focus of future research in pediatric audiology [65].
the presence of CIs in all the studies evaluated. This emphasizes that cochlear implantation is the best option for children with severe to profound hearing loss due to ANSD [35]. Several studies have reported significant improvements in speech perception with CIs, which is comparable to results in children with cochlear hearing loss [19,46–48]. In the present study, 88% of the children with either HAs or CIs achieved an open-set speech perception score in quiet of > 50%, and 47% of them had a score of 70% or higher. Consequently, satisfactory improvements in speech discrimination with a CIs or HAs were evident. On the other hand, there is no reasonable explanation for why two children with good verbal communication skills had an open-set speech discrimination score in quiet of only 35%. There were no statistically significant differences in speech discrimination levels with HAs and CIs in the Freiburgers′ monosyllabic test, possibly due to the small sample size. No speech discrimination tests in noise, e.g., HSM, were performed in the children fitted with a HA. The speech discrimination tests were conducted at different ages (four to 14 years). Humphriss et al. described an equivalent speech recognition capability in CI and HA users in a study sample of 27 subjects [49]. Alternatively, Dean et al. demonstrated that children with ANSD who do not benefit from a HA do well with cochlear implantation at a young age [50]. In the present study, cochlear implantation was recommended at an early age, but actually took place years later, or not at all, due to the wishes of the parents. Children with ANSD are implanted an average of 1.4 years later than those with cochlear hearing loss, due to fluctuating auditory performances, relatively good audiometric thresholds, and the anticipation of an improving hearing function [51]. In the study by Attias et al. [48], all the children with ANSD were implanted with a CI under the age of three and all of them performed equally well in auditory and speech recognition tests in both quiet and noise compared to children with cochlear hearing loss implanted at the same age. Questions thus arise as to: whether the benefits of a CI in ANSD depend on the age at implantation; and whether there is a certain time-window for the development of the auditory system in the children with ANSD. In the present study, observations revealed that the earlier the amplification with either HAs or CIs, the better the results. However, as already stated in the literature [34,39,52,53], hearing benefits and outcomes in speech and language development are worse in children with accompanying disorders than in those with only isolated ANSD. Several early studies have demonstrated more benefits with CIs than with HAs in children with ANSD [54–56]. These promising results possibly depend on the direct electrical stimulation and better synchronization of the neuronal structures. Improvements in CAP (categories of auditory performance) and SIR (speech intelligibility rating) have been found in children with ANSD following cochlear implantation, but this was affected by age at implantation (the younger the better) and the duration of the postoperative follow-up [57]. In terms of long-term outcomes, Breneman et al. demonstrated that 91% of 35 ANSD children with a CI had some degree of open-set word recognition and at least 80% had open-set speech perception [39]. The majority of the children with ANSD benefited from cochlear implantation and achieved speech understanding, language development and communication outcomes equivalent to their peers with cochlear hearing loss [31,32]. In the present study, 75% of the children with CIs had a speech discrimination score in noise of more than 60%, while 50% had a score of 80% and higher. These results are consistent with the studies cited above, but not with those of other authors who have reported very limited benefits of cochlear implantation in 25% of children with ANSD [33–35] or even very poor performances [36]. In their study, Teagle et al. found that half of 140 children achieved open-set speech perception, but, again, some did not benefit at all due to a lack of electricalinduced neural synchronization, CND, or other associated conditions, such as syndromes or developmental delays [34]. One of the children in our study achieved no speech discrimination on the left side. This may have been due to an undetected CND, as this was one of the children
5. Conclusion The diagnosis and treatment of ANSD, especially in children, remains a challenge. Essential for identifying the site of a lesion and determining the objective parameters for suitable implantation candidates is a careful workup with: adequate audiological testing using ABRs, OAEs and electrocochleography (and, if necessary, eBERA); radiological cMRT and CT imaging; and pediatric, neuropediatric and genetic evaluation. Cochlear implantation requires a careful preoperative assessment by audiologists and clinicians, guiding parents to realistic expectations on possible outcomes, especially in children with accompanying disorders. Furthermore, reports of speech understanding/discrimination in quiet and, particularly, noise, are needed to determine which hearing device is most suitable when it comes to achieving extended benefits from amplification. The present study demonstrates satisfactory outcomes regarding hearing and speech discrimination in children with CIs, as well as in those with HAs. The high number of full-time device users supports the benefits of amplification. There was no data available to us on speech in quiet and noise prior to the provision of a CI, and none on speech in noise with HA, meaning that a proper comparison between the devices could not be carried out. Further studies with a higher number of cases and speech in noise tests with CIs and HAs are required to identify possible differences in outcomes. An individual therapeutic concept, multidisciplinary involvement, regular assessments, and intensive hearing and speech therapy are essential in children with ANSD. Those with the condition are not routine candidates for cochlear implantation, and treatment decisions for these children should always be made on a case-by-case basis. Funding This research has not received any specific grant from funding 6
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agencies in the public, commercial or not-for-profit sectors.
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