Auditory neuropathy' and cochlear implantation ... - Wiley Online Library

Cochlear Implants International Cochlear Implants Int. 9(1), 1–7, 2008 Published online 1 February 2008 in Wiley InterScience (www.interscience.wiley.com) DOI: 10.1002/cii.349

Editorial: ‘Auditory neuropathy’ and cochlear implantation – myths and facts

WILLIAM P R GIBSON, Sydney Cochlear Implant Centre, New South Wales, Australia JOHN M GRAHAM, Cochlear Implant Centre, Royal National Throat, Nose and Ear Hospital, London WC1X 8DA, UK

ABSTRACT A review of current opinion concerning ‘auditory neuropathy’ is presented. It is suggested that electrophysiological tests, including electrocochleography, auditory brainstem responses and electrically evoked auditory brainstem responses, together with imaging, can provide information regarding the site of the underlying pathological conditions that may produce the combination of otoacoustic emissions in the absence of auditory brainstem responses in children with hearing loss. It is suggested that in 75% of cases auditory neuropathy can merely be a result of surviving outer hair cells when inner hair cell function is compromised. The remaining cases of auditory neuropathy may have dysfunction of the afferent neural synapse, cochlear nerve, cochlear nucleus, auditory brainstem tracts and central auditory system. Rather than continuing to use a blanket and often misleading term, we are now in a better position to describe each individual case exhibiting this phenomenon according to the correct site of lesion. Copyright © 2008 John Wiley & Sons, Ltd. Keywords: cochlear implant; auditory neuropathy; electrically evoked auditory brainstem response; inner hair cell damage; premature Introduction Initially the problem was supposed to be due to a central auditory dysfunction. A few hearing impaired children were found to obtain far less benefit from a hearing aid than the pure tone audiogram predicted. It was supposed that some complex dysfunction of the central auditory system blocked the perception of speech. In the 1990s, it was realised that many of these hearing impaired children suffering a ‘central auditory dysfunction’ had recordable otoacoustic emissions (OAE)

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and absent or grossly abnormal auditory brainstem responses (ABR). Sininger et al. (1995) coined the term ‘auditory neuropathy’. The next year, the same group (Starr et al., 1996) suggested that the cause of auditory neuropathy might be an abnormality of the cochlear nerve. Starr et al. (2001) proceeded to biopsy other peripheral nerves to try to uncover the exact pathological mechanism. There was a fear that hearing impaired children suffering with an auditory neuropathy might perform poorly using a cochlear implant. The initial report by Miyamoto et al. (1999) was quite gloomy but since then there have been many papers reporting excellent results (Buss et al., 2002; Madden et al., 2002; Mason et al., 2003; Shallop et al., 2001). Electrophysiological tests Electrophysiological tests may hold a key to understanding the mechanisms which cause auditory neuropathy. In 1971, Aran and his co-workers reported an abnormal transtympanic electrocochleography (ECochG) waveform associated with cases of kernicterus who performed poorly with hearing aids. Spoor et al. (1977) drew attention to the discrepancy between poor hearing thresholds and the relatively large ‘summating potential’ found in cases of kernicterus. They suggested that the reason for this ‘must be a neural or synaptic dysfunction causing desynchronisation of the action potentials of individual fibres’. Round window ECochG (Aso and Gibson, 1994) uses a special shaped ‘golf club’ electrode which is placed through a posterior myringotomy into the round window niche: this provides larger and more robust potentials than a transtympanic needle electrode placed on the promontory (Figure 1). All young children enrolled as candidates for a cochlear implant at the Sydney Cochlear Implant Centre are tested using round window ECochG. Large cochlear microphonics (CM) and an abnormal positive potential (APP) were found in hearing impaired ears that had auditory neuropathy as suspected because OAE were present with no recognisable ABR waveform or a wide N1 wave and no other ABR waves (O’Leary et al., 2000). It appeared that the APP was a distortion product associated with large CM. This APP may be derived from an early positive summating potential (SP), although some contribution from synaptic potentials cannot be excluded. It soon became apparent that the large CM and the presence of the OAE were both due to outer hair cell (OHC) activity and that the APP was the cause of the abnormally wide wave ‘NI’ on the ABR waveform. Electrically evoked ABR (EABR) records the function of the cochlear nerve and brainstem neural pathway. EABR can be obtained from electrodes within a cochlear implant, with a second active electrode placed in the scalp at the vertex providing the dipole. The waveforms are similar to an acoustically evoked ABR, except the first potentials (NI and NII) are obscured by electrical artefact and the NV potential has a shorter latency of approximately 4 ms. Gibson and Sanli (2007) reported a series of 60 congenitally deaf children who had ears which had large CM and APP and received a cochlear implant. The Copyright © 2008 John Wiley & Sons, Ltd

Cochlear Implants Int. 9(1), 1–7, 2008 DOI: 10.1002/cii

‘Auditory neuropathy’ and cochlear implantation

Figure 1: Round window electrocochleogram response.

Copyright © 2008 John Wiley & Sons, Ltd


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EABR findings suggested that in most ears (75%), the abnormality was loss of inner hair cells (IHC) with survival of OHC causing abnormal tuning (or dys-synchrony) of the basilar membrane. In the other ears (25%) the hair cell dys-synchrony was associated with an abnormality of the neural pathway causing a ‘true auditory neuropathy’. Those ears affected by only a hair cell dys-synchrony had excellent speech perception outcomes using the cochlear implant, while ears affected by a true auditory neuropathy only achieved limited speech perception scores. Animal models It is commonly supposed that OHC are more fragile than IHC and that if OHC are preserved, the IHC should be intact. This concept is incorrect. Animal models provide supportive evidence that ears which retain OAE but have absent or grossly abnormal ABR have a loss of IHC with preservation of OHC. Studies performed in chinchillas (Harrison, 1998) with carboplatin (an anticancer drug from the same group as cisplatin) have shown an extensive loss of IHC while the OHC remain intact. There are also genetic animal models: such as the Bronx waltzer mouse (Bock et al., 1982) and the Beethoven mouse (Bussoli et al., 1997). These are mouse mutants which have extensive loss of IHC despite the presence of OHC. Chronic hypoxia can also produce a similar loss of IHC and survival of OHC in guinea pig (Harrison, 2001). It has been suggested that the abnormal ABR with the wide NI potential encountered in auditory neuropathy might be due to a disorder affecting the synapse between the hair cell and the cochlear nerve. Animal studies do not support this concept. Synaptic hair cell ribbons are required for faithful synaptic transmission (Khimich et al., 2005). Mouse mutants (Bassoon and Piccolo mice) with disordered hair cell synaptic ribbons have been studied but the ABR findings are not similar to those found in auditory neuropathy. The wave V is present but delayed in a manner similar to when the nerve is affected by an acoustic neuroma. Prevalence Survival of OHC with loss of the IHC may be more common than previously supposed, especially in premature infants. Rea and Gibson (2003) studied a group of 342 children who had a significant congenital hearing loss using round window ECochG. Seventy three (21%) of these children had large CM and APP, and 83% of children with APP had OAE, but absent or abnormal ABR. The presence of APP appears to be a more sensitive measure of the disorder than OAE. Twenty (63%) of 32 congenitally deaf infants born at 30 weeks gestational age or earlier had APP; 11 (33%) of 33 born between 31 and 36 weeks gestational age had APP, and 20 (11%) of 178 born after 36 weeks gestational age had APP. The results were strongly linked to significant periods of hypoxia. This finding correlates with the animal model which showed survival of OAE and abnormal ABR in Copyright © 2008 John Wiley & Sons, Ltd



guinea pigs with loss of IHC and survival of OHC (Harrison, 2001). These findings suggest that screening of premature neonates by OAE may fail to detect 48% of neonatally deaf children born prematurely before 36 weeks and 11% of neonatally deaf children born after 36 weeks. Excessive hyperbilirubinaemia in the neonatal period can cause both cochlear damage and damage to the brainstem auditory nuclei from staining with bile pigments (Oysu et al., 2002). In the Sydney series, there were only seven (9%) such cases and five were also associated with hypoxia. Prediction of the outcome after cochlear implantation Children suffering with abnormal cochlear activity due to IHC damage with surviving OHC perform poorly with conventional hearing aids, even though there is no neuropathy. It is possible that speech perception is adversely affected by abnormal tuning within the cochlea. Conventional hearing aids are designed for ears in which OHC loss causes broad tuning. When there are surviving OHC, the cochlear partition is inappropriately tuned, as the remaining OHC may act chaotically because of loss of efferent control. Perhaps, for such cases, a hearing aid needs to be developed which actually spreads the acoustic signal rather than trying to increase tuning. In general, perinatally deaf premature infants, including those suffering cerebral palsies, who have OHC survival but IHC damage, performed well using cochlear implants providing no true neuropathy was present. In contrast, congenitally deaf children with OHC survival who also had structural abnormalities of the cochlear nerve rarely achieved any open set speech perception using cochlear implants even after two years of training after implant surgery (Bradley et al., 2008). Rare exceptions have occurred. A few children with a true auditory neuropathy have significantly improved their speech perception using hearing aids. Perhaps this is due to loss of those OHC which are acting chaotically and interfering with the function of the remaining IHC. Alternatively, this improvement may be the result of later myelination of cochlear nerve fibres. Interestingly the only child in the Sydney series (Fulcher, 2007) in whom speech perception dramatically improved with hearing aids had a brother who had a similar problem but failed to improve spontaneously. Fortunately he has excelled using his cochlear implant. There are a few deaf siblings who have poor IHC function and surviving OHC. This appears to be unrelated to hypoxia. The Otoferlin gene has been identified in some cases: this gene is known to affect synaptic transmission (Rodriguez-Ballesteros et al., 2003). Children with this probable genetic cause have performed well using cochlear implants. Conclusions The finding that some congenitally deaf children who perform poorly using conventional hearing aids have OAE and absent or abnormal ABR has been labelled as auditory neuropathy. It appears likely that in the majority of these children who Copyright © 2008 John Wiley & Sons, Ltd


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were born prematurely and suffered episodes of perinatal hypoxia the primary abnormality is associated with loss of IHC and survival of OHC. In these cases the OHC are ‘dys-synchronising’ the output of any remaining IHC by providing inappropriate tuning of the basilar membrane. In some cases, there may also an abnormality of the hair cell synapse which probably does not adversely affect the use of a cochlear implant. A ‘true’ auditory neuropathy exists when the OHC survival is associated with abnormalities of the cochlear nerve, and/or brainstem auditory pathways, and/or central auditory pathways. Rapin and Gravel (2003) called for the use of more diagnostic specificity in children labelled as having auditory neuropathy. We agree that continuing to use the blanket terms auditory neuropathy and ‘auditory dys-synchrony’ may be more misleading than helpful. The history of audiology contains several examples of terms that have later turned out to be misleading or incorrect. ‘Nerve deafness’ has now mostly been replaced by the broader and more correct term ‘sensorineural Deafness’ to distinguish it from conductive deafness. The term ‘Mondini defect’ is no longer used to describe the full range of congenital cochlear malformations. In 1854 James Yearsley’s book Deafness Practically Illustrated includes a chapter entitled ‘Deafness from Derangements of the Stomach (Stomach Deafness)’ – in other words, dyspepsia and vomiting were thought to cause hearing loss; seven years later Menière’s work explained why this concept was incorrect. Certain children with hearing loss and absent or abnormal ABR responses are found to have OAE in the absence of ABR. This group of children includes: those who have suffered perinatal hypoxic damage to IHC (some of whom subsequently recover some hearing); those who have developed jaundice, with or without associated haemolytic anaemia; those with congenitally absent or hypoplastic cochlear nerves; those with IHC synaptic damage; and those with other central neural abnormalities such as Freiderich’s ataxia. Current techniques of imaging and of genetic and electrophysiological testing should allow us to identify each of these pathological entities according to the site of the lesion, rather than continuing to use a naïve term that has turned out to be misleading in three out of four cases. This should make decision-making in the field of cochlear implantation considerably easier. This topic clearly needs further discussion. The Editors hope that all readers who wish to contribute to this discussion will write to Cochlear Implants International ([email protected]) and we hope to publish letters in subsequent issues of the journal. References Aran JM, Charlet de Sauvage R, Pelerin J (1971) Comparison des seuls électrocochléographiques et de l’audiogramme: Étude statistique. Revue de Laryngologie 97(supplementum): 613–621. Aso S, Gibson WPR (1994) Electrocochleography in profoundly deaf children: comparison of promontory and round window techniques. American Journal of Otology 15: 376–379. Bock GR, Yates GK, Deol MS (1982) Cochlear potentials in the Bronx waltzer mutant mouse. Neuroscience Letters 34: 19–25.




Bradley J, Bell M, Beale T, Graham J (2008) Variable long term outcomes from cochlear implantation in children with hypoplastic auditory nerves. Cochlear Implants International 9: 34–60. Buss E, Labadie RF, Brown CJ, Gross AJ, Grose JH, Pillsbury HC (2002) Outcome of cochlear implantation in pediatric auditory neuropathy. Otology & Neurotology 23: 328–332. Bussoli TJ, Kelly A, Steel P (1997) Localisation of the Bronx waltzer (bv) deafness gene to mouse chromosome 5. Mammalian Genome 10: 714–717. Fulcher A (2007) Assessments, alerts, actions, afterthought. Critical issues associated with extreme prematurity. Paper presented at The Australasian Conference on Listening and Spoken Language. Brisbane, Australia, 8–10 March 2007. Gibson WPR, Sanli H (2007) Auditory neuropathy: an update. Ear and Hear 28(Suppl): 102S–106S. Harrison RV (1998) An animal model of auditory neuropathy. Ear & Hearing 19: 355–361. Harrison RV (2001) Models of auditory neuropathy based on inner hair cell damage. In: Sinninger Y and Starr A (eds) Auditory Neuropathy: A New Perspective on Hearing Disorders. Cambridge, MA: Singular Press, pp. 51–66. Khimich D, Nouvain R, Pujol R, Tom Dieck S, Egner A, Gundelfinger ED, Moser T (2005) Haircell synaptic ribbons are essential for synchronous auditory signalling. Nature 434: 869–893. Madden C, Hilbert L, Rutter M, Greinwald J, Choo D (2002) Pediatric cochlear implantation in auditory neuropathy. Otology & Neurotology 23: 163–168. Mason JC, De Michelle A, Stevens C (2003) Cochlear implantation in patients with auditory neuropathy of varied etiologies. Laryngoscope 113: 45–49. Miyamoto RT, Kirk KI, Renshaw J, Hussain D (1999) Cochlear implantation in auditory neuropathy. Laryngoscope 109: 181–185. O’Leary SJ, Mitchell TE, Gibson WP, Sanli H (2000) Abnormal positive potentials in round window electrocochleography. American Journal of Otology 21: 813–818. Oysu C, Aslan I, Ulubil A, Baserer N (2002) Incidence of cochlear involvement in hyperbilirubinemic deafness. Annals of Otology Rhinology and Laryngology 111: 1021–1025. Rapin I, Gravel J (2003) ‘Auditory Neuropathy’: physiologic and pathologic evidence calls for more diagnostic specificity. International Journal of Pediatric otorhinolaryngology 62: 707–728. Rea PA, Gibson WPR (2003) Evidence for surviving outer hair cell function in deaf ears. Laryngoscope 113: 2030–2033. Rodriguez-Ballesteros M, del Castillo FJ, Martin Y, Moreno-Pelayo MA, Morera C, Prieto F, Marco J, Morant A, Gallo-Terßn J, Morales-Angulo C, Navas C, Trinidad G, Tapia MC, Moreno F, del Castillo I (2003) Auditory neuropathy in patients carrying mutations in the otoferlin gene (OTOF). Human Mutations 6: 451–456. Shallop JK, Peterso A, Facer GW, Fabry LB, Driscoll CL (2001) Cochlear implants in 5 cases of auditory neuropathy:postoperative findings and progress. Laryngoscope 111: 555–562. Sininger YS, Hood LJ, Starr A, Berlin CT, Picton TW (1995) Hearing loss due to auditory neuropathy. Audiology Today 7: 16–18. Spoor, Atze, Eggermont JJ (1977) Electrocochleography in children with better subjective hearing. Proceedings of the 11th World Congress of Otorhinolaryngology (XI Congresso Mundial D’Otorrhinolaryngologia, Buenos Aires), p. 309. Starr A, Picton TW, Sininger Y, Hood LJ, Berlin CI (1996) Auditory neuropathy. Brain 119: 741–753. Starr A, Picton TW, Kim R (2001) Pathophysiology of auditory neuropathy. In: Sininger Y, Starr A (eds). Auditory neuropathy: a new perspective on hearing disorders. San Diego: Singular Press; pp. 67–82. Address correspondence to: John M Graham, Cochlear Implant Centre, Royal National Throat, Nose and Ear Hospital, London WC1X 8DA, UK. Email: [email protected]



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