Is auditory neuropathy an appropriate term? A systematic literature review on its aetiology and pathogenesis| ACTA Otorhinolaryngologica Italica

Abstract

This article has been corrected. See errata corrige https://doi.org/10.14639/0392-100X-N2062-EC

To clarify the aetio-pathogenesis of Auditory Neuropathy Spectrum Disorder (ANSD), a total of 845 papers were divided into four categories: Review, Audiology, Treatment and Aetiology. Aetiology was the topic analysed categorising papers as: Genetics, Histopathology, Imaging and Medical diseases. Isolated ANs were in relation to Otoferlin, Pejvakin and DIAPH3 deficiency, and the syndromes were mainly Charcot Marie Tooth, Friedreich Ataxia, mitochondrial disorders and those associated with optic neuropathies. In histopathology papers, important information was available from analyses on human premature newborns and on some syndromic neuropathies. From cochlear dysmorphism to cerebral tumours associated with ANs, these are described in what is identified as the Imaging area. Finally, the prevalent clinical pathology was bilirubinopathy, followed by diabetes. In conclusion, AN/ANSDs do not refer to a clear pathological condition, but to an instrumental pattern without any evidence of auditory nerve involvement, except in a few conditions. The terms AN/ANSD are misleading and should be avoided, including terms such as “synaptopathy” or “dis-synchrony”.

Introduction

In 1996, the term Auditory Neuropathy (AN) was proposed by Starr et al. ¹, describing 10 children/young people with normal cochlear outer hair cell function and abnormal auditory nerve functionality. A similar audiological framework was described by Kaga et al. ² in the same year.

The other audiological characteristics of Starr’s patients were: progressive mild to moderate hearing loss, and speech discrimination poorer than expected. The impairment had become symptomatic in childhood or young adulthood, and eight patients out of 10 developed neurological neuropathy after the audiological diagnosis.

At the beginning, indeed, four audiological findings were considered the main signs of the so-called AN: normal otoacoustic emissions (OAE), unexpected absence or altered Auditory Brainstem Response (ABR), poor speech discrimination and mild to moderate hearing loss.

These signs are not different from those used in the past to identify a “retro-cochlear dysfunction”, except for the Oto-Acoustic-Emissions (OAE), because this is a relatively new test that was not available in the past.

From the first report in 1996 to December 2020, more than 800 papers have been written on this topic, extending the possibility of this particular kind of hearing impairment to severe to profound deafness. All degrees of impairment when the absence of or abnormal ABR is associated with the presence of OAE are called AN, without considering as pathognomonic the other two symptoms presented in the original Starr paper, which are unexpected poor speech discrimination and hearing loss not higher than moderate.

The British Association of Audiovestibular Physicians ³ wrote in 2018: “Auditory neuropathy spectrum disorder (ANSD – see later) describes a condition in which a patient’s outer hair cell function, as demonstrated by otoacoustic emissions (OAE) and/or cochlear microphonic (CM), are (or were at one time) present, and auditory brainstem responses (ABR) are abnormal or absent”, without any information about the hearing loss degree.

In this way, the overlapping between the classic signs, definition of retro-cochlear dysfunction and the new AN concept disappeared.

The modification of the original description of AN, also including significant hearing loss, completely distorts the diagnostic role of ABR and Speech Audiometry since they are first altered by the hearing loss degree.

It is a common experience that click ABR cannot be elicited in the case of disabling hearing impairment starting to be absent in some patients at 65 dB of loss in the high frequencies and always absent in severe to profound loss, and speech discrimination is not possible without hearing devices in these degrees of hearing loss.

Due to the changes of the initial definition, it is clear that in severe to profound hearing loss the decisive instrumental sign that should confirm AN diagnosis is limited to the presence of OAE, because ABR and Speech Audiometry are not conclusive as primarily altered in all cases of significant hearing loss.

The modification of the AN description involves various audiological pathologies regarding all stations of the hearing apparatus and all degrees of hearing loss. The AN pathogenesis therefore appears to be multifactorial and the clinical results likely come from a variety of lesions throughout the auditory pathway, from inner hair cells (IHCs) to the cerebral cortex.

A group of experts ⁴ thus decided to modify the term AN to ANSD-Auditory Neuropathy Spectrum Disorder to avoid a precise terminology being able to describe various and different dysfunctions, even if with common involvement of the 8^th nerve.

Rance and Starr ⁵ tried to bring order to the confusing topic, limiting the so-called ANSD to 4 categories. These four categories are: 1. presynaptic disorders, affecting inner hair cells and ribbon synapses; 2. postsynaptic disorders, affecting unmyelinated auditory nerve dendrites; 3. postsynaptic disorders, affecting auditory ganglion cells and their myelinated axons and dendrites; 4. central neural pathway disorders, affecting the auditory brainstem.

ANSD can be unilateral or bilateral, isolated or part of a neurologic syndrome, congenital or acquired, and producing all degrees of hearing loss.

Congenital ANSD is mainly caused by genetic abnormalities, which may be either isolated or associated with other syndromes. The inheritance pattern can include all the four main types of inheritances such as autosomal dominant, autosomal recessive, X- linked and mitochondrial.

An interesting summary by Santarelli ⁶ demonstrates that the degree of loss in neurologic syndromes is almost always mild, but moderate to profound in isolated AN.

The hearing loss can be progressive, starting at childhood or adulthood especially in neurologic syndromes, but many ANs are also congenital with severe to profound hearing loss and can occur in all age groups. Even the evolution of the OHC function is intellectually stimulating, because in some cases the OAE disappears over time.

However, the Kaga experience regarding the evolution of congenital AN is even more interesting.

The author ⁷ found three categories: the first can auto-resolve until normal hearing at around 12 months of life, the second evolves to severe to profound loss starting as mild and the third is part of a wider neurological syndrome.

Regarding aetiology, AN can be due to genetic disorders or can have a wide range of other aetiologies including prematurity, hyper-bilirubinaemia, anoxia, hypoxia, congenital brain anomalies and ototoxic drug exposure. Nevertheless, no aetiologic factor can be identified in approximately half of cases ⁸.

Regarding imaging, this is a fundamental investigation because the anatomical abnormalities of the 8^th nerve can objectively demonstrate the origin of the impairment, as in the case of hypoplasia or aplasia labelled Cochlear Nerve Deficiency (CND) ⁹.

Hence, some criticism is presented in the literature regarding the definition of AN ^10,11 and the observations are not merely academic, since one of the most important medical rules is that the choice of correct treatment and rehabilitation is a consequence of having knowledge of a clear pathogenesis in mind. For example, the first category defined by Race and Starr ⁵ as pre-synaptic relates to a dysfunction of the IHCs (cochleopathy) and the hypothesised nerve dys-synchrony (neuropathy) is secondary and not a primary event.

Thus, we decided to carry out a literature review of medical evidence (genetics, histo-pathology, imaging, medical diseases) in order to obtain objective information about the aetiology and pathogenesis of AN.

Materials and methods

Literature search

A literature search was performed on PubMed, Embase, and the Cochrane Library.

The date of the last search was 31 December 2020.

To identify all relevant studies that described the results of auditory neuropathy spectrum disorders, articles were selected on the basis of the following MeSH terms and synonyms in their title, abstract, keywords, text or medical subject heading such as: “((“auditory neuropathy”[Title/Abstract]) OR “auditory neuropathies”[Title/Abstract]) OR “Auditory neuropathy” [Supplementary Concept]).

The papers extracted from libraries were uploaded to a spreadsheet column, one per cell in the first column. The second column reported the decision to consider each paper eligible or not for the study, following the criteria described below. Finally, the third column had a drop-down menu with seven categories to choose from in order to identify the main topic of the individual paper. The categories were: Review, Audiology, Treatment, Medical aetiology, Genetics, Histopathology and Imaging. The main topic was identified by title and abstract, which was added at the end of the header of each paper. Using the spreadsheet features, we were able to obtain the seven homogenous groups to evaluate.

A total of 845 papers were extracted, but the final review was based on 799 papers disregarding those with incomplete abstracts or not available in English. For some papers, the analysis was completed by retrieving the full text when the article was considered of particular interest for the preparation of the current paper, also taking into account the reference lists.

The papers retrieved as full text are reported in the main reference list.

Study selection

The review was undertaken independently by three researchers (SB, GB and FDB), expert in critical analysis of academic literature. All the abstracts were reviewed using the predetermined inclusion, exclusion and categorisation criteria. The articles considered relevant or of uncertain relevance were retrieved as full-text papers. The full-text papers were reviewed, and data extraction performed independently by each researcher. Any discrepancies between researchers were resolved by mutual consensus. This systematic review was conducted according to the guidelines for reporting Systematic Reviews and Meta-Analysis promulgated by PRISMA ¹².

Results

The first publication on ANs was in 1996 and the maximum production was detected after the year 2010.

The topic mainly treated was audiology (Fig. 1), but the interest of the authors of the current paper was focused on 268 papers regarding Medical aetiology, Genetics, Histopathology and Imaging, being significant for the purpose. In other words, the papers with Audiology and Treatment as well as Review as their topic were analysed only to better understand the aetiology and pathogenesis of AN.

Medical aetiology

The most discussed medical issue related to AN was hyper-bilirubinaemia, but all the pathologies are presented especially metabolic, infectious and toxic diseases (Fig. 2).

Concerning bilirubin, the auditory toxic effect starts at serum levels of 22 mg/dl and the best predictor of the hearing injury is unbound bilirubin ¹³. The percentage of hearing impairment varies widely. For example, Can et al. ¹³ declared an incidence not more than a normal event; 11% for Amin et al. ¹⁴. The data regarding the kind of hearing loss are interesting, because both SNHL and AN can result from bilirubin toxicity ¹⁵. Finally, it is important to know the positive therapeutic effect on hearing loss by exchange transfusion, which worsened if ibuprofen was administered in the presence of hyperbilirubinaemia ¹⁶.

On the topic of diabetes, six papers described the presence of an AN. Interestingly, but to be confirmed with additional studies, the positive effects on hearing impairment due to coffee¹⁷, glycine ¹⁸, rutin ¹⁹, while insulin and oral hypoglycaemic agents seemed to have no therapeutic effect ²⁰.

The ANs described after infections, among the most frequent, were those from CMV ²¹ and parotitis ²².

Some authors describe patients where symptoms only become evident with an elevation of body temperature, particularly in some cases of otoferlin mutations ²³.

Considering the other papers, a case report of platelet dysfunction is particularly interesting, as this was treated using adenosine triphosphate with success ²⁴, the same positive effect that can be seen with thiamine deficiency ²⁵ and biotinidase ²⁶. Other papers described the toxic effect of dioxin ²⁷, xylene ²⁸ and bismuth ²⁹.

Genetics

It is estimated that approximately 40% of AN cases have an underlying genetic basis, which can be inherited in both syndromic and non-syndromic conditions. A total of 63 papers described isolated AN and 70 described syndromic AN.

Considering isolated deafness, it is evident that the otoferlin gene mutation (autosomal recessive DFNB9) is the most frequent aetiology for the so-called AN (Fig. 3), provoking altered vesicle replenishment and delivery of IHC neurotransmitter in the ribbon synapses ³⁰.

The site of action of Pejvakin (autosomal recessive hearing loss - DFNB59) was initially identified in the spiral ganglion ³¹. Today, it is clear that this protein has a role in the mechano-transduction of hair cells, involving both outer and inner hair cells³² or only IHCs.

The cochlear role of connexins (DFNB1) has been well-known for a long time, and for DIAPH3 (AUNA1- autosomal dominant inheritance) the evolution of knowledge is similar to the Pejvakin mutation because initially a neural location was described, and today its clear role in cochlear physiology has been demonstrated ³³. In conclusion, all the mutations described in isolated AN involve cochlear proteins. Finally, some observations on mitochondrial mutation in non-syndromic hearing loss can be made.

While hearing loss is a common symptom, AN has only rarely been reported in these disorders. These kinds of genetic mutations can involve the cochlea in particular, as it is sensitive to energy insufficiency especially in the stria vascularis, and the predisposition to aminoglycoside-induced hearing loss ³⁴.

With regards to the papers describing syndromes, seven conditions were the subject of more than two papers, for a total of 44 (Fig. 4); the remaining 14 papers were case reports of different and rare neurologic diseases.

Interestingly, several of the genes implicated encode mitochondrial proteins, and audiograms report mild to moderate hearing loss for low frequencies ³⁵, and normal or mild hearing loss for higher ones ⁴, as already reported by Soliman in 1987 ³⁶ in the so-called “low frequencies syndrome” or “reverse slope” today. Generally, these syndromes occur phenotypically later in childhood.

The syndromes most frequently cited are: Charcot Marie Tooth (CMT) and its synonymous Hereditary Motor and Sensory Neuropathy (HMSN); Friedreich Ataxia; Mitochondrial disorders; Visual and Hearing impairment (OPA1/LEBER HON/USHER/FDXR/OPA8); Mohr TS Syndrome; Cerebellar ataxia – Areflexia - Pes cavus - Optic atrophy - Sensorineural hearing loss (CAPOS) and Brown Vialetto Syndrome.

CMT is a hereditary demyelinating or axonal ³⁷ early onset neuropathy.

In CMT, also known as HMSN, pure tone detection can be degraded from any loss to mild and severe hearing loss. In other words, the hearing abilities of people with CMT are highly variable as is the site of lesion³⁸. Onset of symptoms is more frequent in adolescence or early adulthood. The gene most frequently mutated is MPZ, encoding a protein included in the compact myelin that plays a crucial role in myelin formation and adhesion, but most of the genes coding for proteins involved in this process have been associated with neurodegenerative diseases³⁹.

CMT can be sensitive to corticosteroid therapy ⁴⁰ when symptoms are associated with infectious signs ⁴¹ and hearing aid use is recommended even if the involvement of the entire auditory nerve associated with hair-cell preservation is likely to be a feature shared by the majority of AN disorders included in the CMT group ⁵.

Hearing sensitivity can also be normal in Friedrich Ataxia syndrome, but in some cases ABR is altered ⁴².

Mohr-Tranebjærg syndrome is a rare X-linked recessive neurodegenerative disorder resulting in early-onset hearing impairment, gradual dystonia and optic atrophy. It can start from the very early years of childhood associated with a severe hearing loss ⁴³. CAPOS syndrome (Cerebellar ataxia, Areflexia, Pes cavus, Optic atrophy, and Sensorineural hearing loss) with acquired hearing impairment as a prominent feature ⁴⁴, is a rare neurological disorder associated with mutation in the ATP1A3 gene. Han et al. ⁴⁵ and Atilgan et al. ⁴⁶ described the remarkable benefits of cochlear implantation, assuming synaptophysin as the hearing loss pathogenesis.

Brown Vialetto Syndrome is a neurodegenerative disorder characterised by hearing loss and ponto-bulbar palsy due to mutations in the genes encoding the riboflavin transporters, and vitamin supplements can thus be useful.

Riboflavin therapy results in improvement of hearing thresholds during the first year of treatment in subjects with recent-onset hearing loss.

The review of Brown Vialetto Syndrome papers revealed contradictory therapeutic experiences because in some subjects the outcomes of cochlear implants were surprising ⁴⁷, especially if associated with riboflavin treatment^48,49, but disappointing in others ⁵⁰.

The syndromes described above are totally disabling neurological diseases compared with diseases where the phenotype is limited to vision and hearing impairment, such as LHON and OPA1. In these pathologies, mitochondrial dysfunction is also thought to be an important pathophysiological player ⁵¹.

In Leber’s hereditary optic neuropathy (LHON), the degree of hearing loss varies ⁵², but the majority of subjects have normal hearing with abnormal ABR. The evaluation of OPA1 disease is of particular interest because for some researchers the origin of hearing impairment is the dendrites of the 8^th nerve ⁶, while for others it is the cochlea ⁵³. Yu-Wai-Man et al. ⁵⁴ confirmed the phenotypical effects of the OPA1 mutation in both the inner ear and in the unmyelinated portion of the auditory nerve.

Histopathology

The papers on histopathology of ANSD consist of 57 involving animals and 7 involving humans.

The 57 papers on animals were categorised into 4 groups.

The experiments described in the first group can be considered methodological because they demonstrate how to reproduce neuronal injury/dysfunction in animals, preserving the cochlear hair cells. These papers do not add any particular new knowledge about the aetiology and pathogenesis of AN.

For the second group, the interest is more practical because they describe the mechanisms underlying drug/toxin-induced damage and above all the anatomical site of lesion/dysfunction. IHCs are the target organ in the case of carboplatin toxicity ⁵⁵ and glutamate effect ⁵⁶ even if in contradiction with Liu et al. ⁵⁷ who described SGN (Spiral Ganglion Neurons) involvement. SGN is also the target of Diphtheria toxin ⁵⁸. Cobalt and chromium are toxic to all sensory cochlear cells ⁵⁹. The same consequence was described in the case of hypoxia, but with a different effect on the two sensory cells with higher vulnerability of IHCs, as hypoxia damage is related to its duration ⁶⁰. Bilirubin toxicity has SGN as its target for Sun et al. ⁶¹, but also IHC synapses for Salvi et al. ⁶² depending on the dosage ⁶³. Moreover, bilirubin did not reveal any auditory nerve involvement in the Gunn rat, but a cochlear toxicity in contradiction with the findings of Uziel et al.⁶⁴ who described a preserved cochlea in the case of bilirubin toxicity in the Gunn rat. In Hidden Hearing Loss, the pathogenesis was identified in axonal fibres ⁶⁵. Axonal fibres were also the target of pyridoxine ⁶⁶ and spectrin ⁶⁷.

Thus, it is interesting to point out the different levels of vulnerability of OHC vs IHC vs nerve considering duration and/or dosages of the same toxic agents or protein deficiency.

The third group is similar to the previous one, also taking into account some genetic mutations of proteins which occur in the cochlea. All the papers describe cochlear proteins located mainly in IHCs except for Pejvakin, which was also identified in OHCs and Cx 29 originally located in SGN in another paper ⁶⁸. A multiple site of lesion was the effect of the abnormal expression of AIFM1 (AIF) even if with a SGN prevalence ⁶⁹.

The last group of papers on animals analyse possible therapies for neuronal injuries. Mesenchymal stem cells ⁷⁰, transcription factor Sox2 ⁷¹; photo-biomodulation ⁷²; cell transplantation ⁷³; taurine⁷⁴; coffee or trigonelline in pyridoxine intoxication ⁷⁵.

There were only seven studies performed on humans, and two of these involved both animals and humans.

Diaz-Horta ⁷⁶ described an interesting case of AN due to mutation of the gene ROR1 in mice because the hearing loss with preserved OAE was found in malformed cochlea (smaller and under-coiled). Less evident regarding the precise site of lesion is the experience described by Amati-Bonneau et al. ⁷⁷ because the R445H mutation in OPA1 does not exclude inner hair cell involvement in the guinea pig, leaving the doubt of a cochleopathy and not of isolated neuropathy. On the other hand, in MPZ gene mutations, the inner hair cells were normal in number, preserving morphology and the anatomical alterations evident along the auditory nerve fibres ⁷⁸.

The paper by Amatuzzi et al. ⁷⁹ is one of the most important clinical contributions because it demonstrates that the so-called AN of premature infants is indeed a cochlear pathology.

Conversely, the AN of the Mohr-Tranebjaerg syndrome, an X-linked hearing loss caused by mitochondrial dysfunction, is due to a degeneration of spiral ganglion cells preserving the cochlear organs ⁸⁰. The Pejvakin distribution was also identified in human spiral ganglion ³¹ in contrast with Harris et al. ⁸¹ who located the protein inside the cochlea.

Imaging

Imaging represents the most important clinical tool to identify an AN on an anatomical basis and its execution is thus mandatory for a correct diagnosis ⁸². We found 18 papers on imaging and AN: 10 described a CND, 2 a dysmorphism involving both the cochlea and the 8^th nerve, 3 intracranial tumours excluding the 8^th nerve, 1 an intracranial haemorrhage and 2 intracranial hypertension.

The papers confirmed that the hearing impairment of some ANs does not involve the 8th nerve, but is actually located in the CNS, leaving the first neuron of the auditory apparatus free from lesions.

Discussion

The first and most impressive evidence from this ANSD literature review is the fact that many dysmorphisms, dysfunctions or pathologies of all the organs of the hearing apparatus can present the pathognomonic audiological combination of “OAE present and ABR absent or altered”. However, in the majority of cases the site of the lesion is the cochlea or the central nervous system and not the acoustic nerve, in contrast with the nomenclature of neuropathy.

The correct and definite attribution to the 8^th nerve as the pathogenesis of hearing impairment can be made only when it is shown by imaging evidence or when electrophysiological tests are altered in normal or mildly impaired hearing, thus when the hearing loss is not the primary origin of the alteration of the acoustic potentials. Berlin et al. ¹⁰ summarised the literature on the clinical meaning of pure tone audiometry, attributing impairment to IHC dysfunction/lack/pathology in the case of profound hearing loss.

Regarding imaging, the prevalence of retro-cochlear dysmorphism varies between 18% and 28% of AN children, frequently associated with brain (40%) or cochlear abnormalities (31%), especially in the case of bilateral CND⁸².

Both imaging and acoustic potential alterations not justified by the degree of hearing loss are the only findings that are able to reliably confirm a neuropathy; other tools or clinical observations cannot be definitive due to the wide variety of pathologies involved.

In fact, the introduction of the concept of “spectrum disorder” confirms the observation that a large number of diseases are involved in AN, but this cannot be passively accepted because in the majority of cases, since in isolated hearing loss nerve involvement is excluded due to mutations of proteins with a well-known role in the cochlea such as otoferlin, pejvakin, DIAPH3 and GJB2.

The cochlea and not the nerve is the site of dysfunction in isolated genetic ANs.

Only in neurologic syndromes for poly-neuropathies and/or Central Nervous System disease can the cochlea be excluded as the origin of the hearing impairment, but can one be sure that the nerve is the cause of the communication difficulties of the patient and not a CNS disease?

Concerning medical aetiology, Amatuzzi et al. ⁷⁹ showed that the cochlea injury is the origin of hearing loss in premature infants and not the auditory nerve. Furthermore, diabetes and hyperbilirubinaemia are identified as the most frequent aetiologies. In diabetes, the vascular side effect ⁸³ is assumed to be the pathogen in the cochlea as in the retina. More difficult to interpret is the pathogenesis of hearing loss in hyperbilirubinaemia. Some authors have described a toxic effect on neural structures, but it must be noted that the most frequent pathology in neonates starts with severe haemolytic anaemia and related hypoxia, which might be the cause of a cochleopathy ⁸⁴, while motor dysfunction and dysarthria can be easily related to central toxic effect of bilirubin. Anaemia related to secondary kernicterus is not described in papers with Gunn rat protagonists⁶⁴ because in that animal hyperbilirubinaemia is primary and the cochlea seems to be preserved, but not for other authors like Salvi et al. ⁶². The reason for the contradiction about the greater or lesser involvement of the cochlea by bilirubin toxicity can be related to the evidence that the injuries are dose-dependent ⁸⁵. Another interesting hypothesis was that proposed by James et al. ⁸⁶ because they consider riboflavin depletion secondary to hyper-bilirubinaemia as a cause of hearing impairment. From these considerations, it is plausible to consider pathologies related to hyperbilirubinaemia as a spectrum disorder with greater or lesser involvement of some neural organs ⁸⁷, but including the possibility of a cochleopathy which is dose-dependent or caused by haemolytic anaemia or by different causes. In any case, some excellent outcomes with CIs can be used as ex juvantibus criterium to confirm the cochlea as the site of the lesion.

In summary, the term AN is the cause of confusion rather than the explanation of a particular framework because in most cases it is not related with the real pathogenesis of hearing impairment as evident in genetic isolated AN and in the main medical pathologies.

We think that the confused opinions about so-called AN could have some historical reasons and could even be related to the innovative knowledge regarding cochlea physiology (old passive scheme vs new active one). Furthermore, the confusion could originate also from the almost contemporary introduction of systems to record Oto-Emissions in the clinical field that do not always seem to be interpreted with the new scheme in mind.

Generally, the lag time between a new medical discovery and the concrete comprehension or utilisation of the new concepts is between 10 and 17 years ⁸⁸.

This is not the case of comprehension of the source of OAE, limited to the OHCs.

The introduction of the first commercial device to record OAE by otodynamics was in 1988 and the first complete description of the active function of OHCs was made by Brownell in 1985 ⁸⁹, even if the idea of a cochlear amplifier had already been described by Gold in 1948 and Kemp ⁹⁰ confirmed the presence of the amplifier in 1978, though with some doubts as he wrote, “…probably located in the cochlea…” explaining the new phenomenon observed.

The very short lag time between the two facts (phenomenon discovery and clinical application) led to the belief that the clinical instrument was a system to evaluate the entire cochlea and not only the OHCs, considered as classic receptors as in the past, and thus similar to the IHCs.

It may be useful to remember that if we consider the entire cochlea as a passive organ, we should simply assume that OHCs and IHCs are similar as hearing receptors except for analysis of sound intensities less than around 50 dB for OHCs and louder for IHCs. Consequently, OHCs should be first considered in the case of mild hearing loss and always disrupted in the case of severe to profound hearing loss together with the IHCs in this case.

In reality, it is correct to blame OHCs in the case of some peripheral hearing loss up to 50 dB due to a lack of IHC tuning, but the same inference is not true in severe to profound hearing loss because the OHCs are not hearing cells.

Thus, the possibility of finding normal OHCs in the case of a cochlear severe-to-profound hearing loss is correct.

Dallos ⁹¹ wrote “Mammals hear with their IHCs – the true sensory receptors of the cochlea”.

Coming back to the definitions of AN, we think that at the beginning some authors considered otoacoustic emission devices as systems that allow evaluation of the entire cochlea, wrongly inferring that IHCs are preserved in the case of normal OHCs, because otoemissions were present. There is some important evidence, physiological as well as pathological, that can confirm the two hair cells are different organs with different functions and behaviours in the case of an ear pathology or dysfunction.

This relates to the following:

1. dysfunctions on a genetic basis involving some proteins, which affect functions of one hair cell and not the other (see otoferlin for example);
2. the histopathological findings in premature infants with hearing impairment due to loss of IHCs and not of OHCs ⁷⁹ ;
3. the existence of deaf mice due to lack of IHCs and normal OHCs, such as the Bronx waltzer mouse ⁹² and the Beethoven mouse ⁹³;
4. the ototoxic effect of some anti-tumour drugs ⁹⁴ limited to the IHCs and not to the OHCs, such as carboplatin and vice versa for other drugs such as aminoglycosides ⁹⁵;
5. different levels of vulnerability between the two hair cells ⁹⁶;
6. different effects of some pathogens limited to IHCs or also involving OHCs on the basis of duration and intensity ⁶³.

Conclusions

Precise terminology in biology is a fundamental issue. According to Rapin and Gravel ¹⁴, the term neuropathy does not apply to cases where hearing loss is attributable to a disease of the central auditory pathway alone, like Rance and Starr’s group 4 ⁵, because central tracts in the white matter of the brain, cerebellum, brainstem and spinal cord are not “nerves,” and their pathologies are not “neuropathies.”

Conversely, Race and Starr’s group 1 consists of “cochlear hearing loss” excluding nerve involvement or other neurological pathologies.

Real neuropathies are CNDs and, probably some ADOA+ due to mutation of the OPA1 gene and other genetic hearing impairments associated with optic nerve pathologies.

In otological clinical practice, it is important to identify the precise site of the lesion for disabling hearing loss since Cochlear Implants (CIs) are contra-indicated in retro-cochlear dysfunctions and the term neuropathy implies the involvement of the auditory nerve. CIs should therefore be contraindicated in the case of the so-called ANs, although the results in clinical practice suggest the opposite in the majority of cases, especially in isolated AN.

The reason for this contradiction is simple: we are talking about cochleopathies and not neuropathies as the literature review has confirmed.

Not considering the misleading attribution to the nerve of some untrue ANs, it could lead many clinicians to feel that implantation should be indicated for all AN patients, even when hearing sensitivity is better than the usual indication ⁴. Theoretically speaking, extending the indications for CIs from isolated genetic ANs to syndromic ANs should be considered a disputable inference: we are comparing two different kinds of disease with only two similar instrumental findings in common (OAE and ABR). The CIs outcomes in AN syndromic patients have been described as satisfying in some papers ⁹⁷ and inadequate in others ⁹⁸. This unexplained contradiction is probably due to a lack of knowledge about the disease itself. In this regard, we suggest considering the literature review reported herein showing that the knowledge concerning inner ear biology changed over time (see Pejvakin or DIAPH3 functions). This dramatically modified, for example, the enthusiastic conclusion of Starr et al. in 2004 ⁹⁹ regarding the therapeutic effects of CI in AUNA1 because the protein in question involves the cochlea and not the nerve, in contrast to what reported in papers based on the knowledge at that time.

These observations confirm the need to consider each patient individually, without following diagnostic models considered conclusive, when instead they are questionable just like the combination “OAE present and ABR absent” in case of severe and profound deafness.

In conclusion, we believe it is more appropriate to abandon the term Auditory Neuropathy when OAEs are present and ABR is altered or absent because it is misleading. Moreover, in case of genetic isolated AN, the terms “synaptopathy” and “dis-synchrony” are also confusing, because they do not describe the causes but the consequences of a receptor dysfunction, i.e. the production or delivery of its neuro-transmitter that is a IHCs “job”, with a secondary and not a primary involvement of nerve dendrites.

For all the reasons above, we suggest to not consider OAEs as pathognomonic for diagnosis of AN, if not confirmed by other signs.

Our final proposal is to consider more appropriate to include the OHC conditions in an overall diagnosis, using the following formula: “Hearing impairment due to (cochlear/neural/central) dysfunction, with preserved OHC function”, as already mentioned by Gibson ¹⁰⁰.

Figures and tables

Figure 1.Main topic of the papers.

Figure 2.Medical aetiology.

Figure 3.More frequent isolated “untrue” ANs - genetics.

Figure 4.Most frequent syndromes.

References

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