10.14639/0392-100X-N0932
This article has been corrected.&nbsp;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”.
text/xml
1827-675X
932
en
Gabriele Bruno
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
cochlear implants
Is auditory neuropathy an appropriate term? A systematic literature review on its aetiology and pathogenesis
Text.Serial.Journal
https://www.actaitalica.it/
41
Review article/Meta-analysis
2021-11-26
2020-06-17
2021-12-22
2021-12-22
496-506
1
Gabriele Bruno
2021/11/26
10.14639/0392-100X-N0932
496
ENT Department, Turin University, Italy
1827-675X
cochlear implants
506
Is auditory neuropathy an appropriate term? A systematic literature review on its aetiology and pathogenesis
https://www.actaitalica.it/article/download/932/701
41
ACTA OTORHINOLARYNGOLOGICA ITALICA 2021;41:496-506; doi: 10.14639/0392-100X-N0932




Review


Is auditory neuropathy an appropriate term?
A systematic literature review on its aetiology
and pathogenesis
Neuropatia uditiva è un termine appropriato?
Revisione sistematica della letteratura sulla sua ezio patogenesi
Sandro Burdo1, Federica Di Berardino2, Gabriele Bruno3
1
    Scientific Coordinator of Italian Association Free to Hear; former Director of Audiovestibology Unit Varese Hospital, Varese, Italy;
2
    Audiology Institute, Milan University, Italy; 3 ENT Department, Turin University, Italy


SUMMARY
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, Histopathol-
ogy, Imaging and Medical diseases. Isolated ANs were in relation to Otoferlin, Pejvakin and
DIAPH3 deficiency, and the syndromes were mainly Charcot Marie Tooth, Friedreich Atax-
ia, 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,       Received: July 10, 2020
the prevalent clinical pathology was bilirubinopathy, followed by diabetes. In conclusion,         Accepted: May 15, 2021
AN/ANSDs do not refer to a clear pathological condition, but to an instrumental pattern            Published online: November 26, 2021
without any evidence of auditory nerve involvement, except in a few conditions. The terms
                                                                                                   Correspondence
AN/ANSD are misleading and should be avoided, including terms such as “synaptopathy”
                                                                                                   Sandro Burdo
or “dis-synchrony”.
                                                                                                   Associazione Italiana Liberi di Sentire onlus
KEY WORDS: auditory neuropathy, synaptopathy, dis-synchrony, snhl, cochlear implants               E-mail: responsabile.scientifico@liberidisentire.it

                                                                                                   Funding
RIASSUNTO                                                                                          The paper was supported with a grant of
Per chiarire la ezio-patogenesi della Neuropatia Uditiva (NU), sono stati identificati 845         Associazione Italiana Liberi di Sentire onlus
articoli divisi in quattro categorie: Revisioni, Audiologia, Trattamenti, Eziologia. Gli arti-     (www.liberidisentire.it).
coli sull’eziologia riguardavano: genetica, istopatologia, patologie mediche, diagnostica
per immagini. La NU isolata è stata descritta nelle deficienze da otoferlina, peivachina e         Conflict of interest
DIAPH3. Tra le sindromi emergono Charcot Marie Tooth, Friedreich Ataxia, i disordini               The Authors declare no conflict of interest.
mitocondriali e le neuropatie visive. Per quanto riguarda l’istopatologia chiarificanti sono
stati gli articoli sui prematuri. Sia la patologia periferica che quella intracranica sono state     How to cite this article: Burdo S, Di Berardino
descritte nella diagnostica per immagini. La patologia medica più frequente è risultata la           F, Bruno G. Is auditory neuropathy an appro-
bilirubinopatia, seguita dal diabete. In conclusione, la cosiddetta neuropatia uditiva non           priate term? A systematic literature review on
è riferibile ad una condizione patologica definita, poiché si tratta di un dato strumentale          its aetiology and pathogenesis. Acta Otorhi-
presente in una ampia serie di condizioni patologiche in cui il nervo acustico è spesso pa-          nolaryngol Ital 2021;41:496-506. https://doi.
radossalmente indenne. La revisione della letteratura porta a suggerire di abbandonare il            org/10.14639/0392-100X-N0932
termine di Neuropatia Uditiva perché fuorviante in molti casi.
                                                                                                   © Società Italiana di Otorinolaringoiatria
PAROLE CHIAVE: neuropatia uditiva, dissincronia, sordità neurosensoriale, impianti                 e Chirurgia Cervico-Facciale
cocleari
                                                                                                                  OPEN ACCESS

                                                                                                   This is an open access article distributed in accordance with
                                                                                                   the CC-BY-NC-ND (Creative Commons Attribution-Non-
Introduction                                                                                       Commercial-NoDerivatives 4.0 International) license. The
                                                                                                   article can be used by giving appropriate credit and mentio-
                                                                                                   ning the license, but only for non-commercial purposes and
In 1996, the term Auditory Neuropathy (AN) was proposed by Starr et al. 1, de-                     only in the original version. For further information: https://
scribing 10 children/young people with normal cochlear outer hair cell func-                       creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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                                                                                            Is auditory neuropathy an appropriate term?




tion and abnormal auditory nerve functionality. A similar        presence of OAE, because ABR and Speech Audiometry
audiological framework was described by Kaga et al. 2 in         are not conclusive as primarily altered in all cases of sig-
the same year.                                                   nificant hearing loss.
The other audiological characteristics of Starr’s patients       The modification of the AN description involves various au-
were: progressive mild to moderate hearing loss, and speech      diological pathologies regarding all stations of the hearing
discrimination poorer than expected. The impairment had          apparatus and all degrees of hearing loss. The AN patho-
become symptomatic in childhood or young adulthood, and          genesis therefore appears to be multifactorial and the clini-
eight patients out of 10 developed neurological neuropathy       cal results likely come from a variety of lesions throughout
after the audiological diagnosis.                                the auditory pathway, from inner hair cells (IHCs) to the
At the beginning, indeed, four audiological findings were        cerebral cortex.
considered the main signs of the so-called AN: normal            A group of experts 4 thus decided to modify the term AN to
otoacoustic emissions (OAE), unexpected absence or al-           ANSD-Auditory Neuropathy Spectrum Disorder to avoid
tered Auditory Brainstem Response (ABR), poor speech             a precise terminology being able to describe various and
discrimination and mild to moderate hearing loss.                different dysfunctions, even if with common involvement
These signs are not different from those used in the past to     of the 8th nerve.
identify a “retro-cochlear dysfunction”, except for the Oto-     Rance and Starr 5 tried to bring order to the confusing top-
Acoustic-Emissions (OAE), because this is a relatively new       ic, limiting the so-called ANSD to 4 categories. These four
test that was not available in the past.                         categories are: 1. presynaptic disorders, affecting inner hair
From the first report in 1996 to December 2020, more than        cells and ribbon synapses; 2. postsynaptic disorders, affect-
800 papers have been written on this topic, extending the        ing unmyelinated auditory nerve dendrites; 3. postsynaptic
possibility of this particular kind of hearing impairment        disorders, affecting auditory ganglion cells and their myeli-
to severe to profound deafness. All degrees of impairment        nated axons and dendrites; 4. central neural pathway disor-
when the absence of or abnormal ABR is associated with           ders, affecting the auditory brainstem.
the presence of OAE are called AN, without considering as        ANSD can be unilateral or bilateral, isolated or part of a
pathognomonic the other two symptoms presented in the            neurologic syndrome, congenital or acquired, and produc-
original Starr paper, which are unexpected poor speech dis-      ing all degrees of hearing loss.
crimination and hearing loss not higher than moderate.           Congenital ANSD is mainly caused by genetic abnormali-
The British Association of Audiovestibular Physicians 3          ties, which may be either isolated or associated with other
wrote in 2018: “Auditory neuropathy spectrum disorder            syndromes. The inheritance pattern can include all the four
(ANSD – see later) describes a condition in which a pa-          main types of inheritances such as autosomal dominant, au-
tient’s outer hair cell function, as demonstrated by otoa-       tosomal recessive, X- linked and mitochondrial.
coustic emissions (OAE) and/or cochlear microphonic              An interesting summary by Santarelli 6 demonstrates that
(CM), are (or were at one time) present, and auditory            the degree of loss in neurologic syndromes is almost al-
brainstem responses (ABR) are abnormal or absent”, with-         ways mild, but moderate to profound in isolated AN.
out any information about the hearing loss degree.               The hearing loss can be progressive, starting at childhood
In this way, the overlapping between the classic signs, defi-    or adulthood especially in neurologic syndromes, but many
nition of retro-cochlear dysfunction and the new AN con-         ANs are also congenital with severe to profound hearing
cept disappeared.                                                loss and can occur in all age groups. Even the evolution of
The modification of the original description of AN, also         the OHC function is intellectually stimulating, because in
including significant hearing loss, completely distorts the      some cases the OAE disappears over time.
diagnostic role of ABR and Speech Audiometry since they          However, the Kaga experience regarding the evolution of
are first altered by the hearing loss degree.                    congenital AN is even more interesting.
It is a common experience that click ABR cannot be elic-         The author 7 found three categories: the first can auto-re-
ited in the case of disabling hearing impairment starting        solve until normal hearing at around 12 months of life, the
to be absent in some patients at 65 dB of loss in the high       second evolves to severe to profound loss starting as mild
frequencies and always absent in severe to profound loss,        and the third is part of a wider neurological syndrome.
and speech discrimination is not possible without hearing        Regarding aetiology, AN can be due to genetic disorders or
devices in these degrees of hearing loss.                        can have a wide range of other aetiologies including prematu-
Due to the changes of the initial definition, it is clear that   rity, hyper-bilirubinaemia, anoxia, hypoxia, congenital brain
in severe to profound hearing loss the decisive instrumen-       anomalies and ototoxic drug exposure. Nevertheless, no aetio-
tal sign that should confirm AN diagnosis is limited to the      logic factor can be identified in approximately half of cases 8.



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S. Burdo et al.




Regarding imaging, this is a fundamental investigation            the preparation of the current paper, also taking into ac-
because the anatomical abnormalities of the 8th nerve can         count the reference lists.
objectively demonstrate the origin of the impairment, as in       The papers retrieved as full text are reported in the main
the case of hypoplasia or aplasia labelled Cochlear Nerve         reference list.
Deficiency (CND) 9.
Hence, some criticism is presented in the literature regard-      Study selection
ing the definition of AN 10,11 and the observations are not       The review was undertaken independently by three re-
merely academic, since one of the most important medical          searchers (SB, GB and FDB), expert in critical analysis of
rules is that the choice of correct treatment and rehabilita-     academic literature. All the abstracts were reviewed using
tion is a consequence of having knowledge of a clear patho-       the predetermined inclusion, exclusion and categorisation
genesis in mind. For example, the first category defined by       criteria. The articles considered relevant or of uncertain
Race and Starr 5 as pre-synaptic relates to a dysfunction of      relevance were retrieved as full-text papers. The full-text
the IHCs (cochleopathy) and the hypothesised nerve dys-           papers were reviewed, and data extraction performed inde-
synchrony (neuropathy) is secondary and not a primary             pendently by each researcher. Any discrepancies between
event.                                                            researchers were resolved by mutual consensus. This
Thus, we decided to carry out a literature review of medi-        systematic review was conducted according to the guide-
cal evidence (genetics, histo-pathology, imaging, medical         lines for reporting Systematic Reviews and Meta-Analysis
diseases) in order to obtain objective information about the      promulgated by PRISMA 12.
aetiology and pathogenesis of AN.
                                                                  Results
Materials and methods
                                                                  The first publication on ANs was in 1996 and the maximum
Literature search                                                 production was detected after the year 2010.
A literature search was performed on PubMed, Embase,              The topic mainly treated was audiology (Fig. 1), but the
and the Cochrane Library.                                         interest of the authors of the current paper was focused on
The date of the last search was 31 December 2020.                 268 papers regarding Medical aetiology, Genetics, Histo-
To identify all relevant studies that described the results       pathology and Imaging, being significant for the purpose.
of auditory neuropathy spectrum disorders, articles were          In other words, the papers with Audiology and Treatment
selected on the basis of the following MeSH terms and             as well as Review as their topic were analysed only to bet-
synonyms in their title, abstract, keywords, text or medical      ter understand the aetiology and pathogenesis of AN.
subject heading such as: “((“auditory neuropathy”[Title/
Abstract]) OR “auditory neuropathies”[Title/Abstract]) OR         Medical aetiology
“Auditory neuropathy” [Supplementary Concept]).                   The most discussed medical issue related to AN was hyper-
The papers extracted from libraries were uploaded to a            bilirubinaemia, but all the pathologies are presented espe-
spreadsheet column, one per cell in the first column. The
                                                                  cially metabolic, infectious and toxic diseases (Fig. 2).
second column reported the decision to consider each paper
                                                                  Concerning bilirubin, the auditory toxic effect starts at se-
eligible or not for the study, following the criteria described
                                                                  rum levels of 22 mg/dl and the best predictor of the hear-
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, Genet-
ics, Histopathology and Imaging. The main topic was iden-
tified 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 incom-
plete abstracts or not available in English. For some pa-
pers, the analysis was completed by retrieving the full text
when the article was considered of particular interest for        Figure 1. Main topic of the papers.



498
                                                                                                  Is auditory neuropathy an appropriate term?




Figure 2. Medical aetiology.                                       Figure 3. More frequent isolated “untrue” ANs - genetics.


ing injury is unbound bilirubin 13. The percentage of hear-        The site of action of Pejvakin (autosomal recessive hearing
ing impairment varies widely. For example, Can et al. 13           loss - DFNB59) was initially identified in the spiral gan-
declared an incidence not more than a normal event; 11%            glion 31. Today, it is clear that this protein has a role in the
for Amin et al. 14. The data regarding the kind of hearing         mechano-transduction of hair cells, involving both outer
loss are interesting, because both SNHL and AN can result          and inner hair cells 32 or only IHCs.
from bilirubin toxicity 15. Finally, it is important to know       The cochlear role of connexins (DFNB1) has been well-
the positive therapeutic effect on hearing loss by exchange        known for a long time, and for DIAPH3 (AUNA1- auto-
transfusion, which worsened if ibuprofen was administered          somal dominant inheritance) the evolution of knowledge is
in the presence of hyperbilirubinaemia 16.                         similar to the Pejvakin mutation because initially a neural
On the topic of diabetes, six papers described the presence        location was described, and today its clear role in cochlear
of an AN. Interestingly, but to be confirmed with additional       physiology has been demonstrated 33. In conclusion, all the
studies, the positive effects on hearing impairment due to         mutations described in isolated AN involve cochlear pro-
coffee 17, glycine 18, rutin 19, while insulin and oral hypogly-   teins. Finally, some observations on mitochondrial muta-
caemic agents seemed to have no therapeutic effect 20.             tion in non-syndromic hearing loss can be made.
The ANs described after infections, among the most fre-            While hearing loss is a common symptom, AN has only
quent, were those from CMV 21 and parotitis 22.                    rarely been reported in these disorders. These kinds of ge-
Some authors describe patients where symptoms only be-             netic mutations can involve the cochlea in particular, as it is
come evident with an elevation of body temperature, par-           sensitive to energy insufficiency especially in the stria vas-
ticularly in some cases of otoferlin mutations 23.                 cularis, and the predisposition to aminoglycoside-induced
Considering the other papers, a case report of platelet dys-       hearing loss 34.
function is particularly interesting, as this was treated using    With regards to the papers describing syndromes, seven
adenosine triphosphate with success 24, the same positive          conditions were the subject of more than two papers, for
effect that can be seen with thiamine deficiency 25 and bio-       a total of 44 (Fig. 4); the remaining 14 papers were case
tinidase 26. Other papers described the toxic effect of di-        reports of different and rare neurologic diseases.
oxin 27, xylene 28 and bismuth 29.                                 Interestingly, several of the genes implicated encode mito-
                                                                   chondrial proteins, and audiograms report mild to moder-
Genetics                                                           ate hearing loss for low frequencies 35, and normal or mild
It is estimated that approximately 40% of AN cases have an         hearing loss for higher ones 4, as already reported by Soli-
underlying genetic basis, which can be inherited in both syn-      man in 1987 36 in the so-called “low frequencies syndrome”
dromic and non-syndromic conditions. A total of 63 papers          or “reverse slope” today. Generally, these syndromes occur
described isolated AN and 70 described syndromic AN.               phenotypically later in childhood.
Considering isolated deafness, it is evident that the otofer-      The syndromes most frequently cited are: Charcot Marie
lin gene mutation (autosomal recessive DFNB9) is the most          Tooth (CMT) and its synonymous Hereditary Motor and
frequent aetiology for the so-called AN (Fig. 3), provoking        Sensory Neuropathy (HMSN); Friedreich Ataxia; Mi-
altered vesicle replenishment and delivery of IHC neuro-           tochondrial disorders; Visual and Hearing impairment
transmitter in the ribbon synapses 30.                             (OPA1/LEBER HON/USHER/FDXR/OPA8); Mohr TS



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                                                                  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 sub-
                                                                  jects 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 neu-
                                                                  rological diseases compared with diseases where the phe-
Figure 4. Most frequent syndromes.                                notype is limited to vision and hearing impairment, such
                                                                  as LHON and OPA1. In these pathologies, mitochondrial
                                                                  dysfunction is also thought to be an important pathophysi-
Syndrome; Cerebellar ataxia – Areflexia - Pes cavus - Optic       ological player 51.
atrophy - Sensorineural hearing loss (CAPOS) and Brown            In Leber’s hereditary optic neuropathy (LHON), the degree
Vialetto Syndrome.                                                of hearing loss varies 52, but the majority of subjects have
CMT is a hereditary demyelinating or axonal 37 early onset        normal hearing with abnormal ABR. The evaluation of
neuropathy.                                                       OPA1 disease is of particular interest because for some re-
In CMT, also known as HMSN, pure tone detection can be            searchers the origin of hearing impairment is the dendrites
degraded from any loss to mild and severe hearing loss. In        of the 8th nerve 6, while for others it is the cochlea 53. Yu-
other words, the hearing abilities of people with CMT are         Wai-Man et al. 54 confirmed the phenotypical effects of the
highly variable as is the site of lesion 38. Onset of symptoms    OPA1 mutation in both the inner ear and in the unmyeli-
is more frequent in adolescence or early adulthood. The           nated portion of the auditory nerve.
gene most frequently mutated is MPZ, encoding a protein
included in the compact myelin that plays a crucial role in       Histopathology
myelin formation and adhesion, but most of the genes cod-         The papers on histopathology of ANSD consist of 57 in-
ing for proteins involved in this process have been associ-       volving animals and 7 involving humans.
ated with neurodegenerative diseases 39.                          The 57 papers on animals were categorised into 4 groups.
CMT can be sensitive to corticosteroid therapy 40 when            The experiments described in the first group can be con-
symptoms are associated with infectious signs 41 and hear-        sidered methodological because they demonstrate how to
ing aid use is recommended even if the involvement of the         reproduce neuronal injury/dysfunction in animals, preserv-
entire auditory nerve associated with hair-cell preservation      ing the cochlear hair cells. These papers do not add any
is likely to be a feature shared by the majority of AN disor-     particular new knowledge about the aetiology and patho-
ders included in the CMT group 5.                                 genesis of AN.
Hearing sensitivity can also be normal in Friedrich Ataxia        For the second group, the interest is more practical because
syndrome, but in some cases ABR is altered 42.                    they describe the mechanisms underlying drug/toxin-in-
Mohr-Tranebjærg syndrome is a rare X-linked recessive             duced damage and above all the anatomical site of lesion/
neurodegenerative disorder resulting in early-onset hearing       dysfunction. IHCs are the target organ in the case of carbo-
impairment, gradual dystonia and optic atrophy. It can start      platin toxicity 55 and glutamate effect 56 even if in contradic-
from the very early years of childhood associated with a se-      tion with Liu et al. 57 who described SGN (Spiral Ganglion
vere hearing loss 43. CAPOS syndrome (Cerebellar ataxia,          Neurons) involvement. SGN is also the target of Diphthe-
Areflexia, Pes cavus, Optic atrophy, and Sensorineural hear-      ria toxin 58. Cobalt and chromium are toxic to all sensory
ing loss) with acquired hearing impairment as a prominent         cochlear cells 59. The same consequence was described in
feature 44, is a rare neurological disorder associated with mu-   the case of hypoxia, but with a different effect on the two
tation in the ATP1A3 gene. Han et al. 45 and Atilgan et al. 46    sensory cells with higher vulnerability of IHCs, as hypoxia
described the remarkable benefits of cochlear implantation,       damage is related to its duration 60. Bilirubin toxicity has
assuming synaptophysin as the hearing loss pathogenesis.          SGN as its target for Sun et al. 61, but also IHC synapses for
Brown Vialetto Syndrome is a neurodegenerative disorder           Salvi et al. 62 depending on the dosage 63. Moreover, bili-
characterised by hearing loss and ponto-bulbar palsy due to       rubin did not reveal any auditory nerve involvement in the



500
                                                                                             Is auditory neuropathy an appropriate term?




Gunn rat, but a cochlear toxicity in contradiction with the       on imaging and AN: 10 described a CND, 2 a dysmorphism
findings of Uziel et al. 64 who described a preserved cochlea     involving both the cochlea and the 8th nerve, 3 intracranial
in the case of bilirubin toxicity in the Gunn rat. In Hidden      tumours excluding the 8th nerve, 1 an intracranial haemor-
Hearing Loss, the pathogenesis was identified in axonal fi-       rhage and 2 intracranial hypertension.
bres 65. Axonal fibres were also the target of pyridoxine 66      The papers confirmed that the hearing impairment of some
and spectrin 67.                                                  ANs does not involve the 8th nerve, but is actually located
Thus, it is interesting to point out the different levels of      in the CNS, leaving the first neuron of the auditory appara-
vulnerability of OHC vs IHC vs nerve considering dura-            tus free from lesions.
tion and/or dosages of the same toxic agents or protein de-
ficiency.                                                         Discussion
The third group is similar to the previous one, also taking
into account some genetic mutations of proteins which oc-         The first and most impressive evidence from this ANSD
cur in the cochlea. All the papers describe cochlear proteins     literature review is the fact that many dysmorphisms, dys-
located mainly in IHCs except for Pejvakin, which was also        functions or pathologies of all the organs of the hearing
identified in OHCs and Cx 29 originally located in SGN            apparatus can present the pathognomonic audiological
in another paper 68. A multiple site of lesion was the effect     combination of “OAE present and ABR absent or altered”.
of the abnormal expression of AIFM1 (AIF) even if with a          However, in the majority of cases the site of the lesion is the
SGN prevalence 69.                                                cochlea or the central nervous system and not the acoustic
The last group of papers on animals analyse possible thera-       nerve, in contrast with the nomenclature of neuropathy.
pies for neuronal injuries. Mesenchymal stem cells 70, tran-      The correct and definite attribution to the 8th nerve as the
scription factor Sox2 71; photo-biomodulation 72; cell trans-     pathogenesis of hearing impairment can be made only when
plantation 73; taurine 74; coffee or trigonelline in pyridoxine   it is shown by imaging evidence or when electrophysiologi-
intoxication 75.                                                  cal tests are altered in normal or mildly impaired hearing,
There were only seven studies performed on humans, and            thus when the hearing loss is not the primary origin of the
two of these involved both animals and humans.                    alteration of the acoustic potentials. Berlin et al. 10 summa-
Diaz-Horta 76 described an interesting case of AN due to          rised the literature on the clinical meaning of pure tone au-
mutation of the gene ROR1 in mice because the hearing             diometry, attributing impairment to IHC dysfunction/lack/
loss with preserved OAE was found in malformed coch-              pathology in the case of profound hearing loss.
lea (smaller and under-coiled). Less evident regarding the        Regarding imaging, the prevalence of retro-cochlear dys-
precise site of lesion is the experience described by Amati-      morphism varies between 18% and 28% of AN children,
Bonneau et al. 77 because the R445H mutation in OPA1              frequently associated with brain (40%) or cochlear abnor-
does not exclude inner hair cell involvement in the guinea        malities (31%), especially in the case of bilateral CND 82.
pig, leaving the doubt of a cochleopathy and not of isolated      Both imaging and acoustic potential alterations not justi-
neuropathy. On the other hand, in MPZ gene mutations, the         fied by the degree of hearing loss are the only findings that
inner hair cells were normal in number, preserving mor-           are able to reliably confirm a neuropathy; other tools or
phology and the anatomical alterations evident along the          clinical observations cannot be definitive due to the wide
auditory nerve fibres 78.                                         variety of pathologies involved.
The paper by Amatuzzi et al. 79 is one of the most important      In fact, the introduction of the concept of “spectrum dis-
clinical contributions because it demonstrates that the so-       order” confirms the observation that a large number of
called AN of premature infants is indeed a cochlear pathology.    diseases are involved in AN, but this cannot be passively
Conversely, the AN of the Mohr-Tranebjaerg syndrome, an           accepted because in the majority of cases, since in isolated
X-linked hearing loss caused by mitochondrial dysfunction,        hearing loss nerve involvement is excluded due to muta-
is due to a degeneration of spiral ganglion cells preserving      tions of proteins with a well-known role in the cochlea such
the cochlear organs 80. The Pejvakin distribution was also        as otoferlin, pejvakin, DIAPH3 and GJB2.
identified in human spiral ganglion 31 in contrast with Har-      The cochlea and not the nerve is the site of dysfunction in
ris et al. 81 who located the protein inside the cochlea.         isolated genetic ANs.
                                                                  Only in neurologic syndromes for poly-neuropathies and/
Imaging                                                           or Central Nervous System disease can the cochlea be ex-
Imaging represents the most important clinical tool to iden-      cluded as the origin of the hearing impairment, but can one
tify an AN on an anatomical basis and its execution is thus       be sure that the nerve is the cause of the communication
mandatory for a correct diagnosis 82. We found 18 papers          difficulties of the patient and not a CNS disease?



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S. Burdo et al.




Concerning medical aetiology, Amatuzzi et al. 79 showed             description of the active function of OHCs was made by
that the cochlea injury is the origin of hearing loss in pre-       Brownell in 1985 89, even if the idea of a cochlear amplifier
mature infants and not the auditory nerve. Furthermore,             had already been described by Gold in 1948 and Kemp 90
diabetes and hyperbilirubinaemia are identified as the most         confirmed the presence of the amplifier in 1978, though
frequent aetiologies. In diabetes, the vascular side effect 83 is   with some doubts as he wrote, “…probably located in the
assumed to be the pathogen in the cochlea as in the retina.         cochlea…” explaining the new phenomenon observed.
More difficult to interpret is the pathogenesis of hearing loss     The very short lag time between the two facts (phenom-
in hyperbilirubinaemia. Some authors have described a toxic         enon discovery and clinical application) led to the belief
effect on neural structures, but it must be noted that the most     that the clinical instrument was a system to evaluate the
frequent pathology in neonates starts with severe haemo-            entire cochlea and not only the OHCs, considered as classic
lytic anaemia and related hypoxia, which might be the cause         receptors as in the past, and thus similar to the IHCs.
of a cochleopathy 84, while motor dysfunction and dysar-            It may be useful to remember that if we consider the en-
thria can be easily related to central toxic effect of bilirubin.   tire cochlea as a passive organ, we should simply assume
Anaemia related to secondary kernicterus is not described           that OHCs and IHCs are similar as hearing receptors except
in papers with Gunn rat protagonists 64 because in that ani-        for analysis of sound intensities less than around 50 dB for
mal hyperbilirubinaemia is primary and the cochlea seems            OHCs and louder for IHCs. Consequently, OHCs should be
to be preserved, but not for other authors like Salvi et al. 62.    first considered in the case of mild hearing loss and always
The reason for the contradiction about the greater or lesser        disrupted in the case of severe to profound hearing loss to-
involvement of the cochlea by bilirubin toxicity can be re-         gether with the IHCs in this case.
lated to the evidence that the injuries are dose-dependent 85.      In reality, it is correct to blame OHCs in the case of some
Another interesting hypothesis was that proposed by James           peripheral hearing loss up to 50 dB due to a lack of IHC
et al. 86 because they consider riboflavin depletion second-        tuning, but the same inference is not true in severe to pro-
ary to hyper-bilirubinaemia as a cause of hearing impair-           found hearing loss because the OHCs are not hearing cells.
ment. From these considerations, it is plausible to consider        Thus, the possibility of finding normal OHCs in the case of
pathologies related to hyperbilirubinaemia as a spectrum            a cochlear severe-to-profound hearing loss is correct.
disorder with greater or lesser involvement of some neu-            Dallos 91 wrote “Mammals hear with their IHCs – the true
ral organs 87, but including the possibility of a cochleopathy      sensory receptors of the cochlea”.
which is dose-dependent or caused by haemolytic anaemia             Coming back to the definitions of AN, we think that at
or by different causes. In any case, some excellent outcomes        the beginning some authors considered otoacoustic emis-
with CIs can be used as ex juvantibus criterium to confirm          sion devices as systems that allow evaluation of the entire
the cochlea as the site of the lesion.                              cochlea, wrongly inferring that IHCs are preserved in the
In summary, the term AN is the cause of confusion rather            case of normal OHCs, because otoemissions were present.
than the explanation of a particular framework because in           There is some important evidence, physiological as well as
most cases it is not related with the real pathogenesis of          pathological, that can confirm the two hair cells are differ-
hearing impairment as evident in genetic isolated AN and            ent organs with different functions and behaviours in the
in the main medical pathologies.                                    case of an ear pathology or dysfunction.
We think that the confused opinions about so-called AN              This relates to the following:
could have some historical reasons and could even be relat-         • dysfunctions on a genetic basis involving some proteins,
ed to the innovative knowledge regarding cochlea physiol-              which affect functions of one hair cell and not the other
ogy (old passive scheme vs new active one). Furthermore,               (see otoferlin for example);
the confusion could originate also from the almost contem-          • the histopathological findings in premature infants with
porary introduction of systems to record Oto-Emissions in              hearing impairment due to loss of IHCs and not of
the clinical field that do not always seem to be interpreted           OHCs 79 ;
with the new scheme in mind.                                        • the existence of deaf mice due to lack of IHCs and nor-
Generally, the lag time between a new medical discovery                mal OHCs, such as the Bronx waltzer mouse 92 and the
and the concrete comprehension or utilisation of the new               Beethoven mouse 93;
concepts is between 10 and 17 years 88.                             • the ototoxic effect of some anti-tumour drugs 94 limited
This is not the case of comprehension of the source of                 to the IHCs and not to the OHCs, such as carboplatin and
OAE, limited to the OHCs.                                              vice versa for other drugs such as aminoglycosides 95;
The introduction of the first commercial device to record           • different levels of vulnerability between the two hair
OAE by otodynamics was in 1988 and the first complete                  cells 96;



502
                                                                                                    Is auditory neuropathy an appropriate term?




• different effects of some pathogens limited to IHCs or           These observations confirm the need to consider each pa-
  also involving OHCs on the basis of duration and inten-          tient individually, without following diagnostic models
  sity 63.                                                         considered conclusive, when instead they are questionable
                                                                   just like the combination “OAE present and ABR absent”
Conclusions                                                        in case of severe and profound deafness.
                                                                   In conclusion, we believe it is more appropriate to abandon
Precise terminology in biology is a fundamental issue. Ac-         the term Auditory Neuropathy when OAEs are present and
cording to Rapin and Gravel 14, the term neuropathy does           ABR is altered or absent because it is misleading. Moreo-
not apply to cases where hearing loss is attributable to a dis-    ver, in case of genetic isolated AN, the terms “synaptopa-
ease of the central auditory pathway alone, like Rance and         thy” and “dis-synchrony” are also confusing, because they
Starr’s group 4 5, because central tracts in the white matter      do not describe the causes but the consequences of a recep-
of the brain, cerebellum, brainstem and spinal cord are not        tor dysfunction, i.e. the production or delivery of its neuro-
“nerves,” and their pathologies are not “neuropathies.”            transmitter that is a IHCs “job”, with a secondary and not a
Conversely, Race and Starr’s group 1 consists of “cochlear         primary involvement of nerve dendrites.
hearing loss” excluding nerve involvement or other neuro-          For all the reasons above, we suggest to not consider OAEs
logical pathologies.                                               as pathognomonic for diagnosis of AN, if not confirmed by
Real neuropathies are CNDs and, probably some ADOA+                other signs.
due to mutation of the OPA1 gene and other genetic hear-           Our final proposal is to consider more appropriate to in-
ing impairments associated with optic nerve pathologies.           clude the OHC conditions in an overall diagnosis, using the
In otological clinical practice, it is important to identify the   following formula: “Hearing impairment due to (cochlear/
precise site of the lesion for disabling hearing loss since        neural/central) dysfunction, with preserved OHC func-
Cochlear Implants (CIs) are contra-indicated in retro-coch-        tion”, as already mentioned by Gibson 100.
lear dysfunctions and the term neuropathy implies the in-
volvement of the auditory nerve. CIs should therefore be
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