Open access peer-reviewed chapter
Abstract
Some patients visit the doctor because of hearing problems in noise. The hearing examination, however, does not show any specifics. Only an extended and targeted investigation leads to the suspicion of auditory neuropathy, which means altered temporal coding of the acoustic signal and explains the problems. Additional investigations show pathology of the synapse between the inner auditory sense and the auditory nerve or the process of conduction along the nerve. The combination of otoacoustic emissions and the auditory brainstem evoked potentials investigations raises the suspicion of auditory neuropathy. Auditory neuropathy occurs in both children and adults. In children, the diagnostic procedure is quite difficult.
Keywords
- auditory nerve
- inner hearing cell
- synapsis
- auditory brainstem responses
- otoacoustic emissions
1. Introduction
Auditory neuropathy (AN) is a hearing impairment which can be recognized by deteriorated speech perception, while pure-tone detection thresholds remain relatively preserved. Affected individuals usually performed abnormal or no auditory brainstem responses (ABR), but normal otoacoustic emissions (OAE). This numerous groups of disorders described as “auditory neuropathy” includes abnormal function of peripheral synaptic sound processing by inner hair cells (synaptopathy) and/or of the generation and spread of action potentials in the auditory nerve (neuropathy). Audiological attributes of AN suggest that it is most certainly caused by the disturbed function of inner hearing cells (IHC) and/or spiral ganglion neurons. Meanwhile, the function of outer hearing cells (OHC) remains normal. This leads to a divergence between the hearing level thresholds and speech audiogram [1].
In neonates, AN can be seen as congenital sensorineural hearing loss (SNHL) of various degrees, usually bilateral with absent or abnormal ABR and mostly preserved otoacoustic emissions (OAE) and/or cochlear microphonics (CM).
In older children, AN is considered as a state where speech understandability is worse than should be expected based on behavioral audiograms while speech comprehension/discernment is poor.
During later lifetime we can recognize AN in affected individuals as a dysfunction of hearing with moderately good results in hearing level measures and bad comprehension abilities especially in loud and/or noisy environments.
2. History
AN is a relatively new audiology disease because some worthwhile methods and electrophysiologic equipment had to be developed for the exact assessment of the auditory pathway. Research in this field started after ABR for assessment of the inner ear were invented. Researches started in 1974 by Hecox and Galambos [2].
The term AN was first used in audiology in the 1980s, following the observation of adult patients who had a feeling of deteriorated hearing level despite their measured hearing levels were within normal range. They had difficulty detecting the sounds, especially in a noisy environment [3]. The term “auditory neuropathy” was till then considered as a part of the clinical picture of hereditary sensorimotor neuropathy [4]. AN as an audiological dysfunction was an object of scientific investigation of Starr. He observed that some patients with hearing problems in noisy environment had normal OHC function but their transmission of sound was impaired [5]. He did some electrophysiologic research and found out that the main pathology was not represented at the level of sound detection, by its transduction through the auditory pathway.
Later AN was identified in the pediatric population a few years later on the basis of bad cochlear implantation results. That was after initiating neonatal hearing screening [6].
Infants and adults without central nervous system disease got the diagnosis confirmed by measuring OAE, ABR, and CM [6, 7, 8]. At that time, OAE began to be routinely used. Similar results have assessed the investigations were also carried out in children with delayed speech development.
Today ABR remains the gold standard for objective hearing assessment with a new function in diagnostic procedure in people with listening problems in noisy environments and children with delayed speech development. In modern audiological diagnostic procedure difunctional parts in auditory pathway, including internal hair cells, auditory nerve fibers, auditory neurons in the spiral ganglia, or a combination of these can be determined [9].
3. Spectrum disease
In the future, some authors propose to rename AN into auditory neuropathy spectrum disease (ANSD) regarding a wide range of possible etiologies. Most importantly, many specific etiologies are identified as causing AN [10, 11]. We do not agree with the nomenclature of spectrum disease regarding that the main pathologies come from synaptic dysfunction [12]. We suggest using the term postsynaptic and presynaptic AN regarding the site of the lesion.
4. Pathophysiology
Examination of temporal bones in subject’s postmortem with diagnosed AN showed that the number, as well as appearance of inner and outer hair cells, remained normal. Auditory ganglion cells and nerve fibers, however, were both reduced in number and demyelinated [13]. Loss of auditory nerve fibers attenuated neural input while demyelination affected the synchrony of neural conduction. We suggest that the loss of auditory nerve fibers and altered neural transmission, due to the reduction of neural synchrony, contribute to the abnormalities of ABRs and hearing.
The conversion of mechanical energy into a molecular change by IHC is the catalyst that initiates an electrical signal which travels along the acoustic neuron. Mechanical energy is generated by the undulation of the tectorial membrane, which begins the process of binding calcium molecules to receptors. This causes the release of neurotransmitters in synapses [14]. The signal then travels further along the peripheral axon of the sensorineural ganglion (SNG) from the synapse towards the central nervous system (CNS) [15]. SNGs are bipolar neurons, frequency-tuned by IHC so that tonotopy is preserved even at higher levels during transmission to the CNS. The effectiveness of coding relies on fast and accurate signal generation in the auditory nerve [16]. The process is called transduction and an error at any stage of the transmission of the acoustic signal means AN.
5. Temporal processing
The auditory system can transmit and process temporal information. This is the so-called temporal processing of sound. Precise detection of the temporal features of sounds is basic for speech perception. This process takes a great metabolic demand because very short electrical phenomena are necessary to achieve the speed which is needed to conduct and transform all the information that is hidden in the incoming sound. Auditory nerve fibers are capable of processing phase-locked signal outcoming from the movement of IHC stereocilia. Two movements are possible, backward and forward. They open or close ionic canals for cation influx. That makes temporal fine structure processing possible. Studies of temporal processing abilities are done by measuring gap detection threshold by noise-burst stimuli. Gap detection is lowered in AN. Temporal processing takes a great metabolic consumption because very short electrical parameters are necessary to achieve rapid temporal processing. IHC and auditory neurons have such characteristics, they have high conductance in the resting state. Any structural deficit in this area enables this high conductance and leads to asynchrony. In AN temporal processing is disrupted mostly as a consequence of asynchronicity. That does not affect the sensation of tone. The temporal processing is important for speech comprehension, localization of sounds, and separating signals from ground noise [3]. The temporal envelope of a sound-how it changes over time is basic for speech perception. It is measured by noise-burst stimuli which represent a very sophisticated way of scientific research. It is measuring how sound changes in amplitude over time. Auditory evoked potentials measure the millisecond-by-millisecond activity of a population of neurons as a form of auditory perception. Time is a parameter to identify and dissolve auditory streams. Deficits in temporal processing were also detected in children with dyslexia and autism. It is also a part of age-related hearing deterioration.
Demielinisation is expressed to a greater extent than the loss of the number of axones [10, 17, 18]. This is the case of type I neuropathy [17], where a concomitant peripheral neuropathy exists which can be hereditary or inflammatory in origin [18]. Another option is type II where the hearing loss is isolated [19].
In AN temporal processing is the major defect and is the reason for the major events in AN. These are clear hearing in a noisy background, sound localization, and a good understanding of spoken language [20].
AN appears to consist of several varieties depending on the site of the lesion of temporal processing [1] presynaptic in inner hair cell ribbon synapses, [2] postsynaptic in auditory nerve dendrites, and [3] postsynaptic in auditory nerve axons.
6. Prevalence
The prevalence of ANSD in children diagnosed with severe to profound hearing loss is uncertain. It ranges from 1 to 14% of hearing-impaired persons, while the prevalence of auditory neuropathy in the non-risk population is unknown [21].
Among neonates from the intensive care unit, it is much higher and is assumed to be up to 30% of hearing-impaired neonates [22].
7. Etiologies
Because the auditory pathway is long and complexly constructed, there are potentially many possible sites for error in signal transmission and thus AN. Because AN is a transduction problem (temporal processing) the site of lesion must be somewhere post or presynaptic or in the nerve where transduction takes place. So there is a range of possible sites of pathology. Transduction in IHC means converting mechanical energy into a molecular signal for the entry of cations into IHC. After the invasion, the cell is depolarized, allowing calcium influx through calcium channels. The pairing of presynaptic ribbon synapse calcium channels between the IHC and the nerve releases glutamate into the synapse. Dysfunction at any level of transduction can disturb the coding of the acoustic signal.
Besides many possibilities of localization of pathological changes in anatomic structures and function in IHC, synapse, there are also many possible etiological factors. They can be divided according to the time of occurrence (prenatal, postnatal, later), the site of the defect according to the anatomy (presynaptic, postsynaptic, axonal), according to the origin of the nox (genetic or non-genetic). The distributions are mixed. 50–60% of children with AN will have significant birth histories. The remaining 40–50% of cases should be explained by a genetic disorder.
Birth histories are pre, peri, and postnatally.
Prenatally they are genetic, morphogenetic failures (cochlear malformations), fetal mumps infections, rubella and cytomegalovirus, and dysmaturity.
Perinatally they are hypoxia and mechanical ventilation.
Postnatally they are also genetic with a delayed onset of the clinical picture, prematurity, icterus, septicemia, ototoxic drugs and meningitis [23].
8. Genetic etiologies
Many gene defects (IHC, Synapses between IHC and auditory nerves) are responsible for the development of AN [24, 25, 26]. This diversity is also responsible for the diversity in the clinical presentations of AN and for variations in therapy success. Genetic analysis predisposes to predict c, as well as the variations in cochlear implantation (CI) success. By direct stimulation of the cochlear nerve, the CI enables the bypass of the defective synapse. However, if the defect is more centrally postsynaptic, CI supplementation may be less successful.
These may code some deficits in glutamate metabolism in synaptic vesicles, the influx of synaptic Ca, and can alter synaptic vesicle turnover.
OTOFERLIN (OF). OF can have a range of possible genetic mistakes because it is a very compleksly formed protein important in presynaptic membrane fusion. It is the most important mutation in synaptopathies [27]. Its role is in bindings ions in exocytosis of synaptic vesicles and fusion [28].
OF mutations are multiple and represent 3.5% of hearing impairments. Patients have normal OAE response, abnormal ABR, and normal balance. Clinical pictures in OF mutations with different clinical pictures and results of electrophysiological measurements.
OHC is normal, but IHC is dysfunctional regarding the malfunctioning ribbons in the synapse [29].
CACNA1D gene defines the structure of the Ca2+ channel important for the glutamate release in the synapse [30]. These channels are located in OHC, IHC, and cardiomyocytes and these gene defects present a syndrome called “sinoatrial node dysfunction and deafness” (SANDD syndrome) [31].
CABP2 gene is involved in Ca channel regulation for glutamate release. It can be a part of profound prelingual deafness and with Marfan phenotype expression [32].
SLC17A8 gene defines another vesicular glutamate transporter type 3 (VGluT3), which regulates glutamate uptake in synapses [33].
12q22-q24 gene mutation defines congenital deafness at DFNA25 locus associated with mutations of SLC17A8 [34, 35]. Neonates have progressive SNHL located in high frequencies. CI demonstrates very good therapy decisions [36].
Postsynaptic genetic synaptopathy. Their clinical appearance can mimic neuropathies (dendritic), afferent nerve axons, or nerve demyelination problems. Transmission of nerve impulse is disrupted.
OPA1 mutations combine two options. As solitary nonsyndromic dominant optic atrophy (DOA) form [37] or the syndromic DOA form associated with hearing impairment due to the degeneration of the terminal nerve fiber [38].
Hearing loss is moderate to profound. DOA is in 60% as syndromic combining hearing loss, sensorimotor neuropathy, myopathy, and ataxia [39].
ROR1 gene defines the receptor tyrosine kinase-like orphan 1 located in plasma. It is important for neural growth. It is an important factor in lowered number of nerve fiber of the auditory nerve. It is XXX fan synaptopathy [40].
ATP1A3 gene defines the morphology of the transmembrane Na/K-ATPase pump. The patient has cerebellar ataxia, pes cavus, optic atrophy, areflexia, and SNHL, called CAPOS syndrome [41, 42, 43].
Overall in both synaptopathies, good CI outcomes were reported [43].
Neurone conduction neuropathies
AN easily occurs in the context of other peripheral nerve disorders, leading to various syndromic conditions.
Charcot–Marie-Tooth is the most common sensory-motor neurological disease, where it is a defect of myelination. Deafness is sensorineural with disproportionally worse speech understanding compared to the measured hearing threshold values. Histologically, the neuronal cell is normal, myelination is pathological. Assessment of hearing rehabilitation after CI gives as poor results [44, 45].
Spino-Cerebellar Ataxia (Friedreich’s) Hereditary Motor and Sensory Neuropathy. Patients have ataxia with a range of progressive features including axonal degeneration of sensory nerves [46].
Synaptopathy and neuropathy Pejvakin, encoded by DFNB 59 gene in hair cells and neurons, acts as a sensor that activates autophagy in case of oxidative stress such as noise-induced damage [47].
Other etiologic factors besides genetics are multiple.
The most prevalent etiologic factor besides genetics is hyperbilirubinemia reported in 10–50% of cases in some studies [48]. Hyperbilirubinemia is the most common cause of AN, especially in its unbound form bilirubin (BR) is very neurotoxic. But fortunately, very high levels of BR can be neurotoxic. Anoxia, prematurity, and low birth weight can predispose to toxic effects of BR in even lower levels. AN can be also a transient one and the hearing level can become normal after the period of time (12–18 months), if BR are corrected to normal level and the child is not a carrier of gen for deafness [49].
Anoxia is the second most important factor in inducing AN. It affects IHC and OHC in different matters. Mild chronic hypoxia causes damage to the IHC, and acute anoxia affects them all. Prematurity is a typical state of mild chronic hypoxia, a well-known anamnestic data in evaluating children with AN [50].
Other etiologic factors may be morphologic developmental changes [51], toxic-metabolic disorders [52]; infections (e.g., meningitis), inflammation (e.g., siderosis), neoplasms (e.g., acoustic neuroma), genetic mutations affecting neural functions [13] and ribbon synapse function [12].
9. Hidden hearing loss (HHL)
It is a kind of hearing impairment by which the clinical picture of hearing dysfunction expresses only in challenging auditory conditions (noise, less or rapidly articulated speech). Audiograme and BERA are normal in a quiet environment. There is a defect in auditory fibers which have defects in responding to sounds of high-intensity sounds [53, 54, 55].
10. Clinical expression of AN
AN refers to a range of different audiological profiles. They are associated with specific changes in auditory perceptions depending on pathologic alteration of managing the spread of acoustic signals. These changes influence speech sensation, space localisation of sound, and perception of sounds in noise [56].
The typical clinical picture of the affected subjects presents speech discrimination difficulties, particularly in background noise, that is out of proportion compared to their pure-tone detection thresholds. AN is usually bilateral. The hearing levels in audiometric exam may very fluctuate as much as 40 dB. Fluctuations are more frequent in children than in adults and the improvement in AN or its disappearance is possible in children [57, 58].
Even in children, AN presents a whole spectrum of different clinical pictures. As the etiologies are very diverse, the clinical picture is also variable. In neonates it is a clinical picture of severe hearing loss. This form of AN neuropathy is mostly diagnosed before the first year of life, while the other milder clinical forms are identified only later, mostly after the first year of age. or later in the form of delayed speech development. In the period after the first year of age, AN manifests itself in the form of slowed speech development.
In those where the synapse is defective, the temporal processing of sound is impaired due to characteristic gaps in sound perception. Gaps are caused by impaired signal transduction and prevent the perception of sounds with multiple short stimuli and therefore require stronger sound intensities to detect changes in frequency. That’s why background noise is extremely annoying for such people. Speech understanding is severely impaired in a noisy environment. Sound localization, which uses the interaural time difference for its functioning, is also impaired.
The clinical picture is slightly different for people with a normal synapse but disturbed conduction along the auditory nerve, as they do not have problems with time processing, but with longer latency times. Ambient noise does not bother them so much, but they have even more problems understanding speech, loud sounds bother them [59].
11. Comparison between SNHL and AN
Approximately 60% of patients with AN have severe or profound hearing loss. But the characteristics of hearing loss are different. Perception of pitch and temporal cues are very distinct [60]. Frequency resolution in AN is regarding the preserved outer hair cell quite good, but the temporal function is disrupted. In SNHL there is weak frequency resolution, temporal processing and listening in noise are normal.
12. Association with other diseases
AN can be associated with other syndromes or neurologic pathologies. We have already listed these neurological diseases, which are in the form of syndromes.
13. Transient AN
AN can be reversible. Some children with well-known AN have documented improvement in electrophysiologic findings over time. We can say that AN is unpredictable. So we recommend not to cure children too soon with cochlear implant, especially if they were from the group with low birth weight [61].
In case of high-risk infants (birth head trauma, ischemia, hyperbilirubinemia, metabolical diseases) ABR exams should be repeated and the time for observation should be prolonged because their ABR abnormalities can recover. Maturation of the nervous system is an ongoing process [62, 63].
14. Diagnostic procedure
Besides OAEs and ABRs, a basic audiological assessment may include stapedial reflex measurements, supraliminal psychoacoustic tests, electrocochleography (ECochG), and audiometry.
14.1 OAE
OAE are sounds produced by the movement of OHCs and their stereocilia. For the sound energy to be strong enough to be detected by the measuring probe in the ear canal, it must be amplified by external stimulation with additional sound. We do this in two ways: with transient stimulation (TOAE) and simultaneous stimulation with two different sounds (DPOAE). Kemp was the first who described the phenomena in 1978 [64]. He studied the sound coming out of OHC after transient stimulation or after two simultaneous tone stimuli [65]. Sound which was detected came from the moving OHC [66].
OHC contribute most of the potential measured in ABR before then I wave. This potential originates from mechanosensitive channels in the stereocilia of OHC cells, to a lesser extent they are also produced by IHC (OHC are more numerous). During movement, the basilar membrane opens and closes the transduction channels in the cilia of these cells. Polarization and depolarization are performed, which are generators of cochlear microphonics (CoM) [67]. These can be shown on an ABR examination using rarefaction and condensation methods. The summation of these two gives us the summation potential (SP) and the compound action potential (CAP). CAP represents wave I on ABR or it can be detected by electrocochleography (ECochG) [68].
In 20 to 80% of OAE, they may disappear. Cases have been described where an initially unsynchronized auditory pathway eventually becomes synchronized [63].
14.2 Electrocochleography (ECochG)
We can do this examination in two ways (extratympanic or transtympanic) to study cochlear microphonics (CoM), summating potential (SP), and cochlear action potential (CAP) [69, 70]. CoM and OAE are the results of the OHC function. SP serves for the assessment of IHC, especially for the study of ototoxine damage on IHC [71]. CoM can be prolonged in subjects with AN [72]. Amplitudes of CoM in AN are normal. CoM in persons with AN due to synaptopathy is not CAP, while CoM and SP are registered [72, 73]. In auditory synaptopathy, the CoM and the SP are preserved, while CAP is not detectable [12].
14.3 ABR investigation
It is an electrophysiologic diagnostic tool for objectively assessing the status of the auditory pathway from the cochlea to the central nervous system. We use it since the late 1960s as a diagnostic tool for adults and children. It was not meant to detect hearing levels, but to test the synchronicity of the auditory pathway. Before its invention patient with AN were hidden among those who were declared to be hard-of-hearing people with SNHL. The proportion of such patients among SNHL is approximately 10–15%, they were soonly named AN ones [74].
The most typical result of this investigation who confirmed AN diagnosis is an inversion of the ABR waveform in area I as a response to a change in a stimulus polarity (rarefaction and condensation cliks). Reversion of polarity is the only sign that helps us to separate AN from purely central processing disorders which have similar OAE and ABR results [75, 76].
Besides wave I which defines the state of IHC, 4 more waves are found during ABR measuring and each of it represents the transmission ability of the sound through a specific part of the auditory pathway.
If OHC is damaged, no atypical ABR patterns are found.
14.4 Audiometry
Audiometry does not show to what extent the auditory pathway is damaged, it is only an assessment of the functioning of the cochlea, better OHC. Audiometry can be in the range of normal to severe hearing loss. Speech audiometry is very poor. Stapedius reflex is pathological [4].
In adults with AN, hearing level threshold is usually pathologic in the low frequency range and quite normal in higher frequencies. It can be also perfectly normal, sometimes pathologic in entire curve or impaired only in high tones.
For children older than 4 years, the hearing threshold can be determined by audiometry, but up to the age of 4 children are not able to participate, so we use two methods. Both are based on observing the body’s response to different intensities and pitches of sound [77].
The first is CBT (conditional behavioral threshold), and the second is VRA (visual reinforcement audiometry). We test children in an open field or through earphones with specific tonal stimulation in the range from 0.5 to 4 kHz.
In newborns, the level of hearing loss is 65% severe to very severe. The percentage is slightly higher because in this age period, we only manage to find more affected children, as neonatal screening is only performed based on OAE measurements immediately after birth, and ABR is performed routinely only in newborns from intensive care.
15. Therapy
The goal of the therapy in AN is to overcome synapse if synaptopathy is the reason for AN or to synchronize the sound transduction through the auditory nerve.
Conventional hearing aids (HA) amplify the signal but fail to overcome the neural dys-synchrony responsible for impaired speech comprehension. HA are recommended as the first step in rehabilitation process as the least harmful. HA have many disadvantages because they are not able to improve temporal processing. So infants need a precise behavioral observation for their fitting or switching to CI [78].
Some studies were done (Berlin) on the success of HA in AN and a good result was only in 3.5% of patients, 10.5% of them were only satisfied, 24.7% noticed only a bit of improvement, 61.1% had no benefit. CI was much more successful with 85% positive results [79].
CI can bypass the synapse and thus the auditory signal is directly transduced to the auditory nerve [23].
But in some cases of only moderate hearing loss or in nerve malformation AN or in syndromic AN, a HA can be a good solution in children. Later on, if their language development stagnates, CI may be suggested [23, 80, 81, 82].
In the rehabilitation process, the site of the lesion ver predisposes to a therapeutic outcome [83].
Despite technologically sophisticated HA or CI, patients with AN do not succeed in fully providing normal sensations of hearing sounds. Ever-new scientific research in the field of genetics has enabled us to very precisely determine the location of the error in the cell and thus the possibility of correcting this error with gene therapy which means a process of changing defective parts of DNK with new genes. It is a very promising procedure for the future. Specially for the field of neurodegeneration of auditory pathways [84].
16. Conclusion
AN is a modern disease, well known only in recent years. Presented in adults and children. The clinical picture in adults is much more benign than in children, by each can be very variable because of potentially many sites of origin, pre or postsynaptic or neurogenic. Multiple etiologic factors (genetic, infectious, environmental, toxic, metabolic) can induce AN in every part of life.
Rehabilitation is still a challenging area of investigation because there are still some deficiencies in rehabilitation in children with AN which have no proper level of hearing. That is why gene therapy promises a lot.
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