By Ioannis Psarommatis MD, PhD

          

Introduction

Auditory Neuropathy: the torment of modern researchers and audiologists and a real challenge to their diagnostic abilities and their understanding of the auditory function.

         At the same time, auditory neuropathy might prove to be an excellent chance for breaking away from the standard audiological traditions and bridge together many scientific fields. It is very possible that the extremely familiar term sensorineural hearing loss will NOT have precise meaning in the near future.

 

Clinical approach to auditory neuropathy

     During the last few years, Auditory Neuropathy (AN) has been established as a well-accepted clinical entity. The term is ascribed to Starr et al  [1]who 10 years ago published the first report on AN. The data he discussed were based  on 10 patients having: (i) mild to severe hearing loss ; (ii) poor speech discrimination scores; (iii) absent or severely disturbed auditory brainstem responses (ABR); (iv) normal otoacoustic emissions (OAEs);and  (v) no central nervous system abnormalities . They have attributed their findings to a functional disorder of the acoustic nerve.  In this context it should be noted that Auditory Neuropathy-like cases had been reported several years earlier [2, 3, 4] The last decade the introduction of OAEs in the everyday clinical practice has resulted in diagnosing AN at increasing rates. It is not surprising, therefore, that numerous reports have appeared recently in the international literature.

     Today we use the definition for auditory neuropathy patients, whose clinical and audiological characteristics are summarized in Table 1.

Table 1*: Typical clinical and laboratory findings in patients with auditory neuropathy

Variable pure tone audiometry (from normal hearing to severe/profound hearing loss). Any configuration possible. Uni- or bilateral. Poor speech recognition scores (worse than that predicted from PTA, particularly in noise). Otoacoustic emissions (TEOAEs or DPOAEs) present. Click-evoked auditory brainstem responses absent or severely abnormal. Cochlear microphonic present. Acoustic stapedious muscle reflexes (ipsi- and contralateral) absent. Suppression of TEOAEs by contralateral noise absent. Masking level difference not detectable. Gap detection absent. No central nervous system abnormalities on MRI to account for these findings.

* Modified from Linda J. Hood, Charles I. Berlin, Thierry Morlet, Shanda Brashears, Kelly Rose, Sonya Tedesco. Considerations in the Clinical Evaluation of Auditory Neuropathy/Auditory Dys-Synchrony. Seminars in Hearing (2002) 23 (3): 201-7.

     However, there is no consensus about the term Auditory Neuropathy;. Neural synchrony disorder, brainstem auditory processing syndrome, central auditory dysfunction, auditory synaptopathy, auditory dys-synchrony and primary auditory neuropathy have also been used to describe patients showing similar audiological findinds.

     The prevalence of the recently described pathology known as ‘‘auditory neuropathy’’ in children with hearing loss has been reported to vary greatly, ranging between 0.5 and 24% [4, 5, 6, 7, 8, 9 ] while the prevalence of auditory neuropathy in the non-risk population is unknown. It is estimated that one in every ten children with hearing loss may suffer from auditory neuropathy [10 ].
     Concerning the etiology of auditory neuropathy, it is not well understood yet. Theoretically, all pathologies which affect transmission of the auditory signal from the level of inner hair cells to auditory cortex could give clinical and physiological evidences of what we today call “auditory neuropathy”. In such cases, if the necessary imaging studies fail to reveal a space occupying lesion or anatomic abnormalities [11] we can conclude that one or more intrinsic factors of the auditory pathway could account for these findings. Therefore, regardless the underlying pathology, auditory neuropathy may be considered as an intrinsic dysfunction of the auditory pathways. Patients meeting the profile of auditory neuropathy may be phenotypically healthy or they may suffer from various and seemingly dissimilar pathologies, including neonatal jaundice and anoxia, infections, neurologic, endocrine, metabolic and genetic diseases (Table 2> from references 9,12, 13, 14, 15, 16).   We can speculate that their harmful effect may be either:

a) Segmental or localized, limited to a certain part of the auditory pathway (eg, otoferlin mutations that result in defective exocytosis of neurotransmitter at the synapses between inner hair cells and auditory nerve [17])
b) Multilevel or generalized, affecting a great part of the auditory pathway (eg, bilirubin-induced damages on auditory nuclei and probably auditory nerve [18, 19,]).

 

     According to the transmission patterns, auditory neuropathy could also be divided in a) genetic and b) non-genetic or acquired. Neonates suffering from hyperbilirubinemia and anoxia may develop acquired auditory neuropathy. On the contrary, mutations in the different chromosomes and genes have been reported to be the cause of autosomal dominant or recessive auditory neuropathy, either non-syndromic or accompanied with other inherited neuropathies [20, 21, 22, 23]. Recently, genetic studies [17, 24,25, 26] showed that mutations in otoferlin gene cause non-syndromic recessive auditory neuropathy by affecting calcium-mediated synaptic exocytosis of inner hair cells. Failure of neurotransmitter release blocks the auditory signals at the level of the synapses between inner hair cells and VIIIth nerve endings, thus resulting in a true “auditory synaptopathy”. Another study [27] has demonstrated that mutations in the gene encoding pejvakin, a newly identified protein of the afferent auditory pathway, cause DFNB59 auditory neuropathy. Since this protein is expressed not only in the cochlear sensory epithelium but in the cochlear nuclei, superior olivary complex and inferior colliculus as well, it is believed that it may have a role in the propagation of action potentials through auditory pathway and, consequently, its deficiency could be responsible for an auditory neuropathy phenotype.

        Prognosis of auditory neuropathy remains unpredictable. There are variable reports in the literature showing clinical or laboratory improvement of some patients [6, 28, 29] while others remain stable over time or even worsen, losing outer hair cells’ function [5, 30, 31]. Moreover, some patients may intermittently suffer from auditory neuropathy [32]. In a large series of high risk infants we found that most infants meeting the auditory neuropathy profile (13 out of 20, or 65%) demonstrated a restoration of their auditory neural transmission, that is normal ABR recordings on re-examination. Remarkably, recovery was significantly more common in infants with low birth weight [see reference 9 for details]. In any case, it becomes obvious that some subjects suffering from auditory neuropathy will get better but we are not able to accurately predict who will restore their auditory performance.

       The remarkable variation in the clinical and laboratory findings and the unpredictable prognosis observed in many auditory neuropathic patients makes their management difficult, without commonly acceptable “rules”. Audiologists and otologists should avoid a strict approach to this unexplained pathology. On the contrary, a flexible attitude must be adopted taking into account individual needs. It is author’s belief that in infants and young children behavioural tests should mainly direct the management of auditory neuropathy, not the results of physiologic tests. Hearing aids and cochlear implants are among treatment modalities but not all auditory neuropathy cases have the indication or would benefit from them.

         Studies have showed that only some of the patients suffering from auditory neuropathy would benefit from hearing aids [5 , 33 ]. Probably, these patients can hear but cannot understand [34]. If auditory neuropathy is purely an expression of de-synchronization of acoustic nerve signalling, then hearing aids do not represent the management of choice. Similar uncertainties and queries are encountered in cases treated with cochlear implantation. Some researchers have reported favourable outcomes while others have described poor speech perception scores in patients with auditory neuropathy who have received a cochlear implant [e.g., 5,35, 36, 37 ]. The site and severity of lesion (-s) and the underlying pathology may play a role for the observed diversity in surgical management of auditory neuropathy. It is also possible electric stimuli provided by the cochlear implant to re-synchronize auditory signalling, operating as a pacemaker for the auditory pathway.

Hearing screening programs and auditory neuropathy

      Since OAEs are generated within the cochlea, OAE-based hearing screening can not detect neural dysfunction. Consequently, infants with auditory neuropathy or neural conduction disorders without concomitant sensory (ie, outer hair cell) dysfunction will not be detected by OAEs [38]. In such cases OAEs will give false negative results. Babies treated in neonatal intensive care units are at increased risk for hearing loss, neural conduction and/or auditory brainstem dysfunction, including auditory neuropathy [38]. Probably OAEs do not represent the method of choice for screening high risk populations. The same could apply to all infants suffering from neurologic, metabolic, endocrine or central nervous system disorder, where a higher rate of central auditory dysfunction is expected. The impact of similar findings -that is the combination present OAEs/abnormal ABR- on neonatal hearing screening programs will probably lead to crucial changes in their schemes. Auditory brainstem responses (either automated or conventional) supplemented by OAEs in cases showing elevated thresholds, atypical or absent responses, may prove more effective methodology for screening high risk neonates.

Case Studies

Case 1: Auditory Neuropathy with present acoustic middle ear reflex.

Comments: In patients suffering from auditory neuropathy acoustic middle ear reflex is typically absent. In this case, present OAEs (left) and absent ABR (top-right) in a phenotypically normal child 1 ½ years old are accompanied by present ipsilateral middle ear reflexes, bilaterally (bottom-right, arrows).The Acoustic stapedious muscle reflex can be present in patients suffering from auditory neuropathy. Tone-evoked stapedious reflex may not need the strict synchronization required for ABR recordings.

Case 2: Auditory neuropathy in a child with pituitary stalk interruption syndrome (PSIS)

Comments: Another unusual case of auditory neuropathy. A boy 2 years old was referred for audiologic evaluation due to a mild speech delay (first true words at the age of 15 months), mild hypotonia, clumsy walking and short stature. Auditory brainstem responses were consistent with severe to profound hearing loss bilaterally (top-left), TEOAEs were normal in both ears (top-right) while free-field audiometry suggested only mild hearing loss, if any. We did not recommend hearing amplification. At the same age (2y.o.) primary hypothyroidism was diagnosed. Physiologic tests were repeated at age 3 ½ yielding similar findings. Subjective tests revealed normal pure tone thresholds bilaterally (bottom-left) and near normal speech discrimination scores. Due to persistent short stature a detailed endocrine investigation was undertaken and growth hormone insufficiency was diagnosed. Pituitary MRI (bottom-right) was characteristic of pituitary stalk interruption with a hypoplastic anterior lobe of hypophysis (arrow) and a bright ectopic posterior lobe, just below the hypothalamus (arrowhead). The pituitary stalk is not visible. Today the child is 9 years old, he is under replacement therapy, he has never used hearing aids and he shows normal speech skills. The combination of PSIS and auditory neuropathy represents a poorly understood pathology of unknown pathogenetic mechanism. It could be attributed to genetic interactions during the fetal growth, between genes which are involved in the embryogenesis of hypophysis and those responsible for auditory neuropathy phenotype.

Conclusions

      Genetic or acquired, syndromic or non-syndromic, segmental or multilevel, permanent, transient or fluctuant, auditory neuropathy is an intrinsic dysfunction of auditory pathways with many unexplored aspects. We must first understand the underlying pathogenetic mechanism (-s) before drawing definitive conclusions about its terminology, etiology (-ies), prognosis and optimal management. Till then, the use of the controversial term “auditory neuropathy” probably represents the less offensive action among those we have taken for this disorder.

Key issues relative to AN

• Interpret a positive screening OAE-test cautiously, especially in neonates from ICUs

• Repeat physiologic tests in newborns diagnosed with auditory neuropathy at about 6 months of age

• Inform/educate parents adequately

• Individualize treatment plan

• Use behavioural tests for decision making concerning hearing amplification and cochlear implantation

• If hearing aids are recommended, consider monaural amplification, low maximum power output, close monitoring with OAEs

• If cochlear implantation is recommended, allow adequate time to elapse because CNS maturation or auditory function restoration may be in progress

• Be well-informed about the latest developments on the subject

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