Auditory neuropathy: a challenge for diagnosis and ...

B-ENT, 2013, 9, Suppl. 21, 65-79

Auditory neuropathy: a challenge for diagnosis and treatment F. Declau1, A. Boudewyns1, J. Van den Ende2 and P. van de Heyning1 Department of Otorhinolaryngology, Head and Neck Surgery, and Communication Disorders; 2Department of Medical Genetics, University of Antwerp, Antwerp, Belgium 1

Key-words. Hearing loss; neuropathy; genetics; electrophysiology; hearing aids; cochlear implants Abstract. Auditory neuropathy: a challenge for diagnosis and treatment. In current terminology, auditory neuropathy spectrum disorder (ANSD) is a disease involving the disruption of the temporal coding of acoustic signals in auditory nerve fibres, resulting in the impairment of auditory perceptions that rely on temporal cues. There is debate about almost every aspect of the disorder, including aetiology, lesion sites, and the terminology used to describe it. ANSD is a heterogeneous disease despite similar audiological findings. The absence of an auditory brainstem response (ABR) and the presence of otoacoustic emissions (OAE) suggest an ANSD profile. However, to determine the exact anatomical site of the disorder, more in-depth audiological and electrophysiological tests must be combined with imaging, genetics and neurological examinations. Greater diagnostic specificity is therefore needed to provide these patients with more ­adequate treatment.

Introduction: historical and theoretical issues The first audiological report of ANSD was probably by Hinchcliffe et al.1 (1972), well before OAEs2 were reported describing degenerative neuropathy in Nigerians due to chronic cyanide intoxication. In 1996, Starr et al.3 introduced the term ‘neuropathy’ after studying ten patients with a unique set of ­auditory problems. Eight patients subsequently ­developed concurrent peripheral neuropathies. In brief: auditory neuropathy was thought to be a ­hearing impairment in which outer hair cell ­function was normal but afferent neural conduction in the auditory nerve was disordered.3 The disorder has also been referred to as type I afferent neuron dysfunction, and neural hearing loss.4,5 In 2001, Berlin et al.6 introduced the term auditory neuropathy/auditory dyssynchrony (AN/AD) to include those cases where no true neuropathy was apparent when the constellation of routine test results did not provide sufficient evidence to ­differentiate between synaptic dysfunction and “true neuropathy” of the cochlear nerve. Recently, the term auditory neuropathy was ­extended to auditory neuropathy spectrum disorder (ANSD) to acknowledge the heterogeneous and multifaceted nature of this condition.7 In current terminology, ANSD is a disorder c­ haracterised by the disruption of the temporal coding

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of acoustic signals in auditory nerve fibres, resulting in the impairment of auditory perceptions that rely on temporal cues. Abnormal discharge results from lesions involving the auditory nerve (postsynaptic AN), inner hair cells and/or the synapses with auditory nerve terminals (presynaptic AN). Starr et al.8 suggested breaking down auditory neuropathy into types such as type I (presynaptic) or type II (postsynaptic). In 2008, the same authors6 proposed refining the terminology on the basis of the site of the disorder. Rapin and Gravel9 also ­adopted an anatomical point of view, suggesting that the term auditory neuropathy should be limited to cases in which the pathology is located at the ­spiral ganglion cells and their axons of the 8th ­cranial nerve. In recent audiological literature, the term “auditory neuropathy” has also been loosely applied to infants who satisfy the first two audiological criteria only (absent ABR and present OAE) without any further audiological or neurological corroboration. In these cases, the term “ANSD profile” is considered to be more appropriate. However, Rapin admitted that strictly localised pathology was in fact exceptional in cases with functional and ­anatomical verification and that, in the majority of cases, there was pathology at multiple levels in the auditory pathway.5 One of these strictly localised pathologies is ­cochlear nerve hypoplasia, which was first described

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by Shelton et al.10 in 1989 and can be considered as a “true“ form of auditory neuropathy.

Diagnostic investigations

Epidemiology

The diagnosis of ANSD is a true challenge and ­audiological evidence must often be combined with imaging, genetics and neurological examinations. As more patients, particularly young children, have been diagnosed, studies have shown that patients with ANSD are a heterogeneous group despite ­similar audiological test findings. According to Berlin et al.13,27 ANSD can be ­characterised by the following list of audiological findings. The first three items are considered to be a minimum test battery for the diagnosis of ANSD:

ANSD occurs in all age groups.3 With the advent of newborn hearing screening, auditory neuropathy became a recognised disorder in the paediatric ­population. The prevalence of ANSD in children with confirmed permanent hearing loss has been reported to vary greatly, ranging from 1.6 to 19%.11,12 According to Berlin, ANSD is also present in 1-10% of children in schools for the deaf.13 ANSD after universal neonatal hearing screening14-17 was found in 0.044% to 0.06% of screened infants, whereas Dowley et al.16 and Foerst et al.17 reported an annual incidence rate of 0.14 to 0.27/1000 live births. Sininger et al.18 reviewed the incidence of the ANSD profile in neonatal intensive care unit (NICU) infants and found a range in the literature extending from 5.3% to 14.8% (with 10-14% being the most frequently reported prevalence). Berg et al.19 found a slightly higher incidence of 24.1% in NICU infants. These data are the results of the ­combination of present TEOAEs and absent ABRs, suggesting an ANSD profile but often without any further diagnostic assessment to confirm the ­tentative diagnosis. On the other hand, some ­hearing disorders underlying ANSD may not have been included in prevalence estimates as the identification of ANSD may require additional tests to be performed that are not invariably included in routine diagnostic measurements. Refined diagnostic tests, together with progress in genetic research, will provide a more accurate calculation of the prevalence of ANSD.20 This variation may reflect the inclusion in some studies of diseases in which ANSD is transient, such as Guillain­Barré syndrome.21 Moreover, in NICU neonates with no auditory brainstem responses and the presence of OAEs at hearing screening, the ABR abnormalities may reflect the delayed maturation of both the brainstem and the auditory nerve.22 Cochlear nerve hypoplasia is seen in 6% to 19% of children with permanent hearing loss, but it is even more common in patients with an ANSD profile.23-26 cochlear nerve deficiencies were identified in children in 16,7 to 26,9 % of ears with an ANSD profile by Buchman et al.23 and Huang et al.26

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Clinical and audiological aspects

1. Test of cochlear hair cell function: evidence of normal outer hair cells in the cochlea: a. Otoacoustic emissions are, or have been, ­present (they sometimes disappear with time or with hearing aid use). Standard screening or ­diagnostic protocols using Transient-Evoked OAEs ­(TEOAEs) or Distortion Product OAEs (DPOAEs) may be used. b. Cochlear microphonics (CM): Auditory brainstem response (ABR) to high-level click stimuli (80-90 dB nHL) including positive and negative polarity clicks in separate trials through insert earphones.28,29 A trial run with the sounddelivery tube clamped will differentiate between the CM and the stimulus artifact.30 CMs generally remain present in individuals with ANSD even when there has been a loss of OAEs.3 The ­investigators reported that 80% of the patients had OAEs but that they disappeared over time in 11% of their patients and OAEs were not recorded in the other 9%.31 2. Evidence of neural impairment: ABR is absent or grossly abnormal. The ABR may also be ­mistakenly thought to be present when in fact a cochlear microphonic (CM) or hair cell response is masquerading as a neural response. Both ­rarefaction and condensation polarities should be evaluated to determine whether a cochlear microphonic is present (Figure 1). Insert earphones must be used and care taken to complete a “no-sound run” by clamping or disconnecting the sound tube from the transducer to eliminate the possibility of stimulus artifacts.32 3. Middle ear muscle reflexes (MEMRs) are absent. There are no normative data for acoustic reflex thresholds in very young infants using high

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Auditory neuropathy

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Figure 1 ABR of a child with an ANSD profile: presence of a cochlear microphonic at 100 dB nHL with rarefaction (R)/condensation (C) ­polarity in the absence of a recognisable neural response.

probe-tone frequencies (1000 Hz) and so this procedure is not required to diagnose ANSD in infants. Sininger and Oba (2001) reported that the vast majority of patients with ANSD have no auditory MEMRs, and about 20% have highly atypical, elevated, auditory MEMRs both ­ipsilaterally and contralaterally in the presence of recordable MEMRs to tactile stimulation.31 The presence of reflexes at levels near 90 dB HL in neonates and infants up to six months of age should in itself result in serious doubts about a diagnosis of ANSD.13,33,34 It has been argued that more standards are needed before we can rely on immittance audiometry as a tool in the diagnosis of ANSD in infants.34 Nevertheless, a complete test battery for ANSD should include middle ear muscle reflex testing whenever ­possible.

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4. Efferent suppression of otoacoustic emissions is absent. Although this test is not in widespread clinical use, it is a potential candidate for further diagnostic studies in individuals with reliably recorded OAEs.7 5. No masking level differences. Highly reduced binaural release from masking targeting a subject’s ability to detect interaural phase (timing) differences confirms the poor temporal processing of subjects with ANSD.5 6. Speech perception, which may be surprisingly good in some patients in a quiet environment, is seriously compromised in noisy surroundings.35 Most affected adults have perceptual deficits that are greater than would be expected from their audiometric (sound detection) levels. In addition, fluctuations in listening abilities have been reported, some associated with body

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F. Declau et al. t­emperature and others with no clear precipitant.36,37 In order to understand running speech, or even to discriminate between sounds within individual words, a listener must be able to ­perceive the characteristic shape of individual phonemes, and be able to follow the rapid ­within-phoneme changes that give cues to coarticulation. It is this need to cope with the ­dynamic nature of speech that poses the greatest challenge for individuals with temporal processing problems.7

The initial diagnosis of an ANSD profile should be based on comprehensive electrophysiological assessment that includes, as a minimum, ABR testing, immittance measurements including tympanometry and acoustic reflex thresholds, and OAEs. Unlike “typical” sensorineural hearing loss, threshold estimation is virtually impossible using ABR or ASSR evaluation. The determination of thresholds for infants and young children with ANSD must therefore include developmentally ­appropriate behavioural measures such as visual ­reinforcement audiometry (VRA) or play audio­ metry.32 The degree of hearing loss in patients with ANSD varies from slight to profound; most losses are bilateral and symmetrical in configuration (66 to 82%), with some patients having normal hearing in either ear, or a unilateral disorder.13,15,38 In a review by Oba, audiogram configurations were usually flat. However, a smaller percentage (28%) had a rising audiometric configuration: thresholds were poorer in the low-frequency regions than the high. Hearing loss was considered stable in 36%, fluctuating by more than 10 dB pure tone ­average in 29%. In some cases, hearing thresholds shift from moment to moment, creating the illusion of a lack of cooperation or malingering. Hearing losses are found to be progressive in 14%, to have an undefined course in 14% and to apparently ­normalise in 3%.38 Numbers of subjects with ANSD who have undergone comprehensive psycho-acoustic studies are limited. Psychophysical measures have shown that disrupted neural activity has minimal effects on intensity-related perception such as loudness discrimination, pitch discrimination at high frequencies, and sound localisation using interaural level differences. By contrast, disrupted neural ­activity significantly impairs timing-related percep-

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tion such as pitch discrimination at low frequencies, temporal integration, gap detection, temporal modulation detection, backward and forward ­masking, signal detection in noise, binaural beats, and sound localisation using interaural time differences.39 In addition, the results of audiological tests can be very confusing in the context of diagnosing ­auditory neuropathy: OAEs may be absent in more than a third of patients on retesting, and any impairment of speech perception may be apparent only in the presence of noise.6 Although the detection of OAEs may indicate preserved OHC function, the physiological consequences of a lesion involving the afferent component of the auditory periphery cannot be evaluated effectively with far-field recording techniques such as ABR due to the low signal-to-noise ratio.28,40,41 ABR should be seen as an objective measure of ­auditory temporal processes. Both receptor (cochlear microphonic, CM; summating potential, SP) and auditory nerve activity (compound action potential, CAP) can be evaluated using a near-field recording technique such as transtympanic electrocochleography (ECochG42). Transtympanic electrocochleography can distinguish between presynaptic and postsynaptic dysfunction.40,43,44 Presynaptic dysfunction implicates the inner hair cell and its environs, while postsynaptic dysfunction implicates neural elements themselves. ECochG potentials have been recorded from children and young adults affected by ANSD.43,45 Cochlear microphonics, which are believed to arise almost exclusively from outer hair cells (OHCs) in the basal portion of the cochlea, were normal.46 Moreover, Santarelli et al.45 showed that the cochlear potentials obtained after CM cancellation from one group of subjects with ANSD consisted only of the SP not followed by a CAP. Since it is ­acknowledged that the SP is generated primarily by inner hair cells (IHCs) in the basal portion of the cochlea47,48, this was thought to be consistent with a pre-synaptic IHC disorder. In other patients, the SP was normal and was followed by a delayed CAP or sustained low-amplitude negative activity consistent with a dendritic origin.49 In addition, unlike acoustic ABRs, electrical auditory brainstem responses (EABR) can differentiate between auditory dyssynchrony and true auditory neuropathy.50 Results for cortical auditory event-related potentials (CAEPs) could provide a way of predicting

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Auditory neuropathy perceptual skills in children since the presence of CAEPs (with age-appropriate latency and ­morphology) was correlated with significant openset-speech-perception abilities and amplification ­benefit. By contrast, the absence of CAEPs ­indicated profound hearing disability evidenced by profound hearing loss and/or extremely poor speech perception.51 ANSD symptomatology can resemble central auditory dysfunction or ‘central auditory processing disorder’52; an absence of, or a severe abnormality in, ABRs beginning at wave I in the presence of preserved otoacoustic emissions is required for a diagnosis of ANSD and can be used in differential diagnosis with central auditory processing disorders.3 Vestibular dysfunction has been reported in some patients with ANSD. Absent caloric responses were reported to be more likely if the patient had concomitant peripheral neuropathies. However, most patients with ANSD do not have symptomatic vestibular complaints.15 Regardless of current technological limitations, it is clear that the standard ABR, OAE and speech reception threshold and supra-threshold speech comprehension measures are inadequate to identify ANSD in the strict sense from hair cell, retro-­ cochlear/brainstem pathologies and thalamo-­ cortical disorders.53 Neonatal hearing screening Universal newborn hearing screening has now been implemented in many countries. In the JCIH 2007 position statement, screening with ABR was recommended for NICU infants who receive care for five days or more so that neural hearing loss will not be missed.22 Children diagnosed with ANSD require a different, multidisciplinary, approach and management, and so it is essential to distinguish between these children and those with other aetiologies of hearing loss.54 Screening well babies for ANSD is more problematic. Typically, screening programmes use a two-stage screening approach (either OAEs repeated twice, OAEs followed by ABR, or automated ABR repeated twice).55 Screening with ABR only or otoacoustic emissions only will introduce diagnostic errors: children who fail ABR-based screening and continue to have poor or no ABR may have ANSD and not respond well to hearing aids. Conversely,

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children with ANSD will have normal otoacoustic emissions and cannot therefore be identified with an OAE-only screening test. In an analysis of risk factors in NICU infants, Berg et al.19 failed to predict which infants would be at risk for the ANSD profile either unilaterally or bilaterally. The absence of ABRs and presence of OAEs suggests an ANSD profile. However, infants should be fully assessed before the diagnosis of ANSD can be firmly established. Many of the assessments recommended for ­infants with ANSD are similar to assessments ­recommended for infants with SNHL.22 The ­recommended assessments for infants with ANSD include7: 1. paediatric and developmental evaluation and history; 2. otological and audiological evaluation with ­imaging of the cochlea and auditory nerve (CT and MRI); 3. medical genetics evaluation; 4. ophthalmologic assessment; 5. neurological evaluation to assess peripheral and cranial nerve function; and 6. communication assessment. Improved auditory function and even “recovery” may be seen during ABR testing in some infants with an initial diagnosis of ANSD.56,57 Particularly in high-risk neonates, repeat ABR testing at the age of 6 months is recommended. Transient hearing losses may also be related to concomitant periods of secretory otitis media. In those infants who “recover” from ANSD, the regular surveillance of developmental milestones, auditory skills, parental concerns, and middle ear status is recommended in line with the Joint Committee on Infant Hearing (JCIH) 2007 Position Statement.22,56 Despite the total absence of an ABR, approximately 7% of infants and children will act as if they have no hearing problems. These children will usually have had neonatal hyperbilirubinaemia, and some actually develop with no apparent speech or hearing problems despite the absence of an ABR.27 Imaging CT/MRI ANSD may be unilateral or bilateral. When there is electrophysiological evidence of unilateral ANSD in association with a profound hearing loss, the

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a

F. Declau et al.

b

Figure 2 (a) T2-weighted CISS axial image of a patient with unilateral cochlear nerve dysplasia at the right side. (A) Right internal auditory canal (IAC) with evidence of superior vestibular and facial nerves. C: Cochlea. (b) Reconstructed sagittal T2 weighted CISS image through the right IAC demonstrates the absence of the right cochlear nerve. FN: facial nerve; VN: superior and inferior vestibular nerves.

c­ linician should be very alert to the possibility of cochlear nerve deficiency.23 Levi et al.58 suggested that a nerve that is 50% smaller than the adjacent facial nerve on MRI constitutes a diagnostic criterion for cochlear nerve hypoplasia. A normal bony internal auditory canal and inner ear morphology are not reliable surrogate markers of cochlear nerve integrity.59,60 MRI is therefore superior to CT as a diagnostic tool and should be performed in all paediatric patients with an ANSD profile (Figure 2). Between 40% and 85% of patients with a cochlear nerve deficiency have associated inner ear abnormalities.26,59-62 There is a higher rate of malformations, both labyrinthine and in the hindbrain, in bilateral cochlear nerve deficiency than in unilateral cases.26,58 In unilateral cochlear dysplasia/aplasia, the left side is involved slightly more frequently.58 Causes of ANSD A variety of risk factors and aetiologies are associated with this heterogeneous form of hearing loss, which may explain the variation in auditory skills in ANSD patients. ANSD may be congenital or acquired. Congenital ANSD affects the development of language, an ability that is strictly related to a period of sensitivity that declines with age.63 During

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this period, the development of language skills is strictly dependent on cortical plasticity and efficient auditory input is required. When the onset of ANSD is delayed until childhood or adult life (acquired ANSD), abnormalities of auditory input lead to the severe impairment of speech perception and ­progressive deterioration. Patients can range from newborns to adults. Sininger and Oba reviewed their patients in 2001,38 finding that onset of the condition was before 10 years in 75% of the cases, and before 2 years in about 40%. Of the children in whom onset was before the age of 2 years, 44% had potential genetic or familial risk factors. Of the ­other children, 12% had histories of hyperbilirubinaemia, 8% were born prematurely, 28% had ­multiple neonatal risk factors, and 52% had no ­other risk factors. A proportion of the unknown causes are also thought to have an underlying ­genetic aetiology. Approximately 40% of auditory neuropathy cases may therefore have a genetic ­basis. A study by Starr et al.64 which also looked into the causes of ANSD shows that the disorder in 42% of patients was associated with hereditary neurological disorders; in 10% of patients, it was associated with toxic, metabolic, immunological, and infectious factors, and the cause was unknown in 48% of ­patients. The majority of cases with ANSD are ­sporadic: there is only one affected

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Auditory neuropathy

Immune/Metabolic

Table 1 Non-genetic causes of ANSD, modified after11,31,78,79

Hyperbilirubinaemia/ Kernicterus

Polyarteritis nodosa

Anoxia /hypoxia

Sarcoidosis

Alcoholism/nutritional Diabetes mellitus Uraemia

Infection/Inflammatory Leprosy

Borreliosis Toxins

Paraproteinaemias

Rheumatoid arthritis

Guillain-Barré Syndrome21 AIDS

Ramsey Hunt syndrome

Heavy metals (lead, cobalt, mercury)80-82 Drugs (Carboplatin)83,84 Trauma

Vascular diseases

i­ndividual. However, research has identified many familial cases with two or more members in a ­family a­ ffected.65 Non-genetic causes of ANSD Although Berg et al.19 were unable to determine a specific risk profile, the identification of risk factors for hearing loss by using the guidelines of the Joint Committee on Infant Hearing 2000 position statement is highly recommended.55,66 Retrospective clinical studies have suggested that perinatal problems like anoxia/hypoxia, hyperbilirubinaemia, dysmaturity and prematurity in particular are non-genetic risk factors for ANSD.67-69 A more comprehensive list of non-genetic causes is given in Table 1. The causes of acquired ANSD are poorly understood because there are only a few relevant ­temporal bone studies.70,71 Amatuzzi provided a histopathological demonstration in a temporal bone study that the mean gestation period for infants with selective inner hair cell loss was 32 weeks, and 36 weeks in infants with normal ears or with more common histopathological patterns of OHC loss or combined OHC and IHC loss.72 Hyperbilirubinaemia is a risk factor for ANSD. Wennberg suggests ≥ 1.2 μg/dl free (unbound) bilirubin as a possible criterion for further studies.73 One of the cardinal clinical signs of acute or chronic classical kernicterus is auditory impair-

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Neoplasma/ intracranial cystic lesions

ment, and all but one of the kernicterus subtypes also include auditory impairment.74 Shapiro and Popelka suggest that bilirubin exposure results in auditory system damage, initially at the level of the brainstem and progressing to the level of the VIII cranial nerve and then to greater neural centres.74 There is no evidence of neural damage at the level of the cochlea. Auditory neural damage from bilirubin toxicity ranges from neural timing deficits, including neural firing delays and dyssynchrony, to neural response reduction and even the elimination of auditory neural responses. Chisin et al.75 were the first to record both the CM and the ABR in patients with hyperbilirubinaemia; they found that the ­majority of their cases had a CM but an atypical or absent ABR, suggesting auditory nerve or brainstem dysfunction. More recently, Rhee et al.76 reported normal OAEs and absent or atypical ABR findings in 4 out of 11 infants with severe hyperbilirubinaemia. Amin et al.77 recorded changes in ABR maturity over the first 5 days in premature ­infants that were correlated with unconjugated ­bilirubin levels. In this subgroup of ANSD, there is a tendency towards spontaneous improvement: Rhee et al.,76 and others, have stressed that most of the initially atypical ABR findings reverse or improve with time, suggesting that neural/brainstem pathology tends to normalise after treatment with exchange transfusion or phototherapy.76

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Non-syndromic

F. Declau et al.

Transmission

Locus

Disease name

Autosomal dominant

13q21-q24

AUNA1

Moderate to profound deafness DIAPH365

Autosomal recessive

2p23-p22

DFNB9

Congenital profound deafness

OTOF86

DFNB1A

Congenital profound deafness

GJB288

Mild deafness with peripheral neuropathy

GJB390

Mild to severe deafness; demyelinating neuropathy

MPZ94

Autosomal recessive Autosomal recessive Syndromic

Table 2 Genetic causes of ANSD, modified after79 and20

Mitochondrial

2q31.1-q31.3

DFNB59

13q12.11

12S rRNA

MTRNR1

Autosomal dominant

17p11.2-p12

CMT 1A

Autosomal dominant

1q22

CMT 1B

Autosomal dominant

8p21

CMT 2E

Autosomal dominant

3q28-q29

Autosomal recessive

8q24.3

Autosomal recessive

11q14.111q22.3

Autosomal recessive

9q13

Autosomal recessive

10p13

X-linked recessive

Xq22.1

X-linked recessive

Xq23-q27.3

Autosomal dominant

X-linked dominant

Mitochondrial

1p34.3

Xp13

MTND4

Congenital profound deafness Moderate to severe deafness

CMT 4D

Genetic markers linked to ANSD

PJVK87

T1095C mutation89

Mild to severe deafness; demyelinating neuropathy

PMP2291,92,93

Normal hearing; axonal neuropathy

NF-L95

Autosomal Optic neuropathy; moderate Dominant Optic deafness Atrophy (ADOA) or Kjer’s Disease Mild to severe deafness; axonal/demyelinating neuropathy

OPA196

NDRG197

Autosomal Optic neuropathy; mild hearing TMEM126A98 Recessive Optic loss Atrophy (AROA)

Friedreich’s Ataxia Ataxia; axonal neuropathy; optic neuropathy; cardiomyopathy; normal hearing threshold to mild deafness Refsum Disease CMT 1X

Progressive deafness

Demyelinating neuropathy

FXN99

PHYH100 GJB1101

Mohr-Tranebjaerg Progressive deafness; dystonia, DDP1 Syndrome (MTS) optic neuropathy; dementia TIMM8A102 or DeafnessDystonia Syndrome DFNX5

Sensory axonal neuropathy; mild-to-severe deafness

Leber Hereditary Optic neuropathy; mild-toOptic Neuropathy moderate deafness (LHON)

However, the decision to treat hyperbilirubinaemia is itself controversial in terms of the criteria and the threshold for treatment.15 Genes involved in ANSD Genetic studies of hearing loss make it clear that the majority (up to 80%) of hereditary deafness is

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Phenotype

AUNX1103 11778mtDNA mutation104

non-syndromic.85 Even though the exact percentage of non-syndromic occurrence of ANSD is not known, a large number of patients with ANSD are non-syndromic. The identification of several genes involved in the pathogenesis of both presynaptic and postsynaptic AN has greatly contributed to the diagnosis and a better understanding of the mechanisms underlying this disorder.20 The inheritance

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Auditory neuropathy pattern can include all the main types of inheritance, such as autosomal dominant, autosomal recessive, X-linked and mitochondrial. About one third to 40% of subjects with ANSD are affected by peripheral neuropathies.13,64 In addition, optic neuropathies and other CNS disorders have been found in association with ANSD. In this group of subjects the hearing disorder is caused by several genetic defects, all ­resulting in neuronal loss and demyelination in ­peripheral and/or cranial nerves, and the site of the lesion is invariably postsynaptic. ANSD can also be associated with hereditary syndromes such as Charcot-Marie-Tooth (CMT) Disease,93-95,97 Leber’s Hereditary Optic Neuropathy (LHON),104 Autosomal Dominant Optic Atrophy (ADOA)96, Autosomal Recessive Optic Atrophy (AROA),98 Fredreich’s Ataxia,99 Mohr-Tranebjaerg Syndrome (MTS),102 Refsum Disease,100 and X-linked disease.103 For a comprehensive overview, the ­reader is referred to Manchaiah et al.79 (2011) and Santarelli (2010).20 Treatment options Auditory impairment ranges across a continuum from mild to severe. A recent evidence-based systematic review by Roush et al.105 (2011) found that the clinical evidence related to intervention for ANSD is in the very preliminary stages. Generally, behavioural audiograms are not valuable in ANSD patients as a management tool for treatment. In contrast to children with most forms of sensorineural hearing loss, perceptual ability in ANSD children cannot be predicted with reasonable accuracy on the basis of the behavioural audiogram. According to Rance and Barker, CAEPs could be used to ­predict in advance children’s linguistic abilities: their results showed that approximately 50% of children with ANSD had speech-recognition scores similar to those of children with sensory hearing loss; the other 50% essentially had no open-set speech-perception ability. Interestingly, the children with no open-set speech perception had no cortical evoked potentials, while the children who had ­measurable speech-recognition scores did have CAEPs.106 Hearing aids Success with hearing aids in quiet as reported by Deltenre et al.106, and Rance et al.107 did not lead to

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age-appropriate language acquisition in the ­majority of patients.13 However, there appears to be a subset of children whose aided speech-perception abilities benefit, and in whom there is improvement in puretone detection thresholds.105 Berlin et al.13 (2010) summarised outcome management in 260 patients with ANSD. Approximately 15% reported some benefits with hearing aids in terms of language learning, while improvement in speech comprehension and language acquisition was reported in 85% of patients with implants. Approximately 5% of the total population developed normal speech and language without intervention. Current evidence-based protocols for fitting hearing aids rely on estimates of hearing threshold levels to determine the recommended gain and output variables. In children with ANSD, the determination of hearing thresholds is typically delayed until the infant is developmentally able to perform reliable behavioural testing using VRA. Recommendations for management include the use of low-gain hearing aids or FM systems, the use of low-gain amplification in one ear only, or the avoidance of hearing aids altogether, in combination with visual and/or sign language exposure. 7,108 Relentless mouth-covered auditory-verbal therapy should be avoided. Usually, hearing aids make the child more aware of environmental sounds but do not result in auditory learning language. The drawback to using powerful hearing aids is that they may destroy outer hair cell function and, if the child is on the road to recovery, may cause a preventable high-frequency sensory loss.109 This population is also unique because of the high rate of comorbidities of up to 54%, which can be very demanding for the therapeutic team.7 A speech language team should monitor the progress of the child quarterly to ensure that appropriate progress is being achieved. Cochlear implants Behavioural pure-tone audiograms are of limited prognostic value in predicting aided benefit in children with ANSD, and so cochlear implantation should be considered even if audiometric thresholds are better than they would be when typically considering implants after progress with conventional amplification has proven inadequate. However, this step should be taken only after adequate attempts have been made to address the case with

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74 amplification, appropriate early-intervention services, and a comprehensive evaluation by a team of professionals.7 No child should receive an implant before a ­behavioural measure of hearing has been obtained. Audiometric criteria used to select paediatric ­cochlear implant candidates with sensorineural hearing loss can also be applied in ANSD cases. Young ANSD candidates should therefore be ­considered for the procedure as soon as ‘stable’ hearing thresholds in the severe/profound range can be established. The age at which this is possible will be determined to some extent by the child’s ability to respond reliably to conditioned audio­ metric testing. Another consideration, however, should be the possibility of improvement in auditory neural function, which has been demonstrated both in the emergence of a repeatable ABR and a decrease in hearing thresholds in some ANSD ­infants (usually in the first year of life).56,57,110 This finding therefore raises issues relating to implantation before the age of 1 year.111 However, the outcome of cochlear implantation varies widely among patients and even between cochlear implant teams.7 According to Breneman et al.112 (2012), the expected outcomes of cochlear implantation for children with ANSD, excluding children with cochlear nerve deficiency, are no different than for children with non-ANSD SNHL. Raveh et al.111 examined the effect of CI intervention on speech and language outcomes in children with ANSD. The authors noted that children with ANSD using CI achieved results in speech production tests that were comparable with age-matched CI users with SNHL. Electrically evoked compound action potentials (ECAPs) in children with implants were not predictors of outcome.113 While it is generally acknowledged that patients with presynaptic AN due to mutations in the OTOF gene invariably benefit49, poor outcome has been reported for implant subjects with postsynaptic AN with an underlying axonal loss and degeneration of the entire nerve fibres, as in Friedreich ataxia114 and deafness dystonia syndrome.115 By contrast, as mentioned by Santarelli,20 two patients with the R445H mutation in the OPA1 gene116 and some subjects with mutations in the DIAPH3 gene8, recovered both speech perception and auditory brainstem ­responses following cochlear implantation.20 Recently, children with Friedreich ataxia have benefited

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F. Declau et al. significantly from an FM listening device in everyday life and in speech perception performance.117 There is lively debate about the optimal treatment for patients with cochlear nerve dysplasia, and the decision about the best therapy depends on whether there is a complete absence of nerve fibres or hypoplasia and on whether the condition is ­unilateral or bilateral, as well as on the possible ­presence of other abnormalities. Kutz et al.118 suggest that the presence of wave V on EABR may have predictive value for cochlear implantation. It is possible that, if some nerve fibres remain, wave V could be generated at high intensities and these patients could therefore benefit from CI to some extent. On the other hand, Carner et al.59 examined patients with cochlear nerve dysplasia who were given a CI and found no response. ­Colleti et al.119 stated that these patients may benefit from an auditory brainstem implant (ABI), although to a lesser extent than other patients. Merkus et al.120 and Sennaroglu et al.121 also stated that ABI could be indicated in the absence of the cochlear nerve when this has been proved by imaging and in testing since this is the only way to secure any chance of hearing. By contrast, Levi et al.58 recommended preferential seating (when CND is unilateral) or amplification as opposed to CI for patients with cochlear nerve dysplasia. However, two recent publications point out that the absence of a visible cochlear nerve on imaging does not preclude the auditory innervation of the cochlea.122,123 Electrically-evoked ABR testing should be performed since this factor is critical for the evaluation of this patient group.122,124 References 1. Hinchcliffe R, Osuntokun BO, Adeuja AO. Hearing ­levels in Nigerian ataxic neuropathy. Audiology. 1972; 11(3):218-230. 2. Kemp DT. Stimulated acoustic emissions from within the human auditory system. J Acoust Soc Am. 1978;64(5): 1386-1391. 3. Starr A, Picton TW, Sininger Y, Hood LJ, Berlin CI. ­Auditory neuropathy. Brain. 1996;119( Pt 3):741-753. 4. Berlin CI, Hood LJ, Cecola RP, Jackson DF, Szabo P. Does type I afferent neuron dysfunction reveal itself through lack of efferent suppression? Hearing research. 1993;65(1):40-50. 5. Rapin I, Gravel J. “Auditory neuropathy”: physiologic and pathologic evidence calls for more diagnostic

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Auditory neuropathy s­ pecificity. Int J Pediatr Otorhinolaryngol. 2003;67(7): 707-728. 6. Starr A, Zeng F, Michalewski H, Moser T. Perspectives on Auditory Neuropathy: Disorders of Inner Hair Cell, Auditory Nerve, and Their Synapse. In: Basbaum AI, Kaneko A, Shepherd GM, Westheimer G, Eds. The ­Senses: A Comprehensive Reference. Academic Press, San Diego; Vol 3 Audition: 2008:397-412. 7. Hayes D, Sininger Y, Northern J. Guidelines for identification and management of infants and young children with auditory neuropathy spectrum disorder. Conference Proceedings. Guidelines Development Conference at NHS, Como, Italy. The Children’s Hospital, Colorado; 2008. 8. Starr A, Isaacson B, Michalewski HJ, Zeng FG, Kong YY, Beale P, Paulson GW, Keats BJB, Lesperance MM. A dominantly inherited progressive deafness affecting distal auditory nerve and hair cells. J Assoc Res Otolaryngol. 2004;5(4):411-426. 9. Rapin I, Gravel J. Auditory neuropathy: a biologically ­inappropriate label unless acoustic nerve involvement is documented. J Am Acad Audiol. 2006;17(2):147-150. 10. Shelton C, Luxford WM, Tonokawa LL, Lo WW, House WF. The narrow internal auditory canal in children: a contraindication to cochlear implants. Otolaryngol Head Neck Surg. 1989;100(3):227-231. 11. Sanyelbhaa Talaat H, Kabel AH, Samy H, Elbadry M. Prevalence of auditory neuropathy (AN) among infants and young children with severe to profound hearing loss. Int J Pediatr Otorhinolaryngol. 2009;73(7):937-939. 12. Maris M, Venstermans C, Boudewyns A. Auditory neuro­ pathy/dyssynchrony as a cause of failed neonatal hearing screening. Int J Pediatr Otorhinolaryngol. 2011;75(7): 973-975. 13. Berlin CI, Hood LJ, Morlet T, Wilensky D, Li L, ­Mattingly KR, Taylor-Jeanfreau J, Keats BJB, St John P, Montgomery E, Shallop JK, B Russell BA, Frisch SA. Multi-site diagnosis and management of 260 patients with auditory neuropathy/dys-synchrony (auditory neuropathy spectrum disorder). Int J Audiol. 2010;49(1):30-43. 14. Kirkim G, Serbetcioglu B, Erdag TK, Ceryan K. The ­frequency of auditory neuropathy detected by universal newborn hearing screening program. Int J Pediatr Oto­ rhinolaryngol. 2008;72(10):1461-1469. 15. Ngo RY, Tan HK, Balakrishnan A, Lim SB, Lazaroo DT. Auditory neuropathy/auditory dys-synchrony detected by universal newborn hearing screening. Int J Pediatr Otorhinolaryngol. 2006;70(7):1299-1306. 16. Dowley AC, Whitehouse WP, Mason SM, Cope Y, Grant J, Gibbin KP. Auditory neuropathy: unexpectedly common in a screened newborn population. Dev Med Child Neurol. 2009;51(8):642-646. 17. Foerst A, Beutner D, Lang-Roth R, Huttenbrink KB, von Wedel H, Walger M. Prevalence of auditory neuropathy/ synaptopathy in a population of children with profound hearing loss. Int J Pediatr Otorhinolaryngol. 2006;70(8): 1415-1422. 18. Sininger Y. A Sound Foundation Through Early Amplification. Proceedings of the Second International Conference. Section V, Chapter 15. In: Seewald R, Gravel J,

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Frank Declau M.D. Ph.D. University of Antwerp Department of Otorhinolaryngology, Head and Neck Surgery, and Communication Wilrijkstraat 10 2650 Edegem, Belgium E-mail: [email protected]

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