Auditory neuropathy spectrum disorder
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"auditory neuropathy spectrum disorder"[MeSH Terms]
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"auditory neuropathy" AND "cochlear implant"
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Auditory Neuropathy Spectrum Disorder (ANSD)
Definition and Terminology
Auditory Neuropathy Spectrum Disorder (ANSD) is a hearing disorder characterized by the presence of normal outer hair cell (OHC) function - evidenced by intact evoked otoacoustic emissions (OAEs) and/or cochlear microphonics (CMs) - but abnormal or absent auditory brainstem response (ABR). The pathology lies in the inner hair cells (IHCs), their synapses, or the auditory nerve and its myelination rather than the OHCs.
The terminology has evolved:
- "Auditory neuropathy" (AN) - first coined by Starr et al. in 1996
- "Auditory neuropathy/dyssynchrony" - 2001, emphasizing the neural synchrony problem
- "ANSD" - adopted in 2008 after international consensus (Como, Italy) to capture the heterogeneous, multifaceted nature of the disorder
The core concept is auditory dyssynchrony: loudness of sound is relatively well perceived, but the synchronization of acoustic signals is not adequate to evoke an ABR, elicit the stapedius reflex, or suppress contralateral OAEs. This requires integrity of cranial nerve VIII.
- Scott-Brown's Otorhinolaryngology Head & Neck Surgery, Vol 2, p. 917-918
Prevalence
-
Estimated in 5-12% of children previously considered to have severe-to-profound hearing loss
-
Approximately 1 in 7,000 neonates assessed by universal newborn hearing screening show abnormal VIII nerve function
-
Up to 1 in 10 children with permanent hearing loss overall
-
Scott-Brown's Otorhinolaryngology, p. 918
Aetiology
ANSD is a heterogeneous disorder with lesions occurring anywhere along the auditory pathway from the IHCs to the auditory brainstem pathways. At least three sites of dysfunction have been identified:
1. Electromechanical Transduction at Inner Hair Cells (IHC/Synapse)
Often called "auditory synaptopathy." Key proteins involved:
- Otoferlin (OTOF) - mutations cause DFNB9; otoferlin is essential for synaptic vesicle fusion at the IHC ribbon synapse
- CaV1.3 calcium channel subunit - regulates neurotransmitter release
- Bassoon - active zone scaffolding protein
- VGLUT3 - vesicular glutamate transporter
- DIAPH3 - mutations cause autosomal dominant nonsyndromic AN (AUNA1)
- WBP2 - mutations (DFNB107) cause glutamate excitotoxicity at primary afferent terminals
2. Axons, Cell Bodies, and Myelin Sheaths
- Charcot-Marie-Tooth disease (CMT): MPZ gene (myelin protein zero, chromosome 1) - demyelinating (CMT type I) or axonal (CMT type II) neuropathy
- Friedrich's ataxia
- CAPOS syndrome - ATP1A3 mutation (Na+/K+-ATPase alpha-3 subunit in spiral ganglion neurons)
- OPA1 gene mutations - optic atrophy plus syndrome, auditory nerve terminal degeneration
- SPTBN4 (beta-spectrin 4) - abnormal ion channel distribution at nodes of Ranvier
- DFNB59 / pejvakin - protein in afferent auditory pathway neuron cell bodies
3. Efferent Olivocochlear Influences
Disruption of the olivocochlear bundle leads to absent contralateral suppression of OAEs, which is a diagnostic finding.
- Cummings Otolaryngology, pp. 425-434; Scott-Brown's, pp. 2226-2236
Congenital / Perinatal Risk Factors
| Category | Examples |
|---|---|
| Toxic/metabolic | Hyperbilirubinaemia (kernicterus), asphyxia, respiratory distress syndrome, low birthweight, cerebral palsy |
| Prematurity | Extreme prematurity (<28 weeks gestation) |
| Neurological | Hypoxic ischaemic encephalopathy, intraventricular haemorrhage, sepsis, prolonged ventilation |
Acquired Causes
| Category | Examples |
|---|---|
| Infection | Herpes zoster (Ramsay Hunt), CMV, HIV/AIDS, basal meningitis (pneumococcal, TB, cryptococcal), syphilis |
| Immune-mediated | Guillain-Barre, Borrelia, SLE, rheumatoid arthritis, sarcoid, Behcet's |
| Demyelination | Multiple sclerosis (VIII nerve or brainstem) |
| Neoplasia | Vestibular schwannoma, meningioma, CPA lesions, carcinomatosis |
| Metabolic/toxic | Uraemia, cisplatin, organic mercury, haemosiderosis, Paget's disease |
| Vascular | PICA syndrome, posterior fossa aneurysms, AV malformations, vascular loops |
- Scott-Brown's, pp. 2061-2083
Pathophysiology
Demyelination produces:
- Reduced membrane resistance and increased capacitance - action potential falls off rapidly
- Slowing of conduction velocity and widening of whole nerve action potential
- Impaired capacity to transmit high-frequency trains of impulses (explaining absent stapedius reflexes and loss of contralateral OAE suppression)
- Ephaptic transmission ("cross-talk") between adjacent nerve fibres - interferes with synchronous auditory signals needed for speech discrimination
- Temperature-sensitive hearing loss - increased sensitivity to temperature increases
Axonal neuropathy - no conduction delay but reduced nerve action potential amplitude; preferentially affects low frequencies (longest cochlear fibres extend to the apex).
In IHC disorders: scattered IHC loss reduces the number of active neural "information channels," degrading speech information reaching the brain, while individual neurons elsewhere can have relatively normal thresholds.
- Scott-Brown's, pp. 2211-2224
Diagnostic Criteria
The diagnosis requires simultaneous presence of:
Evidence of preneural (OHC) response to sound (at least one of):
- Normal OAEs (TEOAEs or DPOAEs)
- Normal cochlear microphonic (CM)
Evidence of abnormal neural synchrony:
- Absent or severely abnormal ABR
Supporting findings:
- Absent contralateral suppression of OAEs
- Absent middle ear muscle (stapedius) reflexes
Plus: Pure-tone thresholds ranging anywhere from normal to severely impaired
Key diagnostic feature: Absent stapedius reflexes in the presence of normal OAEs
- Scott-Brown's, p. 2689-2706 (Key Points box)
Key Audiological Findings
| Test | Finding in ANSD |
|---|---|
| Pure-tone audiometry | Variable - normal to severe/profound loss |
| OAEs (TEOAEs/DPOAEs) | Present (reflect intact OHCs) |
| Cochlear microphonics | Present; inverts polarity with condensation vs rarefaction clicks |
| ABR | Absent or severely abnormal |
| Stapedius reflexes | Absent |
| Contralateral OAE suppression | Absent |
| Speech discrimination | Markedly impaired out of proportion to pure-tone thresholds |
Cochlear Microphonic (CM) - Key Technical Point
When recording ABR with alternating polarity clicks, the CM is cancelled out. To detect CM, condensation and rarefaction polarity clicks must be tested separately - the waveform will completely invert between the two. This reversal confirms CM presence and thus intact OHC function.
Natural History
- Some children improve spontaneously, particularly those with hyperbilirubinaemia - one study found children with hyperbilirubinaemia were more likely to show ABR normalization
- About 1 in 5 ANSD patients show some threshold recovery adequate for speech/language development without amplification (Hospital for Sick Children, Toronto - 75 patients)
- Progressive ANSD occurs with age-related degeneration, noise, mitochondrial disease, genetic and autoimmune disorders
- OAEs may eventually disappear in some patients due to lack of trophic factors from the diseased auditory nerve
Differential Diagnosis
- Sharply sloping high-frequency SNHL of cochlear origin - OHC function will be lost at affected frequencies
- Distinction from brainstem neuropathy - in acoustic neuromas, only wave I of ABR is seen with following waves absent; in AN, ABR is absent or shows abnormal wave I
- Central auditory processing disorder (CAPD) - in CAPD, OAEs and stapedius reflexes are present; in ANSD, absent stapedius reflex and absent contralateral OAE suppression distinguish the two
Management
Newborn Hearing Screening - Important Implication
ANSD is missed by OAE-based screening alone (since OAEs pass). Only ABR (AABR) or diagnostic ABR will detect it. Any child with risk factors (NICU admission, prematurity, hyperbilirubinaemia, asphyxia) must have AABR testing.
Approach to Habilitation
Management must be individualized given the heterogeneity:
1. Early Language Intervention
- Children with auditory dyssynchrony lose the onsets of plosive consonants and transitions essential for speech intelligibility
- Phoneme-based language therapy - addresses auditory and visual communication
- Cued speech - hand shapes synchronized with mouth movement to supplement lip-reading; conveys English phonemes and grammar visually
- Total communication - combines spoken language with elements of sign language; recommended for prelingual children
2. Hearing Aids
- Benefit is variable - some benefit, some do not
- A speech-processing hearing aid with high-frequency emphasis to enhance consonants has been recommended
- Directional microphones and personal FM systems can improve signal-to-noise ratio
- Caution: hearing aids can cause permanent threshold shift (up to 20 dBHL) in some ANSD children; TEOAEs may deteriorate after hearing aid use
- If behavioral thresholds are normal, hearing aids are not indicated
- If behavioral responses are poor, hearing aids may be tried at conservative gain (avoid high-intensity amplification)
3. Cochlear Implantation (CI)
CI bypasses the IHC/synapse and directly electrically stimulates the auditory nerve, producing synchronous ABR even in peripheral nerve demyelination.
Evidence (recent systematic reviews and meta-analyses, 2023-2024):
- A 2023 systematic review (Raza et al.) examined indicators for CI in ANSD children [PMID: 37748323]
- A 2023 umbrella review (Jafari et al.) of CI outcomes in children with auditory neuropathy [PMID: 37647160]
- A 2024 meta-analysis (Bernardes et al.) on CI in ANSD children [PMID: 38016438]
- A 2024 updated systematic review (Sahwan et al.) on CI in ANSD [PMID: 37638998]
Predictors of poor CI outcome:
- Cochlear nerve hypoplasia on MRI
- Absent cochlear nerve - contraindication to CI
- Absent or atypical ECAPs (electrically evoked compound action potentials) during implantation
- Bilateral cochlear nerve deficiency - will not benefit from CI or hearing aids
Multidisciplinary team approach is essential for these complex patients.
- Scott-Brown's, pp. 3178-3310; Cummings, pp. 849-852; Scott-Brown's Vol 2 block1, p. 8241
Summary Table
| Feature | ANSD | Cochlear (SNHL) |
|---|---|---|
| OAEs | Present | Absent (at affected frequencies) |
| ABR | Absent/severely abnormal | Absent or present depending on severity |
| Cochlear microphonic | Present | Absent |
| Stapedius reflex | Absent | Usually present unless severe loss |
| Contralateral OAE suppression | Absent | Present |
| Speech discrimination | Disproportionately poor | Proportionate to PTA |
| Pure-tone thresholds | Variable (normal to profound) | Correlates with speech scores |
Current evidence note: Multiple systematic reviews and meta-analyses published 2023-2024 (PMIDs 37748323, 37647160, 38016438, 37638998) are refining CI candidacy criteria and outcomes in ANSD. Overall the evidence supports CI as highly beneficial for most children with ANSD, but predictors of poor outcome (absent cochlear nerve, absent ECAPs) must guide selection.
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