Auditory Neuropathy Spectrum Disorder Christina L. Runge PhD, CCC-A Chief, Division of Communication Sciences Director, Koss Program Department of Otolaryngology and Communication Sciences Medical College of Wisconsin, Milwaukee, WI

Acknowledgements NIH/NIDCD K23DC008837 Genotype-Phenotype Relationships in Auditory Neuropathy

Koss Cochlear Implant Program Department of Otolaryngology and Communication Sciences Medical College of Wisconsin Milwaukee, WI

Masters Family Speech and Hearing Center Children’s Hospital of Wisconsin Milwaukee, WI

Learning Objectives • Define the clinical audiologic findings necessary to diagnose ANSD • Be familiar with medical conditions requiring further evaluation due to a strong association with ANSD • Understand assessment and intervention option for children with ANSD

1 Multi-Disciplinary Program

ANSD Background

Nomenclature • Auditory neuropathy (AN) • Auditory dys-synchrony (AD) • Auditory neuropathy/dys-synchrony (AN/AD) • Auditory neuropathy spectrum disorder (ANSD)

2 Clinical Definition • Present outer hair cell function – Otoacoustic emissions (OAEs) – Cochlear microphonic (CM) • Dys-synchronous neural activity – Absent or abnormal ABR – Absent or elevated middle ear reflexes

Clinical Definition • Various audiometric configurations • Unusually poor speech perception – Particularly in noise • Temporal processing disorder

Speech Perception with ANSD • Temporal information is important for encoding speech – Low to mid frequencies • Temporal impairment and/or degraded signal (i.e., in noise) significantly impacts speech perception

3 Model of ANSD

Zeng et al., J. Neurophysiol 2005

Sensorineural

X X Unaided X X X X Aided

Adapted from: http://www.ucihs.uci.edu/hesp/Simulations/simulationsmain.htm

Auditory Neuropathy - Mild

X X Unaided X X X X Aided

Adapted from: http://www.ucihs.uci.edu/hesp/Simulations/simulationsmain.htm

4 Auditory Neuropathy - Severe

X X Unaided X X X X Aided

Adapted from: http://www.ucihs.uci.edu/hesp/Simulations/simulationsmain.htm

Diagnosis of ANSD

Newborn Hearing Screening • Newborn Hearing Screening – OAE screen will miss ANSD – ABR screening needed for babies in the NICU or with risk factors • Neonatal risk factors – Family history of ANSD – Anoxia – Hyperbilirubinemia – Premature birth – Exchange transfusion

5 Evoked Potentials • OAEs and/or CM – Outer hair cell function • ABR – Auditory nerve and brainstem function • Middle ear reflexes – Auditory reflex pathway function

Otoacoustic Emissions

• Transient-Evoked (TEOAEs) or Distortion Product (DPOAEs) • General criteria for present OAEs – Must be 4-6 dB above the noise floor – Must be reproducible – Must be present across multiple frequencies/octave bands • Present in approximately 75% with ANSD

Transient-evoked OAEs

6 Auditory Brainstem Response • Use ANSD protocol when ABR absent at high stimulus levels (80-90 dB HL) • Test parameters: – Insert earphones – Click stimuli at 80-90 dB HL – Record ABR to both condensation (+) and rarefaction (-) stimuli – Record ABR to alternating polarity (+,-) stimuli – Record with insert earphone tube pinched

Auditory Brainstem Response Present cochlear microphonic

Condensation and rarefaction recordings V / div) m

Absent neural response Alternating polarity recording Amplitude (0.1

0 2 4 6 8 10 Time (ms) *Do a condensation or rarefaction recording with pinched tube

ABR Interpretation • Cochlear microphonic – Initial peak latency ~0.4 ms – Persists for several milliseconds – 180° phase shift follows reversal in stimulus polarity • ABR – Observed when CM is cancelled out – Absent or abnormal morphology – Pinched tube recording should show no response

7 Middle Ear Muscle Reflexes • Absent if no reflex ≥ 110 dB HL • Elevated if reflex > 95 dB HL • Caution with interpretation in young infants – High frequency probe tones for MEMRs are not established in this population • MEMRs should be confirmed with ABR using the ANSD protocol

Imaging Considerations for ANSD

MRI Evaluation • Abnormalities found in 64% with ANSD – 18% have absent/deficient auditory nerve • Assess status of brain • Assess the status of the auditory nerve • Para-sagittal oblique reconstructions • CN VIII > CN VII (about twice as thick) – at level of brainstem

8 Nerves of the IAC

Facial nerve Superior vestibular nerve

Cochlear nerve Inferior vestibular nerve

Normal MRI

Abnormal MRI

9 PHACE Syndrome

•Infantile hemangiomas •Posterior fossa malformations •Aorta and cardiac defects •Eye abnormalities

Genetic Testing for ANSD

Candidate Genes

• Associated with ANSD: – OTOF, PJVK, SLC19A2 • Associated with SNHL and : – PMP22, MPZ, FXN • Screen for common GJB2 and GJB6

10 Mutations associated with ANSD • Otoferlin (OTOF) – OTOF is expressed in the inner hair cells – Affects calcium binding and vesicle docking

Pujol, 2007 Encyclopedia Britannica, 2004

Otoferlin Mutations • DFNB 9 Phenotype – Profound bilateral hearing loss • Fluctuating Hearing Phenotype – Temperature-sensitive – May be heterozygous for mutation

Temperature-Sensitive ANSD

• 14 year-old boy • Hx of hearing fluctuation – Illness/fever – Physical exercise/exertion – Exposure to warm temperatures • Otoferlin mutation – Allele 1: 2389 T>C – Allele 2: Wildtype

11 Temperature-Sensitive ANSD

Baseline (-6 mo) Fever w/ strep (0) After Illness (+16 d)

Charcot-Marie Tooth

• Peripheral neuropathy • Later manifestations: – Foot deformity (very high arch to feet) – Foot drop (inability to hold foot horizontal) – Loss of lower leg muscle, which leads to skinny calves – Numbness in the foot or leg – "Slapping" gait (feet hit the floor hard when walking) – Weakness of the hips, legs, or feet • No cure

Freidereich’s Ataxia

• Most common ataxia • Nervous system degeneration • Manifestations between 5-15 years old: – Difficulty walking – Muscle weakness – Speech problems – Involuntary eye movements – Scoliosis – Heart palpitations

12 Candidate Mutation Summary

Pheno Gene/Locus Mutation Codon Ex/Intr Pheno Gene/Locus Mutation Codon Ex/Intr Pheno Gene/Locus Mutation Codon Ex/Intr AN/AD OTOF 2p23 1469 C>A P490Q Ex15 AN/AD OTOF 2p23 1601delC Ex16 AN/AD MPZ 1q21.3-q23 434A>C Y145S Ex3 DFNB9 1544T>C I515T Ex15 updated cont'd 2239G>T Ex20 371C>T T124M Ex3 1651 delG Ex16 2649C>A Ex23 308G>A G74E Ex3 1886_1887 insA K629fs Ex17 2684.2685delGG Ex24 293G>C R98P Ex3 2122 C>T R708X Ex19 2732.2735dupAGCT Ex24 293G>A R98H Ex3 2348 delG G783fs Ex21 2891C>A Ex25 292C>T R98C Ex3 2381 G>A R794H Ex21 2905.2923 delinsCTCC… Ex25 290A>T E97V Ex3 2485C>T Q829X Ex22 3400C>T Ex28 242A>G H81R Ex3 3032 T>C L1011P Ex26 3413T>C Ex29 4275G>A W1425X Ex36 4227+1G>T Int35 SNHL PMP22 17p11.2 1.5 Mb dup/del 4491 T>A Y1497X Ex37 4351G>T Ex36 248G>C A67P Ex3 5473 C>G P1825A Ex44 4483C>T Ex37 G94(insG) 5860_5862delATC I1954de Ex48 5011dupT Ex41 6014 G>A R1939Q Ex48 5384T>G Ex44 SNHL FXN 9q GAA rep Int1 6158 C>G P1987R Ex48 5800dupC Ex46 709C>T R237X Ex8 HyperbilUGT1A1 2q37 A(TA)7TAA Promoter IVS 18+1 G>T In18 AN/AD PJVK 2q31.1-3 547C-T R183W Ex4 -3263T>G Promoter IVS 24+1 G>A In24 DFNB59 161C-T T541I Ex2 211G>A G71R Ex1 IVS 28-2 A>C In28 IVS 36+2T>G In36 AN/AD animalSLC19A2 1q23.3 515G>A G172D Ex2 Screen GJB2 35delG IVS39+1G>C In39 animal 724delC del242fs/X259 Ex2 M34T IVS 8-2 A>G In8 750G>A W250X Ex2 167delT Updated 765G>C Ex9 484C>T R162X Ex2 IVS+1G-A OTOF muts 1180dupG Ex13 515G>C G172R Ex2 235delC R-B 2008 1236delC Ex14 GJB6 GJB6-D13S1830

Intervention with ANSD: Hearing Aids and Cochlear Implantation

ANSD Audiometric Profile

3%

30% Normal Aidable 67% Profound

N=258 ears

Berlin et al., IntJAud 2010;49;30-43.

13 Hearing Aids • Fit as early as possible • Fit gain to the hearing loss – Ensure audibility – Do not try to ‘protect’ OAEs with mild -gain HAs • Should improve sound detection • Assess auditory skill progress • Assess speech and language development

Auditory Skill Assessment • Assessment intervals – Before HA fitting (baseline) – Every 3 months after HA fitting – At end of HA trial (if not on a 3-month interval) • LittlEARS: milestone assessment – Receptive auditory behavior (sound detection) – Semantic auditory behavior (comprehension) – Expressive-vocal behavior

LittlEARS • First 24 months of intervention • Standardized on normal hearing children • Track development trajectory – Identify plateaus – Intervention, therapy

14 Speech/Language Assessment • Assessment intervals – At 6 mo of age, or upon identification if older – Every 6 months after – Therapy sessions to become familiar with child • Follow longitudinally – Determine progress – Quantify delay (if present)

Cochlear Implant Candidacy • Is a child with ANSD a CI candidate?

– Profound hearing loss (30%) Yes (if all CI criteria are met) – Normal to severe loss (70%) Acoustic benefit? • Acoustic benefit – Progress in auditory and speech-language skills – Currently no strict criteria for determining implantation in ANSD

Cochlear Implantation • Restore neural synchrony – EABR, ECAP present • Outcomes often positive

Runge-Samuelson et al., 2007 – 85% successful (Berlin et al., 2010) • Potential contraindications to CI – Severe or central neuropathy (kernicterus, Freidereich’s Ataxia) – Absent auditory nerve

15 ANSD – Profound HL and CI 8K • 7 year-old girl 250 500 1K 2K 4K 8K -10 • Cystic fibrosis 0 10 20 • Failed NB screen (ABR) 30 40 • Diagnostic +OAEs, -ABR 50 60 70 • Minimal progress with HAs 80 90 X X • Otoferlin homozygous (Runge et al., 2013) 100 OX O 110 OO O • Cochlear Implant at 1.5 years 120 • 56% PBK words • 90%(Q), 90% (N) HINT-C Sentences

ANSD – Moderate HL and CI 8K • 10 year-old boy 250 500 1K 2K 4K 8K -10 • Hyperbilirubinemia, preemie 0 10 20 • 2 mos: +OAEs, -ABR 30 40 O • Hearing aids at 1 year 50 X X XO 60 O – Improved detection only 70 80 90 • Cochlear implant at 3 years 100 110 • 68% PBK words 120 • 94%(Q), 91% (N) HINT-C Sentences

ANSD – Moderate HL and HAs 8K

250 500 1K 2K 4K 8K

• 8 year-old boy -10 0 • Twin-to-twin transfusion 10 20 30 X OX O • 9 months +CM, -ABR 40 O X O 50 • Mild-moderate hearing loss 60 X 70 80 • Normal speech and language 90 100 development 110 Age 2 years 120 • 76% PBK words in quiet • Difficulty in noise

16 Can AN ‘reverse’? • Very rare • High-risk infants: premature, low birth weight, hyperbilirubinemia • Improvement emerging or complete by 7 - 12 months of age • Repeat ABR testing to ensure stability – Always before a cochlear implant

Summary • ANSD is a unique hearing disorder – Temporal impairment – Distinct from SNHL • Requires special tests and close follow up – Evidence-based protocol • Multi-disciplinary clinical care – Communication among professionals and parents • Research

17