Download Runge - Auditory Neuropathy Spectrum Disorder

Auditory Neuropathy Spectrum
Disorder
Christina L. Runge PhD, CCC-A
Chief, Division of Communication Sciences
Director, Koss Cochlear Implant 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 Hearing Loss
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
Amplitude (0.1 mV / div)
Present cochlear microphonic
Condensation and rarefaction recordings
Absent neural response
0
2
4
6
Alternating polarity recording
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
Cochlear nerve
Superior vestibular
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 peripheral
neuropathy:
– 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
AN/AD OTOF 2p23 1469 C>A
DFNB9
1544T>C
1651 delG
1886_1887 insA
2122 C>T
2348 delG
2381 G>A
2485C>T
3032 T>C
4275G>A
4491 T>A
5473 C>G
5860_5862delATC
6014 G>A
6158 C>G
709C>T
IVS 18+1 G>T
IVS 24+1 G>A
IVS 28-2 A>C
IVS 36+2T>G
IVS39+1G>C
IVS 8-2 A>G
Updated
765G>C
OTOF muts 1180dupG
R-B 2008
1236delC
Codon
P490Q
I515T
K629fs
R708X
G783fs
R794H
Q829X
L1011P
W1425X
Y1497X
P1825A
I1954de
R1939Q
P1987R
R237X
Ex/Intr
Ex15
Ex15
Ex16
Ex17
Ex19
Ex21
Ex21
Ex22
Ex26
Ex36
Ex37
Ex44
Ex48
Ex48
Ex48
Ex8
In18
In24
In28
In36
In39
In8
Ex9
Ex13
Ex14
Pheno Gene/Locus
AN/AD OTOF 2p23
updated cont'd
AN/AD PJVK 2q31.1-3
DFNB59
Mutation
Codon
1601delC
2239G>T
2649C>A
2684.2685delGG
2732.2735dupAGCT
2891C>A
2905.2923delinsCTCC…
3400C>T
3413T>C
4227+1G>T
4351G>T
4483C>T
5011dupT
5384T>G
5800dupC
Ex/Intr
Ex16
Ex20
Ex23
Ex24
Ex24
Ex25
Ex25
Ex28
Ex29
Int35
Ex36
Ex37
Ex41
Ex44
Ex46
547C-T
161C-T
R183W
T541I
Ex4
Ex2
G172D
del242fs/X259
W250X
R162X
G172R
Ex2
Ex2
Ex2
Ex2
Ex2
AN/AD animal
SLC19A2 1q23.3 515G>A
724delC
750G>A
484C>T
515G>C
animal
Pheno Gene/Locus
Mutation
AN/AD MPZ 1q21.3-q23 434A>C
371C>T
308G>A
293G>C
293G>A
292C>T
290A>T
242A>G
Codon
Y145S
T124M
G74E
R98P
R98H
R98C
E97V
H81R
SNHL
PMP22 17p11.2 1.5 Mb dup/del
248G>C
A67P
G94(insG)
SNHL
FXN 9q
Ex/Intr
Ex3
Ex3
Ex3
Ex3
Ex3
Ex3
Ex3
Ex3
Ex3
GAA rep
Int1
HyperbilUGT1A1 2q37
A(TA)7TAA
-3263T>G
211G>A
G71R
Promoter
Promoter
Ex1
Screen GJB2
35delG
M34T
167delT
IVS+1G-A
235delC
GJB6-D13S1830
GJB6
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.
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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
– 85% successful (Berlin et al., 2010)
• Potential contraindications to CI
Runge-Samuelson et al., 2007
– Severe or central neuropathy (kernicterus,
Freidereich’s Ataxia)
– Absent auditory nerve
15
ANSD – Profound HL and CI
•
•
•
•
•
•
•
•
•
250 500
1K
2K
8K
4K
7 year-old girl
-10
0
Cystic fibrosis
10
20
Failed NB screen (ABR)
30
40
50
Diagnostic +OAEs, -ABR
60
70
Minimal progress with HAs
80
90
XX
Otoferlin homozygous (Runge et al., 2013) 100 O
X O O
O O
110
120
Cochlear Implant at 1.5 years
56% PBK words
90%(Q), 90% (N) HINT-C Sentences
ANSD – Moderate HL and CI
•
•
•
•
10 year-old boy
Hyperbilirubinemia, preemie
2 mos: +OAEs, -ABR
Hearing aids at 1 year
– Improved detection only
250 500
1K
2K
4K
8K
8K
8K
-10
0
10
20
30
40
50
60
70
80
90
100
110
120
O
X
X O
X
O
• Cochlear implant at 3 years
• 68% PBK words
• 94%(Q), 91% (N) HINT-C Sentences
ANSD – Moderate HL and HAs
250 500
•
•
•
•
•
8 year-old boy
Twin-to-twin transfusion
9 months +CM, -ABR
Mild-moderate hearing loss
Normal speech and language
development
• 76% PBK words in quiet
• Difficulty in noise
1K
2K
4K
8K
8K
-10
0
10
20
30
40
50
60
70
80
90
100
110
120
X O
X O
X O
O
X
Age 2 years
16
Can AN ‘reverse’?
• Very rare
• High-risk infants: premature, low birth
weight, hyperbilirubinemia
• Improvement emerging or complete by 712 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