The Pathophysiology of Auditory Neuropathy Spectrum Disorders…for Dr. Jie Wang Beijing Symposium Sept 2011

Charles I. Berlin PhD Research Professor Otolaryngology Head and Neck Surgery University of South Florida and Clinical Coordinator of the All Childrens Hospital Center for Auditory Neuropathy Spectrum Disorders, St. Petersburg FLCharles.Berlin@allkids.org

All slides and teaching material will be posted online at:

•www.kresgelab.com

How different is Auditory Neuropathy/Dys-synchrony from “regular hearing loss”?

• What do they sound like? (Simulations of filtered speech from Berlin, CI, Ed. Hair Cells and Hearing Aids, Singular Press, 1996 and The Auditory Tour, U of Wisconsin http://www.neurophys.wisc.edu/ftp/pub/aud-tour/windows/index.html; and F. G. Zeng et al. http://www.ucihs.uci.edu/com/hesp/newversion/procSim/simulations.htm.)

• What are the underlying physiologic differences?• How is it diagnosed and what difference does it make…

shouldn’t we still rely on the audiogram to provide guidelines for treatment and management? Anectdotal Evidence says the audiogram can be very misleding.

A brief review of how the diagnosis of AN/AD is made?• Absent or abnormal ABR or Electrocochleography. • Normal, or at one time normal, otoacoustic emissions, in the

presence of…• ABSENT or Elevated Middle Ear Muscle Reflexes.• Other signs…

Using physiology to IDENTIFY patients with auditory dys-synchrony/neuropathy

• Our first patient was thought to have a peripheral (cochlear) hearing loss after a space-occupying lesion was ruled out.

• History:• Female, 47 years old• Hearing loss first documented at 11 years, possibly

congenital• Problems understanding many words and hearing in

background noise

Pure-Tone Audiogram

Middle Ear MeasuresMiddle Ear Measures

• Tympanograms

• Ipsilateral reflexes

• Contralateral reflexes

• Non-acoustic reflexes

• Normal

• Absent

• Absent

• Present

Speech AudiometrySpeech Audiometry

• Word recognition in quiet:• Right ear: 12% at 85 dB HL• Left ear: 20% at 80 dB HL

• Word and sentence recognition in noise: 0% at signal-noise ratio of +10 dB

Auditory Brainstem Auditory Brainstem ResponseResponse

• No synchronous neural discharge

• Cochlear microphonic present and reversed with polarity reversals

Masking Level DifferenceMasking Level Difference (MLD)(MLD)

• No masking level differences at 250 or 500 No masking level differences at 250 or 500 Hz.Hz.

• Normal MLDs for these stimuli are 10-12 Normal MLDs for these stimuli are 10-12 dB.dB.

• MLDs take advantage of the ability to MLDs take advantage of the ability to process phase differences at the level of process phase differences at the level of the brainstem and are sensitive to auditory the brainstem and are sensitive to auditory nerve and lower brainstem problems.nerve and lower brainstem problems.

RadiologyRadiology

CT Scan with contrast: – Normal internal auditory

canals

Magnetic Resonance Imaging:– No tumors at the

cerebellar pontine angle– No intracranial neoplasm

Initial Management Plan

• With negative results of radiology and an apparent cochlear disorder, trial of hearing aids was recommended.

• Low-frequency emphasis hearing aids were fit with an earmold that allowed natural use of HF information (in the range of her normal hearing).

• She tried the hearing aids for several weeks but reported no benefit.

• She used lipreading and occasional notes to communicate.

When OAEs arrived…

OAEs are normal suggesting normal outer hair cell function and helping to explain why hearing aids didn’t help.

Cochlear Hearing Loss Cochlear Hearing Loss (Patient MS)(Patient MS)

Auditory Neuropathy PatientAuditory Neuropathy Patient

To avoid missing these patients, or confusing them with CAPD patients, we recommend the following triage with each new patient as follows:

• Tympanometry• Middle Ear Muscle Reflexes• Otoacoustic Emissions.• See blank Chart …

Construct Desk Chart for Triage or sorting.

Test Normal Outer Hair Cell

Inner Hair cell/nerve fibers

Conductive

Tymps/Reflectance

A

Reflexes PRESENT 95 DB OR <

Emissions 6 dB S/N ormore

ABR Normal latency-intensity

Construct Desk Chart for Triage or sorting.

Test Normal Outer Hair Cell

Inner Hair cell/nerve fibers

Conductive

Tymps/Reflectance

a a B and c

Reflexes Normal levels

Elevated or absent

Absent or elevated

Emissions absent Present or one time present

Absent or reduced

ABR Normal untilthreshold

Absent desynchronized

Shifted to right

At present, how do we test outer vs. inner hair cells?• Outer Hair Cells can be tested

with two procedures:• 1. Otoacoustic Emissions.• 2. Cochlear microphonics

using insert earphones and reversing the polarity of the click at least once at the end of a completed average. (Berlin, Hood, et al. 1998)

• Inner Hair Cells can be tested with FIVE procedures:• EcochG• ABR (remember to separate

CM from AP). CLIP the TUBE to rule out induction artifacts !!

• Summating Potentials.• Cochlear Microphonics• MIDDLE EAR MUSCLE

REFLEXES. If these are absent or elevated above 95dB HL, in the presence of normal emissions, it warrants further careful investigation. (Berlin, Hood et al. 2005)

Insert versus supra-aural earphones

CM

neural components do not.

AN/AD patient - all CM, no neural response

ABR and Cochlear Microphonics (CM - electrical responses generated in part by the outer hair cells)

Normal ABR to condensation and rarefaction clicks; CM inverts -

A Normal ABR on the Left, a Potential Trap or Misdiagnosis of Central Brain Disorder on the Right

Reverse the Click Polarity and What Looked Like an ABR is Revealed as a Cochlear Microphonic

A review of the underlying physiology• The normal human ear in motion.• The paradox of the human threshold detection vs. the 65 dB

dynamic range of the inner hair cell.• Outer hair cell function vs. Inner Hair Cell Function (Spoendlin,

Brownell, Ruggero, Jont Allen)

HOW DO THE OUTER HAIR CELLS APPEAR TO OVERCOME THIS PARADOX?

Hair Cell in Action from Jonathan Lear Ashmore and/or Bogota Colombia Laboratory.

Displacement of the Chinchilla Basilar Membrane Relative to the Stapes Adapted from Ruggero in Berlin, 1996

Idealized Gain Function of a Hearing Aid Which Would Do Somewhat the Same Thing in the Intensity Domain and Whose Compression Knee Begins at 40 dB Input Adapted from Berlin, 1996

Siblings with AN/AD

• Tympanometry normal• Reflexes absent

• Emissions Present• ABR…• Management…

• Video of Patient before implantation.

• Video after cochlear implantation, done at the mother’s insistence…

ABR from subjects with “corner audiograms” and Otoferlin mutations affecting inner hair cells.

Temporal Bone of Premature, Amatuzzi et al. June 2001 Arch Otolaryngology

Temporal Bone of Premature, Courtesy of Mass. Eye and Ear Published in June 2001 Arch Otolaryngology

Normal nerve fiber count insidethe habenula perforata,

Temporal Bone of Premature, Courtesy of Mass. Eye and Ear Published in June 2001 Arch Otolaryngology

Note missing Inner Hair cell, Normal nerve fiber count insidethe habenula perforata,

Temporal Bone of Premature, Courtesy of Mass. Eye and Ear Published in June 2001 Arch Otolaryngology

Note missing Inner Hair cell, Normal nerve fiber count insidethe habenula perforata, and normal outer hair cells which would lead to and normal outer hair cells which would lead to normal emissions and NO ABRnormal emissions and NO ABR

A Normal ear; B selective OHC loss; C combined IHC andOHC loss; D–F complete IHC loss with scattered or no OHC loss.

From Amatuzzi. Liberman and Northrop JARO 2011

Alternatively, Starr et al. show this type of pathophysiology

Comparing a normal cochlea (right) to one with Auditory Neuropathy

From Starr et al. MPZ Gene paper

My patients are mostly adults,

Does this happen much in adults?See Brian CJ Moore and Chris Turner and their work on Dead Zones and see for example:Dead regions and noisiness of pure tones. Huss M, Moore BC.Int J Audiol. 2005 Oct;44(10):599-611.3 A clinical perspective on cochlear dead regions: intelligibility of speech and subjective hearing aid benefit. Preminger JE, Carpenter R, Ziegler CH.J Am Acad Audiol. 2005 Sep;16(8):600-13;

Patient who acquired AN/AD• History of normal hearing until she was beaten

unconscious by an abusive boyfriend• Claimed subsequently to be totally deaf to speech

and pure tones• Tympanometry normal• Emissions normal• Initially diagnosed from emissions alone as

“hysterical” or “malingering”• BUT Reflexes (done only by us) ABSENT

Rt Lt

Nr Nr

Nr Nr

SRT

Disc

Reflexes?:

Emissions?:

ABR?:

Movie of a patient I (CB) initially mis-diagnosed as having CAPD• ..\Teaching Material and papers\Ali's Film

AN/AD versus and central auditory processing disorders

Case Study

- Male, first seen at age 13 years

- Difficulty in school

- Doesn’t hear instructions

- Doesn’t pay attention

- Sometimes “off in own world”

- In regular classroom, “C student”

Audiogram and DPOAEs: First Test

DPOAE

Noise Level

Speech Audiometry

• Word recognition in quiet:• Right ear: 84% at 40 dB SL• Left ear: 8% at 40 dB SL, 48% at 60 dB HL

• Word and sentence recognition in noise: 0% at signal-noise ratio of +10 dB

Middle Ear Measures

• Tympanograms: Normal

• Ipsilateral reflexes: Absent

• Contralateral reflexes: Absent

• Non-acoustic reflexes: Present

Auditory Evoked Potentials

Cochlear microphonics

Audiogram and OAEs: Second Test

Radiological and neurological evaluations

• CT Scan with contrast and MRI:CT Scan with contrast and MRI: Normal

• Neurological evaluationNeurological evaluation – Dx of Charcot-Marie-Tooth syndrome

• A group of genetically determined polyneuropathies with distal muscle weakness, atrophy and sensory nerve involvement; demyelinating

• ManagementManagement– Lipreading, preferential seating, visual information,

note-taking service, real-time closed captioning,

AN/AD versus CAPD

• AN/AD:AN/AD:– Synchrony disorder, possible pre-neural site

• Inner hair cells, synapse, VIIIth nerve– ABR, MEMR absent– Cochlear implants beneficial

• Central APD:Central APD:– More diffuse in nature

• Peripheral neural synchrony usually normal (VIIIth n.)– ABR, MEMR usually normal or near normal– Cochlear implants not useful

AN/AD: Otoacoustic Emissions

Cochlear Hair Cell Loss

Phenotyping AN/AD: Variable Characteristics and Time Courses

• OnsetOnset– Congenital, later onset, acquired

• ProgressionProgression• Progressive worsening (loss of peripheral auditory integrity; component of other

progressive peripheral neuropathy)• Stays the same• Partial recovery of auditory ability (improved pure tones and sound awareness

despite continued dys-synchrony)

• Genetic patternsGenetic patterns• Dominant, recessive, non-syndromic, syndromic, mitochondrial

• Auditory sensitivity and ability to utilize speech informationAuditory sensitivity and ability to utilize speech information

Kresge Lab AN/AD Database• Total confirmed patients with AN/AD = 225

– Based on present OAEs and/or CM and absent/abnormal ABR

• Age– 0-24 months 67– 25-48 months 42– 4-6 years 36– 7-12 years 38– 13-18 years 5– 19-30 years 13– >30 years 16– Unknown 8

• 46% female; 54% male

Tests Results: Hair Cell Function

- Normal otoacoustic emissions (despite abnormal pure tone thresholds)

- Present cochlear microphonics

- - Absent middle ear muscle reflexesAbsent middle ear muscle reflexes- Absent auditory brainstem responses- Absent auditory brainstem responses- No suppression of otoacoustic emissions- No suppression of otoacoustic emissions- No masking level differences- No masking level differences- Variable audiograms- Variable audiograms- iNORDINATELY Poor speech recognition in noise- iNORDINATELY Poor speech recognition in noise

Most cases in the Australian and Brazilian literature are Inner Hair cell based

• Inner Hair Cell Based (Kirsty Gardner Berry and Prof WPR Gibson)• Temporal Bones Amatuzzi, Liberman and Northrop 2011.

Abnormal nerves seen on MRI (trans-IAM view)

Should be 4 separate nerves:1. Facial2. Superior Vestibular.3. Inferior Vestibular.4. Auditory. Sometimes only 1, 2 or 3 can be

seen because they haven’t developed properly.

Pattern of results for 5 Babies with a Compromised VIIIth nerve

Baby 1 - Right CI 2 - Right CI 3 - Right CI 4 - Left CI 5 - Right CI

Cochlear Mondini dysplasia Displastic basal turn, not dilineated.

Modiolus not demonstrated

Normal Normal

VIIIth nerve

VIIIth nerve hypoplastic/

absent

VIIIth nerve hypoplastic/ absent

VIIIth nerve hypoplastic/

absent

Absent Thin nerve

ECochG 8kHz

Pre-op TTEABR

ImpEABRMP1+2

Rt TT EABR

50µV

1

323

50µV

2

410

50µV

3

256

50µV

4

439

50µV

5

1024

Rt TT EABR

50µV

1

314

50µV

2

663

50µV

3

484

50µV

4

621

50µV

5

416

50µV

6

577

Rt TT EABR

20µV

1

306

20µV

2

327

20µV

3

332(5)

20µV

4

326(5)

20µV

5

377(9)

20µV

6

334(3)

20µV

7

399(12)

Lt TT EABR

50µV

1

1024(13)

50µV

2

946(15)

50µV

3

1024(18)

50µV

4

362(5)

Lt TT EABR

50µV

1

571

50µV

2

481

Misc Re MP1+2 Response MP1+2

Rt 8kHz ECochG

ECochG 100dB

10ms 10µV 70 dBnHL

1

128

ECochG 90dB

10ms 10µV 60 dBnHL

2

128

ECochG 80dB

10ms 10µV 50 dBnHL

3

128

ECochG 70dB

10ms 10µV 40 dBnHL

4

128

ECochG 60dB

10ms 10µV 30 dBnHL

5

128

Rt 8kHz ECochG

ECochG 110dB

10ms 20µV 80 dBnHL

1

31

ECochG 100dB

10ms 20µV 70 dBnHL

2

28

ECochG 90dB

10ms 20µV 60 dBnHL

3

36

ECochG 80dB

10ms 10µV 50 dBnHL

4

35ECochG 70dB

10ms 5µV 40 dBnHL

5

54

ECochG 60dB

10ms 1µV 30 dBnHL

6

64ECochG 50dB

10ms 2µV 20 dBnHL

7

64

Rt 8kHz ECochG

ECochG 110dB

10ms 2µV 80 dBnHL

1

128

Lt 8kHz ECochG

ECochG 110dB

10ms 2µV 80 dBnHL

1

256

ECochG 100dB

10ms 2µV 70 dBnHL

2

128

Lt 8kHz ECochG

ECochG 110dB

10ms 2µV 80 dBnHL

1

256

ECochG 100dB

10ms 2µV 70 dBnHL

2

128

Acknowledgements:

Drs. Linda J. Hood and Thierry Morlet for slides and data collection.Drs. Kirsty Gardner-Berry and Professor WPR Gibson and Halit Sanli For access to their data.Collaborators include Harriet Berlin, Li Li MD, and the staff of the LSUHSC Audiology and Otolaryngology Departments. Donors include the Marriott, Oberkotter and Hearing Research Foundations , NIDCD and BMDR-1549.Technical Assistance by Benjamin Russell Au.D. is especially appreciated,