Transcript Gubbels - Waisman Center

Special Considerations in Pediatric
Cochlear Implantation
Samuel P. Gubbels, MD, FACS
Assistant Professor
Director, UW Cochlear Implant Program
Department of Surgery – Otolaryngology
Waisman Center
Conflict of Interest
• I have no financial relationships to disclose
• I will discuss a non-FDA approved indication
for cochlear implantation
Topics
• Hearing loss in children
• CI evaluation in children
• Timing for cochlear
implantation
• One or two ears?
• Predicting outcomes in
children
• Regenerative therapies
– Significance for
children today
www.bcm.edu
Hearing Loss
• 538 million worldwide with hearing loss3
• Permanent hearing loss in 3 in 1000 newborns5
– Most common birth defect
– 12,000 children per year in the US6
• 31 million Americans with hearing loss2
– 10.5% of population
– 14% of baby boomers (48-66 yo)
– 7% of Generation X (33-48 yo)
• $297,000 to $1,000,000 lifetime cost per individual1,4
1Mohr (2000) Int. j. technol. assess. health care 16:1120-1135
2Kochin (2005)Hearing Review 12(7): 16-29
3Stevens et al., Eur J Public Health (2011) Epub
4 Johnson et al., (1993) Seminar in Hearing 14(1):105-119
5 Ross et al., (2008) Trends in Amplification 1291): 27
6 White (1997)Workshophttp://www.infanthearing.org/resources/fact.pdf
Hearing Loss in Children
• Early intervention leads to better
developmental outcomes1
• Progress at age-appropriate rates with
appropriate intervention2
• 92% of children with hearing loss have normal
hearing parents3
• Parents suspect hearing loss before
physicians4
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Holt & Svirsky, (2008) Ear & Hearing 29(4):492-511
Geers et al., (2009) Journal of Deaf Education 14(3): 371-85
Mitchell and Karchmer, (2004) Sign Language Studies 4(2): 138-63
Harrison and Roush, (1996) Ear & Hearing 17(1): 55-62
Causes of Hearing Loss in Children
Figure 3 Environmental and genetic contributions to total congenital SNHL
Richard JH Smith , James F Bale Jr , Karl R White
Sensorineural hearing loss in children
The Lancet Volume 365, Issue 9462 2005 879 - 890
http://dx.doi.org/10.1016/S0140-6736(05)71047-3
Presentation of HL in children
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Failed newborn hearing screening test
Head turning to sound in infants
Family history of congenital hearing loss
Failed hearing screening tests
Delayed speech and language development
Cochlear Implant Evaluation
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Audiological
Medical - Otologist
Radiological
Pediatric patients
– Speech and language evaluation
– Educational assessment
– Social work consult with patient and
parents
UW CI Program
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Audiologists
Surgeons
Speech Pathologists
Social Worker
Educational Audiologist
Program Coordinator
Administrative
Assistants
• Multidisciplinary
conference
Cochlear Implant Indications
• Bilateral severe to profound sensorineural HL
– FDA - 12 months old minimum
– Speech discrimination score < 40%*
• Sentence level material in best-aided condition
• Inability to benefit from hearing aids in 6
month trial
• No medical, behavioral or radiological
contraindications
* Varies depending on insurance status
Cochlear Implant Audiological
Assessment
• Unaided and aided audiogram
• Age appropriate aided speech perception
assessment
– Sentence level tests in best aided conditions
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Auditory Brainstem Response (ABR, BAER)
Auditory Steady State Response (ASSR)
Otoacoustic emissions (OAE)
Hearing aid trial period (at least 6 months in
length)
Pediatric Audiological Assessment
• Behavioral Observation Audiometry
– Birth to 6 months old
• Visual Reinforced Audiometry
– 7 months to 2.5/3 years old
• Conditioned Play Audiometry
– 3-7 years old
• Speech Testing
Candidacy – Parental Factors
• Appropriate expectations
• Enrollment educational and rehabilitation programs
– Development of auditory and verbal skills
• Able to bring child to regularly scheduled training,
mapping and follow-up sessions
• Motivation to function within community that
depends on spoken communication
CI Radiological Evaluation
• CT versus MRI?
– CT – Bone anatomy
– MRI – Soft tissue
• Congenital
• Auditory nerve
McClay et al., Arch Otol (2008);134(9):945-952
Auditory Neuropathy
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Sound transmission to the brain in impaired
Sound enters the ear normally
Poor speech perception abilities
Disease of the auditory nerve
Cause is unclear
– Gene mutation present in some (Otoferlin)
• Debate on role of cochlear implantation
versus hearing aid usage
www.health.state.mn.us
CI Radiological Evaluation
• CT versus MRI?
– CT – Bone anatomy
– MRI – Soft tissue
• Congenital
• Auditory nerve
• Cochlear malformation
CI Radiological Evaluation
• CT versus MRI?
– CT – Bone anatomy
– MRI – Soft tissue
• Congenital
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Auditory nerve
Cochlear malformation
Skull thickness
Otomastoiditis
Labyrinthitis ossificans
Contraindications to CI
• Active otitis media
• Absent auditory
nerve
• Relative
Contraindications
– Cochlear dysplasia
– Labyrinthitis ossificans
– Canal-wall down
mastoidectomy
– Psychiatric disease
– Unrealistic expectations
– Neurofibromatosis Type 2
CI Components – Internal Device
Antenna
Magnet
Cochlear electrode
Receiver stimulator
Ground electrode
www.cochlearamericas.com
CI Components – External Device
Magnet
Inductive Coil
Microphone
Speech Processor
www.cochlearamericas.com
Current Devices in Use
Cochlear Nucleus
www.cochlearamericas.com
Advanced Bionics
www.bionicear.com
Med-El
www.medel.com
Immunization for Pediatric
Cochlear Implantees
• Pneumonia (Streptococcus pneumoniae) vaccination
– Routine immunization for all children
– Additional vaccinations may be needed for cochlear implantees
• Meningococcal and Haemophilus vaccinations as otherwise
recommended
• UW Cochlear Implant Program
– Communicates recommendations with family and assists in
coordination of vaccination with pediatrician
http://www.cdc.gov/vaccines/vpdvac/mening/cochlear/dis-cochlear-gen.htm
CI Surgery
• General anesthesia
• Outpatient or overnight
stay
• 1.5 - 2.5 hours
• Minimal hair shaving
• Operating microscope
• Facial nerve monitoring
• One month healing time
Risks of CI Surgery
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Device failure
Infection
Disequilibrium
Facial stimulation
Facial weakness
“Technological”
• CI-related risks
generally less than 5%
– Major complications less
than 1%
How Well does a CI Work?
• Significant improvement in
open set speech
recognition
• Improved quality of life
across multiple age groups*
– Quality of life assays
validated for hearing loss
• >219,000 worldwide
• Variability exists
*Vermeire (2005) Otol
Neurotol 26:188-195
Life with a Cochlear Implant
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Sound quality
Batteries
Usage
Externals
MRI
Surgical implications
When to Implant?
• 1 year old minimum – per FDA
• Implantation in younger patients safe
– Pediatric team, surgical considerations
• Developmental window for speech and
language acquisition
– In absence of normal stimulation1
• 3.5 years maximal brain plasticity
• >7 years plasticity greatly reduced
1Sharma,
Dorman, Spahr (2002), Ear & Hearing:23;532-39
Cochlear Implantation in Infants
• FDA Age
requirements
– 1970 - Profound HL in
adults
– 1980 – Children age 2
years
– 1990 – Children age
18 months
– 1998 – Children age
12 months to adult
• Is there additional
benefit to earlier
implantation (<1
year)?
– Do the benefits
outweigh the risks of
surgery in very young
patients?
Early Implantation
• Connor et al. (2006)
– ”Growth burst” after
CI*
– Lost after 7 y for
consonant production
– Lost after 3.5y for
vocabulary
-*Controlled for years of
device usage
• Robbins et al. (2004)– Percentages of
children achieving
communication levels
equal to normal
hearing
counterparts**
– 12-18 mo
50%
– 19-23 mo
25%
– 24-36 mo
10%
**Infant Toddler Meaningful Auditory Integration
Scale
Cochlear Implantation in Infants
• Safety of cochlear implantation in patients
demonstrated in multiple studies
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Roland et al. (2010) – 50 children, 5-11 mo
Valencia et al. (2008) – 15 pts, 6-11 mo
Roland et al. (2005) – 18 pts, 6-11 mo
Coletti et al. (2005) – 10 pts, 4-11 mo
• All studies emphasize importance of experienced
pediatric care providers
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Audiological evaluation pitfalls
Anesthetic considerations
Surgical considerations
Programming and rehabilitation challenges
Early Implantation Summary
• Improved receptive and language
development when implanted before 1 year
• More likely to achieve potential and reduce
need for “catch up” period
– Auditory perception
– Linguistic development
• Risk to benefit ratio favorable under
appropriate conditions
Cosetti & Roland (2010) Trends in Amplification 14(1):46-57
Bilateral Cochlear Implantation
• Pro
– Speech
– Localization
– Better ear always
implanted
– Continued stimulation
if one device fails,
infected
• Cons
– Surgical considerations
– Vestibular deficit
• Risk appears acceptable
– Preserving ear for future
regenerative strategies
• Hybrid Implant
– Cost
– Healthcare resource
distribution
Advantages of Bilateral Cochlear
Implantation
• Speech intelligibility
– Advantage in noise
more than quiet
– Adults –
• 56% improvement in
speech intelligibility in
noise
• 21-28% receptive
improvement in noise
– Children
• Sequentially
implanted children
21% speech
improvement in noise
• Postlingually deaf
• Prelingually deaf*
– *Intelligibility
advantage does not
require prior binaural
experience
*Litovsky RY et al. Int J Audiol 2006; 45 (Suppl 1):S78–S91.
Advantages of Bilateral Cochlear
Implantation
• Localization accuracy*
• Subjective measures
– Unilateral CI 50-67°
– Bilateral CI 24-30°
– 70% of bilateral <20°
• Children**
• Adults 1-2 mo after
second implant
• Children 1-2 years after
second implant**
*Verschuur CAet al. Auditory localization abilities
in bilateral cochlear implant recipients. Otol Neurotol 2005; 26:965–
971.
** Litovsky et al. Ear Hear (2006) 27(1):43-59
– Improved speech in noise
and localization
– Quality of life measures
conflicting on advantage
of bilateral CI*
• Especially children
*Summerfield QA et al. Int J Audiol 2006; 45 (Suppl
1):S99–S107.
Predicting CI Outcomes
• Predictive factors…
– Duration of deafness
• Most important factor
– Cause of hearing loss
– Age when deafness occurred
– Prior speech and language skills
– Consistent usage of the device
– Age at implantation
Language Outcomes
• Individual outcomes challenging to predict
• General findings
– Earlier age associated with better outcomes
– Children with CI outperform those with hearing aids
– Some children acquire language at a rate similar to
normal-hearing children
– Wide range of benefit observed
– Many children with CI achieve literacy skills
approaching those of peers
• Variability exists
Ganek, Robbins & Niparko (2012) Oto Clinics of N. America 45:173-85
Regenerative Therapies for Hearing Loss
• Inner Ear Hair cell loss
– Approx. 80% of cases
• Nerve degeneration
follows
Scale bars: h - 20
μm; j - 2 μm
http://depts.washington.edu/hearing/InnerEar
HairCellRegeneration.php
Gubbels et al., Nature (2008):455;537-541
Hair Cell Regeneration
– Gene transfer
• Cell cycle modulators
• Transcription factors
• Gene replacement
– Inner ear stem cells
– Cell transplantation
• Stem Cells
Gubbels et al., Nature (2008):455;537-541
Mouse Atonal Homologue 1 (Atoh1)
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“Pro-hair cell gene”
Necessary for inner ear hair cell formation
Focal point of hair cell regeneration
Forced expression of Atoh1
– Multiple in vitro1,2 and animal models3-6
1Woods,
C., Montcouquiol, M. & Kelley, M.W. Nat. Neurosci. 7, 1310–1318 (2004).
2Zheng, J.L. & Gao,W.Q. Nat. Neurosci. 3, 580–586 (2000).
3Gubbels, S.P., Woessner, D.W., Mitchell, J.C., Ricci, A.J. & Brigande, J.V. Nature
455, 537–541 (2008).
4Kawamoto., Ishimoto, S.,Minoda, R., Brough, D.E. & Raphael, Y. J. Neurosci. 23,
4395–4400 (2003).
5 Izumikawa, M. et al. Nat. Med. 11, 271–276 (2005).
6Lumpkin, E.A. et al. Gene Expr. Patterns 3, 389–395 (2003).
Atoh1 Generated Supernumerary
Bear Stereociliary Bundles
P35 Whole
Mount
Scale bars: h,I
20 um; j,k 2 um
Gubbels et al., Nature (2008):455;537-541
Innervation of Atoh1 Generated Hair Cells
Scale bars: 10 um
Gubbels et al., Nature (2008):455;537-541
Atoh1 Generated Hair Cells are
Functional
Gubbels et al., Nature (2008):455;537-541
Akil O et al., Neuron (2012) 75:283-293
Gene Transfer for Hair Cell Regeneration
• Evidence
– Functional auditory hair
cells using Atoh1 gene
transfer in vivo
– Improvements in ABR
thresholds of deafened
guinea pigs
• Challenges
– Cochlear access
• Damage
– Viral delivery
• Safety
• Distribution
– Patterning
• Ectopic locations
• Effect on hearing
Mizutari K et al., Neuron (2012) 77:58-69
Pharmacothereutic approaches
• Advantages
– Avoid cell-related
concerns
– Avoid concerns with
gene transfer
– Large number of
compounds
• Disadvantages
– Toxicity
– Side effects
– Duration of effect
Hair Cell Regeneration
– Gene transfer
• Cell cycle modulators
• Transcription factors
• Gene replacement
– Inner ear stem cells
– Cell transplantation
• Stem Cells
Why use pluripotent stem cells?
• Availability
– Approved banks in existence
• Consistent and well-defined supply
• Malleable  Pluripotency
• Self-renewing
Mouse Embryonic Stem Cells Generate Hair Cell – like
Cells
Oshima K. et al., Cell (2010); 141(4): 704-716
Mouse Embryonic Stem Cells Generate Hair Cell – like
Cells
Oshima K. et al., Cell (2010); 141(4): 704-716
Hair Cells from Human Pluripotent
Stem Cells
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No reports to date
Ongoing work in many laboratories
Embryonic stem cells
Induced pluripotent stem cells
– Avoid the ethical debate
Neural Differentiation Paradigm
Cells:
- Human H9 Embryonic Stem Cells (ESC)
- Human IMR90-4 Induced Pluripotent Stem Cells (iPSC)
Pankratz TM, Zhang SC et al., Stem Cells (2007):25(6):1511-20
Hu BY, Weick JP et al., PNAS (2010):107(9):4335-40
Otic Gene Expression – H9 ESC Neural
Differentiation
Co-Expression of Otic Markers
Chen W et al. Nature (2012) 490: 278-282
Stem Cells as a Novel Therapy
for Hearing Loss
• Stem cells can generate hair cells in vitro
– Multiple types
– Rodent
– Functional
• Challenges in transplantation into the cochlea
– Access
– Engraftment, integration, functionality
Stem Cell Clinical Trial
• Houston – Children’s
Memorial Hermann
Hospital
• PI - Dr. Samer Fakhri
• Cord Blood
• Safety Study
• 10 Children
• 6wk-18 months
• “Post-Birth HL”
• IV infusion
Regenerative Therapies for HL
• When?
– Remains unclear
• How?
– Gene transfer, stem cells, pharmaceuticals
– Intravenous, Injections into middle/inner ear
– Delivered by a cochlear implant electrode
• Where?
– Hopefully at UW-Madison!
Current Relevance -Should my infant
have cochlear implants on both sides?
• Candidacy for future
regenerative therapies
– Electrode trauma
– Lifetime of ongoing
research in regenerative
therapies
• Benefits of CI clear
– Bilateral
• Cellular degeneration
over time
– Organ of Corti
– Auditory nerve
– Central networks
Summary
• Special considerations in children
– Candidacy assessment
– Multidisciplinary team critical
• Advancements in CI in children
– Early implantation
– Bilateral implantation
• Active investigations into novel therapies for hearing
loss
• Regenerative therapies factoring into current clinical
decision making
Acknowledgements
• Department of Surgery
– Otolaryngology
• Waisman Center
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Parul Trivedi
Cynthia Chow
Megan Duffey
SuChun Zhang
Funding
– NIH/NIDCD
• 1 R03 DC012432-01
– Institute for Clinical and
Translational Research*
• Type I Pilot
• KL2
– Department of Surgery
*The project described was supported by P30 HD003352 and the
Clinical and Translational Science Award (CTSA) program, previously
through the National Center for Research Resources (NCRR) grant
1UL1RR025011, and now by the National Center for Advancing
Translational Sciences (NCATS), grant 9U54TR000021.
Thank You!
Immunization for Pediatric
Cochlear Implantees
• Routine PCV13 vaccination
• Age 2-5 years - PCV13 X 2 if they have not received any PCV7
or PCV13 previously
– If four-dose PCV7 series completed then one dose of
PCV13 through age 71 months.
• Age 6-18 years - PCV13 X 1, regardless of previous PCV7 or
pneumococcal polysaccharide vaccine (PPSV) (Pneumovax®)
• One dose of PPSV at age 2 or older, and after completing all
recommended doses of PCV13
• Meningococcal and Haemophilus vaccinations as otherwise
recommended
http://www.cdc.gov/vaccines/vpdvac/mening/cochlear/dis-cochlear-gen.htm