Special Considerations in Pediatric
Cochlear Implantation
Samuel P. Gubbels, MD, FACS
Assistant Professor
Director, UW Cochlear Implant Program
Department of Surgery – Otolaryngology
Waisman Center

• I have no financial relationships to disclose
• I will discuss a non-FDA approved indication for cochlear implantation

• 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

• 538 million worldwide with hearing loss 3
• Permanent hearing loss in 3 in 1000 newborns 5
– Most common birth defect
– 12,000 children per year in the US 6
• 31 million Americans with hearing loss 2
– 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 individual 1,4
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

• Early intervention leads to better developmental outcomes 1
• Progress at age-appropriate rates with appropriate intervention 2
• 92% of children with hearing loss have normal hearing parents 3
• Parents suspect hearing loss before physicians 4
1 Holt & Svirsky, (2008) Ear & Hearing 29(4):492-511
2 Geers et al., (2009) Journal of Deaf Education 14(3): 371-85
3 Mitchell and Karchmer, (2004) Sign Language Studies 4(2): 138-63
4 Harrison and Roush, (1996) Ear & Hearing 17(1): 55-62

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

• 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

• Audiological
• Medical - Otologist
• Radiological
• Pediatric patients
– Speech and language evaluation
– Educational assessment
– Social work consult with patient and parents

• Audiologists
• Surgeons
• Speech Pathologists
• Social Worker
• Educational Audiologist
• Program Coordinator
• Administrative
Assistants
• Multidisciplinary conference

• 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

• Unaided and aided audiogram
• Age appropriate aided speech perception assessment
– Sentence level tests in best aided conditions
• Auditory Brainstem Response (ABR, BAER)
• Auditory Steady State Response (ASSR)
• Otoacoustic emissions (OAE)
• Hearing aid trial period (at least 6 months in length)

• 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

• 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

• CT versus MRI?
– CT – Bone anatomy
– MRI – Soft tissue
• Congenital
• Auditory nerve
McClay et al., Arch Otol (2008);134(9):945-952

• 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

• CT versus MRI?
– CT – Bone anatomy
– MRI – Soft tissue
• Congenital
• Auditory nerve
• Cochlear malformation

• CT versus MRI?
– CT – Bone anatomy
– MRI – Soft tissue
• Congenital
• Auditory nerve
• Cochlear malformation
• Skull thickness
• Otomastoiditis
• Labyrinthitis ossificans

• Active otitis media
• Absent auditory nerve
• Relative
Contraindications
– Cochlear dysplasia
– Labyrinthitis ossificans
– Canal-wall down mastoidectomy
– Psychiatric disease
– Unrealistic expectations
– Neurofibromatosis Type 2

Antenna
Cochlear electrode
Ground electrode
Magnet
Receiver stimulator www.cochlearamericas.com

Magnet
Inductive Coil
Microphone
Speech Processor www.cochlearamericas.com

Cochlear Nucleus www.cochlearamericas.com
Advanced Bionics www.bionicear.com
Med-El www.medel.com

• 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

• General anesthesia
• Outpatient or overnight stay
• 1.5 - 2.5 hours
• Minimal hair shaving
• Operating microscope
• Facial nerve monitoring
• One month healing time

• Device failure
• Infection
• Disequilibrium
• Facial stimulation
• Facial weakness
• “Technological”
• CI-related risks generally less than 5%
– Major complications less than 1%

• 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

• Sound quality
• Batteries
• Usage
• Externals
• MRI
• Surgical implications

• 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 stimulation 1
• 3.5 years maximal brain plasticity
• >7 years plasticity greatly reduced
1 Sharma, Dorman, Spahr (2002), Ear & Hearing :23;532-39

• 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?

• 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
– 19-23 mo
– 24-36 mo
50%
25%
10%
**Infant Toddler Meaningful Auditory Integration
Scale

• Safety of cochlear implantation in patients demonstrated in multiple studies
– 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
• Audiological evaluation pitfalls
• Anesthetic considerations
• Surgical considerations
• Programming and rehabilitation challenges

• 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

• 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

• 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.

• Localization accuracy*
– 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**
• Subjective measures
– Improved speech in noise and localization
– Quality of life measures conflicting on advantage of bilateral CI*
• Especially children
*
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
*Summerfield QA et al. Int J Audiol 2006; 45 (Suppl
1):S99–S107.

• 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

• 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 http://depts.washington.edu/hearing/InnerEar
HairCellRegeneration.php
Scale bars: h - 20
μm; j - 2 μm
Gubbels et al., Nature (2008):455;537-541

– 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

• “Pro-hair cell gene”
• Necessary for inner ear hair cell formation
• Focal point of hair cell regeneration
• Forced expression of Atoh1
– Multiple in vitro 1,2 and animal models 3-6
1 Woods, C., Montcouquiol, M. & Kelley, M.W. Nat. Neurosci. 7, 1310–1318 (2004).
2 Zheng, J.L. & Gao,W.Q. Nat. Neurosci. 3, 580–586 (2000).
3 Gubbels, S.P., Woessner, D.W., Mitchell, J.C., Ricci, A.J. & Brigande, J.V. Nature
455, 537–541 (2008).
4 Kawamoto., Ishimoto, S.,Minoda, R., Brough, D.E. & Raphael, Y. J. Neurosci. 23,
4395–4400 (2003).
5
6
Izumikawa, M. et al. Nat. Med. 11, 271–276 (2005).
Lumpkin, E.A. et al. Gene Expr. Patterns 3, 389–395 (2003).

P35 Whole
Mount
Scale bars: h,I
20 um; j,k 2 um
Atoh1 Generated Supernumerary
Bear Stereociliary Bundles
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

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

• Advantages
– Avoid cell-related concerns
– Avoid concerns with gene transfer
– Large number of compounds
• Disadvantages
– Toxicity
– Side effects
– Duration of effect

– Gene transfer
• Cell cycle modulators
• Transcription factors
• Gene replacement
– Inner ear stem cells
– Cell transplantation
• 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

• 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

Chen W et al. Nature (2012) 490: 278-282

• Stem cells can generate hair cells in vitro
– Multiple types
– Rodent
– Functional
• Challenges in transplantation into the cochlea
– Access
– Engraftment, integration, functionality

• Houston – Children’s
Memorial Hermann
Hospital
• PI - Dr. Samer Fakhri
• Cord Blood
• Safety Study
• 10 Children
• 6wk-18 months
• “Post-Birth HL”
• IV infusion

• 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!

• 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

• 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
• 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.

• 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