Congenital Cytomegalovirus and Hearing Loss

1
Congenital Cytomegalovirus and Hearing Loss

• Dr Simone Walter
• SpR Audiological Medicine
• St Georges Hospital
• Simone.walter_at_stgeorges.nhs.uk
• Simone.walter_at_nhs.net

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CMV-Related SNHL

• Burden of Disease
• Diagnosis
• Pathogenesis
• Predictive factors
• Characteristics
• Management
• Prevention and Treatment
• Research
• Summary

Cytomegalovirus
3
CMV Definitions

• Congenital CMV
• CMV infection before birth, diagnosed on testing
  body fluids/tissue samples taken prior to Day 21
• May cause SNHL
• Perinatal CMV
• CMV infection acquired perinatally i.e acquired
  during or after birth (up to Day 28)
• Does not cause SNHL

4
Burden of Disease in the UK

• 1 in 200 births
• Major cause of neurodisability
• SNHL is the commonest sequel
• Proportion of Childhood SNHL due to CMV
• Retrospective studies 3 Das 1996
• But Prospective studies 12 Peckham 1987
• 75 not attributed to congenital CMV

5
Incidence of significant SNHL due to Congenital
CMV Copied from Pass 2005
108 children in England and Wales each year
Peckham1987
6
Why the discrepancy between retrospective and
prospective studies?
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Diagnosis of CMV-Related SNHL is difficult

• Asymptomatic at birth
• Samples need to be taken before Day 21
• Presentation is too late
• Negative IgG exclude CMV
• Positive serology congenital or
  perinatal/acquired
• Clues Hx of IUGR, rash at birth, motor delay,
  neurological deficit, microcephaly, white matter
  lesions brain MRI
• But SNHL may be the only finding

Arav-Boger 2002, Griffiths 2005, Lee 2005
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Differential diagnosis of isolated SNHL in a
healthy child
Symptomatic 1/3
Unknown ? Genetic
CMV
Asymptomatic 2/3
What proportion of these children have SNHL due
to CMV? How can we find out?
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Retrospective Diagnosis on Dried Blood Spots
(Guthrie cards)

• Quantitative Polymerase Chain Reaction (PCR) for
  CMV DNA
• Sensitivity
• 75 of confirmed cases
• 85 of those destined to develop disease (BPSU)
• Parental consent

Shibata 1994, Barbi 2000, guidelineshttp//www.ic
h.ucl.ac.uk/newborn/resources/policies.htm
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Diagnosis by Polymerase Chain Reaction (PCR) for
CMV DNA

• Barbi 2003
• 130 Guthrie cards unexplained SNHL
• Positive for
• 10 diagnosed age 0-2m
• 34.2 diagnosed in early childhood
• 42.7 with SNHLgt70dB
• 20-30 of SNHL due to CMV

• Also
• White matter lesions
• Cerebral palsy
• Developmental delay
• Blood, Urine, Amniotic fluid, Perilymph at
  Cochlear Implant
• van der Knaap 2004, Suigura 2004

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Pathogenesis

• Intracellular pathogen
• Cell damage and death
• T cell response
• Inflammation
• CMV Immune escape mechanisms
• Reactivation

Large CMV infected cells in the Organ of Corti,
Photograph courtesy of Professor Leslie Michaels
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Pathogenesis Unanswered Questions

• Host susceptibility
• Genetic factors
• Effect of timing of infection
• Mechanism of delayed onset and progression
• Site of lesion

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Possible Predictive Factors

• Disseminated disease
• IUGR, petechiae, hepatosplenomegaly
• Rivera 2002
• Increased Viral Load
• Boppana 2005

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Characteristics

• Any configuration on PTA
• Progressive-50
• Fluctuates-30
• High Frequency 20-30

Dahle 2000, Williamson 1992 Dahle 1979,
Fowler 1997
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Onset

• Delayed Onset in up to 50
• Mostly pre-lingual
• Over half will be missed by NHSP
• Also missed by risk-based screening
• Fowler 1999, Hicks 1993

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Cumulative Incidence

• Symptomatic Group Most occur by age 2y
• Asymptomatic Group
• Most occur by age 6y

Fowler 1999
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CMV and the Vestibular System

• Vestibular abnormalities in 6/11
• Hypofunction/arreflexia
• Unilateral/bilateral
• May be independent of SNHL
• 3 cases Delayed endolymphatic hydrops
• Motor delay
• Pappas 1983 Huygen 1996

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Management

• Risk of late-onset SNHL and of progression
• Unilaterals Risk to other ear
• Regular review till age 6y
• Early ref for CI
• Vision
• Motor delay
• Precautions

CMV Association http//mysite.freeserve.com/CMVsu
pport congenitalcmv.association_at_ntlworld.com
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Primary Prevention of CMV-related SNHL

• Vaccines are currently in trial
• Women of child bearing age
• Adolescents
• Patients awaiting solid organ transplantation

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Secondary Prevention of CMV-Related SNHL

• Antenatal screening
• Prenatal diagnosis
• Counselling
• Intravenous CMV hyperimmune globulin?
• Antiviral Rx in pregnancy?

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Treatment of Congenital CMV to prevent SNHL

• Ganciclovir preserves hearing in symptomatic
  neonates with CNS involvement
• Kimberlin 2003
• Offered to neonates with symptomatic congenital
  CMV with CNS involvement

Ganciclovir is IV
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Problems with Ganciclovir

• IV (via longline)
• Neutropenia
• Limited period of treatment
• Long term safety (and efficacy)?

Valganciclovir is oral
23
National Study of Symptomatic Congenital CMV
(BPSU)

• Incidence/disease burden/treatment
• Feb 2001-March 2003
• 54 confirmed and 26 possible cases
• In 11/51 cases maternal infection diagnosed
  prenatally U/S or flu illness
• 50 had CNS signs 8 given GCV
• 5 infants died

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CMV in Hearing Impaired Children (CHIC) Study

• What is the relationship between the CMV viral
  load on DBS and hearing thresholds?

?
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Future studies

• MRCT of Valganciclovir
• (Outcome hearing)
• Pilot screen /- NHSP
• Pathogenesis
• Predictive factors
• Site of lesion testing
• CAPD
• Role of OAEs
• CMV and the Vestibular System

Valganciclovir
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Neonatal Screening for Congenital CMV

• Aim to allow early identification of sequelae
  including SNHL
• Follow up those at risk
• Early amplification, rehabilitation (and possibly
  treatment)
• Practicalities
• Cost-benefit? Barbi 2006, Nance 2006, Pass 2005

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Summary CMV-related SNHL

• Accounts for 12-40 SNHL
• May be the only feature of cCMV
• Will be missed by the NHSP in 50
• Often progresses
• Can now be diagnosed by Guthrie PCR
• May be prevented by antiviral therapies and/or
  vaccine in the future

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What can we do?

• Consider CMV in children with unexplained SNHL
• (including unilateral SNHL)
• Try to exclude CMV
• Consider Guthrie testing when CMV urine or
  serology positive
• Monitor any children known to have congenital CMV
  for SNHL till age 6y at least
• Ophthalmological and Vestibular assessment
• Inform families about the CMV Association

Thank you very much for listening
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Acknowledgements

• Dr Mike Sharland, Supervisor, and Chief
  Investigator
• Professor Paul Griffiths, Virologist RFH
• Dr Ewa Raglan, Supervisor
• Claire Atkinson, Virologist RFH
• Dr Philip Rice, Virologist SGH
• Jan Poloniecki, Statistician, SGH
• Dr Deirdre Lucas, Local Principal Investigator ,
  RNTNEH
• Dr Tracey Davis, Local Principal Investigator,
  Northampton Gen Hospital
• Mr Kevin Gibbin, Local Principal Investigator,
  Queens Medical Centre
• Dr Jeff Baron and Julia Rider, Regional Infant
  Screening Service, ESH
• All participating families,Consultants, SpRs, and
  clinic/lab staff
• Keri Stephenson, Congenital CMV Association
• SGHSt Georges Hospital
• RFHRoyal Free Hospital
• ESHSt Helier Hospital
• RNTNEHRoyal National Throat Nose and Ear
  Hospital

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Congenital CMV information for families

• Congenital CMV Association
• Carmen Burton, 32 Grosvenor Street Derby DE24
  8AU, Tel [phone] congenitalcmv.association_at_n
  tlworld.com
• http//mysite.freeserve.com/CMVsupport
• http//www.astdhpphe.org/infect/cytomegalo.html

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References

• Das VK. 1996 Aetiology of bilateral sensorineural
  hearing impairment in children a 10 year study.
  Arch Dis Child. Jan74(1)8-12
• Peckham CS 1987, Stark O, Dudgeon JA, Martin JA,
  Hawkins G. Congenital cytomegalovirus infection
  a cause of sensorineural hearing loss. Arch Dis
  Child. Dec62(12)1233-7
• Harris S 1984, Ahlfors K, Ivarsson S, Lernmark B,
  Svanberg L. Congenital cytomegalovirus infection
  and sensorineural hearing loss. Ear Hear.
  Nov-Dec5(6)352-5
• Hicks T 1993, Fowler K, Richardson M, Dahle A,
  Adams L, Pass R Congenital cytomegalovirus
  infection and neonatal auditory screening. J
  Pediatr. Nov123(5)779-82.
• Arav-boger 2002 Pass RF Diagnosis and Management
  of Cytomegalovirus infection in the Newborn
  Paediatric annals Nov31,11 pg719-25

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References

• Griffiths PD 2005 Walter S Cytomegalovirus Curr
  Opin Infect Dis. Jun 18(3) 241-5
• Lee DJ 2005, Lustig L, Sampson M, Chinnici J,
  Niparko JK. Effects of cytomegalovirus (CMV)
  related deafness on pediatric cochlear implant
  outcomes.Otolaryngol Head Neck Surg
  Dec133(6)900-5. Shibata M 1994, Takano H,
  Hironaka T, Hirai K. Detection of human
  cytomegalovirus DNA in dried newborn blood filter
  paper. J Virol Methods. Feb46(2)279-85
• Barbi M 2000, Binda S, Primache V, Caroppo S,
  Dido P, Guidotti P, Corbetta C, Melotti D.
  Cytomegalovirus DNA detection in Guthrie cards a
  powerful tool for diagnosing congenital
  infection. J Clin Virol. Sep 117(3)159-65.
• Barbi M 2003, Binda S, Caroppo S, Ambrosetti U,
  Corbetta C, Sergi P A wider role for congenital
  cytomegalovirus infection in sensorineural
  hearing loss. Pediatr Infect Dis J.
  Jan22(1)39-42.
•  .

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References

• Dahle AJ (2000) Fowler KB, Wright JD, Boppana
  SB, Britt WJ, Pass RF Longitudinal Investigation
  of Hearing Disorders in Children with Congenital
  CMV. Journal of American Audiology 11 283-290
•   Fowler KB (1997) McCollister FP, Dahle AJ,
  Boppana S, Britt WJ, Pass RF. Progressive and
  fluctuating sensorineural hearing loss in
  children with asymptomatic congenital
  cytomegalovirus infection. J Pediatr 130(4)
  624-630
• Fowler KB (1999) Dahle AJ, Boppana SB, Pass RF.
  Newborn hearing screening will children with
  hearing loss caused by congenital cytomegalovirus
  infection be missed? J Pediatr 135(1) 60-64.
• Bradford RD (2005) Cloud G, Lakeman AD, Boppana
  S, Kimberlin DW,Jacobs R et al. Detection of
  cytomegalovirus (CMV) DNA by polymerase chain
  reaction is associated with hearing loss in
  newborns with symptomatic congenital CMV
  infection involving the central nervous system. J
  Infect Dis 191(2) 227-233.

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References

• Boppana S (2005) Congenital CMV infection
  Association between virus burden in infancy and
  hearing loss Journal of Pediatrics June p817-823
• Rivera LB (2002) Boppana SB, Fowler KB, Britt WJ,
  Stagno S, Pass RF. Predictors of hearing loss in
  children with symptomatic congenital
  cytomegalovirus infection. Pediatrics 110(4)
  762-767.
• Kimberlin DW (2003) Lin CY, Sanchez PJ, Demmler
  GJ, Dankner W, Shelton M et al. Effect of
  ganciclovir therapy on hearing in symptomatic
  congenital cytomegalovirus disease involving the
  central nervous system a randomized, controlled
  trial. J Pediatr 143(1) 16-25.

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References

• McCollister FP 1996, Simpson LC, Dahle AJ, Pass
  RF, Fowler KB, Amos CS, Boll TJ.Hearing loss and
  congenital symptomatic cytomegalovirus infection
  a case report of multidisciplinary longitudinal
  assessment and intervention. J Am Acad Audiol.
  1996 Apr7(2)57-62.
• Barbi M 2006 Binda S, Caroppo S, Primache V
  Neonatal screening for congenital cytomegalovirus
  infection and hearing loss. J Clin Virol. Feb
  35(2) 206-9. Epub 2005 Dec 27.
• J Nance WE 2006 Lim BG, Dodson KM Importance of
  congenital cytomegalovirus infections as a cause
  for pre-lingual hearing loss. Clin Virol.
  Feb35(2)221-5. Epub 2005 Dec 27.

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Cumulative of SNHL according to Age
Dahle 2000
37
Degree of SNHL
Dahle 2000
38
860 children with Congenital CMV
Dahle 2000
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Cochlear Implant in Congenital CMV

• High risk of progression and some risk to vision
• Additional difficulties
• Speech and language disorders
• Central auditory
• Learning disorders
• Developmental delay

Careful counselling tailored towards the
individual child. Benefit is seen in many. Lee
2005, Ramirez Inscoe 2004
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Vision in Congenital CMV

• Symptomatic
• 22 mod/sev VI
• Optic atrophy 37
• Macular scars 13
• Cortical VI 50
• Strabismus 29

• Asymptomatic
• 1 mild unilateral VI
• Macular scar
• 1.2 strabismus
• Coats 2000

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Information required to find the correct Guthrie
card

• Mothers address at the time of birth
• Mothers name
• All previous names for the baby
• DOB
• Birthweight
• Name of hospital if inpatient at Day 5-7
• Signed Informed consent