Acta Neuropathologica

, Volume 122, Issue 6, pp 763–774 | Cite as

Inner ear lesions in congenital cytomegalovirus infection of human fetuses

  • Natacha Teissier
  • Anne-Lise Delezoide
  • Anne-Elisabeth Mas
  • Suonavy Khung-Savatovsky
  • Bettina Bessières
  • Jeannette Nardelli
  • Christelle Vauloup-Fellous
  • Olivier Picone
  • Nadira Houhou
  • Jean-François Oury
  • Thierry Van Den Abbeele
  • Pierre Gressens
  • Homa Adle-BiassetteEmail author
Original Paper


Congenital cytomegalovirus (CMV) infection is the leading cause of non-hereditary congenital sensorineural hearing loss (SNHL). The natural course and the pathophysiology of inner ear lesions during human fetal CMV infection have not yet been reported. Inner ear lesions were investigated in six CMV-infected fetuses aged 19–35 postconceptional weeks and correlated with central nervous system (CNS) lesions. All the fetuses had high viral loads in the amniotic fluid and severe visceral and CNS lesions visible by ultrasound. Diffuse lesions consisting of both cytomegalic cells containing inclusion bodies and inflammation were found within all studied structures including the inner ear, brain, other organs, and placenta, suggesting hematogenous dissemination. Cochlear infection was consistently present and predominated in the stria vascularis (5/6), whereas the supporting cells in the organ of Corti were less often involved (2/6). Vestibular infection, found in 4/6 cases, was florid; the non-sensory epithelia, including the dark cells, were extensively infected. The endolymphatic sac was infected in 1 of 3 cases. The severity of inner ear infection was correlated with the CNS lesions, confirming the neurotropism of CMV. This study documenting infection of the structures involved in endolymph secretion and potassium homeostasis in fetuses with high amniotic fluid viral loads suggests that potassium dysregulation in the endolymphatic compartment of the inner ear may lead to secondary degeneration of the sensory structures. In addition, the occurrence of SNHL depends on the intensity and duration of the viral infection and inflammation.


Congenital CMV infection Sensorineural hearing loss Potassium recycling Stria vascularis 



This work was supported by grants from the Inserm and University Paris Diderot-Paris 7. We thank Evelyne Ferrary for contributing her expertise in inner ear physiology. We also thank the technicians of the Department of Pathology and Department of Developmental Biology for their help.

Supplementary material

401_2011_895_MOESM1_ESM.tif (36.5 mb)
Supplementary Figure 1. a-d: Serial sections from case 5. a: Scala media of a cochlea displaying numerous cytomegalic cells with CMV inclusion bodies in the marginal cell layer of the stria vascularis and Reissner’s membrane (arrows) (HES). b: In situ hybridization on a serial section confirming the presence of CMV RNA in these cells. c: CK7 immunostaining showing that the infected cells are epithelial cells. d: CD8 infiltration of the stria vascularis with a few lymphocytes in Reissner’s membrane. Scale bars: 100 μ in a, c; 50 μ in d. (TIFF 37366 kb)
401_2011_895_MOESM2_ESM.tif (26.8 mb)
Supplementary Figure 2. Case 3: The non-sensory epithelial cells of the crista ampullaris expressed CK7; whereas the neurosensory epithelium delimitated by the two asterisks was not labeled. Transitory cells show focal CK7 staining on the left side, but are not infected. The infected dark cells were CK7-positive. Scale bars: 100 μ (TIFF 27419 kb)
401_2011_895_MOESM3_ESM.doc (48 kb)
Supplementary Data 1 (DOC 48 kb)


  1. 1.
    Bachor E, Sudhoff H, Litschel R, Karmody CS (2000) The pathology of the temporal bones of a child with acquired cytomegalovirus infection: studies by light microscopy, immunohistochemistry and polymerase-chain reaction. Int J Pediatr Otorhinolaryngol 55:215–224PubMedCrossRefGoogle Scholar
  2. 2.
    Beltramello M, Piazza V, Bukauskas FF, Pozzan T, Mammano F (2005) Impaired permeability to Ins(1, 4, 5)P3 in a mutant connexin underlies recessive hereditary deafness. Nat Cell Biol 7:63–69PubMedCrossRefGoogle Scholar
  3. 3.
    Boettger T, Hubner CA, Maier H, Rust MB, Beck FX, Jentsch TJ (2002) Deafness and renal tubular acidosis in mice lacking the K-Cl co-transporter Kcc4. Nature 416:874–878PubMedCrossRefGoogle Scholar
  4. 4.
    Cheeran MC, Lokensgard JR, Schleiss MR (2009) Neuropathogenesis of congenital cytomegalovirus infection: disease mechanisms and prospects for intervention. Clin Microbiol Rev 22:99–126 (Table of contents)PubMedCrossRefGoogle Scholar
  5. 5.
    Ciuman RR (2009) Stria vascularis and vestibular dark cells: characterisation of main structures responsible for inner-ear homeostasis, and their pathophysiological relations. J Laryngol Otol 123:151–162PubMedCrossRefGoogle Scholar
  6. 6.
    Davis GL (1969) Cytomegalovirus in the inner ear. Case report and electron microscopic study. Ann Otol Rhinol Laryngol 78:1179–1188PubMedGoogle Scholar
  7. 7.
    Davis GL, Spector GJ, Strauss M, Middlekamp JN (1977) Cytomegalovirus endolabyrinthitis. Arch Pathol Lab Med 101:118–121PubMedGoogle Scholar
  8. 8.
    Davis LE, Johnsson LG, Kornfeld M (1981) Cytomegalovirus labyrinthitis in an infant: morphological, virological, and immunofluorescent studies. J Neuropathol Exp Neurol 40:9–19PubMedGoogle Scholar
  9. 9.
    Davis LE, Rarey KE, Stewart JA, McLaren LC (1987) Recovery and probable persistence of cytomegalovirus in human inner ear fluid without cochlear damage. Ann Otol Rhinol Laryngol 96:380–383PubMedGoogle Scholar
  10. 10.
    Demmler GJ (1991) Infectious Diseases Society of America and Centers for Disease Control. Summary of a workshop on surveillance for congenital cytomegalovirus disease. Rev Infect Dis 13:315–329PubMedCrossRefGoogle Scholar
  11. 11.
    Eatock RA, Rusch A, Lysakowski A, Saeki M (1998) Hair cells in mammalian utricles. Otolaryngol Head Neck Surg 119:172–181PubMedCrossRefGoogle Scholar
  12. 12.
    Foulon I, Naessens A, Foulon W, Casteels A, Gordts F (2008) A 10-year prospective study of sensorineural hearing loss in children with congenital cytomegalovirus infection. J Pediatr 153:84–88PubMedCrossRefGoogle Scholar
  13. 13.
    Goegebuer T, Van Meensel B, Beuselinck K, Cossey V, Van Ranst M, Hanssens M, Lagrou K (2009) Clinical predictive value of real-time PCR quantification of human cytomegalovirus DNA in amniotic fluid samples. J Clin Microbiol 47:660–665PubMedCrossRefGoogle Scholar
  14. 14.
    Harari A, Zimmerli SC, Pantaleo G (2004) Cytomegalovirus (CMV)-specific cellular immune responses. Hum Immunol 65:500–506PubMedCrossRefGoogle Scholar
  15. 15.
    Katano H, Sato Y, Tsutsui Y, Sata T, Maeda A, Nozawa N, Inoue N, Nomura Y, Kurata T (2007) Pathogenesis of cytomegalovirus-associated labyrinthitis in a guinea pig model. Microbes Infect 9:183–191PubMedCrossRefGoogle Scholar
  16. 16.
    Lazzarotto T, Guerra B, Gabrielli L, Lanari M, Landini MP (2011) Update on the prevention, diagnosis and management of cytomegalovirus infection during pregnancy. Clin Microbiol Infect 17:1285–1293PubMedGoogle Scholar
  17. 17.
    Lazzarotto T, Varani S, Guerra B, Nicolosi A, Lanari M, Landini MP (2000) Prenatal indicators of congenital cytomegalovirus infection. J Pediatr 137:90–95PubMedCrossRefGoogle Scholar
  18. 18.
    Lee DJ, Lustig L, Sampson M, Chinnici J, Niparko JK (2005) Effects of cytomegalovirus (CMV) related deafness on pediatric cochlear implant outcomes. Otolaryngol Head Neck Surg 133:900–905PubMedCrossRefGoogle Scholar
  19. 19.
    Li L, Kosugi I, Han GP, Kawasaki H, Arai Y, Takeshita T, Tsutsui Y (2008) Induction of cytomegalovirus-infected labyrinthitis in newborn mice by lipopolysaccharide: a model for hearing loss in congenital CMV infection. Lab Invest 88:722–730PubMedCrossRefGoogle Scholar
  20. 20.
    Malinger G, Lev D, Zahalka N, Ben Aroia Z, Watemberg N, Kidron D, Sira LB, Lerman-Sagie T (2003) Fetal cytomegalovirus infection of the brain: the spectrum of sonographic findings. AJNR Am J Neuroradiol 24:28–32PubMedGoogle Scholar
  21. 21.
    Marcus DC, Shipley AM (1994) Potassium secretion by vestibular dark cell epithelium demonstrated by vibrating probe. Biophys J 66:1939–1942PubMedCrossRefGoogle Scholar
  22. 22.
    Myers EN, Stool S (1968) Cytomegalic inclusion disease of the inner ear. Laryngoscope 78:1904–1915PubMedCrossRefGoogle Scholar
  23. 23.
    Nyholm JL, Schleiss MR (2010) Prevention of maternal cytomegalovirus infection: current status and future prospects. Int J Womens Health 2:23–35PubMedGoogle Scholar
  24. 24.
    Park AH, Gifford T, Schleiss MR, Dahlstrom L, Chase S, McGill L, Li W, Alder SC (2010) Development of cytomegalovirus-mediated sensorineural hearing loss in a Guinea pig model. Arch Otolaryngol Head Neck Surg 136:48–53PubMedCrossRefGoogle Scholar
  25. 25.
    Pass RF (2005) Congenital cytomegalovirus infection and hearing loss. Herpes 12:50–55PubMedGoogle Scholar
  26. 26.
    Rarey KE, Davis LE (1993) Temporal bone histopathology 14 years after cytomegalic inclusion disease: a case study. Laryngoscope 103:904–909PubMedCrossRefGoogle Scholar
  27. 27.
    Ravassard P, Chatail F, Mallet J, Icard-Liepkalns C (1997) Relax, a novel rat bHLH transcriptional regulator transiently expressed in the ventricular proliferating zone of the developing central nervous system. J Neurosci Res 48:146–158PubMedCrossRefGoogle Scholar
  28. 28.
    Reuter JD, Gomez DL, Wilson JH, Van Den Pol AN (2004) Systemic immune deficiency necessary for cytomegalovirus invasion of the mature brain. J Virol 78:1473–1487PubMedCrossRefGoogle Scholar
  29. 29.
    Rivera LB, Boppana SB, Fowler KB, Britt WJ, Stagno S, Pass RF (2002) Predictors of hearing loss in children with symptomatic congenital cytomegalovirus infection. Pediatrics 110:762–767PubMedCrossRefGoogle Scholar
  30. 30.
    Royackers L, Christian D, Frans D, Ermelinde R (2011) Hearing status in children with congenital cytomegalovirus: up-to-6-years audiological follow-up. Int J Pediatr Otorhinolaryngol 75:376–382PubMedCrossRefGoogle Scholar
  31. 31.
    Stagno S, Pass RF, Cloud G, Britt WJ, Henderson RE, Walton PD, Veren DA, Page F, Alford CA (1986) Primary cytomegalovirus infection in pregnancy. Incidence, transmission to fetus, and clinical outcome. JAMA 256:1904–1908PubMedCrossRefGoogle Scholar
  32. 32.
    Stagno S, Reynolds DW, Amos CS, Dahle AJ, McCollister FP, Mohindra I, Ermocilla R, Alford CA (1977) Auditory and visual defects resulting from symptomatic and subclinical congenital cytomegaloviral and toxoplasma infections. Pediatrics 59:669–678PubMedGoogle Scholar
  33. 33.
    Strauss M, Davis GL, Spector GJ, Middlekamp JN (1985) A clinical pathologic study of hearing loss in congenital cytomegalovirus infection. Laryngoscope 95:951–962PubMedGoogle Scholar
  34. 34.
    Sugiura S, Yoshikawa T, Nishiyama Y, Morishita Y, Sato E, Hattori T, Nakashima T (2003) Detection of human cytomegalovirus DNA in perilymph of patients with sensorineural hearing loss using real-time PCR. J Med Virol 69:72–75PubMedCrossRefGoogle Scholar
  35. 35.
    Tang HJ, Liu YC, Yen MY, Chen YS, Wann SR, Lin HH, Lee SS, Lin WR, Huang CK, Su BA, Chang PC, Li CM, Tseng HH (2006) Opportunistic infections in adults with acquired immunodeficiency syndrome: a comparison of clinical and autopsy findings. J Microbiol Immunol Infect 39:310–315PubMedGoogle Scholar
  36. 36.
    Tsutsui Y (2009) Effects of cytomegalovirus infection on embryogenesis and brain development. Congenit Anom (Kyoto) 49:47–55CrossRefGoogle Scholar
  37. 37.
    Van der Knaap MS, Vermeulen G, Barkhof F, Hart AA, Loeber JG, Weel JF (2004) Pattern of white matter abnormalities at MR imaging: use of polymerase chain reaction testing of Guthrie cards to link pattern with congenital cytomegalovirus infection. Radiology 230:529–536PubMedCrossRefGoogle Scholar
  38. 38.
    Verney C, Alvarez C, Geffard M, Berger B (1990) Ultrastructural double-labeling study of dopamine terminals and GABA-containing neurons in rat anteromedial cerebral cortex. Eur J Neurosci 2:960–972PubMedCrossRefGoogle Scholar
  39. 39.
    Zagolski O (2008) Vestibular-evoked myogenic potentials and caloric stimulation in infants with congenital cytomegalovirus infection. J Laryngol Otol 122:574–579PubMedCrossRefGoogle Scholar
  40. 40.
    Zdebik AA, Wangemann P, Jentsch TJ (2009) Potassium ion movement in the inner ear: insights from genetic disease and mouse models. Physiology (Bethesda) 24:307–316CrossRefGoogle Scholar
  41. 41.
    Zhao HB, Kikuchi T, Ngezahayo A, White TW (2006) Gap junctions and cochlear homeostasis. J Membr Biol 209:177–186PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Natacha Teissier
    • 1
    • 2
  • Anne-Lise Delezoide
    • 3
    • 4
  • Anne-Elisabeth Mas
    • 5
  • Suonavy Khung-Savatovsky
    • 3
  • Bettina Bessières
    • 6
  • Jeannette Nardelli
    • 2
  • Christelle Vauloup-Fellous
    • 7
  • Olivier Picone
    • 8
  • Nadira Houhou
    • 9
  • Jean-François Oury
    • 4
    • 10
  • Thierry Van Den Abbeele
    • 1
    • 2
    • 4
  • Pierre Gressens
    • 2
    • 4
    • 11
  • Homa Adle-Biassette
    • 2
    • 4
    • 12
    • 13
    Email author
  1. 1.Pediatric ENT DepartmentRobert Debré Hospital, APHPParisFrance
  2. 2.Inserm UMR 676, Physiopathology and Neuroprotection of the developing brainRobert Debré HospitalParisFrance
  3. 3.Department of Developmental BiologyRobert Debré Hospital, APHPParisFrance
  4. 4.Faculté de Médecine Denis DiderotUniversité Paris 7ParisFrance
  5. 5.Department of PathologyBéclère Hospital, APHPClamartFrance
  6. 6.Department of Fetal PathologyInstitut de Puériculture de ParisParisFrance
  7. 7.Department of VirologyBéclère Hospital, APHPClamartFrance
  8. 8.Department of ObstetricsBéclère HospitalClamartFrance
  9. 9.Department of VirologyBichat-Claude Bernard Hospital, APHPParisFrance
  10. 10.Department of ObstetricsRobert Debré HospitalParisFrance
  11. 11.Department of Reproductive Biology IRDB, Perinatal Brain Injury GroupCentre for the Developing Brain, Imperial CollegeLondonUnited Kingdom
  12. 12.Department of PathologyLariboisière Hospital, APHPParisFrance
  13. 13.Homa Adle-Biassette Inserm U676Hôpital Robert DebréParisFrance

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