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Viral Aetiology in Anterior Uveitis – The Tip of an Iceberg?

European Ophthalmic Review, 2012;6(2):119–24 DOI:


Identification of an infectious cause in intraocular inflammation is of crucial importance since their treatment and prognosis differ from non-infectious aetiologies. Herpes simplex and varicella-zoster viruses are well known causes of anterior uveitis. Furthermore, cytomegalovirus (CMV) and rubella virus (RV) are also detected in a significant number of patients. Despite their different aetiology, viral anterior uveitis may have similar features and often presents with unilateral diffuse, fine, stellate keratic precipitates, iris atrophy or ocular hypertension. Viruses are increasingly recognised as aetiology of anterior uveitis that has previously been referred as idiopathic. RV, for example, causes a distinct clinical spectrum of ocular signs and symptoms presenting as Fuch’s uveitis syndrome (FUS) in Europe, strongly suggesting a role in its pathogenesis. Interestingly, CMV may also be involved in the pathogenesis of both FUS and Posner–Schlossman syndrome in particular in the Asian population.
Keywords: Anterior uveitis, cytomegalovirus, Fuch’s uveitis syndrome, herpes simplex virus, Posner–Schlossman syndrome, rubella virus, varicella-zoster virus
Disclosure: The authors have no conflicts of interest to declare.
Received: December 16, 2011 Accepted: February 01, 2012
Correspondence: Dicle Hazirolan, Eryaman 2, Etap, Demire A1-1 Blok, No:54, Ankara, Turkey. E:

Intraocular viral infections have various presentations. They may be detected as anterior uveitis, intermediate uveitis, acute retinal necrosis (ARN), progressive outer retinal necrosis (PORN) and neuroretinitis (see Figure 1).1,2
Anterior uveitis (AU) in most patients is either idiopathic or associated with HLA-B27 positivity. However, a viral cause of AU is often underestimated. The most common viruses in the aetiology of viral AU (VAU) are herpes simplex virus (HSV), varicella-zoster virus (VZV), cytomegalovirus (CMV) and rubella virus (RV).1–3
Recently, the aetiology of some ‘idiopathic’ AU syndromes are proved to be viral. RV and CMV, for example, cause a distinct clinical spectrum of ocular symptoms presenting as Fuch’s Uveitis syndrome (FUS) which strongly suggest that they might be involved in the pathogenesis of FUS.4,5 Interestingly, CMV may also be involved in the pathogenesis of Posner-Schlossman syndrome (PSS).4,6
Diagnosis of VAU depends mostly on clinical findings. The clinical features commonly described in association with VAU include diffuse, fine, stellate or dendritiform keratic precipitates, ocular hypertension and iris atrophy.4,5,7–14 Although clinical features of different VAUs overlap, there are some characteristic findings depending on the causative viral agent.
In this review, the clinical features of the most common VAUs (HSV, VZV, CMV and RV) are presented.
Herpes Viridae Family (Herpes Simplex Virus, Varicella-zoster Virus, Cytomegalovirus)
These DNA viruses are ubiquitous and following primary infection, lifelong latency is a characteristic feature. The three main viruses responsible for ocular inflammation are HSV-1, VZV and CMV. Epstein-Barr virus (EBV) and HSV-2 have also infrequently been detected in ocular disease.15
The worldwide seroconversion to herpes viruses ranges from 60 to 90 %.16–21 VAU, due to either HSV or VZV is reported to be 5 to 10 % of all uveitis cases.22,23 However, other viruses such as CMV and RV are also increasingly being implicated as causative factors, particularly in patients presenting with hypertensive AU.4,5,7–11
Interestingly, the clinical features of herpetic ocular infection depend to a certain extent on the immune status of the patient. CMV infection, for example, predominantly manifests as retinitis in immunocompromised patients.24,25 In contrast, it almost always occurs as AU in otherwise healthy immunocompetent patients.24,25 Similarly, in VZV infection, posterior segment involvement is more likely to occur in immunocompromised patients and they are also more likely to develop chronic disease.26
  1. Jap A, Chee SP, Emerging forms of viral uveitis in the developing world, Int Ophthalmol Clin, 2010; 50:155–71.
  2. Pleyer U, Winterhalter S, Diagnostic and therapeutic aspects of herpes virus associated uveitis, Klin Monbl Augenheilkd, 2010;227:407–12.
  3. Jap A, Chee SP, Viral anterior uveitis, Curr Opin Ophthalmol, 2011;22:483–8.
  4. Chee SP, Bacsal K, Jap A, et al., Clinical features of cytomegalovirus anterior uveitis in immunocompetent patients, Am J Ophthalmol, 2008;145:834–40.
  5. Ruokonen PC, Metzner S, Ucer A, et al., Intraocular antibody synthesis against rubella virus and other microorganisms in Fuchs’ heterochromic cyclitis, Graefes Arch Clin Exp Ophthalmol, 2010;248:565–71.
  6. Takusagawa HL, Liu Y, Wiggs JL, Infectious theories of Posner-Schlossman syndrome, Int Ophthalmol Clin, 2011;51:105–15.
  7. Van Boxtel LA, van der Lelij A, van der Meer J, et al., Cytomegalovirus as a cause of anterior uveitis in immunocompetent patients, Ophthalmology, 2007;114:1358–62.
  8. De Schryver I, Rozenberg F, Cassoux N, et al., Diagnosis and treatment of cytomegalovirus iridocyclitis without retinal necrosis, Br J Ophthalmol, 2006;90:852–5.
  9. De Visser L, Braakenburg A, Rothova A, et al., Rubella virus-associated uveitis: clinical manifestations and visual prognosis, Am J Ophthalmol, 2008;146:292–97.
  10. Quentin CD, Reiber H, Fuchs heterochromic cyclitis: rubella virus antibodies and genome in aqueous humor, Am J Ophthalmol, 2004;138:46–54.
  11. Suzuki J, Goto H, Komase K, et al., Rubella virus as a possible etiological agent of Fuchs heterochromic iridocyclitis, Graefes Arch Clin Exp Ophthalmol, 2010;248:1487–91.
  12. Van der Lelij A, Ooijman FM, Kijlstra A, et al., Anterior uveitis withsectoral iris atrophy in the absence of keratitis: a distinct clinical entity among herpetic eye diseases, Ophthalmology, 2000;107:1164–70.
  13. Sungur GK, Hazirolan D, Yalvac IS, et al., Incidence and prognosis of ocular hypertension secondary to viral uveitis, Int Ophthalmol, 2010;30:191–4.
  14. Tugal-Tutkun I, Otük-Yasar B, Altinkurt E, Clinical features and prognosis of herpetic anterior uveitis: a retrospective study of 111 cases, Int Ophthalmol, 2010;30:559–65.
  15. Van Gelder RN, Ocular pathogens for the twenty-first century, Am J Ophthalmol, 2010;150:595–7.
  16. Smith JS, Robinson NJ, Age-specific prevalence of infection with herpes simplex virus types 2 and 1: a global review, J Infect Dis, 2002;186:S3–S28.
  17. Wong A, Tan KH, Tee CS, et al., Seroprevalence of cytomegalovirus, toxoplasma and parvovirus in pregnancy, Singapore Med J, 2000;41:151–5.
  18. Taechowisan T, Sutthent R, Louisirirotchanakul S, et al., Immune status in congenital infections by TORCH agents in pregnant Thais, Asian Pac J Allergy Immunol, 1997;15:93–7.
  19. Tookey PA, Ades AE, Peckham CS, Cytomegalovirus prevalence in pregnant women: the influence of parity, Arch Dis Child, 1992;67:779–83.
  20. Gratacap-Cavallier B, Bosson JL, Morand P, et al., Cytomegaloviru seroprevalence in French pregnant women: parity and place of birth as major predictive factors, Eur J Epidemiol, 1998;14:147–52.
  21. Sengupta N, Breuer J, A global perspective of the epidemiology and burden of varicella-zoster virus, Curr Pediatr Rev, 2009;5:207–28.
  22. Cunningham ET Jr, Diagnosing and treating herpetic anterior uveitis, Ophthalmology, 2000;107:2129–30.
  23. Tabbara KF, Chavis PS, Herpes simplex anterior uveitis, Int Ophthalmol Clin, 1998;38:137–47.
  24. Sanghera NK, Newman TL, Cytomegaloviral retinitis from chronic immunosuppression following solid organ transplant surgery, Clin Exp Optom, 2010;93:261–3.
  25. Chee SP, Jap A, Cytomegalovirus anterior uveitis: outcome of treatment, Br J Ophthalmol, 2010;94:1648–52.
  26. Westeneng AC, Rothova A, de Boer JH, et al., Infectious uveitis in immunocompromised patients and the diagnostic value of polymerase chain reaction and Goldmann-Witmer coefficient in aqueous analysis, Am J Ophthalmol, 2007;144:781–5.
  27. Matoba A, Ocular viral infections, Pediatr Infect Dis, 1984;3:358–68.
  28. Kido S, Sugita S, Horie S, et al., Association of varicella zoster virus load in the aqueous humor with clinical manifestations of anterior uveitis in herpes zoster ophthalmicus and zoster sine herpete, Br J Ophthalmol, 2008;92:505–8.
  29. Gershon AA, Varicella-zoster virus infections, Pediatr Rev, 2008; 29:5–11.
  30. Scott FT, Leedham-Green ME, Barrett-Muir WY, et al., A study of zoster and the development of postherpetic neuralgia in East London, J Med Virol, 2003;(suppl 1):S24–S30.
  31. Ragozzino MW, Melton LJ III, Kurland LT, et al., Population-based study of herpes zoster and its sequelae, Medicine, 1982;61:310–6.
  32. Goldman GS, Universal varicella vaccination: efficacy trends and effect on herpes zoster, Int J Toxicol, 2005;24:205–13.
  33. Tyndall MW, Nasio J, Agoki E, et al., Herpes zoster as the initial presentation of human immunodeficiency virus type 1 infection in Kenya, Clin Infect Dis, 1995;21:1035–7.
  34. Falcon MG, Williams HP, Herpes simplex kerato-uveitis and glaucoma, Trans Opthalmol Soc UK, 1978;98:101–4.
  35. Harding SP, Lipton JR, Wells JC, Natural history of herpes zoster ophthalmicus: predictors of postherpetic neuralgia and ocular involvement, Br J Ophthalmol, 1987;71:353–8.
  36. Womak LW, Liesegang TJ, Complications of herpes zoster opthalmicus, Arch Ophthalmol, 1983;101:42–5.
  37. Cobo ML, Foulks GN, Liesegang T, et al., Oral acyclovir in the treatment of acute herpes zoster ophthalmicus, Ophthalmology, 1986;93:763–70.
  38. Liesegang TJ, Varicella-zoster virus eye disease, Cornea, 1999;18:511–31.
  39. Thygeson P, Hogan MI, Kimura SJ, Observations on uveitis associated with viral disease, Trans Am Ophthalmol Soc, 1957–1958;55:333–49.
  40. Kimura SJ, Herpes simplex uveitis: a clinical and experimental study, Trans Am Ophthalmol Soc, 1962;60:441–70.
  41. Wensing B, Relvas LM, Caspers LE, et al., Comparison of rubella virus- and herpes virus-associated anterior uveitis: clinical manifestations and visual prognosis, Ophthalmology, 2011;118:1905–10.
  42. Wilhelmus KR, Falcon MG, Jones BR, Herpetic iridocyclitis, Int Ophthalmol, 1981;4:143–50.
  43. Goldstein DA, Mis AA, Deschenes JG, Iris atrophy in herpes simplex uveitis, Invest Ophthalmol Vis Sci, 1995;36:S150.
  44. Yamamoto S, Pavan-Langston D, Kinoshita S, Detecting herpesvirus DNA in uveitis using the polymerase chain reaction, Br J Ophthalmol, 1996;80:465–8.
  45. Marsh RJ, Easty DL, Jones BR, Iritis and iris atrophy in herpes zoster ophthalmicus, Am J Ophthalmol, 1974;78:255–61.
  46. Naumann G, Gass JD, Font RL, Histopathology of herpes zoster ophthalmicus, Am J Ophthalmol, 1968;65:533–41.
  47. Khan AO, Al-Assiri A, Wagoner MD, Ring corneal infiltrate and progressive ring thinning following primary varicella infection, J Pediatr Ophthalmol Strabismus, 2008;45:116–7.
  48. Fernández de Castro LE, Sarraf OA, Hawthorne KM, et al., Ocular manifestations after primary varicella infection, Cornea, 2006;25:866–7.
  49. Piebanga LW, Laibson PR, Dendritic lesions in herpes zoster ophthalmicus, Arch Ophthalmol, 1973;90:268.
  50. Wilhelmus KR, Gee L, Hauck WW, et al., Herpetic Eye Disease Study. A controlled trial of topical corticosteroids for herpes simplex stromal keratitis, Ophthalmology, 1994;101:1883–95; discussion 1895–6.
  51. Parrish CM, Herpes simplex virus eye disease. Focal points: Clinical modules for ophthalmologists, San Fancisco: American Academy of Ophthalmology, 1997;101:1871-82.
  52. Siverio Júnior CD, Imai Y, Cunningham ET Jr, Diagnosis and management of herpetic anterior uveitis, Int Ophthalmol Clin, 2002;42:43–8.
  53. Rodriguez A, Power WJ, Neves RA, et al., Recurrence rate of herpetic uveitis in patients on long-term oral acyclovir, Doc Ophthalmol, 1995;90:331–40.
  54. Colin J, Prisant O, Cochener B, et al., Comparison of the efficacy and safety of valacyclovir and acyclovir for the treatment of herpes zoster ophthalmicus, Ophthalmology, 2000;107:1507–11.
  55. Seale H, MacIntyre CR, Gidding HF, et al., National Survey of cytomegalovirus in Australia Clin Vaccine Immunol, 2006;13:1181–4.
  56. Staras SA, Dollard SC, Radford KW, et al., Seroprevalence of cytomegalovirus infection in the United States, 1988-1994, Clin Infect Dis, 2006;43:1143–51.
  57. Kothari A, Ramachandran VG, Gupta P, et al., Seroprevalence of cytomegalovirus among voluntary blood donors in Delhi, India, J Health Popul Nutr, 2002;20:348–51.
  58. Kositanont U, Wasi C, Chandanayingyong D, et al., Prevalence of cytomegalovirus antibodies in Thai blood donors, Asian Pac J Allergy Immunol, 1985;3:179–82.
  59. Stroffolini T, Ngatchu T, Chiaramonte M, et al., Prevalence of cytomegalovirus seropositivity in an urban childhood population in Cameroon, New Microbiol, 1993;16:83–5.
  60. Ahmed SA, Al-Joudi FS, Zaidah AW, et al., The prevalence of human cytomegalovirus seropositivity among blood donors at the Unit of Blood Transfusion Medicine, Hospital Universiti Sains Malaysia, Southeast Asian J Trop Med Public Health, 2006;37:294–6.
  61. Daicker B, Cytomegalovirus panuveitis with infection of corneo-trabecular endothelium in AIDS, Ophthalmologica, 1988;197:169–75.
  62. Teoh SB, Thean L, Koay E, Cytomegalovirus in aetiology of Posner- Schlossman syndrome: evidence from quantitative polymerase chain reaction, Eye, 2005;19:1338–40.
  63. Bloch-Michel E, Dussaix E, Cerqueti P, et al., Possible role of cytomegalovirus infection in the etiology of the Posner- Schlossmann syndrome, Int Ophthalmol, 1987;11:95–6.
  64. Markomichelakis NN, Canakis C, Zafirakis P, et al., Cytomegalovirus as a cause of anterior uveitis with sectoral iris atrophy, Ophthalmology, 2002;109:879–82.
  65. Chee SP, Bascal K, Jap A, et al., Corneal endotheliitis associated with evidence of cytomegalovirus infection, Ophthalmology, 2007;114:798–803.
  66. Chee SP, Jap A, Presumed Fuchs heterochromic iridocyclitis and Posner–Schlossman syndrome: comparison of cytomegalovirus-positive and negative eyes, Am J Ophthalmol, 2008;146:883–9.
  67. Givens KT, Lee DA, Jones T, et al., Congenital rubella syndrome: ophthalmic manifestations and associated systemic disorders, Br J Ophthalmol, 1993;77:358–63.
  68. Biswas J, Narayana KM, Gupta S, et al., Panuveitis due to acquired rubella and isolation of rubella virus from the aqueous humour, J Pediatr Ophthalmol Strabismus, 2003;40:240–2.
  69. Birnbaum AD, Tessler HH, Schultz KL, et al., Epidemiologic relationship between fuchs heterochromic iridocyclitis and the United States rubella vaccination program, Am J Ophthalmol, 2007;144:424–8.
  70. Kitaichi N, Ariga T, Ohno S, et al., Acute unilateral conjunctivitis after rubella vaccination: the detection of the rubella genome in the inflamed conjunctiva by reverse transcriptase-polymerase chain reaction, Br J Ophthalmol, 2006;90:1436–7.
  71. Islam SM, El-Sheikh HF, Tabbara KF, Anterior uveitis following combined vaccination for measles, mumps, and rubella (MMR): a report of two cases, Acta Ophthalmol Scand, 2000;78:590–2.
  72. Sever JL, South MA, Shaver KA, Delayed manifestations of congenital rubella, Rev Infect Dis, 1985;1:S164–S9.
  73. Boger WP, Late ocular complications in congenital rubella syndrome, Ophthalmology, 1980;87:1244–52.
  74. Rothova A, The riddle of Fuchs heterochromic uveitis, Am J Ophthalmol, 2007;144:447–8.
  75. Goto H, Mochizuki M, Yamaki K, et al., Epidemiological survey of intraocular inflammation in Japan, Jpn J Ophthalmol, 2007;51:41–4.
  76. Tran VT, Auer C, Guex-Crosier Y, et al., Epidemiological characteristics of uveitis in Switzerland, Int Ophthalmol, 1994;18:293–8.
  77. Bouchenaki N, Herbort CP, Fluorescein angiographic findings and clinical features in Fuchs’ uveitis, Int Ophthalmol, 2010;30:511–9.
  78. Mohamed Q, Zamir E, Update on Fuchs' uveitis syndrome, Curr Opin Ophthalmol, 2005;16:356–63.
  79. Velilla S, Dios E, Herreras JM, et al., Fuchs’ heterochromic iridocyclitis: a review of 26 cases, Ocul Immunol Inflamm, 2001;9:169–75.
  80. Bonfioli AA, Curi AL, Orefice F, Fuchs' heterochromic cyclitis, Semin Ophthalmol, 2005;20:143–6.
  81. Al-Mansour YS, Al-Rajhi AA, Al-Dhibi H, et al., Clinical features and prognostic factors in Fuchs’ uveitis, Int Ophthalmol, 2010;30:501–9.
  82. De Groot-Mijnes JD, Rothova A, Van Loon AM, et al., Polymerase chain reaction and Goldmann-Witmer coefficient analysis are complimentary for the diagnosis of infectious uveitis, Am J Ophthalmol, 2006;141(2):313–8.
  83. Gaynor BD, Margolis TP, Cunningham ET Jr, Advances in diagnosis and management of herpetic uveitis, Int Ophthalmol Clin, 2000;40:85–109.
  84. Bodaghi B, LeHoang P, Testing ocular fluids in uveitis, Ophthalmol Clin North Am, 2002;15:271–9.
  85. Errera MH, Goldschmidt P, Batellier L, et al., Real-time polymerase chain reaction and intraocular antibody production for the diagnosis of viral versus toxoplasmic infectious posterior uveitis, Graefes Arch Clin Exp Ophthalmol, 2011;249(12):1837–46.
Keywords: Anterior uveitis, cytomegalovirus, Fuch’s uveitis syndrome, herpes simplex virus, Posner–Schlossman syndrome, rubella virus, varicella-zoster virus