Ocular Immunology & Inflammation, Early Online, 1–6, 2014 ! Informa Healthcare USA, Inc. ISSN: 0927-3948 print / 1744-5078 online DOI: 10.3109/09273948.2014.950384
ORIGINAL ARTICLE
Characteristics of Cytomegalovirus Uveitis in Immunocompetent Patients
Ocul Immunol Inflamm Downloaded from informahealthcare.com by University of Newcastle on 01/06/15 For personal use only.
Jyh Haur Woo1,2, Wee K. Lim1,2, Su L. Ho2, and Stephen C. Teoh, MBBS, MMed(Ophth), FRCSEd, FAMS2 1
Singapore National Eye Centre, Singapore and 2National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore
ABSTRACT Purpose: To present the clinical characteristics of patients with anterior uveitis who had evidence of cytomegalovirus (CMV) infection on polymerase chain reaction PCR-based assays for viral DNA in aqueous samples. Methods: This was a retrospective observational case series of 16 patients with CMV infection on qualitative polymerase chain reaction PCR-based assays for viral DNA in aqueous samples. Case records of 16 patients were reviewed and relevant clinical information was collected using a standardized data sheet. Results: There were 10 male and 6 female patients, with 16 eyes included. The median age at the first attack was 52 years (range 27–77 years). Thirteen patients (81.3%) presented with an initial BCVA of 20/40 or better. Eleven eyes (68.8%) had anterior chamber inflammation of 1+ cells or less. Eight eyes (50.0%) had concomitant sectoral iris atrophy, while 2 eyes were noted to have heterochromic irides. Eleven patients (68.8%) presented with an elevated intraocular pressure. Seven patients (43.8%) had clinical features that led to a presumptive diagnosis of Posner-Schlossman syndrome, while 3 patients (18.8%) were initially diagnosed with Fuchs heterochromic iridocyclitis. Six patients were initially treated for uveitic glaucoma or anterior uveitis of unknown cause. Conclusions: There is a spectrum of clinical manifestations of CMV anterior uveitis. A high index of suspicion of a possible viral etiology, especially CMV, and subsequent accurate identification of the virus involved are fundamental to the overall therapeutic approach. Keywords: Anterior uveitis, cytomegalovirus, hypertensive uveitis, immunocompetent
been described, varying from self-limiting anterior uveitis to severe chronic and/or relapsing disease with features overlapping with those of herpetic uveitides. We present the clinical characteristics of 16 immunocompetent patients with anterior uveitis who had evidence of CMV infection on polymerase chain reaction (PCR)-based assays of aqueous samples for viral DNA.
Cytomegalovirus (CMV), a member of the Herpesviridae family, is a well-established cause of opportunistic ocular infection in the immunocompromised, which usually manifests as a characteristic retinitis. However, in recent years, cytomegalovirus has been linked to a hypertensive anterior uveitis in immunocompetent individuals.1–5 A range of clinical presentations of CMV anterior uveitis, though still uncommon, has since
Received 24 August 2013; revised 22 July 2014; accepted 28 July 2014; published online 5 September 2014 Correspondence: Stephen C. Teoh, National Healthcare Group Eye Institute, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433. Tel: (65) 6357 7726. Fax: (65) 6357 7718. Email: [email protected]
1
2
J. H. Woo et al.
Ocul Immunol Inflamm Downloaded from informahealthcare.com by University of Newcastle on 01/06/15 For personal use only.
MATERIALS AND METHODS This was a retrospective observational case series. The study was approved by the local ethical review board. All patients were reviewed at the Uveitis Subspeciality Clinic between 2005 and 2010. Patients’ records were reviewed and relevant information on demographics, medical and ophthalmic history, best corrected Snellen visual acuity (BCVA) and intraocular pressure (IOP), and clinical findings. Information was collected using a standardized data sheet. All patients were examined and reviewed by attending uveitis specialists (WKL, SLH, and SCT) throughout the follow-up period. The patients included in the study had either hypertensive anterior uveitis or chronic anterior uveitis of unknown cause. We were able to classify all patients under 3 clinical pictures: PSS, characterized by recurrent attacks of unilateral, acute secondary open-angle glaucoma associated with mild anterior uveitis; FHI, based on features of chronicity, mild anterior chamber reaction, characteristic stellate keratitic precipitates, diffuse stromal iris atrophy, heterochromia iridis, and absence of posterior synechiae; and cases in which the features were not suggestive of either of the above hypertensive uveitic syndromes. The patients underwent a standard uveitis screening protocol comprising physical examination, laboratory testing, including complete blood count, blood chemistry, erythrocyte sedimentation rate (ESR), human immunodeficiency virus (HIV), syphilis and human leukocyte antigen (HLA)-B27 serologic analysis, and tuberculin skin testing (TST). Referrals to relevant physicians for further evaluation were also made as indicated. Patients were initially managed with topical steroid medications and antiglaucoma therapy if the IOP was high (defined as greater than 21 mmHg), which were increased or tapered in a stepwise manner according to the severity of inflammation and IOP at each review. An anterior chamber (AC) paracentesis was performed for all patients during an active episode under aseptic technique after obtaining informed consent. At least a 100-mL aliquot of aqueous humor was aspirated and sent for qualitative PCR analysis of CMV, herpes simplex virus (HSV), varicella zoster virus (VZV), and Toxoplasma gondii DNA. The collected samples were first frozen at 20 C and delivered to the laboratory in cold within 24–48 h. The extraction of DNA was performed using QIAGEN kits, either with the manual DNA mini kit or automated QIAcube with DNA mini kit. Samples were then detected by real-time tetraplex PCR, with primers adapted from published literature and probes designed using Primer3Plus software. The clinical findings, disease course, and activity of uveitis were reported using the grading scheme and
terminology proposed by the Standardization of Uveitis Nomenclature (SUN) Working Group.6 The complication of glaucoma was diagnosed when the subjects developed characteristic optic nerve cupping with corresponding glaucomatous visual field defect on automated Humphrey visual field (HVF) testing.
RESULTS Sixteen patients with 16 affected eyes were included in this case series. All eyes were positive for CMV DNA on qualitative PCR analysis of aqueous humor and negative for HSV, VZV, and Toxoplasma gondii DNA. The clinical findings are summarized in Table 1. There were 10 male and 6 female patients, all of whom were Chinese. The median age at the first reported attack was 52 years (range 27–77 years). All patients had unilateral involvement. None of the patients had any significant medical history of systemic disease except one patient who has diabetes. Eleven patients (68.8%) experienced sudden onset of eye pain, redness, and/or blurring of vision at initial consultation. Of these, 2 patients (18.2%) also had headache and 4 patients (25.0%) presented with an insidious onset of blurring of vision. One patient was asymptomatic, but was found to have signs of uveitis on routine diabetic retinopathy screening. Thirteen patients (81.3%) presented with an initial BCVA of 20/40 or better. Eleven eyes (68.8%) had anterior chamber inflammation of 1+ cells or less, while 5 eyes had 2+ cells or more. Flare was seen in 3 eyes (18.8%). Keratitic precipitates (KPs) were found in all eyes. Six eyes had characteristic fine stellate KP, while a large confluent KP was seen in 1 eye. None of the patients had posterior synechiae at presentation. Eight eyes (50.0%) had concomitant sectoral iris atrophy, while 2 eyes were noted to have heterochromic irides. At initial presentation, diffuse microcystic corneal edema was seen in 5 eyes. One patient was observed to have a geographic corneal endothelial plaque. Eleven patients (68.8%) presented with an elevated IOP. The median IOP at presentation for patients in this series was 34 mmHg (range 10–67). All patients had anterior uveitis without posterior segment involvement. Notably, 6 patients (37.5%) had enlarged cup–disc ratios 0.6 at presentation, out of which 5 patients (31.3%) had corresponding glaucomatous visual field defect on automated Humphrey visual field (HVF) testing. These 5 patients were diagnosed with glaucoma and were managed accordingly. Seven patients (43.8%) had features that led to a presumptive clinical diagnosis of PSS. Three patients (18.8%) were initially diagnosed with FHI. The remaining 6 patients had clinical features that were not consistent with either of the above hypertensive Ocular Immunology & Inflammation
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7
8 9
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F
M
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M
M
M
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M M
F
F
M
F
F
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F
Gender
Cells 0.5%, flare +, KP
Cells 0.5+, old KPs
Cells 0.5+, old KPs
Cells 0.5+, KP (stellate)
Cells +, KP
Cells 0.5+, KP (stellate)
Cells 3+, flare 2+, large KP (confluent in visual axis) Endothelial plaque Cells 2+, KP Cells 0.5+, KP (confluent, stellate) Cells +, KP (stellate)
Cells +, KP
Cells +, KP
Cells 2+, flare +, KP (Stellate) Cells +, KP
Cells 2+, KP
Cells 2+, KP (stellate)
Inflammation
Corneal edema Iris atrophy
Iris atrophy RAPD
Iris atrophy
Corneal edema
Heterochromia Iris atrophy –
Corneal edema Heterochromia Iris atrophy – Corneal edema Iris atrohy –
6/15
6/18
6/9
6/7.5
6/7.5
6/18
6/9
6/12 6/6
6/9
6/9
6/9
6/9
– Corneal edema Peripheral anterior synechiae –
6/12
6/6
6/9
Initial BCVA
Iris atrophy, RAPD Corneal oedema Iris atrophy
–
Anterior segment
Ocular findings
67
13
15
61
27
36
12
32 52
48
17
42
10
27
62
50
Initial IOP (mmHg)
Recurrent
Recurrent
Recurrent
Recurrent
Recurrent
Recurrent
Chronic
Chronic Chronic
Chronic
Recurrent
Recurrent
Recurrent
Chronic
Chronic
Chronic
Disease course
Uveitic glaucoma Posner-Schlossman syndrome Anterior uveitis of unknown cause Posner-Schlossman syndrome Posner-Schlossman syndrome Posner-Schlossman syndrome Anterior uveitis of unknown cause Fuchs heterochromic iridocyclitis Posner-Schlossman syndrome
Anterior uveitis of unknown cause Uveitic glaucoma
Posner-Schlossman syndrome Fuchs heterochromic iridocyclitis Fuchs heterochromic iridocyclitis Anterior uveitis of unknown cause Posner-Schlossman syndrome
Diagnosis
IOP, intraocular pressure; KP, keratitic precipitates; BCVA, best corrected visual acuity (Snellen); RAPD, relative afferent pupillary defect.
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1
Patient
Age at onset (years)
Presentation
TABLE 1. Patient characteristics with CMV anterior uveitis.
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48
1
17
1
216
27
2 38
24
26
7
3
14
3
18
Time to diagnosis (months)
Glaucoma
Glaucoma
Glaucoma
Glaucoma
Glaucoma
Complications
Cytomegalovirus Uveitis 3
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uveitic syndromes and hence they were provisionally treated for anterior uveitis of unknown cause, complicated by glaucoma. The median follow-up period was 46.5 months (range 13–240), while the median time to diagnosis was 39.0 months (range 1–216). Nine patients (56.3%) had a recurrent course of disease while 7 patients (43.7%) developed a chronic uveitis.
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DISCUSSION The majority of patients with CMV anterior uveitis presented with sudden onset unilateral eye redness, pain, and mild blurring of vision. Such symptoms often coincided with findings of anterior chamber inflammation, keratitic precipitates, and elevated IOP. Some patients also had associated findings of sectoral iris atrophy and heterochromia. Our findings were in general agreement with the variable clinical presentation of CMV uveitis patients in existing literature. Bloch-Michel et al. first suggested the possible role of CMV in the pathogenesis of PSS after demonstrating local production of CMV-specific antibodies in the aqueous humor.7 This was further substantiated by evidence of CMV DNA from quantitative PCR in a patient during an acute relapse of clinical PSS.5 Markomichelakis et al. reported 2 cases of recurrent anterior uveitis with sectoral iris atrophy and ocular hypertension during attacks caused by CMV, as proven by PCR assay of aqueous.1 De Schryver et al., on the other hand, described 5 immunocompetent patients with unilateral anterior uveitis without iris atrophy.2 Similarly, van Boxtel et al. reported 7 cases of mild isolated unilateral chronic and/or recurrent anterior uveitis associated with increased IOP and findings of diffuse keratitic precipitates and focal corneal haze/ edema secondary to endotheliitis. Examination of the aqueous humor by PCR demonstrated CMV-DNA in 6 of these patients, while the Goldmann-Witmer coefficient was strongly positive in 80% of patients.4 More recently, in a retrospective case series, Chee et al. noted 24 out of 105 eyes with hypertensive anterior uveitis to be positive for CMV, for which 18 presented with clinical PSS and 5 presented with FHI.3 In the current series, we also observed a preponderance of disease onset in the middle or older age groups, especially among male patients, similar to previously reported findings.1–5,8–12 Most patients in the current study had good initial BCVA and lowgrade anterior chamber inflammation. Six patients had an abnormal cup–disc ratio, out of which 5 demonstrated corresponding glaucomatous visual field defects suggestive of undetected chronic subclinical disease with recurrent episodes of ocular hypertension. However, not all patients presented
with an elevated IOP. It was noted that 5 patients had presented with IOP ranging from 10 to 17 mmHg. However, on further follow-up, maximal IOP values ranging from 18 to 35 mmHg were recorded for these patients, which may be complicated by steroid response. Elevated IOP is a common (though not pathognomonic) feature of CMV uveitis3 and has been attributed to direct viral trabeculitis or obstruction of the trabeculum by inflammatory debris. However, our observations suggest that CMV uveitis patients may present without any elevation in IOP during episodes of acute attacks. Therefore, careful longitudinal monitoring of IOP is warranted in order to detect any significant rise in IOP or visual field defects. Half of the eyes (8 out of 16) had sectoral iris atrophy on examination, a common feature in herpetic uveitis, which is postulated to be due to ischemic necrosis of the iris stroma as a result of direct viral invasion or vasculitis. This is also consistent with findings of CMV in the smooth muscle cells of the iris.13 Both diffuse3 and sectoral1 iris atrophy have been reported in CMV uveitis, although the latter may be more specific for herpetic anterior uveitis caused by either HSV or VZV.14 Only 1 patient presented with an endothelial plaque, suggestive of concurrent corneal endotheliitis, a unique feature that may represent a more severe disease. It has been postulated that corneal endothelial damage may have resulted from the interplay of the immunologic response triggered by the reactivation of latent CMV infection in the anterior chamber and the dynamic immunoregulatory processes in anterior chamber-associated immune deviation (ACAID).15 It is important to note that the constellation triad of anterior uveitis, diffuse iris atrophy, and elevated IOP are not specific to CMV infection. Similar features have been observed and described in herpetic uveitides caused by HSV and VZV. Various pathogens, other than CMV, have also been implicated in the pathogenesis of PSS and FHI-like syndromes. Yamamoto et al. demonstrated the presence of amplified genomic fragments of HSV in the aqueous samples of PSS patients during acute attacks, using PCR assay and Southern blot hybridization.16 In addition, HSV and Rubella DNA have also been implicated in FHI.17–20 There is considerable overlap between different viruses with regards to their purported role in causing hypertensive anterior uveitis.21 As such, the variable features seen in CMV uveitis may represent a spectrum of clinical expression of viral infection in the eye, not specific to any particular pathogen. Hypertensive uveitic syndromes such as PSS and FHI, which also exhibit wide variations in clinical manifestations,22 may be part of this spectrum of ocular infections, rather than distinct clinical entities. In addition, the confinement of CMV Ocular Immunology & Inflammation
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Cytomegalovirus Uveitis infection to the anterior segment bears testament to host immunocompetency. In the immunocompetent murine model, CMV only causes a transient, self-limiting anterior segment reaction with minimal posterior segment involvement. However, in immunocompromised mice, the ocular infection is potentiated, culminating in necrotizing retinitis, analogous to the CMV retinitis in immunosuppressed humans.23 We believe that the infective process is represented clinically by a range of inflammatory responses (in the individual eye) to the inciting virus, subjected to factors such as the immune status of the host, the unique immune-privileged properties of the anterior chamber, and virulence of the pathogen. Qualitative PCR analysis of aqueous was performed with the finding of CMV DNA as the presumptive evidence of infection. We acknowledge the limitation of PCR, as the possibility of falsepositive results cannot be excluded because PCR is highly sensitive; moreover, CMV may be latent in leucocytes in the anterior chamber during active inflammation. As the study was retrospective in design, only subjects with either hypertensive anterior uveitis or chronic anterior uveitis of unknown cause and positive results on qualitative PCR analysis of aqueous were included. Information on patients with similar clinical presentation but negative results on PCR analysis was not available. As such, the lack of controls in this series may further limit the validity of detecting CMV DNA in our patients. Ideally, real-time PCR should be performed to demonstrate active viral replication together with quantification of CMV DNA in order to correlate clinical symptoms with viral load. The GoldmannWitmer coefficient is not performed locally, hence we were unable to demonstrate the production of local CMV-specific antibodies in the anterior chamber. Serum CMV IgG antibody levels were also not determined, although isolated titers may not be meaningful, as the seropositivity rate in the local population is around 87%.24 However, we feel the consistent findings of CMV DNA in our patients justify the use of qualitative PCR analysis in the diagnosis of CMV uveitis. In conclusion, our patients represent a spectrum of clinical manifestations of CMV anterior uveitis. The majority of our patients presented with eye redness, pain, good initial visual acuity, mild anterior chamber inflammation, keratitic precipitates, sectoral iris atrophy, and high IOP. However, some patients may have mild or no symptoms with normal IOP. In view of the overlapping features with other herpetic ocular infections and hypertensive uveitic syndromes, a high index of suspicion of a possible viral etiology and subsequent accurate identification of the virus involved are fundamental to the overall therapeutic approach. !
2014 Informa Healthcare USA, Inc.
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DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES 1. Markomichelakis NN, Canakis C, Zafirakis P, et al. Cytomegalovirus as a cause of anterior uveitis with sectoral iris atrophy. Ophthalmology. 2002;109:879–882. 2. de Schryver I, Rozenberg F, Cassoux N, et al. Diagnosis and treatment of cytomegalovirus iridocyclitis without retinal necrosis. Br J Ophthalmol. 2006;90:852–855. 3. Chee SP, Bacsal K, Jap A, et al. Clinical features of cytomegalovirus anterior uveitis in immunocompetent patients. Am J Ophthalmol. 2008;145:834–840. 4. 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: 1358–1362. 5. Teoh SB, Thean L, Koay E. Cytomegalovirus in aetiology of Posner-Schlossman syndrome: evidence from quantitative polymerase chain reaction. Eye. 2005;19: 1338–1340. 6. Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140:509–516. 7. 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: 95–96. 8. Chee SP, Jap A. Presumed Fuchs heterochromic iridocyclitis and Posner-Schlossman syndrome: comparison of cytomegalovirus-positive and negative eyes. Am J Ophthalmol. 2008;146:883–889. 9. Mietz H, Aisenbrey S, Ulrich Bartz-Schmidt K, et al. Ganciclovir for the treatment of anterior uveitis. Graefes Arch Clin Exp Ophthalmol. 2000;238:905–909. 10. Chung RS, Chua CN. Intravitreal ganciclovir injections in aqueous cytomegalovirus DNA positive hypertensive iritis. Eye. 2006;20:1078–1080. 11. Yamauchi Y, Suzuki J, Sakai J, et al. A case of hypertensive keratouveitis with endotheliitis associated with cytomegalovirus. Ocul Immunol Inflamm. 2007;15:399–401. 12. Sira M, Murray PI. Treatment of cytomegalovirus anterior uveitis with oral valaciclovir. Ocul Immunol Inflamm. 2007; 15:31–32. 13. Daicker B. Cytomegalovirus panuveitis with infection of corneo-trabecular endothelium in AIDS. Ophthalmologica. 1988;197:169–175. 14. Siverio Junior CD, Imai Y, Cunningham Jr ET. Diagnosis and management of herpetic anterior uveitis. Int Ophthalmol Clin. 2002;42:43–48. 15. Koizumi N, Suzuki T, Uno T, et al. Cytomegalovirus as an etiologic factor in corneal endotheliitis. Ophthalmology. 2008;115:292–297. 16. Yamamoto S, Pavan-Langston D, Tada R, et al. Possible role of herpes simplex virus in the origin of Posner-Schlossman syndrome. Am J Ophthalmol. 1995;119:796–798. 17. Barequet IS, Li Q, Wang Y, et al. Herpes simplex virus DNA identification from aqueous fluid in Fuchs heterochromic iridocyclitis. Am J Ophthalmol. 2000;129: 672–673.
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J. H. Woo et al. 22. Brooks AM, Grant G, Young T, et al. Cyclitic glaucoma. Aust N Z J Ophthalmol. 1989;17:157–164. 23. Bale Jr JF, O’Neil ME, Folberg R. Murine cytomegalovirus ocular infection in immunocompetent and cyclophosphamide-treated mice: potentiation of ocular infection by cyclophosphamide. Invest Ophthalmol Vis Sci. 1991;32: 1749–1756. 24. Wong A, Tan KH, Tee CS, et al. Seroprevalence of cytomegalovirus, toxoplasma and parvovirus in pregnancy. Singapore Med J. 2000;41:151–155.
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18. Quentin CD, Reiber H. Fuchs heterochromic cyclitis: rubella virus antibodies andgenome in aqueous humor. Am J Ophthalmol. 2004;138:46–54. 19. de Groot-Mijnes JD, de Visser L, Rothova A, et al. Rubella virus is associated with Fuchs heterochromic iridocyclitis. Am J Ophthalmol. 2006;141:212–214. 20. de Visser L, Braakenburg A, Rothova A, et al. Rubella virus-associated uveitis: clinical manifestations and visual prognosis. Am J Ophthalmol. 2008;146:292–297. 21. Jap A, Chee SP. Viral anterior uveitis. Curr Opin Ophthalmol. 2011;22:483–488.
Ocular Immunology & Inflammation
ORIGINAL ARTICLE
Characteristics of Cytomegalovirus Uveitis in Immunocompetent Patients
Ocul Immunol Inflamm Downloaded from informahealthcare.com by University of Newcastle on 01/06/15 For personal use only.
Jyh Haur Woo1,2, Wee K. Lim1,2, Su L. Ho2, and Stephen C. Teoh, MBBS, MMed(Ophth), FRCSEd, FAMS2 1
Singapore National Eye Centre, Singapore and 2National Healthcare Group Eye Institute, Tan Tock Seng Hospital, Singapore
ABSTRACT Purpose: To present the clinical characteristics of patients with anterior uveitis who had evidence of cytomegalovirus (CMV) infection on polymerase chain reaction PCR-based assays for viral DNA in aqueous samples. Methods: This was a retrospective observational case series of 16 patients with CMV infection on qualitative polymerase chain reaction PCR-based assays for viral DNA in aqueous samples. Case records of 16 patients were reviewed and relevant clinical information was collected using a standardized data sheet. Results: There were 10 male and 6 female patients, with 16 eyes included. The median age at the first attack was 52 years (range 27–77 years). Thirteen patients (81.3%) presented with an initial BCVA of 20/40 or better. Eleven eyes (68.8%) had anterior chamber inflammation of 1+ cells or less. Eight eyes (50.0%) had concomitant sectoral iris atrophy, while 2 eyes were noted to have heterochromic irides. Eleven patients (68.8%) presented with an elevated intraocular pressure. Seven patients (43.8%) had clinical features that led to a presumptive diagnosis of Posner-Schlossman syndrome, while 3 patients (18.8%) were initially diagnosed with Fuchs heterochromic iridocyclitis. Six patients were initially treated for uveitic glaucoma or anterior uveitis of unknown cause. Conclusions: There is a spectrum of clinical manifestations of CMV anterior uveitis. A high index of suspicion of a possible viral etiology, especially CMV, and subsequent accurate identification of the virus involved are fundamental to the overall therapeutic approach. Keywords: Anterior uveitis, cytomegalovirus, hypertensive uveitis, immunocompetent
been described, varying from self-limiting anterior uveitis to severe chronic and/or relapsing disease with features overlapping with those of herpetic uveitides. We present the clinical characteristics of 16 immunocompetent patients with anterior uveitis who had evidence of CMV infection on polymerase chain reaction (PCR)-based assays of aqueous samples for viral DNA.
Cytomegalovirus (CMV), a member of the Herpesviridae family, is a well-established cause of opportunistic ocular infection in the immunocompromised, which usually manifests as a characteristic retinitis. However, in recent years, cytomegalovirus has been linked to a hypertensive anterior uveitis in immunocompetent individuals.1–5 A range of clinical presentations of CMV anterior uveitis, though still uncommon, has since
Received 24 August 2013; revised 22 July 2014; accepted 28 July 2014; published online 5 September 2014 Correspondence: Stephen C. Teoh, National Healthcare Group Eye Institute, Tan Tock Seng Hospital, 11 Jalan Tan Tock Seng, Singapore 308433. Tel: (65) 6357 7726. Fax: (65) 6357 7718. Email: [email protected]
1
2
J. H. Woo et al.
Ocul Immunol Inflamm Downloaded from informahealthcare.com by University of Newcastle on 01/06/15 For personal use only.
MATERIALS AND METHODS This was a retrospective observational case series. The study was approved by the local ethical review board. All patients were reviewed at the Uveitis Subspeciality Clinic between 2005 and 2010. Patients’ records were reviewed and relevant information on demographics, medical and ophthalmic history, best corrected Snellen visual acuity (BCVA) and intraocular pressure (IOP), and clinical findings. Information was collected using a standardized data sheet. All patients were examined and reviewed by attending uveitis specialists (WKL, SLH, and SCT) throughout the follow-up period. The patients included in the study had either hypertensive anterior uveitis or chronic anterior uveitis of unknown cause. We were able to classify all patients under 3 clinical pictures: PSS, characterized by recurrent attacks of unilateral, acute secondary open-angle glaucoma associated with mild anterior uveitis; FHI, based on features of chronicity, mild anterior chamber reaction, characteristic stellate keratitic precipitates, diffuse stromal iris atrophy, heterochromia iridis, and absence of posterior synechiae; and cases in which the features were not suggestive of either of the above hypertensive uveitic syndromes. The patients underwent a standard uveitis screening protocol comprising physical examination, laboratory testing, including complete blood count, blood chemistry, erythrocyte sedimentation rate (ESR), human immunodeficiency virus (HIV), syphilis and human leukocyte antigen (HLA)-B27 serologic analysis, and tuberculin skin testing (TST). Referrals to relevant physicians for further evaluation were also made as indicated. Patients were initially managed with topical steroid medications and antiglaucoma therapy if the IOP was high (defined as greater than 21 mmHg), which were increased or tapered in a stepwise manner according to the severity of inflammation and IOP at each review. An anterior chamber (AC) paracentesis was performed for all patients during an active episode under aseptic technique after obtaining informed consent. At least a 100-mL aliquot of aqueous humor was aspirated and sent for qualitative PCR analysis of CMV, herpes simplex virus (HSV), varicella zoster virus (VZV), and Toxoplasma gondii DNA. The collected samples were first frozen at 20 C and delivered to the laboratory in cold within 24–48 h. The extraction of DNA was performed using QIAGEN kits, either with the manual DNA mini kit or automated QIAcube with DNA mini kit. Samples were then detected by real-time tetraplex PCR, with primers adapted from published literature and probes designed using Primer3Plus software. The clinical findings, disease course, and activity of uveitis were reported using the grading scheme and
terminology proposed by the Standardization of Uveitis Nomenclature (SUN) Working Group.6 The complication of glaucoma was diagnosed when the subjects developed characteristic optic nerve cupping with corresponding glaucomatous visual field defect on automated Humphrey visual field (HVF) testing.
RESULTS Sixteen patients with 16 affected eyes were included in this case series. All eyes were positive for CMV DNA on qualitative PCR analysis of aqueous humor and negative for HSV, VZV, and Toxoplasma gondii DNA. The clinical findings are summarized in Table 1. There were 10 male and 6 female patients, all of whom were Chinese. The median age at the first reported attack was 52 years (range 27–77 years). All patients had unilateral involvement. None of the patients had any significant medical history of systemic disease except one patient who has diabetes. Eleven patients (68.8%) experienced sudden onset of eye pain, redness, and/or blurring of vision at initial consultation. Of these, 2 patients (18.2%) also had headache and 4 patients (25.0%) presented with an insidious onset of blurring of vision. One patient was asymptomatic, but was found to have signs of uveitis on routine diabetic retinopathy screening. Thirteen patients (81.3%) presented with an initial BCVA of 20/40 or better. Eleven eyes (68.8%) had anterior chamber inflammation of 1+ cells or less, while 5 eyes had 2+ cells or more. Flare was seen in 3 eyes (18.8%). Keratitic precipitates (KPs) were found in all eyes. Six eyes had characteristic fine stellate KP, while a large confluent KP was seen in 1 eye. None of the patients had posterior synechiae at presentation. Eight eyes (50.0%) had concomitant sectoral iris atrophy, while 2 eyes were noted to have heterochromic irides. At initial presentation, diffuse microcystic corneal edema was seen in 5 eyes. One patient was observed to have a geographic corneal endothelial plaque. Eleven patients (68.8%) presented with an elevated IOP. The median IOP at presentation for patients in this series was 34 mmHg (range 10–67). All patients had anterior uveitis without posterior segment involvement. Notably, 6 patients (37.5%) had enlarged cup–disc ratios 0.6 at presentation, out of which 5 patients (31.3%) had corresponding glaucomatous visual field defect on automated Humphrey visual field (HVF) testing. These 5 patients were diagnosed with glaucoma and were managed accordingly. Seven patients (43.8%) had features that led to a presumptive clinical diagnosis of PSS. Three patients (18.8%) were initially diagnosed with FHI. The remaining 6 patients had clinical features that were not consistent with either of the above hypertensive Ocular Immunology & Inflammation
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Cells 0.5%, flare +, KP
Cells 0.5+, old KPs
Cells 0.5+, old KPs
Cells 0.5+, KP (stellate)
Cells +, KP
Cells 0.5+, KP (stellate)
Cells 3+, flare 2+, large KP (confluent in visual axis) Endothelial plaque Cells 2+, KP Cells 0.5+, KP (confluent, stellate) Cells +, KP (stellate)
Cells +, KP
Cells +, KP
Cells 2+, flare +, KP (Stellate) Cells +, KP
Cells 2+, KP
Cells 2+, KP (stellate)
Inflammation
Corneal edema Iris atrophy
Iris atrophy RAPD
Iris atrophy
Corneal edema
Heterochromia Iris atrophy –
Corneal edema Heterochromia Iris atrophy – Corneal edema Iris atrohy –
6/15
6/18
6/9
6/7.5
6/7.5
6/18
6/9
6/12 6/6
6/9
6/9
6/9
6/9
– Corneal edema Peripheral anterior synechiae –
6/12
6/6
6/9
Initial BCVA
Iris atrophy, RAPD Corneal oedema Iris atrophy
–
Anterior segment
Ocular findings
67
13
15
61
27
36
12
32 52
48
17
42
10
27
62
50
Initial IOP (mmHg)
Recurrent
Recurrent
Recurrent
Recurrent
Recurrent
Recurrent
Chronic
Chronic Chronic
Chronic
Recurrent
Recurrent
Recurrent
Chronic
Chronic
Chronic
Disease course
Uveitic glaucoma Posner-Schlossman syndrome Anterior uveitis of unknown cause Posner-Schlossman syndrome Posner-Schlossman syndrome Posner-Schlossman syndrome Anterior uveitis of unknown cause Fuchs heterochromic iridocyclitis Posner-Schlossman syndrome
Anterior uveitis of unknown cause Uveitic glaucoma
Posner-Schlossman syndrome Fuchs heterochromic iridocyclitis Fuchs heterochromic iridocyclitis Anterior uveitis of unknown cause Posner-Schlossman syndrome
Diagnosis
IOP, intraocular pressure; KP, keratitic precipitates; BCVA, best corrected visual acuity (Snellen); RAPD, relative afferent pupillary defect.
45
1
Patient
Age at onset (years)
Presentation
TABLE 1. Patient characteristics with CMV anterior uveitis.
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53
48
1
17
1
216
27
2 38
24
26
7
3
14
3
18
Time to diagnosis (months)
Glaucoma
Glaucoma
Glaucoma
Glaucoma
Glaucoma
Complications
Cytomegalovirus Uveitis 3
4
J. H. Woo et al.
uveitic syndromes and hence they were provisionally treated for anterior uveitis of unknown cause, complicated by glaucoma. The median follow-up period was 46.5 months (range 13–240), while the median time to diagnosis was 39.0 months (range 1–216). Nine patients (56.3%) had a recurrent course of disease while 7 patients (43.7%) developed a chronic uveitis.
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DISCUSSION The majority of patients with CMV anterior uveitis presented with sudden onset unilateral eye redness, pain, and mild blurring of vision. Such symptoms often coincided with findings of anterior chamber inflammation, keratitic precipitates, and elevated IOP. Some patients also had associated findings of sectoral iris atrophy and heterochromia. Our findings were in general agreement with the variable clinical presentation of CMV uveitis patients in existing literature. Bloch-Michel et al. first suggested the possible role of CMV in the pathogenesis of PSS after demonstrating local production of CMV-specific antibodies in the aqueous humor.7 This was further substantiated by evidence of CMV DNA from quantitative PCR in a patient during an acute relapse of clinical PSS.5 Markomichelakis et al. reported 2 cases of recurrent anterior uveitis with sectoral iris atrophy and ocular hypertension during attacks caused by CMV, as proven by PCR assay of aqueous.1 De Schryver et al., on the other hand, described 5 immunocompetent patients with unilateral anterior uveitis without iris atrophy.2 Similarly, van Boxtel et al. reported 7 cases of mild isolated unilateral chronic and/or recurrent anterior uveitis associated with increased IOP and findings of diffuse keratitic precipitates and focal corneal haze/ edema secondary to endotheliitis. Examination of the aqueous humor by PCR demonstrated CMV-DNA in 6 of these patients, while the Goldmann-Witmer coefficient was strongly positive in 80% of patients.4 More recently, in a retrospective case series, Chee et al. noted 24 out of 105 eyes with hypertensive anterior uveitis to be positive for CMV, for which 18 presented with clinical PSS and 5 presented with FHI.3 In the current series, we also observed a preponderance of disease onset in the middle or older age groups, especially among male patients, similar to previously reported findings.1–5,8–12 Most patients in the current study had good initial BCVA and lowgrade anterior chamber inflammation. Six patients had an abnormal cup–disc ratio, out of which 5 demonstrated corresponding glaucomatous visual field defects suggestive of undetected chronic subclinical disease with recurrent episodes of ocular hypertension. However, not all patients presented
with an elevated IOP. It was noted that 5 patients had presented with IOP ranging from 10 to 17 mmHg. However, on further follow-up, maximal IOP values ranging from 18 to 35 mmHg were recorded for these patients, which may be complicated by steroid response. Elevated IOP is a common (though not pathognomonic) feature of CMV uveitis3 and has been attributed to direct viral trabeculitis or obstruction of the trabeculum by inflammatory debris. However, our observations suggest that CMV uveitis patients may present without any elevation in IOP during episodes of acute attacks. Therefore, careful longitudinal monitoring of IOP is warranted in order to detect any significant rise in IOP or visual field defects. Half of the eyes (8 out of 16) had sectoral iris atrophy on examination, a common feature in herpetic uveitis, which is postulated to be due to ischemic necrosis of the iris stroma as a result of direct viral invasion or vasculitis. This is also consistent with findings of CMV in the smooth muscle cells of the iris.13 Both diffuse3 and sectoral1 iris atrophy have been reported in CMV uveitis, although the latter may be more specific for herpetic anterior uveitis caused by either HSV or VZV.14 Only 1 patient presented with an endothelial plaque, suggestive of concurrent corneal endotheliitis, a unique feature that may represent a more severe disease. It has been postulated that corneal endothelial damage may have resulted from the interplay of the immunologic response triggered by the reactivation of latent CMV infection in the anterior chamber and the dynamic immunoregulatory processes in anterior chamber-associated immune deviation (ACAID).15 It is important to note that the constellation triad of anterior uveitis, diffuse iris atrophy, and elevated IOP are not specific to CMV infection. Similar features have been observed and described in herpetic uveitides caused by HSV and VZV. Various pathogens, other than CMV, have also been implicated in the pathogenesis of PSS and FHI-like syndromes. Yamamoto et al. demonstrated the presence of amplified genomic fragments of HSV in the aqueous samples of PSS patients during acute attacks, using PCR assay and Southern blot hybridization.16 In addition, HSV and Rubella DNA have also been implicated in FHI.17–20 There is considerable overlap between different viruses with regards to their purported role in causing hypertensive anterior uveitis.21 As such, the variable features seen in CMV uveitis may represent a spectrum of clinical expression of viral infection in the eye, not specific to any particular pathogen. Hypertensive uveitic syndromes such as PSS and FHI, which also exhibit wide variations in clinical manifestations,22 may be part of this spectrum of ocular infections, rather than distinct clinical entities. In addition, the confinement of CMV Ocular Immunology & Inflammation
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Cytomegalovirus Uveitis infection to the anterior segment bears testament to host immunocompetency. In the immunocompetent murine model, CMV only causes a transient, self-limiting anterior segment reaction with minimal posterior segment involvement. However, in immunocompromised mice, the ocular infection is potentiated, culminating in necrotizing retinitis, analogous to the CMV retinitis in immunosuppressed humans.23 We believe that the infective process is represented clinically by a range of inflammatory responses (in the individual eye) to the inciting virus, subjected to factors such as the immune status of the host, the unique immune-privileged properties of the anterior chamber, and virulence of the pathogen. Qualitative PCR analysis of aqueous was performed with the finding of CMV DNA as the presumptive evidence of infection. We acknowledge the limitation of PCR, as the possibility of falsepositive results cannot be excluded because PCR is highly sensitive; moreover, CMV may be latent in leucocytes in the anterior chamber during active inflammation. As the study was retrospective in design, only subjects with either hypertensive anterior uveitis or chronic anterior uveitis of unknown cause and positive results on qualitative PCR analysis of aqueous were included. Information on patients with similar clinical presentation but negative results on PCR analysis was not available. As such, the lack of controls in this series may further limit the validity of detecting CMV DNA in our patients. Ideally, real-time PCR should be performed to demonstrate active viral replication together with quantification of CMV DNA in order to correlate clinical symptoms with viral load. The GoldmannWitmer coefficient is not performed locally, hence we were unable to demonstrate the production of local CMV-specific antibodies in the anterior chamber. Serum CMV IgG antibody levels were also not determined, although isolated titers may not be meaningful, as the seropositivity rate in the local population is around 87%.24 However, we feel the consistent findings of CMV DNA in our patients justify the use of qualitative PCR analysis in the diagnosis of CMV uveitis. In conclusion, our patients represent a spectrum of clinical manifestations of CMV anterior uveitis. The majority of our patients presented with eye redness, pain, good initial visual acuity, mild anterior chamber inflammation, keratitic precipitates, sectoral iris atrophy, and high IOP. However, some patients may have mild or no symptoms with normal IOP. In view of the overlapping features with other herpetic ocular infections and hypertensive uveitic syndromes, a high index of suspicion of a possible viral etiology and subsequent accurate identification of the virus involved are fundamental to the overall therapeutic approach. !
2014 Informa Healthcare USA, Inc.
5
DECLARATION OF INTEREST The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
REFERENCES 1. Markomichelakis NN, Canakis C, Zafirakis P, et al. Cytomegalovirus as a cause of anterior uveitis with sectoral iris atrophy. Ophthalmology. 2002;109:879–882. 2. de Schryver I, Rozenberg F, Cassoux N, et al. Diagnosis and treatment of cytomegalovirus iridocyclitis without retinal necrosis. Br J Ophthalmol. 2006;90:852–855. 3. Chee SP, Bacsal K, Jap A, et al. Clinical features of cytomegalovirus anterior uveitis in immunocompetent patients. Am J Ophthalmol. 2008;145:834–840. 4. 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: 1358–1362. 5. Teoh SB, Thean L, Koay E. Cytomegalovirus in aetiology of Posner-Schlossman syndrome: evidence from quantitative polymerase chain reaction. Eye. 2005;19: 1338–1340. 6. Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature (SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical data. Results of the First International Workshop. Am J Ophthalmol. 2005;140:509–516. 7. 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: 95–96. 8. Chee SP, Jap A. Presumed Fuchs heterochromic iridocyclitis and Posner-Schlossman syndrome: comparison of cytomegalovirus-positive and negative eyes. Am J Ophthalmol. 2008;146:883–889. 9. Mietz H, Aisenbrey S, Ulrich Bartz-Schmidt K, et al. Ganciclovir for the treatment of anterior uveitis. Graefes Arch Clin Exp Ophthalmol. 2000;238:905–909. 10. Chung RS, Chua CN. Intravitreal ganciclovir injections in aqueous cytomegalovirus DNA positive hypertensive iritis. Eye. 2006;20:1078–1080. 11. Yamauchi Y, Suzuki J, Sakai J, et al. A case of hypertensive keratouveitis with endotheliitis associated with cytomegalovirus. Ocul Immunol Inflamm. 2007;15:399–401. 12. Sira M, Murray PI. Treatment of cytomegalovirus anterior uveitis with oral valaciclovir. Ocul Immunol Inflamm. 2007; 15:31–32. 13. Daicker B. Cytomegalovirus panuveitis with infection of corneo-trabecular endothelium in AIDS. Ophthalmologica. 1988;197:169–175. 14. Siverio Junior CD, Imai Y, Cunningham Jr ET. Diagnosis and management of herpetic anterior uveitis. Int Ophthalmol Clin. 2002;42:43–48. 15. Koizumi N, Suzuki T, Uno T, et al. Cytomegalovirus as an etiologic factor in corneal endotheliitis. Ophthalmology. 2008;115:292–297. 16. Yamamoto S, Pavan-Langston D, Tada R, et al. Possible role of herpes simplex virus in the origin of Posner-Schlossman syndrome. Am J Ophthalmol. 1995;119:796–798. 17. Barequet IS, Li Q, Wang Y, et al. Herpes simplex virus DNA identification from aqueous fluid in Fuchs heterochromic iridocyclitis. Am J Ophthalmol. 2000;129: 672–673.
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J. H. Woo et al. 22. Brooks AM, Grant G, Young T, et al. Cyclitic glaucoma. Aust N Z J Ophthalmol. 1989;17:157–164. 23. Bale Jr JF, O’Neil ME, Folberg R. Murine cytomegalovirus ocular infection in immunocompetent and cyclophosphamide-treated mice: potentiation of ocular infection by cyclophosphamide. Invest Ophthalmol Vis Sci. 1991;32: 1749–1756. 24. Wong A, Tan KH, Tee CS, et al. Seroprevalence of cytomegalovirus, toxoplasma and parvovirus in pregnancy. Singapore Med J. 2000;41:151–155.
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18. Quentin CD, Reiber H. Fuchs heterochromic cyclitis: rubella virus antibodies andgenome in aqueous humor. Am J Ophthalmol. 2004;138:46–54. 19. de Groot-Mijnes JD, de Visser L, Rothova A, et al. Rubella virus is associated with Fuchs heterochromic iridocyclitis. Am J Ophthalmol. 2006;141:212–214. 20. de Visser L, Braakenburg A, Rothova A, et al. Rubella virus-associated uveitis: clinical manifestations and visual prognosis. Am J Ophthalmol. 2008;146:292–297. 21. Jap A, Chee SP. Viral anterior uveitis. Curr Opin Ophthalmol. 2011;22:483–488.
Ocular Immunology & Inflammation
