Topical Ganciclovir in Cytomegalovirus Anterior Uveitis

Abstract

Purpose:

To study the effects of topical ganciclovir 0.15% gel on cytomegalovirus (CMV) anterior uveitis in a tertiary uveitis referral center in Brussels, Belgium.

Methods:

A retrospective study of patients with a clinical diagnosis of CMV anterior uveitis/endotheliitis demonstrated by a positive polymerase chain reaction and/or Goldmann–Witmer coefficient (GWc).

Results:

We report a series of 15 patients presenting clinical characteristics of CMV anterior uveitis. Patients had a pretreatment follow-up of 13.00 ± 12.78 months and a posttreatment follow-up of 42.64 ± 31.23 months. The 14 non-Asian patients (93.3%) had clinical characteristics of Posner–Schlossman syndrome, and the only Asian patient (6.7%) had keratic precipitates like Fuchs heterochromic iridocyclitis. At presentation, uveitis was unilateral in all patients, visual acuity (VA) was 0.91 ± 0.25, and all patients had an increased intraocular pressure (IOP), with a mean IOP of 41.40 ± 10.35 mmHg. At the end of the follow-up, 5 patients (33.3%) had glaucoma, 2 needed glaucoma surgery (13.3%). The mean final VA was 0.93 ± 0.11; 13 patients (86.5%) reached a final VA of 0.7 to 1. Patients had a significantly lower number of recurrences/year posttreatment (0.76 ± 0.57) than in the pretreatment period (3.76 ± 2.44) (P = 0.001). The mean time to recurrence increased from 4.03 months before treatment to 12.58 months after treatment (P = 0.003).

Conclusion:

Our results suggest that patients treated with 0.15% topical ganciclovir have a decreased frequency of CMV anterior uveitis recurrences, most preserve a relatively good central vision over time. However, glaucoma is a frequent and severe complication.

Introduction

Although the majority of anterior uveitis is noninfectious, viruses represent up to 10% of anterior uveitis cases.¹ Until recently, only herpes simplex virus (HSV) and varicella zoster virus (VZV) were identified as a potential cause of herpetic anterior uveitis. However, recent polymerase chain reaction (PCR) techniques have shown that cytomegalovirus (CMV), another member of the Herpesviridae family, could also be responsible for anterior uveitis cases previously considered as idiopathic.^2,3

Since then, CMV was identified by PCR in immunocompetent patients having typically 2 forms of clinical manifestations as follows: an acute recurrent hypertensive form, also known as Posner–Schlossman syndrome (PSS), and a chronic anterior uveitis, with clinical characteristics of Fuchs heterochromic iridocyclitis.^3–5 Endotheliitis may be isolated or associated with anterior uveitis.

Current management of CMV anterior uveitis consists of appropriate antiviral medications and topical antiglaucoma agents with or without topical steroids. CMV infection must be treated with ganciclovir or its prodrug, valganciclovir, because of its resistance to acyclovir. Oral valganciclovir has shown efficacy for the treatment of acute episodes of CMV anterior uveitis with or without endotheliitis.^6–8 Additional approaches include systemic or intravitreal ganciclovir.^6,9 However, repeated injections of intravitreal ganciclovir have obvious limitations,^10,11 as does the long-term use of intravenous ganciclovir or oral valganciclovir, whose long-term side effects include bone marrow suppression and impairment of fertility, has a high cost, and is not available for uveitis treatment in all the countries.

Because CMV anterior uveitis may require years of antiviral therapy to avoid recurrences, there is a need for a safe, effective, and less expensive approach for its management. Topical application of ganciclovir has been shown to penetrate the corneal stroma and achieve therapeutic levels in the aqueous humor.¹² It has been used for the treatment of CMV anterior uveitis, but its effectiveness has been reported in only a limited number of studies.^12–17

The purpose of our study was to study the effects of topical ganciclovir 0.15% gel on CMV anterior uveitis in a tertiary uveitis referral center in Brussels, Belgium.

Methods

We retrospectively retrieved and reviewed the charts of 14 immunocompetent patients and 1 patient under anti-TNFα treatment with CMV anterior uveitis treated with 0.15% topical ganciclovir gel between January 1, 2006 and June 30, 2016 in CHU Saint Pierre, a tertiary referral hospital for uveitis in Brussels, Belgium. The data of those 15 patients with unilateral hypertensive uveitis with a positive CMV in the aqueous humor demonstrated by PCR and/or Goldmann–Witmer coefficient (GWc) were included in our study. The study design adhered to the Declaration of Helsinki. The use of ganciclovir gel 0.15% was approved by each patient, and an institutional review board approval for the record review was obtained.

Aqueous analysis

An anterior chamber paracentesis was performed in all patients during an active episode of uveitis. In the operating room, the eye was sterilized using 5% diluted povidone–iodine, and an eyelid speculum was inserted. The tap was performed using a sterile syringe with a 27G needle. A 0.1–0.2 mL sample of aqueous humor was collected and sent immediately to the laboratory where standard PCR-real time procedure for CMV, HSV1, HSV2, VZV, and rubella viruses was performed. In selected cases highly suggestive of CMV anterior uveitis with negative PCR results for CMV, the aqueous tap was repeated for new PCR analysis, and/or, in some of them, sent for a GWc calculation to the laboratory of virology at Utrecht.¹⁸ The GWc was considered positive when its value exceeded 3.

Inclusion and exclusion criteria

Patients with positive PCR and/or GWc were classified as having anterior recurrent or chronic inflammation according to the Standardization of Uveitis Nomenclature (SUN) criteria.¹⁹

PSS diagnosis was made after the following features were identified: recurrent attacks of unilateral mild anterior uveitis (few large keratic precipitates, flare, and cells ≤1+) with highly elevated intraocular pressure (IOP) and initially rapid resolution after the administration of topical steroids and hypotensive drugs.

Fuchs heterochromic iridocyclitis was diagnosed in patients presenting diffuse stellate keratic precipitates, mild anterior chamber reaction with or without Koeppe's nodules, atrophy and depigmentation of the iris, with or without heterochromia, and a variable grade of vitreous inflammation, but who show no ciliary reaction, no posterior synechiae, and no retinal involvement unless the patient had been previously submitted to surgery.

CMV corneal endotheliitis was defined as corneal edema, which may be localized or diffused, with keratic precipitates posteriorly located to the inflamed endothelial cells (coin-shaped lesions) with variable anterior chamber cells, absence of posterior synechiae, vitritis, and retinitis; this is a typical coin-shaped appearance.²⁰

Exclusion criteria were patients with other associated diagnosis of uveitis, including patients with positive PCR or positive GWc for other virus (HSV, rubella, and VZV) or toxoplasmosis, patients treated with any other form of ganciclovir therapy (intravitreal or systemic), and patients with posterior CMV (retinitis) in immunocompromised patients.

Main outcome measures

Main outcome measures were initial and final best corrected visual acuity (BCVA) using decimal charts, number of recurrences/year before and after initiation of treatment, development of glaucoma at the end of the follow-up period, and mean time to recurrence before and after treatment.

Course of uveitis

Recurrence was defined as the presence of active inflammation, the apparition of new endothelial keratic precipitates, with or without elevated IOP. Time-to-recurrence was defined as the duration between the end of 1 episode of uveitis to the start of the next episode. The number of recurrences, as well as the time to recurrence, was evaluated before and after the initiation of topical ganciclovir.

Glaucoma was diagnosed when patients developed characteristic optic nerve cupping with corresponding glaucomatous visual field defect on automated Humphrey visual field testing and/or defects in retinal nerve fiber layer thickness measured by optical coherence tomography (OCT RNFL) as previously described.²¹ The number and type of antiglaucomatous medications were recorded, as well as the number and type of glaucoma surgery.

Statistical analysis

Continuous variables are summarized by means and corresponding standard deviations. Categorical data are presented by frequencies and percentages.

Statistical analysis was performed using the Shapiro–Wilk test to compare the number of attacks per year before and after the initiation of treatment.

Results

Fifteen patients presenting with CMV anterior uveitis were included in our study (Fig. 1). The results are summarized in Table 1. Ten patients (66.7%) were males and 5 (33.3%) were females. Mean age at diagnosis was 36.93 ± 12.36 years.

FIG. 1.

Cornea of the left eye of a patient with unilateral CMV related anterior uveitis and endotheliitis (PCR: CMV+, HSV1−, HSV2−, VZV−, Rubeole−). Top left: slit lamp view showing a keratic precipitate on the inferior part of the cornea related to the anterior uveitis and keratic precipitates located at the superior part of the cornea associated with endotheliitis (coin-shape lesion). Top right: CMV related endotheliitis and stromal inflammation with immune ring, down: pigmented large keratic precipitates related to the CMV anterior uveitis. CMV, cytomegalovirus; HSV, herpes simplex virus; PCR, polymerase chain reaction; VZV, varicella zoster virus.

Table 1.

Demographic Data and Initial Clinical Manifestations of Patients with Cytomegalovirus-Positive Patients Presenting with Posner–Schlossman Syndrome or Fuchs Heterochromic Iridocyclitis

Patients characteristics
Number of diseased eyes (n)	15
Age at diagnosis (years) (mean ± SD)	36.93 ± 12.36
Sex, n (%)
M	10 (66.7)
F	5 (33.3)
Uveitis, n (%)
PSS	14 (93.3)
FHI	1 (6.7)
Associated endotheliitis, n (%)	4 (26.7)
Lens status, n (%)
Phakic	13 (86.7)
Pseudophakic	2 (13.3)
Mean IOP at diagnosis (mmHg) (mean ± SD)	41.40 ± 10.35
Initial BCVA (mean ± SD)	0.91 ± 0.25
Follow-up duration before diagnosis (months) (mean ± SD)	13.00 ± 12.78
Diagnosis confirmation, n (%)
PCR	12 (80.0)
GWc	3 (20.0)

BCVA, best corrected visual acuity; F, female; FHI, Fuchs heterochromic iridocyclitis; GWc, Goldmann–Witmer coefficient; IOP, intraocular pressure; M, male; N, number; PCR, polymerase chain reaction; PSS, Posner–Schlossman syndrome; SD, standard deviation.

Uveitis was unilateral in all patients (100%). The 14 non-Asian patients (93.3%) had clinical characteristics of PSS, and the only Asian patient (6.7%) had the typical keratic precipitates of Fuchs heterochromic iridocyclitis with very rare cells in the vitreous. No patient had posterior synechiae or iris atrophy. Four patients (26.7%) had associated endotheliitis. Two patients (13.3%) were pseudophakic at presentation; uveitis started 3 months after cataract surgery in 1 patient. The posterior changes observed in our patients were limited to glaucomatous change. In particular, the vitreous was quiet in all patients. All patients had an increased IOP at presentation, with a mean IOP of 41.40 ± 10.35 mmHg [23–56 mmHg] and 1 patient presented initially with glaucoma (6.7%). Mean BCVA at presentation was 0.91 ± 0.25.

The diagnosis was confirmed by a positive PCR in 12 patients (80%) and by a positive GWc in 3 patients (20%) who had initially a negative PCR with clinical characteristics highly suggestive of PSS and had, therefore, a GWc secondary performed.

Patients had a pretreatment follow-up of 13.00 ± 12.78 months and a posttreatment follow-up of 42.64 ± 31.23 months.

Patients were initially managed with topical steroids and topical antiglaucoma therapy (mainly beta-blockers, alpha-2 adrenergic agonists, or carbonic anhydrase inhibitor) or systemic acetazolamide when the IOP was elevated (defined as greater than 21 mmHg), which was tapered progressively according to the severity of inflammation and IOP at each recurrence.

Once the diagnosis was confirmed, at each recurrence, patients were started on topical ganciclovir minimum 5 times a day, tapered based on anterior chamber inflammation over the course of 3 months, and subsequently kept on long-term maintenance therapy (3–4 times/day). They were concurrently treated with topical steroids and topical antiglaucoma medications as necessary.

At the end of the follow-up, 5 patients had cataract and 3 (23.08%) had a cataract surgery consisting in a phacoemulsification and intraocular lens (IOL) insertion without any complication. Five patients (33.3%) had glaucoma; 2 had a glaucoma surgery (13.3%) by trabeculectomy with mitomycin C. The mean final BCVA was 0.93 ± 0.11; 13 patients (86.5%) reached a final VA of 0.7 to 1. However, 2 patients had a final BCVA of counting fingers, resulting from severe glaucomatous damage of the optic nerve, despite intensive medical and surgical glaucoma treatment.

Mean pretreatment duration of anterior inflammation of each recurrence was 1.97 weeks; mean posttreatment duration was 2.23 weeks (P = 0.68). However, patients had a significantly lower number of recurrences/year posttreatment (0.76 ± 0.57) than in the pretreatment period (3.76 ± 2.44) (P = 0.001) (Fig. 1). The mean time to recurrence before treatment was 4.03 months, and it was significantly increased after treatment to 12.58 months (P = 0.003). No significant side effects, such other than ocular discomfort from topical ganciclovir application or slight ocular surface toxicity, were noted in our patients.

Discussion

CMV anterior uveitis and endotheliitis are recent diagnoses. Most studies focused on etiological factors of anterior segment inflammation with ocular hypertension or corneal endotheliitis in immunocompetent individuals,^2,22–25 but few studies debated on the clinical course, the treatment, and long-term visual prognosis of CMV anterior uveitis, especially in Europe.¹⁷

CMV has been implicated in the etiology of PSS and Fuchs heterochromic iridocyclitis after the recent advances in the identification of the viral genome by PCR or the calculation of the GWc. PCR is a better early detection test especially when a cellular inflammation in the anterior chamber is present, while the GWc allows for a later diagnosis, when no cells are observed in the anterior chamber. The combination of the 2 tests gives naturally a higher probability of diagnosis.^18,26

The most appropriate therapy for CMV anterior uveitis in immunocompetent patients has not yet been established. Once the diagnosis is confirmed, management of CMV anterior uveitis with or without endotheliitis is based on antiviral treatment usually with topical antiglaucoma medication and topical corticosteroids.

Several studies have evaluated the safety and efficacy of oral valganciclovir, intravenous or intravitreal ganciclovir in the treatment of acute CMV uveitis, with complete remission of inflammation, keratic precipitates, and corneal edema in the majority of cases.^6,10 However, the long-term use of systemic ganciclovir is limited by its systemic side effects and cost. Hence, topical ganciclovir therapy has been proposed to treat the acute episodes and to prevent recurrences.

A recent study by Koizumi et al.¹² showed that detectable levels of ganciclovir were found in the aqueous humor of all the eyes treated with 0.15% topical ganciclovir 6 times daily for 12 weeks, confirming the drug transfer of this molecule into the anterior chamber, with clinical improvement of keratic precipitates, corneal edema, and anterior chamber inflammation in patients with CMV corneal endotheliitis. Five other studies^13–17 have equally displayed positive results with topical ganciclovir for the treatment of CMV anterior uveitis with or without endotheliitis, as shown in Table 2, but the series had a limited number of patients, the concentration of the drug was different, and the treatment schedule proposed was not identical in all these studies. The number of patients included in previous studies varied between 1 and 68 patients, the concentration of topical ganciclovir ranged between 0.15% and 2%, it was applied 6 to 8 times/day as an induction therapy, and kept for 1 to 4 times/day as a maintenance therapy. The follow-up duration after initiation of therapy varied between 3 and 87 months (Table 2).

Table 2.

Summary of the Major Published Series of Cytomegalovirus AU ± E Treated with Topical Ganciclovir

Authors	Number of eyes	Treatment	Results	Follow-up duration (months)
Wong et al.¹³	33	Topical ganciclovir 0.15% 6 times/day, tapered over 3 months, then kept on long-term maintenance therapy (3–4 times/day) for 9.1 ± 2.5 months	Reduction of the frequency of recurrence, but no significant influence on the time-to-recurrence or the time-to-quiescence in patients with CMV anterior uveitis	Unknown
Fan et al.¹⁴	10	Topical ganciclovir 0.5%, 8 times a day then kept on long-term maintenance therapy 4 times/day	Long-term preservation of corneal endothelial function in patients with cytomegalovirus corneal endotheliitis	48 ± 25 [17–78]
Delwig et al.¹⁵	1	1% valganciclovir ointment at night as maintenance therapy	No recurrence of PSS episodes	9
Koizumi et al.¹²	7	Topical 0.15% ganciclovir 6 times daily for 3 months	Detectable levels of ganciclovir were confirmed in the aqueous humor of all the eyes.	3
			Clinical improvement and reduced number of CMV copies in the aqueous humor were confirmed in the CMV corneal endotheliitis cases.
Su et al.¹⁶	68	Topical 2% ganciclovir, every 2–3 h daily as an induction therapy, then every 4 h as a long-term maintenance therapy	Ganciclovir treatment was effective for clearing the viral load, assisting the IOP control, and preserving the corneal endothelium of CMV-positive PSS patients	39.79 ± 14.96
Accorinti et al.¹⁷	15	Topical ganciclovir, 5 times daily for 2 weeks then 3 times daily for at least 4 weeks	Reduction of the frequency of relapses in cytomegalovirus anterior uveitis	58 ± 29.6

AU, anterior uveitis; CMV, cytomegalovirus; E, endotheliitis; IOP, intraocular pressure; PSS, Posner–Schlossman syndrome.

Our study confirms these previous studies and shows that an initial attack treatment with 0.15% topical ganciclovir applied at least 5 times a day then tapered to be maintained 3 times/day as a maintenance treatment decreases the frequency of recurrences of CMV anterior uveitis/endotheliitis with a longer mean time to recurrence. The choice to administer the topical ganciclovir 5 times daily was based on the herpetic use of this drug. On a pure empirical basis, to decrease a potential toxic effect of the drug, we decided to taper the ganciclovir to achieve the minimum dose that controls the inflammation. In 1 patient treated after the recent publications showing the partial efficacy of topical ganciclovir results 6 times daily, we decided to administer the topical ganciclovir 8 times daily without corticosteroid and had consequently no recurrence for 1 year (unpublished data). Most treated patients preserved a relatively good central vision over time. However, the period of follow-up and observation after initiation of topical ganciclovir 0.15% gel were larger than the period before initiation of therapy. This discrepancy in the follow-up period could have influenced the results obtained, but we evaluated the number of attacks/year to limit the influence of this confounding factor.

Current management of CMV anterior uveitis/endotheliitis emphasizes the importance of early diagnosis and prompt treatment to avoid the severe ocular complications, characterized by severe glaucomatous damage, cataract, and corneal decompensation.²⁷

In our series, 5 patients (33.3%) had glaucoma with alteration of visual field, RNFL, and OCT, and 2 patients had glaucoma surgery (13.3%) to control IOP. The posterior changes observed in our patients were limited to glaucomatous change. In particular, the vitreous was quiet. Our results are similar to Wong et al. and Woo et al. who reported 31% of glaucoma among their patients with 21% requiring glaucoma surgery.^13,22 Cataract, and the consecutive cataract surgery, is the second most frequent complication of CMV uveitis in our series (23.08%). Cataract is principally due to the inflammation and corticosteroid therapy. Phacoemulsification and IOL implantation were a safe procedure in all the patients. From our data, we cannot ascertain whether a prompt specific uveitis treatment with topical ganciclovir was able to avoid or to delay glaucoma progression or cataract formation, because of the absence of a control group.

In CMV endotheliitis, previous retrospective studies showed that recurrences of CMV endotheliitis produce a detrimental effect on corneal endothelium, with 40% of patients failing to retain corneal clarity.^24,28 We were unable to get reliable endothelial cell count in most patients, especially when there was a corneal edema, to confirm this finding. Thus we cannot confirm if 0.15% topical ganciclovir gel prevented the decrease of corneal endothelial cells but none of our patients presented irreversible corneal decompensation in our series.

In conclusion, CMV anterior uveitis is an uncommon cause of uveitis in Europe, while probably underdiagnosed. It might present either typically as a sudden onset entity with an acute limited course, as described in PSS in most patients of our study, or with an insidious onset and a persistent chronic course like Fuchs heterochromic iridocyclitis in the only Asian patient of study. Glaucoma is the most common and harmful complication, with the need in some cases for a surgery to control the IOP.

Our results suggest that patients treated with 0.15% topical ganciclovir gel have a decreased frequency of CMV anterior uveitis recurrences, have no ocular or systemic side effects due to treatment, and preserve a relatively good central vision over time.

However, larger multicenter clinical trials are needed to consolidate and fully validate our results.

Footnotes

Acknowledgment

Thanks to Mr. Jean-François Fils for performing the statistics.

Author Disclosure Statement

No competing financial interests exist.

References

Rodriguez

, Calonge

, Pedroza-Seres

, Akova

Y.A.

, Messmer

E.M.

, D'Amico

D.J.

, et al. Referral patterns of uveitis in a tertiary eye care center. Arch. Ophthalmol., 114:593–599, 1996.

Teoh

S.-B.

, Thean

, and Koay

Cytomegalovirus in aetiology of Posner-Schlossman syndrome: evidence from quantitative polymerase chain reaction. Eye Lond. Engl., 19:1338–1340, 2005.

Markomichelakis

N.N.

, Canakis

, Zafirakis

, Marakis

, Mallias

, and Theodossiadis

Cytomegalovirus as a cause of anterior uveitis with sectoral iris atrophy. Ophthalmology. 109:879–882, 2002.

van Boxtel

L.A.A.

, van der Lelij

, van der Meer

, and Los

L.I.

Cytomegalovirus as a cause of anterior uveitis in immunocompetent patients. Ophthalmology. 114:1358–1362, 2007.

de Schryver

, Rozenberg

, Cassoux

, Michelson

, Kestelyn

, Lehoang

, et al. Diagnosis and treatment of cytomegalovirus iridocyclitis without retinal necrosis. Br. J. Ophthalmol., 90:852–855, 2006.

Chee

S.-P.

, and Jap

Cytomegalovirus anterior uveitis: outcome of treatment. Br. J. Ophthalmol., 94:1648–1652, 2010.

Sira

, and Murray

P.I.

Treatment of cytomegalovirus anterior uveitis with oral valaciclovir. Ocul. Immunol. Inflamm., 15:31–32, 2007.

Wong

V.W.

, Chan

C.K.

, Leung

D.Y.

, and Lai

T.Y.

Long-term results of oral valganciclovir for treatment of anterior segment inflammation secondary to cytomegalovirus infection. Clin. Ophthalmol., 6:595–600, 2012.

Mietz

, Aisenbrey

, Ulrich Bartz-Schmidt

, Bamborschke

, and Krieglstein

G.K.

Ganciclovir for the treatment of anterior uveitis. Graefes Arch. Clin. Exp. Ophthalmol., 238:905–909, 2000.

10.

Hwang

Y.-S.

, Lin

K.-K.

, Lee

J.-S.

, Chang

S.H.L.

, Chen

K.-J.

, Lai

C.-C.

, et al. Intravitreal loading injection of ganciclovir with or without adjunctive oral valganciclovir for cytomegalovirus anterior uveitis. Graefes Arch. Clin. Exp. Ophthalmol., 248:263–269, 2010.

11.

Sampat

K.M.

, and Garg

S.J.

Complications of intravitreal injections. Curr. Opin. Ophthalmol., 21:178–183, 2010.

12.

Koizumi

, Miyazaki

, Inoue

, Ohtani

, Kandori-Inoue

, Inatomi

, et al. The effect of topical application of 0.15% ganciclovir gel on cytomegalovirus corneal endotheliitis. Br. J. Ophthalmol., 101:114–119, 2017.

13.

Wong

J.X.H.

, Agrawal

, Wong

E.P.Y.

, and Teoh

S.C.

Efficacy and safety of topical ganciclovir in the management of cytomegalovirus (CMV)-related anterior uveitis. J. Ophthalmic. Inflamm. Infect., 6:10, 2016.

14.

Fan

N.-W.

, Chung

Y.-C.

, Liu

Y.-C.

, Liu

C.J.-L.

, Kuo

Y.-S.

, and Lin

P.-Y.

Long-term topical ganciclovir and corticosteroids preserve corneal endothelial function in cytomegalovirus corneal endotheliitis. Cornea, 35:596–601, 2016.

15.

Delwig

, Keenan

J.D.

, and Margolis

T.P.

Topical valganciclovir for the treatment of hypertensive anterior uveitis. Cornea, 34:1513–1515, 2015.

16.

C.-C.

, Hu

F.-R.

, Wang

T.-H.

, Huang

J.-Y.

, Yeh

P.-T.

, Lin

C.-P.

, et al. Clinical outcomes in cytomegalovirus-positive Posner-Schlossman syndrome patients treated with topical ganciclovir therapy. Am. J. Ophthalmol., 158:1024–1031.e2, 2014.

17.

Accorinti

, Gilardi

, Pirraglia

M.P.

, Amorelli

G.M.

, Nardella

, Abicca

, et al. Cytomegalovirus anterior uveitis: long-term follow-up of immunocompetent patients. Graefes Arch. Clin. Exp. Ophthalmol., 252:1817–1824, 2014.

18.

Van der Lelij

, Ooijman

F.M.

, Kijlstra

, and Rothova

Anterior uveitis with sectoral iris atrophy in the absence of keratitis: a distinct clinical entity among herpetic eye diseases. Ophthalmology. 107:1164–1170, 2000.

19.

Trusko

, Thorne

, Jabs

, Belfort

, Dick

, Gangaputra

, et al. The Standardization of Uveitis Nomenclature (SUN) Project. Development of a clinical evidence base utilizing informatics tools and techniques. Methods Inf. Med., 52:259–265, S1–S6, 2013.

20.

Chee

S.-P.

, and Jap

Immune ring formation associated with cytomegalovirus endotheliitis. Am. J. Ophthalmol., 152:449–453.e1, 2011.

21.

Lewkowicz

, Willermain

, Relvas

L.J.

, Makhoul

, Janssens

, et al. Clinical outcome of hypertensive uveitis. J. Ophthalmol., 2015:974870, 2015.

22.

Woo

J.H.

, Lim

W.K.

, Ho

S.L.

, and Teoh

S.C.

Characteristics of cytomegalovirus uveitis in immunocompetent patients. Ocul. Immunol. Inflamm., 23:378–383, 2015.

23.

Takase

, Kubono

, Terada

, Imai

, Fukuda

, Tomita

, et al. Comparison of the ocular characteristics of anterior uveitis caused by herpes simplex virus, varicella-zoster virus, and cytomegalovirus. Jpn. J. Ophthalmol., 58:473–482, 2014.

24.

Koizumi

, Inatomi

, Suzuki

, Shiraishi

, Ohashi

, Kandori

, et al. Clinical features and management of cytomegalovirus corneal endotheliitis: analysis of 106 cases from the Japan corneal endotheliitis study. Br. J. Ophthalmol., 99:54–58, 2015.

25.

Hedayatfar

, and Chee

S.-P.

Posner-Schlossman syndrome associated with cytomegalovirus infection: a case series from a non-endemic area. Int. Ophthalmol., 34:1123–1129, 2014.

26.

Yamamoto

, Pavan-Langston

, Kinoshita

, Nishida

, Shimomura

, and Tano

Detecting herpesvirus DNA in uveitis using the polymerase chain reaction. Br. J. Ophthalmol., 80:465–468, 1996.

27.

Sobolewska

, Deuter

, Doycheva

, and Zierhut

Long-term oral therapy with valganciclovir in patients with Posner-Schlossman syndrome. Graefes Arch. Clin. Exp. Ophthalmol., 252:117–124, 2014.

28.

Ang

, Sng

C.C.A.

, Chee

S.-P.

, Tan

D.T.H.

, and Mehta

J.S.

Outcomes of corneal transplantation for irreversible corneal decompensation secondary to corneal endotheliitis in Asian eyes. Am. J. Ophthalmol., 156:260–266.e2, 2013.