Cytomegalovirus-associated anterior segment infection

Transcription

1 Expert of Ophthalmology ISSN: (Print) (Online) Journal homepage: Cytomegalovirus-associated anterior segment infection Aliza Jap & Soon-Phaik Chee To cite this article: Aliza Jap & Soon-Phaik Chee (2011) Cytomegalovirus-associated anterior segment infection, Expert of Ophthalmology, 6:5, , DOI: /eop To link to this article: Published online: 09 Jan Submit your article to this journal Article views: 285 Citing articles: 4 View citing articles Full Terms & Conditions of access and use can be found at

2 For reprint orders, please contact Cytomegalovirus-associated anterior segment infection Expert Rev. Ophthalmol. 6(5), (2011) Aliza Jap 1,2 and Soon-Phaik Chee 1,3,4 1 Singapore National Eye Centre, 11 Third Hospital Avenue, , Singapore 2 Division of Ophthalmology, Changi General Hospital, 2 Simei Street 3, , Singapore 3 Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore, 10 Kent Ridge Crescent, , Singapore 4 Singapore Eye Research Institute, 11 Third Hospital Avenue, , Singapore Author for correspondence: Tel.: Fax: chee.soon.phaik@snec.com.sg Cytomegalovirus (CMV) has increasingly been found as a cause of anterior segment infection in immunocompetent patients. This may manifest as an endotheliitis or as an acute episodic or chronic recurrent anterior uveitis, which is often associated with ocular hypertension. Its diagnosis is based on aqueous ana lysis for CMV DNA by PCR or for CMV-specific antibodies. Although it has a high response rate to systemic, intravitreal and ganciclovir implant, the relapse rate is also high, and patients may require prolonged treatment. Topical ganciclovir gel has a lower response rate but also a lower relapse rate and fewer adverse effects. The main cause of visual loss in CMV anterior uveitis is glaucoma, and endothelial failure in endotheliitis. Therefore, early diagnosis and treatment is vital, and glaucoma therapy is an important adjunctive modality of management. Keywords: anterior uveitis corneal decompensation endotheliitis ganciclovir ocular hypertension Posner Schlossman syndrome valganciclovir Medscape: Continuing Medical Education Online This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of Medscape, LLC and Expert s. Medscape, LLC is accredited by the AC to provide continuing medical education for physicians. Medscape, LLC designates this Journal-based activity for a maximum of 1 AMA PRA Category 1 Credit(s). Physicians should claim only the credit commensurate with the extent of their participation in the activity. All other clinicians completing this activity will be issued a certificate of participation. To participate in this journal activity: (1) review the learning objectives and author disclosures; (2) study the education content; (3) take the post-test with a 70% minimum passing score and complete the evaluation at (4) view/print certificate. Release date: October 6, 2011; Expiration date: October 6, 2012 Learning objectives Upon completion of this activity, participants will be able to: Describe the clinical presentation of CMV-associated anterior segment infection Describe the diagnosis of CMV-associated anterior segment infection Describe the treatment of CMV-associated anterior segment infection /EOP Expert s Ltd ISSN

3 Jap & Chee Financial & competing interests disclosure Editor Elisa Manzotti Editorial Director, Future Science Group, London, UK. Disclosure: Elisa Manzotti has disclosed no relevant financial relationships. Author Laurie Barclay, MD Freelance writer and reviewer, Medscape, LLC. Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships. Authors and Credentials Aliza Jap, FRCOphth Singapore National Eye Centre, Division of Ophthalmology, Changi General Hospital, Singapore. Disclosure: Aliza Jap, FRCOphth, has disclosed no relevant financial relationships. Soon-Phaik Chee, FRCOphth Singapore National Eye Centre, Department of Ophthalmology, Yong Loo Lin School of Medicine, National University of Singapore; Singapore Eye Research Institute, Singapore. Disclosure: Soon-Phaik Chee, FRCOphth, has disclosed no relevant financial relationships. Cytomegalovirus (CMV) is a member of the herpes virus family and, as with other DNA viruses, life-long latency is a hallmark of CMV infection. Primary CMV infection in immunocompetent individuals is often asymptomatic or may present with only mild nonspecific systemic symptoms, such as fever, generalized fatigue, myalgia and sore throat. However, in patients with AIDS, it can cause severe disease, including encephalitis and pneumonia. Ocular infection from reactivation of latent CMV was originally described in patients with AIDS, where it manifests predominantly as retinitis. In recent years, more and more cases of CMV infection of the anterior segment have been recognized in immunocompetent people also. In developed countries, the seroprevalence of CMV is approximately 50%, whereas it is approximately 90% in lessdeveloped regions [1 4]. Hence, not surprisingly, most of these cases have been from Asian countries, where there is a large reservoir of dormant CMV. In these immunocompetent individuals, ocular involvement consists predominantly of a unilateral anterior uveitis, which may have either an acute recurrent or a chronic persistent course, or as a corneal endotheliitis. Clinical features Anterior uveitis In the past 5 years, 113 cases (110 patients) of CMV-positive anterior uveitis were reported [5 12]; of which, only 13 (11.5%) were from non-asian populations [7,9,11], and CMV-positive anterior uveitis constituted 23% of all hypertensive uveitis eyes seen in one institution [13]. Of these 113 cases, 72 (64%) had an acute recurrent course, 30 eyes (27%) had chronic persistent uveitis, one had sector iris atrophy resembling herpes simplex virus (HSV)/varicella zoster virus (VZV) anterior uveitis and ten had an unknown course [5 14]. Although these eyes shared certain common features, such as elevated intraocular pressure (IOP; 106 eyes [94%]), diffuse iris atrophy (29 eyes [26%]), absence of both posterior synechiae (100%) and posterior segment involvement (99%), there were also important differences between these two entities (Table 1) [5 14]. Acute recurrent uveitis Out of 72 eyes, 71 with acute recurrent disease had been diagnosed previously as having Posner Schlossman syndrome, as the clinical features of both entities were very similar. It typically presents with recurrent episodes of mild iritis with a few keratic precipitates (KPs), a grade of less than 2+ for anterior chamber (AC) cells and epithelial edema from elevated IOP. The eye is quiet with normal IOP inbetween attacks. KPs are usually white and fine-to-medium sized (Figure 1), although one-quarter of the eyes (nine eyes) were also noted to have nodular endothelial lesions [14], which consist of white medium-sized nodular deposits on the endothelium, surrounded by a translucent halo and occasionally accompanied by a spot of brown pigment. Chronic persistent uveitis The KPs in eyes with chronic persistent uveitis are more numerous and diffusely distributed. There is usually a mix of different-sized KPs, ranging from fine stellate or filiform to medium-sized, and occasionally, even of mutton fat appearance [7,8,15]. Nodular endothelial lesions (Figure 2) were seen in 60% (nine eyes) [14]. The AC cellular reaction, again, is generally mild, with 2+ cells or less. Elevated IOP was also a prominent feature, being present in all except seven eyes (76.7%). However, the maximum pressure elevation (mean: 32 mmhg) was lower than that seen in eyes with acute recurrent uveitis (mean: 49 mmhg). Diffuse iris atrophy and cataracts were more common in eyes with chronic persistent disease (67 and 75%, respectively) than in acute recurrent disease (39 and 15%, respectively), and patients with chronic uveitis tended to be older (mean: 55 years) than those with acute recurrent uveitis (mean: 39 years) [14]. One eye also developed arteriolar attenuation with diffuse pigmentary changes, despite the absence of any overt retinitis. This was attributed to possible subclinical CMV retinitis or an auto immune retinopathy, as the patient antiretinal autoantibodies [15]. 518 Expert Rev. Ophthalmol. 6(5), (2011)

4 Cytomegalovirus-associated anterior segment infection Table 1. Literature review of clinical features of cytomegalovirus anterior uveitis in non-hiv-positive patients. Study (year) Eyes (n) Keratic precipitates/ anterior chamber inflammation Intraocular pressure >21 mmhg Iris atrophy Clinical course Glaucoma surgery/ glaucomatous atrophy Comments Ref. Chee (2010, 2008, 2008) 72 (70 patients) Few and fine in acute recurrent disease Diffuse stellate in chronic persistent disease Nodular endothelial lesions: 18 eyes Mild inflammation 14 chronic persistent All acute recurrent Diffuse: 24 eyes Sector iris atrophy: 1 eye Absent: 26 eyes Unknown: 21 eyes 21 chronic persistent 50 acute recurrent 1 presumed HSV/VZV 21 eyes 7 eyes were positive only on repeat taps No clinical difference between CMVpositive and -negative eyes [5,13,14] Hwang (2011) 19 (18 patients) Non-HSV/VZV inflammatory ocular hypertension syndrome All Unknown 16 acute recurrent 3 unknown 5 eyes 2 had persistent corneal edema [6] van Boxtel 7 Fine: 3 eyes Mutton fat: 1 eye Trace to 1+ cells Focal corneal edema (endotheliitis): 2 eyes All Present: 3 eyes Absent: 4 eyes 6 chronic persistent 1 acute recurrent 2 eyes 2 eyes were positive for CMV DNA only at second tap [7] Miyanaga 7 Fine: 2 eyes Mutton fat: 5 eyes 1 2+ cells All Present: 2 eyes Absent: 5 eyes Unknown 2 eyes Association between viral load and corneal endothelial cells loss [8] de Schryver (2006) 5 Grey white or brown medium-to-large keratic precipitates Corneal edema: 2 eyes Mild-to-moderate inflammation All Absent 3 chronic persistent 2 acute recurrent 2 eyes [9] Kawaguchi 1 Whitish small mutton fat Yes Absent Acute recurrent Yes Correlation between laser flare photometry with viral load [10] Sira 1 Single white keratic precipitates 1+ cells Yes Absent Acute recurrent 0 [11] Chung (2006) 1 Medium-sized stellate keratic precipitates Mild inflammation CMV: Cytomegalovirus; HSV: Herpes simplex virus; VZV: Varicella zoster virus. Yes Unknown Acute recurrent 0 [12] 519

5 Jap & Chee Figure 1. Slit-lamp photograph of an eye with acute recurrent cytomegalovirus anterior uveitis showing a few fine- to medium-sized keratic precipitates. Corneal endotheliitis During the same period, 51 eyes of 48 patients with CMV endotheliitis (Figure 3) were analyzed, and all were from Asian populations [6,8,16 24]. Unlike eyes with anterior uveitis, the KPs in eyes with corneal endotheliitis tended to be pigmented, and were often arranged in a linear or coin-shaped pattern (Table 2). The linear KPs tended to occur at the leading edge of the stromal edema. The coin-shaped KPs are usually medium sized, and arranged in a circular pattern around an area of corneal edema [17]. Owl s eyes lesions were seen in two eyes: one on confocal microscopy [20] and one on histology [21]. These owl s eye lesions consist of intranuclear inclusion bodies, and are characteristic of CMV infection [25]. The cornea edema may be localized or diffuse, and the AC inflammation is very mild, having cells less than 1+, and may be absent in some eyes. Rarely, KPs may also be absent [24]. Elevated IOP was a less prominent feature than in anterior uveitis, with only 37 eyes (73%) having elevated IOP and nine eyes (18%) requiring glaucoma surgery. Iris atrophy was less obvious in these eyes, being noted in only 12 eyes (24%). One patient had a simultaneous onset of localized areas of retinitis [19]. Endotheliitis in eyes with previous anterior uveitis It is interesting that 20 eyes had been treated previously for hypertensive anterior uveitis and were receiving corticosteroids at the time of diagnosis of the endotheliitis [6,16 18,23]. Furthermore, two eyes with anterior uveitis had been noted to have concomitant endotheliitis lesions [7]. This suggests that endotheliitis and anterior uveitis are part of the same spectrum of possible clinical presentation of CMV anterior segment infection, and that the particular pattern of manifestation may depend on the host s immune status and/or viral load. The younger age and tendency to a lower viral load in eyes with acute uveitis [14] suggest that it may represent an inflammatory response to a small or short-lived release of viral load, whereas endotheliitis represents direct tissue damage, and the prior use of corticosteroids may have been responsible for transformation in these eyes. Post-corneal graft endotheliitis Of further interest, 14 eyes were diagnosed following corneal graft surgery [6,17 19,22] and one eye had a history of both previous uveitis and graft [21]. These eyes had initially been thought to display endothelial rejection, until linear or coin-shaped KPs were noted, the endothelial cell count decreased unexpectedly or the edema worsened despite an increase in immunosuppressive therapy [19,22]. The source of the CMV infection in these eyes is uncertain. The indications for the initial graft included keratoconus [22], posterior polymorphous dystrophy, pseudophakic bullous keratopathy [18,19], herpetic keratouveitis, Fuchs uveitis syndrome [19], Fuchs endothelial dystrophy [17], recurrent corneal endotheliitis [17] and corneal opacities [17]. Other than the eye that received a graft for keratoconus, whether these eyes already had CMV endotheliitis prior to the graft, the CMV was transmitted from the donor or the prolonged immunosuppressive therapy caused a reactivation of latent CMV, cannot be determined. However, these cases demonstrate that the possibility of CMV infection should be excluded prior to performing a graft or when graft rejection occurs, especially in the presence of atypical KPs. Complications of CMV anterior segment infection Glaucoma At least 42 eyes (26%) required glaucoma surgery or had glaucomatous optic neuropathy [5 10,16,18,19]. However, these figures may under-represent the prevalence of glaucomatous damage as, although glaucoma surgery was indicated when required, most authors did not define nor systemically describe the presence of any glaucomatous optic neuropathy. Endothelial cell loss &/or corneal decompensation Anshu [19] and Miyanaga [8] found severe endo thelial cell loss in their patients, ranging from 35 to 77% (15 eyes [9%]), and, particularly for the 48 treatment episodes of eyes with endotheliitis, 12 (25%) had significant persistent corneal edema despite resolution of inflammation [6,16 19,22,23]. In addition, persistent edema was also seen in two eyes with anterior uveitis [6], of which one was severe enough to require a corneal graft. Focal areas of endotheliitis were also seen in two eyes with anterior uveitis [7]. Cataract formation The prevalence of cataract was also not systemically recorded in most of the studies. However, it was seen in 23 (32%) of the eyes in a large series [5] and, not unexpectedly, it was more prevalent in eyes with chronic uveitis [14]. Pathogenesis The reactivation of CMV in the eye causing ocular disease in immunocompetent patients, especially in Asia, is not unexpected given its high seroprevalence and the life-long latency of this virus in hematopoietic and endothelial cells [26]. Similar to the other herpetic infections, recurrent disease is well documented, and has been attributed to a temporary breakdown in the ocular immune defense mechanisms, as in times of stress 520 Expert Rev. Ophthalmol. 6(5), (2011)

6 Cytomegalovirus-associated anterior segment infection or other illnesses. Furthermore, in eyes with endotheliitis that had a history of prior uveitis or corneal graft, the use of corticosteroids or other immunosuppressants may have enhanced viral replication, resulting in a more severe manifestation of the disease. However, owing to the existence of the blood ocular barrier, the cellular-mediated response to the infection is limited and, hence, it is difficult to control or suppress CMV, even in immunocompetent patients. Differential diagnosis Idiopathic hypertensive anterior uveitis Acute recurrent CMV anterior uveitis has many features in common with Posner Schlossman syndrome, and constituted half of the cases of presumed Posner Schlossman syndrome in one series [14]. The chronic persistent form also has features that resemble Fuchs uveitis syndrome, and CMV was found in 42% of such eyes by Chee and Jap [14]. One eye also presented with sector iris atrophy and was initially diagnosed as HSV/VZV anterior uveitis [13]. The lack of distinguishing features between the CMV-positive and -negative cases in eyes with acute recurrent uveitis [14], as well as the 95% positive predictive value of these features in the series from Hwang [6], suggests that, in Asia certainly, CMV infection should be excluded in eyes with hypertensive anterior uveitis. present as an acute mild uveitis with ocular hypertension or as a chronic, persistent uveitis with the features described previously. These criteria are applied regardless of the descent of the patient. The presence of intraocular CMV may be established by qualitative or quantitative PCR methods [27,28], or by comparing the intraocular CMV-specific antibody levels to serum levels (Goldmann Witmer coefficient). By combining these two techniques the yield may be improved, since, in some of the eyes, the PCR was positive only at repeat taps. This could possibly be owing to a small viral load in a small volume of aqueous available for ana lysis or a short-lived release of the virus, which may be missed on PCR alone, whereas antibody production remains throughout the course of the disease [29]. On the other hand, in immunocompromised patients, PCR may be a more sensitive test [30 32]. Hence, ideally, both of these tests should be done if they are available, as they complement each other. Endothelial rejection post corneal graft In eyes with previous grafts, the KPs occurred on both the donor and host corneas [17,19], unlike in endothelial rejection, where the KPs are seen on the donor. Idiopathic endotheliitis In the series from Kandori, none of the eyes with epithelial or stromal keratitis were positive for CMV, but seven out of 29 cases (24%) of endotheliitis were CMV-positive [18], and CMV was found in at least 90% of cases of endotheliitis in two studies [6,16]. Hence, CMV needs to be excluded in eyes with an apparently idiopathic cause of endotheliitis. Diagnostic tests Although there are certain clinical features that may be useful in increasing the positive-predictive values of aqueous sampling, such as the presence of coin-shaped KPs in eyes with endotheliitis, anterior uveitis with ocular hypertension, diffuse iris atrophy and absence of epithelial or stromal keratitis [6,18], there are no clinical features with sufficient sensitivity nor specificity for the diagnosis of CMV infection to be made on purely clinical grounds [14]. Hence, the diagnosis can only be confirmed on aqueous sampling for evidence of intraocular CMV. However, aqueous ana lysis is an invasive procedure and, therefore, is not practiced for this reason, even in some developed countries. In cases of anterior uveitis, we routinely tap all eyes after having excluded other common causes, such as syphilis, TB, sarcoidosis or HLA-B27-associated anterior uveitis, or unless they have an obvious cause for the inflammation, for example, those with corneal or skin lesions or iris changes typical of HSV/VZV uveitis. Specifically, we would tap those that Figure 2. A 73-year-old male with chronic persistent cytomegalovirus anterior uveitis of the right eye presents with mild redness and a raised intraocular pressure. (A) Slit-lamp photograph of an eye with chronic persistent cytomegalovirus anterior uveitis showing nodular endothelial lesions (arrows) and diffuse iris atrophy. (B) Confocal microscopy of the same eye showing the nodular endothelial lesion (arrow)

7 Jap & Chee Figure 3. Slit-lamp photograph of an eye with cytomegalovirus endotheliitis showing edema of the superior two-thirds of the cornea and a few small keratic precipitates. Management The optimal therapy of CMV anterior segment infection has yet to be established. Current therapy protocols have been based on the results of treatment of CMV retinitis in patients with AIDS. In patients with AIDS, ganciclovir or, more recently, valganciclovir therapy, is efficacious and can often be discontinued as immune recovery occurs in patients on retroviral therapy. Ganciclovir is a synthetic purine nucleoside analogue with good anti-cmv activity and relatively fewer adverse effects. It has been used for the treatment of CMV retinitis since the late 1980s in intravenous, oral or intravitreal formulations, with the route being determined by the location, severity of the retinitis, immune status of the patient, costs and occurrence of side effects. Valganciclovir is a prodrug of ganciclovir, which is rapidly converted to ganciclovir following oral administration, and is able to achieve similar plasma levels with a once-daily dosing as ganciclovir. In accordance with the management of CMV retinitis in AIDS patients, systemic ganciclovir or valganciclovir has been the first line of treatment of CMV anterior segment infection in most centers, with intravitreal ganciclovir as a second-line therapy. The ganciclovir implant (Vitrasert, Bausch and Lomb Inc., CA, USA), which releases 4.5 mg of ganciclvoir over 5 8 months, is an alternative modality for patients who have recurrent inflammation following previous response to systemic therapy but had issues with side effects. Topical ganciclovir was originally developed for the treatment of herpetic keratitis, but it has been found to achieve high concentrations in the cornea, iris tissue and aqueous, especially with the 0.2% gel [33]. It is commercially available as an ophthalmic gel under the trade names of Virgan and Zirgan from Laboratories Thea (Clermont-Ferrand, France). However, various concentrations of ganciclovir eye drops have also been used in the literature for the treatment of CMV anterior uveitis [18,20,21]. The results of treatment are difficult to evaluate as they are derived from nonrandomized case series or single case reports, and there is considerable variation in the route, dose and duration of treatment. Furthermore, the outcome measures are not well defined, with most authors reporting a clinical improvement, and the duration of follow-up post-treatment has been relatively short in most studies. However, what has been a consistent outcome in these studies is the fact that, in these immunocompetent patients, although the response to antiviral therapy is high, the relapse rate has also been high, and a prolonged period of treatment may be required (Tables 3 & 4). In particular, the relapse rate with intravitreal ganciclovir has been 100%. On the other hand, it may be a useful adjunct to systemic therapy, although the number of cases in this series is small and the follow-up period is relatively short [6]. Ganciclovir gel has a relatively low response rate, but it also has a lower relapse rate and, more importantly, owing to its low cost and minimal adverse effects, it may be considered for use as maintenance therapy for prolonged periods. The potential role of valaciclovir is uncertain as it was noted to be effective in only a single case report [11]. Another result that has been consistent is the potential need for adjunctive measures, whereby, although the inflammation and/or viral load is controlled with antiviral therapy, the complications, such as IOP elevation, glaucomatous optic neuropathy and corneal decompensation, may still ensue and require surgical management, as evidenced by the 34 eyes (21%) who had either glaucomatous optic neuropathy or required glaucoma surgery, and the 14 eyes (12 with endotheliitis [24%]) that had persistence of significant corneal edema. Moreover, not all CMV-positive eyes require antiviral treatment. Among the eyes with anterior uveitis, approximately half who had milder disease refused treatment without any apparent disadvantage [5]. Similarly, two eyes with small areas of endotheliitis also refused antiviral therapy without any adverse outcome [16]. Expert commentary Infection by CMV of the anterior segment in the immunocompetent is a spectrum of diseases that varies from an acute relapsing somewhat self-limiting disease to an endotheliitis. Two of the features commonly seen in all these cases were elevated IOP and iris atrophy. CMV has been found in the smooth muscle cells of the iris and ciliary body [34]. The exact mechanisms whereby it causes the IOP rise remain unknown, but it may cause a trabeculitis, as is the case with HSV [35]. There may be an overlap in the signs; for example, some of the eyes with anterior uveitis may also have patches of endotheliitis. These differences in manifestations of the same disease in different eyes, as well as in the same eye over time, is probably a result of an interaction between the viral load and the immune status of the eye, as discussed previously. 522 Expert Rev. Ophthalmol. 6(5), (2011)

8 Cytomegalovirus-associated anterior segment infection Table 2. Literature review of clinical features of cytomegalovirus endotheliitis in non-hiv-positive patients. Study (year) Chee Hwang (2011) Koizumi (2008) Kandori Miyanaga Anshu (2009) Shiraishi Shimazaki Sonoyama Yamauchi Chiang (2011) Eyes (n) 12 (10 patients) Keratic precipitates/ anterior chamber inflammation Filiform, fine-to-medium in size Pigmented with linear and/or circular pattern cells 10 Coin-shaped keratic precipitates Mild inflammation 8 Linear and coin-shaped keratic precipitates at leading edge Localized stromal edema Minimal inflammation 8 (7 patients) Localized or diffuse edema Linear or coin-shaped keratic precipitates at leading edge Zero-to-mild inflammation 4 Diffuse stromal edema: 3 eyes Localized edema: 1 eye Fine and mutton fat: 1 to 2+ cells 4 Pigmented keratic precipitates Linear pattern 0 1+ cells 1 Coin-shaped lesions Multiple keratic precipitates Localized edema 1 Diffuse edema Pigmented keratic precipitates Coin-shaped keratic precipitates 0 cells 1 Diffuse edema Coin-shaped keratic precipitates at leading edge Mild inflammation 1 Diffuse edema Fine pigmented keratic precipitates 1 Temporal 2/3 edema No keratic precipitates or cells Intraocular pressure >21 mmhg Iris atrophy Comments All 8 eyes 4 eyes required glaucoma surgery 11 eyes had had previous hypertensive anterior uveitis All had been receiving steroids at the time of diagnosis of endotheliitis 5 eyes 2 eyes 2 presented as Posner Schlossman syndrome 1 noted post corneal graft 1 had glaucoma surgery 6 eyes Unknown 3 had previous uveitis 4 had previous corneal grafts 2 eyes Unknown 4 had previous corneal graft 3 had previous uveitis 1 had glaucoma surgery All 2 eyes Association between viral load and corneal endothelial cells loss No glaucoma All Unknown All were post-corneal graft 3 had glaucoma surgery 1 patient also had retinitis Yes Unknown Confocal microscopy showed owl s eye endothelial cells Yes Unknown Post corneal graft and previous uveitis Histology: owl s eye endothelial cells Ref. Yes Unknown Previous corneal graft [22] Yes 0 Previous recurrent uveitis [23] No Unknown [24] [16] [6] [17] [18] [8] [19] [20] [21] The current practice of therapy is to use systemic ganciclovir as a first-line treatment. However, the results of the various studies suggest that a longer duration of treatment may be required, as the recurrence rate is high. This is not only costly, but also may not be tolerated owing to adverse reactions, such as neutropenia. Other modes of therapy, such as administering a loading dose of an intravitreal injection of ganciclovir together with valganciclovir, have been tried, with apparently good outcomes. However, the numbers treated in this manner is small, and the duration of follow-up is relatively short [6,12]. PCR and/or CMV-specific antibody tests are not widely available at present, and aqueous sampling is also an invasive procedure, which not all patients are willing to undergo. On the other hand, since the prevalence of CMV infection is rather high in Asia, it may be prudent to limit the use of corticosteroids in eyes with idiopathic hypertensive anterior uveitis, in cases where there is no 523

9 Jap & Chee Table 3. Literature review of outcomes of treatment of cytomegalovirus anterior uveitis in non-hiv-positive patients. Study (year) Treatment episodes (n) Systemic therapy Treatment modality and duration (months) Outcome Duration of follow-up (months) Ref. Chee and Jap 19 Intravenous ganciclovir 10 mg/kg/day for 6 weeks followed by oral ganciclovir 3 g/day for another 6 weeks or Valganciclovir 1800 mg/day for 6 weeks followed by 900 mg/day for another 6 weeks 17 responded, but 14 had recurrences 2 had no response post-treatment [5] Miyanaga 7 Valganciclovir 1800 mg/day for more than 3 weeks All responded Unknown [8] de Schryver (2006) 5 Intravenous ganciclovir or foscarnet for 2 weeks followed by valganciclovir 900 mg/day for 8 weeks: 4 treatment episodes Valganciclovir 900 mg/day for 10 weeks: 1 treatment episode All responded, but 3 had recurrences Retreated with valganciclovir for 6 months, responded with no recurrence 9 24 [9] van Boxtel (2006) 5 Oral valganciclovir 1800 mg/day for 3 weeks followed by 900 mg/day for 3 12 months All responded, 1 had a recurrent episode [7] Hwang (2011) 3 Valganciclovir 1800 mg/day for 3 13 months All responded, but 1 had recurrences and 1 had persistent corneal edema 1 36 [6] Sira and Murray 1 11 months oral valaciclovir 2 g/day Responded with no recurrence 11 [11] Intravitreal ganciclovir Hwang (2011) 9 1 dose intravitreal ganciclovir 2 mg All responded 1 36 [6] Chee 7 Intravitreal ganciclovir 2 mg per week for 12 weeks 3 had no response 4 responded, but all had recurrences post-treatment [5] Chung (2006) 1 1 dose intravitreal ganciclovir 2 mg Responded with no recurrence Unknown [12] Other treatment regimens Hwang (2011) 7 1 dose of intravitreal ganciclovir 2 mg with valganciclovir 1800 mg/day for months All responded, but 1 had persistent corneal edema 1 36 [6] Chee and Jap 17 Ganciclovir gel 0.15% four-times daily for at least 3 months 6 had no response 11 responded, but 5 recurred post-treatment [5] Chee and Jap 4 Ganciclovir implant All responded, but all had recurrences post-treatment [5] 524 Expert Rev. Ophthalmol. 6(5), (2011)

10 Cytomegalovirus-associated anterior segment infection access to such tests. Endothelial rejection following corneal graft should be carefully examined for a possible CMV etiology, as early treatment can result in restoration of graft clarity. Glaucoma is another important complication of CMV anterior segment infection, with at least 26% of the eyes either requiring surgery or having glaucomatous damage. Hence, glaucoma therapy is an essential component in the management of these eyes. Five-year view Although the diagnosis of CMV infection will still require aqueous sampling, we look toward more readily available, cheaper and more sensitive confirmatory tests. Subsequently, less invasive tests may then be used to monitor the effects of treatment, for example, flare values [10] endothelial cell loss [8] or confocal microscopy to look for owl s eye changes in the cornea. Table 4. Literature review of outcomes of treatment of cytomegalovirus endotheliitis in non-hiv-positive patients. Study (year) Systemic therapy Treatment episodes (n) Treatment modality and duration (months) Chee 10 Intravenous ganciclovir 10 mg/kg for 6 weeks followed by oral ganciclovir 3 g/day for another 6 weeks, or valganciclovir 1800 mg/day for 6 weeks followed by 900 mg/day for another 6 weeks Koizumi (2008) Kandori 7 Miyanaga Outcome All responded, but 3 eyes had persistent corneal edema 8 Ganciclovir 10 mg/kg/day for 10 days Responded, but 2 had persistent corneal edema Intravenous ganciclovir 5 or 10 mg/kg/day for 5 21 days with topical ganciclovir 0.15, 0.3 or 0.5% 4 Valganciclovir 1800 mg/day for more than 3 weeks Anshu (2009) 4 Valganciclovir 1800 mg/day for 6 weeks followed by 900 mg/day for another 6 weeks All responded, but 2 had persistent edema Duration of follow-up (months) posttreatment Ref. [16] [17] 7 14 [18] All responded Unknown [8] All responded, but 2 had recurrences 1 had persistent corneal edema Hwang (2011) 1 Valganciclovir 1800 mg day for 3 13 months Responded, but needed corneal graft for persistent corneal edema Sonoyama 1 Intravenous ganciclovir 10 mg/kg/day for 10 days Responded, but had persistent edema 4 9 [19] 1 36 [6] 21 [22] Chiang (2011) 1 Valganciclovir 1800 mg/day for 4 months Responded Unknown [24] Yamauchi Other treatment regimens 1 Valganciclovir 1800 mg/day for 4 months Responded, but had persistent corneal edema Hwang (2011) 6 1 dose of intravitreal ganciclovir 2 mg with valganciclovir 1800 mg/day for months Responded, but 1 eye needed corneal graft for persistent corneal edema 16 months posttreatment [23] 2 17 [6] Hwang (2011) 2 1 dose intravitreal ganciclovir 2 mg Responded [6] Shiraishi Shimazaki 1 Topical ganciclovir 0.5% eight-times daily and intravenous ganciclovir 500 mg/day for 2 weeks followed by topical ganciclovir 0.5% four-times daily for 3 months 1 Ganciclovir 10 mg/kg/day for 7 days followed by topical ganciclovir 0.5% six-times daily, then three-times daily for 20 months Responded 3 [20] Responded 20 [21] Kandori 1 Topical ganciclovir 0.5% Responded 7 14 [18] 525

11 Jap & Chee Another important area of development is to have improved sustained local drug-delivery systems that can deliver consistent levels of medication over a longer term without being invasive and costly. One such potential technique is to use nanoparticles to deliver the drug. More research into understanding the role of AC-associated immune deviation in the pathogenesis of CMV in the anterior segment of the eye will be useful in order to provide us with other means of preventing or treating this disease, such as by modifying the immune response. Key issues Cytomegalovirus (CMV) infection in the immunocompetent patient manifests predominantly in the anterior segment and, generally, the posterior segment is uninvolved. It may present as an acute recurrent hypertensive anterior uveitis, a chronic anterior uveitis with or without ocular hypertension, an endotheliitis or a combination of the uveitis with endotheliitis. CMV endotheliitis may develop following penetrating keratoplasty or Descemet s membrane automated endothelial keratoplasty, and may be mistakenly diagnosed as an endothelial rejection episode. Both the acute and chronic CMV anterior uveitis eyes may develop patchy or diffuse iris atrophy, but do not develop posterior synechiae. In most cases, diagnosis was made by PCR ana lysis of aqueous for CMV DNA and by CMV-specific antibody ana lysis in a few centers. CMV anterior segment infection responds to specific antiviral therapy, but is associated with a tendency to relapse in 75% of cases. Eyes with CMV anterior uveitis may lose vision as a result of glaucomatous optic neuropathy. Eyes with CMV endotheliitis may develop visual loss from endothelial failure, despite control of infection with antiviral therapy. Topical and systemic immunosuppressive therapy in the absence of specific antiviral therapy should be avoided, as the disease may progress. References Papers of special note have been highlighted as: of interest of considerable interest 1 Wong A, Tan KH, Tee CS, Yeo GS. Seroprevlance of cytomegalovirus, toxoplasma and parvovirus in pregnancy. Singapore Med. J. 41(4), (2000). 2 Taechowisan T, Sutthent R, Louisirirotchanakul S, Puthavathana P, Wasi C. Immune status in congenital infections by TORCH agents in pregnant Thais. Asian Pac. J. Allergy Immunol. 15(2), (1997). 3 Tookey PA, Ades AE, Peckham CS. Cytomegalovirus prevalence in pregnant women: the influence of parity. Arch. Dis. Child. 67(7), (1992). 4 Gratacap-Cavallier B, Bosson JL, Morand P Cytomegalovirus seroprevalence in French pregnant women: parity and place of birth as major predictive factors. Eur. J. Epidemiol. 14(2), (1998). 5 Chee SP, Jap A. Cytomegalovirus anterior uveitis: outcome of treatment. Br. J. Ophthalmol. 94(12), Large series analyzing the outcome of treatment with various modalities of ganciclovir. 6 Hwang YS, Shen CR, Chang SH The validity of clinical feature profiles for cytomegaloviral anterior segment infection. Graefes Arch. Clin. Exp. Ophthalmol. 249(1), (2011). 7 van Boxtel LA, van der Lelij A, van der Meer J, Los LI. Cytomegalovirus as a cause of anterior uveitis in immunocompetent patients. Ophthalmology 114(7), One of the earliest papers to describe cytomegalovirus (CMV) anterior segment infection. 8 Miyanaga M, Sugita S, Shimizu N A significant association of viral loads with corneal endothelial cell damage in cytomegalovirus anterior uveitis. Br. J. Ophthalmol. 94(3), de Schryver I, Rozenberg F, Cassoux N Diagnosis and treatment of cytomegalovirus iridocyclitis without retinal necrosis. Br. J. Ophthalmol. 90(7), (2006). 10 Kawaguchi T, Sugita S, Shimizu N, Mochizuki M. Kinetics of aqueous flare, intraocular pressure and virus-dna copies in a patient with cytomegalovirus iridocyclitis without retinitis. Int. Ophthalmol. 27(6), Sira M, Murray PI. Treatment of cytomegalovirus anterior uveitis with oral valaciclovir. Ocul. Immunol. Inflamm. 15(1), Chung RS, Chua CN. Intravitreal ganciclovir injections in aqueous cytomegalovirus DNA positive hypertensive iritis. Eye 20(9), 1080 (2006). 13 Chee SP, Bacsal K, Jap A, Se-Thoe SY, Cheng CL, Tan BH. Clinical features of cytomegalovirus anterior uveitis in immunocompetent patients. Am. J. Ophthalmol. 145(5), (2008). 14 Chee SP, Jap A. Presumed Fuchs heterochromic iridocyclitis and Posner Schlossman syndrome: comparison of cytomegalovirus-positive and negative eyes. Am. J. Ophthalmol. 146(6), (2008). There is a high prevalence of CMV infection in eyes with hypertensive uveitis, and there are no clinical features that are either sensitive or specific enough to make possible a diagnosis of CMV infection. 15 Cheung CM, Chee SP. Anti-retinal autoantibodies-positive autoimmune retinopathy in cytomegalovirus-positive anterior uveitis. Br. J. Ophthalmol. 94(3), Chee SP, Bacsal K, Jap A, Se-Thoe SY, Cheng CL, Tan BH. Corneal endotheliitis associated with evidence of cytomegalovirus infection. Ophthalmology 114(4), Immunosuppressive therapy may cause a change in pattern of manifestation of CMV infection from an anterior uveitis to an endotheliitis. 17 Koizumi N, Suzuki T, Uno T Cytomegalovirus as an etiologic factor in corneal endotheliitis. Ophthalmology 115(2), (2008). 526 Expert Rev. Ophthalmol. 6(5), (2011)

12 Cytomegalovirus-associated anterior segment infection One of the earliest papers on CMV endotheliitis. Describes the characteristic coin-shaped pattern of keratic precipitates. 18 Kandori M, Inoue T, Takamatsu F Prevalence and features of keratitis with quantitative polymerase chain reaction positive for cytomegalovirus. Ophthalmology 117(2), Anshu A, Chee SP, Mehta JS, Tan DT. Cytomegalovirus endotheliitis in Descemet s stripping endothelial keratoplasty. Ophthalmology 116(4), (2009). CMV endotheliitis may present as an apparent corneal graft rejection. 20 Shiraishi A, Hara Y, Takahashi M Demonstration of owl s eye morphology by confocal microscopy in a patient with presumed cytomegalovirus corneal endotheliitis. Am. J. Ophthalmol. 143(4), Shimazaki J, Harashima A, Tanaka Y. Corneal endotheliitis with cytomegalovirus infection of corneal stroma. Eye 24(6), Sonoyama H, Araki-Sasaki K, Osakabe Y Detection of cytomegalovirus DNA from cytomegalovirus corneal endotheliitis after penetrating keratoplasty. Cornea 29(6), Yamauchi Y, Suzuki J, Sakai J, Sakamoto S, Iwasaki T, Usui M. A case of hypertensive keratouveitis with endotheliitis associated with cytomegalovirus. Ocul. Immunol. Inflamm. 15(5), Chiang CC, Lin TH, Tien PT, Tsai YY. Atypical presentation of cytomegalovirus endotheliitis: a case report. Ocul. Immunol. Inflamm. 19(1), (2011). 25 Herriot R, Gray ES. Images in clinical medicine. Owl s-eye cells. N. Engl. J. Med. 331(10), 649 (1994). 26 Koffron AJ, Hummel M, Patterson BK Cellular localization of latent murine cytomegalovirus. J. Virol. 72(1), (1998). 27 Sugita S, Shimizu N, Watanabe K Use of multiplex PCR and real-time PCR to detect human herpes virus genome in ocular fluids of patients with uveitis. Br. J. Ophthalmol. 92(7), (2008). 28 Brantsaeter AB, Holberg-Petersen M, Jeansson S, Goplen AK, Bruun JN. CMV quantitative PCR in the diagnosis of CMV disease in patients with HIV-infection a retrospective autopsy based study. BMC Infect. Dis. 6(7), De Groot-Mijnes JD, Rothova A, Van Loon AM Polymerase chain reaction and Goldmann Witmer coefficient analysis are complimentary for the diagnosis of infectious uveitis. Am. J. Ophthalmol. 141(2), (2006). 30 Doornenbal P, Seerp Baarsma G, Quint WG, Kijlstra A, Rothbarth PH, Niesters HG. Diagnostic assays in cytomegalovirus retinitis: detection of herpesvirus by simultaneous application of the polymerase chain reaction and local antibody analysis on ocular fluid. Br. J. Ophthalmol. 80(3), (1996). 31 de Boer JH, Verhagen C, Bruinenberg M Serologic and polymerase chain reaction analysis of intraocular fluids in the diagnosis of infectious uveitis. Am. J. Ophthalmol. 121(6), (1996). 32 Fardeau C, Romand S, Rao NA Diagnosis of toxoplasmic retinochoroiditis with atypical clinical features. Am. J. Ophthalmol. 134(2), (2002). 33 Castela N, Vermerie N, Chast F Ganciclovir ophthalmic gel in herpes simplex virus rabbit keratitis: intraocular penetration and efficacy. J. Ocul. Pharmacol. 10(2), (1994). 34 Daicker B. Cytomegalovirus panuveitis with infection of corneo-trabecular endothelium in AIDS. Ophthalmologica 197(4), (1988). 35 Amano S, Oshika T, Kaji Y, Numaga J, Matsubara M, Araie M. Herpes simplex virus in the trabeculum of an eye with corneal endotheliitis. Am. J. Ophthalmol. 127(6), (1999)

13 Jap & Chee Cytomegalovirus-associated anterior segment infection x To obtain credit, you should first read the journal article. After reading the article, you should be able to answer the following, related, multiple-choice questions. To complete the questions (with a minimum 70% passing score) and earn continuing medical education () credit, please go to journals/expertophth. Credit cannot be obtained for tests completed on paper, although you may use the worksheet below to keep a record of your answers. You must be a registered user on Medscape.org. If you are not registered on Medscape.org, please click on the New Users: Free Registration link on the left hand side of the website to register. Only one answer is correct for each question. Once you successfully answer all post-test questions you will be able to view and/or print your certificate. For questions regarding the content of this activity, contact the accredited For technical assistance, American Medical Association s Physician s Recognition Award (AMA PRA) credits are accepted in the US as evidence of participation in activities. For further information on this award, please refer to org/ama/pub/category/2922.html. The AMA has determined that physicians not licensed in the US who participate in this activity are eligible for AMA PRA Category 1 Credits. Through agreements that the AMA has made with agencies in some countries, AMA PRA credit may be acceptable as evidence of participation in activities. If you are not licensed in the US, please complete the questions online, print the AMA PRA credit certificate and present it to your national medical association for review. Activity Evaluation Where 1 is strongly disagree and 5 is strongly agree 1. The activity supported the learning objectives. 2. The material was organized clearly for learning to occur. 3. The content learned from this activity will impact my practice. 4. The activity was presented objectively and free of commercial bias Your patient is a 45-year-old, immunocompetent Asian man thought to have cytomegalovirus (CMV)-associated ocular infection. Based on the review by Drs Jap and Chee, which of the following features would be most likely consistent with that diagnosis? A Exclusive involvement of the posterior segment B Acute recurrent hypertensive anterior uveitis C Posterior synechiae D Associated encephalitis and pneumonia 2. Based on the review by Drs Jap and Chee, which of the following statements about diagnosis of CMV-associated anterior segment infection in the patient described in question 1 is most likely correct? A Diagnosis can be made exclusively on clinical grounds B Diagnosis requires CMV-specific antibody analysis C Aqueous analysis is noninvasive D Ideally, diagnosis is made both by polymerase chain reaction methods and by comparing the intraocular CMV-specific antibody levels to serum levels 3. Based on the review by Drs Jap and Chee, which of the following statements about treatment of CMV-associated anterior segment infection is most likely correct? A Response to specific antiviral therapy is poor B Relapse rate after specific antiviral therapy is low C Glaucoma therapy is an important adjunctive modality of management D Topical and systemic immunosuppressive therapy should be given without specific antiviral therapy 528 Expert Rev. Ophthalmol. 6(5), (2011)