Identification of cytomegalovirus and human herpesvirus-6 DNA in a patient with corneal endotheliitis

Purpose

To report the case of a patient with unilateral corneal endotheliitis in which both cytomegalovirus (CMV) and human herpesvirus-6 (HHV6) DNA was identified in the aqueous humor.

Case

A 67-year-old man with corneal endotheliitis OD was referred to us for decreased visual acuity. Local corneal stromal edema, pigmented keratic precipitates, a coin-shaped lesion and minimal anterior chamber reaction were observed by slit-lamp biomicroscopy. Cells with owl’s eye appearance in the endothelial cell layer were observed by in vivo laser confocal microscopy. The patient had rheumatoid arthritis, which was treated by oral prednisolone and intravenous abatacept. Polymerase chain reaction analysis of aqueous humor samples detected both CMV and HHV6 DNA, but not other HHVs. Treatment with topical ganciclovir and systemic valganciclovir resulted in a clear cornea.

Conclusions

A patient with corneal endotheliitis had both CMV and HHV6 DNA identified in the aqueous humor. Although both viruses were identified in this case, clinical manifestations resembled CMV corneal endotheliitis, and it was unclear whether HHV6 could affect the clinical course. Systemic abatacept and corticosteroid therapy might play a positive role in cases with both CMV and HHV6 DNA in this corneal endotheliitis.     

Mapping owl’s eye cells of patients with cytomegalovirus corneal endotheliitis using in vivo laser confocal microscopy

Purpose

To produce a two-dimensional reconstruction map of owl’s eye cells using in vivo laser confocal microscopy in patients with cytomegalovirus (CMV) corneal endotheliitis, and to demonstrate any association between owl’s eye cells and coin-shaped lesions observed with slit-lamp biomicroscopy.

Method

Two patients (75- and 77-year-old men) with polymerase chain reaction-proven CMV corneal endotheliitis were evaluated in this study. Slit-lamp biomicroscopy and in vivo laser confocal microscopy were performed. Images of owl’s eye cells in the endothelial cell layer were arranged and mapped into subconfluent montages. Montage images of owl’s eye cells were then superimposed on a slit-lamp photo of the corresponding coin-shaped lesion. Degree of concordance between the confocal microscopic images and slit-lamp photos was evaluated.

Results

In both eyes, a two-dimensional reconstruction map of the owl’s eye cells was created by computer software using acquired confocal images; the maps showed circular patterns. Superimposing montage images of owl’s eye cells onto the photos of a coin-shaped lesion showed good concordance in the two eyes.

Conclusions

This study suggests that there is an association between owl’s eye cells observed by confocal microscopy and coin-shaped lesions observed by slit-lamp biomicroscopy in patients with CMV corneal endotheliitis. The use of in vivo laser confocal microscopy may provide clues as to the underlying causes of CMV corneal endotheliitis.     

Relationship between the number of cytomegalovirus in anterior chamber and severity of anterior segment inflammation

Purpose

To characterize the cytomegalovirus-associated anterior segment inflammation and to determine whether the number of cytomegalovirus is significantly correlated with the disease characteristics.

Methods

Retrospective consecutive case series. Seventy-three patients with refractory anterior segment inflammation due to iridocyclitis, corneal endotheliitis and keratouveitis were studied. All the patients were suspected to have cytomegalovirus infection and had undergone real-time PCR of the aqueous humor to determine the amount of cytomegalovirus DNA.

Results

Cytomegalovirus DNA was detected in 24 of the 73 cases. The cytomegalovirus copy number was significantly correlated with the number of recurrent episodes and glaucoma treatment levels, but was not significantly correlated with the disease type. A high cytomegalovirus copy number was a significant risk factor for IOP elevation [Odds ratio (OR) per logarithm CMV amount: 2.5 (95 % confidence interval (CI) 1.1–5.4), presence of coin-shaped lesions (2.3 (1.3–4.0)), recurrent inflammation (2.1 (1.3–3.5)), and reduction of endothelial cell densities (1.7 (1.2–2.5))]. An IOP elevation [OR 18.2 (95 % CI 2.2–153.0)], reduction of endothelial cell densities [13.2 (2.9–60.0)], and recurrent inflammations [11.9 (2.5–56.6)], but not the disease type, were significant predictors of the presence of >10³ copies/ml cytomegalovirus in the aqueous.

Conclusions

Measurements of the cytomegalovirus DNA amount is useful for evaluating the severity of the anterior segment inflammation.     

Viral causes of unexplained anterior uveitis in Thailand

Aims

To assess the possible role of virus infection in patients with unexplained anterior uveitis (AU).

Methods

Intraocular fluid and plasma samples of 30 HIV-negative AU patients who were unresponsive or poorly responsive to topical steroid therapy were analyzed for nucleic acid of cytomegalovirus (CMV), herpes simplex virus (HSV), and varicella zoster virus (VZV) by real-time polymerase chain reaction (PCR) and for intraocular antibodies against these viruses by Goldmann–Witmer coefficient (GWC) analysis. Of these 30 cases, 21 were tested for rubella virus by GWC analysis, 16 of which also had PCR assessment of aqueous for rubella virus.

Results

Viral uveitis determined by either real-time PCR and/or GWC was documented in 20 out of 30 patients (67%). Of 30 paired samples tested by both methods for HSV, CMV, and VZV, 15 showed positive results (CMV (10), HSV (4), and VZV (1)). Real-time PCR was positive in 8/15 (53%), whereas GWC was positive in 10/15 (67%). Out of 10 CMV-positive patients, four had endotheliitis, two had Posner–Schlossman syndrome, and one Fuchs heterochromic uveitis syndrome (FHUS). Five out of 21 (24%) samples tested by GWC for Rubella virus were positive, three of which exhibited clinical features of FHUS.

Conclusions

Our results indicate that CMV is a major cause of AU in Thailand and show that FHUS can be caused by both CMV and Rubella virus.     

Cytomegalovirus in aqueous humor from an eye with corneal endotheliitis

PURPOSE: To report cytomegalovirus (CMV) DNA in aqueous humor from a patient with unilateral corneal endotheliitis. DESIGN: Case report. METHODS: A 51-year-old man presented with unilateral corneal endotheliitis with linear keratic precipitates and coin-shaped lesions. Tear and aqueous humor samples were subjected to polymerase chain reaction to look for DNA from herpes simplex virus (HSV), varicella zoster virus (VZV), and CMV. RESULTS: Aqueous humor from the diseased eye contained DNA from CMV but not HSV or VZV. Its specificity was confirmed by Southern blot tests. Intravenous ganciclovir treatment resulted in the localization of his corneal edema and the reduction in keratic precipitates. There was severe destruction of corneal endothelial cells. CMV DNA was not detected in tears or control samples. CONCLUSIONS: In this healthy man with corneal endotheliitis, we detected CMV DNA in aqueous humor from the affected eye, but not HSV or VZV. This suggests that CMV may cause corneal endotheliitis in patients without immunodeficiency.     

Clinical characteristics and treatment outcomes of cytomegalovirus anterior uveitis and endotheliitis: A systematic review and meta-analysis

Cytomegalovirus (CMV) anterior uveitis is the most common form of ocular manifestation of CMV in immunocompetent individuals. The difficulty in diagnosing CMV anterior uveitis may delay adequate treatment and affect outcomes. We sought to review systemically the overall clinical characteristics and compare treatment outcomes in CMV anterior uveitis and endotheliitis. A literature search was performed, and studies describing clinical characteristics, treatment regimens, and outcomes that included more than 5 treated eyes were included. In these 23 studies, acute CMV anterior uveitis commonly presented with high intraocular pressure (95.31%, 95% CI 90.45–98.60) and mild anterior chamber inflammation (cells >2+ = 3.18%, 95% CI 0.21–0.54). About two-thirds of CMV endotheliitis cases presented with high intraocular pressure and coin-shaped corneal lesions. Acute CMV anterior uveitis showed good clinical response to topical 0.15% ganciclovir (GCV) gel or oral valganciclovir (VGCV) (90%, 95% CI 74–100% and 95%, 95% CI 88–100%, respectively). For chronic CMV anterior uveitis, both topical GCV and oral VGCV yielded comparable results. Topical 0.5–2% GCV or a combination of topical and oral VGCV for CMV endotheliitis both resulted in good clinical response. Recurrence of inflammation was common after cessation of maintenance therapy. Overall, topical GCV resulted in an optimal outcome for CMV anterior uveitis. Escalated concentration and frequency of usage are needed for chronic CMV anterior uveitis and endotheliitis. Adequate induction and maintenance phases of anti-CMV treatment seem necessary to prevent recurrences.     

Cytomegalovirus and the eye

Following primary infection, cytomegalovirus (CMV) establishes latent infection in myeloid progenitor cells and intermittent viral reactivation from activated macrophages or dendritic cells, which is brought under control by strong virus-specific CD4+ T-cell and CD8+ T-cell responses. CMV retinitis characterized by spreading retinal necrosis due to viral cytopathic effect occurs in patients who have impaired T-cell function as a result of transplantation, AIDS, or immuno-suppressive treatment. The diagnosis of CMV retinitis can be confirmed by PCR amplification of viral DNA in aqueous. When administered intravenously, the antiviral drugs Ganciclovir and Foscarnet have modest penetration into the vitreous compared with direct intra-vitreal injection. In randomized trials of HIV-associated CMV retinitis, a Ganciclovir implant was consistently superior to intravenous Ganciclovir in preventing progression of retinitis. CMV is also implicated in two forms of anterior segment disease in immuno-competent adults, namely CMV anterior uveitis and CMV corneal endotheliitis.     

Cytomegalovirus-related corneal endotheliitis: A review article

Cytomegalovirus (CMV)-related corneal endotheliitis is an inflammation of the corneal endothelium caused by CMV. It typically presents as coin-shaped keratic precipitates (KPs), with or without corneal edema, in otherwise healthy individuals. It may be associated with anterior uveitis and raised intraocular pressure (IOP). Patients with CMV-related corneal endotheliitis respond to systemic and topical ganciclovir with the use of topical steroid. Making an accurate early diagnosis is crucial in preventing loss of corneal endothelial cells and unnecessary treatment resulting from misdiagnosis in these patients.     

Treatment outcome and risk factors for visual loss in <Emphasis Type="Italic">Cytomegalovirus</Emphasis> endotheliitis

Background  

To determine treatment outcome and risk factors for visual loss in Cytomegalovirus (CMV) endotheliitis.     

DNA of cytomegalovirus detected by PCR in aqueous of patient with corneal endotheliitis after penetrating keratoplasty

PURPOSE: Corneal endotheliitis often leads to severe endothelial dysfunction and can be caused by herpes simplex virus (HSV), varicella zoster virus (VZV), and other viruses (eg, the mumps virus). We report a case of corneal endotheliitis caused by cytomegalovirus (CMV) that developed after a penetrating keratoplasty. METHODS: A complete ophthalmologic examination was performed on a patient with corneal endotheliitis that developed after a penetrating keratoplasty. To determine the cause of the endotheliitis, polymerase chain reaction (PCR) was used to amplify the DNA of HSV, VZV, and CMV in samples of the aqueous humor. RESULTS: Slit-lamp biomicroscopy showed a moderate stromal edema in the upper temporal part of the transplanted cornea along with keratic precipitates (KPs) arranged in a coin-shaped pattern. Repeated treatments with steroids and acyclovir were only temporarily successful. PCR detected the DNA of CMV in an aqueous sample, and the treatment was switched to topical and systemic application of ganciclovir. This resulted in the disappearance of the KPs and resolution of the stromal edema within 2 weeks. CONCLUSIONS: From the PCR results and the favorable response to ganciclovir, the corneal endotheliitis was most likely caused by cytomegalovirus in this case.     

The Effect of Topical Ganciclovir and Corticosteroid on Cytomegalovirus Corneal Endotheliitis in Korean Patients

Purpose: To report long-term outcomes of topical ganciclovir (GCV) and corticosteroids in Korean patients with cytomegalovirus (CMV) corneal endotheliitis.

Methods: This retrospective study included 13 eyes from 13 patients with CMV corneal endotheliitis, with a follow-up period of 24.5 ± 8.2 months. The patients were consistently maintained with topical 2% GCV and 1% prednisolone acetate eyedrop.

Results: All patients demonstrated unilateral typical coin-shaped keratic precipitates (KPs) or linear KP, and positive CMV polymerase chain reaction of aqueous humor. After 2 weeks of treatment, all patients showed decrease of clinical signs. During the follow-up, four patients developed mild anterior chamber inflammation with increased intraocular pressure without typical coin-shaped KPs or edema, started to use the initial dose, and resolved the clinical signs. One patient showed recurrence of corneal edema twice, and was administered systemic valgancyclovir for 2 weeks upon second recurrence with resolution of clinical signs.

Conclusion: Long-term maintenance therapy with topical GCV and corticosteroids are effective and maintain corneal endothelial function in Korean patients with CMV endotheliitis.     

Clinical Evaluation of Intravitreal Injection of Ganciclovir in Refractory Corneal Endotheliitis

ABSTRACT

Purpose: To evaluate the efficacy and safety of intravitreal ganciclovir (GCV) injection in refractory endotheliitis.

Methods: Retrospectively recruited 25 eyes with endotheliitis, proved by clinical manifestations, positive PCR for viral DNA and responded poor to topical and systemic antiviral medications. All patients received additional continued intravitreal GCV injections.

Results: Cytomegalovirus (CMV), varicella zoster virus (VZV), and herpes simplex virus (HSV) DNA were detected in 64.0%, 28.0%, and 8.0% of the eyes, respectively. Within 2 weeks after the last injection, 16/25 eyes recovered corneal clarity; active keratic precipitates (KPs) were eliminated in 21/25 eyes; intraocular pressure (IOP) was controlled in 12/15 eyes with elevated IOP on study entry. Best-corrected visual acuity increased at the last follow-up (p = 0.016). Clinical recurrence occurred in three patients. No complications were detected.

Conclusions: CMV endotheliitis was the main type of refractory endotheliitis. Despite its invasive nature, intravitreal GCV injection appears to be an effective method for refractory endotheliitis.     

Early changes in corneal edema following torsional phacoemulsification using anterior segment optical coherence tomography and Scheimpflug photography

Purpose  

To assess corneal edema after torsional phacoemulsification using anterior segment optical coherence tomography (AS-OCT) and Scheimpflug photography (Pentacam).     

Experimental corneal endotheliitis in rabbit

PURPOSE: Corneal endotheliitis may cause permanent visual loss due to endothelial decompensation. The pathogenesis underlying this distinct clinical entity is not known. In the current study, a rabbit herpetic corneal endotheliitis model was made of induced anterior chamber-associated immune deviation (ACAID). METHODs: One group of rabbits received left-eye intracameral inoculation of UV-inactivated herpes simplex virus (HSV)-1 (strain McKrae). The second group received cell medium in the same manner as the first group. The third group subcutaneously received the same inoculum as the first group. Seven days later, all right eyes were intracamerally infected with 2.5 x 10(4) plaque-forming units of infectious HSV-1. Eyes were evaluated by slit lamp examination. Two weeks after infection, rabbits were killed, and right eyes were examined by immunohistochemical staining and electron microscopy. Aqueous humor was detected for HSV-1 DNA and antibody. RESULTS: Nonspecific inflammation occurred in the anterior segments of the eyes from the second and third groups. In contrast, at 14 days after infection, the first group of rabbits showed a specific pattern of inflammation that greatly resembled clinical features of corneal endotheliitis. Viral antigen was detected only in the endothelial layer. Electron microscopy revealed enlarged intercellular gaps and infiltration of inflammatory cells that are characteristic of endothelial defects. HSV-1 DNA was detected at a significantly higher number in the aqueous humor aspirates from endotheliitis rabbits. In addition, ACAID was shown to be induced in the rabbits with corneal endotheliitis. CONCLusIONS: HSV-1 infection can induce corneal endotheliitis and ACAID may play the pivotal role in this entity.     

Demonstration of "owl's eye" morphology by confocal microscopy in a patient with presumed cytomegalovirus corneal endotheliitis

PURPOSE: To report confocal microscopic observations of characteristic corneal endothelial lesions in a patient with presumed cytomegalovirus (CMV) corneal endotheliitis. DESIGN: Case report. METHODS: A 77-year-old, immunocompetent man was admitted with corneal edema, keratic precipitates, and coin-shaped lesions in the right eye. Confocal microscopy was performed to examine the corneal endothelium. Polymerase chain reaction (PCR) was used to identify viral DNA in an aqueous humor sample. RESULTS: CMV DNA was detected by PCR. Confocal microscopy showed large corneal endothelial cells with an area of high reflection in the nucleus surrounded by a halo of low reflection. This "owl's eye" morphology is characteristic of CMV infection. Topical and intravenous ganciclovir treatment resulted in rapid resolution of the corneal precipitates and edema, followed by disappearance of the owl's eye morphology. CONCLUSIONS: Confocal microscopy can detect the owl's eye morphology in the corneal endothelium of patients with presumed CMV corneal endotheliitis.     

Host Immune Response and Associated Clinical Features in a Primary Cytomegalovirus Eye Infection Model Using Anterior Chamber Inoculation

PurposeTo investigate the pathogenesis of cytomegalovirus (CMV)-associated anterior segment infection in immunocompetent hosts and evaluate the effects of ganciclovir and glucocorticoid treatment in management of the disease.MethodsWe used an inoculation model to reproduce CMV anterior segment infection in immunocompetent rats. Flow cytometry, cytokine analysis, histopathological sections, and quantitative polymerase chain reaction were performed to investigate the immune response after CMV infection. The effects of ganciclovir and glucocorticoid treatment were also assessed.ResultsAnterior chamber inoculation of CMV in rats provoked characteristic pathological features of human CMV anterior segment infection. The innate and adaptive immunity sequentially developed in an anterior segment after inoculation, and the elevation of intraocular pressure (IOP) was highly associated with ocular infiltration and inflammation. Early ocular immune response reduced virus DNA in the anterior segment and alleviated viral lymphadenopathy. Early intervention with ganciclovir enhanced the release of cytokines associated with T response and facilitated recruitment of NKT and T cells in drainage lymph nodes. Glucocorticoid treatment, alone or combined with ganciclovir, decreased elevation of IOP but also impeded DNA clearance.ConclusionsThe inoculation model reproduced characteristic pathological features of human CMV anterior segment infection. The use of glucocorticoid in current practice may hinder viral clearance, and ganciclovir therapy can assist cytokine expression to combat the virus.     

Cloning and characterization of cell strains derived from human corneal stroma and sclera

Purpose  

To establish human corneal stroma- and sclera-derived cells as models for studying diseases of the anterior segment of the eye.     

Clinical results of triple Descemet's stripping and automated endothelial keratoplasty (DSAEK)

PurposeTo evaluate visual acuity (VA), refractive outcome, endothelial cell loss rate and complications of Descemet's stripping and automated endothelial keratoplasty (DSAEK) combined with phacoemulsification and intraocular lens (IOL) implantation in patients with coexisting corneal endothelial dysfunction and cataracts.MethodsSeventeen patients underwent phacoemulsification and posterior chamber IOL implantationthrough temporal corneal incision, followed by DSAEK. The selection of IOL power was predicted by preoperative lens power calculations of fellow eye plus 0.5 to 1.0 diopters (D).ResultsThere were five cases of laser iridotomy induced corneal dysfunction, four cases of Fuch's dystrophy, three cases of cytomegalovirus (CMV) endotheliitis, three cases of iridocorneal endothelial (ICE) syndrome, one case of herpes simplex virus (HSV) endotheliitis, and one case with an unknown cause. The BSCVAs were all under 0.2 preoperatively, and the average BSCVA was 0.3 postoperatively. The postoperative spherical equivalent (SE) refractive error was ?0.11 D on an average. The endothelial cell loss rate was ?36.86% at 6 months and ?38.60% at 12 months. There was one case of graft rejection at 6 months, and one case of primary graft failure. Complications such as donor detachment, pupillary block, donor graft folds, epithelial ingrowth, or interface scar did not occur.ConclusionThis case series of DSAEK combined with phacoemulsification and IOL implantation suggests that the procedure provides rapid visual rehabilitation and allows the selection of an appropriate IOL.     

Clinical Features of CMV-Associated Anterior Uveitis

Cytomegalovirus (CMV) anterior uveitis is the most common ocular manifestation of CMV disease in immunocompetent individuals. It is thought to be due to a local reactivation of latent CMV and is usually unilateral. The acute form presents as Posner-Schlossman Syndrome, a recurrent hypertensive anterior uveitis with few granulomatous keratic precipitates. There are geographic differences in the chronic form of CMV anterior uveitis. Asian patients commonly present as Fuchs Uveitis Syndrome with diffuse stellate keratic precipitates, while the European patients present with a chronic hypertensive anterior uveitis with fewer keratic precipitates that are brown in color and located inferiorly. Characteristic features of CMV anterior uveitis include mild anterior chamber inflammation, elevated intraocular pressure, stromal iris atrophy. Synechiae, macular edema and retinitis are typically absent. CMV disease may also be associated with the development of corneal endotheliitis with a reduced endothelial cell count. Long-term complications include glaucomatous optic neuropathy and cataract formation.