Cytomegalovirus as an Etiologic Factor in Corneal Endotheliitis

doi:10.1016/j.ophtha.2007.04.053

Ophthalmology

Volume 115, Issue 2, February 2008, Pages 292-297.e3

https://doi.org/10.1016/j.ophtha.2007.04.053 Get rights and content

Purpose

To investigate clinical manifestations and response to antiviral therapy of 8 patients with cytomegalovirus (CMV)-induced corneal endotheliitis who were diagnosed and treated at 2 university hospitals in Japan.

Design

Retrospective, consecutive, multicenter case series.

Participants

Eight eyes of 8 patients diagnosed with active CMV corneal endotheliitis at Kyoto Prefectural University of Medicine and Ehime University School of Medicine. The diagnosis was made based on the detection by polymerase chain reaction assay of CMV, but not herpes simplex virus (HSV) and varicella zoster virus (VZV) DNA, in the aqueous humor from the affected eye.

Methods

Retrospective review of the clinical manifestations and responses to antiviral treatment.

Main Outcome Measures

Patient profiles, including duration of corneal endotheliitis, systemic disease, intraocular pressure, and clinical manifestation of anterior and posterior segments. The clinical response to systemic and topical antiviral treatment was evaluated by slit-lamp examination. Corneal endothelial density was examined by specular microscopy.

Results

The average observation period after CMV detection was 10.4 months (range, 2–24 months). None of the patients had systemic immunodeficiency. Corneal manifestations included linear keratic precipitates associated with multiple coin-shaped lesions and local corneal stromal edema. Of the 8 patients, 4 had undergone penetrating corneal transplantation. Systemic ganciclovir therapy was used in 7 patients, and in 1 patient, valacyclovir was administered, with the corneal endotheliitis responding quickly to the early administration of galovir. At the final examination, 6 eyes had a clear cornea, but 2 eyes had bullous keratopathy.

Conclusions

Besides HSV and VZV, CMV must be considered as an etiologic agent in patients with corneal endotheliitis. Cytomegalovirus corneal endotheliitis may be a newly identified clinical entity of reactivated CMV in the anterior chamber of individuals free of accompanying systemic symptoms.

Section snippets

Patients and Methods

The study population consisted of 8 consecutive patients whose active corneal endotheliitis was diagnosed and treated between November 2004 and May 2006 at the Departments of Ophthalmology of Kyoto Prefectural University of Medicine (patients 1–5) and Ehime University School of Medicine (patients 6–8). Of these 8 patients, patients 1 and 6 were previously reported as individual case reports by these 2 departments independently13, 14; they are also included here with more detailed information of

Results

The aqueous humor collected from the affected eyes of patients 1 through 5 contained CMV, but not HSV or VZV DNA. For these 5 eyes, the specificity of the amplified band was confirmed by Southern blot analysis.¹⁷ Under the same PCR conditions, none of 5 aqueous samples from cataract patients nor 7 aqueous samples from patients with uveitis demonstrated positive results for CMV, HSV, or VZV DNA. Likewise, the aqueous humor from the affected eyes of patients 6 through 8 contained CMV, but neither

Patient 4

A 51-year-old man began to experience recurrent episodes of bilateral corneal endotheliitis of unknown origin in the 1980s (Fig 1C). Aqueous humor samples subjected to PCR at the time of his previous attack returned negative results for HSV and VZV; CMV was not examined at that time. Despite HSV-targeting combination treatment consisting of oral acyclovir and topical acyclovir and corticosteroid, his corneal endotheliitis recurred often and he experienced bullous keratopathy. He had undergone

Discussion

The mechanisms regulating the latency and reactivation of CMV in the course of natural infection remain poorly understood. Cytomegalovirus DNA has been detected in human peripheral blood monocytes24, 25 and CD34⁺ bone marrow progenitors.²⁶ The clinical observations that corneal endothelial lesions always start from the periphery and move toward the center of the cornea imply that tissues surrounding the cornea such as the trabecular meshwork or ciliary body may be the reservoir for CMV. The

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Cytomegalovirus (CMV) can cause a wide panel of ocular infections. The involvement of CMV as a cause of anterior uveitis in the immunocompetent patient is recent and remains poorly understood.
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We collected aqueous humor, iris, and ciliary body from both eyes of 25 donors died at the Limoges University Hospital between January 2020 and July 2021. CMV serology was determined for all patients from post-mortem blood sample. Ocular tissues were split in 2 fragments for qPCR and 2 for histological analysis. CMV genomes copies were quantified by Multiplex qPCR after DNA extraction.
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CMV DNA was found in iris and ciliary body of immunocompetent seropositive patients, but also, although less frequently, from seronegative donors. These results highlight mechanisms of infection, latency and reactivation of CMV in ocular tissues.
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Citation Excerpt :
CMVE seems much more common in Asia than in the other parts of the world (e.g. 24 % of endotheliitis in Japan) [83]). CMVE can present either with one of the classic forms of HSK or VZK endotheliitis (i.e. disciform, diffuse or linear) [84], or multifocal “owl eyes” or “coins” morphologic features (Fig. 5) that are very suggestive of CMVE [82,85,86]. There are two main scenarios that warrant considering a diagnosis of CMVE: cases with owl eyes or coins endothelial lesions or; cases of presumed “herpetic” endotheliitis that resist conventional anti-HSV1 treatments [such as acyclovir (ACV) or valacyclovir (VACV)], especially in the context of keratoplasty.
Keratitis due to Herpes simplex virus (HSK), Varicella-Zoster virus (VZK) and Cytomegalovirus remains a frequent source of concern for many ophthalmologists. They are a frequent cause of emergency consultations at eye care centers and carry the risk of permanent loss of visual acuity or visual quality and/or chronic neurotrophic keratitis, resulting in a significant decrease in the quality of life. HSK and VZK can affect the corneal epithelium, stroma, or endothelium or a combination of layers. In contrast, most cases of CMV keratitis present as isolated endothelitis (CMVE), a clinical entity that has been described within the last 2 decades. These three types of viral keratitis are characterized by a high frequency of recurrences and each new episode increases the risk of sequelae. Hence, ophthalmologists must adapt the treatment to the clinical presentation of each recurrent episode in order to mitigate the immediate consequences of viral replication and the immune response on corneal transparency. In patients with frequent recurrences, preventive long-term antiviral treatment is strongly recommended. However, in some rare cases, continuous exposure to antivirals may promote the emergence of resistant viral strains, which can be difficult to manage. In the future, the introduction of new antiviral drugs, with differing modes of action compared to current medical therapy, could be an alternative until a truly effective preventive solution, such as a vaccine, is available.
Clinical characteristics and treatment outcomes of cytomegalovirus anterior uveitis and endotheliitis: A systematic review and meta-analysis
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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.
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Manuscript no. 2007-125.

The authors have no commercial or financial interests associated with the article.

: Supported in part by research grants from the Ministry of Education, Culture, Sports, Science, and Technology, Tokyo, Japan.

¹: Drs Koizumi and Suzuki contributed equally as co–first authors.

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Original articleCytomegalovirus as an Etiologic Factor in Corneal Endotheliitis

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Section snippets

Patients and Methods

Results

Patient 4

Discussion

Am J Ophthalmol

Ophthalmology

Am J Ophthalmol

Am J Ophthalmol

Am J Ophthalmol

Am J Ophthalmol

Am J Ophthalmol

Ophthalmology

Am J Ophthalmol

Lancet

Am J Ophthalmol

Am J Ophthalmol

Am J Ophthalmol

Idiopathic corneal endotheliopathy: a report of two cases

Arch Ophthalmol

Herpetic endothelial keratitis: a case report

Acta Ophthalmol (Copenh)

Varicella-zoster virus in the human corneal endothelium: a case report

Bull Soc Belge Ophtalmol

Acyclovir treatment for linear endotheliitis on grafted corneas

Cornea

Classification of herpes simplex virus keratitis

Cornea

Original article
Cytomegalovirus as an Etiologic Factor in Corneal Endotheliitis