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Corneal endotheliitis, a specific inflammation targeted primarily to the corneal endothelium, is characterised by cornea oedema, keratic precipitates (KPs) and a mild anterior chamber reaction.1–3 Several viruses, including herpes simplex virus (HSV), varicella zoster virus (VZV), mumps and cytomegatovirus (CMV), have been implicated in the aetiology of the disease.1–3 Based on its definition, allograft endothelial rejection after keratoplasty can be included in the corneal endotheliitis. Here, we report a patient with corneal endotheliitis occurring after penetrating keratoplasty for Fuchs corneal endothelial dystrophy.
Case report
A 65-year-old Taiwanese female without previous ocular illness but arrhythmias and mitral valve prolapse history presented with progressive corneal oedema and decreased vision in the right eye in 1994. She was diagnosed as having bilateral Fuchs endothelial dystrophy, confirmed by slit-lamp biomicroscopy and specular microscopy (figure 1). The best-corrected vision was 20/50 in her right eye and 20/30 in her left eye, and the corneal thickness as measured with pachymetry was 550 μm in her right eye and 510 μm in her left eye in 2004. The patient then received her first penetrating keratoplasty (PK) in March 2004. Elevated intraocular pressure (IOP) measured 41 mm Hg at the highest with KPs, but a clear corneal graft was found 7 months after transplantation. Despite antiglaucomatous medication use, pigmented and non-pigmented KPs with stromal oedema as well as intractable high IOP remained. Trabeculectomy was performed 3 months prior to a second PK with extracapsular cataract extraction and intraocular lens implantation in June 2005. Elevated IOP persisted postoperatively (31.8 mm Hg at the highest), so the patient received trans-scleral cyclophotocoagulation in September 2005; IOP has returned to normal since then. In October 2005, pigmented KPs with a silent anterior chamber reaction were noted, progressing to cornea graft oedema at the inferior portion in April 2006. Generalised graft oedema developed in May 2006, despite topical antirejection medication. In February 2009, a third PK was performed on the patient's right eye. KPs with minimal inflammation reaction in the anterior chamber were noted 2 months postoperatively (figure 2A). The corneal module on the HRT III system with in vivo confocal microscopy (Heidelberg retina tomograph III Rostock corneal module) revealed the findings shown in figure 2B.
Specular microsopy showing diffuse guttata in both eyes (arrowheads). OD, right eye; OS, left eye.
(A) Photograph of the right eye of the patient showing multiple coin-shaped keratic precipitates (arrowheads). (B) Confocal microscope of the right eye of the patient showing the owl's eye appearance in the corneal endothelium (arrowheads).
Questions
Describe the findings of external eye photography and confocal microscopy (figure 2A,B).
What is the diagnosis, and how can it be confirmed?
What is the upcoming management for this patient?
See page 308 for answer
Answers
From questions on page 300
Describe the findings of external eye photography and confocal microscopy (figure 2A,B).
Multiple coin-shaped KPs, defined as medium-sized KPs arranged circumferentially with associated localised corneal oedema, were noted on the external eye photography (figure 2A). Such findings are characteristic of CMV corneal endotheliitis.2 4 The owl's eye appearance of the corneal endothelium, a pathogonomic sign of CMV infection,5 was found on confocal microscopy (figure 2B).
What is the diagnosis, and how can it be confirmed?
CMV endotheliitis should be highly suspected based on the findings of slit-lamp biomicroscopy and confocal microscopy. As a result, anterior chamber paracentesis sampling for PCR micro-organism analysis in the aqueous humour performed in April 2009 revealed positive CMV DNA, negative Epstein–Barr virus, HSV and VZV DNA. The result confirmed the diagnosis of CMV endotheliitis.
What is the upcoming management for this patient?
In patients with CMV endotheliitis, oral valganciclovir, intravenous ganciclovir, topical ganciclovir and intravitreal injection of ganciclovir have been suggested to suppress the infection.1 2 6 7 This patient received intravitreal injection of ganciclovir (2 mg/0.05 ml) as the loading dose once and took oral valganciclovir 450 mg twice daily for 3 months. The condition improved significantly after treatment, and the cornea graft cleared up with diminishing coin-shaped KPs. The graft remained clear, and the best-corrected visual acuity in December 2009 was 20/50 in the right eye and 20/40 in the left eye.
Discussion
Our patient was diagnosed as having Fuchs endothelial dystrophy and received PK in the right eye three times. Graft failure manifested as KPs, corneal oedema and elevated IOP refractory to medication on the first two occasions. Coin-shaped KPs were noted on the third corneal graft. CMV endotheliitis was confirmed by the owl's eye appearance of the endothelium on confocal specular microscope and positive aqueous viral PCR result. The patient responded to intravitreal injection of ganciclovir and oral valganciclovir.
CMV infection has recently been found to cause corneal endotheliitis, in addition to previously known pathogens HSV, VZV and mumps virus. In immunocompetent patients, CMV infection may not be as rare as previously thought,8 and the associated inflammation in the anterior segment of eyes may manifest either as anterior uveitis with elevated IOP or as corneal endotheliitis.9 To date, more than 30 cases with CMV endotheliitis have been reported; one-third were diagnosed after keratoplasty.2 9–11
There are several possible causes for the higher incidence of CMV endotheliitis reported after keratoplasty.9 First, cases of presumed corneal decompensation such as pseudophakic or aphakic corneal oedema, HSV/VZV endotheliitis and ‘idiopathic’ endotheliitis may have really been CMV endotheliitis with reactivation after keratoplasty. This possibility corresponds to most of the previously reported postkeratoplasty CMV endotheliitis, except for one patient diagnosed as having Fuchs endothelial dystrophy (although no detailed history was provided),2 as was our patient. Second, these patients may have latent CMV in the cornea and anterior segment structures. The use of immunosuppressants after keratoplasty results in virus reactivation. Third, transmission of CMV from the donor corneal tissue into the recipient may lead to viral replication and infection after keratoplasty. The exact pathogenesis of postkeratoplasty corneal endotheliitis has not yet been elucidated. Whether prekeratoplasty tests should include CMV detection on both donors and recipients requires more discussion to reach consensus.
Post-PK CMV endotheliitis may mimic rejection. Differentiating allograft rejection from CMV endotheliitis is important to prevent subsequent graft failure, as in our patient. Elevated IOP, coin-shaped KPs in both donor and recipient corneas, as well as localised corneal oedema refractory to steroid treatment, should be considered signs of CMV endotheliitis rather than graft rejection.9 Our patient received PK three times. We do not know the precise cause of the previous graft failures in our patient. Only after reading the report of coin-shaped KPs as the presentation of CMV endotheliitis4 did we notice the KP pattern on the cornea. To explore if CMV existed in the patient's own cornea and in the two failed grafts, we retrospectively performed CMV PCR and immunohistological chemical staining (IHC staining) with CMV antibodies on all three corneal buttons, but could find no positive results (data not shown); however, H&E staining revealed rare and almost cell-free endothelia on all three corneas. Hwang et al, reporting the same observation in one CMV endotheliitis patient, postulated it as the result of a direct attack of CMV on the cornea endothelium.12 Since few endothelial cells were left, our chance of detecting CMV-infected endothelial cells was slight, which may explain the negative test results of PCR and IHC staining in our case. Thus, we still cannot confirm whether the previous episodes of corneal decompensation were related to CMV infection.
CMV endotheliitis can occur after keratoplasty for diseases unrelated to endotheliitis preoperatively, such as Fuchs endothelial dystrophy. Hence, clinicians should be alert to the possibility of CMV endotheliitis whenever postkeratoplasty allograft rejection is considered, for the two disease entities share common features. When new signs cannot be explained by previously known pathogenesis, a further investigation such as aqueous tapping should be conducted. Accurate and prompt treatment should ensue immediately after a confirmed diagnosis to prevent deleterious results.
Footnotes
Competing interests None.
Patient consent Obtained.
Provenance and peer review Not commissioned; externally peer reviewed.