Objective
To demonstrate the clinical significance of owl eye morphologic features observed by in vivo laser confocal microscopy in patients with cytomegalovirus (CMV) corneal endotheliitis.
Design
Observational case series.
Methods
participants: Six eyes of 6 patients (6 men; mean age, 73.3 years) with cytomegalovirus corneal endotheliitis diagnosed by clinical manifestations together with polymerase chain reaction from aqueous humor samples. intervention: All patients were examined by slit-lamp biomicroscopy and in vivo laser confocal microscopy. main outcome measures: Clinical manifestations were summarized by reviewing medical records. Selected confocal images of corneal layers were evaluated qualitatively for shape and degree of light reflection of abnormal cells and deposits.
Results
All patients had long histories of anterior uveitis with intraocular pressure elevation, corneal edema with keratic precipitates, and decrease of endothelial cell densities. Coin-shaped lesions were observed by slit lamp only in 1 patient at the first visit and in 2 additional patients at subsequent follow-up. In all patients, confocal microscopy demonstrated reduced subepithelial nerves, subepithelial opacity, increased reflectivity of keratocytes, highly reflective dots, and needle-shaped bodies. Owl eye morphologic features were observed consistently in all patients at the initial visit, and highly reflective round bodies were detected in 5 patients; most notably, these confocal features were reversible after resolution of endotheliitis.
Conclusions
Owl eye morphologic features and highly reflective round bodies observed by confocal microscopy may be useful as an adjunct for the noninvasive diagnosis of cytomegalovirus corneal endotheliitis. Reversibility of these features after resolution of endotheliitis may be useful for monitoring the therapeutic effects without multiple anterior chamber tap.
Corneal endotheliitis, characterized by corneal edema associated with linear keratic precipitates and endothelial dysfunction, may be caused by herpes simplex virus (HSV), varicella zoster virus (VZV), or other viruses such as mumps. It often leads to irreversible corneal endothelial cell damage and severe visual disturbance. Most recently, cytomegalovirus (CMV) was recognized as a new etiologic factor for corneal endotheliitis. Clinical manifestations of CMV endotheliitis are characterized by linear keratic precipitates associated with multiple coin-shaped lesions and local corneal stromal edema with minimal anterior chamber reactions. The intraocular pressure (IOP) of these patients frequently is increased, and they often are treated with topical or systemic antiglaucoma medication because of the diagnosis of secondary glaucoma of unknown origin. The patients also may have had past histories of several penetrating keratoplasties.
In vivo white-light confocal microscopy has been used as a noninvasive technique for the observation of normal and pathologic corneal microstructures at the cellular level in real time. Most recently, new-generation scanning laser in vivo confocal microscopy (Heidelberg Retina Tomograph 2 Rostock Cornea Module [HRT 2-RCM]; Heidelberg Engineering GmbH, Dossenheim, Germany) has become available. This new device provides high-definition histologic-like images of corneal microstructures in vivo, with an axial resolution of approximately 4 μm and improved resolution compared with conventional white-light confocal microscopes (for example, 10 μm axial optical resolution with ConfoScan 2 [Nidek Technologies, Vigonza, Italy]). Previously, Shiraishi and associates demonstrated large corneal endothelial cells with an area of high reflection in the nucleus surrounded by a halo of low reflection in a single patient with CMV corneal endotheliitis using the HRT 2-RCM. The authors suggest that these owl eye morphologic features in the corneal endothelium may be characteristic of CMV endotheliitis. A small number of case reports also have suggested an association of owl eye morphologic features in the corneal endothelium and CMV corneal endotheliitis.
In this article, we report clinical manifestations in 6 Japanese patients with polymerase chain reaction (PCR)-proven CMV corneal endotheliitis and the results of detailed investigations of in vivo corneal microstructures of all cell layers with laser scanning confocal microscopy using the HRT 2-RCM. The diagnostic value and usefulness of monitoring the therapeutic effects of this device in CMV corneal endotheliitis also are described.
Methods
The study population consisted of 6 eyes of 6 consecutive patients (6 men; mean, 73.3 years), whose active CMV corneal endotheliitis was diagnosed and treated between April 2010 and March 2011 at the Department of Ophthalmology, Kanazawa University Hospital, Kanazawa, Japan (Patients 1 through 5), or the Department of Ophthalmology, Fukui-ken Saiseikai Hospital, Fukui, Japan (Patient 6; Table ). The clinical diagnosis was performed based on slit-lamp findings of active corneal endotheliitis (such as corneal edema and keratic precipitates) and the detection of CMV by PCR assay in the aqueous humor from the affected eye. HSV, VZV, Epstein-Barr virus, human herpes virus 6, and human herpes virus 7 DNA were not detected. Clinical manifestations of the patients were reviewed retrospectively, with special attention paid to slit-lamp findings, IOP measurements, and corneal endothelial cell density. Also, responses to antiviral treatment were evaluated.
| Case No. | Gender/Age (y) | Age (y) | Affected Eye | History of Ocular Disease and Duration (mos) | Slit-Lamp Findings | Endothelial Cell Density (cells/mm 2 ) | Systemic Disease | Intraocular Pressure (mm Hg) (No. Antiglaucoma Eye Drops) | Visual Acuity before/after Treatment | CMV DNA by PCR of Aqueous Humor | Treatment | Clinical Outcomes (Follow-up Period after CMV Detection, mos) |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | M | 77 | Left | Anterior uveitis, secondary glaucoma (72) | Corneal edema, pigmented KPs (coin-shaped lesions during follow-up), AC cell | 692 | DM, mixed connective tissue disease (oral prednisolone 2.5 mg/day) | 18 (1) | 20/25/20/25 | Positive | Systemic ganciclovir 10 mg/kg daily × 7 days, 0.5% ganciclovir, 8 times daily, 0.1% betamethasone, 4 times daily | Clear cornea (8) |
| 2 | M | 75 | Left | Anterior uveitis, secondary glaucoma (24), diagnosed as Posner- Schlossman syndrome | Corneal edema, pigmented KPs, coin-shaped lesions, AC cell | 1730 | Lung cancer (treated) | 25 (3+Dx) | 20/40/20/40 | Positive | 0.5% ganciclovir 8 times daily, 0.1% betamethasone 4 times daily | Clear cornea (5) |
| 3 | M | 63 | Right | Anterior uveitis, secondary glaucoma (108), diagnosed as Posner- Schlossman syndrome | Corneal edema, pigmented KPs (coin-shaped lesions during follow-up), AC cell+, iris atrophy | 1677 | Hyperlipidemia, fatty liver | 24 (3+Dx) | 20/25/20/25 | Positive | Systemic ganciclovir 10 mg/kg daily × 7 days, 0.5% ganciclovir 8 times daily, 0.1% betamethasone 4 times daily, cataract surgery for secondary cataract | Edema reduction (5) |
| 4 | M | 83 | Right | Anterior uveitis, secondary glaucoma (60) | Corneal edema, Pigmented KPs AC cell+, fibrin+ | 645 | Essential thrombocythemia | 26 (2) | 20/100/20/40 | Positive | 0.5% ganciclovir 8 times daily, 0.1% betamethasone 4 times daily | Clear cornea (4) |
| 5 | M | 56 | Left | Anterior uveitis, secondary glaucoma, (144), diagnosed as Posner- Schlossman syndrome | Corneal edema, pigmented KPs, AC cell+, iris atrophy | <1000 | DM | 15 (4) | 20/100/12/40 | Positive | Systemic ganciclovir 1800 mg daily × 12 days, 0.5% ganciclovir 8 times daily, 0.1% betamethasone 4 times daily | Edema reduction (2) |
| 6 | M | 86 | Left | Anterior uveitis, secondary glaucoma (96), diagnosed as Posner- Schlossman syndrome | Corneal edema, pigmented KPs, AC cell, depigmented iris | 550 | Hypertension | 43 (3+Dx) | 20/22/20/16 | Positive | Systemic ganciclovir 10 mg/kg daily × 14 days, 0.5% ganciclovir 8 times daily, 0.1% betamethasone 4 times daily | Edema reduction (1) |
In Vivo Laser Confocal Microscopy
Before examination, written informed consent was obtained from all subjects after explaining the nature and possible consequences of this study, such as superficial punctate keratopathy. After applying a large drop of contact gel (Comfort Gel ophthalmic ointment; Bausch & Lomb GmbH, Berlin, Germany) on the front surface of the microscope lens and ensuring that no air bubbles had formed, a Tomo-Cap (Heidelberg Engineering GmbH, Dossenheim, Germany) was mounted on the holder to cover the microscope lens. The central and affected areas of the cornea then were examined layer by layer using the HRT 2-RCM. The HRT 2-RCM uses a ×60 water-immersion objective lens (Olympus Europa GmbH, Hamburg, Germany) and uses a 670-nm diode laser as the light source with a 400-μm 2 area of observation.
Results
Clinical Manifestations
The Table summarizes the clinical manifestations for 6 eyes of 6 patients. The mean follow-up period for all patients was 4.2 ± 2.5 months (range, 1 to 8 months). All patients were male (6/6; 100%) and had long histories (more than 2 years) of anterior uveitis (6/6; 100%) and IOP elevation of unknown origin (6/6; 100%) that was treated by corticosteroids and antiglaucoma agents (duration, 24 to 144 months; mean ± standard deviation, 84.0 ± 41.6 months). All patients had corneal edema (6/6; 100%) and pigmented keratic precipitates (6/6; 100%). Three patients had mild anterior chamber reaction (Patients 3 through 5; 50%), and the remaining 3 patients had no anterior chamber reaction. Iris atrophy was observed in 3 patients (Patients 3, 5, and 6; 3/6; 50%). Three patients experienced strong iridocyclitis with fibrin reaction after cataract surgery (3/4; 75%); the surgery was performed before the diagnosis of CMV endotheliitis in 1 patient and after the treatment of CMV endotheliitis in 2 patients. A tentative diagnosis of Posner-Schlossman syndrome was made in 4 patients (Patients 2, 3, 5, and 6; 4/6; 66.7%), and 5 patients (5/6, 83.3%) initially were referred to our glaucoma service. Severe glaucomatous visual field defects were observed in 2 patients (2/6; 33.3%).
Coin-shaped lesions were observed only in Patient 2 at the first visit. At subsequent follow-up visits, 2 additional patients had coin-shaped lesions (Patients 1 and 3; total, 3/6; 50%: Figure 1 ). The coin-shaped lesions were not detectable in the remaining 3 patients (Patients 4 through 6) throughout the follow-up period. Endothelial cell density (ECD) was decreased in all eyes (6/6; 100%); 4 patients (Patients 1, 4, 5, and 6) had an ECD of less than 1000/mm 2 , and the remaining 2 patients had an ECD of less than 2000/mm 2 . Patients 1 and 5 had diabetes mellitus, and Patient 1 also had mixed connective tissue disease treated with oral prednisolone 2.5 mg/day. The aqueous humor samples of all eyes contained CMV DNA (6/6; 100%), but not HSV, VZV, Epstein-Barr virus, human herpes virus 6, or human herpes virus 7 DNA. All patients were treated with topical 0.5% ganciclovir (8 times daily) and 0.1% betamethasone (4 times daily). In addition, all patients (except Patients 2 and 4) were administrated intravenous ganciclovir 10 mg/kg daily for 7 days based on the severity of clinical manifestations. After 1 to 2 months of treatment, corneal edema, keratic precipitates (KPs), and IOP were improved in all patients. In Patients 1 and 3, CMV DNA was not detected by PCR in aqueous humor samples after treatment. CMV DNA was not tested again in the remaining patients.
In Vivo Laser Confocal Microscopy
In vivo laser confocal microscopy demonstrated normal epithelial layers in 4 patients (Patients 1, 2, 4, and 5; 66.7%) and slightly increased cell body size with higher intensity indicative of epithelial edema in 2 patients (Patients 3 and 6; 33.3%: Figure 2 , Top right). A few subepithelial nerves were detected in 2 patients (Patients 3 and 4; 33.3%; Figure 2 , Second row left), but no subepithelial nerves were detected in the remaining 4 patients (Patients 1, 2, 5, and 6; 66.7%; Figure 3 , Second row left; Figure 4 , Second row left). Stromal nerves were detected in 2 patients (Patients 2 and 3; 33.3%). Subepithelial opacity, increased reflectivity of keratocytes, highly reflective dots, and needle-shaped bodies were observed uniformly in all patients (6/6; 100%; Figure 3 , Second row center and Second row right; Figure 4 , Second row center and Second row right; Figure 2 , Second row center and Second row right). The most characteristic feature was large cells whose nuclei had a high reflection area surrounded by a halo of low reflection (owl eye morphologic features), and these were observed in the corneal endothelial cell layer in all eyes (6/6; 100%; Figure 2 , Bottom left and Bottom center, Figure 3 , Third row left, Third row center, Third row right, and Bottom center; Figure 4 , Bottom left and Bottom center). In contrast, owl eye morphologic features were not detected by noncontact specular microscopy in any of the patients (data not shown). Highly reflective round bodies on the surface of the endothelial cell layer also were detectable in 5 patients (Patients 1 through 3, 5, and 6; 83.3%; Figure 2 , Bottom right, Figure 3 , Bottom left, Bottom center, Bottom right; Figure 4 , Bottom right). These owl eye cells and highly reflective round bodies disappeared in all patients after treatment. Subepithelial and stromal nerves were visible in all patients after resolution of the CMV endotheliitis.
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