Introduction
Corneal endotheliitis, first characterized by Khodadoust and Attarzadeh [
1], is characterized by the presence of linear keratic precipitates (KPs) similar to that found in eyes with corneal endothelial rejection. Later, Ohashi et al. [
2] reported on a unique corneal endothelialitis that consisted of severe stromal edema associated with keratic precipitates. This endotheliitis was of viral origin, especially the herpes simplex virus (HSV). Additionally, Amano [
3] reported that the herpes simplex virus can cause trabeculitis and increased intraocular pressure (IOP) in patients with corneal endotheliitis. In 2006, Koizumi et al. [
4] identified cytomegalovirus (CMV) as one of the causative agents of corneal endotheliitis and this was confirmed by Chee et al. [
5]. Subsequently, the characteristics of this clinical entity, such as coin-shaped regions and Khodadoust line-like KPs with corneal edema, were reported in eyes with corneal endotheliitis by a multicenter clinical study [
6].
CMV endotheliitis is associated with a marked decrease in corneal endothelial cell densities even with mild anterior chamber inflammation. This corneal endothelial cell damage is associated with recurrent inflammations, IOP elevations, and mostly high CMV viral loads [
7,
8]. To prevent the visual loss by corneal decompensation in CMV endotheliitis, an appropriate strategy for the treatment based on the DNA viral load is necessary. However, viral infection can sometimes evoke strong immune reactions even with slight amount of virus. To the contrary, anterior chamber-associated immune deviation (ACAID) can mask the clinical phenomenon of the endotheliitis [
9,
10]. Therefore, the clinical severity of the anterior chamber inflammation does not always reflect the amount of virus DNA and it is very difficult to predict the amount of virus only from the severity of inflammation such as injection and number of cells in the aqueous humor.
From our clinical experience with many cases of CMV-associated corneal endotheliitis, we noted that the type of KPs and corneal edema could be a marker of the morbidity of the anterior segment inflammation caused by CMV.
Thus, the purpose of this study was to determine whether there is a correlation between various clinical characteristics and the copy number of the DNA of CMV in the aqueous humor of four patients with CMV-proven corneal endotheliitis.
Discussion
There are two major difficulties that need to be considered when treating CMV endotheliitis. First, there is no definitive evidence on the need of steroids along with anti-viral drugs for a successful outcome. Second, there are no experimentally derived criteria for when to terminate the GCV treatment. There are some concerns that immunosuppressive agent such as steroids might evoke a viral re-activation because this disease is well known to have high recurrence rates [
12,
13]. Both of these difficulties are due to the inability to determine the activity of CMV activity or virus titers from the clinical manifestations.
We have classified the clinical characteristics with various kinds of KPs into four types based on Moshirfar’s review [
14]. We found that the clinical characteristics were related to the copy number of DNA of CMV in the aqueous humor.
Kandori et al. [
7] and Miyanaga et al. [
8] had already reported on the relationship between the type of KPs and viral level. However, they examined only one time point in each case and did not describe the changes during the course of the disease process. We have followed the changes of the DNA amounts along with the treatment process and found new findings on the relationships between the clinical characteristics and the copy numbers of the DNA of CMV. First, the eyes with coin-shaped KPs had copy numbers of the DNA of CMV of ≥ 10
3 copies/ml in the aqueous humor. This observation is supported by Kandori’s report [
7]. Shiraishi [
15] also reported that the edema with the coin-shaped KPs was observed as “owl’s eye” lesions by specular microscopy which is similar to the virus plaque of cells in vitro. Taken together with our findings, the coin-shaped lesions must be the site where the endothelial cells are infected with high titers of CMV. This characteristic appearance indicates the need for rigorous anti-viral treatment.
Second, the copy numbers of CMV DNA in eyes with sectoral corneal edema with/without the Khodadoust line-like KPs ranged from 5.0 × 10
2 to 9.4 × 10
4 copies/ml. Khodadoust line-like KPs were not always accompanied by high copy numbers of the DNA of CMV. As was reported in HSV endotheliitis [
3], experimental research has shown that CMV infects the cells of the trabecular meshwork [
16,
17]. And sectoral corneal triangular edema with or without Khodadoust line-like KPs usually appears connected to the limbus. Thus, we suggest that sectoral corneal edema is occasionally accompanied by Khodadoust line-like KPs which might be a reactive phenomenon due to active CMV infection in the trabecular meshwork tissue. Khodadoust line-like KPs are usually accompanied by the sectoral peripheral corneal edema [
6] which can sometimes be difficult to observe because of the edematous opacity. The variations in the severity of Khodadoust line-like KPs on sectoral corneal edema might be correlated with a range of copy numbers of the DNA of CMV.
Third, the mutton-fat KPs in the inferior part of the cornea are usually observed in various types of anterior uveitis as immune reactions regardless of the type or titer of the organisms. From all of these observations, sectoral corneal edema with and without Khodadoust line-like KPs and mutton-fat KPs might indicate the necessity of the steroid therapy along with the anti-virus therapy.
Fourth, the eyes with fine KPs had low or no copy number of CMV DNA. The fine-pigmented KPs were specifically observed after the resolution of corneal endotheliitis in all of the eyes. Thus, the fine KPs might be a marker to terminate the anti-viral drug therapy.
Several clinical signs are usually seen concomitantly, and the most severe conditions affect the copy numbers of the DNA of CMV. For example, if coin-shaped KPs were observed with sectoral edema with Khodadoust line-like KPs or mutton-fat KPs, the coin-shaped KPs would be the most affected characteristic to determine the DNA amount.
Previously, Miyanaga et al. [
8] reported that there was no significant correlation between the viral load and type of KPs. They studied seven cases of iridocyclitis and four cases of endotheliitis and observed only mutton-fat KPs and fine KPs. They focused on the association of viral loads and endothelial cell loss. They did not examine the relationships between the types of KPs and CMV copy numbers. Therefore, our observations are not in conflict with their observations.
Glucocorticoid resistance was recently reported in cases of CMV ulcerative colitis because of receptor alterations [
18]. Cases 3 and 4 had recurrences of the anterior chamber inflammation while being treated with topical steroids and GCV. These recurrences might be related to the resistance against steroid used for the CMV infection. Further studies on the viral load may be helpful in clarifying the resistance of CMV to steroid therapy and IOP elevation.
This study has some limitations including its retrospective nature. All cases had been treated with steroid eye drop for iridocyclitis before they were referred to us. The use of steroids might have affected the copy numbers. The use of anti-viral drug also might have affected the results. In addition, the timing of sample collection was not standardized in each patient. Another limitation is the small sample size of four patients. However, the speculation of the copy numbers of CMV-DNA during the course of anti-viral treatment is important in clinical practice. Thus, we believe that the results of current study would propose some information to speculate the copy numbers of CMV-DNA in the treatment of CMV corneal endotheliitis.
In conclusion, the clinical characteristics and different types of KPs and edemas with their chronological changes might be important signs of the viral load in eyes with CMV corneal endotheliitis. In the era of the development of ganciclovir gel for the treatment of anti-CMV endotheliitis [
19], further large-scale studies are needed to conclude the contribution of various characteristics with different KPs in the management of CMV endotheliitis.
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