Clinical characteristics of virus-related uveitic secondary glaucoma: focus on cytomegalovirus and varicella zoster virus

This retrospective study was approved by the Institutional Review Board of the Eye and ENT Hospital of Fudan University, Shanghai, China (no. 2017006–2), in accordance with the norms of the 1964 Declaration of Helsinki.

We enrolled patients who visited the glaucoma clinic at the Eye and ENT Hospital of Fudan University between January 2016 and August 2019. We used our electronic health records system and searched the diagnosis field of patients. The search terms we used were “anterior uveitic secondary glaucoma”, “anterior uveitis”, and “secondary glaucoma”. Patients diagnosed with “anterior uveitic secondary glaucoma” or diagnosed with both “anterior uveitis” and “secondary glaucoma” were identified. Finally, a total of 132 patients diagnosed with anterior uveitic secondary glaucoma were screened in the electronic records system of our hospital. The detailed flow chart of the patients’ inclusion in the study is shown in Fig. 1. Finally, a total of 60 patients were included in this study, including 47 patients with PSS and 13 VZV-AUSG. Among the enrolled patients with PSS, 25 were CMV-positive and 22 CMV-negative cases (also negative for herpes simplex virus and VZV). Three of CMV-positive and two of CMV-negative patients were bilateral. For bilateral cases, the more severe eye was included in this study. All the 13 patients with VZV-AUSG were unilateral. All the included patients were immunocompetent without human immunodeficiency virus (HIV) infection and they all had evidence or history of one episode. All the patients had previously received topical corticosteroid and antiglaucoma treatment; however, none had received antiviral therapy before the first visit to our glaucoma clinic where the aqueous humor was sampled. The exclusion criteria were as follows: 1) secondary glaucoma of other known causes; 2) anterior uveitis of other known non-infective causes, including abnormal autoimmunity and phacolytic factor; 3) presence of dendritic keratitis, vitreitis, or retinitis; 4) eyes treated with antiviral agents before aqueous tap; 5) incomplete data record. Topical 2% ganciclovir solution were applied to patients with CMV-positive PSS and VZV-AUSG 4 times per day during the follow-up period after receiving the results of aqueous viral antibody. The frequency of corticosteroid use was in accordance to the severity of ocular inflammation.

We reviewed the following demographic data of the patients from the medical records: gender, age at onset (first uveitis episode), age at diagnosis (CMV- or VZV-positive), laterality, disease duration (prior to aqueous tap), and attack frequency. The patients underwent thorough ophthalmologic examination based on their clinical requirements, including slit-lamp microscopy, indirect ophthalmoscopy, best corrected visual acuity (BCVA), IOP, visual field, and corneal endothelial cell count. Further, we collected the following information: cup-to-disc ratio, keratic precipitates (KPs), anterior chamber inflammation, clinical appearance of the iris, presence of cataracts, follow-up time, medical treatment at the first and last visit (including the use of antiglaucoma agents and corticosteroids), corticosteroid dependency, and surgical intervention. In patients with VZV-positive AUSG, we also obtained data regarding facial and periocular herpes zoster, conjunctival congestion, corneal edema, and pupillary configuration. Clinical data were noted at the time of the first visit of PSS and VZV-AUSG patients and after a short-time follow-up of PSS patients.

We measured the corneal endothelial cell (CEC) density in both diseased and healthy eyes and calculated the relative CEC loss rate as follows: CECs loss (%) = (1-CEC density in the diseased eye/CEC density in the healthy eye) × 100%. Iris depigmentation was determined when iris color of the disease eye was lighter than the fellow eye, which was observed by slit-lamp microscopy.

The diagnostic criteria of PSS were based on clinical manifestations, including recurrent anterior chamber inflammation, elevated IOP during the attack, diffuse cornea edema and characteristic KPs, and the absence of anterior or posterior synechiae. Between attacks, the IOP is usually normal and the anterior chamber angles are constantly open.

The diagnosis criteria of VZV-AU were based on a positive aqueous virus antibody test and clinical manifestations, including keratitis, elevated IOP, iris sector atrophy developing over time, and facial or periocular varicella zoster with subsequent keratouveitis. Regarding patients with AU, secondary glaucoma was defined as elevated IOP (> 21 mmHg) with optic disc abnormalities. The diagnosis of secondary glaucoma was confirmed by a glaucoma specialist (XK).

After aqueous sample collection, we used enzyme-linked immunosorbent assay (ELISA, Virion/Serion, Germany) to detect CMV and VZV IgG antibodies. Further, we corrected the viral antibody in the aqueous humor using aqueous and serum albumin as follows: (aqueous CMV or VZV IgG/serum CMV or VZV IgG)/ (aqueous albumin concentration/serum albumin concentration). The corrected ratio was abbreviated as s/co. The result was considered positive when viral IgG was detected in aqueous humor and the aqueous humor/serum correction ratio was larger than 0.6 s/co. The diagnostic performance of the corrected ratio on ocular virus infection has been evaluated by the ROC curve [20‐22]. The area under the ROC curve for the corrected ratio was 0.942 (95% CI: 0.859 to 0.984) as described in our previous study [22].

Data were expressed as mean with 95% C.I. We used the χ² test or Fisher’s exact test to compare proportions, when appropriate. We used the Mann-Whitney U test for between-group comparisons of continuous variables. We used SPSS ver. 26 to perform statistical analysis and between-group differences were considered significant at P < .05.

Table 1 presents the demographic data and basic characteristics of both patients with CMV-positive and CMV-negative PSS. There was no significant between-group difference in the basic characteristics, including the age at the first onset, age at the clinic visit, gender, eye literality, and disease duration (p = .975, p = .654, p = 730, p = .654, and p = .115, respectively).

Table 2 presents the ocular manifestations of the patients with CMV-positive and CMV-negative PSS. Compared with patients with CMV-negative PSS, patients with CMV-positive PSS exhibited a significantly larger cup-to-disc ratio and higher CECs loss rate (p = .043 and p = .001, respectively). Regarding ocular morphological alterations, 20/25 (80%) and 9/22 (40.9%) of the patients in the CMV-positive and CMV-negative PSS groups, respectively, had iris depigmentation, which was a significant proportion (p = .006). There was no significant between-group difference in the IOP and BCVA (p = .839 and p = .554, respectively). Further, the proportion of eyes with mutton-fat KPs, coin-shaped KPs, Tyndall effect, and cataract was also similar between these two groups (p = .095, p = .894, p = 1.000, and p = .085, respectively).

Table 3 presents the applied treatments upon diagnosis with CMV-positive PSS and the relevant outcomes after a follow-up period. The CMV-positive group used fewer IOP-lowering agents at the initial visit compared with the CMV-negative group (p = .005). All patients with CMV-positive PSS were treated with topical 2% ganciclovir during the follow-up. After an approximately equal follow-up duration (mean: 4.9 and 5.9 weeks, respectively), the IOP of all patients in both groups, except two who were CMV-negative, was within the normal range after medical treatment (< 21 mmHg). Further, the IOP of patients with CMV-positive PSS was lower than that of CMV-negative PSS (p = .016), indicating that fewer antiglaucoma agents were sufficient to control the IOP in patients in the CMV-positive group with the treatment of topical 2% ganciclovir. Further, there was no significant between-group difference in the mutton-fat KPs, coin-shaped KPs, and Tyndall effect after the follow-up. Moreover, at the end of the short-term follow-up, there was complete disappearance of the KPs of 10 (52.6%) CMV-positive and 10 (40%) CMV-negative eyes, respectively. Tyndall effect turned negative in all the patients in both groups.

Further, we analyzed 13 patients with VZV-positive AU with secondary glaucoma. Table 4 presents their basic characteristics.

Table 5 presents the similarities and differences between patients with VZV-AUSG and those with CMV-positive PSS. The patients with VZV-AUSG were significantly older than those with CMV-positive PSS (p = .003). The patients with VZV-AUSG manifested significantly higher IOP (p = .015) and worse BCVA compared to those with CMV-positive PSS (p < .001). The visual acuity of 2 of the 13 patients in the VZV-AUSG group was finger count, which corresponded to LogMAR visual acuity 2.0. The visual acuity of 1 of the 25 patients in the CMV-positive PSS group was hand movement, which corresponded to LogMAR visual acuity 3.0. Mutton-fat KPs were more often seen in patients with CMV-positive PSS, while characteristic pigmented KPs were more often seen in patients with VZV-AUSG (shown in Fig. 2). Additionally, the prevalence of Tyndall effect was higher in the VZV-AUSG group (p < .001). Consistent with their higher IOP, patients with VZV-AUSG were treated with more antiglaucoma agents simultaneously than those with CMV-positive PSS (p < .001); however, there was no significant between-group difference in the application of corticosteroid. 4 of 13 eyes (30.8%) with VZV-AUSG received antiglaucoma surgery, including trabeculectomy in 3 eyes and CDPI in 1 eye. The surgical treatment of CMV-positive PSS has been detailed described before. The proportion of eyes requiring antiglaucoma surgery was similar between CMV-positive PSS and VZV-AUSG.