Study design
This multicenter, open-label, prospective study was conducted in accordance with the Declaration of Helsinki and with the approval of the Institutional Review Board of the University of Tsukuba Hospital and Mito Kyodo General Hospital. All the patients and normal subjects provided informed consent prior to inclusion in the study. Treatment-naïve patients with CRVO who were referred to the Tsukuba University Hospital or Mito Kyodo General Hospital were enrolled in this study. The inclusion criteria for participation were as follows: (1) center-involving macular edema secondary to CRVO, (2) central foveal thickness (CFT) > 250 μm, (3) patients aged 18 years or above, but younger than 85 years, and (4) patients who provided written informed consent. The exclusion criteria were as follows: (1) previous history of vitreoretinal surgery, (2) previous history of ophthalmic disorders, except mild refractive errors and mild cataract, (3) patients who underwent treatment for macular edema within the last 90 days (including sub-tenon triamcinolone acetonide, intravitreal bevacizumab, intravitreal ranibizumab [IVR], intravitreal aflibercept, topical steroid, and carbonic anhydrase inhibitors), (4) patients who underwent intraocular surgery within the past 90 days, (5) the contralateral eye of patients with CRVO, (6) patients with poorly controlled hypertension and diabetic mellitus, and (7) patients who underwent laser treatment within the last 30 days. We also included age-matched normal controls in this study.
Study visits and assessments
The stereopsis, best-corrected visual acuity (BCVA), and retinal microstructure were examined every month before treatment and over a period of 12 months after treatment. The VR-QOL was examined before treatment and at 3, 6, and 12 months following treatment. We converted the BCVA measured using the Landolt chart to the logarithm of the minimum angle of resolution (logMAR) for use in the subsequent analysis. The Titmus Stereo Test (TST) and the TNO stereotest (TNO) were performed under appropriate spectacle corrections with a standard viewing distance of 40 cm to evaluate the stereopsis. We flipped the stereo target and asked the patient if the target was in front or behind the page, and checked the response to ensure that the patient did not use monocular clues during the TST. The results for TST and TNO were expressed in "seconds of arc." These values were converted to logarithms for statistical evaluation [11].
The macular structure was evaluated using spectral-domain optical coherence tomography (OCT) (Cirrus high-definition OCT; Carl Zeiss, Dublin, CA). Five-line Raster Cross scanning was performed using the Cirrus analysis software version 3.0., and scans with a signal strength of more than 6/10 were considered appropriate. The CFT was evaluated using the OCT image.
The VFQ-25 was administered to investigate the VR-QOL in patients with CRVO. The VFQ-25 consists of 25 items that permit patients to self-assess specific visual symptoms and difficulty with daily activities. The responses to the 25 questions are assigned to one of the following 12 subscales: general health, general vision, ocular pain, near activities, distance activities, social functioning, mental health, role limitations, dependency, driving, color vision, and peripheral vision. The composite VFQ-25 score is calculated as the average of the 11 subscale scores, excluding “general health.” Subscales are scored on a scale of 0–100 points, with 100 indicating the best possible functioning or minimal subjective impairment. This study utilized the Japanese version of the VFQ-25, which was modified to fit Japanese culture and lifestyle. The reliability and validity of the modified NEI VFQ-25 questionnaire have been assessed, and the questionnaire was proven to accurately measure the VR-QOL in Japanese individuals [30].
Intraocular injections
The patients with CRVO were administered three successive monthly injections of IVR (3 injections during months 0–2) (0.5 mg. Lucentis; Genetech) followed by pro re nata administration (3+PRN). After 3 injections (month 2), the participants were examined monthly and treated with intravitreal injections on a PRN basis according to the retreatment protocol. The criteria for PRN re-injection were as follows: (1) CFT ≥ 300 μm in the study eye as assessed by OCT, (2) detection of new cystoid changes in the retina, retinal bleeding or subretinal fluid on OCT, and (3) a decrease in visual acuity > 0.1 logMAR compared to the values obtained at the last visit.
The injection protocol was as follows: an eyelid opener was applied following topical anesthesia instillation and the injection site was washed with povidone iodine. A 30-gauge needle was inserted through the pars plana and 0.05 mL of ranibizumab was injected. All the procedures were performed at our clinic by experienced vitreoretinal surgeons (T.M., Y.S., and S.M.).
Statistical analysis
The mean and standard deviation values were calculated for each parameter. The
unpaired t-test was used to compare the age, stereopsis, and BCVA between patients with CRVO and normal controls. The chi-squared test was performed to determine the presence of any sex-based between-group differences. The Wilcoxon signed-rank test was performed to investigate changes in the visual function (TST, TNO, and BCVA), CFT, and composite VFQ-25 score. The associations between stereopsis and the composite VFQ-25 score and BCVA were examined using the Spearman rank-correlation test. Multivariate analysis was performed to investigate the relationship between the VR-QOL and visual functions. All the analyses were conducted using SPSS (version 27, IBC Corp., Chicago, IL, USA). P-values less than 0.05 were considered statistically significant.