Purpose
To evaluate the association between initial subfoveal choroidal thickness and response to anti–vascular endothelial growth factor (anti-VEGF) therapy in central retinal vein occlusion (CRVO) eyes.
Design
Retrospective cohort study.
Methods
Forty-three eyes from 42 patients with treatment-naïve CRVO were included. All patients included were treated with a standard algorithm of 3 monthly anti-VEGF injections. Serial enhanced depth imaging optical coherence tomography scans were used to measure subfoveal choroidal thickness and central macular thickness (CMT). Baseline predictors (particularly choroidal thickness) for functional response (best-corrected visual acuity gain ≥2 lines) were assessed at 3 months follow-up using univariate and multivariate analyses.
Results
Forty-three eyes from 42 patients were included. Initial choroidal thickness in CRVO eyes (246 ± 102 μm) was greater than in their fellow eye (197 ± 86 μm; P = .023). In addition, mean choroidal thickness at baseline for functional responders (272.2 ± 107.3 μm) was greater than that of nonresponders (209.6 ± 85.8 μm; P = .039). A higher baseline choroidal thickness (for every 100-μm increase in choroidal thickness) was found to be a positive predictor for functional response (regression coefficient: 0.7; P = .04) on univariate analysis, whereas age (<70 years old) was the only positive predictor for functional response with an odds ratio of 6.49 (95% confidence interval: 1.11-38.1; P = .03) on multivariate regression analysis.
Conclusions
Baseline choroidal thickness and age may help predict which patients with CRVO have favorable visual outcomes following short-term anti-VEGF therapy.
Anti–vascular endothelial growth factor (VEGF) therapy has become the initial treatment of choice for patients with macular edema secondary to branch and central retinal vein occlusion (BRVO and CRVO).
Following an initial report by Spaide and associates using enhanced depth imaging spectral-domain optical coherence tomography (EDI-OCT) to visualize the choroid, numerous studies have described choroidal thickness in various retinal diseases. More recently, several groups have evaluated choroidal thickness measurements in the setting of retinal vein occlusion (RVO). In a study by Tsuiki and associates, choroidal thickness in eyes with CRVO was significantly thicker than the uninvolved fellow eye. Similarly, Lee and associates demonstrated a greater choroidal thickness in eyes with RVO compared with the fellow eye. Conversely, Du and associates found no difference in choroidal thickness between eyes with RVO and their corresponding fellow eye.
Although there is growing evidence suggesting the choroidal vasculature may be altered during the pathophysiology of CRVO, to our knowledge no study has evaluated choroidal thickness as a predictor for anti-VEGF treatment response in patients with macular edema secondary to CRVO. Accordingly, the purpose of this study was to determine whether baseline choroidal thickness may be a prognostic indicator for visual outcomes in patients with treatment-naïve CRVO.
Methods
Following approval by the institutional review board at Wills Eye Hospital, a retrospective consecutive case series of patients diagnosed with CRVO was performed. Billing records from January 1, 2010 through January 31, 2014 at Mid Atlantic Retina and the Retina Service of Wills Eye Hospital were used to identify patients diagnosed with CRVO using the respective ICD-9 code 362.35.
The inclusion criteria for this study consisted of treatment-naïve patients who were newly diagnosed with macular edema due to CRVO and who were treated initially with 3 monthly anti-VEGF injections. Patients who had any of the following therapy in the study eye either prior to or during the initial 3 anti-VEGF injections were excluded: focal/grid laser photocoagulation, panretinal photocoagulation (PRP), or intravitreal injections (eg, intravitreal or sub-Tenon injections of corticosteriods). Patients were also excluded if they had any of the following concomitant ocular diseases: diabetic macular edema, age-related macular degeneration, prior ocular surgery (except cataract surgery), and choroidal neovascularization.
Patient charts were reviewed to collect the following data: age, sex, past medical history (hypertension, diabetes mellitus), lens status, best-corrected Snellen visual acuity (BCVA) based on spectacle correction with pinhole, and anti-VEGF injection dates, as well as drug used.
Imaging Protocol
All patients included in the study received EDI-OCT using the Heidelberg Spectralis (Heidelberg Engineering, Heidelberg, Germany) platform. Subfoveal choroidal thickness was measured at baseline and 3 months follow-up using the built-in caliper software at a single point below the fovea extending from the bottom of the hyperreflective layer corresponding to Bruch’s membrane to the hyperreflective layer at the sclerochoroidal junction. All scans were interpreted by 2 experienced reviewers (N.R. and M.P.), and any differences were resolved by a third interpreter (E.R.), who were all masked to patient clinical data. Furthermore, central macular thickness (CMT) was recorded for all patients using the automated software present in the 25-line raster scan pattern.
Statistical Analysis
Data were analyzed using SAS v9.3 (SAS Institute Inc, Cary, North Carolina, USA). BCVA was converted to logarithm of the minimal angle of resolution (logMAR) for statistical analysis. Paired 2-tailed t test was used to compare continuous data at baseline and 3 months follow-up. Linear regression was used to determine if baseline factors (eg, subfoveal choroidal thickness) were predictors for functional response (ie, change in logMAR vision from baseline) after 3 months of follow-up, with outcomes modeled as a continuous variable. Subsequently, data were analyzed for baseline predictors of anti-VEGF treatment outcomes at 3 months follow-up using a model that defined functional responders as patients who had BCVA gains of ≥2 lines from baseline. Unpaired 2-tailed t test was performed to deduce any differences between responders and nonresponders. Univariate analysis followed by multivariate logistic regression analysis was used to determine baseline predictors for functional response.
Results
A total of 43 eyes from 42 patients diagnosed with treatment-naïve CRVO were included in this study. Baseline characteristics are reported in Table 1 . Initial subfoveal choroidal thickness for eyes diagnosed with CRVO was 246 ± 102 μm, which was significantly greater than that of their fellow eye (197 ± 86 μm; P = .023). Similarly, baseline CMT was greater in the study eye (560 ± 181 μm) compared with the fellow eye (293 ± 54 μm; P < .0001). Table 2 contains data for the outcome measures of the study (visual acuity, choroidal thickness, and CMT) at baseline and at 3 months follow-up.
| Baseline Characteristics | CRVO (N = 43 Eyes From 42 Patients) |
|---|---|
| Age (y) | |
| Mean (SD) | 71 (15.2) |
| Median (min, max) | 74 (21, 95) |
| Sex | |
| Male | 19 (44.2%) |
| Female | 24 (55.8%) |
| Hypertension | |
| No | 8 (18.6%) |
| Yes | 35 (81.4%) |
| Lens status | |
| Pseudophakic | 10 (23.3%) |
| Phakic | 33 (76.7%) |
| Ellipsoid zone at baseline | |
| Intact | 10 (23.3%) |
| Disrupted | 20 (46.5%) |
| Absent | 13 (30.2%) |
| Drug treated in 3 months | |
| Bevacizumab only | 25 (58.1%) |
| Ranibizumab only | 5 (11.6%) |
| Aflibercept only | 1 (2.33%) |
| Mixture | 12 (27.9%) |
| Baseline BCVA (logMAR) | |
| Mean (SD) | 1.26 (0.69) |
| Baseline SFCT (μm) in study eye | |
| Mean (SD) | 246 (103) |
| Baseline SFCT (μm) in fellow eye | |
| Mean (SD) | 195 (86.1) |
| Baseline CMT in study eye | |
| Mean (SD) | 560 (181) |
| Baseline CMT in fellow eye | |
| Mean (SD) | 293 (53.5) |
| Outcomes | At Baseline | At 3 Months | P Value |
|---|---|---|---|
| Mean (SD) | Mean (SD) | ||
| BCVA (logMAR) | |||
| Study eye | 1.26 (0.69) | 0.96 (0.76) | <.001 ∗ |
| SFCT (μm) | |||
| Study eye | 246 (102) | 197 (72) | <.001 ∗ |
| Fellow eye | 197 (86) | 199 (87) | .776 |
| CMT (μm) | |||
| Study eye | 560 (181) | 349 (125) | <.001 ∗ |
| Fellow eye | 293 (54) | 300 (73) | .50 |
Functional Responders and Nonresponders
Twenty-five CRVO eyes treated with 3 monthly anti-VEGF injections were functional responders (gain ≥2 Snellen lines), whereas 18 eyes were functional nonresponders (gain <2 Snellen lines). The mean age of functional responders was 67.9 ± 18.4 years, which was significantly younger than the nonresponders (76.6 ± 7.4 years; P = .040). Mean baseline logMAR BCVA for functional responders was 1.11 ± 0.67 (Snellen equivalent: 20/259), which was similar to nonresponders’ 1.46 ± 0.70 (Snellen equivalent: 20/577; P = .104). At 3 months follow-up, BCVA improved to 0.55 ± 0.52 (Snellen equivalent: 20/71; P < .0001) in responders, but there was no improvement in BCVA for nonresponders 1.53 ± 0.68 (Snellen equivalent: 20/677; P = .170).
Mean subfoveal choroidal thickness at baseline was 272.2 ± 107.3 μm in the functional responder group, which was greater than in nonresponders (209.6 ± 85.8 μm; P = .039). Furthermore, initial choroidal thickness in CRVO eyes of responders was significantly thicker than their corresponding fellow eye (197.2 ± 98.5 μm; P = .014), whereas baseline choroidal thickness in nonresponder CRVO eyes was similar to their fellow eye (192.8 ± 66.2 μm; P = .867). Following 3 monthly anti-VEGF injections, mean subfoveal choroidal thickness significantly decreased for functional responders (206.8 ± 74.3 μm; P < .001), but not for functional nonresponders (182.6 ± 68.3 μm; P = .062). At 3 months follow-up, choroidal thickness was comparable between responders and nonresponders ( P = .275). No change in choroidal thickness from baseline was detected in the fellow eyes of either responders ( P = .893) or nonresponders ( P = .1).
Mean baseline CMT for functional responders (592.1 ± 170.2 μm) was similar to that of nonresponders (516.2 ± 191.7 μm; P = .177). At 3 months follow-up, mean CMT decreased to 322.6 ± 60.0 μm in responders ( P < .001), and to 385.3 ± 176.8 μm in nonresponders ( P = .016). Conversely, there was no change in CMT from baseline in the fellow eyes of either responders ( P = .586) or nonresponders ( P = .287).
Baseline Predictors for Functional Response
Univariate analysis for predictors of functional response (gain ≥2 Snellen lines) after 3 monthly anti-VEGF injections is outlined in Table 3 . Increasing age was found to be a moderately negative predictor (regression coefficient: −0.05 for every year increase; P = .052), whereas a higher baseline choroidal thickness (for every 100-μm increase in choroidal thickness) was found to be a positive predictor (regression coefficient: 0.7; P = .04) for functional response. Treatment with a combination of anti-VEGF agents or ranibizumab only was a moderately positive predictor for functional response compared with receiving bevacizumab only ( P = .055). Furthermore, change in choroidal thickness at 3 months had a low positive Spearman correlation with change in BCVA (r = 0.47; P = .002) and change in CMT (r = 0.43; P = .004). In addition, change in CMT at 3 months had a low positive Spearman correlation with change in BCVA (r = 0.40; P = .008). Multivariate regression analysis demonstrated that age (<70 years old) was a positive predictor for functional response, with an odds ratio of 6.49 (95% confidence interval: 1.11-38.1; P = .03).
| Baseline Predictors | CRVO (N = 43 Eyes) | ||
|---|---|---|---|
| # of Eyes | ≥2 Lines Gain in BCVA Yes (%) | P Value | |
| Age (y) | .009 ∗ | ||
| <70 | 15 | 13 (86.7%) | |
| ≥70 | 28 | 12 (42.9%) | |
| As continuous regression coefficient | −0.05 | .052 ∗ | |
| Sex | .12 | ||
| Male | 19 | 14 (73.7%) | |
| Female | 24 | 11 (45.8%) | |
| Hypertension | .11 | ||
| No | 8 | 7 (87.5%) | |
| Yes | 35 | 18 (51.4%) | |
| Injected drug | .055 ∗ | ||
| Bevacizumab only | 25 | 11 (44.0%) | |
| Ranibizumab only | 5 | 3 (60.0%) | |
| Combination | 13 | 11 (84.6%) | |
| Lens status | .48 | ||
| Pseudophakic | 10 | 7 (70.0%) | |
| Phakic | 33 | 18 (54.6%) | |
| Ellipsoid zone | .69 | ||
| Intact | 10 | 7 (70.0%) | |
| Disrupted | 20 | 11 (55.0%) | |
| Absent | 13 | 7 (53.9%) | |
| Baseline logMAR BCVA | .22 | ||
| ≤1.00 | 20 | 14 (70.0%) | |
| >1.00 | 23 | 11 (47.8%) | |
| As continuous regression coefficient | −0.76 | .12 | |
| Baseline SFCT in study eye (μm) | .20 | ||
| ≤200 | 16 | 7 (43.8%) | |
| >200 | 27 | 18 (66.7%) | |
| As continuous regression coefficient | 0.7 | .04 ∗ | |
| Baseline CMT in study eye (μm) | .33 | ||
| ≤440 | 13 | 6 (46.2%) | |
| >440 | 30 | 19 (63.3%) | |
| As continuous regression coefficient | 0.25 | .17 | |
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