Central retinal vein occlusion (CRVO) is one of the more common retinal vascular diseases leading to vision loss, which is often a result of macular edema.1,2 In a Canadian cohort study, the annual incidence of visual loss due to macular edema associated with CRVO was 0.021%.3 As a potent cytokine, vascular endothelial growth factor (VEGF) plays a key role in the development of macular edema.4 The likely mechanism involves vascular hyperpermeability and breakdown of the blood-retinal barrier.5 Accumulating evidence has demonstrated the effectiveness of anti-VEGF therapy for macular edema secondary to CRVO, with improved visual acuity (VA) and reduced central macular thickness.6–8 These studies included a wide age range, however, and did not specifically describe the outcomes of young patients with CRVO following anti-VEGF therapy.
CRVO in younger adults is less common, with the underlying etiology still poorly understood. Little is known about the prevalence and pathogenesis of macular edema in these patients. Furthermore, the clinical course, predisposing factors, and treatment outcomes for this population are not well established. Prior studies have reported the efficacy of intravitreal corticosteroids, such as the dexamethasone implant or triamcinolone, for young CRVO patients with macular edema.9,10 However, long-term side effects, including cataract formation and high intraocular pressure (IOP), remain concerns with steroid therapy. Although the phase 3 CRUISE study clearly established the effectiveness of ranibizumab (Lucentis; Genentech, South San Francisco, CA) for macular edema associated with CRVO, the age range of treated patients was between 38 years and 90 years (mean ± standard deviation: 69.7 years ± 11.6 years) in the 0.3 mg ranibizumab arm.11 Similarly, the average age of CRVO patients, who received intravitreal aflibercept (Eylea; Regeneron, Tarrytown, NY) injections, was 65.5 ± 13.57 years in the COPERNICUS study.12 As a result, the purpose of our study was to explore the outcomes of anti-VEGF therapy in young patients 40 years old or younger with macular edema due to CRVO.
Patients and Methods
This retrospective, noncomparative case series included 17 consecutive patients with macular edema due to CRVO who received at least one intravitreal anti-VEGF injection at the Retina Service of Wills Eye Hospital and the outpatient offices of Mid Atlantic Retina from January 2012 to January 2017. Eligible participants were aged between 18 and 40 years, had Snellen VA ranging from 20/400 to 20/40 (corresponding to 1.30 logarithm of the minimal angle of resolution [logMAR] and 0.30 logMAR), and had central retinal thickness (CRT) greater than 250 μm at presentation. Patients with diabetic macular edema, vitreomacular traction syndrome, neovascular glaucoma secondary to CRVO, or history of treatment with laser therapy or intravitreal steroid injection were excluded from the study. The clinical visit closest to 12 months, ranging from 9 months to 15 months, was defined as 12-month follow-up.13 This study was conducted in accordance with the tenets of the Declaration of Helsinki and in accordance with the Health Insurance Portability and Accountability Act. Ethical approval was obtained from the institutional review board at Wills Eye Hospital.
Clinical Examination and Outcome Measures
Patient demographics, examination, and treatment data were extracted from medical records. Laboratory testing results including plasma homocysteine level, protein C activity, protein S activity, and antithrombin III activity were obtained. Snellen VA measurements were collected using distance correction or best pinhole correction. IOP was measured using the hand-held Tono-Pen XL (Reichert, Depew, NY) prior to dilation and injection. Spectral-domain optical coherence tomography (Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany) scans were obtained from all eyes using eye tracking for follow-up measurements at each visit. CRT values were determined as the thickness of the center subfield (1 mm diameter around the central macula) using the integrated software.12 Repeated intravitreal injections were performed on a treat-and-extend or pro re nata basis at the discretion of the injecting physician when any subretinal or intraretinal fluid was detected.
Intravitreal Anti-VEGF Injections
All intravitreal injections were performed in an office-based setting. Following two cycles of topical anesthesia, the conjunctival fornices of the eyes were irrigated with 5% povidone-iodine (Betadine 5%; Alcon Labs, Fort Worth, TX). An intravitreal injection of 1.25 mg/0.05 mL bevacizumab (Avastin; Genentech, South San Francisco, CA), 0.5 mg/0.05 mL ranibizumab or 2 mg/0.05 mL aflibercept was injected via pars plana using a 30-gauge needle at 3.0 to 4.0 mm from the limbus.
The primary endpoint was the mean change in logMAR VA from baseline to 12 months. Secondary outcomes included the mean change in logMAR VA and CRT from baseline to months 1, 3, 6 and 12 and the number of anti-VEGF injections during the course of 12 months.
Snellen VA was converted into logMAR scores for statistical analysis. The paired Student t-test was performed to evaluate the changes in logMAR VA and CRT. Multiple linear regression analysis was used to determine the significant predictors for logMAR VA at 12 months and improvement of logMAR VA. All analyses were performed using SPSS version 17.0 (SPSS, Inc., Chicago, IL). A P value of less than .05 was considered statistically significant.
Seventeen eyes of 17 patients with macular edema secondary to CRVO were identified and received intravitreal anti-VEGF injections in this study. There were nine males (52.9%) and eight females (47.1%), with a mean age of 28.5 years ± 7.3 years. The mean follow-up duration was 26.9 months (range: 10 months to 70 months). Among these, 10 patients had more than 2 years of follow-up.
The demographics data are shown in Table 1. All the cases had unilateral involvement, with nine right eyes and eight left eyes. The majority (94.1%) was phakic, including four eyes with cataracts. Five patients had systemic hypertension, three were smokers, and there were no diabetics. The laboratory test results showed that one patient had an elevated protein C and protein S activity, four patients had increased activity of antithrombin III, and none of the patients had abnormally high blood level of homocysteine. None of the patients had been on oral contraceptives at the time of diagnosis.
Demographic, Clinical, and Laboratory Characteristics for Central Retinal Vein Occlusion Patients 40 Years or Younger
At the 12-month follow-up visit, the mean VA improved to 0.14 logMAR (20/28 Snellen equivalent) from a baseline of 0.64 logMAR (20/87 Snellen equivalent), an average improvement of 0.5 logMAR units (P < .001). Twelve of the 17 eyes (70.6%) gained three or more lines of vision. No patients had worsened VA compared with baseline.
The mean VA improved to 0.30 logMAR (20/40 Snellen equivalent) by the 1-month follow-up visit (P = .002), 0.37 logMAR (20/47 Snellen equivalent) by the 3-month visit (P = .024), 0.18 logMAR (20/30 Snellen equivalent) by the 6-month visit (P < .001), and 0.14 logMAR (20/28 Snellen equivalent) by the final 12-month follow-up visit (P < .001) (Figure 1).
Mean change of logarithm of the minimum angle of resolution visual acuity from baseline to 1 month, 3 months, 6 months, and 12 months following treatment. The plotted bars indicate the 95% confidence intervals. Statistically significant change compared with baseline values, *P < .05 and **P < .001.
The mean changes in CRT during the 12-month study period are shown in Figure 2. Mean CRT decreased from a baseline of 619 μm ± 238 μm to 326 ± 47 μm at the 1-month visit (P < .001), 389 μm ± 124 μm at the 3-month visit (P = .002), 310 μm ± 48 μm at the 6-month visit (P < .001), and 290 μm ± 34 μm at the 12-month visit (P < .001). Twelve months after initiating anti-VEGF therapy, none of the eyes showed an increase in CRT. Eleven eyes (64.7%) had an improvement of at least 30.0% in CRT, and 11 eyes (64.7%) had CRT of 300 μm or less. At baseline, 16 patients (94.1%) had intraretinal edema and 11 (64.7%) had subretinal fluid (SRF) on OCT. At 12-month follow-up, only four patients still had evidence of intraretinal edema and none had SRF. Figure 3 shows a representative case in a young CRVO patient receiving intravitreal anti-VEGF injections during 12-month follow-up.
Mean change of central retinal thickness from baseline to 1 month, 3 months, 6 months, and 12 months following treatment. The plotted bars indicate the 95% confidence intervals. Statistically significant change compared with baseline values, *P < .05 and **P < .001.
A representative case in a young patient with central retinal vein occlusion (CRVO) with anti-vascular endothelial growth factor treatment. (A) Color photography demonstrates CRVO changes in a treatment-naïve 31-year-old male patient (Case 13), with engorged retinal veins, extensive retinal hemorrhages, and macular edema. (B) Fluorescein angiography shows staining along the large retinal veins, with hypofluorescence due to masking by retinal hemorrhages. (C) Baseline optical coherence tomography (OCT) reveals macular edema before treatment, with intraretinal and subretinal fluid. (D to G) OCT images demonstrate resolution of macular edema and decreased central retinal thickness at 1-month, 3-month, 6-month, and 12-month follow-up visits following intravitreal ranibizumab injections.
Injection Numbers and Medicines
Patients underwent a mean of 4.9 injections over the course of 1 year, with a mean interval of 45.8 days between injections (Figure 4). Following the initial injection, 13 eyes (76.5%) underwent a second injection at a mean interval of 57.1 days (range: 28 days to 280 days) and 10 eyes (58.8%) received a third injection at a mean of 39.0 days (range: 28 days to 70 days). After a single injection, five eyes (29.4%) showed an improvement in logMAR VA of more than 0.2 log units or a decrease in CRT of more than 30.0% at 1 month following treatment. In total, 17 injections of bevacizumab, 48 injections of ranibizumab, and 19 injections of aflibercept were used during the first 12 months of treatment. Of note, among 12 patients who had follow-up visits of more than 12 months, five of them (41.7%) needed further treatment for persistent or recurrent macular edema after 12-month follow-up.
Number and duration of all injections in 12-months follow-up.
Multiple Linear Regression Analysis
The results of a multiple linear regression analysis are shown in Table 2 with logMAR VA at 12 months and improvement of logMAR VA as dependent variables. An inverse correlation was found between baseline logMAR VA and improvement of logMAR VA (95% confidence interval, −1.052 to −0.588, P < .001), indicating that worse VA at baseline had better gains in VA following treatment. No correlation was detected between baseline and 12-month logMAR VA. The analysis also revealed that age and baseline CRT were not significant predictors of logMAR VA improvement (P > .05).
Multivariate Linear Regression for VA at 12 Months and Improvement of VA During 12 Months
No ocular or systemic complications related to anti-VEGF injections were noted during the 12 months of this study.
In this retrospective study, we report that intravitreal anti-VEGF injection resulted in significant improvements in retinal thickness and VA in young adults with macular edema secondary to CRVO. Twelve of the 17 eyes (70.6%) achieved an improvement of three or more lines in VA, and 11 eyes (64.7%) had a decrease in CRT by 30.0% at 12-month follow-up. In addition, no obvious adverse events were observed during the treatment. These findings support the role of anti-VEGF therapy as a potentially effective treatment for macular edema due to CRVO in patients 40 years or younger.
The etiology and risk factors remain unclear for CRVO in young patients, especially for those with macular edema. Commonly associated systemic conditions include hypertension, diabetes, and hyperlipidemia.14 A recent study showed that the prevalence of systemic hypertension and diabetes was 25.7% and 11.4%, respectively, in CRVO adults aged 50 years or younger in a retrospective chart review.15 In our study, 29.4% patients had systemic hypertension, whereas none had diabetes. However, only patients with macular edema and VA from 20/400 to 20/40 were included, and patients with underlying diabetic macular edema were excluded in our series. Another potential risk factor is coagulopathies, although there is no clear consensus on how frequently it plays an underlying role. Several previous reports showed that hypercoagulable states, such as elevated plasma homocysteine, were associated with CRVO.16–18 More recent studies have argued that these risk factors appear to be uncommon in young patients with CRVO.19,20 Although only a few patients were found to have abnormal anticoagulant activity and none of them had elevated plasma homocysteine in our study, the small sample of this series makes it hard to determine how often hypercoagulability plays a role in younger patients. Further studies are needed to clarify the etiology and risk factors for this population.
Currently, there is no consensus on the natural history and prognosis for young patients with CRVO and macular edema. In one case series of 57 CRVO patients who were 55 years or younger, six patients with at least 24 months of follow-up experienced further declining vision after the 12-month follow-up visit, mostly attributed to the development of macular edema and vitreous hemorrhage. However, there are no more details of natural history for the patients with macular edema.21 Another study investigated 20 subjects 40 years or younger with CRVO and found evidence of macular edema in 11 cases at the first visit. After the follow-up duration of 6 months to 158 months, the macular edema had worsened in six cases and resolved in only one case.22 In another retrospective case review of CRVO in a young Chinese population, seven out of 22 (31.8%) patients 40 years or younger had macular edema after a mean follow-up of 37 months. However, all seven of these patients received treatment, including intravitreal triamcinolone acetonide in four patients, vitrectomy in three patients, radial optic neurotomy in three patients, and panretinal photocoagulation in one patient. After therapy, 28.6% patients had an improvement in VA, 14.3% worsened, and 57.1% remained stable.23 In contrast, 82.4% of our patients had an improvement in VA with anti-VEGF therapy and none worsened.
Many treatments have been used for young patients with CRVO and macular edema, although no studies support a clear standard of care. The Central Vein Occlusion Study Group found that macular grid photocoagulation significantly reduced macular edema, but there was limited VA benefit in the subgroup of CRVO patients younger than 60 years old.24 In a prospective case series of 16 CRVO patients under the age of 50 years, the dexamethasone implant was found to improve both VA and central foveal thickness after 12 months of follow-up. Elevated IOP was found in five eyes (31%), although this was controlled with topical therapy.9 More recently, the SCORE2 study investigated the efficacy of intravitreal injections of bevacizumab or aflibercept for macular edema secondary to CRVO and hemi-retinal vein occlusion.25 In patients 65 years old and younger, 97 of 131 (74.0%) patients had improvement in visual acuity at 6 months compared with only 123 of 217 patients (56.7%) in the older cohort. Multivariate analysis confirmed that younger age was associated with greater 6-month VA improvement. These findings are consistent with our study in which 70.6% of our young CRVO population experienced a gain of three or more lines of vision at the 1-year follow-up. Thus, our results provide further evidence of the beneficial effect of intravitreal anti-VEGF therapy in young subjects.
We performed multiple linear regression to identify the significant factors associated with visual outcome after anti-VEGF treatment. Our results suggested that patients with lower visual acuity at baseline had better visual gain at 12 months. Similarly, it is indicated in prior studies that patients with better preoperative VA had less range of improvement.26,27
There are several limitations to our retrospective study. First, we had a limited number of patients. However, this is consistent with the rare presentation of CRVO in young adults under 50 years of age, in which the prevalence has been reported to be 7.5% to 19.8%.14 Our study included subjects who were even younger, in whom CRVO is likely even more uncommon. Additionally, different anti-VEGF drugs were used with some heterogeneity in the treatment algorithm, which was dictated by each individual provider, and may have affected outcomes. Furthermore, our study lacks a control group for comparison because some suggest it is unethical to observe rather than to treat in this scenario. Unfortunately, there are no studies focusing on the natural history of CRVO patients 40 years old or younger. Therefore, we cannot exclude the possibility that spontaneous resolution may have contributed to the good outcomes.
In conclusion, intravitreal anti-VEGF injections appear effective in improving VA and decreasing CRT in young patients with macular edema due to CRVO. Future prospective studies with larger numbers of patients and longer follow-up will be helpful to confirm these findings and determine long-term outcomes and prognosis.
- Braithwaite T, Nanji AA, Lindsley K, Greenberg PB. Anti-vascular endothelial growth factor for macular oedema secondary to central retinal vein occlusion. Cochrane Database Syst Rev. 2014;(5):Cd007325.
- McIntosh RL, Rogers SL, Lim L, et al. Natural history of central retinal vein occlusion: An evidence-based systematic review. Ophthalmology. 2010;117(6):1113–1123. doi:10.1016/j.ophtha.2010.01.060 [CrossRef]
- Petrella RJ, Blouin J, Davies B, Barbeau M. Incidence and characteristics of patients with visual impairment due to macular edema secondary to retinal vein occlusion in a representative Canadian cohort. J Ophthalmol. 2012;2012:723169.
- Funk M, Kriechbaum K, Prager F, et al. Intraocular concentrations of growth factors and cytokines in retinal vein occlusion and the effect of therapy with bevacizumab. Invest Ophthalmol Vis Sci. 2009;50(3):1025–1032. doi:10.1167/iovs.08-2510 [CrossRef]
- Miller JW, Le Couter J, Strauss EC, Ferrara N. Vascular endothelial growth factor a in intraocular vascular disease. Ophthalmology. 2013;120(1):106–114. doi:10.1016/j.ophtha.2012.07.038 [CrossRef]
- Larsen M, Waldstein SM, Boscia F, et al. Individualized ranibizumab regimen driven by stabilization criteria for central retinal vein occlusion: Twelve-month results of the CRYSTAL study. Ophthalmology. 2016;123(5):1101–1111. doi:10.1016/j.ophtha.2016.01.011 [CrossRef]
- Rajagopal R, Shah GK, Blinder KJ, et al. Bevacizumab versus ranibizumab in the treatment of macular edema due to retinal vein occlusion: 6-month results of the CRAVE study. Ophthalmic Surg Lasers Imaging Retina. 2015;46(8):844–850. doi:10.3928/23258160-20150909-09 [CrossRef]
- Scott IU, VanVeldhuisen PC, Ip MS, et al. Effect of bevacizumab vs aflibercept on visual acuity among patients with macular edema due to central retinal vein occlusion: The SCORE2 randomized clinical trial. JAMA. 2017;317(20):2072–2087. doi:10.1001/jama.2017.4568 [CrossRef]
- Battaglia Parodi M, Iacono P, Sacconi R, Parravano M, Varano M, Bandello F. Dexamethasone implant for macular edema secondary to central retinal vein occlusion in patients younger than 50 years. Retina. 2015;35(7):1381–1386. doi:10.1097/IAE.0000000000000494 [CrossRef]
- Al-Dhibi H, Chaudhry IA, Al-Saati A, Shamsi FA. Efficacy of intravitreal triamcinolone for macular oedema due to CRVO after anti-androgen therapy for hirsutism in a young monocular female. Br J Ophthalmol. 2007;91(11):1564–1565. doi:10.1136/bjo.2007.114843 [CrossRef]
- Brown DM, Campochiaro PA, Singh RP, et al. Ranibizumab for macular edema following central retinal vein occlusion: Six-month primary end point results of a phase III study. Ophthalmology. 2010;117(6):1124–1133. doi:10.1016/j.ophtha.2010.02.022 [CrossRef]
- Brown DM, Heier JS, Clark WL, et al. Intravitreal aflibercept injection for macular edema secondary to central retinal vein occlusion: 1-year results from the phase 3 COPERNICUS study. Am J Ophthalmol. 2013;155(3):429–437.e7. doi:10.1016/j.ajo.2012.09.026 [CrossRef]
- Brynskov T, Kemp H, Sorensen TL. Intravitreal ranibizumab for retinal vein occlusion through 1 year in clinical practice. Retina. 2014;34(8):1637–1643. doi:10.1097/IAE.0000000000000111 [CrossRef]
- Fong AC, Schatz H. Central retinal vein occlusion in young adults. Surv Ophthalmol. 1993;37(6):393–417. doi:10.1016/0039-6257(93)90138-W [CrossRef]
- Sinawat S, Bunyavee C, Ratanapakorn T, Sinawat S, Laovirojjanakul W, Yospaiboon Y. Systemic abnormalities associated with retinal vein occlusion in young patients. Clin Ophthalmol. 2017;11:441–447. doi:10.2147/OPTH.S128341 [CrossRef]
- Biousse V, Newman NJ, Sternberg P Jr, . Retinal vein occlusion and transient monocular visual loss associated with hyperhomocystinemia. Am J Ophthalmol. 1997;124(2):257–260. doi:10.1016/S0002-9394(14)70800-1 [CrossRef]
- Lahey JM, Tunç M, Kearney J, et al. Laboratory evaluation of hypercoagulable states in patients with central retinal vein occlusion who are less than 56 years of age. Ophthalmology. 2002;109(1):126–131. doi:10.1016/S0161-6420(01)00842-9 [CrossRef]
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- Di Crecchio L, Parodi MB, Sanguinetti G, Iacono P, Ravalico G. Hyperhomocysteinemia and the methylenetetrahydrofolate reductase 677C-T mutation in patients under 50 years of age affected by central retinal vein occlusion. Ophthalmology. 2004;111(5):940–945. doi:10.1016/j.ophtha.2003.08.028 [CrossRef]
- Ahluwalia J, Rao S, Varma S, et al. Thrombophilic risk factors are uncommon in young patients with retinal vein occlusion. Retina. 2015;35(4):715–719. doi:10.1097/IAE.0000000000000366 [CrossRef]
- Recchia FM, Carvalho-Recchia CA, Hassan TS. Clinical course of younger patients with central retinal vein occlusion. Arch Ophthalmol. 2004;122(3):317–321. doi:10.1001/archopht.122.3.317 [CrossRef]
- Giuffrè G, Randazzo-Papa G, Palumbo C. Central retinal vein occlusion in young people. Doc Ophthalmol. 1992;80(2):127–132. doi:10.1007/BF00161238 [CrossRef]
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- Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion. The Central Vein Occlusion Study Group M report. Ophthalmology. 1995;102(10):1425–1433. doi:10.1016/S0161-6420(95)30849-4 [CrossRef]
- Scott IU, VanVeldhuisen PC, Ip MS, et al. Baseline factors associated with 6-month visual acuity and retinal thickness outcomes in patients with macular edema secondary to central retinal vein occlusion or hemiretinal vein occlusion: SCORE2 study report 4. JAMA Ophthalmol. 2017;135(6):639–649. doi:10.1001/jamaophthalmol.2017.1141 [CrossRef]
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Demographic, Clinical, and Laboratory Characteristics for Central Retinal Vein Occlusion Patients 40 Years or Younger
|Cases||Gender||Age (Y)||Eye Involvement||Lens Status||Systemic Disease||Smoking||Family History||Baseline Visual Acuity (Snellen)||Protein C Activity||Protein S Activity||Antithrombin III Activity||Plasma Homocysteine||Follow-Up (Mon)|
|15||Female||36||R||Phakia||HTN, Migraine||No||Heart disease, HTN||20/40||Normal||Normal||Normal||Normal||10|
Multivariate Linear Regression for VA at 12 Months and Improvement of VA During 12 Months
|Independent Variables||logMAR VA at 12 Months||Improvement of logMAR VA During 12 Months|
|Beta Coefficient||95% CI||P Value||Beta Coefficient||95% CI||P Value|
|Age||−0.148||−0.014 to 0.008||0.571||−0.058||−0.014 to 0.008||.573|
|Baseline logMAR VA||0.478||−0.054 to 0.413||0.121||−0.866||−1.052 to −0.588||< .001|
|Baseline CRT||−0.363||0.000 to 0.000||0.235||−0.142||0.000 to 0.000||.238|