retninal vein occlusion

clinical practice

T h e n e w e ngl a nd j o u r na l o f m e dic i n e

n engl j med 363;22 nejm.org november 25, 2010 2135

This Journal feature begins with a case vignette highlighting a common clinical problem. Evidence supporting various strategies is then presented, followed by a review of formal guidelines,

when they exist. The article ends with the authors clinical recommendations.

An audio version of this article is available at NEJM.org

Retinal-Vein OcclusionTien Y. Wong, M.D., Ph.D., and Ingrid U. Scott, M.D., M.P.H.

From the Singapore Eye Research Insti-tute, Singapore National Eye Centre, Na-tional University of Singapore, Singapore (T.Y.W.); the Centre for Eye Research Aus-tralia, University of Melbourne, Mel-bourne, VIC, Australia (T.Y.W.); and Penn State College of Medicine, Penn State Hershey Eye Center, Hershey, PA (I.U.S.). Address reprint requests to Dr. Wong at the Singapore Eye Research Institute, Singapore National Eye Centre, 11 Third Hospital Ave., Singapore 168751, Singa-pore, or at [email protected].

N Engl J Med 2010;363:2135-44.Copyright 2010 Massachusetts Medical Society.

A 69-year-old man, a former smoker with a history of hypertension and hyperlipid-emia, presents with acute visual loss in his right eye of 2 weeks duration. Examina-tion of the eye reveals a visual acuity of 20/60 and a sectoral area of retinal hemor-rhages, cotton-wool spots, and swelling in the center of the retina (macular edema). A diagnosis of right-branch retinal-vein occlusion is made. How should he be treated?

The Clinic a l Problem

Retinal-vein occlusion is a common cause of vision loss in older persons, and the second most common retinal vascular disease after diabetic retinopathy. There are two distinct types, classified according to the site of occlusion.1 In branch retinal-vein occlusion, the occlusion is typically at an arteriovenous intersection (Fig. 1); in central retinal-vein occlusion, the occlusion is at or proximal to the lamina cribrosa of the optic nerve, where the central retinal vein exits the eye (Fig. 2).

Retinal-vein occlusion has a prevalence of 1 to 2% in persons older than 40 years of age2,3 and affects 16 million persons worldwide.4 Branch retinal-vein oc-clusion is four times as common as central retinal-vein occlusion.4 In a popula-tion-based cohort study, the 10-year incidence of retinal-vein occlusion was 1.6%.5 Bilateral retinal-vein occlusion is uncommon (occurring in about 5% of cases), although in 10% of patients with retinal-vein occlusion in one eye, occlusion de-velops in the other eye over time.6 Both branch retinal-vein occlusion and central retinal-vein occlusion are further divided into the categories of perfused (non-ischemic) and nonperfused (ischemic), each of which has implications for progno-sis and treatment.

Pathogenesis and Risk Factors

The pathogenesis of retinal-vein occlusion is believed to follow the principles of Virchows triad for thrombogenesis, involving vessel damage, stasis, and hypercoagu-lability. Damage to the retinal-vessel wall from atherosclerosis alters rheologic properties in the adjacent vein, contributing to stasis, thrombosis, and thus occlu-sion. Inflammatory disease may also lead to retinal-vein occlusion by means of these mechanisms. However, evidence of hypercoagulability in patients with retinal-vein occlusion is less consistent. Although individual studies have reported associa-tions between retinal-vein occlusion and hyperhomocysteinemia,7 factor V Leiden mutation,8 deficiency in protein C or S,8 prothrombin gene mutation,9 and anticar-diolipin antibodies,10,11 a meta-analysis of 26 studies suggested that only hyperho-mocysteinemia and anticardiolipin antibodies have significant independent asso-ciations with retinal-vein occlusion.11

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n engl j med 363;22 nejm.org november 25, 20102136

The strongest risk factor for branch retinal-vein occlusion is hypertension,12-15 but associa-tions have been reported for diabetes mellitus,13-15dyslipidemia,15 cigarette smoking,2 and renal dis-ease.16 For central retinal-vein occlusion, an ad-ditional ocular risk factor is glaucoma or elevated intraocular pressure, which may compromise retinal venous outflow.2

Natural History and Complications

Macular edema, with or without macular non-perfusion, is the most frequent cause of vision loss in patients with retinal-vein occlusion.17-21Vision loss may also be due to neovascularization, leading to vitreous hemorrhage, retinal detach-ment, or neovascular glaucoma.

The natural history of branch retinal-vein oc-clusion is variable.22 Many patients with branch retinal-vein occlusion have a good prognosis,

with one study showing that half have a return to 20/40 vision or better within 6 months, with-out treatment.23 Nevertheless, many patients con-tinue to have poor vision in the affected eye. Among participants enrolled in the Branch Vein Occlusion Study, a randomized trial of the effects of laser treatment for branch retinal-vein occlu-sion, only a third of untreated eyes with macular edema and presenting vision of 20/40 or worse improved to better than 20/40 after 3 years.17Retinal neovascularization developed in one third of untreated eyes.17

The visual prognosis is generally worse for patients with central retinal-vein occlusion, par-ticularly when nonperfused, than in patients with branch retinal-vein occlusion.6 A systematic re-view suggested that neovascularization may de-velop in 20% of eyes and neovascular glaucoma in 60% when nonperfused central retinal-vein oc-

A B

DC

Figure 1. Branch Retinal-Vein Occlusion in the Superotemporal Quadrant of the Right Eye.

A fundus photograph (Panel A) shows a sectoral area of dilated veins, retinal hemorrhages (white arrows), cotton-wool spots (black arrows), and retinal edema, and a fluorescein angiogram (Panel B) reveals blockage (white arrows) and leakage of dye (yellow arrows). Optical-coherence tomographic scans (horizontal scan in Panel C and vertical scan in Panel D) show retinal thickening (white arrows), as compared with normal retinal thickness (black arrow), and macular edema (yellow arrows). NT denotes a nasal-to-temporal cut of the retinal scan, and IS an inferior-to-superior cut.



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clusion is present.6 In addition, in one third of eyes initially classified as having perfused cen-tral retinal-vein occlusion, the occlusion may be-come nonperfused within the first year.21 Visual acuity at the time of presentation is a strong indicator of the ultimate quality of the patients vision. In the Central Vein Occlusion Study, a randomized trial of the use of laser treatment for central retinal-vein occlusion, 65% of pa-tients eyes maintained 20/40 vision or better if acuity at the time of presentation was 20/40 or better, but only 1% achieved this level if acuity was initially 20/200 or worse.19,21,24

Despite its associations with vascular risk fac-tors, retinal-vein occlusion does not appear to be an independent risk factor for death from car-diovascular causes.25-27 In a pooled analysis of two population-based studies, retinal-vein occlu-sion was not independently associated with in-

creased cardiovascular mortality,27 although a post hoc analysis revealed an association among persons younger than 70 years of age.

S tr ategies a nd E v idence

Diagnosis and Assessment

Patients with retinal-vein occlusion typically pre-sent with sudden, unilateral, painless loss of vision. The degree of vision loss depends on the extent of retinal involvement and on macular-perfusion status. Some patients with branch retinal-vein occlusion report only a peripheral visual-field defect.

Retinal-vein occlusion has a characteristic appearance on fundus examination. In branch retinal-vein occlusion, there is a wedge-shaped area in which retinal vascular signs (hemor-rhages, cotton-wool spots, edema, and venous

A B

DC

Figure 2. Nonperfused Central Retinal-Vein Occlusion in the Left Eye.

A fundus photograph (Panel A) shows scattered retinal hemorrhages (white arrows), cotton-wool spots (black arrows), optic-disk edema and hyperemia, and venous dilatation and tortuosity (yellow arrow), and a fluorescein angiogram (Panel B) reveals areas of capillary nonperfusion (white arrows) and disk leakage (yellow arrow). Optical-coherence tomographic scans (horizontal scan in Panel C and vertical scan in Panel D) show marked retinal thickening (white arrows) and edema (yellow arrows). NT denotes a nasal-to-temporal cut of the retinal scan, and IS an inferior-to-superior cut.





dilatation and tortuosity) arise from an arterio-venous crossing, usually in the superotemporal quadrant (Fig. 1A). In central retinal-vein occlu-sion, extensive retinal signs, with dilated and tortuous veins, are seen in all quadrants, often along with optic-disk edema (Fig. 2A).

The diagnosis of retinal-vein occlusion is usu-ally made on the basis of the clinical examina-tion alone. Nonperfused central retinal-vein oc-clusion is suggested by vision that is worse than 20/200, a relative afferent pupillary defect, and the presence of cotton-wool spots and large, con-fluent hemorrhages.28 Fundus fluorescein angi-ography (Fig. 1B and 2B) is commonly per-formed to assess the severity of macular edema and perfusion status. Optical-coherence tomog-raphy is a noninvasive imaging technique used to quantify macular edema and assess treatment response (Fig. 1C, 1D, 2C, and 2D).

Evaluation of patients with retinal-vein occlu-sion should include a detailed history taking, clinical assessment, and laboratory investigations to check for the presence of cardiovascular risk factors (Table 1). Although evidence is lacking to

show that treatment of hypertension and other conditions associated with cardiovascular disease can alter the visual prognosis for patients with retinal-vein occlusion, this condition should be considered end-organ damage,29 with appropriate risk-management strategies routinely instituted. Tests for coagulation abnormalities (Table 1) are commonly performed in selected patients, such as those younger than 50 years of age or those with bilateral retinal-vein occlusion, although evidence is lacking to indicate that coagulation disorders are more common in these patients.

Management

Until recently, laser photocoagulation was the only treatment supported by data from high-quality randomized trials30-32; data are now also available from several trials assessing the use of intraocular glucocorticoids and agents inhibiting vascular endothelial growth factor (VEGF). These more recent treatment options are increasingly being used in clinical practice. (For summaries of the recommendations for the management of branch retinal-vein occlusion and central retinal-

Table 1. Assessment of Cardiovascular Risk in Patients with Retinal-Vein Occlusion.

History and clinical assessment

Hypertension

Diabetes mellitus

Dyslipidemia

Cardiovascular disease (e.g., stroke, coronary artery disease, peripheral artery disease)

Medications (e.g., oral contraceptives, diuretics)

Hypercoagulable states and hyperviscosity syndromes (e.g., leukemia, polycythemia vera)

Routine investigations

Complete blood count

Renal function (levels of serum electrolytes, urea, creatinine)

Fasting serum levels of glucose and glycated hemoglobin

Fasting levels of lipids

Additional investigations (consider in select cases, such as in patients who are younger than 50 years of age, who have bilateral retinal-vein occlusion, or who may have thrombophilic or coagulation disorders)

Homocysteine levels

Levels of functional protein C and protein S

Antithrombin III levels

Antiphospholipid antibodies lupus anticoagulant, anticardiolipin antibodies

Activated protein C resistance polymerase-chain-reaction assay for factor V Leiden mutation (R506Q)

Factor XII

Prothrombin gene mutation (G20210A)



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vein occlusion, see Tables 2 and 3, respectively. For the outcomes of trials conducted to gauge the effects of various treatments on each condi-tion, see the Supplementary Appendix, available with the full text of this article at NEJM.org.)

Branch Retinal-Vein OcclusionLaser Treatment

Grid laser photocoagulation is used for the treat-ment of macular edema resulting from branch retinal-vein occlusion, and scatter laser photoco-agulation is used for the prevention and treat-ment of neovascularization. In the Branch Vein Occlusion Study,17,18 which included patients with branch retinal-vein occlusion and macular edema in one or both eyes (a total of 139 eyes were stud-ied), eyes treated with grid laser photocoagula-tion were almost twice as likely as untreated eyes to enable patients to read two additional lines on an eye chart at 3 years (65% vs. 37%).17 However, in some patients, poor vision persisted despite treatment; vision in 40% of treated eyes was

worse than 20/40 and that in 12% of treated eyes was worse than 20/200 at 3 years. In eyes with extensive nonperfusion, scatter laser photocoag-ulation markedly reduced the risks of retinal neovascularization (12%, vs. 22% in controls) and vitreous hemorrhage (29% vs. 60%).18

GlucocorticoidsCase series have suggested that intravitreal injec-tion of triamcinolone acetonide may be useful for the treatment of macular edema in patients with branch retinal-vein occlusion.33 However, the use of this treatment was not supported by the Stan-dard Care versus Corticosteroid for Retinal Vein Occlusion (SCORE) Study, a randomized trial in which 411 patients with branch retinal-vein occlu-sion and vision loss from macular edema were treated with intravitreal injection of preservative-free triamcinolone acetonide (1 mg or 4 mg, in-jected as frequently as every 4 months) or stan-dard care (grid laser treatment of eyes without dense macular hemorrhage).34 From baseline to

Table 2. Recommendations for the Management of Branch Retinal-Vein Occlusion.

Intervention Guidelines Evidence* Comments

Macular grid laser photocoagu-lation

Associated with reduced macular edema and improved vision in patients with macular edema and visual acuity 20/40

A-I May not be effective in presence of macular ischemia

Scatter laser photocoagulation Recommended for treatment of ischemic retina if retinal or disk neovascularization is also present

A-I

Intravitreal injection of tri-amcinolone acetonide

No more effective than macular grid laser photocoag-ulation in improving visual acuity in patients with macular edema from branch retinal-vein occlusion and associated with a higher risk of adverse events

A-I

Intravitreal injection of ranibizumab

Associated with greater improvement in visual acuity, as compared with sham injection, over 12-mo period in patients with macular edema from branch retinal-vein occlusion

A-II May be administered monthly in 0.5-mg doses, depending on per-sistence or recurrence of macular edema

Intravitreal dexamethasone implant

Associated with more rapid improvement in visual acuity than sham implant in patients with macular edema from branch retinal-vein occlusion

B-II May be administered in 0.7-mg doses every 6 mo, depending on persis-tence or recurrence of macular edema; contraindicated in pa-tients with advanced glaucoma

Hemodilution Not recommended for routine use to improve visual acuity or prevent neovascularization

B-III

Pars plana vitrectomy with adventitial sheathotomy

Not routinely recommended to improve visual acuity or prevent neovascularization

B-III

Ticlopidine, troxerutin Not routinely recommended to improve visual acuity or prevent neovascularization

B-III

* For the ranking of the importance of the recommendation with respect to the clinical outcome, A denotes most important or critical for a good clinical outcome and B moderately important; for the strength of the evidence, I denotes strong evidence in support of the recommen-dation, II strong evidence in support of the recommendation but lacking in some respects (e.g., longer-term efficacy or safety uncertain), and III insufficient evidence to provide support for or against the recommendation.





1 year, the rate of the primary outcome the proportion of eyes with an improvement in visual acuity that enabled patients to read 15 or more additional letters (or 3 lines) on an eye chart was similar among the three groups (27% in the group treated with the 4-mg dose of triamcino-lone, 26% in the group treated with the 1-mg dose, and 29% in the control group). Adverse events principally, elevated intraocular pres-sure and progression of cataracts were more frequent in the groups treated with triamcino-lone. The percentage of eyes treated with glau-coma medications was 41% in the group receiving 4 mg of triamcinolone, 8% in the group receiving 1 mg, and 2% in the control group; for cataract progression, the percentages were 35%, 25%, and 13%, respectively.

An alternative glucocorticoid, dexamethasone, was evaluated in a randomized trial involving

1267 patients who had vision loss owing to macular edema caused by branch retinal-vein occlusion or central retinal-vein occlusion.35 The primary end point the time required to achieve a visual-acuity gain of 3 lines or more on an eye chart was significantly shorter among patients receiving dexamethasone (in a dose of 0.7 mg or 0.3 mg) than among patients who received a sham injection. The proportion of eyes with this degree of improvement was also significantly higher in both dexamethasone groups than in the placebo group at 1 month and 3 months but not at the prespecified time point of 6 months. Dexamethasone showed similar benefits in preplanned subgroup analy-ses of branch and central retinal-vein occlusion, although details on the extent of improvement in visual acuity at 3 and 6 months were not provided. However, the proportion of eyes in

Table 3. Recommendations for the Management of Central Retinal-Vein Occlusion.

Intervention Guidelines Evidence* Comments

Scatter laser photocoagulation Not recommended for patients without neovascular-ization unless regular follow-up is not possible

A-I

Recommended for patients with anterior-segment neovascularization

A-I

Macular grid laser photo-coagulation

Not recommended for treatment of macular edema from central retinal-vein occlusion

A-I

Intravitreal injection of tri-amcinolone acetonide

Associated with greater improvement in visual acuity, as compared with observation, in patients with macular edema from central retinal-vein occlusion

A-I May be administered every 4 mo in 1-mg doses, depending on persis-tence or recurrence of macular edema

Intravitreal injection of rani-bizumab

Associated with greater improvement in visual acuity, as compared with sham injection, over 12-mo period in patients with macular edema from central retinal-vein occlusion

A-II May be administered every mo in 0.5-mg doses, depending on per-sistence or recurrence of macular edema

Intravitreal dexamethasone implant

Associated with more rapid improvement in visual acuity, as compared with sham implant, in patients with macular edema from central retinal-vein occlusion

B-II May be administered in 0.7-mg doses every 6 mo depending on persis-tence or recurrence of macular edema; contraindicated in patients with advanced glaucoma

Laser-induced chorioretinal anastomosis

May improve visual acuity in patients with nonper-fused central retinal-vein occlusion but may be associated with significant ocular complications

B-II

Hemodilution May improve visual outcome in some patients if per-formed as inpatient procedure following a protocol with a statistically relevant clinical outcome

B-II Difficult to generalize recommenda-tion due to variations in protocols (e.g., inpatient and outpatient) and use of different agents

Ticlopidine, troxerutin, epo-prostenol

Not routinely recommended to improve visual acuity or prevent neovascularization

B-III

* For the ranking of the importance of the recommendation with respect to the clinical outcome, A denotes most important or critical for a good clinical outcome and B moderately important; for the strength of the evidence, I denotes strong evidence in support of the recommen-dation, II strong evidence in support of the recommendation but lacking in some respects (e.g., longer-term efficacy or safety uncertain), and III insufficient evidence to provide support for or against the recommendation.



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which elevated intraocular pressure developed was higher with dexamethasone treatment than with the sham injection (4% for both dexameth-asone doses vs. 0.7%, P



ies, elevated intraocular pressure was a significant adverse event for patients receiving these drugs.

Anti-VEGF AgentsRanibizumab and bevacizumab are widely used in the treatment of central retinal-vein occlusion, as well as in the treatment of branch retinal-vein occlusion.41,42,46 In the Ranibizumab for the Treatment of Macular Edema after Central Reti-nal Vein Occlusion (CRUISE) trial, which included 392 patients with central retinal-vein occlusion and macular edema, the proportion of patients with clinically significant improvement in visual acuity was higher in the ranibizumab groups than in the sham-injection group (46% of pa-tients receiving 0.3 mg of ranibizumab and 48% of those receiving 0.5 mg vs. 17% of those under-going sham injection).47 Like the BRAVO trial,43 which assessed the same ranibizumab interven-tion in patients with branch retinal-vein occlu-sion and in those with central retinal-vein occlu-sion, the CRUISE study showed no significant between-group differences in the incidence of systemic vascular events among the patients with central retinal-vein occlusion, and the vision gain with ranibizumab treatment was maintained at 12 months.47

A r e a s of Uncerta in t y

Although retinal-vein occlusion is much more common in persons older than 50 years of age, it can also arise in younger persons with no identi-fiable risk factors.48 In younger patients, retinal-vein occlusion may have a different pathogenesis, but it is not clear whether systemic coagulation abnormalities are more common in such patients.

Trials of treatments with intraocular gluco-corticoid and anti-VEGF agents have had relative-ly short periods of follow-up. Longer-term trials are needed to determine whether visual gains will be maintained after 1 year, to establish optimal dosing regimens, and to ascertain the risks of these therapies. In some trials, treatment was delayed to allow for spontaneous improvement; thus, it is not clear how different treatments would compare if used earlier in the course of disease.

In post hoc analyses of two trials addressing neovascular age-related macular degeneration,36,37 rates of nonocular hemorrhage, including cere-bral hemorrhage, were higher among patients

treated for 2 years with monthly intravitreal in-jections of ranibizumab than among controls (7.8% vs. 4.2%, P = 0.01).49 Although an increased rate of vascular events was not identified in trials of intraocular anti-VEGF agents, more data are needed to assess whether anti-VEGF treatment increases the risk of cardiovascular events, par-ticularly stroke, in patients with retinal-vein oc-clusion.50

Data are lacking from randomized trials com-paring glucocorticoids and anti-VEGF therapies head to head and assessing the effects of various combination therapies (e.g., laser plus anti-VEGF therapy). Most trials have largely excluded pa-tients with poor visual acuity and nonperfused retinal-vein occlusion, and it is unclear what type of treatment is appropriate for these patients.

Other systemic therapies have been tried (e.g., hemodilution, streptokinase, and anticoagulants such as troxerutin and ticlopidine), as have surgi-cal approaches (e.g., radial optic neurotomy, per-formed to improve venous outflow at the optic disc, and vitrectomy with arteriovenous sheathot-omy, performed to relieve venous compression at the arteriovenous junctions),30-32 but these treat-ments have not been rigorously studied. Surgical procedures are increasingly being replaced by intraocular injections, which can be given in a physicians office.

Guidelines from Professiona l So cie ties

The United Kingdom Royal College of Ophthal-mologists has published guidelines for the man-agement of retinal-vein occlusion,51 but these guidelines do not take into account data from recent clinical trials.

Conclusions a nd R ecommendations

The patient described in the vignette has a supero-temporal branch retinal-vein occlusion with mac-ular edema. We recommend a thorough ocular evaluation, including the use of fundus fluores-cein angiography to assess macular perfusion and leakage and optical coherence tomography to quantify macular edema. Systemic evaluation by the patients general physician and appropriate management of modifiable cardiovascular risk factors (e.g., hypertension and hyperlipidemia) are



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indicated. We do not recommend further workup for coagulation abnormalities in this patient.

We would discuss with the patient the risks and potential benefits of grid laser photoco-agulation or intraocular injections of anti-VEGF agents. The advantages of using grid laser for first-line treatment of branch retinal-vein occlu-sion include the availability of longer-term data from clinical trials showing improvement in vi-sual acuity, lower rates of adverse effects, and lower costs with this treatment than with anti-VEGF therapy. In selected cases (e.g., dense macu-lar hemorrhage that precludes the use of laser therapy), we would consider intraocular injection of an anti-VEGF agent for first-line treatment;

we would inform the patient of the increased risk of arterial thromboembolic events. Treat-ment with a dexamethasone implant is another option, but evidence is lacking to demonstrate an improvement in visual acuity beyond 3 months. The patient should be monitored closely for signs of neovascularization (e.g., new vessels or vitre-ous hemorrhage), which would require scatter laser photocoagulation.

Dr. Wong reports receiving consulting fees from Allergan, Novartis, and Pfizer and speaking fees and grant support from Allergan; and Dr. Scott reports receiving consulting fees from Genentech. No other potential conflict of interest relevant to this article was reported.

Disclosure forms provided by the authors are available with the full text of this article at NEJM.org.

References

1. Hayreh SS. Prevalent misconceptions about acute retinal vascular occlusive dis-orders. Prog Retin Eye Res 2005;24:493-519.2. Mitchell P, Smith W, Chang A. Preva-lence and associations of retinal vein oc-clusion in Australia: the Blue Mountains Eye Study. Arch Ophthalmol 1996;114: 1243-7.3. Klein R, Klein BE, Moss SE, Meuer SM. The epidemiology of retinal vein oc-clusion: the Beaver Dam Eye Study. Trans Am Ophthalmol Soc 2000;98:133-41.4. Rogers S, McIntosh RL, Cheung N, et al. The prevalence of retinal vein occlu-sion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology 2010;117(2): 313.e1-319.e1.5. Cugati S, Wang JJ, Rochtchina E, Mitchell P. Ten-year incidence of retinal vein occlusion in an older population: the Blue Mountains Eye Study. Arch Ophthal-mol 2006;124:726-32.6. McIntosh RL, Rogers SL, Lim L, et al. Natural history of central retinal vein oc-clusion: an evidence-based systematic re-view. Ophthalmology 2010;117(6):1113.e15-1123.e15.7. Chua B, Kifley A, Wong TY, Mitchell P. Homocysteine and retinal vein occlu-sion: a population-based study. Am J Oph-thalmol 2005;139:181-2.8. Greiner K, Hafner G, Dick B, Peetz D, Prellwitz W, Pfeiffer N. Retinal vascular occlusion and deficiencies in the protein C pathway. Am J Ophthalmol 1999;128:69-74.9. Incorvaia C, Lamberti G, Parmeggiani F, et al. Idiopathic central retinal vein oc-clusion in a thrombophilic patient with the heterozygous 20210 G/A prothrombin ge-notype. Am J Ophthalmol 1999;128:247-8.10. Lahey JM, Tun 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;109:126-31.11. Janssen MC, den Heijer M, Cruysberg JR, Wollersheim H, Bredie SJ. Retinal vein occlusion: a form of venous thrombosis or a complication of atherosclerosis? A meta-analysis of thrombophilic factors. Thromb Haemost 2005;93:1021-6.12. Rath EZ, Frank RN, Shin DH, Kim C. Risk factors for retinal vein occlusions: a case-control study. Ophthalmology 1992; 99:509-14.13. Hayreh SS, Zimmerman B, McCarthy MJ, Podhajsky P. Systemic diseases asso-ciated with various types of retinal vein occlusion. Am J Ophthalmol 2001;131:61-77.14. Elman MJ, Bhatt AK, Quinlan PM, Enger C. The risk for systemic vascular diseases and mortality in patients with central retinal vein occlusion. Ophthal-mology 1990;97:1543-8.15. Wong TY, Larsen EK, Klein R, et al. Cardiovascular risk factors for retinal vein occlusion and arteriolar emboli: the Atherosclerosis Risk in Communities & Cardiovascular Health studies. Ophthal-mology 2005;112:540-7.16. Cheung N, Klein R, Wang JJ, et al. Traditional and novel cardiovascular risk factors for retinal vein occlusion: the Multi-ethnic Study of Atherosclerosis. Invest Ophthalmol Vis Sci 2008;49:4297-302.17. The Branch Vein Occlusion Study Group. Argon laser photocoagulation for macular edema in branch vein occlusion. Am J Ophthalmol 1984;98:271-82.18. Idem. Argon laser scatter photocoag-ulation for prevention of neovasculariza-tion and vitreous hemorrhage in branch vein occlusion: a randomized clinical trial. Arch Ophthalmol 1986;104:34-41.19. The Central Vein Occlusion Study Group. Baseline and early natural history report: the Central Vein Occlusion Study. Arch Ophthalmol 1993;111:1087-95.

20. Idem. A randomized clinical trial of early panretinal photocoagulation for is-chemic central vein occlusion: the Central Vein Occlusion Study Group N report. Ophthalmology 1995;102:1434-44.21. Idem. Natural history and clinical man-agement of central retinal vein occlusion. Arch Ophthalmol 1997;115:486-91. [Erra-tum, Arch Ophthalmol 1997;115:1275.]22. Rogers SL, McIntosh RL, Lim L, et al. Natural history of branch retinal vein oc-clusion: an evidence-based systematic re-view. Ophthalmology 2010;117(6):1094.e5-1101.e5.23. Finkelstein D. Ischemic macular ede-ma: recognition and favorable natural history in branch vein occlusion. Arch Ophthalmol 1992;110:1427-34.24. The Central Vein Occlusion Study Group. Evaluation of grid pattern photo-coagulation for macular edema in central vein occlusion: the Central Vein Occlusion Study Group M report. Ophthalmology 1995;102:1425-33.25. Tsaloumas MD, Kirwan J, Vinall H, et al. Nine year follow-up study of mor-bidity and mortality in retinal vein occlu-sion. Eye (Lond) 2000;14:821-7.26. Christoffersen N, Gade E, Knudsen L, Juel K, Larsen M. Mortality in patients with branch retinal vein occlusion. Oph-thalmology 2007;114:1186-9.27. Cugati S, Wang JJ, Knudtson MD, et al. Retinal vein occlusion and vascular mor-tality: pooled data analysis of 2 popula-tion-based cohorts. Ophthalmology 2007; 114:520-4.28. Hayreh SS, Rojas P, Podhajsky P, Mon-tague P, Woolson RF. Ocular neovascular-ization with retinal vascular occlusion. III. Incidence of ocular neovasculariza-tion with retinal vein occlusion. Ophthal-mology 1983;90:488-506.29. Wong TY, Mitchell P. Hypertensive reti-nopathy. N Engl J Med 2004;351:2310-7.30. McIntosh RL, Mohamed Q, Saw SM,




clinical pr actice

Wong TY. Interventions for branch retinal vein occlusion: an evidence-based system-atic review. Ophthalmology 2007;114:835-54.31. Mohamed Q, McIntosh RL, Saw SM, Wong TY. Interventions for central retinal vein occlusion: an evidence-based system-atic review. Ophthalmology 2007;114:507-19.32. Lazo-Langner A, Hawel J, Ageno W, Kovacs MJ. Low molecular weight heparin for the treatment of retinal vein occlu-sion: a systematic review and meta-analy-sis of randomized trials. Haematologica 2010;95:1587-93.33. Jonas JB, Akkoyun I, Kamppeter B, Kreissig I, Degenring RF. Branch retinal vein occlusion treated by intravitreal tri-amcinolone acetonide. Eye (Lond) 2005; 19:65-71.34. Scott IU, Ip MS, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triam-cinolone with standard care to treat vi-sion loss associated with macular edema secondary to branch retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study re-port 6. Arch Ophthalmol 2009;127:1115-28. [Erratum, Arch Ophthalmol 2009;127: 1655.]35. Haller JA, Bandello F, Belfort R Jr, et al. Randomized, sham-controlled trial of dexamethasone intravitreal implant in patients with macular edema due to reti-nal vein occlusion. Ophthalmology 2010; 117(6):1134.e3-1146.e3.36. Brown DM, Kaiser PK, Michels M, et al. Ranibizumab versus verteporfin for neovascular age-related macular degen-eration. N Engl J Med 2006;355:1432-44.37. Rosenfeld PJ, Brown DM, Heier JS,

et al. Ranibizumab for neovascular age-related macular degeneration. N Engl J Med 2006;355:1419-31.38. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in oc-ular fluid of patients with diabetic reti-nopathy and other retinal disorders. N Engl J Med 1994;331:1480-7.39. Campochiaro PA, Hafiz G, Shah SM, et al. Ranibizumab for macular edema due to retinal vein occlusions: implication of VEGF as a critical stimulator. Mol Ther 2008;16:791-9.40. Spaide RF, Chang LK, Klancnik JM, et al. Prospective study of intravitreal ra-nibizumab as a treatment for decreased visual acuity secondary to central retinal vein occlusion. Am J Ophthalmol 2009; 147:298-306.41. Wu L, Arevalo J, Berrocal MH, et al. Comparison of two doses of intravitreal bevacizumab as primary treatment for macular edema secondary to central reti-nal vein occlusion: results of the Pan Amer-ican Collaborative Retina Study Group at 24 months. Retina 2010;30:1002-11.42. Prager F, Michels S, Kriechbaum K, et al. Intravitreal bevacizumab (Avastin) for macular oedema secondary to retinal vein occlusion: 12-month results of a pro-spective clinical trial. Br J Ophthalmol 2009;93:452-6.43. Campochiaro PA, Heier JS, Feiner L, et al. Ranibizumab for macular edema following branch retinal vein occlusion: six-month primary end point results of a phase III study. Ophthalmology 2010; 117(6):1102.e1-1112.e1.44. McAllister IL, Gillies ME, Smithies LA, et al. The Central Retinal Vein Bypass Study: a trial of laser-induced chorioreti-nal venous anastomosis for central retinal

vein occlusion. Ophthalmology 2010;117: 954-65.45. Ip MS, Scott IU, VanVeldhuisen PC, et al. A randomized trial comparing the efficacy and safety of intravitreal triam-cinolone with observation to treat vision loss associated with macular edema sec-ondary to central retinal vein occlusion: the Standard Care vs Corticosteroid for Retinal Vein Occlusion (SCORE) study re-port 5. Arch Ophthalmol 2009;127:1101-14. [Erratum, Arch Ophthalmol 2009;127: 1648.]46. Kinge B, Stordahl PB, Forsaa V, et al. Efficacy of ranibizumab in patients with macular edema secondary to central reti-nal vein occlusion: results from the sham-controlled ROCC study. Am J Ophthalmol 2010;150:310-4.47. 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.e1-1133.e1.48. Rouhani B, Mandava N, Olson JL. Central retinal vein occlusion after in-tense exercise in healthy patients. Retinal Cases Brief Rep 2010;4:105-8.49. Gillies MC, Wong TY. Ranibizumab for neovascular age-related macular de-generation. N Engl J Med 2007;356:748-9.50. Wong TY. Age-related macular degen-eration and cardiovascular disease in the era of anti-vascular endothelial growth factor therapies. Am J Ophthalmol 2009; 148:327-9.51. Retinal vein occlusion (RVO) interim guidelines. London: The Royal College of Ophthalmologists, February 2009. (http://www.rcophth.ac.uk.)Copyright 2010 Massachusetts Medical Society.

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