Retinal vein occlusion (RVO) is a major cause of significant visual impairment. After diabetic retinopathy, it is the second most common retinal vascular disease leading to vision loss. Once a patient is diagnosed with either a branch retinal vein occlusion (BRVO [see Figure 1]) or a central retinal vein occlusion (CRVO [see Figure 2]), close follow-up is essential in order to manage the potential ocular complications. Consultation between the ophthalmologist and other physicians is also important to investigate and optimise any underlying medical risk factors.

Epidemiology

The incidence of RVO ranges between 0.5-1.8%. The Beaver Dam Eye Study, a review of 4,068 participants in the US, estimated the cumulative 15-year incidence of BRVO to be 1.8% and that of CRVO to be 0.5%.¹ A pooled analysis of population-based studies from the US, Europe, Asia and Australia that included data from 49,869 individuals from 11 studies found that the prevalence of RVO was 5.2 per 1,000 individuals; the prevalence of BRVO was 4.42 per 1,000; and that for CRVO was 0.8 per 1,000.² There was no gender predilection for this disease, but prevalence varied by race/ethnicity and increased with age.²

Figure 1. Left supero-temporal branch retinal vein occlusion, showing significant haemorrhage and extensive cotton-wool spots (retinal nerve fibre layer infarction)(click to enlarge)

Risk factors

The main risk factors for RVO are:

• Older age
• Hypertension 
• Hyperlipidaemia (cholesterol > 6.5mmol/L)
• Diabetes mellitus
• Congenital thrombophilia: factor V Leiden, hyperhomocysteinaemia, protein C deficiency, protein S deficiency and antithrombin 3 deficiency
• Acquired thrombophilia: myeloproliferative disorders, antiphospholipid antibody syndrome, and oral contraceptive pill use
• Vasculitides: Behçet’s disease, polyarteritis nodosa, sarcoidosis and Wegener’s granulomatosis
• Glaucoma.

RVO and cardiovascular disease risk

Although RVO shares the same risk factors with cardiovascular (CV) disease, it is controversial whether RVO is an independent CV risk factor. Cugati et al found that RVO is associated with higher CV mortality among individuals younger than 70 years of age, after adjusting for other risk factors.³ On the other hand, Werther et al concluded that the rate of cerebrovascular, but not cardiovascular, adverse events is increased in patients with RVO.⁴

Figure 2. Left central retinal vein occlusion, showing dilated tortuous veins, optic disc oedema, retinal haemorrhages and cotton wool spots in all retinal quadrants (click to enlarge)

Pathophysiology and complications of RVO

The mechanism of RVO is based on the factors governing thrombosis, namely Virchow’s triad: hypercoagulability, endothelial dysfunction and haemodynamic changes. Central and peripheral retinal veins share common adventitial sheaths with their corresponding retinal arterioles. This common adventitial sheath is found at arteriovenous crossing points in the case of branch retinal veins and at the lamina cribrosa of the optic nerve head for the central retinal vein.⁵

In the presence of arteriosclerosis due to systemic disease, compression of the thin-walled vein by a neighbouring thickened arteriole is thought to induce turbulence of venous blood flow leading to endothelial cell damage and, hence, thrombosis. Vascular blockage increases the intravascular hydrostatic pressure leading to exudation of fluid into the interstitial space. If this occurs at the macula, it may result in macular oedema. The resultant rise in interstitial pressure may subsequently compromise the capillary blood flow, leading to retinal ischaemia. When large areas of the retina are ischaemic, oxygen-deprived cells produce vascular endothelial growth factor (VEGF), stimulating neovascularisation of the retina and iris (rubeosis iridis). 

The main causes of morbidity due to RVO are: macular oedema, macular ischaemia and neovascularisation of the retina and iris. Rubeosis iridis may cause secondary glaucoma, due to new blood vessel formation at the irido-corneal angle, restricting the normal aqueous outflow. The resulting elevated intraocular pressure (IOP) may then lead to corneal oedema, further blurring of vision, and pain. Retinal neovascularisation produces new blood vessels that are prone to bleed, causing vitreous haemorrhage, which may result in sudden, painless, profound loss of vision.

Clinical presentation and classification

The most common presenting complaint of RVO is painless blurring of vision or a visual field defect. The degree of reduction in visual acuity (VA) and the extent of visual field loss depend on the site of obstruction and the extent of tissue oedema and ischaemia. Anterior segment examination can potentially reveal any of the following: red eye, corneal oedema, elevated IOP, and/or rubeosis iridis. Elevated IOP that occurs as a result of rubeosis iridis may cause neovascular glaucoma and classically occurs approximately three months after an ischaemic CRVO. It is commonly referred to as ‘100-day glaucoma’. A relative afferent pupillary defect (RAPD) may be present on pupillary examination and is an important prognostic sign, as it may indicate severe retinal damage due to ischaemia, which is associated with a poorer visual prognosis. 

Fundoscopic findings include dilated, tortuous retinal veins distal to the obstruction, intraretinal haemorrhages (dot, blot and flame-shaped), cotton-wool spots, macular oedema, and vitreous haemorrhage in complicated cases. The division of RVO into ischaemic and non-ischaemic subtypes is not always exact, as some cases fall between these two ends of the spectrum. However, it is very useful clinically and of prognostic value to try to differentiate these two categories, depending on the clinical features and findings on fundus fluorescein angiography (see Figure 3). Notably, up to one-third of patients initially diagnosed with non-ischaemic CRVO will undergo ischaemic transformation. 

Figure 3. Fundus fluorescein angiogram of Figure 1, showing significant supero-temporal retinal ischaemia secondary to BRVO(click to enlarge)

Investigations

Ocular

• Full history and clinical examination, including: best corrected VA
• Pupillary reactions, including: ‘swinging light test’ for the presence of RAPD
• Intraocular pressure (IOP) measurement
• Gonioscopy
• Slit lamp biomicroscopy of the anterior and posterior segments.

Retinal imaging

• Colour fundus photography
• Optical coherence tomography (OCT): to detect and monitor macular oedema
• Fundus fluorescein angiography (FFA): to assess retinal ischaemia and neovascularisation. Only useful if its interpretation will not be confounded by the presence of significant intraretinal haemorrhage.

Systemic

• For all patients at baseline:
• Blood pressure measurement
• Electrocardiography (ECG)
• Full blood count (FBC)
• Urea and electrolytes (U+E) and creatinine
• Erythrocyte sedimentation rate (ESR)
• Random glucose
• Random lipids
• Thyroid function testing (TFT)
• Plasma protein electrophoresis.

Additional tests as indicated, especially for young patients, may include: thrombophilia screening, anti-cardiolipin antibody, lupus anticoagulant, C-reactive protein (CRP), serum ACE, auto-antibodies (rheumatoid factor, ANA, anti-DNA, ANCA), fasting homocystine level and chest x-ray (CXR).

Management

Management of RVO has undergone significant change recently, particularly since the introduction of anti-VEGF therapies. Recent trials have shown the benefit of early intervention in the treatment of macular oedema, which can readily be assessed by OCT.^6,7,9 However, there is still variation in practice and no universally agreed treatment algorithm in the management of RVO.¹⁰ Current management options include: observation, argon grid laser for macular oedema, intravitreal anti-VEGF and/or steroid injections, intra-cameral anti-VEGF injections to treat rubeosis iridis, and pan-retinal photocoagulation (PRP) laser to treat proliferative retinopathy. 

Evidence-based guidance governing many of the above management options is provided by several important clinical trials. The Central Vein Occlusion Study (CVOS) did not show any benefit to grid laser for macular oedema in patients with non-ischaemic CRVO.⁷ However, grid laser treatment was shown to be beneficial in patients with macular oedema secondary to non-ischaemic BRVO in the Branch Vein Occlusion Study (BVOS).⁸

Treatment of macular oedema, secondary to CRVO, using intravitreal steroid injection (triamcinolone acetonide) was found to be useful in the Standard care versus COrticosteroid for REtinal vein occlusion (SCORE) study. However, there may be an increased incidence of steroid-related glaucoma and cataractogenesis. Furthermore, they concluded that grid laser is as effective as, yet safer than, intravitreal triamcinolone injection for macular oedema secondary to BRVO. 

Injection of a longer-acting dexamethasone biodegradable implant (Ozurdex) may be as beneficial and be associated with a lower incidence of the aforementioned steroid-related adverse effects, as shown by the Ozurdex GENEVA study group. Intravitreal injection of the anti-VEGF agent ranibizumab (Lucentis – licensed for this indication) or bevacizumab (Avastin – off-label use) has been shown to be beneficial for the treatment of macular oedema secondary to BRVO by the BRAVO study,⁹ and secondary to CRVO by the CRUISE study.⁶

Longer-term data from the HORIZON study have shown that, in the second year of treatment of macular oedema due to retinal vein occlusion, patient follow-up and treatment should be individualised. The forthcoming BevaCizumab Versus RAnibizumab in Treatment of Macular Edema from VEin Occlusion (CRAVE) study will investigate the relative safety and efficacy of these two agents for this indication. 

The COPERNICUS study has evaluated the use of aflibercept (VEGF Trap-Eye) in the treatment of macular oedema due to CRVO, demonstrating statistically significant improvement in VA at week 24, following monthly intravitreal aflibercept injections, which was maintained through week 52 with intravitreal aflibercept PRN dosing.

Management of ischaemic CRVO also involves very close observation for neovascular complications, PRP laser to treat proliferative changes, and management of secondary glaucoma, as required, which may include topical and/or systemic anti-ocular-hypertensive medication, intra-cameral anti-VEGF injections, cyclodestructive procedures, and/or glaucoma filtration surgery. It is essential to remember that a key cornerstone of RVO management includes treatment of any underlying systemic disease, and physician involvement is paramount.

Prognosis

Significant prognostic value can be placed on the presenting VA in patients with CRVO. Patients with an initial VA of 6/12 or better in the affected eye have a better prognosis for retaining vision than those with worse VA at presentation. Only 20% of eyes with an initial VA of between 6/15 and 6/60 improve spontaneously to 6/15, while 80% of patients with a baseline VA worse than 6/60 in the affected eye remain at this level or get even worse. Furthermore, the longer the duration of macular oedema, the greater the structural damage at the fovea, justifying the initiation of early treatment.

In patients with BRVO, the average improvement in VA over time does not result in a final VA better than 6/12. Macular oedema develops in 5-15% of eyes over a one-year period; however, of those that had macular oedema at presentation, 18-40% may show some resolution. 

Approximately 20% of untreated eyes experienced significant visual deterioration over time. In the BVOS, approximately 50% of untreated eyes with BRVO retain vision of 6/12 or better while 25% have a final VA of < 6/60. BRVO may occur in the fellow eye in 10% of patients over time.¹⁰

References

1. Klein R, Klein BE, Meuer SM et al. The 15-year cumulative incidence of retinal vein occlusion: the Beaver Dam Eye Study. Arch Ophthalmol 2008; 126(4): 513-518
2. Rogers S, McIntosh RL, Cheung RL et al. The prevalence of retinal vein occlusion: pooled data from population studies from the United States, Europe, Asia, and Australia. Ophthalmology 2010; 117(2): 313-319
3. Cugati S, Wang JJ, Knudtson MD  et al. Retinal vein occlusion and vascular mortality: pooled data analysis of 2 population-based cohorts. Ophthalmology 2007; 114(3): 520-524
4. Werther W, Chu L, Holekamp N et al. Myocardial infarction and cerebrovascular accident in patients with retinal vein occlusion. Arch Ophthalmol 2011; 129(3): 326-331
5. Zhao J, Sastry SM, Sperduto RD et al. Arteriovenous crossing patterns in branch retinal vein occlusion. The Eye Disease Case-Control Study Group. Ophthalmology 1993; 100(3): 423-428
6. 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
7. Aref AA, Scott IU. Management of macular edema secondary to central retinal vein occlusion: an evidence-based. Adv Ther 2011; 28(1): 40-50
8. Argon laser photocoagulation for macular edema in branch vein occlusion. The Branch Vein Occlusion Study Group. Am J Ophthalmol 1984; 98(3): 271-282
9. 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): 1102-1112
10. The Royal College of Ophthalmologists. Interim Guidelines for Management of Retinal Vein Occlusion. December 2010