Retinal vein occlusions (RVOs) are the second most common type of retinal vascular disorder after diabetic retinal disease.¹ They can occur at almost any age (although typically in middle to later years - most in those aged over 65 years) and their severity ranges from asymptomatic to a painful, blind eye.

Pathophysiology

Occlusion of the retinal venous system by thrombus formation is the most common cause but other causes include disease of the vein wall and external compression of the vein.² Retinal arteries and arterioles and their corresponding veins share a common adventitial sheath. It is thought that the thickening of the arteriole compresses the vein, eventually causing occlusion.

A backlog of stagnated blood combined with associated hypoxia results in extravasation of blood constituents, causing further stagnation and so on, resulting in the creation of a vicious circle of events. Ischaemic damage to the retina stimulates increased production of vascular endothelial growth factor (VEGF) which, in turn, may lead to neovascularisation - a process that can result in haemorrhage (as the new vessels are of poor quality) or neovascular glaucoma (the new vessels grow into the aqueous drainage system, so clogging it up). Factors contributing to this pathophysiology include:²

• Advancing age - over 50% of cases occur in patients over 65 years old, although up to 15% may affect individuals under the age of 45.³
• Systemic conditions such as hypertension (found in 64% of patients with retinal vein occlusion (RVO)²), hyperlipidaemia, diabetes, smoking and obesity.
• Raised intraocular pressure.
• Inflammatory diseases such as sarcoidosis, Behçet's syndrome.
• Hyperviscosity states such as myeloma.
• Thrombophilic disorders (to be considered in patients <45 years old), such as hyperhomocysteinaemia, lupus anticoagulant, anticardiolipin antibodies; or inherited disorders such as factor V Leiden, protein C or S deficiencies.³

There are more unusual associations, including chronic renal failure, other secondary causes of hypertension and diabetes (e.g. Cushing's syndrome), secondary causes of hyperlipidaemia (e.g. hypothyroidism), polyarteritis nodosa, Wegener's granulomatosis and Goodpasture's syndrome.²

Central retinal vein occlusion

Central retinal vein occlusion (CRVO) has two broad categories, which may overlap:

• The milder form of the disease is non-ischaemic CRVO (accounting for ~75% of CRVOs). This may resolve fully with good visual outcome or progress to the ischaemic type.
• The severe form of the disease is ischaemic CRVO. Patients may be left with with neovascular glaucoma and a painful blind eye.

In some cases, the cut-off between the two can be arbitrarily based on angiographic findings but it is a useful predictor of outcome and complication development.

Epidemiology

This is a common condition with a reported incidence of 7 per 1,000 at 49-60 years and 46 per 1,000 at 80 years. There is an equal sex distribution.²

Presentation

The patient (usually aged >50) frequently presents with sudden unilateral painless loss of vision or blurred vision, often starting on waking.⁴

• Non-ischaemic - mild or absent afferent pupillary defect. There are widespread dot-blot and flame haemorrhages throughout the fundus and some disc oedema.
• Ischaemic - severe visual impairment with a marked afferent pupillary defect. The fundus looks similar to the non-ischaemic picture but disc oedema is more severe. Haemorrhages scattered throughout the fundus in typical blood-storm pattern with cotton wool spots (sparse scattered haemorrhages with less complete blockage). There may occasionally be an associated retinal detachment.

Differential diagnosis³

• Ocular ischaemic syndrome.
• Diabetic retinopathy.
• Other cause of optic disc swelling.
• Radiation retinopathy.

Management

Currently, there are no proven treatment options available so management has the two-fold aim of identifying/managing modifiable risk factors and recognising/treating complications. Where there is development of blindness due to a secondary complication, e.g. neovascular glaucoma, the management aim is to keep the eye pain-free.

• Refer within 24 hours to the on-call ophthalmologist.
• The ophthalmologist will seek certain features that distinguish ischaemic from non-ischaemic CRVO. The former will be observed every 2 to 3 months ± treated with laser (panretinal photocoagulation) should any neovascularisation - particularly around the iris - occur.²
• Reduction of intraocular pressure is needed if this is elevated.
• Intravitreal anti-vascular endothelial growth factor (anti-VEGF) agents, in combination with use of laser panretinal photocoagulation (PRP), should be used when iris new vessels or angle new vessels are visible.² PRP results in dramatic regression of the new vessels. The effect is short-lived and new vessels recur commonly, so repeated treatment (typically every six weeks) with these agents (and PRP) may be required.
• Intravitreal triamcinolone has been proposed as a treatment option for some of the associated complications (macular oedema and optic neuropathy) but has no proven effect on anterior neovascularisation.²
• Intravitreal steroids have also been studied with regards to treating post-CRVO macular oedema. Currently, the response has been found to be positive but limited temporally and there are a number of complicating side-effects.¹
• Other experimental treatments are being investigated (particularly operative) but are still in early stages in their respective trials. Laser-induced chorioretinal venous anastomosis (L-CRA) has been used as a treatment for non-ischaemic CRVO. Where an anastomosis was successfully made, significant improvement was noted in visual acuity at 18 months after follow-up.⁵
• Any underlying modifiable risk factors will need to be identified and addressed.

Complications

• Retinal neovascularisation (and secondary glaucoma or vitreous haemorrhage - the '90-day glaucoma').
• Macular oedema ± lamellar or full-thickness macular hole.
• Permanent macular degeneration or 'cellophane maculopathy'.
• Optic atrophy.

Outcome

Most have persisting reduced central vision due to long-term macular oedema. Occasionally, vision may improve without treatment.

• Non-ischaemic - <10% recover normal visual acuity. Most have persistent visual impairment (50% have 6/60 vision or worse) and a third develop ischaemic CRVO within three years.⁶ The prognosis of the remaining cases depends on the visual acuity at presentation. Those with 6/18 or better are likely to stay that way; there is a variable prognosis between 6/18 and 6/60 and a very poor visual prognosis at 6/60 or less.
• Ischaemic - this is very poor on account of macular oedema and ischaemia. >90% will have impaired vision of 6/60 or worse. About 50% of patients develop neovascularisation around the iris (rubeosis iridis), usually between 2 and 4 months and so need careful monitoring around this time, as they may require PRP.² 60% develop neovascularisation.

There is no risk of increased long-term mortality (in contrast to retinal artery occlusion). However, there is a 10% risk of developing CRVO in the fellow eye within two years.⁶

Branch retinal vein occlusion

Description

Branch retinal vein occlusions (BRVOs) are three times more common than central retinal vein occlusions (CRVOs).² There are various subclassifications of this depending on whether a major branch, a minor macular branch or a peripheral branch is affected. Each carries its own prognosis. A hemiretinal vein occlusion refers to an occlusion that is proximal enough to affect half of the retinal drainage (i.e. the superior or inferior portion) as opposed to the smaller portion affected by a BRVO.

Presentation

This largely depends on the amount of compromise to macular drainage. The most common presentation is of unilateral, painless blurred vision, metamorphopsia (image distortion) ± a field defect (usually altitudinal). Peripheral occlusions may be asymptomatic. Visual acuity depends on the degree of macular involvement. Fundoscopy will reveal vascular dilatation and tortuosity of the affected vessels, with associated haemorrhages in that area only (look for an arc of haemorrhages, like a trail left behind a cartoon image of a shooting star).

Management

• Refer within 24 hours to an on-call ophthalmologist.
• Management depends on the area and degree of occlusion.
• Some patients benefit from panretinal photocoagulation (PRP) laser treatment if they develop macular oedema (where visual acuity is ≤6/12 and there is no spontaneous improvement by 3-6 months) or neovascularisation.²
• They will be monitored in an outpatient clinic.
• Treatment with triamcinolone produces anatomical and functional improvement of macular oedema due to BRVO. This is similar to the results from laser treatment. However there is a higher incidence of raised intraocular pressure, incidence of cataract formation and progression and need for cataract surgery than in patients having laser treatment.² The TRIVARIS® preparation (which was used in the trials) is not currently available for clinical use anywhere in the world and is different from the commonly available Kenalog®.
• Dexamethasone biodegradable implants are licensed for treatment of macular oedema secondary to BRVO.
• Use of anti-vascular endothelial growth factor (anti-VEGF) for BRVO is currently off-license but has been shown to have sustained benefit for macular oedema resulting from BRVO.⁷

Complications

These are similar to those of CRVO. New vessels tend to occur only when at least one quadrant of the retina is affected, and appear about six months after the original occlusion.² The rate of complication for hemiretinal vein occlusions is greater than that of BRVO but less than that of CRVO.

Outcome

The outcome is reasonably good depending on the number of collateral veins that develop. 50% of patients return to a visual acuity of 6/12 or better. Over half will develop macular oedema and about one in five may develop retinal neovascularisation.

Investigations

These are common to both central and branch vein occlusions and should help to identify systemic problems. All patients should have:²

• BP (the most common association with BRVO).
• Blood glucose and lipids (if abnormal, TFTs too).
• FBC, ESR.
• Plasma protein electrophoresis.
• ECG.

Depending on individual circumstances (e.g. a young patient), other tests may include:

• Thrombophilia screen including antiphospholipid antibodies and lupus anticoagulant.
• CRP, serum ACE, auto-antibodies, CXR, fasting homocysteine levels.

In the eye clinic, further evaluation includes:

• Measurement of intraocular pressure.
• Fluorescein angiography is the investigation of choice in central retinal vein occlusion (CRVO). It evaluates retinal capillary non-perfusion, neovascularisation and macular oedema. It is not often necessary in branch retinal vein occlusion (BRVO).²
• Optical coherence tomography (OCT) scan. This is non-invasive, transpupillary imaging. It measures the retina and can detect macular oedema that fluorescein angiography has missed because of blockage from haemorrhage.⁸

Non-ophthalmological management of retinal vein occlusions

The ophthalmology team is primarily concerned with the diagnosis of a retinal vein occlusion (RVO) and the management of the ocular complications. Baseline investigations should be carried out by the ophthalmology team at the time of diagnosis. It is also their responsibility to impart this information effectively to the patient's GP, as underlying risk factors need to be assessed and addressed urgently. Rarer causes (such as those encountered in younger patients) need managing by relevant specialists. Initiation of medical management should occur within two months of diagnosis.

Risk factors have been identified in 'Pathophysiology', above. The principle area of investigation and management will be the cardiovascular risk factors which should be managed according to the joint guidelines of the British Hypertension Society, British Hyperlipidaemia Association and the British Diabetic Association.⁹

Issues which may arise in the context of general practice

• Hormone replacement therapy (HRT) - historically, HRT was contra-indicated and discontinued in women experiencing an RVO. However, more recent studies have shown that continued use does not appear to be associated with a higher rate of recurrence. Thus, although it is not advised to start it following an RVO, the decision as to whether to continue previously prescribed HRT can now be made on a case-by-case basis depending on the menopausal symptoms experienced by the patient.
• The management of younger patients - although the visual outcome in this group of patients appears to be better, RVOs are associated with underlying systemic conditions which should be managed appropriately. In females, the most common association is with the oral contraceptive pill. Thus, an RVO is a contra-indication for this. Sometimes, no underlying cause can be found despite extensive investigations - this group presents a management problem and is likely to be under ophthalmological observation for a much longer period of time.

Document references

1. Gewaily D, Greenberg PB; Intravitreal steroids versus observation for macular edema secondary to central retinal vein occlusion. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD007324. DOI: 10.1002/14651858.CD007324.pub2
2. Interim Guidelines for Management of Retinal Vein Occlusion, Royal College of Ophthalmologists (December 2010)
3. Fonrose M, Retinal Vein Occlusion, Medscape, Jan 2011
4. Retinal Vein Occlusion, Handbook of Ocular Disease Management
5. McAllister IL, Gillies ME, Smithies LA, et al; The Central Retinal Vein Bypass Study: a trial of laser-induced chorioretinal Ophthalmology. 2010 May;117(5):954-65. Epub 2010 Feb 16. [abstract]
6. Kooragayala LM, Central Retinal Vein Occlusion, Medscape, Jan 2011
7. Brown DM, Campochiaro PA, Bhisitkul RB, et al; Sustained benefits from ranibizumab for macular edema following branch retinal Ophthalmology. 2011 Aug;118(8):1594-602. [abstract]
8. Catier A, Tadayoni R, Paques M, et al; Characterization of macular edema from various etiologies by optical coherence tomography. Am J Ophthalmol. 2005 Aug;140(2):200-6. [abstract]
9. No authors listed, JBS 2: Joint British Societies' guidelines on prevention of cardiovascular disease in clinical practice. Heart. 2005 Dec;91 Suppl 5:v1-52