Non-diabetic Retinal Vascular Disease

Retinal anatomy

The retina has two main components. The outer pigmented layer of the retina consists of a single layer of cells known as the retinal pigment epithelium (RPE). This lies adjacent to the richly vascular choroid. The inner neural retina is made up of multiple layers of neural cells, starting with the photoreceptors which sit on the RPE and overlaid by ganglion cells with associated neuronal and supporting connective tissue. These overlying layers vary in thickness around the retina, generally getting thinner towards the fovea and disappearing altogether at the fovea centralis (the point where vision is maximal), leaving a small area of uncovered photoreceptors.

Retinal blood supply

There are two sources of blood supply to the retina:

• The outer RPE, the photoreceptors and a few of the overlying tissue layers are supplied by the choroid, itself supplied by the various ciliary arteries (branches of the ophthalmic artery - itself a branch of the internal carotid artery). There is a blood-retina barrier between the RPE and the photoreceptors such that this portion of the neural retina is protected from large toxic molecules and the molecular environment is tightly controlled.
• The inner neural retina is supplied by the central retinal artery and vein - directly derived from the ophthalmic artery and the associated veins respectively. The artery divides into two equal superior and inferior branches nasally (medially) and temporally (laterally) which supply all the inner layers of the neural retina. There is corresponding venous drainage. There are no arteriovenous anastomoses.

Clinical significance of the two blood supplies

Depending on the problem and at what level it occurs, different layers of the retina can be affected or spared. Thus, an embolus occurring in the opthalmic artery will have a devastating effect as all layers of the entire retina loose their blood supply whereas a small embolus lodged in a distal end branch of the artery will only affect the inner neural retina of that part of the retina, sparing the photoreceptors and limiting any symptoms.

These may occur in the central retinal artery (CRAO) or one of its branches (BRAO). The underlying causes are common to both conditions and include:

• Atherosclerosis related thrombus - this accounts for about 80% of CRAOs.
• Carotid embolism - this may be a cholesterol, fibrinoplatelet or calcific embolus.
• Giant cell arteritis.
• Cardiac embolism - this may be calcific, vegetations from the cardiac valves or a thrombus.
• Periarteritis - as might be found in patients with such conditions as systemic lupus erythematosus, polyarteritis nodosa or Wegener granulomatosis.
• Thrombophilic disorders such as antiphospholipid antibody syndrome.
• Rarely, retinal migraine - this might be seen in young individuals where all other causes have been excluded.

Central retinal artery occlusion (CRAO)

• Description - the central retinal artery occludes before it branches out, as it emerges from the optic nerve so resulting in pan-retinal ischaemia.
• Presentation³ - sudden (over a few seconds), unilateral painless visual loss. In 94% of cases, vision is reduced to counting fingers. There may be a history of amaurosis fugax. Examination reveals an afferent pupillary defect, a pale retina with attenuation of the vessels. There may be segmentation of the blood column in the arteries ('cattle-trucking') and the centre of the macula (supplied by the intact underlying choroid) stands out as a cherry-red spot.
• Management - if the patient presents within 90-120 minutes of onset of symptoms, you could try an ocular massage (repeated massage the globe over the closed lid for 10 seconds with 5 second interludes) - the idea is to try to dislodge the obstruction. However, this only works very occasionally and immediate referral is best. Lowering of intraocular pressure with an an anterior chamber paracentesis may be attempted (withdrawal of a little fluid from the anterior chamber under local anaesthetic, done in the clinic) and acetazolamide given but again, the outcome is variable. Other treatment options have been variously tried but have enjoyed only very modest success. Long-term management aims are to identify and address any underlying cause in order to prevent further ischaemic events.
• Outcome - unless the above measures work (time is of the essence but even then, the outcome is very variable) the prognosis is generally very poor as the inner neural layer becomes atrophic and all useful vision is generally lost. These patients are monitored in the outpatient clinic for evidence of neovascularization which can give rise to a different set of problems.

Branch retinal artery occlusion (BRAO)

• Description - one or multiple branches of the central retinal artery may be affected.
• Presentation - as above but only part of the vision is lost: the defect is usually altitudinal or sectoral. The retinal pallor corresponds to the area supplied by the affected artery. Occasionally, an embolus can be seen within the artery and cotton wool spots may eventually occur around that area.
• Management - refer. There is no proven effective management and as with CRAOs, every effort should be made to address underlying causes.
• Outcome - generally, the outcome is poor for that patch of retina affected and there is no recovery of the corresponding vision. Occasionally, recanalisation of the artery occurs but this is rare.

Retinal arteries and arterioles and their corresponding veins share a common adventitial sheath. Atherosclerosis is an important contributing factor to retinal vein occlusions as 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. This is a common group of conditions, the second most common type of retinal vascular disorder after diabetic retinal disease. Factors contributing to this pathophysiology include:¹

• Advancing age - over 50% of cases occur in patients over 65 years old.
• Systemic conditions such as hypertension, hyperlipidaemia, diabetes, smoking and obesity.
• Raised intraocular pressure.
• Inflammatory diseases such as sarcoidosis.
• Hyperviscosity states such as myeloma.
• Thrombophilic disorders, acquired such as hyperhomocysteinaemia, or inherited such as factor V Leiden.

Central retinal vein occlusion (CRVO)

• Description - this may be non-ischaemic (accounting for ~75% of CRVOs) or ischaemic, the exact pathophysiology depending on the causative factor (see above). Papillophlebitis (optic disc vasculitis) and hemiretinal vein occlusion (occlusion of the superior or inferior branch of the central retinal vein) also fall into this category of diseases but are less common. Their presentation is similar to those described below, the severity of the symptoms and the outcome depending on the extent of disease and which part of the retina has been affected.
• Presentation ^1,5
  • Non-ischaemic - sudden, unilateral, painless blurring of vision with a mild or absent afferent pupillary defect. There are wide-spread dot-blot and flame haemorrhages throughout the fundus and some disc oedema.
  • Ischaemic - sudden, unilateral, severe painless visual impairment with a marked afferent pupillary defect. The fundus looks similar to the non-ischaemic picture but disc oedema is severe.
• Management - refer. Some of these patients may benefit from laser treatment either at the time of presentation or subsequently if neovascularisation develops (on the fundus or around the iris - the latter may precipitate acute angle closure glaucoma).
• Outcome
  • Non-ischaemic - up to ~35% of cases become ischaemic within 3 years (see below). 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). About 50% of patients develop neovascularisation around the iris (rubeosis iridis), usually between 2 and 4 months (the '100 day glaucoma') and so need careful monitoring around this time.

Branch retinal vein occlusion (BRVO)

• Description - 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.
• 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. 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.
• Management - this depends on the area and degree of occlusion. Some patients benefit from laser treatment if they develop macular oedema or neovascularization. They will be monitored in outpatient clinic.
• 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.

Hypertensive retinopathy²

• Description - this can occur over time when there is a persistently raised blood pressure. Initially, there is arterial narrowing which is followed by vascular leakage and subsequent arteriosclerosis, graded 1-4. This has a characteristic appearance on fundoscopy (described below). Rarely, choroidal changes may occur: this tends to be in a context of an acute hypertensive crisis (accelerated hypertension) in young adults. These patients are at risk of developing the retinal vascular occlusions described above, particularly when there are concurrent risk factors (such as smoking and hyperlipidaemia).²
• Presentation
  • Chronic hypertension - usually asymptomatic or may have slightly decreased vision. Fundoscopy reveals bilateral attenuation of arterial vessels ('copper or silver wiring'), arteriovenous nipping (where the arteries cross the veins) and eventually, haemorrhage and exudates.
  • Malignant hypertension - may have decreased vision and headaches. On fundoscopy, you may see hard exudates appear as a 'macular star' (thin white streaks radiating around the macula), cotton wool spots, flame haemorrhages and arterial or venous occlusions.
• Management - this should be aimed at controlling the hypertension.
• Outcome - this depends on the blood pressure control.

Ocular ischaemic syndrome³

• Description - this uncommon condition arises as a result of chronic ocular hypoperfusion secondary to severe ipsilateral atherosclerotic carotid stenosis.
• Presentation - it usually presents in the 7th decade of life (range 50-80 years), often in association with diabetes, hypertension, ischaemic heart disease or cerebrovascular disease. Male: female is 2:1. Symptoms are unilateral and include a gradually decreasing vision (over weeks or months, rarely this can be sudden), periorbital pain, prolonged recovery of images after exposure to bright light and there may be a history of amaurosis fugax. Signs include a red eye, corneal oedema, a mid-dilated poorly reacting pupil and there may be rubeosis iridis. Fundoscopy will show venous dilatation, microaneurysms, neovascularisation and disc oedema.
• Management - refer. These patients will be variously treated with topical steroids and mydriatics and laser to any new vessel growth. The underlying carotid disease needs addressing.
• Outcome - both visual recovery and systemic outcome is poor. There is a ~40% 5-year mortality rate, usually from cardiac disease.¹

Sickle cell retinopathy

• Description - the most severe forms of retinopathy are associated with sickle-cell C disease and sickle-cell thalassaemia but all types of sickle cell disease can give rise to retinopathy. The impacted sickle-cells occlude arteries (stage 1), giving rise to peripheral arteriovenous anastomoses (stage 2) and then sprouting of new vessels from these anastomoses (stage 3). Trivial ocular trauma may precipitate vitreous haemorrhage (stage 4) resulting in subsequent fibrovascular proliferation and tractional retinal detachment (stage 5).
• Presentation - usually there are no ocular symptoms until stage 4 when there may be floaters and stage 5 which presents with flashes and floaters ± loss of vision (in advanced disease). Signs will depend on the stage of the disease as described above.
• Management - there are no well-established treatment options for the early stages. Later on (stages 3-5), patients may benefit from laser treatment to abnormal vessels and surgery to address tractional fibrosis and detachment.
• Outcome - this depends on the stage and to what degree neovascularisation can be controlled. This ultimately depends on the underlying systemic illness.

Purtscher retinopathy⁶

• Description - this is the retinopathy resulting from microvascular damage and occlusion occurring as a result of severe head trauma, chest compression injury or other crush injuries involving broken bones, fat embolisms or a number of systemic diseases (e.g. pancreatic disease, connective tissue diseases, lymphomas, thrombocytic thrombocytopenic purpura and following bone marrow transplantation). It can also occur during pregnancy or delivery.
• Presentation - there is sudden, severe, bilateral (unusually, unilateral) visual loss. Fundoscopy reveals multiple white retinal patches and haemorrhages around the disc.
• Management - there is no established ocular treatment (management of the underlying cause is the mainstay of treatment).
• Outcome - although the fundus changes often resolve within a few weeks, there is variable visual recovery, particularly where macular or optic nerve damage has occurred.

Retinopathy of prematurity (ROP)⁷

• Description - the greatest risk of ROP is in pre-term (especially less than 31 weeks), low birth weight (<1,500gm) babies who have been exposed to high ambient oxygen concentrations, or who have experienced hypoxaemia and hypercarbia. This occurs as a result of the fact that there is incomplete vascularisation of the retina until about 1 month after delivery (at the end of a normal gestation) and the incompletely vascularised retina is susceptible to oxygen damage. It is said to be active at the outset when there is compensatory fibrovascular proliferation with associated vitreous haemorrhage and retinal detachment. About 20% of infants then go on the develop cicatricial ROP which describes the range of subsequent complications. These include:
  • Myopia
  • Vitreoretinal fibrosis (± contractures and retinal folds)
  • Partial or total retinal detachment ± associated forward movement of the lens/iris which can lead to acute angle-closure glaucoma.
• Presentation - leucocoria (pupil looks white), poor pupillary dilatation despite adequate dilating drops (0.5% cyclopentolate ± 2.5% phenylephrine), engorgement of iris vessels. Older children may present with decreased visual acuity, myopia, strabismus and retinal changes / detachment.
• Management - screening and regular review of premature, low-birth weight babies is mandatory (starting at 6-7 weeks postnatal age and carrying on fortnightly until the degree of ROP progression is established) and the problems are managed as they arise. This may range from simple observation in mild cases to cryotherapy, laser treatment to surgery.
• Outcome - this depends on whether or not the developments described above occur. Blindness is a possibility.

Noninfectious retinal microvascular retinopathy ('HIV retinopathy')³

• Description - HIV patients can suffer from a variety of ocular complications, many of these infectious in nature. However, 50-70% develop HIV retinopathy which may even be the first sign of AIDS.
• Presentation - this tends to be asymptomatic but in 3% of patients, there is severe visual loss. Fundoscopy reveals a diabetic-type of appearance (cotton wool spots and microaneurysms) ± ischaemic maculopathy.
• Management - there is no specific treatment and management lies in concentrating on anti-retroviral therapy.
• Outcome - opportunistic infections and the systemic disease often overtake any visual impairment developing from HIV retinopathy.

Retinopathy in blood dyscrasias

• Anaemia - the various anaemias can cause retinal changes including flame haemorrhages with pale centres (Roth spots), cotton wool spots and venous tortuosity. Optic neuropathies are also described - particularly in pernicious anaemia. However, these changes are often innocuous and rarely of diagnostic importance. Management lies in treating the underlying cause of anaemia.
• Leukaemia - retinopathy is relatively common in the leukaemias and is characterised by similar findings to those described for anaemia. The cotton wool spots may represent leukaemic infiltrates. There may also be orbital involvement (particularly in children), spontaneous subconjunctival haemorrhage and optic neuropathy.
• Hyperviscosity states - retinopathy is characterised by venous dilatation, tortuosity and retinal haemorrhages. Management is of the underlying condition.

Retinal artery macroaneurysm

• Description - this localised dilatation of a retinal arteriole tends to occur in older (60-80year old), hypertensive women.² It is distinct from the microaneurysms of diabetic retinopathy in that macroaneurysms are larger in size, they tend to occur singly and form in much the same manner as aneurysms found elsewhere in the body (i.e. they are an idiopathic weakening of the vessel wall which leads to focal outpouching and aneurysm formation).
• Presentation - this is usually unilateral (90% of cases) and may be an incidental finding or may present with sudden painless visual loss from haemorrhage. However, more commonly there is gradual visual impairment due to insidious macular oedema and hard exudate formation (seen around the aneurysm on fundoscopy).
• Management - a rupture leads to haemorrhage which is observed until this involutes (as laser treatment cannot be carried out through the haemorrhage) and laser treatment is then performed to the lesion.
• Outcome - involution of the haemorrhage is very common but occasionally, there is a chronic leak resulting in permanent loss of central vision.

Primary retinal telangiectasia

• Description - this describes a group of rare, idiopathic disorders which may be congenital or acquired. There are a variety of vessels abnormalities (tortuosities, leakages, aneurysms and deposition of hard exudates) which often progress over time.
• Presentation - they may be asymptomatic until later on in life when they have progressed and then manifest themselves with (usually unilateral) painless, blurring of vision. Coats disease is the most severe of this group of disorders and often presents early (typically affecting boys, presenting in the first decade of life, often by 5 years of age). There may be a retinal detachment associated with this form of disease (often seen as leucocoria).
• Management - this depends on the subtype and severity of the condition. Management ranges from observation to photocoagulation laser therapy, cryotherapy and vitreoretinal surgery.
• Outcome - this is generally poor.

Radiation retinopathy

• Description - this may develop following treatment of intraocular tumours with radiation therapy. It can also occur following treatment of sinus, orbital or nasopharyngeal tumours.
• Presentation - patients usually present 6 months to 3 years post therapy with a (usually) painless gradual loss of vision. Fundoscopy will reveal microaneurysms, macular oedema, hard exudates and flame-shaped retinal haemorrhages. There may be associated disc oedema ± proliferative retinopathy and tractional retinal detachment.
• Management - it depends on the exact findings but this may include topical steroids, laser treatment or surgery.
• Outcome - this depends on the degree of retinopathy. Poor prognostic features include optic nerve involvement and neovascularisation.