Diabetic retinopathy boils down to two basic problems, leaky capillaries and retinal ischaemia.

The number of patients with diabetes and the number with diabetic retinopathy are high in many countries and, over the next twenty years, are projected to increase significantly [1,2]. Diabetic retinopathy is a major cause of visual loss worldwide.

Diabetic retinopathy can be divided into the following subtypes: nonproliferative diabetic retinopathy, proliferative diabetic retinopathy and diabetic macula oedema.

Both type 1 and type 2 diabetes cause diabetic retinopathy.

UNDERLYING DISEASE MECHANISM

The retina is the thin layer of light-sensitive tissue at the back of the eye. It consists predominantly of photoreceptors (rods and cones), and nerve cells. Like the brain, the retina is metabolically very active and requires a rich blood supply. This gives it its characteristic orange-red colour on fundoscopy.

The macula is a specialised area of the retina. It measures about 6 mm in diameter and is a yellowish colour. It is situated in the posterior pole of the eye to the lateral or temporal side of the optic disc. The macula contains the fovea and, within this, the foveola. The macula is responsible for high resolution, central vision and colour vision. To enable this, cones are the predominant photoreceptor cells. The foveola is densely packed with cones.

Diabetic retinopathy is a microvascular process that affect the retinal capillaries. The two basic problems are

• increased capillary permeability and leakage of serous fluid into the delicate retinal tissues leading to retinal and macula oedema
• retinal ischaemia leading to new vessel formation and retinal fibrosis

The walls of the retinal capillaries are made of a single layer of endothelial cells resting on an outer basement membrane. Endothelial cells are joined by tight junctions that help form the inner blood retinal barrier. Tight junctions limit the permeability of capillary walls. They only allow essential nutrients to diffuse from the blood into the retina and, thus, prevent the transfer of harmful substances.

The endothelial cells are supported by pericytes. Pericytes attach themselves to the basement membrane of the endothelial cells by way of their cytoplasmic processes. Pericytes provide structural support, regulate capillary blood flow and help control the formation of new blood vessels. They are also an important part of the blood retinal barrier

In diabetes, hyperglycaemia prolonged over many years leads to a number of metabolic changes that affect the retinal capillary endothelial cells. At present, we do not have a complete understanding of these processes.

RETINAL AND MACULAR OEDEMA

Hyperglycaemic metabolic changes lead to the disruption of endothelial tight junctions and loss of pericytes resulting in increased capillary permeability and structural weakness of capillary walls.

Weakened capillary walls lead to microaneurysm formation. These are round bulges or outpouchings that arise from capillaries. They are seen as red dots on ophthalmoscopy. Fluorescein angiography and optical coherence tomography angiography have revealed that microaneurysms are much more numerous than can be seen from traditional fundoscopy or retinal photography. Microaneurysms allow additional leakage of serous fluid. They can also cause small, round haemorrhages. These dot or blot haemorrhages occur in the middle layers of the retina. The bleeding is limited by the structure of the retina resulting in their characteristic, round appearance. The more superficial haemorrhages seen in hypertension are flame shaped.

Leaked, serous fluid tends to collect mainly in the extracellular space in and around the macula rather than the peripheral retina. From there, it diffuses into macular cells causing cellular dysfunction and cell death. It is also thought to cause low-grade inflammatory change. Macular oedema can result in temporary or permanent changes to central vision.

Some of the serous fluid is gradually reabsorbed leaving residual deposits of lipoprotein called hard exudates. Hard exudates appear as well demarcated white or yellow patches. They are not thought to cause visual impairment. Hard exudates around the macula may be an indicator of underlying macular oedema.

RETINAL ISCHAEMIA

White blood cells attach themselves to damaged, sticky endothelial cells. They obstruct capillary lumens and cause retinal ischaemia. Some capillaries break down completely and disappear. The resulting areas of retinal ischaemia are pale with blurred or fluffy margins. They are called soft exudates or cotton wool spots.

Various chemical mediators are produced by ischaemic retinal cells. Vascular endothelial growth factor (VGEF) is considered to be one of the most important. It promotes the formation of new retinal blood vessels (neovascularisation). It also increases capillary permeability. The new vessels are presumably intended to help revascularize ischaemic areas. Unfortunately, they tend to be of poor quality. They are thin, fragile and tortuous. They leak and may break down and haemorrhage. New vessels grow in spray-like patterns. They run along the surface of the retina and migrate up into the vitreous body.

New vessel formation can lead to low grade retinal inflammation and the formation of fibrous tissue. The fibrous tissue itself affects vision by replacing normal retinal tissue. With time it can contract and cause traction. Shrinkage of the retinal fibrous tissue can lead to traction retinal detachment. Shrinkage of fibrous tissue around new blood vessels that are migrating into the vitreous can lead to vitreous haemorrhage. Both these complications can cause sudden, severe loss of vision.

This progression of retinal damage is not seen in all patients who have retinal ischaemia due to diabetes. In some, there is little in the way of new vessel formation and, in others, little production of fibrous tissue.

Some retinal changes come and go. Fluid and blood leaking into the retina may be reabsorbed. Hard exudates may gradually disappear. Microaneurysms may resolve.

OTHER RETINAL MICROVASCULAR CHANGES

VENOUS BEADING

Retinal veins may become dilated with irregular outlines making them look like strings of sausages. These changes are thought to be secondary to ischaemia and vessel wall weakness.

INTRARETINAL MICROVASCULAR ABNORMALITIES (IRMAs)

These are arterio-venous shunts that occur in ischaemic areas. They are thicker and straighter than new vessels and do not leak. They may herald the development of neovascularisation.

NONPROLIFERATIVE DIABETIC RETINOPATHY

In non-proliferative diabetic retinopathy, there may be microaneurysms, haemorrhages, lipoprotein deposits, intraretinal microvascular abnormalities and ischaemic areas but no new vessel formation or fibrosis. Non-proliferative diabetic retinopathy can be subdivided into mild, moderate and severe categories depending on the degree of damage.

PROLIFERATIVE DIABETIC RETINOPATHY

Proliferative diabetic retinopathy includes the abnormalities found in nonproliferative diabetic retinopathy. In addition, there will be neovascularisation and, in some patients, retinal fibrosis.

Occasionally, patients with marked visual loss have extensive areas of pale, ischaemic retina with no new vessel formation or fibrosis.

Poor control of diabetes, hypertension and hyperlipidaemia all play a role in the development and progression of diabetic retinopathy.

Diabetic retinopathy can progress rapidly in pregnancy. These patients need close monitoring.

NEOVASCULARISATION OF THE IRIS (RUBEOSIS IRIDIS)

Occasionally neovascularisation can spread from the retina onto the iris, often visible close to the pupil. It can obstruct the outflow of aqueous humour and cause neovascular glaucoma.

Like diabetic retinopathy, diabetic nephropathy and diabetic neuropathy are considered to be due to microvascular disease. It is now thought that this can affect other organs including the heart (cardiomyopathy), the brain (vascular dementia) and the skin (delayed wound healing and ulceration). Presumably, the pathological changes found will be slightly different for each specific organ system.

NEURODEGENERATIVE DIABETIC RETINOPATHY

There is evidence from advanced imaging techniques that degeneration of retinal nerve cells can occur independently of microvascular disease. This is thought to have an important role in the early development of diabetic retinopathy [3].

CLINICAL FEATURES

Many patients with diabetic retinopathy do not have symptoms or may only be aware of subtle disturbances in vision. Because of this, retinal screening is very important to pick up and monitor early changes. In the United Kingdom, this is carried out by regular retinal photography.

TRACTION RETINAL DETACHMENT

Traction retinal detachment can cause floaters, flashing lights and the appearance of a grey curtain in the periphery of the visual field.

VITREOUS HAEMORRHAGE

Vitreous haemorrhage may cause blurred or hazy vision, floaters, red discolouration and areas of loss of vision (blind spots or scotomas).

MACULAR OEDEMA

Macular oedema causes blurred vision. There may be difficulty with reading or fine tasks. Patients may experience metamorphopsia (distortion of straight lines or shapes) or micropsia (objects appearing smaller than their actual size). Colours are less intense. Enlarged blind spots or scotomas may occur. The Amsler grid is a simple grid diagram that patients can use to detect macular visual changes at an early stage: they look out for any distortion of the lines or squares in the grid.

INVESTIGATIONS

FLUORESCEIN ANGIOGRAPHY

Fluorescein dye is injected intravenously and photographs taken of the retinal vessels.

Fluorescein angiography can show areas of reduced blood perfusion, microaneurysms and leakage from microaneurysms and new vessels. It can help differentiate between microaneurysms and dot or blot haemorrhages.

OPTICAL COHERENCE TOMOGRAPHY (OCT)

This is a non-invasive test that uses light waves to take high resolution cross-sectional images of the retina and choroid.

The structure of the retina can be seen and retinal thickness measured. Oedema causes thickening of areas of the retina, and the technique is particularly useful for identifying this. Fluid within the retina may form cystic areas. Optical coherence tomography can be used to confirm suspected traction retinal detachment.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY (OCTA)

This is a similar imaging method that allows us to focus on blood vessels of the retina and choroid.

TREATMENT

Improved diabetic control [4] and treatment of hypertension [5] have both been shown to be important in preventing the development and slowing the progress of retinopathy in type 2 diabetes. There is limited evidence [6] showing that lipid lowering drugs slow the progress of diabetic retinopathy and, possibly, macular oedema.

Treatment is usually started in patients considered to have vision threatening proliferative diabetic retinopathy or macular oedema.

PANRETINAL LASER TREATMENT

Panretinal laser treatment destroys a large part of the peripheral retina whilst avoiding central areas, hence preserving central vision. By destroying retinal cells, it reduces the amount of vascular endothelial growth factor produced. This prevents further neovascularisation and fibrosis. It can cause existing new vessels to regress.

FOCAL AND GRID LASER TREATMENT

These techniques are used for macula oedema. They work by reducing the leakage of serous fluid into the macula. Focal laser photocoagulation is aimed at destroying leaking microaneurysms and intraretinal microvascular abnormalities around but outside the central part of the macula. In grid laser photocoagulation, a larger area is treated using a blanket approach. Great care needs to be taken to avoid damage to the central part of the macula including the fovea because of possible loss of central vision.

Laser retinal photocoagulation is painful and can cause temporary blurring of vision. Treatment is usually completed over two to three sessions. Side effects include macula oedema, development of an epiretinal membrane and loss of part of the visual field. This may be severe enough to prevent driving.

Laser treatment has the advantage that treatment is completed over a relatively short period of time and long-term follow-up is not as important as it is for anti-vascular endothelial growth factor injections. Because of this, there is an argument for giving it as an initial measure to all patients who require treatment.

Laser treatment techniques are gradually being refined to try to optimise benefits and reduce adverse effects.

ANTI-VASCULAR ENDOTHELIAL GROWTH FACTOR (ANTI-VEGF) AGENTS

As we have said, vascular endothelial growth factor promotes the proliferation of new blood vessels and increases capillary permeability. Anti-vascular endothelial growth factor agents neutralise its effects. They are given by injection into the vitreous humour. They have been shown to be effective in the treatment of both proliferative diabetic retinopathy and diabetic macula oedema [7].

AFLIBERCEPT is a glycoprotein that binds and blocks vascular endothelial growth factor receptors on capillary endothelial cells.

BEVACIZUMAB and RANIBIZUMAB are both monoclonal antibodies. They bind to and inactivate vascular endothelial growth factor.

PEGAPTANIB is an aptamer or nucleotide chain. It also binds to and inactivates vascular endothelial growth factor.

At present, not all these drugs are licensed for the treatment of diabetic retinopathy. They may be given off license.

The injections are well tolerated by patients. They are usually given monthly for 3 months to start with. Subsequent frequency of injections depends on progress. Treatment may take twelve months or more and may need to be restarted if retinopathy recurs.

The most important side effect is infection within the eye (endopthalmitis). Other side effects include haemorrhage and cataract formation.

Neovascularisation of the iris can be treated with panretinal laser, anti-vascular endothelial growth factor agents or a combination of the two.

INTRA-VITREAL STEROD INJECTION

This can be used to treat macula oedema. It is thought to work by improving the integrity of capillary endothelial tight junctions and reducing inflammation. Injections are usually given monthly to start with. However, some long-acting preparations are available.

Intra-vitreal steroid injection is often effective in pregnancy.

Side effects of intra-vitreal steroid injections include infection, raised intraocular pressure and cataract formation.

VITRECTOMY

Vitrectomy may be used for persistent vitreal haemorrhage or traction retinal detachment.

Some patients need combinations of these different treatments.

REFERENCES

1. Saeedi P, Petersohn I, Salpea P, et al. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9th edition. Diabetes Res Clin Pract. 2019;157:107843. doi:10.1016/j.diabres.2019.107843
2. Teo ZL, Tham YC, Yu M, et al. Global Prevalence of Diabetic Retinopathy and Projection of Burden through 2045: Systematic Review and Meta-analysis. Ophthalmology. 2021;128(11):1580-1591. doi:10.1016/j.ophtha.2021.04.027
3. Antonetti DA, Barber AJ, Bronson SK, et al. Diabetic retinopathy: seeing beyond glucose-induced microvascular disease. Diabetes. 2006;55(9):2401-2411. doi:10.2337/db05-1635
4. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):837-853.
5. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ. 1998;317(7160):703-713.
6. Shi R, Zhao L, Wang F, et al. Effects of lipid-lowering agents on diabetic retinopathy: a Meta-analysis and systematic review. Int J Ophthalmol. 2018;11(2):287-295. Published 2018 Feb 18. doi:10.18240/ijo.2018.02.18
7. Bahrami B, Hong T, Gilles MC, Chang A. Anti-VEGF Therapy for Diabetic Eye Diseases. Asia Pac J Ophthalmol (Phila). 2017;6(6):535-545. doi:10.22608/APO.2017350