Diabetic retinopathy

Summary

Diabetic retinopathy is characterised by damage to the microvasculature supplying the eye due as a result of diabetes mellitus. It can result in progressive loss of vision. Diabetic retinopathy is one of the leading causes of preventable blindness in the working-age population. It predominantly arises from chronic hyperglycaemia which causes metabolic and vascular changes within the retina.

Aetiology

The aetiology of diabetic retinopathy is multifactorial and is associated with several factors:

• Overproduction of vascular endothelial growth factor (VEGF): chronic hyperglycaemia induces retinal hypoxia, which in turn causes an overproduction of vascular endothelial growth factor (VEGF). This promotes the growth of new, fragile blood vessels (a process known as neovascularisation), and increases the permeability of existing blood vessels, leading to macular oedema.
• Polyol Pathway Activation: In hyperglycaemic conditions, glucose is converted to sorbitol via the enzyme aldose reductase. Accumulation of sorbitol causes osmotic stress, leading to cell swelling and dysfunction, particularly in the retinal nerve cells and vascular endothelial cells.
• Advanced Glycation End-products (AGEs): Chronic exposure to high glucose levels results in the non-enzymatic glycation of proteins, forming AGEs. These compounds accumulate on cells and extracellular matrix, leading to vascular stiffness, altered protein function, and the induction of pro-inflammatory pathways.
• Protein Kinase C (PKC) Activation: Hyperglycaemia activates the diacylglycerol-PKC pathway. Certain isoforms of PKC are associated with increased vascular permeability, altered blood flow, and the production of growth factors, contributing to diabetic retinopathy.
• Oxidative Stress: Excess glucose metabolism generates reactive oxygen species (ROS), leading to oxidative stress. This promotes inflammation, damages cellular structures, and triggers apoptotic pathways, all of which contribute to retinal injury.

Other contributory factors:

• Duration of diabetes: The longer a person has diabetes, the higher the risk of developing diabetic retinopathy. Most individuals with type 1 DM and a significant proportion of those with type 2 DM will show some signs of retinopathy after 20 years of disease.
• Hypertension: high blood pressure is a risk factor for diabetic retinopathy. High blood pressure can exacerbate the microvascular damage in the retina. It is important to manage blood pressure optimally in individuals with diabetes to reduce risk of progression.
• Dyslipidaemia: altered lipid profiles, particularly elevated levels of low-density lipoprotein (LDL) cholesterol, are associated with the progression and severity of diabetic retinopathy.
• Genetic factors: some individuals with diabetes mellitus are more genetically predisposed to developing diabetic retinopathy than others. The specific genes linked to the susceptibility of diabetic retinopathy are under investigation.
• Diabetic nephropathy: the presence of diabetic nephropathy, another microvascular complication of diabetes, is strongly associated with the risk and progression of diabetic retinopathy.

Clinical features

Non-proliferative diabetic retinopathy

Non-proflierative diabetic retinopathy is the initial stage of diabetic retinopathy, and is also known as background retinopathy. It causes increased capillary permeability, and macular oedema may occur due to fluid leakage from capillaries.

The fundoscopic findings of non-proliferative diabetic retinopathy include:

• Microaneurysms: these are tiny, round, red spots seen on fundus examination. They are the earliest clinical sign of diabetic retinopathy.
• Dot and blot haemorrhages: these are small haemorrhages in the deeper layers of the retina.
• Hard exudates: these are lipid residues of serous leaks from damaged capillaries. They appear as yellow, well-defined lesions scattered in the macular area.
• Cotton-wool spots: these are areas of retinal ischaemia. They appear as soft, fluffy, white areas on the retina.
• Venous beading: this is irregularity and dilation of the retinal veins.
• Retinal oedema: this is swelling of the retina, especially in the macular region, known as macular oedema. This is a primary cause of vision loss in diabetic retinopathy.

Proliferative diabetic retinopathy

Diabetic retinopathy can progress onto a more advanced form of the disease, known as proliferative diabetic retinopathy. This is characterised by the formation of new and abnormal blood vessels in the inner surface of the retina. This process is called neovascularisation and occurs as a response to retinal ischaemia.

Features include:

• Neovascularisation: new, fragile blood vessels form on the surface of the retina and optic disc. These blood vessels can bleed easily.
• Vitreous haemorrhage: this is bleeding from the neovascular vessels which can fill the vitreous cavity and leads to sudden onset vision loss.
• Fibrovascular proliferation: scar tissue can develop and cause retinal detachment.
• Rubeosis iridis: this is when neovascularisation occurs on the surface of the iris, leading to neovascular glaucoma, which is a severe and painful condition.

Diabetic macular oedema

Diabetic macular oedema can occur at any stage of diabetic retinopathy, however, it is more common in the later stages. It is a significant cause of visual impairment in diabetic retinopathy.

Features include:

• Macular thickening: fluid accumulates in the macula, the central part of the retina.
• Hard exudates: often seen in a circinate or star pattern around the macula.

Symptoms of diabetic retinopathy

In the early stages, diabetic retinopathy may not cause noticeable symptoms. However, as the condition progresses, symptoms include:

• Blurred/distorted vision
• Floaters or dark spots in vision
• Sudden loss of vision
• Difficulty with colour perception

Diagnosis

History

• Establish the duration of diabetes — the longer a person has had diabetes, the higher the risk of developing diabetic retinopathy.
• Glycaemic control — establish the person’s control over their blood sugars. Poor control over blood sugar levels can increase the likelihood of diabetic retinopathy.
• Associated medical conditions — assess for hypertension, dyslipidaemia, nephropathy and pregnancy which can influence the progression and presentation of diabetic retinopathy.

Examination

• Visual acuity
• Slit-lamp examination
• Dilated fundus examination: this may allow signs of diabetic retinopathy to be identified such as microaneurysms, haemorrhages, exudates and neovascularisation.

Imaging

• Fundus photography: this captures images of the back of the eye, which can be useful for documentation and follow-up comparisons.
• Fluorescein angiography (FA): fluorescein, a dye, is injected into the bloodstream and then images of the retina are captured in rapid succession. This can identify leaking blood vessels, areas of non-perfusion and neovascularisation.
• Optical coherence tomography (OCT): this is a non-invasive imaging which captures cross-sectional images of the retina. It can help detect and quantify retinal thickening and macular oedema, and allows monitoring of responses to treatment.
• Ultrasound: if there is dense vitreous haemorrhage present, obscuring a clear view of the retina, ultrasound can be used to detect retinal detachment or other abnormalities.

Screening

• Type 1 diabetes: screening should begin five years after the onset of diabetes, then annually thereafter.
• Type 2 diabetes: screening should commence at the time of diagnosis, then annually thereafter.
• Pregnant women with pre-existing diabetes: should have a comprehensive eye examination in the first trimester, with follow-up exams throughout pregnancy, as diabetic retinopathy can rapidly progress during pregnancy.

Management

Management of diabetic retinopathy aims to prevent, slow down or reverse the progression of retinal changes and preserve vision. It depends on the stage and severity of disease.

Systemic control

Effective control of systemic factors can slow the progression of diabetic retinopathy and reduce the risk of vision loss.

• Glycaemic control: maintaining optimal blood sugar levels is highly important and involves a combination of dietary modifications, hypoglycaemic agents and insulin.
• Blood pressure control: hypertension accelerates the progression of diabetic retinopathy, so antihypertensive medications and lifestyle changes are essential.
• Lipid control: dyslipidaemia can exacerbate diabetic retinopathy so statins and other lipid-lowering drugs may be used.
• Nephropathy management: diabetic nephropathy is often associated with diabetic retinopathy. Controlling renal disease can also aid in managing retinopathy.

Regular monitoring and screening

• Regular eye examinations: regular eye examinations can detect diabetic retinopathy changes early.
• Patient education: patients should be informed about regular screening and about visual symptoms that should warrant immediate medical attention.

Ophthalmic interventions

The choice of intervention depends on the diabetic retinopathy stage and the presence or absence of diabetic macular oedema.

• Laser Photocoagulation:
• Focal/Grid Laser Treatment: Used for localised diabetic macular oedema. Laser burns are applied directly to leaking microaneurysms or in a grid pattern in areas of retinal thickening.
• Panretinal Photocoagulation (PRP): Used for proliferative diabetic retinopathy (PDR). Laser burns are applied to the peripheral retina, reducing the ischaemic drive and thereby reducing neovascularisation and its complications.
• Anti-VEGF Injections: Agents like ranibizumab (Lucentis), aflibercept (Eylea), and bevacizumab (Avastin) target vascular endothelial growth factor (VEGF), reducing vessel permeability and neovascularisation. They’re injected directly into the vitreous cavity and are especially useful for central DME and PDR.
• Corticosteroid Injections: Intravitreal steroids like triamcinolone or dexamethasone implants can reduce macular oedema. However, potential side effects, such as increased intraocular pressure and cataract progression, necessitate careful patient selection.
• Vitreoretinal Surgery: In advanced cases, especially with non-resolving vitreous haemorrhage or tractional retinal detachment, pars plana vitrectomy is performed to remove blood, scar tissue, and relieve traction.

Emerging therapies

Research continues into new treatments for diabetic retinopathy including oral therapy such as PKC inhibitors and combination therapy such as combining laser, anti-VEGF and steroids to maximise therapeutic benefit.

Lifestyle management

• Smoking cessation: smoking exacerbates diabetic complications. Patients should be counselled and provided resources to quit.
• Diet and exercise: adopting a balanced diet and regular exercise regimen can improve glycaemic control and overall health.

References

1. ‘Diabetic Retinopathy Guidelines’. The Royal College of Ophthalmologists, https://www.rcophth.ac.uk/resources-listing/diabetic-retinopathy-guidelines/. Accessed 22 Sept. 2023.
2. ‘Diabetic Retinopathy – Eye Disorders’. MSD Manual Professional Edition, https://www.msdmanuals.com/en-gb/professional/eye-disorders/retinal-disorders/diabetic-retinopathy. Accessed 22 Sept. 2023.
3. ‘Diabetic Retinopathy: Causes, Symptoms, Treatment’. American Academy of Ophthalmology, 27 Oct. 2022, https://www.aao.org/eye-health/diseases/what-is-diabetic-retinopathy.
4. Safi, Sher Zaman, et al. ‘Molecular Mechanisms of Diabetic Retinopathy, General Preventive Strategies, and Novel Therapeutic Targets’. BioMed Research International, vol. 2014, 2014, p. 801269. PubMed Central, https://doi.org/10.1155/2014/801269.
5. UpToDate. https://www.uptodate.com/contents/diabetic-retinopathy-classification-and-clinical-features. Accessed 22 Sept. 2023.