Diabetic Retinopathy

1. Diabetic Retinopathy Image Courtesy of National Eye Institute, National Institutes of Health Farhan Zaidi PhD MBBS (Hons) FRCS FRCOphth Consultant Ophthalmologist and Ophthalmic Surgeon Clinical Lead South-West London Diabetic Eye Screening Programme

2. Normal eye Images Courtesy of National Eye Institute, National Institutes of Health

3. What is Diabetes ? • Type 1 – the pancreas stops producing Insulin - an auto-immune condition. Usually this starts in young people / children. • Type 2 – the amount of Insulin is insufficient to control blood sugar, and may be abnormal. Usually this starts in middle age or older people but can happen in young people. 90% of sufferers have Type 2 diabetes. • Gestational – in pregnancy. • Rare – Monogenic diabetes (arising from specific gene defects e.g. MODY and MIDD), cystic fibrosis-related diabetes. Diabetes is a condition where the blood sugar is high. The high blood sugar causes damage to various organs in the body and can cause other complications. Blood sugar is normally regulated by Insulin and Glucagon. Insulin produced from Beta cells in the pancreas causes blood sugar to transit from the extracellular to the intracellular space so reducing circulating levels of sugar and allowing the sugar to be used for energy within cells. In diabetes the production or ability of Insulin to work is ineffective.

4. Insulin The Insulin molecule consists of 2 chains linked by disulphide bonds B Cells in the Islets of Langerhans in the Pancreas secreting Insulin (stained red) Credit: T Blundell and N Campillo / Wellcome Images Credit: Anne Clark, University of Oxford / Wellcome Images

5. Prevalence & Common symptoms Almost 3.6 million people in the UK are diagnosed diabetics, and many are undiagnosed. The rate is increasing as the population becomes more obese and lives longer. Diabetes is a worldwide problem and is increasing rapidly in prevalence and frequency >250 million sufferers. After 20 years of diabetes the vast majority of Type 1 diabetics will have some degree of retinopathy and up to 80% of Type 2 diabetics will. Worldwide 1/3 diabetics have retinopathy of whom 1/3 have sight-threatening retinopathy e.g. macular oedema . • Often asymptomatic – role of Diabetic Eye Screening rogrammes. Screening works by catching treatable disease early. • Thirst, polyuria, itching • Propensity to infections (e.g. skin, urinary, postoperative) • Blurring of vision from retinopathy • Diabetic Cataract – blurred vision, glare • Ketoacidosis (classic presentation of undiagnosed Type 1 Diabetes, rarely Type 2)

6. Risk factors for retinopathy in type 2 diabetes • A persistently high blood sugar (blood glucose) / duration of suffering from diabetes • Hypertension or poorly controlled hypertension (‘blood pressure’) • To a lesser extent dyslipidaemia • Overweight (high Body Mass Index (BMI)) • Pregnancy • Asian or Afro-Caribbean background

7. Important and/or common complications Organs Metabolic and Infective • Keto-acidosis • Non-ketotic hyperglycaemia • Hypoglycaemia from treatment Any of the above can result in coma and death • Infections especially skin e.g. boils, pustules, infections of the feet, carbuncles Macrovascular • Strokes • Myocardial ischaemia / infarcts • Large vessels – peripheral vascular disease Microvascular – no less dangerous than macrovascular disease • Eyes – diabetic retinopathy and papillitis. Microvascular retinopathy shows typical features of micro-occlusive disease – micro-aneuryms, haemorrhages and cotton wool spots • Nerves – peripheral neuropathy and papillitis • Kidneys – microalbuminuria, later frank protein and renal failure

8. Normal layers of the retina in sd-oct Image Courtesy of Retina Gallery

9. Early Changes in Diabetic retinopathy (dR) • Most studies suggest in the first 4 years of diabetes there is a reduction in the calibre of retinal blood vessels, after which they start to dilate. • The higher the HbA1c the lower the retinal perfusion. • Electroretinograms (ERGs) show damage mainly in the inner retina, but in very advanced disease the outer retina also becomes involved. Changes also occur in the ganglion cells. • The retina has 2 vascular sieves in it – the inner and outer blood-retina barriers (BRBs). The outer is formed by junctions between retinal pigment epithelial cells, the inner by junctions between retinal capillaries. The latter are first to break down in diabetic retinopathy, regulated in part by Vascular Endothelial Growth Factor (VEGF). This causes diabetic macular oedema (edema– known as DMO or DME respectively), the commonest cause of sight loss in DR. VEGF is an important target in treatment of DMO. Eventually the outer BRB may also break down. • 2 main pathogenic elements underpin the key histological changes – biochemical dysregulation and a low-grade inflammation.

10. Cellular changes • Damage to the NeuroVascular Unit comprising Ganglion cells, Capillaries and Glia (Muller cells). • Basement Membrane Thickening – loss of structural and biochemical support for vascular endothelial cells and pericytes hence compromising their integrity. • Loss of capillaries – the 3 key cells in the retinal capillaries disintegrate and none repair very well - endothelial cells, pericytes and smooth muscle cells (loss of the latter causes further loss of capillary autoregulation and leakage). Pericytes in the retina are found with substantially greater frequency than other vascular beds in a ratio of 1:1 to endothelial cells. Several biochemical pathways are implicated eg increased polyol pathway activity. • Microaneurysms form – with time they change shape and location and can sclerose. Early lesions show inflammation, an important pathogenic cause of DR alongside the biochemical. • Neural damage – ganglion cell loss, Muller glial cell over-production of glutamate. END RESULT: leakage of fluid from the capillaries (‘exudative DR’), the blood vessels bleed and change shape (venous beading / duplication). Ischaemia (‘ischaemic DR’) may develop which can be followed by growth of new vessels (‘proliferative DR’). The new vessels often bleed and via fibrosis pull on the retina making oedema worse and causing more bleeding and tractional retinal detachment. They can even grow into the drainage angle in the anterior chamber of the eye where they are a cause of rubeotic glaucoma. The natural history and end result without treatment can be an eye with severe sight loss which may also be a blind and potentially painful eye.

11. Normal Appearance of Central Retina Image courtesy National Eye Institute, National Institutes of Health

12. Mapping the retina in disc diameters

13. The Visual World in Severe Diabetic Maculopathy Image courtesy National Eye Institute, National Institutes of Health

14. Maculopathy Exudates in right macula Exudates in left macula (different subject)

15. Peri-Foveal Exudates A small clump of hard exudates very near the fovea leaking from a micro-aneurysm. Despite the small size of these exudates their proximity to the fovea (within one disc diameter) means they require close monitoring and assessment for potential treatment.

16. Mild diabetic retinopathy Scattered micro-aneurysms. Sometimes called ‘background’ retinopathy L superotemporal hard exudates well away from the fovea so of low risk to sight

17. Cotton Wool Spots Once called ‘soft exudates’ they in fact are micro-infarcts in the nerve fibre layer. One is shown in the inferior macula in this image.

18. Typical appearance of severe maculopathy Image Courtesy of Retina Gallery

19. Eyes with macula laser scars Nowadays intravitreal injections are used directly inserted into the eye. At present these are either anti-VEGF agents or steroid-based compounds. Macula laser may still be used in select cases, but there is a risk of ‘burn creep’ over years that can damage central vision if the eye’s ongoing reaction to the burn spreads to involve the fovea. Image Courtesy of Retina Gallery

20. examples of Some venous changes Colour fundus photo Fluorescein angiogram of same fundus Images Courtesy of Retina Gallery

21. Proliferative retinopathy shown in a red-free image Red-free camera light shows anything that is red as black. It is good for studying red structures in the eye like (as here) blood vessels. These are new vessels growing in an area of retinal ischaemia. They need treatment or will bleed and/or pull on the retinal structures (traction) which can cause more bleeding, oedema and tractional retinal detachment.

22. A red-free image of a new vessel

23. Bleeding from Proliferative retinopathy Sub-hyaloid ‘boat-shaped’ pre-retinal bleeding seen through an eye with asteroid hyalosis (an association of diabetes and hyperlipidemia) A combination of sub-hyaloid and intra-retinal bleeding. The darker fundus compared to the adjacent image is a racial feature in heavily pigmented patients

24. Appearance of pan-retinal photocoagulation (‘prp’) laser burns Burns like this can cause loss of peripheral vision (while diabetic maculopathy affects central vision) This type of laser can lead to a diabetic not being able to drive or perform some occupations If proliferative diabetic retinopathy is caught early (for example by patients attending for Diabetic Eye Screening) then with careful treatment after a few years the retinopathy ‘burns out’ and vision can be saved with often no need for further treatment for life.

25. Examples of eyes that have vitreous haemorrhage from proliferative dr This eye has a plume of blood in the vitreous coming from new vessels growing at the optic disc In this eye the fundus is hard to visualise as the vitreous contains a lot of blood. Sometimes the fundus may not be visible at all. Such eyes may need surgical drainage of blood if it does not resolve (typically by about 3 months)

26. Diabetes control of risk factors • Recommended HbA1c range for most diabetics - under 48 mmols/mol (under 6.5%). • If at risk of hypoglycaemia patients may be advised by their doctors to keep their HbA1c below 59 mmols/mol (under 7.5%). • Blood pressure – treat it if raised (approximately >140/90). Lisinopril can reduce risk of diabetic retinopathy - in Type 1 normotensive diabetics it reduced progression to diabetic retinopathy in studies. But most physicians do not advise reducing blood pressure in normotensive diabetics to reduce the risk of retinopathy. • Control of dyslipidaemia is probably beneficial. • Stopping Glitazones may be beneficial for macular oedema (controversial) – worth trying if macular oedema develops provided systemic control permits.

27. Early detection - Screening grades The UK has a national screening programme run by the National Health Service (NHS). Since 2003 approx. 2.3 million diabetics are invited annually for photography of the type just shown using fundus cameras based in the community at screening locations near to where patients live. The benefits: diabetes was the leading cause of blindness in people of working age for half a century – owing to the National Screening Programme by 2014 this was no longer the case. All diabetics aged 12 or above are invited for screening unless they opt out. Early detection works. Screening involves dilating the pupil usually with Tropicamide 1% eye drops and taking 2 photos - of the central and nasal retina. Patients are seen annually and those at higher risk seen more often or sent into hospital. The basic screening terminology is to grade eyes using: R Retinopathy R1 (‘background’), R2 (‘pre-proliferative’) or R3 (‘proliferative) which can be R3active or R3stable M Maculopathy – M0 or M1 (clinically significant) P Previous laser scars

28. Healthy Lifestyle changes in diabetics • Exercise • Diet • Reduce and Prevent Stress

29. Diet Image courtesy National Eye Institute, National Institutes of Health

30. Diet for diabetics and those at risk • Take a well-balanced diet. • Reduce the amount of sugars and processed carbohydrate. • Remember starches get converted to sugar in the body – bread, potatoes, pasta, rice are all starchy and should be taken in moderation. Sugars come in seemingly ‘healthy’ forms – fruits and fruit juices – both are good as they have vitamins and trace elements but must be taken in moderation by diabetics. • A good diet for a diabetic or someone at risk of it will contain lots of green vegetables and white meat (chicken) and fish. ‘Slow release carbs’ like pulses / lentils (‘daal’) are useful. • Remember, these are guidelines. If a diabetic is suspected to be having a hypoglycaemic attack give them sugar or sugary foods – the brief hyperglyacaemia will save their life and won’t harm them in the long-term. It is long-term control of sugar levels that is important.