DIABETIC RETINOPATHY Dr. Kshama Dwivedi Asst. Professor MLNMCollege Allahabad

Diabetes Mellitus Diabetes Mellitus is a group of diseases characterized by high blood glucose levels. Diabetes results from defects in the body's ability to produce and/or use insulin. Type 1 diabetes is usually diagnosed in children and young adults, and was previously known as juvenile diabetes. In type 1 diabetes, the body does not produce insulin. 5% of people with diabetes have this form of the disease. Type 2 diabetes, either the body does not produce enough insulin or the cells ignore the insulin. This is the most common form of diabetes. http://www.diabetes.org/diabetes-basics/?loc=GlobalNavDB

DIABETIC RETINOPATHY About 2% of type 2 diabetics have CSME at diagnosis and 10.2% have other signs of DR already present when their diabetes is discovered. Mitchell and co- workers found that 15.8 % of undiagnosed diabetics in an elderly Australian population had signs of DR, according to the recent Blue Mountains Eye Study. Indeed it may often take from 9-12 years for type 2 diabetes to be diagnosed.

RETINA

Healthy Retina Diabetic Retinopathy

Epidemiology The best predictor of diabetic retinopathy is the duration of the disease 33% of patients with diabetes have signs of diabetic retinopathy People with diabetes are 25 times more likely to become blind than the general population. Ophthalmology Myron Yanoff MD and Jay S. Duker Basic and Clinical Science Course, Section 12: Retina and Vitreous AAO http://www.aao.org/eyecare/news/upload/Eye-Health-Fact-Sheet.pdf -

Ref: A. Foster S. Resnikoff Ref: A. Foster S.Resnikoff. The impact of vision 2020 on global blindness. Eye 2005; 19:1133-1135

DR 20 years AFTER diagnosis After 20 years of diabetes, nearly 99% of patients with type 1 diabetes and 60% with type 2 have some degree of diabetic retinopathy

Ref: Meta analysis and review on the effect on bevacizumab id diabetic macular edema Graefes Arch Clin Exp Ophthalmol(2011) 249:15-27

Pathophysiology Microangiopathy Microvascular occlusion Retinal Ischemia AV Shunt Neovascularisation Capillary leakage and hemorrhage Microaneurysm Retinal Oedema Hard exudates

Microvascular Occlusion Microvascular occlusion is caused by: Thickening of capillary basement membranes Abnormal proliferation of capillary endothelium Increased platelet adhesion Increased blood viscosity Defective fibrinolysis Ref: Retina in systemic disease : a color manual of ophthalmoscopy / Homayoun Tabandeh, Morton F. Goldberg 2009

Microvascular leakage Microvascular leakage is caused by: Impairment of endothelial tight junctions Loss of pericytes Weakening of capillary walls Elevated levels of vascular endothelial growth factor (VEGF) Ref: Retina in systemic disease : a color manual of ophthalmoscopy / Homayoun Tabandeh, Morton F. Goldberg 2009

Diabetic retinopathy symptoms ASYMPTOMATIC INITIALLY As the disease progresses symptoms may include: Blurred vision Floaters Fluctuating vision Distorted vision Dark areas in the vision Poor night vision Impaired color vision Partial or total loss of vision

CLASSIFICATION OF Dr (ETDRS) Non- proliferative Diabetic Retinopathy ( NPDR) -Very mild -Mild -Moderate -Severe -Very severe Proliferative Diabetic Retinopathy ( PDR) with or without high risk

MODIFIED AIRLIE HOUSE CLASSIFICATION

VERY MILD NPDR Microaneurysms only

MILD NPDR Microaneurysm Haemorrhages and exudates upto the level of mod NPDR No IRMA

Moderate NPDR Ret haem. > 20 in 1-3 quadrant Mild IRMA Venous beading =1 quad Cotton wool spots

SEVERE NPDR Severe NPDR (4-2-1 rule) Any of the following > 20 intraret. Heam. in all four quadrants 8- 10 cotton wool spots Definite venous beading in ≥2 quadrants Prominent IRMA in ≥ 1 quadrant

Very severe NPDR Any two or more of the changes in severe NPDR

Microaneurysms Focal dilatations of retinal capillaries, 10-100 microns in diameter, and appear as red dots. Usually seen at the posterior pole, especially temporal to the fovea. First ophthalmoscopically detectable change in diabetic retinopathy. Have a life cycle of 120 days.

Beginning as dilatations in areas in the capillary wall where pericytes are absent, they are initially thin-walled.   Fibrin and erythrocytes may accumulate within the aneurysm. Despite multiple layers of basement membrane, they are permeable to water and large molecules, allowing the accumulation of water and lipid in the retina.

When the wall of a capillary or microaneurysm is sufficiently weakened, it may rupture, giving rise to an intraretinal haemorrhage. If the hemorrhage is deep (i.e., in the inner nuclear layer or outer plexiform layer), it usually is round or oval - “Dot and blot" If the hemorrhage is in the superficial nerve fiber layer, it takes a flame shape. Their presence strongly suggests the co- existence of systemic hypertension. Retinal Haemorrhages

Cotton Wool Spots Cotton wool spots result from occlusion of retinal pre- capillary arterioles supplying the nerve fibre layer with concomitant swelling of local nerve fibre axons. Also called "soft exudates" or "nerve fibre layer infarctions" they are white, fluffy lesions in the nerve fibre layer. FFA shows no capillary perfusion in the area of the soft exudate. They are very common in DR, especially if the patient is also hypertensive.

Cotton Wool Spots

Hard exudates ( Intra-retinal lipid exudates ) They are yellow deposits of lipid and protein within the sensory retina. Hyperlipidaemia may correlate with the development of hard exudates. Actually are tombstones.

Hard exudates ( Intra-retinal lipid exudates ) Lipids leaking from capillaries and microaneurysms may surround the leaking point to form a circinate pattern.

Late non proliferative changes Intra-retinal microvascular abnormalities ( IRMA) are dilated retinal capillaries or intraretinal neovacularization which has not breached the internal limiting membrane of the retina. Venous beading is sausage-shaped dilatation . Venous looping They indicate severe NPDR that may rapidly progress to PDR.

Late non proliferative changes

Diabetic mACULOPATHY (FFA) Focal Diffuse Mixed Ischemic Circinate ( ophthalmoscopic)

Clinically Significant Macular Edema ( CSME) The leading cause of visual loss amongst diabetics. Diagnosed by stereoscopic assessment of retinal thickening, usually by slit lamp biomicroscopy and OCT Laser grid photocoagulation reduces the risk of visual loss by 50% at 2 years

ROLE OF OPTICAL COHERENCE TOMOGRAM

CSME

Ischaemic Maculopathy It is due to drop out of the perifoveal capillaries with non perfusion resulting in ischaemic maculopathy. Irregular enlargement of the foveal avascular zone (FAZ) is seen on fluorescein angiography. Ischaemic Maculopathy  

Ischaemic Maculopathy

Proliferative diabetic retinopathy   Retinal ischaemia due to widespread capillary non perfusion results in the production of vasoproliferative substances and to the development of neovascularization. Bleeding from fragile new vessels can result in vitreous or retinal haemorrhage. Retinal damage can result from persistent vitreous haemorrhage. Pre-retinal haemorrhages are often associated with retinal neovascularization, they may dramatically reduce vision within a few minutes. Proliferative diabetic retinopathy

Proliferative diabetic retinopathy EARLY PDR – Presence of new vessels, criteria not met for high risk High-risk PDR- Any of the following NVD > 1/3rd DD Any NVD with VH or pereretinal haemorrhage NVE >1/2 DD with VH or preretinal haemorrhage HRC were defined by DRS

Rubeosis Iridis

Neovascularisation of disc

Neovascularisation elsewhere

End Stage Disease Contraction of associated fibrous tissue formed by proliferative disease tissue can result in deformation of the retina and tractional retinal detachment

A protocol for diabetic screening and Monitoring Screening doctors should always look for the onset of clinically significant macular oedema (CSME ) Patients without retinopathy should be screened annually after the onset of puberty until the onset of non- proliferative diabetic retinopathy (NPDR).

Diabetic Eye Disease Key Points RECOMMENDED EYE EXAMINATION SCHEDULE Diabetes Type Recommended Time of First Examination Recommended Follow-up Type 1 3-5 years after diagnosis Yearly Type 2 At time of diagnosis Prior to pregnancy (type 1 or type 2) Prior to conception and early in the first trimester No retinopathy to mild moderate NPDR every 3-12 months Severe NPDR or worse every 1-3 months. Diabetic Eye Disease Key Points Treatments exist but work best before vision is lost Abnormal findings may dictate more frequent follow-up examinations

FOLLOW UP EXAMINATION Severity of DR Follow up (mnths) Mild NPDR 12 Mod NPDR 6-12 Sev NPDR 4 PDR High risk PDR ME CSME 1

RISK FACTORS Duration of DM Control of DM; will not prevent but delays Hypertension Renal Disease Pregnancy Obesity Hyperlipidaemia Smoking Anaemia Hyperhomocystienemia

The Effect of Intensive Diabetes Treatment On the Progression of Diabetic Retinopathy In Insulin-Dependent Diabetes Mellitus The Diabetes Control and Complications Trial Research Group Intensive control reduced the risk of developing retinopathy by 76% and slowed progression of retinopathy by 54%; intensive control also reduced the risk of clinical neuropathy by 60% and albuminuria by 54%. Knowing that worse sugar control is associated with worse retinopathy is not quite the same as knowing that good sugar control can alter the natural history of retinal disease. And so the Diabetes Control and Complications Trial Research Group set out to answer this question prospectively. They looked at over 700 diabetic pts with no retinopathy and over 700 pts with mild to moderate retinopathy and treated some with conventional therapy bid shots and some with intensive control qid shots or a pump and found that intensive control reduced risk of developing retinoapthy by 75% and reduced the risk of progression by 54% and that neuropathy and nephropathy were reduced as well. Risk factor control is key. Ref: Arch Ophthalmol. 1995; 113:36-51

Tightening Glycaemic control Tightening of glycaemic control may initially produce worsening of DR. The postulated mechanism includes lowering of retinal blood flow or overproduction of IGF-1 by the liver. So monitoring of DR is increased if major changes to glycaemic control are made particularly in previously poorly controlled diabetics. Ideally HbA1c should be maintained below 7%.

hypertension and DR in type 2 diabetes The risk of reduction of visual acuity was lowered by 47%. Atenolol and Captopril were equally effective in reducing the risk of progression of retinopathy in type 2 diabetics.   The Hypertension Optimal Treatment ( HOT ) study indicates that the lowest incidents of cardiac events occurs when blood pressure is lowered to 82.6 mmHg diastolic and 136 mmHg systolic.

Diabetic nephropathy Diabetic nephropathy accelerates the progression of DR, especially macular oedema, via increased levels of fibrinogen and lipoprotein and associated hypertension The visual prognosis is often better if the nephropathy is managed by renal transplantation rather than by dialysis Any anaemia resulting from renal disease must be aggressively treated.

ANEMIA It is a relevant factor related to the progression of DR The severity of anaemia correlates with the degree of progression

Pregnancy Screening at confirmation of pregnancy and every two months during pregnancy if no retinopathy is present, or monthly, if retinopathy is present. Retinal status should not preclude pregnancy Untreated PDR at the onset do poorly unless they are treated with panretinal photocoagulation. Treated PDR do not worsen during the pregnancy.

ACE inhibitors The EUCLID study - prophylactic treatment of type 1 diabetics with the ACE Inhibitor Lisinopril and the progression of nephropathy and other microvascular disease including DR . Preliminary reports claimed 50% reduction in progression of DR in type 1 diabetics. The study did not look at maculopathy- so that implications are unclear for type 2 diabetics, although no specific advantage of ACE inhibitors (Captopril) over Atenolol was seen in UKPDS.

Hyperlipidaemia and diabetic maculopathy There is evidence in the literature that diabetics who have exudative maculopathy with extensive lipid exudates benefit from active treatment of hyperlipidaemia

Cataract surgery Cataract surgery may lead to progression of pre-existing macular oedema and proliferative diabetic retinopathy. However, cataracts may impede fundoscopy and therefore interfere with the treatment of diabetic retinopathy. If possible, diabetic retinopathy should be treated prior to cataract surgery

DIAGNOSIS CLINICAL FUNDUS EXAMINATION FUNDUS FLUORESCEIN ANGIOGRAPHY (leakage and ischaemia) OPTICAL COHERENCE TOMOGRAPHY (oedema and traction) All three are evaluated simultaneously

Research Studies Eye Institute, Bethesda, USA has supported various trials (DRS, ETDRS. DRVS) Laser treatment is beneficial for DR and vitreous surgery may be beneficial in some. Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR), Diabetes Control and Complications Trial (DCCT), and United Kingdom Prospective Diabetes Study (UKPDS) Intense control of hyperglycemia, control of high blood pressure and lipid control have positive and beneficial effect on prevention / postpone / halting the progression of DR.

DIABETIC RETINOPATHY TREATMENT Once DR threatens vision treatments can include: Laser therapy to seal leaking blood vessels (focal laser) Laser therapy to reduce retinal oxygen demand (scatter laser) Surgical removal of blood and fibrous tissue from the Retinal Surface (Vitrectomy)

Panretinal laser photocoagulation for proliferative DR The mainstay of treatment of PDR is retinal laser photocoagulation, an ablative treatment. Laser therapy is highly effective; the rate of severe visual loss at 2 years due to PDR can be reduced by 60%. Laser photocoagulation causes a retinal burn which is visible on fundoscopy. Retinal and optic disc neovascularization can regress with the use of retinal laser photocoagulation.

Panretinal laser photocoagulation

Laser therapy for CSME   CSME is treated with a macular laser grid or treatment of focal lesions depending on site of leakage revealed on FFA. There is a reduction in the rate of loss of vision by 50% at 2 years with macular grid therapy. Pregnancy is not a contraindication for laser.

INTRAVITREAL INJECTIONS FOR CSME Anti-VEGF Ranibizumab 0. 3-0. 8mg in 0. 0 5ml Bevacizumab 1.25mg in 0. 0 5ml Aflibercept 2mg in 0. 0 5ml Steroid Dexamethasone Implant-Ozurdex 0.7mg

VITRECTOMY Plays vital role in the management of severe complications of diabetic retinopathy. The major indications are nonclearing vitreous hemorrhage, traction retinal detachment, and combined traction/rhegmatogenous retinal detachment. Less common indications are macular edema with a thickened and taut posterior hyaloid, macular heterotopia, and tight preretinal macular hemorrhage.

TAKE HOME MESSAGE Any diabetic can develop DR which is asymptomatic Majority(80%) need only regular follow up and management of systemic risk factors Only 20% need active intervention by retina specialists

Take Home Message Treatment of retinopathy will at the best stabilise vision/ decrease the rate of loss of vision Hence regular screening by general ophthalmolgists may be pivotal in controlling this cause of preventable blindness