Diabetic retinopathy

Diabetic retinopathy - introduction,type, risk factors, etdrs classification, airlie classification , diabetic macular edema, dme treatment, diabetic retinopathy screening, diabetic retinopathy studies , diabetic retinopathy treatment, anti-vegf injections

1. DIABETIC RETINOPATHY BY DR ANJALI MAHESHWARI

2. INTRODUCTION Classification of diabetes is as follows:  Type 1 diabetes  T ype 2 diabetes  Gestational diabetes Other less common types of diabetes are monogenic and secondary diabetes.

3. Diabetes Mellitus (DM) is a systemic disease characterized by the presence of hyperglycemia, caused by impaired insulin secretion, defective insulin action or both. Chronic elevated blood sugar level in diabetes is associated with microvascular complications involving the eyes, kidneys, nerves, and increased cardiovascular complications.

4. Diagnosis and classification of diabetes is based on glycemic levels and microvascular disease, particularly retinopathy.

5. PREDIABETES Not a diagnosis but a condition which places the individual at risk of developing diabetes and its complications. The risk factors for prediabetes are the same as for Type 2 diabetes (obesity, poor diet, lack of exercise, family history, and smoking) Prediabetes is also caused by decreased insulin sensitivity or increased insulin resistance.

6. Prediabetes is a term used for E levated blood glucose levels above the normal range and below the diabetes diagnostic thresholds that meets the criteria for impaired glucose tolerance (IGT) b ased on :  Two-hour post 75-gram oral glucose load, or  I mpaired fasting glucose (IFG), or  Glycated hemoglobin (A1c) of 6.0% to 6.4%.

7. TYPE 1 DM Type 1 is an autoimmune disease and is associated with decreased insulin production by the pancreas. Insulin is the hormone that allows glucose from food to be absorbed and used as fuel by the cells of the body. As a result, the body cannot control the blood sugar levels.

8. CHARACTERESTIC OF TYPE 1 DM Its onset is early childhood or juvenile and it is insulin dependent (IDDM). It usually affects people of younger age (10-20 years of age). It is treated with insulin replacement and recently with organ transplant. It is the less common type of diabetes and only 5-10% of people living with diabetes have Type 1 diabetes.

9. TYPE 2 DM Metabolic disorder and is associated with a decreased response to insulin by target tissues (liver, muscles, and adipose/fat). Body becomes progressively more resistant to insulin. The pancreas tries to overcome the resistance by producing even more insulin to keep stable glucose levels. With time, there is pancreatic damage leading to lower insulin production and compromising glycemia .

10. CHARACTERSTIC OF TYPE 2 DM It is usually adult onset (NIDDM). It most frequently affects people of middle and working age (50 -70 years of age).  It is treated with oral medications and possibly with insulin. It is the more common type of diabetes, about 90-95% of people living with diabetes have Type 2 diabetes. Type 2 diabetes more likely occurs among obese people and people with genetic predisposition; some ethnic groups have higher incidence of Type 2 diabetes.

11. PATHOGENESIS It is a microangiopathy caused by effect of hyperglycemia on small blood vessels leading to – • Retinal capillary occlusion • Retinal capillary leakage

12. CAPILLARY Abnormalities Characterized by- • Death of pericytes • Thickening of capillary basement membrane ( sorbitol pathway) • Loss of vascular smooth muscle cells (capillary acellularity ) • Endothelial proliferation • Abnormalities of RBCs (leading to defective oxygen transport) and WBCs • Increased platelet stickiness and adhesion Increased plasma viscosity • Defective fibrinolysis and prolonged clot lysis time

13. CELLULAR DAMAGE Caused by- • Sorbitol accumulation (Glucose Sorbitol ) • Free radical mediated oxidative stress • Accumulation of advanced glycation end products (AGEs) • Excessive activation of protein kinase C and diacyl glycerol Aldose reductase

14.  BREAKDOWN OF BLOOD RETINAL BARRIER Blood retinal barrier is composed of 2 parts:  Inner BRB – tight junctions of retinal capillaries, endothelial cells  Outer BRB – tight junctional complexes ( zonula occludens and zonula adherens ) located between adjacent RPE cells Breakdown of this BRB leads to leakage of lipoproteins responsible for formation of exudates.

15. RISK FACTORS Non modifiable risk factor  Duration most important risk factor associated with the development of diabetic retinopathy.

16. For Type 1 DM: At the time of diagnosis, it is uncommon to have DR. 25% of patients will have DR after 5 years, 60% after 10 years and 80% after 15 years 50% of patients under 30 years old will develop PDR if duration of DM is 20 years or more (WESDR) 18% of patients after 15 years of diagnosis will develop PDR with no difference between type 1 and 2

17. For Type 2 DM: At the time of diagnosis about 5% will already have DR. Patients >30 year 19 years, percentages are 84% and 53% respectively. PDR will develop in 2% of patients if duration of DM is < 5 years and 25% if > 25 years

18. Age of onset Age is a major risk factor for diabetes. Type 1 diabetes - usually diagnosed in the second to third decade of life. Type 2 diabetes - risk increases with age. Testing should begin at age 45 for all patients, particularly those who are overweight or obese.

19. Genetic factor and ethnicity Some epidemiological studies have suggested a link between genetics and the risk of developing diabetes. HLA DR 3 & 4 more prone Research shows that diabetes is more common in some ethnic groups such as: African Americans, Native Americans, Asians, Pacific Islanders, and Hispanic Americans.

20. Cystic fibrosis and hemochromatosis are genetic conditions that can damage the pancreas resulting in the secondary development of diabetes.

21. Modifiable risk factors  Diabetic control / HbA1c Key modifiable risk factor Recommendation: Hb A1c 7% or 6.5% in selected cases

22. Studies have shown that: Tight control has preventive value for retinopathy. Improving control does not reverse existing retinopathy. Sudden tight control may inversely cause rapid progression of retinopathy.

23. Blood pressure High blood pressure or high cholesterol -greater risk of developing diabetic retinopathy. Various studies have established guidelines for hypertension in diabetes: Intensify therapy aiming for systolic ≤ 130mmHg in those with established retinopathy and/or nephropathy. Encourage regular monitoring of blood pressure in a health care setting and at home if possible.

24. Lipid level Patients with Type 2 diabetes have an increased prevalence of lipid abnormalities which contributes to a higher risk of cardiovascular disease. Decreasing lipid levels - reduce the risk of progression of diabetic retinopathy, especially macular edema and exudation.

25. Results of various studies recommended the following for lipid management of diabetes: For patients with overt cardiovascular disease, it is recommended to have LDL < 70mg/ dL . For patients without overt cardiovascular disease, it is recommended to have LDL < 100mg/ dL . The lowering of LDL levels can be achieved through lifestyle modifications and use of statin therapy.

26. Pregnancy Gestational diabetes does not require an eye examination during pregnancy and does not increase the risk of diabetic retinopathy. Diabetic retinopathy can worsen during pregnancy; patients should have an eye examination before pregnancy and during the first trimester. If a patient has no retinopathy or mild to moderate NPDR, examinations should be performed every 3 to 12 months.

27. If a pregnant patient has severe NPDR or worse, eye examinations should be performed every 1 to 3 months. If neovascularization is detected during pregnancy, laser therapy should be performed. Macular edema in pregnant patients can improve with delivery, no intravitreal anti-VEGF is recommended. Consider intravitreal steroids. Diabetic retinopathy in a pregnant patient is not a contraindication for natural vaginal delivery.

28. Lifestyle Eating the wrong food, inactivity, and being overweight are all contributing factors to diabetes Type 2. Poor diet (high in calories, fat, and cholesterol) increases body’s resistance to insulin leading to the development of diabetes. Symptoms of Type 2 diabetes can frequently be controlled by lifestyle changes – losing weight, healthy diet, and exercise.

29. Cataract surgery  W hen performed in diabetic patients may lead to relatively rapid progression of DR, precipitate vitreous hemorrhage, induce iris neovascularization , and ultimately lead to decrease or loss of vision  Where cataract surgery is undertaken before lens opacities obscure adequate macular assessment preventing the recognition of retinal thickening, the risk of DME is decreased and the visual outcome may be improved considerably.

30. Nephropathy Obesity Anemia Smoking Metabolic harmones - leptin , adiponectin Oxidative stress Vitamin D deficiency Local inflammatory factors

31. modified Airlie House Classification It was modified for use in the Early Treatment of Diabetic Retinopathy Study (ETDRS) It is based on grading of stereophotographs of 7 fields and classifies DR into 13 complex levels ranging from level 10 (absence of retinopathy) to level 85 (severe vitreous hemorrhage or retinal detachment involving the macula)

32. CLASSIFICATION OF DIABETIC RETINOPATHY Modern ETDRS classification  Mild NPDR Earliest stage where microaneurysms occur. Defined as presence of at least one microaneurysm on retinal exam. Use of red free light for examination helps better appreciation of the early changes in DR.

33. Moderate NPDR Progressively b lood vessels that nourish the retina are blocked Moderate NPDR is characterized by lesions like dot-and-blot hemorrhages, venous beading, and/or cotton wool spots.

34. Severe NPDR - “4-2-1 rule” Microaneurysm /hemorrhages in 4 quadrants Venous beadings in 2 quadrants IRMA in ! quadrant

35. Proliferative DR hallmark of PDR is the presence of extraretinal neovascularization on the retinal surface or fibrous tissue on the inner retina, disc or into the vitreous. Due to chronic ischemia, the retinal cells respond by releasing angiogenic signals such as vascular endothelial growth factor (VEGF). VEGF triggers the growth of new blood vessels referred to as neovascularization .

36. These new vessels are abnormal and fragile. The new vessels from the retina may extend into the vitreous and as the vitreous shrinks with age, it can pull the fragile vessels leading to retinal tears and vitreous hemorrhage. The new vessels may also scar and form fibrotic changes and can lead to tractional retinal detachment.

37. Characteristics of PDR:  Neovascularization  Vitreous hemorrhage  Fibrous proliferation  Membranes and scar tissue formation  Tractional retinal detachments  Neovascularization of the iris and angle ( neovascular glaucoma)  Can have all NPDR findings, including macular edema

38. Diabetic macular oedema DME may occur with NPDR or PDR. Involves retinal thickening of the macula and is the major vision threatening complication. Swelling of the macula is caused by the leakage of fluid and blood through the walls of dilated blood vessels.

39. DME can be classified as  Focal -discrete and has a clearly identifiable source and is is due to leak from microaneurysms .  Diffuse - usually involves large areas and/or more central in location with occult leakage pattern and is due to leakage from the capillaries.  Ischemic  Mixed

40. Clinically significant macular oedema :  Retinal edema within 500 um of foveal centre  Hard exudates with adjoining retinal thickening within 500um of fovea  1 disc diameter of retinal edema encroaching within 1 disc diameter (1500um) of foveal centre.

41. ACCORDING TO ICO

42. OCT based classification of DME Type 1 : Focal macular thickening Type 2 : Diffuse non cystoid macular thickening Type 3 : Diffuse cystoid macular thickening Type 4 : Tractional macular edema due to:  4a : Posterior hyaloid traction  4b : Epiretinal membrane Type 5 : Serous retinal detachment

43. DME is more likely to be seen in patients with :  PDR  Poor glycemic control  Poor blood pressure control  S ignificant retinal ischemia.

44. TERMINOLOGIES COMMONLY USED  Simple Background DR Microaneurysms Hemorrhages- dot blot , flame shaped Hard exudates – arranged in circinate pattern Retinal edema (In the OPL)

45. Preproliferative DR Venous beading and looping Dark blot hemorrhages Multiple cotton wool spots IRMA ( Intra retinal microvacular anamolies ) adjacent to areas of capillary non-perfusion.

46. Proliferative DR Neovascularization on disc and elsewhere Vitreous hemorrhage , subhyaloid hemorrhage\ Tractional and combined RD

47. Diabetic maculopathy  Diffuse retinal edema is caused by extensive capillary leakage and localized edema is caused by focal leakage from microaneurysms and dilated capillary segments.  The fluid is initially located between outer plexiform and inner nuclear layers; later it may also involve the inner plexiform and the nerve fibre layers, until eventually the entire thickness of the retina becomes edematous.

48. Diabetic maculopathy Focal maculopathy - focal leakage causing hard exudate formation Diffuse maculopathy – diffuse macular edema Ischemic maculopathy – extensive macular capillary non-perfusion. Mixed

49. FOCAL DIABETIC MACULOPTHY  SIGNS:  Micro aneurysm  Hemorrhages  W ell circumscribed macular edema  hard exudates arranged in a circinate pattern. FA: Focal area or hyperfluorescence due to leakage and good macular perfusion.

50. FOCAL DIABETIC MACULOPTHY

51. DIFFUSE DIABETIC MACULOPATHY SIGNS: Diffuse retinal edema and thickening throughout the posterior pole with relatively few hard exudates. FA: Extensive hyper fluorescence at the posterior pole due to leakage.

52. ISCAHEMIC DIABETIC MACULOPATHY It occurs due to microvascular blockage. SIGNS:  micro aneurysms  dot and blot hemorrhage  mild or no macular edema and few hard exudates. FA: capillary non perfusion at the fovea and frequently other areas of capillary non-perfusion at the posterior pole and periphery.

53. TERMINOLOGIES Microaneurysms  E arliest clinically detectable lesions in the early stages of retinopathy.  Local distensions of retinal capillaries described as outpouchings of capillary walls seen as tiny, round red dots of varying size.  R eflect an abortive attempt to form a new vessel or simply be a weakness of capillary vessel wall through loss of normal structural integrity.  U ndetectable on OCT or present as a small area of hyper-reflectivity in the inner retinal layers

54. Dot - Blot hemorrhages  F ormed where clusters of capillaries occlude, leading to formation of intraretinal blot hemorrhages.  O ccur throughout the full thickness of the retina.  These hemorrhages are considered to represent a deep retinal infarct.  Dot haemorrhages lie deeper in the retina than blot haemorrhages and can be difficult to distinguish from microaneurysms  may be undetectable on OCT or present as an area of hyper-reflectivity. 

55. Hard exudates (lipid deposit)  D eposits of extravasated lipoproteins and lipid filled macrophages in the outer plexiform layer.  They often appear in clusters or rings.   Appear as hyper-reflective deposits in the outer retina

56. Soft exudates  A lso called cotton wool spots or micro-infarctions, appear when terminal retinal arterioles are obstructed.  small, whitish lesions with blurry edges.  O ccur most frequently where the nerve fiber is densest such as the nasal side of the optic nerve.  R esult from ischaemia in the retinal nerve fibre layer (RNFL)

57. Intraretinal microvascular anomalies (IRMA) - D ilated capillary remnants following extensive closure of the capillary network between arteriole and venule . Associated features include:  Venous beading  - venous caliber changes consisting of alternating areas of venous dilation and constriction. Represent foci of venous endothelial cell proliferation that failed to develop into new vessels.

58.  Venous reduplication  - rare finding and occurs in conjunction with venous beading.  Venous loops  - due to small vessel occlusion and opening of alternative circulation.

59.  Retinal pallor  - noted most in hindsight on red-free photographs and on fluorescein angiography, mostly temporal to the macula in patients with unexplained presence of new vessels.  White lines   often accompany retinal pallor and represent thrombosed arterioles. White lines are also found in areas of extensive capillary closure.

60. SCREENING GUIDELINES The recommendations of the American Academy of Ophthalmology Preferred Practice Pattern® Guidelines states :  Type 1 diabetes should have annual screenings for diabetic retinopathy beginning 5 years after the onset of their disease  Type 2 diabetes should have a prompt examination at the time of diagnosis and at least yearly examinations thereafter

61. The 2017 Guidelines for Diabetic Eye Care developed by the International Council of Ophthalmology (ICO) address the needs and requirements for the following levels of service:  High-Resource Settings: Advanced or state-of-the-art screening and management of DR based on current evidence and clinical trials.  Low- and Intermediate-Resource Settings: Essential or core to mid-level service for screening and management of DR with consideration of availability and access to care in different settings.

62. Who should screen? Ophthalmologist Physician Optometrist/ Ophthalmic assistant: Who have skill of screening of DR learnt either during his training or after training by a doctor engaged in screening. Any field level worker or health volunteer: Who either had training in grading images at any institution or has been trained with doctor engaged in active screening for at least 3 months.

63. How to screen? Indirect Ophthalmoscopy Slit-lamp bio microscopic examination Dilated Direct Ophthalmoscopy Non- Mydriatic photography Mydriatic photography Hand held fundus cameras

64. Whom to screen? People with known diabetes. Foe screening DR, it is not cost effective to first screen for Diabetes and then retinopathy. Opportunistic screening: Screening for DR in all patients attending an eye clinic Mass screening: Having specific camps for DR screening as an outreach activity in individuals having 2 hourpost prandial Glucose (PP2BS) >140 mg/dl or fasting blood sugar (FBS) >110 mg/dl.

65. Minimum Screening Components Current guidelines for the minimum screening components include a screening vision examination (before pupil dilation) and a retinal examination sufficient for DR classification .

66. The screening vision exam include :  Refracted visual acuity examination using a 3- or 4-meter visual acuity lane and a high contrast visual acuity chart.  Presenting visual acuity examination using a near or distance eye chart and a pinhole option if visual acuity is reduced.  Presenting visual acuity examination using a 6/12 (20/40) equivalent handheld chart consisting of at least 5 standard letters or symbols and a pinhole option if visual acuity is reduced.

67. Detailed Ophthalmic Assessment of Diabetic Retinopathy Initial Patient Assessment  Detailed patient assessment should include: Visual acuity Identification and grading of severity of DR and presence of DME for each eye Patient history focused on diabetes and its modifiers

68. Patient History (Key Elements) • Duration of diabetes • Past glycemic control (hemoglobin A1c) • Medications (especially insulin, oral hypoglycemics , anti hypertensives , and lipid-lowering drugs) • Systemic history (e.g., renal disease, systemic hypertension, serum lipid levels, pregnancy) • Ocular history

69. Initial Physical Exam (Key Elements) • Visual acuity • Measurement of intraocular pressure (IOP) • Gonioscopy when indicated (e.g., when neovascularization of the iris is seen or in eyes with increased IOP) • Slit-lamp bio microscopy • Fundus examination

70. Fundus Examination Assessment Methods  Tw o most sensitive methods for detecting DR are retinal photography and slit-lamp bio microscopy through dilated pupils.  Both depend on interpretation by trained eye health professionals

71. REFERAL GUIDELINES Visual acuity below 6/12 (20/40) or symptomatic vision complaints. If visual acuity or retinal examination cannot be obtained at the screening examination: refer to ophthalmologist Patients who have had laser treatment should also be referred for ophthalmic review

72. SCREENING IN SPECIAL CONDITIONS Pregnancy Cataract

73. pREGNANCY Development of DR is a significant risk in pregnancy. The following are recommendations:  Patients with preexisting diabetes planning pregnancy should be informed of the need for assessment of DR, both before and during pregnancy.  Pregnant women with preexisting diabetes should be offered retinal examination following their first antenatal clinic appointment and again at 28 weeks gestation if the first assessment is normal.  If any DR is present, additional retinal examination should be performed again at 16-20 weeks gestation.

74. Note: Diabetic retinopathy should not be considered a contraindication to rapid optimization of glycemic control in women who present with a high HbA1c in early pregnancy. Diabetic retinopathy should not be considered a contraindication to vaginal birth. The main treatment for PDR and DME in pregnancy is blood glucose control and laser. There is very limited data on the safety of the use of anti-VEGF during pregnancy. Anti-VEGF is contraindicated in pregnancy.

75. cataract DR and DME progress more rapidly after cataract surgery. The following are proposed guidelines for management:  Mild cataract Carefully assess DR status. Patients without vision loss and with a clear view of the fundus may not require cataract surgery.  Moderate cataract Carefully assess DR status. Before cataract surgery, attempt to treat any severe NPDR with laser PRP, and/or DME with focal/grid laser or anti-VEGF therapy. Consider cataract surgery to improve vision once DR or DME is stable.

76.  Severe-to-advanced cataract with poor view of the fundus If DR status cannot be adequately assessed, consider early cataract surgery followed by assessment and treatment as necessary. If DME is present, consider intravitreal anti-VEGF/steroids prior to, at the time of, or after cataract surgery if DME is discovered when the media is cleared.

77. FOLLOW UP GUIDELINES IN INDIAN SETTING

78. Follow-Up Schedule for Low- to Intermediate-Resource Settings

79. Follow-Up Schedule for High-Resource Settings

80. Follow-up Examination Follow-up History Visual symptoms Glycemic status ( Haemoglobin A1c) Systemic status (e.g., pregnancy, blood pressure, serum lipid levels, renal status)

81. Follow-up Physical Exam • Visual acuity • Measurement of IOP • Gonioscopy when indicated • Slit-lamp bio microscopy • Fundus examination

82. Ancillary Tests  Fluorescein angiography is not needed to diagnose DR, proliferative DR or DME, all of which are diagnosed by means of the clinical exam.  Fluorescein angiography can be used as a guide for treating DME and as a means of evaluating the cause(s) of unexplained decreased visual acuity.  Fluorescein angiography can also identify macular capillary non-perfusion or sources of capillary leakage resulting in DME as possible explanations for visual loss.  OCT is the most sensitive method to identify sites and severity of DME.

83. Patient Education  Discuss results or exam and implications.  Encourage patients with DM but without DR to have annual screening eye exams.  Inform patients that effective treatment for DR depends on timely intervention, despite good vision and no ocular symptoms.  Educate patients about the importance of maintaining near-normal glucose levels, near-normal blood pressure and to control serum lipid levels.

84.  Communicate with the general physician (e.g. family physician, internist or endocrinologist) regarding eye findings.  Provide patients whose conditions fail to respond to surgery and for whom treatment is unavailable with proper professional support (i.e. offer referrals for counseling, rehabilitative, or social services as appropriate).  Refer patients with reduced visual function for vision rehabilitation and social services.

85. STUDIES RELATED TO DIABETIC RETINOPATHY

86. Diabetes Control and Complications Trial - DCCT (1983) Purpose  Effect of tight glycemic control on complications of diabetes for persons with type 1 diabetes Inclusion criteria  DM, age 13–39 years  Absence of hypertension  Hypercholesterolemia  Severe diabetic complications

87. Result  Intensive therapy delays the onset and slows the progression of microvascular complications of diabetes (diabetic retinopathy, nephropathy, and neuropathy) in IDDM

88. United Kingdom Prospective Diabetes Study - UKPDS (1977) Purpose  To determine whether the risk of cardiovascular and microvascular complications in type 2 diabetes can be reduced by intensive blood glucose control.  In patients with high blood pressure, to determine whether the risk of complications can be reduced by tight control of blood pressure.  To determine if any specific treatment for type 2 diabetes like sulfonylureas (first or second generation), metformin , or insulin or anti- hypertensives like ACE inhibitor ( captopril ) or β- blocker ( atenolol ) confer any particular benefit.

89. Inclusion criteria Newly diagnosed type 2 diabetes patients Result Intensive blood glucose control and tight blood pressure control reduces the risk of diabetic complications, the greatest effect being on microvascular complications

90. Wisconsin Epidemiological Study of Diabetic Retinopathy- WESDR (1979) Purpose  Prevalence, incidence, and progression of diabetic retinopathy and its component lesions along with visual loss Inclusion criteria  Patients with diabetes diagnosed before 30 years of age  Diabetics diagnosed at 30 years of age or older

91. Result  71% of younger-onset persons had retinopathy.  In the older-onset group, 50% had retinopathy  6% of the younger and 5% of the older-onset subjects had CSME  Both the frequency and severity of retinopathy and CSME increased with increasing duration of diabetes

92. Epidemiology of Diabetes Interventions and Complications - EDIC Purpose  To examine the persistence of the original treatment effects 10 years after the DCCT Inclusion criteria Patients aged 19–45 years, who were participants of the DCCT Result  The persistent difference in diabetic retinopathy between former intensive and conventional therapy continues for at least 10 years but may be waning

93. Appropriate Blood Pressure Control in NIDDM - ABCD (1993) Purpose  Intensive BP control vs moderate control in the prevention and progression of nephropathy, retinopathy, cardiovascular disease, and neuropathy in NIDDM Inclusion criteria  Hypertensive subjects with NIDDM Result  The more intensive blood pressure control decreased all-cause mortality

94. Diabetic Retinopathy Study - DRS Purpose  To determine if photocoagulation helps in preventing severe visual loss from proliferative diabetic retinopathy (PDR).  To determine if difference exists in the efficacy and safety of argon versus xenon photocoagulation for PDR. Inclusion criteria  BCVA of 20/100 or better in each eye and the presence of PDR in at least one eye or severe NPDR in both eyes

95. Result  Photocoagulation reduced the risk of severe visual loss by 50% compared with no treatment.  Xenon laser resulted in more harmful effects than Argon laser. Defined high risk PDR  Eyes with high-risk PDR should receive prompt PRP

96. Early Treatment Diabetic Retinopathy Study -ETDRS (1979) Purpose:  Determine best time to initiate PRP in DR  Efficacy of photocoagulation in DME  Effectiveness of aspirin in altering course of DR. Inclusion criteria  Patients with moderate or severe NPDR or mild PDR in both eyes and with  visual acuity of 20/40 or better (20/200 or better if macular edema was present)

97. Result  Scatter treatment is not indicated for eyes with mild to moderate NPDR. Scatter treatment should be considered in severe NPDR or early PDR. Scatter treatment should be performed without delay for high-risk PDR Focal photocoagulation is recommended for eyes with CSME (reduces risk of MVL to half) Aspirin had no effect on DR

98. Diabetic Retinopathy Vitrectomy Study - DRVS (1976) Purpose  Early vitrectomy vs conventional management for recent severe vitreous hemorrhage  Early vitrectomy vs conventional management for eye with good vision but a poor prognosis Inclusion criteria  Extensive active neovascular or fibrovascular proliferations and visual acuity of 10/200 or better

99. Result Early vitrectomy is of benefit especially in those with both fibrous proliferations and at least moderately severe new vessels, in which extensive scatter photocoagulation has been carried out or is precluded by vitreous hemorrhage

100. Diabetic Retinopathy Clinical Research Network (DRCR.net) The Diabetic Retinopathy Clinical Research Network (DRCR.net) is a collaborative network dedicated to facilitating multicenter clinical research of diabetic retinopathy (DR), diabetic macular edema (DME) and associated conditions. It supports the identification, design, and implementation of multicenter clinical research initiatives focused on diabetes induced retinal disorders.

101. Protocol A: Pilot Study of Laser Photocoagulation for Diabetic Macular Edema (DME) Purpose  To compare 2 laser photocoagulation techniques for treatment of DME: the modified Early Treatment Diabetic Retinopathy Study ( mETDRS ) technique and a mild macular grid (MMG) technique. Result  At 12 months after treatment, the MMG technique was less effective at reducing retinal thickening than the current mETDRS laser photocoagulation approach. VA outcome with both approaches was not considerably different.

102. Application to Clinical Practice Modified ETDRS photocoagulation should continue as a standard approach for treating DME.

103. Protocol B: Randomized Trial Comparing Intravitreal Triamcinolone Acetonide (IVTA) and Laser Photocoagulation for DME Purpose  To evaluate the efficacy and safety of 1 mg and 4 mg doses of IVTA in comparison with focal/grid photocoagulation (LP) for DME.

104. Result  Over a 2 as well as 3 year period, LP was more effective and had fewer side effects than 1 mg or 4 mg doses of IVTA for most patients with DME.  Most eyes receiving 4 mg of IVTA were likely to require cataract surgery. Application to Clinical Practice  The results of this study also support that focal/grid photocoagulation currently should be the benchmark of treatment of DME.

105. Protocol C: Temporal Variation in OCT Measurements of DME Purpose  To evaluate diurnal variation in OCT measured retinal thickness in centre involving DME Result  Although on average there are slight decreases in retinal thickening during the day, most eyes with DME have little meaningful change in OCT CMT between 8 am and 4 pm. Application to Clinical Practice  The clinical impact of diurnal variation of macular edema is likely to be small and not significant8

106. Protocol D: Evaluation of Vitrectomy for DME Purpose  To evaluate vitrectomy for DME in eyes with at least moderate vision loss and vitreomacular traction (VMT). Result Following vitrectomy performed for DME and VMT, retinal thickening was reduced in most eyes. ---Between 28% and 49% of eyes were likely to have improvement of VA, while between 13% and 31% are likely to have worsening Results suggested that removal of ERM may favourably affect visual outcome after vitrectomy . The surgical complication rate is low

107. Application to Clinical Practice  Vitrectomy performed for eyes with at least moderate vision loss and VMT usually result in a reduction in macular thickening.  VA results are less consistent with some eyes improving and some eyes worsening.

108. Protocol E: A Randomized Trial of Peribulbar Triamcinolone Acetonide (TA) with and without Focal Photocoagulation for Mild DME—a Pilot Study Purpose  To provide data on the safety and efficacy of anterior or posterior sub- Tenon’s injections of TA either alone or in combination with focal photocoagulation in the treatment of mild DME.

109. Result  In cases of DME with good VA, peribulbar TA, with or without focal photocoagulation, is unlikely to be of substantial benefit.  Based on these results, a phase 3 trial to evaluate the benefit of these treatments for mild DME was not justified. Application to Clinical Practice  It is unlikely that significant clinical benefit exists for peribulbar TA in cases of DME with good VA.

110. Protocol F: Observational Study of the Development of DME Following Scatter Laser Photocoagulation Purpose  To compare the effects of single-sitting vs. four-sitting panretinal photocoagulation (PRP) on macular edema in subjects with severe nonproliferative or early proliferative DR with relatively good VA and no or mild center involved macular edema

111. Result  Clinically meaningful differences are unlikely in OCT thickness or VA following application of PRP in 1 sitting compared with 4 sittings in subjects in this cohort. Application to Clinical Practice  PRP for diabetic retinopathy can be safely administered in a single sitting in patients with relatively good VA and no or mild preexisting center involved DME

112. Protocol G: Subclinical Diabetic Macular Edema Study Purpose  To determine the rate of progression of eyes with subclinical DME to clinically apparent DME or DME necessitating treatment during a 2-year period. Result  study suggests that between one-quarter and one-half of eyes with subclinical DME will progress to more definite thickening or be judged to need treatment for DME within 2 years after its identification. Application to Clinical Practice  Patients with subclinical DME should be monitored more closely for progression.

113. Protocol H: Phase 2 Randomized Clinical Trial of Intravitreal Bevacizumab (IVB) for DME Purpose  To provide data on the short-term effect of IVB for DME Result  IVB can reduce DME in some eyes, but the study was not designed to determine whether treatment is beneficial.

114. Protocol I: Laser- Ranibizumab - Triamcinolone Study for DME Purpose To evaluate intravitreal 0.5 mg ranibizumab or 4 mg triamcinolone combined with focal/grid laser compared with focal/grid laser alone for treatment of DME Result  Intravitreal Ranibizumab with prompt or deferred laser is more effective at 2 year compared with prompt laser alone for the treatment of DME involving the central macula.  In pseudophakic eyes, intravitreal triamcinolone + prompt laser seem more effective than laser alone but frequently increase the risk of IOP elevation.

115. Application to Clinical Practice  Ranibizumab  should be considered for patients with DME including vision impairment with DME involving the center of the macula.

116. Protocol J: Laser- Ranibizumab - Triamcinolone Study for DME + PRP Purpose  To evaluate 14 weeks intravitreal ranibizumab or TA in eyes receiving laser photocoagulation (LP) for DME and PRP Result  The addition of 1 IVTA or 2 ranibizumab  injections in eyes receiving LP for DME and PRP is associated with better VA and decreased DME by 14 weeks.  Whether continued long-term intravitreal treatment is beneficial could not be determined from this study.

117. Application to Clinical Practice  The risk of short-term exacerbation of macular edema and associated VA loss following prompt PRP in eyes also receiving focal/grid laser for DME can be reduced by intravitreal triamcinolone or ranibizumab .

118. Protocol K: The Course of Response to Focal Photocoagulation for DME Purpose  To determine whether eyes with center involved DME, treated with LP, in which there is a reduction in CMT measured with OCT after 16 weeks, will continue to improve if retreatment is deferred. Result  Sixteen weeks following LP for DME, in eyes with a definite reduction, but not resolution, of central edema, 23–63% will continue to improve without additional treatment.

119. Application to Clinical Practice  Eyes undergoing focal/grid laser especially eyes with greater macular thickening may continue to have improvement in VA and macular thickness even after 16 weeks

120. Other Important Conclusions of Various DRCR.net Studies There is a decline in best-corrected ETDRS VA after dilation in diabetic subjects. The post-dilation ETDRS VA should not be used as a substitute for undilated VA. Central subfield mean thickness is the preferred OCT measurement for the central macula because of its higher reproducibility and correlation with other measurements of the central macula. Total macular volume may be preferred when the central macula is less important.

121. A low rate of endophthalmitis (for intravitreal injections) can be achieved using topical povidone -iodine, use of a sterile lid speculum and topical anesthetic but does not require topical antibiotics. Transformation of OCT retinal thickness data to logOCT may assist in the assessment of clinically meaningful changes in retinal thickness just as use of the logMAR scale has helped assess clinically meaningful changes in VA

122. DRCR.net Ongoing Studies Effects of Diabetes Education during Retina Examinations on Diabetes Control, Medical Care Compliance and Ocular Complications. An Evaluation of Topical NSAIDs on Progression of Non-Center Involved DME. Prompt PRP versus Intravitreal Ranibizumab with Deferred PRP for Proliferative Diabetic Retinopathy (PDR). Intravitreal Ranibizumab for Vitreous Hemorrhage from PDR Study. Comparison of Time Domain OCT & Spectral Domain OCT in DME.

123. Ranibizumab for Edema of the Macula in Diabetes: A Phase 2 Study - READ-2 (2006) Purpose  Compare RBZ with focal/ grid laser or combination of both in DME Inclusion criteria  DME with CFT ≥ 250 µ, VA ≤20/40 but ≥20/320

124. Results  At 6 months, RBZ injections had a better visual outcome than focal/grid laser  RBZ provided benefit in DME for at least 2 years  When combined with focal/ grid laser , the amount of residual edema was reduced, as were the frequency of injections.

125. A Study of Ranibizumab Injection in Subjects with Clinically Significant Macular Edema with Center Involvement Secondary to Diabetes Mellitus - RIDE AND RISE (2007) Purpose  E fficacy and safety of intravitreal RBZ in DME patients Inclusion criteria  Adults with DME with CFT ≥275 microns  BCVA of 20/40 to 20/320 and hbA1C ≤12%

126. Results  RBZ rapidly and sustainably improved vision, reduced the risk of further vision loss  Improved macular edema in patients with DME, with low rates of ocular and nonocular harm.

127. Safety and Efficacy of Ranibizumab in Diabetic Macular Edema with Center Involvement- RESoLVE (2005) Purpose  Safety and efficacy of RBZ in DME involving the foveal centre Inclusion criteria  Adults T ype 1 or 2 diabetes  CFT ≥300 μm  BCVA of 73–39 ETDRS letters Result  RBZ is effective in improving BCVA and is well tolerated in DME

128. Ranibizumab Monotherapy or Combined with Laser Versus Laser Monotherapy for Diabetic Macular Edema - RESToRE (2008) Purpose  Superiority of RBZ 0.5 mg monotherapy or combined with laser over laser alone in DME Inclusion criteria  Adults Type 1 or 2 DM  Visual impairment due to DME Result RBZ monotherapy and combined with laser provided superior visual acuity over laser in patients with DME

129. A Prospective Randomized Trial of Intravitreal Bevacizumab or Laser Therapy in the Management of Diabetic Macular Edema BoLT (2007) Purpose  Bevacizumab vs Macular Laser Therapy (MLT) in CSME Inclusion criteria  Patients with center-involving CSME At least 1 prior MLT  BCVA 20/40 to 20/320 Result  The study supports the use of bevacizumab in patients with center-involving CSME without advanced macular ischemia

130. DME and VEGF Trap-Eye: Investigation of Clinical Impact - DA VINCI (2008) Purpose  VEGF Trap-Eye vs laser in DME Inclusion criteria  Adults >18 years  CSME with central involvement  BCVA 20/40 to 20/320 Result  VEGF Trap-Eye produced a statistically significant and clinically relevant improvement in BCVA compared with macular laser in DME at 24 and 52 weeks

131. VEGF Trap-Eye in Vision Impairment Due to DME - VISTA DME (2011) Purpose  Efficacy of VEGF TrapEye on BCVA in DME with central involvement Inclusion criteria  Adults >18 years  DME  BCVA 20/40 to 20/320 Result  Awaited

132. Fluocinolone Acetonide in Diabetic Macular Edema - FAME (2011) Purpose  Low dose & high dose fluocinolone acetonide implant (FA) in DME Inclusion criteria Persistent DME despite at least 1 macular laser treatment

133. Results  FA inserts improved BCVA over 2 years, and the risk-to-benefit ratio was superior for the low-dose insert.  Almost all phakic patients in the FA groups developed cataract.  The incidence of incisional glaucoma surgery at month 36 was 4.8% in the low dose group and 8.1% in the high-dose insert group

134. Treatment Laser Intra- vitreal injections Surgical

135. Treatment Based on Severity Non-proliferative Diabetic Retinopathy (NPDR)  The patient with minimal to moderate NPDR without macular edema should be re-examined on a regular basis  There is no clear treatment directive for these patients besides the systemic medical management of their diabetes, hypertension and dyslipidemia .

136.  For patients with severe NPDR the risk of progression to proliferative disease is high.  Early panretinal photocoagulation (PRP) should be considered if the risk of progression is high or if there is poor compliance with follow-up.  I mpending cataract extraction, pregnancy, and status of the fellow eye should be considered when determining the proper timing of PRP.

137. Proliferative Diabetic Retinopathy (PDR)  A pproximately 50% of high-risk PDR evolving to severe visual loss in 5 years.  M ain goal of the treatment is to control ischemia and reduce ocular VEGF levels so there can be an involution or regression of the neovascularization .  Can be done with photocoagulation of the ischemic retina or with administration of anti-VEGF drugs.

138. Laser PRP is considered the mainstay of treatment for PDR. PRP : A blates the ischemic retina targeting the photoreceptors and RPE, the cells with the highest metabolic activity in the retina  Cause overall reduced metabolism  D ecrease the source of VEGF and promote regression of proliferation.

139. Therapy with anti-VEGF agents can be a reasonable first-line alternative to PRP due to its highly effective regression of intraocular neovascularization and a generally favorable safety profile. A combined therapy is defended by some ophthalmologists, stating that initial anti-VEGF will promote a quick regression of the neovascularization while the long-term effect of PRP will reduce the number of injections needed. Complications of the proliferative disease or its treatments may require vitreoretinal surgical interventions.

140. Panretinal Photocoagulation (PRP) Pretreatment Discussion with Patients  Patients usually need numerous follow-up visits and may require supplementary laser treatment.  PRP reduces the risk of visual loss and blindness.  Although laser treatment is effective, some patients may still develop vitreous haemorrhage .

141.  The haemorrhage is caused by the diabetes and not by the laser; it may mean the patient needs more laser treatment.  Laser treatment often reduces peripheral and night vision; treatment may moderately reduce central vision.  This short-term side effect is compensated by the significant long-term reduction in severe vision loss and blindness in laser-treated patients.

142. Lenses for PRP  The three-mirror Goldmann contact lens has a central opening for treating the posterior pole and side mirrors for treating the mid peripheral and peripheral retina.  Disadvantages: small field of view, which requires continual manipulation of the lens to complete treatment. Spot size is set at 500µm.

143.  Newer wide-angle contact lenses are often used.  Although the image is inverted, there is a large field of view allowing for many burns with the field while easily maintaining orientation to the disc and macula.  Scatter treatment can be applied to a large area of retina in a single image, and it is easy to visualize the disk and the macula.

144. Technique for PRP The pupil should be fully dilated and topical anaesthesia is used. Retrobulbar or subtenons anaesthesia to reduce pain and decrease eye motion can be employed as necessary. The most common wavelengths used are Argon green, blue green (generally avoided currently) and 532 green laser, using the slit-lamp delivery system. In case of hazy media, Krypton red or diode red laser (814 nm) can be used.

145. Slit-lamp treatment is most commonly done through a contact lens but can also be performed using indirect ophthalmoscopy . Typical initial settings on the Argon laser would be 500 μm spot size, a 0.1 second exposure and 250-270 mw power. The power is gradually increased until a whitish reaction is obtained on the retina. The lesions are placed 1 burn width apart.

146. A total of 1600-3000 burns are placed in 1 or more sittings, avoiding macular area and any areas of tractional elevation of the retina. The burns are placed 2 to 3 disc diameters away from the centre of the macula and 1 disc diameter away from the disc, usually outside the arcades and extended peripherally up to the equator and beyond.

147. Laser treatment should not be applied over major retinal veins, pre retinal haemorrhages , darkly pigmented chorio retinal scars, or within 1 DD (200-300 μm ) of centre of macula, to avoid risk of haemorrhage or large scotomas .

148. Other considerations: • Additional photocoagulation is needed if there is evidence of worsening of proliferative DR. • Add laser burns in between scars of initial treatment further peripherally and also at the posterior pole, sparing the area within 500-1500 μm from the centre of the macula.

149. • Favour quadrants with active new vessels or areas with intra retinal micro vascular abnormalities where scars are more widely spaced and areas of severe ischemia not previously treated, such as the temporal part of the posterior pole. • Direct treatment of NVE in between scars is possible.

150. Treatment of dme Optimize medical treatment: Improve glycemic control if HbA1c > 7.5% as well as associated systemic hypertension or dyslipidemia . Mild or moderate DME without centre involvement (e.g., circinate HE ring threatening the centre of the macula or when no vision loss has occurred in spite of centre involvement): Consider focal laser to leaking micro aneurysms. No treatment is applied to lesions closer than 300 μm from the centre of the macula.

151. Severe DME with centre involvement and associated vision loss: intra- vitreal anti- VEGF treatment :  R anibizumab [ Lucentis ] 0.3 or 0.5mg  B evacizumab [ Avastin ] 1.25mg  Aflibercept [ Eylea ]) 2mg therapy). Consideration should be given to monthly injections followed by treatment interruption and re-initiation based on visual stability and OCT.

152. Patients should be monitored almost monthly with OCT to consider the need for treatment. Persistent retinal thickening and leaking points: consider laser treatment after 24 weeks. Treatment with intra- vitreal triamcinolone may be considered, especially in pseudophakic eyes.

153. DME associated with proliferative DR: combined intra- vitreal anti-VEGF therapy and PRP should be considered. Vitreomacular traction or epiretinal membrane on OCT: pars plana vitrectomy may be indicated .

154. Lasers in dme Focal macular treatment includes focal laser treatment of micro aneurysms and grid treatment of areas of diffuse leakage and focal non-perfusion within 2DD of centre of the macula. Laser parameters used are 50-100 μm spot size, 120-150 mW energy and very light gray intensity of the burn. Care is taken to demarcate and avoid the foveal avascular zone. If DME is associated with large areas of macular ischemia, only the areas of retinal thickening are treated.

155. RECENT GRID LASER MARKS

156. Complications  Proper avoidance of the macular region and correct selection of laser wavelength, power, exposure time and spot size are important factors to avoid complications in laser treatment. PRP may induce or exacerbate existing macular edema, so DME should be treated before starting PRP.

157. Retinal lesions  Photocoagulation with intense parameters can cause full-thickness retinal holes, fibrous proliferation and foveal distortion with metamorphopsia or even diplopia .  Focal laser treatment with high intensity and small spots can pierce blood vessels, causing preretinal or vitreous hemorrhage

158. Bruch’s membrane rupture  Rupture of Bruch's membrane can be caused by high intensity, small spot size and short duration applications.  The ruptures can generate choriocapillaris hemorrhage and the future development of choroidal neovascularization .

159. Accidental Foveal Burn  Great care should always be taken to avoid the fovea with frequent identification of its center during procedure to help maintaining orientation.

160. Exudative retinal and choroidal detachment  A photocoagulation   procedure that is too intense and extensive can lead to chorioretinal edema with resulting serous retinal and/or choroidal detachment.  The choroidal detachment can progress with forward rotation of the ciliary body, resulting in elevated intraocular pressure with peaks 1-3 days after procedure.  The reaction can resolve spontaneously within a few weeks, but corticosteroids may help treating massive exudation.

161. ANTI-VEGF TREATMENT

162. Visual acuity is said to be stabilised when:  No improvement in BCVA at the last 2 consecutive visits or  BCVA of 6/6 at last 2 consecutive visits Decrease in BCVA is confirmed by OCT and clinical assesment

163. Intra- vitreal technique for Anti-VEGF or steroids Location of the Procedure :  S terile Operation theatre-based procedure is strongly recommended. Pre-operative Assessment –  T horough pre-injection check of the eye and ocular adnexa to rule out ocular infections is mandatory.  High risk patients, especially, those receiving Intravitreal Bevacizumab ( Avastin ), preferably, ought to be assessed by a physician for fitness for the procedure.

164. Surgeons and Staff –  The personnel involved in the procedure need to follow the sterile precautions as mandated for a regular surgical procedure.  Conventional wearing of sterile surgical gowns and the use of sterile surgical gloves, cap and masks for the procedure.  The patient’s identity, case record and adequate pupillary dilation is verified prior to the procedure.

165. Local Asepsis & Anaesthesia –  The patients need to be draped using a standard surgical drape after the conventional betadine cleansing of the external lids.  2-3 drops of 5% Povidone -Iodine Solution ( Betadine ) may be instilled into the conjunctival sac and flushed with saline after 30 seconds.  Local anaesthesia may be achieved using 4% Lignocaine drops.  Alternatively, a cotton pledget /swab soaked in 4% lignocaine may be dabbed onto the site of injection

166. The Injection procedure –  A sterile syringe containing the drug mounted with a 30 Gauge needle is used.  The preferred site of injection is the inferotemporal quadrant (4mm from the limbus for phakic patients; 3.5mm for pseudophakic patients; 3mm for aphakic patients).  The drug is injected into the midvitreous cavity after visualizing the needle tip.

167.  The injection site is tamponaded with a sterile cotton pledget to reduce reflux.  Indirect ophthalmoscopy may be done to assess for central retinal artery pulsations (which would necessitate an anterior chamber paracentesis to relieve the same), to confirm drug delivery and check the site of injection.

168. Postoperatively, topical antibiotics may be prescribed for 5 days. Bilateral simultaneous Intra- vitreal injections are to be avoided barring exceptional cases such as pediatric patients or mentally challenged patients requiring general anaesthesia for the procedure.

169. The standard doses for the conventional pharmacotherapies are:  Ranibizumab ( Lucentis ) – 0.5mg/0.05 ml  Bevacizumab ( Avastin ) – 1.25mg/0.05ml -  Triamcinolone – 4mg/0.1ml or 2mg/0.05ml

170. complications Foreign body sensation Subconjunctival hemorrhage “Medication floaters” (particularly in triamcinolone injection) Development of elevated intraocular pressure, retinal detachment Inflammation and endophthalmitis . Corneal endothelial toxicity is a complication exclusive to dexamethasone sustained-release implants in cases of implant migration to the anterior chamber.

171. Indications for Surgery for Complications of DR Vitreous hemorrhage of 1-3 months duration that does not clear spontaneously

172. Recurring vitreous hemorrhage or advanced active PDR that persists despite maximal PRP treatment.

173. Dense subhyaloid hemorrhage over the macular region.

174. Tractional retinal detachment involving or threatening the macular region.

175. Combined tractional and rhegmatogenous retinal detachment.

176. Tractional macular edema or epiretinal membrane involving the macula, including vitreomacular traction.

177. Red blood cell-induced glaucoma and “ghost cell” glaucoma.

178. Anterior segment neovascularization with opacities that prevent PRP treatment.

179. Diabetic macular edema with taut posterior hyaloid

180. THANK YOU