ETDRS

ETDRS

Rolf Meyer MD

History

Meyer introduced photocoagulation to coagulate patches of new vessels on the surface of the retina Spalter described the photocoagulation of circinate maculopathy in diabetic retinopathy. Up the early 1968s there was no uniform Classification schemes to categorize diabetic retinopathy severity.

Definitions

A micro aneurysm red spot <125 microns(approx width of vein at disc margin) sharp margins. Hemorrhage red spot ,irregular margins Flame hemorrhages are supercial hemorrhages just under the nerve bre layer Blot hemorrhages are deeper hemorrhages, which are a sign of retinal ischaemia Hard exudates -(HEs) as small white or yellowish-white deposits with sharp margins, located typically in the outer layers of the retina soft exudates- uffy white opaque areas caused by an accumulation of axoplasm in the nerve bre layer of the retina

Definitions

Venous loops and/or reduplication Venous loop is an abrupt curving deviation of a vein from its normal path. Reduplication is dilation of a preexisting channel or proliferation of a new channel adjacent to and approximately the same caliber as the original vein

Venous loops and/or reduplication

Definitions

Intraretinal microvascular abnormality(IRMA)tortuous intraretinal vascular segments varying in caliber Intraretinal microvascular abnormalities are derived from remodeling of the retinal capillaries and small collateral vessels in areas of microvascular occlusion.

Intraretinal microvascular abnormality(IRMA) use RED free

Definitions

New vessels on and/or within 1 DD of the disc (NVD) New vessels elsewhere (NVE) are new immature vessels developing more than 1 disc diameter away from the edge of the optic disc

History

In 1968 the US Public Health Service held a symposium at the Airlie House in Warrington to develop a classification system for diabetic retinopathy Airlie House classification system used five standard photographic fields classified into one of three categories: absent, mild to moderate, or severe But this did not define enough distinction between mild to moderate lesions and severe lesions

History

In 1971, the Diabetic Retinopathy Study (DRS) modified Airlie House classification system. Two additional photographic fields were analyzed (field 6 superonasal and field 7 inferonasal) to the optic nerve head DRS Study Question - Is photocoagulation effective for treating diabetic retinopathy? 50% reduction in severe visual loss in eyes that had received photocoagulation. But DRS results were not helpful in determining whether immediate photocoagulation was a better treatment strategy as compared to deferral of scatter photocoagulation until high-risk characteristics developed.

ETDRS
Early Treatment Diabetic Retinopathy 1979-1989

a multicenter, randomized clinical trial

Study Sponsor: National Eye Institute (NEI) NCT00000151 First received: September 23, 1999 Last updated: September 1, 2006 Study Questions 1. Is photocoagulation effective for treating diabetic macular edema? 2. Is early photocoagulation effective for treating diabetic retinopathy? 3. Is aspirin effective for preventing progression of diabetic retinopathy?

ETDRS

Eligibility-Mild nonproliferative diabetic retinopathy early proliferative diabetic retinopathy, with visual acuity 20/200 or better in each eye Randomization, 3711 participants. Study pattern - All ETDRS patients were randomly assigned to 650 mg aspirin per day or placebo in order to assess whether the antiplatelet effects of aspirin would affect the microcirculation of the retina and slow the development of PDR . One eye of each patient was randomly assigned to immediate photocoagulation, while the fellow eye was assigned to deferral of photocoagulation, that is, careful followup and prompt scatter photocoagulation if high-risk retinopathy developed

ETDRS

Eyes assigned to immediate photocoagulation received different treatments depending on the severity of the retinopathy: (1) eyes without DME were randomly assigned to full or mild scatter; (2) eyes with DME and severe NPDR or early PDR were randomly assigned to full or mild scatter and focal/grid treatment; (3) eyes with mild to moderate NPDR randomly assigned to either immediate focal/grid treatment or immediate scattermild or full (with deferred focal/grid treatment)

ETDRS

The comparison of early photocoagulation versus deferral in the ETDRS revealed a small reduction in the incidence of severe visual loss in the early-treated eyes but 5-year rates were low in both the earlytreatment group and the deferral group (2.6% and 3.7%), respectively. For eyes with only mild-tomoderate NPDR, rates of progression to severe vision loss were even lower; early photocoagulation benefits were not sufficient to compensate for the unwanted side effects However, with very severe nonproliferative or early proliferative stages, the riskbenefit ratio was more favorable and consideration of initiating scatter photocoagulation before the development of high-risk PDR is suggested

Results

Outcome variables: Visual acuity less than 5/200 for at least 4 months; visual acuity worsening by doubling of initial visual angle (e.g, 20/40 to 20/80); retinopathy progression. Aspirin use results: 1. Aspirin use did not alter progression of diabetic retinopathy. 2. Aspirin use did not increase risk of vitreous hemorrhage. 3. Aspirin use did not affect visual acuity. 4. Aspirin use reduced risk of cardiovascular morbidity and mortality.

Results

Early scatter photocoagulation results: 1. Early scatter photocoagulation resulted in a small reduction in the risk of severe visual loss (<5/200 for at least 4 months). 2. Early scatter photocoagulation is not indicated for eyes with mild to moderate diabetic retinopathy 3. Early scatter photocoagulation may be most effective in patients with type 2 diabetes.

Results

Macular edema results: 1. Focal photocoagulation for DME decreased risk of moderate visual loss (doubling of initial visual angle). 2. Focal photocoagulation for DME increased chance of moderate visual gain (halving of initial visual angle . 3. Focal photocoagulation for DME reduced retinal thickening. Present status: Study completed.

ETDRS FINAL SCALE

ETDRS

1. Early PDR New vessels; and definition not met for High risk 2 . High risk PDR New vessels on or within 1 disc diameter of the optic disc (NVD) standard photograph 10A(about 1/4 to 1/3 disc area), with or without vitreous or pre retinal hemorrhage; or vitreous and/or pre retinal hemorrhage accompanied by new vessels, either NVD standard photograph 10A or new vessels elsewhere (NVE) 1/4 disc area 10A - NVD covers approximately one third the area of the standard disc

10A

ETDRS

The ETDRS defined clinically significant macular edema (CSME) and recommended treatment with focal laser photocoagulation for the following:

Following ETDRS studies, guideline of scatter laser treatment for diabetic retinopathy has provided the following recommendations.

1 Argon laser photocoagulation using 12002000 burns of 500micron spot size for an exposure time of 0.1S and distance between two spot is one-half spot width apart 2 Power is adjusted to obtain mild bleaching that doe snot spread to be appreciably larger than 500 microns and Not more than 900 burns are to be applied in a single setting

3 This number of burns to be applied in two or more episodes at least 4 days apart but no less than 2 weeks apart and treatment completed within 6 weeks
4 The posterior extent of the initial scatter laser treatment is an oval area dened by a line passing 2 DDs above, temporal to and below the centre of the macula , and 500 microns from the nasal half of the disc margin. From this line scatter laser treatment extends peripherally to or beyond the equator avoiding direct treatment of major vessels (and chorioretinal scars if present).

6 feared of vitreous hemorrhage -inferior quadrants are treated rst.

SHORT COMING
ETDRS classification scheme moderate NPDR (level 47)carries an 8.6% 1-year risk of developing high-risk PDR severe NPDR (level 53e) carries a 45%risk of developing high-risk PDR Therefore, a jump in a single numerical level of severity (4753) results in a big jump in risk (8.6 45%). Ideally, the risk of developing high-risk PDR will show a linear change in risk as one progresses along the severity scale. ETDRS severity levels are too complex for clinical use.

AAO Comes with 4:2:1 rule

A simplified technique to identify severe NPDR is the 4:2:1 rule. One or more of severe hemorrhages in all 4 quadrants significant venous beading in 2 or more quadrants moderate IRMA in 1 or more quadrants 4:2:1description of severe NPDR describes a level of disease severity that is less than the DRS definition of severe NPDR and also less than the ETDRS definition of severe NPDR.

What is ETDRS severe NPDR ?

In the first description , soft exudates, venous beading, and IRMA all have to be present in at least two photo-graphic fields (quadrants). The 4:2:1 rule makes no mention of soft exudates and it requires IRMA in only one quadrant. The second ETDRS description ,hemorrhages in all four quadrants (but only greater than standard photograph 2A in one of them) and also with two of the following three lesions (soft exudates, venous beading, or IRMA) present in two fields. The 4:2:1 rule requires only hemorrhages in four quadrants or venous beading in two quad-rants or IRMA in one quadrant. The third ETDRS description of severe NPDR stipulates IRMA in four quadrants with at least two of the quadrants having severity standard photograph 8A. The 4:2:1 rule therefore describes a level of diabetic retinopathy severity which is probably intermediate between the ETDRS definition of moderate and severe NPDR

Confusion

The Global Diabetic Retinopathy Project Group severity scale

International Diabetic Macular Edema Severity Scale

Diabetes Control and Complications Trial

Diabetes Control and Complications Trial Study questions: Will intensive control of blood glucose slow development and progression of diabetic retinopathy? Results: 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 albumin uria by 54%. Present status: Study completed.

United Kingdom Prospective Diabetes Study

1. Will intensive control of blood glucose, in patients with type 2 diabetes, reduce risk of retinopathy progression? 2. Will intensive control of blood pressure, in patients with type 2 diabetes and elevated blood pressure, reduce the risk of retinopathy progression? Eligibility: 1. 4209 patients with newly diagnosed type 2 diabetes. 2. 1148 hypertensive patients with newly diagnosed type 2 diabetes. Randomization: 1. Patients were randomly assigned to conventional policy starting with diet (1138 patients) or to intensive policy starting with a sulfonyl urea chlorpropamide (788 patients), glibenclamide (615 patients), or glipizide (170 patients)or with insulin (1156 patients). If overweight and in the intensive group, patients were assigned to start treatment with metformin (342 patients). 2. Patients were randomly assigned to tight control of blood pressure (400 with angiotensin converting enzyme lACE) inhibitor and 398 with beta blockers) or to less tight control (390 patients).

UKPDS

Results: 1. Intensive control of blood glucose slowed progression of retinopathy and reduced the risk of other microvascular complications of diabetes. Sulfonylureas did not increase the risk of cardiovascular disease. 2. Intensive control of blood pressure slowed progression of retinopathy and reduced the risk of other microvascular and macrovascular complications of diabetes. No clinically or statistically significant difference was found in the comparison of blood pressure lowering with ACE inhibitors versus beta blockers. Present status: Study completed

The Wisconsin Epidemiologic Study of Diabetic Retinopathy

(WESDR), an ongoing study on the progression of diabetic retinopathy 11-county area of southern Wisconsin. Between 1979 and 1980, 1210 patients with type J diabetes and 1780 patients with type 2 diabetes were entered into the study Findings of WESDR - The duration of diabetes was directly associated with an increased prevalence of diabetic retinopathy After 20 years of diabetes, 99% of patient s with type 1 and 60% with type 2 had some degree of diabetic retinopathy, and 3.6% of younger-onset patients (aged <3 0 years at diagnosis, an operational definition of type J diabetes) and 1.6% of olderonset patients (aged ~30 years at diagnosis, an operational definition of type 2 diabetes) were found to be legally blind. In the younger-onset group, 86% of blindness was attributable to diabetic retinopathy. In the older-onset group, where other eye diseases were more common, one third of the cases of legal blindness were the result of diabetic retinopathy.

Diabetic Retinopathy Vitrectomy Study

The DRVS was a prospective, randomized clinical trial investigating the role of vitrectomy in managing eyes with severe PDR. The DRVS evaluated the benefit of early (1 - 6 months after onset of vitreous hemorrhage) versus late (at I year) vitrectomy for eyes with severe vitreous hemorrhage and visual loss (';5/200). Patients with type 1 diabetes with severe vitreous hemorrhage clearly demonstrated the benefit of early vitrectomy, but no such advantage was found in mixed or type 2 patients. The DRVS also showed an advantage for early vitrectomy compared with conventional management in eyes with very severe PDR.

Current Indications for Pars Plana Vitrectomy in Patients With Diabetes

1. dense, non clearing vitreous hemorrhage 2. tractional retinal detachment involving or threatening the macula 3. combined tractional and rhegmatogenous retinal detachment 4. diffuse DME associated with posterior hyaloidal traction 5. significant recurrent vitreous hemorrhage despite maximal PRP

New studies

1.Diabetic retinopathy research network laser-ranibizumabtriamcinolone study - 0.5mg ranibizumab 3months interval significantly improves oct outcomes and triamcinolone more effective in pseudophakic. 2. 2006, the PKC-DRS Study Group4 reported result sfrom 685 patients randomized at 70 clinical sites. Mean visual acuity (VA) was bette rin the ruboxistaurin (32 mg/day) -treated patients after 12 months 3.Two Phase Trials of an Intravitreous Injection of Highly Purified Ovine Hyaluronidase (Vitrase) for the Management of Vitreous Hemorrhage 4.The EUCLID study is currently investigating the prophylactic treatment of type 1 diabetics with the Angiotensin Converting Enzyme (ACE) Inhibitor Lisinopril and the progression of nephropathy and other microvascular disease including DR . Preliminary reports are of a specific benefit are encouraging,

New studies

5.DRCR.net Trial with Bevacizumab in DME: A randomized Phase 2 trial examined the short-term effect of intravitreal bevacizumab in DME. Results showed reduce DME 6.READ-2 Study: A Phase 2 randomized, open-label, parallel assignment, safety-efficacy study compared intravitreal ranibizumab and focal/grid laser treatment in DME 7.BOLT Study: A prospective, randomized, masked single-center, 2 year, 2 arm trial examined whether intravitreal ranibizumab results in superior outcomes compared to modified ETDRS laser treatment in patients with persistent CSME. At 12 mo, the bevacizumab arm gained a median of 8 letters, whereas the laser arm lost a median of 0.5 letters

Current Treatment

DME (2.7-11% Prevalence)

MEDICAL

SURGICAL

Traditional

NEW

VITRCTOMY (TRACTION DME)

Traditional management of DM E

1. Diastolic blood pressure 2 Serum cholesterol/triglycerides

3 Glycosolated Hemoglobin 4 Renal function 5 Focal/grid photocoagulation
6.Anemia

Blood pressure
Blood pressure 1990s, Chase and Joner Blood pressure and retinopathy in type I DM systemic hypertension retinopathy progress UKPDS 7.5 years of follow-up the group assigned to tight blood pressure control had a 34% relative risk reduction

TAKE REGULAR BP AND CONTROLE IT

Lipid levels

elevated serum lipids are associated with macular exudates and that moderate visual loss 1996 Chew reported an association of elevated serum lipid levels with retinal hard exudates in diabetic patients from the ETDRS and Fong later reported that patients with persistent severe visual loss in the ETDRS ad higher levels of cholesterol Lyons demonstrated in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Study cohort new association between serum lipoproteins and severity of retinopathy ACCORD Eye Study showed significant reduction in retinopathy progression when fenofibrate was added to simvastatin, compared to simvastatin alone.

Do and control lipid profile and see

HbA1c

For non-diabetics, the usual reading is 4-5.9%. For people with diabetes, an HbA1c level of 6.5%7% is considered good control, although some people may prefer their numbers to be closer to that of non-diabetics. People at greater risk of hypoglycemia may be given a target HbA1c of 7.5% Tightening of

glycaemic control may initially produce worsening of retinopathy. The postulated mechanism includes lowering of retinal blood low or overproduction of IGF-1 by the liver

Smoking

progression of diabetic retinopathy in type 1 diabetes as described by Muhlhauser and Karamanos. However, in type 2 disease the evidence is controversial and smoking may protect against the progression of retinopathy in some patients despite the fact that it is an independent risk factor for cardiovascular disease in all patients with diabetes. ( reference DCCT STUDY )

Focal / Grid Laser

The ETDRS defined clinically significant macular edema (CSME) and recommended treatment with focal laser photocoagulation for the following:

Focal / Grid laser other indications

Focal

Spot size = 50-100um Time = 0.1s Area = 500 to 3000um from centre of macula Power = gentle whitening of microaneuryms In case of persistent CSMO 300um from centre of macula for 0.05s

Grid

Retinal thickening leave 500um around centre of macula leave 500um from temporal margin of disc Spot size = 100um Time = 0.1s Power = gentle whitening

Complications

New

A Intravitreous injection of anti-VEGF B Corticosteroid therapy: 1 Biodegradable intravitreous devices 2 NonBiodegradable intravitreous device 3 intravitreous injection of triamcinolone(4mg) C Oral Protein Kinase C inhibitor ruboxistaurin 32mg/day

Intravitreous injection of AntiVEGF

Bevacizumab (Avastin) 1.25mg/0.05ml Ranibizumab (Lucentis) 0.5mg/0.05ml No difference in effect on DME of 1.25 X 2.25mg of Bevacizumab comparative study

Biodegradable intravitreous device s

Ozurdex or Posurdex is composed of a biodegradable copolymer of lactic acid and glycolic acid with micronized dexamethasone (700ug)/0.45 m per day This implant is placed into the vitreous cavity through the pars plana incision provides intravitreal dexamethasone for up to 6 months contraindications - Advanced Glaucoma , Aphakic Eyes with Rupture of the Posterior Lens Capsule ,hypersensitivity.

NonBiodegradable intravitreous de vice

Retisert- sterile implant consists of a tablet containing 0.59 mg fluocinolone acetonide, a synthetic corticosteroid that is less soluble in aqueous solution than dexamethasone. The tablet is encased in a silicone elastomer cup with a release orifice and membrane; the entire elastomer cup assembly is attached to a suture tab. Following implantation (via pars plana incision and suturing) in the vitreous, the implant releases the active drug at a rate of 0.30.4 mcg/day over a period of approximately 2.5 years. Iluvien- is a rod-shaped device made of polyimide and polyvinyl alcohol (PVA). It is small enough to be placed using an inserter with a 25-gauge needle and is expected to provide sustained delivery of fluocinolone acetonide for up to 3 years.

Follow up