detected by fundus photography (and not fluorescein angiography). In the ETDRS, the indication for benefiting from laser photocoagulation was clinically significant macular edema diagnosed clinically and confirmed by professional graders interpreting stereo fundus photography (and not fluorescein angiography). The Global Diabetic Retinopathy Project Group did not include fluorescein angiographic characteristics in their disease severity scales. The 4:2:1 rule does not include fluorescein angiographic findings. Although a greater severity of fluorescein leakage, capillary loss, and arteriolar abnormalities were associated with a greater risk of progression to proliferative retinopathy, the ETDRS did not find this to be of clinical importance because the information available from color photography alone was sufficient to predict progression and to make recommendations for treatment.16 The information gained from fluorescein angiography may certainly change the extent and pattern of laser application.17 In the ETDRS, the protocol laser treatment specified a grid pattern of laser to areas of nonperfusion18 and direct treatment to areas of focal leakage. However, it is possible that modifying the precise treatment parameters of the ETDRS may not adversely affect treatment outcome.19

Although the ETDRS utilized fluorescein angiography to direct laser therapy, current clinical practice suggests that fluorescein angiograms are not universally utilized. In a recent study of the DRCR Network utilizing 35 clinical centers across the United States, laser treatment of diabetic macular edema was directed by fluorescein angiography in only 51% of cases.20 Although this suggests that clinicians believe that laser treatment without fluorescein guidance is effective, to date there is no clinical trial to compare the vision outcomes of laser treatment for diabetic macular edema with and without fluorescein guidance.

Ultrawide field fluorescein angiography systems provide information from the retinal periphery (ischemia and vascular leakage) outside of the area investigated by the standard fields of the ETDRS.21 Pending the results of clinical trials it is unclear as to whether this additional information will have prognostic value for diabetic patients or will provide information to alter therapy.

5.1 Summary of Key Points

Terms in italics are specific definitions. Understanding these definitions helps foster better communication to improve patient outcomes.

The 4:2:1 rule approximates the ETDRS definition of severe NPDR.

Laser therapy of clinically significant macular edema reduces the risk of moderate visual loss, whereas laser therapy of macular edema did not show benefit over 24 months.

Identification of high-risk characteristicsof PDR and application of scatter laser photocoagulation lead to a significant reduction in the risk of severe visual loss.

ETDRS severity levels are too complex for clinical use.

Clinical examination and fundus photography provide sufficient information for classifying diabetic retinopathy. Information from fluorescein angiography may help guide therapy but does not affect classification schemes.

5.2 Future Directions

Determination of whether additional information from imaging studies (optical coherence tomography and ultrawide field fundus photography/fluorescein angiography) is helpful in subclassifying diabetic retinopathy.

Determination of whether utilizing the simplified definitions of the ‘‘International Clinical Diabetic Retinopathy and Diabetic Macular Edema Disease Severity Scales’’ alters patient outcomes.

Determination of whether response to therapeutic interventions for diabetic macular edema or highrisk PDR varies dependent upon baseline hemoglobin A1c or systemic blood pressure control.

5.3 Practice Exercises

Exercise 1 – Does this patient have ‘‘severe NPDR’’? (see Figs. 5.8–5.14)

Severe NPDR:

ETDRS definition 1: Soft exudates, venous beading, and intraretinal microvascular abnormalities all definitely present in at least two of fields 4 through 7 (Table 5.9).

Fig. 5.14 Exercise 1: Field 7

Table 5.9 Table for grading fundus photographs using ETDRS definition 1 in exercise 1

SE

VB

IRMA

DRS definition 1: Any three of the following: Soft exudates definitely present in 2 of photographic fields 4–7; IRMA definitely present in 2 of photographic fields 4–7; venous beading definitely present in 2 of photographic fields 4–7; hemorrhages/microaneurysms standard photo 2A in 1 of photographic fields 4–7 (Table 5.12).

Table 5.12 Table for grading fundus photographs using DRS definition 1 in exercise 1

SE

VB

IRMA

4:2:1 rule: four quadrants of > 20 hemorrhages or two quadrants of venous beading or one quadrant of IRMA (Table 5.13).

Table 5.13 Table for grading fundus photographs using 4:2:1 rule in exercise 1

SE

VB

IRMA

ETDRS definition 2: Two of the preceding three lesions present in at least two of fields 4 through 7 and hemorrhages and microaneurysms present in these four fields, equaling or exceeding standard photograph 2A in at least one of them (Table 5.10).

Table 5.10 Table for grading fundus photographs using ETDRS definition 2 in exercise 1

SE

VB

IRMA

ETDRS definition 3: Intraretinal microvascular abnormalities present in each of fields 4 through 7 and equaling or exceeding standard photograph 8A in at least two of them (Table 5.11).

Table 5.11 Table for grading fundus photographs using ETDRS definition 1 in exercise 1

SE

VB

IRMA

Exercise 2 – Systemic control of blood sugars22,23 and hypertension24 reduces the risk of diabetic retinopathy progression. Elevated serum lipids25 and serum triglyceride levels26 are associated with a greater risk of developing more severe diabetic retinopathy. The ETDRS began enrollment of patients in 1980. Almost three decades ago 42% of patients in the ETDRS had a hemoglobin A1c 10%. Thirtysix percent of patients had a serum cholesterol 240 mg/100 ml. Twenty-six percent of patients had a low density lipoprotein cholesterol 160 mg/ 100 ml.27 The DCCT demonstrated that the initial level of hemoglobin A1c was the greatest predictor of the risk of diabetic retinopathy progression. A 10% lower initial hemoglobin A1c was associated with a 45% decreased risk of diabetic retinopathy progression.28 There was a 19% increased risk of retinopathy progressing 3 steps on the ETDRS scale for every 1% increase in baseline hemoglobin A1c.29 We may be in a current medical environment where systemic medical factors are under better control. The DRCR.net reported results of its first clinical trial in 2007 in which the mean hemoglobin A1c was 8.2.30 To date it has not been demonstrated that poor vs.

good control of systemic medical factors should change one’s recommendation for treatment of clinically significant macular edema or proliferative diabetic retinopathy with high-risk characteristics.

However, some clinicians will logically defer therapy of diabetic macular edema if blood sugars or blood pressure is acutely out of control. Randomized clinical trials will usually collect information on systemic medical factors (Hgb A1c, blood pressure, lipid levels) to ascertain that such medical factors are evenly distributed among treatment groups. This implies that subclassifying diabetic retinopathy with regard to systemic medical factors may modify the response to therapy. One example of such subclassification arises from analysis of the ETDRS data for early scatter photocoagulation for patients with severe NPDR. For patients with severe NPDR, early scatter photocoagulation was beneficial only in patients with Type 2 diabetes mellitus but not in patients with Type 1 diabetes mellitus.31

Should systemic medical factors be utilized by clinicians to subclassify diabetic retinopathy?

Exercise 3 – Severe NPDR as characterized by the 4:2:1 rule requires four quadrants of > 20 hemorrhages or two quadrants of venous beading or one quadrant of IRMA. With extensive capillary closure, these fundus lesions may disappear producing what has been described as ‘‘featureless’’ retina. These patients have been described as being at significant risk for developing high-risk PDR. The following patient has been described by the Wisconsin Reading Center as ‘‘featureless’’ retina (Figs. 5.15–5.21).

How would this patient be characterized by the ETDRS? By the Global Diabetic Retinopathy Project?

Exercise 4

How many high-risk characteristics does this photograph demonstrate? (Fig. 5.22)

Would a fluorescein angiogram affect the classification?

Answer Key

Exercise 1 Answer:

Severe NPDR:

ETDRS definition 1: Soft exudates (SE), venous beading (VB), and intraretinal microvascular

Fig. 5.15 Exercise 3: Field 1

Fig. 5.16 Exercise 3: Field 2

abnormalities (IRMA) all definitely present in at least two of fields 4 through 7 (Table 5.14).

ETDRS definition 2: Two of the preceding three lesions present in at least two of fields 4 through 7 and hemorrhages and microaneurysms present in these four fields, equaling or exceeding standard photograph 2A in at least one of them (Table 5.15).

ETDRS definition 3: Intraretinal microvascular abnormalities present in each of fields 4 through 7 and equaling or exceeding standard photograph 8A in at least two of them (Table 5.16).

DRS definition 1: Any three of the following: Soft exudates definitely present in 2 of photographic fields 4–7; IRMA definitely present in 2 of photographic fields 4–7; venous beading definitely present in 2 of photographic fields 4–7; hemorrhages/microaneurysms standard photo 2A in 1 of photographic fields 4–7 (Table 5.17).

4:2:1 rule: four quadrants of > 20 hemorrhages or two quadrants of venous beading or one quadrant of IRMA (Table 5.18).

Exercise 2 Answer:

Subclassification of diabetic retinopathy as to whether systemic medical factors are well controlled or poorly controlled has not undergone evaluation to determine whether such subclassification would change the response to therapy (it has been shown to affect the natural history). Such information would be helpful for clinicians to know.

Exercise 3 Answer:

ETDRS classification: Moderate NPDR