Chapter 113D
The Role of Fluorescein Angiography in Diabetic Retinopathy
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Diabetic retinopathy is the leading cause of blindness in Americans between 20 and 74 years of age.1 Fluorescein angiography has helped in the diagnosis, management, and study of the pathophysiologic mechanisms of this disease. The specific indications for fluorescein angiography will be described in this chapter, underscoring the established basic guidelines outlined in the recently published Preferred Practice Pattern by the American Academy of Ophthalmology.1
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Fluorescein angiography is not indicated as a screening tool for diabetic retinopathy nor as a baseline measurement of background diabetic retinopathy. The signs of background diabetic retinopathy include microaneurysms, intraretinal hemorrhages, hard exudates, and macular edema, all of which should be visible on clinical examination.2–8 Ophthalmoscopy of a well-dilated fundus performed by trained ophthalmologists and technical personnel has been shown to agree with fundus photography in at least 85% of cases; disagreement occurred in cases of the earliest stages of retinopathy whereby a photographically observable microaneurysm may not be visualized ophthalmoscopically.9,10 The risk of underevaluating retinopathy consistently occurred in eyes with minimal changes. Clinical identification of more severe changes was almost always consistent and in agreement with the photographic findings.

Stereo fundus photography provides a permanent record of the fundus appearance and can be used to document the severity and progression of disease.1,5,6,9–11 The seven standard fields of stereo color fundus photography as specified by the modified Airlie House classification3 allows for both detailed grading and documentation of progression of disease, or conversely, a response to treatment. Fundus photography is clearly valuable in documenting retinopathy that is changing rapidly, or immediately prior to treatment, once the decision to treat has been made on clinical grounds. Large 60° fields will give a more complete view of the midperipheral regions than 30° photography and may be the field of choice for scanning for retinopathy. If fundus photography is considered to be 100% sensitive in detecting retinopathy, ophthalmoscopy correlates with retinopathy detected by photography 86% of the time.9 For proliferative diabetic retinopathy, between 79% to 96% agreement was seen between ophthalmoscopic examination and fundus photography.9,10 This assumes, however, a dilated fundus examination, as the sensitivity of ophthalmoscopy has been shown to diminish by 50% in an undilated eye.12

Given the high specificity and sensitivity of the clinical ophthalmoscopic examination, several screening strategies have been studied.5,6 An annual dilated ophthalmoscopic examination for eyes with no retinopathy has been recommended in several cost-effectiveness models.1,5,6 Although in such a cost-effectiveness model photography does not enhance the outcome, fundus photographs are nevertheless medically useful for documenting the course of disease.

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Fluorescein angiography can be helpful in determining the cause of unexplained visual loss in an eye with visual complaints out of proportion to the retinopathy clinically seen.1,8,13,14 An eye may have both minimal peripheral changes and minimal macular edema but visual acuity far worse than the clinical examination. Causes may include an optic neuropathy or a markedly ischemic macula, the latter of which could be confirmed by angiography (Color Plate. 1, Fig. 1).

Color Plate. 1

Fig. 1. Case 1 is a 60-year old man with a 20-year history of noninsulin dependent diabetes and chronic open-angle glaucoma controlled by topical medications who complained of decreased vision in his right eye. Visual acuity was 20/100. Minimal background retinopathy, intraretinal hemorrhages inferior to the fovea, and macular thickening, with an enlarged cup-to-disk ratio are noted on dialated fundus examination with visual loss out of proportion to his clinical examination (A; Color Fig. 1). Fluorescein angiography was therefore obtained, revealing marked irregularity of the capillary-free zone and perifoveal nonperfusion (B). There is no evidence of central leakage in the mid- and late frames (C, D). His visual loss can be explained by his macular ischemia secondary to diabetic retinopathy. Comment: This is an example of a patient with unexplained visual loss, out of proportion to the clinical examination; a fluorescein angiogram is indicated in this situation.

Occlusion of the perifoveal capillaries is readily shown on angiography2,4,13,14 as abnormalities of the foveal avascular zone (FAZ). These angiographic characteristics include an irregularity of the margins of the FAZ, budding of capillaries into the FAZ, and the development of wide intercapillary spaces within bridging vessels in the perifoveal capillary bed.2,13 The perifoveal capillaries may actually be more apparent due to both dilation of the remaining capillaries and their contrast to the larger zone of nonperfusion seen angiographically as hypofluorescence. The enlargement of the FAZ is presumed to cause a loss of visual acuity due to macular ischemia.1,2,13–15

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Macular edema is the leading cause of visual loss in eyes with diabetic retinopathy.15 Numerous randomized clinical trials have demonstrated the efficacy of laser photocoagulation in preventing visual loss due to diabetic macular edema.15–21

The Early Treatment Diabetic Retinopathy Study (ETDRS)19,22–24 stated that patients with clinically significant macular edema be considered for treatment. They have shown that focal treatment substantially reduces the risk of visual loss from clinically significant diabetic macular edema regardless of initial visual acuity. Any of the following characteristics fulfills the definition of clinical significance: thickening of the retina at or within 500 μm of the center of the macula; hard exudates at or within 500 μm of the center of the macula, if associated with thickening of adjacent retina (not residual hard exudates remaining after disappearance of retinal thickening); or a zone or zones of retinal thickening one disc area or larger, any part of which is within one disc diameter of the center of the macula.

The diagnosis of clinically significant macular edema is based on examination by stereo slit-lamp biomicroscopy and/or stereo fundus photography. Fluorescein angiography is not indicated to diagnose the presence of clinically significant macular edema. Angiographic evidence of fluorescein leakage without clinical evidence of retinal thickening does not fulfill the criteria for clinical significance. However, once the diagnosis and the decision to treat macular edema have been made, fluorescein angiography is extremely useful in helping to guide the treatment pattern. Angiography will identify treatable lesions and delineate the foveal avascular zone and the status of the macular perfusion. Fluorescein angiography will also confirm the presence of thickening and edema by leakage in the late stage of the angiogram, which also can be used as a guide to treatment (Color Plate. 2 ,Fig. 2).

Color Plate. 2

Fig. 2. Case is a 57-year-old man with a 15-year history of nonisulin dependent diabetes who complained of decreased vision in his right eye. Visual acuity was 20/40. Examination revealed clinically significant macular edema by slit lamp biomicroscopy using ETDRD criteria (A; Color Fig. 2). Laser photocoagulation was recommended and a fluorescein angiogram was obtained (B, C). Focal treatment was performed (D), and on follow-up examination 4 months later, resolution of the thickening was seen, with a visual acuity of 20/20. Because no further traetment was indicated, no further angiograms were performed. Serial follow-up examinations showed complete resolution of his macular edema without recurrence, and 2 years after treatment his visual acuity remained at 20/20 (E). Comment: This is an example of a patient who required fluorescein angiography after the initial decision to treat his diabetic macular edema had resolved and no further treatment was indicated, no additional fluorescein angiograms were needed.

Although the ETDRS showed a treatment benefit at all levels of visual acuity, if an eye has good vision and is asymptomatic, one can elect to follow the patient, rather than treat immediately. That patient should be followed at close intervals at least every 3 months; a fluorescein angiogram is not indicated until the decision to treat has been made based on the clinical examination (Color Plate. 3, Fig. 3).

Color Plate. 3

Fig. 3. Case is a 31-year-old man with a 2-year history of insulin-dependent diabetes who on routine annual examination presented with early clinically significant diabetic macular edema in his right eye (A; Color Fig. 3). Visual acuity was 20/25 in the right eye, and it was elected to follow the patient at intervals of 3 to 4 months. Partial spontaneous resolution of the macular thickening was noted two years later (B); complete resolution of the macular thickening without recurrence was noted 4 years after initial presentation (C) with visual acuity remaining at 20/25 in his right eye. Comment: This case illustrates an example in which fluorescein angiography was not indicated as the decision was made to not institute treatment and to follow the patient clinically.

The ETDRS has emphasized the use of focal treatment in the treatment of diabetic macular edema characterized by focal leakage. Diffuse diabetic macular edema may present a different pathophysiologic mechanism. Focal edema is a product mainly of individual leaking microaneurysms, whereas diffuse diabetic macular edema may be produced by a combination of a breakdown of the inner blood retinal barrier at the level of the retinal capillaries and arterioles and at the outer blood retinal barrier at the level of the retinal pigment epithelium.2,25 Other treatment protocols including Olk's modified grid photocoagulation emphasize the use of grid treatment for diffuse macular edema greater than 2 disc diameters in area and involving any portion of the foveal avascular zone.20,21,26 Again the diagnosis of diffuse macular edema is made on the clinical biomicroscopic examination, whereas the fluorescein angiogram is obtained only after the decision to treat has been made, and is used as a guide to treatment (Color Plate. 4, Fig. 4).

Color Plate. 4

Fig. 4. Case 4 is a 59-year-old woman witha 25-year history of insulin-dependent diabetes who presented with diffuse retinal thickening involving the FAZ, hard exudates scatteres throughout the parafoveal region, and a central foveal cyst in the left eye (A; Color Fig. 4). Visual acuity was 20/60. Modified grid laser photocoagultion was recommended and fluorescein angiography performed (B). Modified grid photocoagultion was applied to all areas of the retinal thickening up to and including the edge of the FAZ (C). She returned for follow-up 4 months later with some reduction of her intraretinal lip and thickening; however, the central retinal thickening and central foveal cyst persisted (D). Supplemental photocoagulation was advised and a fluorescein angiogram was repeated (E). Supplemental modified grid laser photocoagultion was applied to all areas of residual retinal thickening (F). Four months later she returned with near-complete resorption of the intraretinal lipis and flattening of the central FAZ (G); visual acuity had improved to 20/30. Because no additional treatment was required, fluorescein angiography was not repeated. One year later visual acuity had improved to 20/20 without evidence of any recurrence (H). Comment: This case illustrates that fluorescein angiography is indicated once the decision to treat or to do supplemental treatment has been made based on clinical findings. Once the central thickening involving the FAZ has resolved and no further supplemental treatment is indicated, fluorescein angiography is no longer required.

Supplemental macular treatment was required by the ETDRS if macular edema involved or threatened the center of the macula. Supplemental treatment was allowed for any degree of edema, which met one of the definitions for clinical significance.19,22,23 Fluorescein angiography is again useful in guiding the treatment once the clinical need for retreatment has been determined. Supplemental modified grid macular photocoagulation is recommended by Olk if residual central thickening involving the foveal avascular zone is seen on clinical examination.20,21,26 Only if retreatment is being considered does one obtain a fluorescein angiogram to delineate the areas of leakage, to identify the foveal avascular zone, and to guide in the pattern of treatment (Color Plate. 4, Fig. 4).

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The Diabetic Retinopathy Study (DRS) has determined four retinopathy risk factors: the presence of new vessels, the location of new vessels on or within one disc diameter of the optic disc, the severity of new vessels, and the presence of preretinal or vitreous hemorrhage.27–30 If an eye has both neovascularization of the disc (NVD) and neovascularization elsewhere (NVE), the severity applies to the NVD because in eyes with NVD, the presence of moderate to severe NVE did not further increase the risk of severe visual loss. The presence of three or four retinopathy risk factors characterizes an eye as being “high-risk”; these characteristics include any of the following: NVD greater than one fourth to one third disc diameter in area and vitreous or preretinal hemorrhage associated with less extensive NVD or with NVE greater or equal to one half disc diameter in area. The DRS has shown the clear benefit of scatter panretinal photocoagulation to these high-risk eyes in preventing severe visual loss from the consequences of proliferative disease. Fluorescein angiography is not needed to diagnose the presence of high-risk retinopathy. The clinical examination is highly sensitive in detecting this stage of retinopathy and is adequate for the determination of the need for photocoagulation.1,9–11 Color fundus photography, as previously stated, employing the seven standard stereo fields may be helpful in gauging the response to therapy once panretinal photocoagulation has been instituted.

As it has been shown that diabetic macular edema may be exacerbated by panretinal photocoagulation,31–33 any eye that shows clinical evidence of retinal thickening falling within the definition of clinically significant macular edema should have a fluorescein angiogram to guide in the treatment of the macular edema either prior to or in combination with the panretinal treatment of the proliferative disease (Color Plate. 5, Fig. 5).

Color Plate. 5.

Fig. 5. Case 5 is a 41-year-old man with a 16-year history of insulin-dependent diabetes who complained of recent decrease in vision in the right eye. He receives previous focal laser photocoagulation for macular edema 5 years prior to presentation; his visual acuity was 20/40. On clinical examination diffuse diabetic macular edema with cystoid macular edema involvong the FAZ and proliferative diabetic retinopathy with NVE and preretinal hemorrhage were noted (A;Color Fig. 5.). Combined treatment of the macular edema and proliferative disease was recommended and fluorescein angiography was performed (B). Modified grid laser photocoagultion combined with panretinal photocoagultion to the interior half of the retina was performed (C, D), followed 2 weeks later with treatment of the superior half of the retina with panretianl photocoagultion (E). Three months later onvolution of the neovascularization and absorbtion of the hemorrhage were seen; however, persistent central macular edema was noted on clinical examination (F). Therefore, fluorescein angiography was performed (G), and supplemental grid laser photocoagultion was given (H). Four months later no residual retinal thickening was observed on clical examination (I). On further follow-up 1 year later, visual acuit remained 20/40 without recurrence of either proliferative or macular disease (J). Comment: Here is a case in which fluorescein angiography is needed for the treatment of diffuse macular edema present in combination with proliferative diabetic retinopathy. The Fluorescein angiogram was obtained because the macular thickening required treatment, and not to determine the need for panretinal photocoagulation.

Fluorescein angiography may be helpful in searching for subtle patches of neovascularization or capillary nonperfusion when either significant preproliferative signs are present or proliferative disease is suspected and media opacity precludes a good view. In this last circumstance, fluorescein angioscopy may be more helpful in scanning the retina to detect areas of leakage from neovascularization; however, fluorescein angioscopy is not helpful in the confirmation nor the guidance of treatment for macular edema. Angiography may also be helpful in detecting specific fronds of neovascularization when blood from a vitreous hemorrhage obscures the view; this can guide the ophthalmologist to areas of active neovascularization that may be treated with focal ablation.

In general, indications for retreatment include increasing neovascularization, new areas of neovascularization, new vitreous hemorrhage, and failure of the initial neovascularization to regress.1,30,34 Each of these findings should be determined on clinical examination and do not usually need fluorescein angiography for confirmation. However, the progression or regression of neovascularization can be readily followed by serial clinical examinations and on color fundus photography, and can be used as a permanent record for comparison.

The significance of capillary nonperfusion in the midperipheral retina has been illustrated in the fluorescein angiographic studies by Shimizu.35,36 Clinically the angiographic demonstration of a significant amount of capillary nonperfusion or dropout may be helpful in those special circumstances where photocoagulation treatment is being considered for severe preproliferative or early proliferative disease. These special circumstances include accelerated retinopathy during pregnancy, imminent cataract surgery or worsening cataract, unreliable or inadequate follow-up, concomitant presence of carotid occlusive disease, and the comparative status of the fellow eye.

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Fluorescein angiography may be helpful in differentiating between macular edema secondary to pseudophakia or to diabetes, as the clinical diagnosis between the two is often difficult. Typically, in pseudophakic macular edema, cysts distributed in a petalloid pattern can be appreciated by slitlamp biomicroscopy.37 Fluorescein angiography will usually show early dye leakage from the parafoveal capillaries in a uniform fashion with the later phases revealing a polycystic pattern of dye accumulation caused by serous exudation into the extracellular space. In addition, the capillaries of the optic nerve head will frequently leak dye in the later frames of the angiogram. Diabetic macular edema, however, is sometimes accompanied by a cystoid component such that the differential between the two can be difficult (Color Plate. 6, Fig. 6).

Color Plate. 6.

Fig. 6. Case 6 is a 65-year-old woman with a 5-year history of non-insulin dependent diabetes and was seen visual acuity of 20/80 in her right eye 5 months following uncomplicated extracapsular cataract extraction and intraocular implant. Clinical examination revealed cystic thickening of the macula without evidence of diabetic retinopathy (A; Color Fig. 6). A fluorescein angiogram was obtained, which confirmed the diagnosis of psuedophakic cystoid edema. The early frames of the angiogram revealed an intact FAZ (B); as the study progressed, uniform leakage was noted (C) with the petalloid appearence of dye accumulation (D) seen in the latest frame. Note also the late staining of the optic disc. Comment: The differntial between psuedophakic or aphakic cystoid macular edema and diabetic macular edema is often difficult despite fluorescein angiography. The angiogram shown here is characteristic of classic psuedophakic cystoid macular edema.

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In conclusion, fluorescein angiography is a useful guide in the treatment of clinically significant macular edema, in the means of evaluating an eye with unexplained visual loss, and sometimes in identifying subtle areas of neovascularization or capillary nonperfusion. It is not indicated for the diagnosis of either clinically significant diabetic macular edema or proliferative diabetic retinopathy. Nor is it used as a screening tool or a baseline examination in patients with diabetic retinopathy.
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1. American Academy of Ophthalmology: Preferred Practice Pattern: Diabetic Retinopathy. American Academy of Ophthalmology, San Francisco, CA 1989

2. Bresnick GH: Background diabetic retinopathy. In Ryan SJ (ed): Retina, pp 327–366. St. Louis, CV Mosby, 1989

3. Diabetic Retinopathy Study Research Group: A modification on the Airlie House classification of diabetic retinopathy. Report No. 7. Invest Ophthalmol Vis Sci 21:210, 1981

4. Frank RN: Etiologic mechanisms in diabetic retinopathy, In Ryan SJ (ed): Retina, pp 301–326. St. Louis, CV Mosby, 1989

5. Javitt JC, Canner JK, Sommer A: Cost effectiveness of current approaches to the control of retinopathy in Type I diabetes. Ophthalmology 96:255, 1989

6. Javitt JC, Canner JK, Frank RG et al: Detecting and treating retinopathy in patients with Type I diabetes mellitus. Ophthalmology 97:483, 1990

7. Kohner EM, Sleightholm M, Kroc Collaborative Study Group (appended): Does microaneurysm count reflect severity of early diabetic retinopathy? Ophthalmology 93:586, 1986

8. Wilkinson CP: The clinical examination: Limitation and over-utilization of angiographic services. Ophthalmology 93:410, 1986

9. Moss SE, Klein R, Kessler SD et al: Comparison between ophthalmoscopy and fundus photography in determining severity of diabetic retinopathy. Ophthalmology 92:62, 1985

10. Sussman EJ, Tsiaras WG, Soper KA: Diagnosis of diabetic eye disease. JAMA 247:3231, 1982

11. Klein R, Davis MD, Segal P et al: Diabetic retinopathy: Assessment of severity and progression. Ophthalmology 91:10, 1984

12. Klein R, Klein BEK, Neider NW et al: Diabetic retinopathy as detected using ophthalmoscopy, a nonmydriate camera and standard fundus camera. Ophthalmology 92:485, 1985

13. Bresnick GH, Condit R, Syrjala S et al: Abnormalities of the foveal avascular zone in diabetic retinopathy. Arch Ophthalmol 102: 1286, 1984

14. Bresnick GH, Engerman R, Davis MD et al: Patterns of ischemia in diabetic retinopathy. Trans Am Acad Ophthalmol Otolaryngol 81:694, 1976

15. Patz A, Schatz H, Berkow JE et al: Macular edema: An overlooked complication of diabetic retinopathy. Trans Am Acad Ophthalmol Otolaryngol 77:34, 1973

16. Multicentered Controlled Study: Photocoagulation in treatment of diabetic maculopathy. Lancet 2:1110, 1975

17. Blankenship GW: Diabetic macular edema and argon laser photocoagulation: A prospective randomized study. Ophthalmology 86:69, 1979

18. Townsend C, Bailey J, Kohner E: Xenon arc photocoagulation for the treatment of diabetic maculopathy: Interim report of a multicenter controlled clinical study. Br J Ophthalmol 64:385, 1980

19. Early Treatment Diabetic Retinopathy Study Research Group: Photocoagulation for diabetic macular edema. ETDRS Report No. 1. Arch Ophthalmol 103: 1796, 1986

20. Olk RJ: Modified grid argon (blue-green) laser photocoagulation for diffuse diabetic macular edema. Ophthalmology 93:938, 1986

21. Olk RJ: Argon green (514 nm) versus krypton red (647 nm) modified grid laser photocoagulation for diffuse diabetic macular edema. Ophthalmology 97:1101, 1990

22. Early Treatment Diabetic Retinopathy Study Research Group: Treatment techniques and clinical guidelines for photocoagulation of diabetic macular edema. ETDRS Report No. 2. Ophthalmology 94:761, 1987

23. Early Treatment Diabetic Retinopathy Study Research Group: Photocoagulation for diabetic macular edema: Early Treatment Diabetic Retinopathy Study Report No. 4. Int Ophthalmol 27:265, 1987

24. Early Treatment Diabetic Retinopathy Study Research Group: Detection of diabetic macular edema: Ophthalmoscopy vs. photography. ETDRS Report No. 5. Ophthalmology 96:746, 1989

25. Bresnick GH: Diabetic maculopathy: A critical review highlighting diffuse macular edema. Ophthalmology 90: 1301, 1983

26. Lee CM, Olk RJ: Modified grid laser photocoagulation for diffuse diabetic macular edema: Long-term visual results. (submitted)

27. Diabetic Retinopathy Study Research Group: Photocoagulation treatment of proliferative diabetic retinopathy: The second report of the Diabetic Retinopathy Study findings. Ophthalmology 85:82, 1978

28. Diabetic Retinopathy Study Research Group: Four risk factors for severe visual loss in diabetic retinopathy: The third report of Diabetic Retinopathy Study findings. Arch Ophthalmol 97:654, 1979

29. Diabetic Retinopathy Study Research Group: Indication for photocoagulation treatment of diabetic retinopathy: Diabetic Retinopathy Study Report No. 14. Int Ophthalmol Clin 27:239, 1987

30. Davis MD: Proliferative diabetic retinopathy. In Ryan SJ (ed): Retina. St. Louis, CV Mosby, 1989

31. McDonald HR, Schatz H: Macular edema following panretinal photocoagulation. Retina 5:5, 1985

32. McDonald HR, Schatz H: Visual loss following panretinal photocoagulation for proliferative diabetic retinopathy. Ophthalmology 92:388, 1985

33. Meyers SM: Macular edema after scatter laser photocoagulation for proliferative diabetic retinopathy. Am J Ophthalmol 90:210, 1980

34. Early Treatment Diabetic Retinopathy Study Research Group: Techniques for scatter and local photocoagulation treatment of diabetic retinopathy: The Early Treatment Diabetic Retinopathy Study Report No. 3. Int Ophthalmol Clin 27:254, 1987

35. Shimizu K, Kobayashi Y, Muraoka K: Midperipheral fundus involvement in diabetic retinopathy. Ophthalmology 88:601, 1981

36. Niki T, Muraoka K, Shimizu K: Distribution of capillary nonperfusion in early stage diabetic retinopathy. Ophthalmology 91:1431, 1984

37. Gass JD: Retinal capillary diseases. In Gass JD (ed): Stereoscopic Atlas of Macular Diseases, p 368. St. Louis, CV Mosby, 1987

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