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Figure 44-6.  Moderate temporal dragging of the macula caused by regressed retinopathy of prematurity.

Table 44-1.  Differential Diagnosis of Retinopathy of Prematurity

treatment may be particularly helpful with posterior ROP. To date, no large randomized studies have been able to demonstrate systemic safety with this treatment, which is concerning with fragile, growing infants. These injections may reduce or eliminate the need for destructive retinal ablation and further evaluation is warranted.

21.What can be done for more advanced stages of retinopathy of prematurity?

Stage 4B and progressive stage 4A retinal detachments may be managed with lens-sparing vitrectomy. There is a 70% to 85% rate of retinal reattachment. Vitrectomy surgery may be tried for more advanced stage 5 ROP. However, the anatomic and visual success rates are extremely poor.

22.What are some of the late complications of retinopathy of prematurity?

The late complications of ROP include myopia, retinal pigmentation, dragging of the retina (Fig. 44-6), lattice-like vitreoretinal degeneration, retinal holes, retinal detachment, and angle-closure glaucoma. Obviously, these children need long-term follow-up by both a retina specialist and a pediatric ophthalmologist. Amblyopia and strabismus are also common.

23.What is the differential diagnosis for retinopathy of prematurity?

The differential diagnosis differs depending on the extent of the disease (Table 44-1). In less severe ROP, conditions that lead to peripheral retinal vascular changes and retinal dragging should be considered. In more severe disease the differential diagnosis of a white pupillary reflex must be considered.

Bibliography

American Academy of Pediatrics: Screening examination of premature infants for retinopathy of prematurity, Pediatrics 108:809–811, 2001.

An International Committee for the Classification of Retinopathy of Prematurity: The International Classification of Retinopathy of Prematurity revisited, Arch Ophthalmol 123:991–999, 2005.

Committee for the Classification of Retinopathy of Prematurity: An international classification of retinopathy of prematurity, Arch Ophthalmol 102:1130–1134, 1984.

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Cryotherapy for Retinopathy of Prematurity Cooperative Group: Multicenter trial of cryotherapy for retinopathy of prematurity: Snellen visual acuity and structural outcome at 5½ years after randomization, Arch Ophthalmol 114:417–424, 1996.

McNamara J, Tasman W, Brown G, Federman J: Laser photocoagulation for stage 3+ retinopathy of prematurity, Ophthalmology 98:576–580, 1991.

McNamara J, Tasman W, Vander J, Brown G: Diode laser photocoagulation for retinopathy of prematurity preliminary results, Arch Ophthalmol 110:1714–1716, 1992.

Early Treatment For Retinopathy of Prematurity Cooperative Group: Revised indications for the treatment of retinopathy of prematurity: results of the early treatment of retinopathy of prematurity randomized trial, Arch Ophthalmol 121: 1684–1694, 2003.

Hartnett ME, Maguluri S, Thompson HW, McColm JR: Comparison of retinal outcomes after scleral buckling or lens-sparing vitrectomy for stage 4 retinopathy of prematurity, Retina 24:753–757, 2004.

International Committee for the Classification of the Late Stages of Retinopathy of Prematurity: An international classification of retinopathy of prematurity. II: The classification of retinal detachment, Arch Ophthalmol 105:906–912, 1987.

Lakhanpal RR, Sun RL, Albini TA, Holz ER: Anatomic success rate after 3-port lens-sparing vitrectomy in stage 4A or 4B retinopathy of prematurity, Ophthalmology 112:1569–1573, 2005.

Quinn G, Dobson V, Barr C, et al.: Visual acuity in infants after vitrectomy for severe retinopathy of prematurity, Ophthalmology 98:5–13, 1991.

Vander J, Handa J, McNamara J, et al.: Early laser photocoagulation for posterior retinopathy of prematurity: randomized controlled clinical trial, Ophthalmology 104:1731–1734, 1997.

1.How is diabetic retinopathy classified? What fundus features are characteristic of each category?

•Nonproliferative diabetic retinopathy (NPDR): This form is arbitrarily divided into three categories based on severity: mild, moderate, and severe. Features of mild and moderate nonproliferative retinopathy result predominantly from loss of capillary integrity (i.e., microaneurysms, dot-and-blot hemorrhages, hard yellow exudates, and macular edema) (Fig. 45-1). Cotton-wool spots are also seen. Features of more severe NPDR are related to early signs of ischemia. In addition to the features found in mild nonproliferative disease, the fundus shows venous beading and intraretinal microvascular abnormalities (IRMAs) as well as more extensive intraretinal hemorrhages (Fig. 45-2).

•Proliferative diabetic retinopathy (PDR): Typical features are related to the consequences of extensive retinal capillary nonperfusion. Fundus findings include those of NPDR as well as the development of neovascularization of the disc (NVD; Fig. 45-3), neovascularization elsewhere in the retina (NVE), preretinal and/or vitreous hemorrhage, and vitreoretinal traction with tractional retinal detachment.

2.What is the most common cause of vision loss in diabetic retinopathy?

The most common cause of vision loss in diabetic retinopathy is macular edema.

3.Who is at risk for the development of diabetic retinopathy?

All patients with diabetes mellitus are at risk for diabetic retinopathy. Relative risk factors include the following:

•Duration of diabetes: The longer diabetes has been present, the greater the risk of some manifestation of diabetic retinopathy. After 10 to 15 years, more than 75% of patients show some signs of retinopathy.

•Age: Diabetic retinopathy is uncommon before puberty even in patients who were diagnosed shortly after birth. NPDR appears sooner in patients diagnosed with diabetes after the age of 40. This may be related to duration of disease before diagnosis.

•Diabetic control: The Diabetic Control and Complications Trial (DCCT) clearly demonstrated a correlation between poor long-term glucose control and subsequent development of diabetic retinopathy as well as other complications of diabetes.

•Renal disease: Proteinuria is a particularly good marker for the development of diabetic retinopathy. This association may not be causal, but a patient with renal dysfunction should be followed more closely.

•Systemic hypertension: Again, the causal nature of the relationship is not certain.

•Pregnancy: Diabetic retinopathy may progress rapidly in patients who are pregnant. Patients with preexisting retinopathy are at particular risk.

Figure 45-1.  Nonproliferative diabetic retinopathy with exudates, hemorrhages, and edema.

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Figure 45-2.  Severe nonproliferative retinopathy with venous beading and intraretinal microvascular abnormalities.

Figure 45-3.  Neovascularization of the disc in proliferative retinopathy.

KEY POINTS: MECHANISMS OF VISION LOSS IN DIABETES

1.Macular edema

2.Macular ischemia

3.Vitreous hemorrhage

4.Macular traction detachment

5. Combined rhegmatogenous/tractional retinal detachment

4.What is the significance of the hemoglobin A1C? What is its correlation with the development of diabetic retinopathy?

Hemoglobin A1C is serum glycosylated hemoglobin. It is an indicator of the average level of serum glucose for the preceding 3 months. Thus it provides a report card of the adequacy of glucose control for the preceding 3 months without identifying peaks, valleys, or timing of glucose fluctuation. The hemoglobin

A1C has been found to correlate most closely with the development of diabetic retinopathy. Nondiabetic patients typically have a level of 6 or less. The DCCT demonstrated that hemoglobin A1C of less than 8 was associated with a significantly reduced risk of retinopathy compared with a value greater than 8.

5.What is the recommendation for screening patients with diabetes?

Patients with juvenile insulin-dependent diabetes should have a dilated ophthalmologic examination 5 years after diagnosis. Patients with type II adult-onset diabetes should be examined at diagnosis. All diabetic patients should have an annual dilated funduscopic examination; more frequent examinations depend on the findings.

6.What are the fluorescein angiographic features of nonproliferative and proliferative diabetic retinopathy?

•In mild-to-moderate nonproliferative retinopathy the large vessels fill normally. Pinpoint areas of early hyperfluorescence correspond to microaneurysms, whereas dot-and-blot hemorrhages are hypofluorescent. Microaneurysms leak in the later frames with blurring of margins and diffusion of fluorescein dye, whereas hemorrhages remain hypofluorescent throughout the study. Telangiectasis hyperfluoresces with late leakage. Hard yellow exudate generally does not appear on a fluorescein angiogram unless it is extremely thick, in which case it is hypofluorescent. Macular edema usually is apparent as fluorescein leaks into the retina as the angiogram progresses (Figs. 45-4 and 45-5).

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Figure 45-4.  Early phase fluorescein angiogram shows pinpoint hyperfluorescence corresponding to microaneurysms.

Figure 45-5.  Later phase fluorescein angiogram shows leakage with diffusion of dye and blurring of the microaneurysms.

Figure 45-6.  Neovascularization (arrow) is markedly hyperfluorescent early and develops at the border of perfused and nonperfused retina.

•More severe nonproliferative retinopathy has the features noted above as well as evidence of retinal capillary loss. Cotton-wool spots are usually hypofluorescent, sometimes with late hyperfluorescence along the margins. Areas of capillary dropout appear as smooth, hypofluorescent “ground-glass” patches, with staining at the margins in the later frames of the angiogram. IRMAs fill in the arterial phase of the angiogram and does not leak significantly in the later frames (Fig. 45-6).

•Proliferative retinopathy. Extensive retinal capillary loss is seen early in the angiogram with diffuse leakage at the edges of the ischemic areas in the later frames. NVD and NVE show intense early hyperfluorescence with marked leakage developing rapidly (Fig. 45-7).

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Figure 45-7.  Intraretinal microvascular abnormalities do not leak on fluorescein angiography.

Figure 45-8.  Four months after focal laser, the edema and exudate are gone.

7.What is the definition of clinically significant macular edema?

Clinically significant macular edema (CSME), as defined in the Early Treatment Diabetic Retinopathy Study (ETDRS), is present in patients with any one of the following:

•Retinal thickening within 500 microns of the center of the fovea

•Hard yellow exudate within 500 microns of the center of the fovea with adjacent retinal thickening (Fig. 45-8)

•At least one disc area of retinal thickening, any part of which is within one disc diameter of the center of the fovea

CSME describes the fundus features as seen on stereoscopic high-magnification viewing of the

macula. Visual acuity is not relevant; a patient with 20/20 vision may still have CSME. The fluorescein angiographic appearance is not relevant for the definition of CSME. Monocular viewing of the macula with a direct ophthalmoscope or a solitary color photograph is not adequate for diagnosing CSME, nor is the low-magnification view provided by the indirect ophthalmoscope.

KEY POINTS: CLINICAL FEATURES OF CLINICALLY SIGNIFICANT MACULAR EDEMA

1. Macular thickening within 500 microns of the center of the fovea or

2. Hard exudates within 500 microns of the center of the fovea with adjacent thickening or

3. Macular thickening of one disc area, any part of which is within one disc diameter of the center of fovea

8.What are the results of the ETDRS concerning treatment of diabetic macular edema?

The ETDRS showed that macular laser treatment for patients with CSME reduced the risk of doubling of the visual angle (for example, 20/40 worsening to 20/80) from 24% to 12% over a 3-year period. This benefit was detected over all levels of visual acuity. Significant visual improvement is uncommon after macular laser treatment. The goal is to prevent worse vision in the future. Treatment is directed at areas of diffuse leakage by using a grid pattern and at areas of focal leakage by direct treatment of the leaking abnormality (Fig. 45-9). Resolution of macular edema may take several months and re-treatment is occasionally necessary.

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Figure 45-9.  Clinically significant macular edema with thickening and exudate within 500 microns of the center of the fovea.

Figure 45-10.  Panretinal photocoagulation several months after treatment.

9.What other findings did the ETDRS report?

The ETDRS also was designed to determine whether aspirin use was helpful or harmful in patients with diabetic retinopathy; the study concluded that it was neither. The study also assessed the role of early panretinal laser treatment for proliferative disease (see further discussion).

10.What is the definition of high-risk characteristics?

High-risk characteristics (HRC) was used by the Diabetic Retinopathy Study (DRS) to describe patients at a high risk of severe vision loss from PDR. The study found that patients with (1) NVE and vitreous hemorrhage, (2) mild NVD and vitreous hemorrhage, and (3) moderate or severe NVD with or without vitreous hemorrhage are at high risk for severe vision loss over the ensuing 3 years. Initiation of full-scatter panretinal photocoagulation (PRP) greatly reduced the risk of severe vision loss in patients with HRC (Fig. 45-10). Subsequently, the EDTRS found that for patients with severe nonproliferative retinopathy and/or early proliferative retinopathy without HRC, there was no clear-cut benefit to initiation of full-scatter PRP. As long as careful follow-up can be ensured, PRP may be safely withheld in such cases.

KEY POINTS: DRS HIGH-RISK CHARACTERISTICS

1. Neovascularization of the disc of ¼ to 1⁄3 of the disc area 2. NVD of <¼ of the disc area with any vitreous hemorrhage

3. Neovascularization elsewhere in the retina with any vitreous hemorrhage

11.What are the side effects of PRP?

PRP does not improve vision but is performed to prevent the blinding complication of proliferative retinopathy. Loss of peripheral vision and night vision are the major concerns. Loss of central vision also may result from exacerbation of macular edema. Thus, if possible, macular focal laser should be performed before PRP when both are indicated. Other complications include impaired accommodation, papillary dilation, and inadvertent macular burns.

12.Do all patients treated with PRP show resolution of HRC?

No. As many as one-third of patients do not show resolution of NVD or NVE, and in some cases there will be no apparent regression.

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13.What is the role of supplemental PRP?

The DRS evaluated the placement of 2000 spots of PRP. For patients who do not show regression of high-risk characteristics or who have persistent vitreous hemorrhage, it is not clear whether additional PRP improves the long-term visual prognosis. Patients have been reported with 7000 or more spots of PRP, and in some cases recurrent vitreous hemorrhage persists.

14.What are the indications for fluorescein angiography in diabetic retinopathy?

Fluorescein angiography is not part of the definition of either clinically significant macular edema for patients with nonproliferative retinopathy or HRC for patients with proliferative disease. The indications for treatment are based on clinical rather than angiographic features. Nevertheless, fluorescein angiography is important, particularly for patients with diabetic maculopathy. Most patients considered for treatment of macular edema should have a fluorescein angiogram to determine the focal and diffuse areas of leakage and thus to guide the treating physician during placement of the laser. Areas of capillary nonperfusion also are treated with a grid pattern, which can be determined angiographically. The proximity of focal areas of leakage to the foveal avascular zone (FAZ) also can be demonstrated on fluorescein angiography. Treatment too close to the FAZ carries a higher risk of vision loss and therefore should be done with caution. In patients with unexplained vision loss, the cause may be macular ischemia, which is nicely demonstrated on fluorescein angiography. Finally, patients with a vitreous hemorrhage of uncertain etiology may benefit from a fluorescein angiogram. In patients with significant media opacity a fluorescein angiogram may demonstrate retinal neovascularization that was not apparent clinically.

15.What are the possible uses of optical coherence tomography in the management of diabetic retinopathy?

Optical coherence tomography (OCT) provides a noninvasive, photographic method for obtaining a cross-sectional view of the macula. Macular thickness and volume may be quantified, providing an objective measurement that is especially useful when serial studies are available and progression or response to treatment can be evaluated. Significant vitreomacular traction, if present, lends insight into a possible mechanism for the presence of macular edema and points toward vitrectomy as a therapeutic option. OCT may also show significant macular thinning as can sometimes occur after treatment of macular edema. This may explain a poor visual result in an eye after resolution of intraretinal fluid.

16.What is the differential diagnosis of diabetic retinopathy?

The differential diagnosis includes branch or central retinal vein obstruction, ocular ischemic syndrome, radiation retinopathy, hypertensive retinopathy, and miscellaneous proliferative retinopathies such

as sarcoidosis, sickle cell hemoglobinopathy, and other less common causes. In patients with typical macular features of nonproliferative retinopathy such as microaneurysms and macular edema, but no evidence of diabetes mellitus, the disease usually is categorized as idiopathic juxtafoveal telangiectasia.

17.What is the significance of neovascularization of the iris in diabetes?

Neovascularization of the iris (NVI) is an ominous sign of severe PDR and generally requires urgent treatment. NVI may progress to occlude the trabecular meshwork in a relatively short period, leading to severe neovascular glaucoma. This dreaded complication of proliferative disease usually can be avoided if heavy PRP can be placed before the angle has become occluded.

18.What are the indications for vitrectomy in diabetic retinopathy?

•Vitreous hemorrhage: Vitreous hemorrhage obscuring the visual axis causes severe vision loss. Although it generally clears spontaneously, for patients with more extensive hemorrhage,

vitrectomy may be indicated. The Diabetic Retinopathy Vitrectomy Study concentrated on eyes with vitreous hemorrhage reducing vision to 5/200 or worse. The study demonstrated a strong benefit for patients with type I diabetes, perhaps related to extensive fibrovascular proliferation. Guidelines are variable, but most surgeons wait at least 3 months for patients to clear spontaneously unless occupational or personal needs demand early intervention or extensive untreated fibrovascular proliferation is known to be present. The development of NVI also may prompt earlier vitrectomy.

•Tractional retinal detachment: Most surgeons agree that tractional retinal detachment involving the macula is an indication for diabetic vitrectomy. If the vitreoretinal traction can be relieved within weeks or a few months of onset, visual results are excellent. Long-standing tractional retinal detachments generally do not respond favorably in terms of visual recovery. Progressive extramacular tractional retinal detachment moving toward the fovea is occasionally an indication for surgery, although this is controversial.