Chapter 123 – Retinal Arterial Macroaneurysms

Chapter 123 – Retinal Arterial Macroaneurysms

 

JANICE E. CONTRERAS

ROBERT A. MITTRA

WILLIAM F. MIELER

JOHN S. POLLACK

 

 

 

 

 

DEFINITION

• Localized fusiform or saccular dilation of a retinal arterial vessel within the first three orders of bifurcation.

 

KEY FEATURES

• Retinal hemorrhage (intraretinal, subretinal, preretinal, and vitreous).

• Protein and lipid exudation.

• Macular edema.

 

ASSOCIATED FEATURES

• Leaking, telangiectatic vessels in the capillary bed that surrounds the macroaneurysm.

• Retinal artery occlusion.

• Retinal vein occlusion.

 

 

 

INTRODUCTION

Although aneurysms of the retinal arteries have been noted since the early 1900s, Robertson[1] in 1973 was the first to coin the term macroaneurysm to describe a distinct clinical entity that consisted of an acquired focal dilation of a retinal artery within the first three orders of bifurcation. Macroaneurysms vary from 100–250?µm in diameter, are saccular or fusiform in shape, and are differentiated readily from capillary microaneurysms, which are usually less than 100?µm in diameter. Retinal arterial macroaneurysms can be further differentiated from the vessel dilations seen in Coats’ disease, which are multiple saccular outpouches of predominantly the venous and capillary system, associated with marked telangiectasia and lipid exudation, primarily found in young males.

Although the clinical course of a retinal arterial macroaneurysm is often benign, in some cases significant visual morbidity results from macular hemorrhage, exudate, or edema, or from the development of a vitreous hemorrhage.

EPIDEMIOLOGY AND PATHOGENESIS

Retinal arterial macroaneurysms tend to occur in older people; most case series include subjects over the age of 60 years. [2] [3] [4] [5] [6] [7] Multiple studies conclusively confirm a marked female preponderance, in the range of 60–100%. [2] [3] [4] [5] [6] [7] [8] Macroaneurysms typically occur in one eye, with bilaterality in less than 10%. [9] The most consistent systemic association of retinal arterial macro-aneurysms is with hypertension—a large controlled study reported it in 79% of patients. [7]

The exact pathogenesis of a macroaneurysm is unknown, but several authors have developed compelling theories. Many have compared retinal arterial aneurysms to cerebral arterial aneurysms, which are generally 100–300?µm in diameter, are also more common in women than men, and occur in patients over 50 years of age with a history of hypertension.[1] [6] [10] Chronic hypertension, along with the replacement of arterial smooth muscle by collagen associated with aging, may effect a focal dilation of the arterial wall in an area of weakness or prior damage. Lavin et al.[6] postulated that macroaneurysms are detected more frequently at arteriovenous crossings, because at these locations the arterial and venous walls are in contact without an adventitial layer, which results in an area of limited structural support. Other investigators have noted the development of macroaneurysms at the sites of previously detected emboli.[4] [11] They hypothesize that focal arterial damage secondary to embolization can lead to aneurysm formation. Gass now believes that the focal, yellow arterial plaques present are actually atheromas that occur at the site of defects in the arterial wall.[12] He proposes that the previously reported emboli were, in fact, atheromas.

Abdel-Khalek and Richardson[5] detected specific differences between aneurysms that led to hemorrhagic complications and those that resulted in lipid exudation. They found that saccular or “blowout” aneurysms were more prone to bleed, possibly as a result of a thin, stretched aneurysmal sac. This type of lesion develops closer to the optic nerve head, where perfusion pressures are higher.[6] In addition, systolic blood pressures above 200?mmHg are more common in patients who have bleeding macroaneurysms. Fusiform dilations, on the other hand, are more prone to result in exudation and to be associated with venous occlusions.[5] [6] It is possible that the cause of those aneurysms that eventually lead to hemorrhagic complications is more dependent on hypertension and vessel wall damage, while the cause of those that lead to exudation is more contingent upon local vascular factors.

OCULAR MANIFESTATIONS

The clinical picture of macroaneurysms can be highly variable, dependent on whether the macroaneurysm is hemorrhagic or exudative in nature. Hemorrhagic macroaneurysm can result in acute loss of vision with evidence of subretinal, intraretinal, or preretinal hemorrhage on ocular examination ( Fig. 123-1 ). Often the hemorrhage obscures the site of the aneurysm, but the presence of a localized preretinal and subretinal hemorrhage over a major retinal artery should suggest the possibility of its presence. A nonclearing vitreous hemorrhage without evidence of retinal tear or posterior vitreous detachment may be the result of a macroaneurysm. Because bleeding tends to thrombose the aneurysm, detection once the hemorrhage has cleared may be difficult. The involved artery often retains a focal tortuosity or Z-shaped kink at the location of the involuted aneurysm, which lends indirect evidence in support of the diagnosis.

Patients also can experience a more gradual decline in vision secondary to serous fluid and lipid accumulation in the macula ( Fig. 123-2 ). Exudative macroaneurysms most often are located on the temporal vascular arcades, although rarely macroaneurysms can occur on the optic nerve head, cilioretinal artery, and nasal vessels.[13] [14] They frequently demonstrate a circinate lipid pattern (see Fig. 123-2 ). Finally, asymptomatic macroaneurysms

 

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Figure 123-1 Hemorrhagic macroaneurysm. Note the preretinal and subretinal hemorrhages directly above and below the artery.

 

 

Figure 123-2 Exudative macroaneurysm. Note the aneurysm along the superotemporal arcade, with marked lipid exudation that extends into the central macula.

may be discovered on routine examination. These have only a small (or absent) cuff of hemorrhage and lipid exudation associated with them. Up to 10% of macroaneurysms may be pulsatile initially; although some investigators maintain that this shortly precedes rupture, most believe it is of no prognostic significance.[9]

A well-documented association of macroaneurysms occurs with retinal vein occlusions, often in the artery that serves the vascular territory of the occluded vein.[7] Distal arterial narrowing and arterial occlusion of the involved vessel also are common and have been reported to occur in 26% and 8% of cases, respectively.[7] In addition, one report exists of the development of retinal macroaneurysms in a 62-year-old patient who has a history of congenital arteriovenous communications. [15]

DIAGNOSIS AND ANCILLARY TESTING

Diagnosis of lesions is based on the characteristic fundus appearance, as described above. Macroaneurysms which have undergone closure may be recognized by Z-shaped deformities in the involved vessel (see above).

Fluorescein angiography may reveal or confirm the presence of a macroaneurysm, usually demonstrating immediate, complete filling of the aneurysm ( Fig. 123-3 ). In some cases, irregular and incomplete filling may be associated with partial thrombosis, and a faint shell (or no) fluorescence may be displayed with a completely involuted macroaneurysm. [9] Leakage from the wall of the aneurysm is common in active lesions. Evidence of arteriolar narrowing usually is present proximal and distal to the macroaneurysm.[12] In many cases, microvascular abnormalities

 

 

Figure 123-3 Fluorescein angiogram of a typical macroaneurysm. Note the complete early filling of the macroaneurysm with fluorescein dye.

 

 

 

 

Figure 123-4 Macroaneurysm with surrounding dilated and telangiectatic capillary bed. A, Note the large bilobed macroaneurysm with surrounding circinate lipid. B, The fluorescein angiogram shows dilated, tortuous capillaries and microaneurysms surrounding the macroaneurysm. (Courtesy of Susan Fowell, MD.)

surround the aneurysm, including a wider capillary-free zone, capillary dilation, capillary nonperfusion, microaneurysms, and intra-arterial collateral vessels[12] ( Fig. 123-4 ).

In cases with dense hemorrhage when fluorescein angiography does not provide definitive evidence of a retinal arterial macroaneurysm, indocyanine green angiography may be a useful adjunct.[16] Because the absorption and emission spectra are in the near-infrared range, the dye can better penetrate through dense hemorrhages, revealing structures that may otherwise be obscured. Additionally, in treatment of a macroaneurysm, indocyanine green dye may leak less than fluorescein, thus providing well-defined images.[16]

 

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Figure 123-5 Venous macroaneurysm secondary to branch retinal vein occlusion. A, Note the venous aneurysm superior to the disc occurring in the setting of a branch retinal vein occlusion. B, Fluorescein angiogram showing hyperfluorescence in the venous anerysm. There was no late leakage from this lesion. (Courtesy of Susan Anderson-Nelson.)

DIFFERENTIAL DIAGNOSIS

Many clinical entities simulate retinal arterial macroaneurysms. Schulman et al.[17] reported large-capillary aneurysms secondary to retinal venous obstruction. These aneurysms are similar in dimension to macroaneurysms, but they originate from the venous side of the capillary bed and may result in visual loss from macular edema, serous elevation of the macula, and circinate lipid exudation.

Venous macroaneurysms also are seen after retinal vein obstruction [18] [19] ( Fig. 123-5 ). Cousins et al.[19] recently reviewed their patients involved in the Branch Vein Occlusion Study and noted four types of aneurysms in the area of the vein occlusion:

• Arterial macroaneurysms

• Capillary macroaneurysms (Schulman et al. [17] )

• Venous macroaneurysms

• Collateral-associated macroaneurysms

All four types were associated with hemorrhagic and lipid exudation and were found in areas of capillary nonperfusion.

Kimmel et al.[20] reported a case of a temporal branch retinal vein obstruction that masqueraded as a macroaneurysm with the Bonet sign, which consists of hemorrhage at an arteriovenous crossing that indicates an incipient branch vein occlusion. Given the similar patient characteristics and that these two entities are seen together often, differential diagnosis can be difficult. One patient was reported to have had a Valsalva episode that resulted in rupture of a retinal arterial macroaneurysm.[21] In another report, a lesion that simulated an optic nerve head tumor associated with a branch retinal arterial obstruction was eventually diagnosed as a macroaneurysm after 6 months of follow-up.[13]

 

 

 

 

Figure 123-6 Coats’ disease. A, The classic fundus picture of Coats’ disease with massive lipid exudation causing an exudative retinal detachment. B, Fluorescein angiogram from the same patient with large telangiectatic vessels and numerous leaking aneurysms.

Retinal telangiectasia of Coats’ disease can be differentiated from a macroaneurysm based on age of onset, gender predilection, multiplicity of aneurysmal dilations that involve mainly the venous and capillary systems, and association with a large net of telangiectatic vessels, as revealed on fluorescein angiography ( Fig. 123-6 ). The adult–Coats’ or juxtafoveal telangiectasis syndrome also can be distinguished on the basis of multiple, small-caliber telangiectatic vessels observed in the characteristic temporal macular location; however, one report of a typical macroaneurysm that developed into a Coats’ disease–like picture demonstrates that the distinction can sometimes be blurred.[8]

Capillary hemangiomas of the retina usually are associated with retinal edema, exudate, and hemorrhage-like macroaneurysms, but they are typically peripheral and generally have large dilated, tortuous afferent and efferent vessels. Angiomas also can occur on the optic nerve head, where differentiation from macroaneurysms may be particularly difficult. Capillary hemangiomas usually are inherited and often are seen as part of Von Hippel–Lindau disease, which is autosomal dominant with multiple systemic findings that include cerebellar hemangioblastoma, renal cell carcinoma, and pheochromocytoma. A nonfamilial form of acquired angioma, however, which lacks the characteristic large dilated vessels, has been described and more easily can be confused with macroaneurysm[22] ( Fig. 123-7 ). The acquired lesions are either primary, idiopathic, or secondary to a variety of underlying ocular conditions, most commonly retinitis pigmentosa and uveitis.[23] These lesions, or vasoproliferative tumors, can display considerable growth seen on long-term follow-up, which further differentiates them from macroaneurysms.[24]

The accumulation of a subretinal hemorrhage in the macula from a macroaneurysm in an elderly patient with evidence of drusen and pigmentary changes may be confused with a choroidal

 

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Figure 123-7 Idiopathic retinal vasoproliferative tumor. A typical inferiorly located lesion with conspicuous lack of dilated feeder and drainage vessels. (From McCabe CM, Mieler WF. Arch Ophthalmol. 1996;114[5]:617.)

 

 

 

 

Figure 123-8 Submacular hemorrhage simulating choroidal neovascularization. A, Prominent submacular hemorrhage in an elderly patient simulating choroidal neovascular membrane. B, Same patient 3 months later following spontaneous resolution of hemorrhage.

 

neovascular membrane from age-related macular degeneration ( Fig. 123-8 ). If suspicion of a macroaneurysm exists, then careful examination of the nearby artery and fluorescein angiography are indicated.

There are several reported cases of retinal arterial macroaneurysms with massive subretinal hemorrhage appearing as a dark mass simulating choroidal melanoma.[25] Fluorescein angiography and ultrasonography can aid in the diagnosis.

A distinct entity of multiple aneurysms that involve all the major retinal vessels in both eyes, with neuroretinopathy, vitreous and anterior chamber inflammation, and angiographic evidence of arteritis, has been called the IRVAN (idiopathic retinal vasculitis, aneurysms, and neuroretinitis) syndrome[12] [26] [27] ( Fig. 123-9 ). The cause of this rare disorder is unknown. The disparate clinical findings and the young age range of the patients readily differentiate it from macroaneurysms.

 

 

 

 

Figure 123-9 IRVAN syndrome. A, Multiple arterial dilations in a patient with IRVAN syndrome. B, Fluorescein angiogram readily documents the numerous aneurysms in the juxtapapillary region.

SYSTEMIC ASSOCIATIONS

The only consistent systemic association with retinal arterial aneurysms is systemic arterial hypertension. In a case-control series this was observed in 79% of patients with macroaneurysm and 55% of controls. The difference was found to be statistically significant. The evaluation of a patient who has a macroaneurysm but who has no previous history of hypertension should include the measurement of blood pressure.

PATHOLOGY

Gold et al.[28] described a pathology specimen from a patient with a single macroaneurysm and a large ring of circinate lipid in the macula. They found a macroaneurysm located at an arteriovenous crossing, surrounded by dilated capillaries and a heterogeneous accumulation of collagen, hemosiderin, and lipid, with a paramacular deposition of lipid and proteinaceous exudate in the outer plexiform layer. It was proposed that the dilated capillary network that surrounded the macroaneurysm was the source of serous and lipid exudation into the macula. Other reports of ruptured aneurysms have shown evidence of a break in the artery covered by a dense fibrin–platelet clot that contains blood, exudate, lipid-laden macrophages, hemosiderin, and fibroglial reaction products in amounts that vary among patients[29] ( Fig. 123-10 ).

TREATMENT, COURSE, AND OUTCOME

Although treatments using the xenon arc[4] [5] and argon[6] [10] [30] and dye yellow [30] [31] [32] [33] lasers, both directly at and around the macroaneurysm, have been described, a laser approach remains controversial. Most authors agree that hemorrhagic macroaneurysms, especially those which cause vitreous or preretinal hemorrhage, tend to thrombose and ultimately result in a better visual outcome than do exudative macroaneurysms, which may

 

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Figure 123-10 Retinal arteriolar macroaneurysm. PAS-stained trypsin-digest preparation. (Courtesy Streeten BW. In: Yanoff M, Fine BS. Ocular pathology, ed 4. London: Mosby; 1995.)

eventually cause macular edema.[2] [3] [5] [10] Therefore, patients who have decreased acuity secondary to retinal or vitreous hemorrhage probably should be followed for several months to enable spontaneous clearance. Many investigators believe that patients who have exudative macroaneurysm and significant macular involvement should undergo photocoagulation treatment, either directly to the lesion[4] [5] [32] [33] or to the surrounding capillary bed,[10] in an effort to close the macroaneurysm and the leaking perianeurysmal vessels. The rationale is that the poorest visual outcomes are observed when macular edema and lipid are allowed to remain for many months.

However, no prospective trial of laser therapy for macroaneurysm has been performed, and the several small uncontrolled clinical series demonstrate mixed results. Abdel-Khalek and Richardson[5] treated 10 eyes and noted visual improvement in two, with no change in seven, and a visual decrease in one. Palestine et al.[10] were unable to show a visual benefit using laser for eyes with macular pathology in six treated eyes versus five controls. Joondeph et al. [33] reported improvement in visual acuity in 8 of 12 cases using the dye yellow laser, while another recent case-control study showed that direct laser treatment resulted in a significantly greater risk for a visual acuity of less than 20/80 when compared with controls.[30] Laser surgery also is associated with an increased threat of arteriolar occlusion, which theoretically may be amplified when using the dye yellow laser.[7] [31] Until further definitive studies are performed to elucidate the proper role of and method for using lasers in the treatment of macroaneurysms, laser therapy should be reserved for select exudative macroaneurysms that involve the macula and threaten the fovea with the progressive accumulation of lipid. When employing laser, argon green or dye yellow lasers can be used with long-duration burns (0.2–0.5 seconds) and large spot sizes (500?µm in diameter).

Several additional modalities have been advocated for treatment of premacular and submacular hemorrhage associated with retinal arterial macroaneurysms. The neodymium: yttrium–aluminum–garnet laser (Nd:YAG) has been employed in the treatment of dense premacular hemorrhage in order to speed visual recovery and potentially limit tractional macular detachment. [34] [35] [36] Nd:YAG photodisruption creates a focal opening in the anterior surface of the preretinal hemorrhage to allow for drainage of entrapped hemorrhage into the vitreous cavity. In a study of six eyes with preretinal hemorrhage secondary to macroaneurysm formation, all eyes showed improvement of vision within 1 week of Nd:YAG photodisruption.[35] In a retrospective review of 21 eyes with premacular hemorrhage secondary to various causes, visual improvement occurred within 1 month in 16 of 21 eyes.[36] However, seven patients required an additional vitrectomy for nonclearing vitreous hemorrhage and complications including a macular hole and retinal detachment. The macular hole occurred in an eye with a premacular subhyaloid hemorrhage of only one disc diameter. The authors postulated that the small size of the hemorrhage did not provide a sufficient dampening effect for the laser burst, and they recommend laser drainage only if the hemorrhage is beyond three disc diameters in size.[36] This treatment modality can be used for rapid visual recovery, but it probably results in visual outcome no better than that with the natural course of the disease. Long-term studies are needed to better define the risks and benefits of laser photodisruption, especially in for hemorrhage associated with a retinal macroarterial aneurysm.

Pars plana vitrectomy with the use of tissue plasminogen activator (t-PA) has been advocated for the removal of dense, thick subretinal hemorrhage. [37] [38] Patients with submacular hemorrhage secondary to a retinal arterial macroaneurysm have had generally favorable visual outcomes with this technique.[3] However, it appears that patients with submacular hemorrhage secondary to retinal arterial macroaneurysms may obtain better visual outcomes than those with hemorrhage from other causes, such as age-related macular degeneration. McCabe et al.[39] recently reviewed the cases of 41 patients with macular hemorrhage secondary to retinal artery macroaneurysms managed with observation alone and found that good visual outcomes often could be achieved with observation alone (see Fig. 123-9 ). Furthermore, visual outcomes were similar to those of reported cases of patients with submacular hemorrhage secondary to retinal arterial macroaneurysm treated surgically.

Most recently, investigators have treated submacular hemorrhage using pneumatic displacement both with and without the adjunct of intravitreous t-PA. [40] [41] [42] Pneumatic displacement is a technique initially suggested by Heriot[40] for subfoveal hemorrhage. It consists of pretreatment with intravitreal t-PA followed by injection of perfluoropropane or sulfur hexafluoride gas, with prone positioning for at least 24 hours in order to compress the macula directly and displace the submacular hemorrhage inferiorly. His initial experience demonstrated displacement of the hemorrhage in 19 of 20 eyes with few complications. Hassan and colleagues[41] reviewed the cases of 15 eyes treated with t-PA and pneumatic displacement and found that subfoveal blood can be displaced effectively, often with substantial initial improvement in visual acuity. Because retinal toxic effects from t-PA have been observed in animal studies, investigators recommend avoiding intravitreous injections of t-PA in concentrations greater than 25?µg/0.1?ml.[41] Likewise, caution was advised in the use of intravitreous t-PA injection in patients with arterial macroaneurysm because of a possible increased risk of vitreous hemorrhage. Amid concerns of the toxicity of t-PA, Ohji et al. [42] reported a series of five patients treated with perfluoropropane gas followed by prone positioning, without pretreatment with t-PA. Vision improved and blood was displaced from the fovea partially or completely in all five patients. Nevertheless, they speculate that solid blood clots present longer than 1 week may not be displaced with gas compression alone.[42]

In summary, the preferred treatment for patients with macular hemorrhage secondary to retinal arterial macroaneurysm remains controversial. The precise role of these advanced vitreoretinal techniques in the treatment of macroaneurysm will be clarified only with further study.

 

 

REFERENCES

 

1. Robertson DM. Macroaneurysms of the retinal arteries. Trans Am Acad Ophthalmol Otolaryngol. 1973;77:OP55–67.

 

2. Cleary PE, Kohner EM, Hamilton AM, Bird AC. Retinal macroaneurysms. Br J Ophthalmol. 1975;59:355–61.

 

3. Nadel AJ, Gupta KK. Macroaneurysms of the retinal arteries. Arch Ophthalmol. 1976;94:1092–6.

 

4. Lewis RA, Norton EW, Gass JDM. Acquired arterial macroaneurysms of the retina. Br J Ophthalmol. 1976;60:21–30.

 

5. Abdel-Khalek MN, Richardson J. Retinal macroaneurysm: natural history and guidelines for treatment. Br J Ophthalmol. 1986;70:2–11.

 

6. Lavin MJ, Marsh RJ, Peart S, Rehman A. Retinal arterial macroaneurysms: a retrospective study of 40 patients. Br J Ophthalmol. 1987;71:817–25.

 

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7. Panton RW, Goldberg MF, Farber MD. Retinal arterial macroaneurysms: risk factors and natural history. Br J Ophthalmol. 1990;74:595–600.

 

8. Asdourian GK, Goldberg MF, Jampol LM, Rabb M. Retinal macroaneurysms. Arch Ophthalmol. 1977;95:624–8.

 

9. Rabb MF, Gagliano DA, Teske MP. Retinal arterial macroaneurysms. Surv Ophthalmol. 1988;33:73–96.

 

10. Palestine AG, Robertson DM, Goldstein BG. Macroaneurysms of the retinal arteries. Am J Ophthalmol. 1982;93:164–71.

 

11. Wiznia RA. Development of a retinal artery macroaneurysm at the site of a previously detected retinal artery embolus. Am J Ophthalmol. 1992;114:642–3.

 

12. Gass JDM. Stereoscopic atlas of macular diseases: diagnosis and treatment, vol 1, ed 4. St Louis: Mosby–Year Book; 1997:472–6.

 

13. Brown GC, Weinstock F. Arterial macroaneurysm on the optic disk presenting as a mass lesion. Ann Ophthalmol. 1985;17:519–20.

 

14. Giuffre G, Montalto FP, Amodei G. Development of an isolated retinal macroaneurysm of the cilioretinal artery. Br J Ophthalmol. 1987;71:445–8.

 

15. Tilanus MD, Hoyng C, Deutman AF, et al. Congenital arteriovenous communications and the development of two types of leaking retinal macroaneurysms. Am J Ophthalmol. 1991;112:31–3.

 

16. Townsend-Pico WA, Meyers SM, Lewis H. Indocyanine green angiography in the diagnosis of retinal arterial macroaneurysms associated with submacular and preretinal hemorrhages: a case series. Am J Ophthalmol. 2000;129:33–7.

 

17. Schulman J, Jampol LM, Goldberg MF. Large capillary aneurysms secondary to retinal venous obstruction. Br J Ophthalmol. 1981;65:36–41.

 

18. Sanborn GE, Magargal LE. Venous macroaneurysm associated with branch retinal vein obstruction. Ann Ophthalmol. 1984;16:464–8.

 

19. Cousins SW, Flynn HW, Clarkson JG. Macroaneurysms associated with retinal branch vein occlusion. Am J Ophthalmol. 1990;109:567–74.

 

20. Kimmel AS, Magargal LE, Morrison DL, Robb-Doyle E. Temporal branch retinal vein obstruction masquerading as a retinal arterial macroaneurysm: the Bonet sign. Ann Ophthalmol. 1989;21:251–2.

 

21. Avins LR, Krummenacher TK. Valsalva maculopathy due to a retinal arterial macroaneurysm. Ann Ophthalmol. 1983;15:421–3.

 

22. Shields JA, Decker WL, Sanborn GE, et al. Presumed acquired retinal hemangiomas. Ophthalmology. 1983;90:1292–300.

 

23. Shields CL, Shields JA, Barrett J, DePotter P. Vasoproliferative tumors of the ocular fundus. Arch Ophthalmol. 1995;113:615–23.

 

24. McCabe CM, Mieler WF. Six-year follow-up of an idiopathic retinal vasoproliferative tumor. Arch Ophthalmol. 1996;114:617.

 

25. Fritsche PL, Flipsen E, Polak BCP. Subretinal hemorrhage from retinal arterial macroaneurysm simulating malignancy. Arch Ophthalmol. 2000;118:1704.

 

26. Kincaid J, Schatz H. Bilateral retinal arteritis with multiple aneurysmal dilations. Retina. 1983;3:171–8.

 

27. Chang TS, Aylward W, Davis JL, et al. Idiopathic retinal vasculitis, aneurysms, and neuro-retinitis. Ophthalmology. 1995;102:1089–97.

 

28. Gold DH, La Piana FG, Zimmerman LE. Isolated retinal arterial aneurysms. Am J Ophthalmol. 1976;82:848–57.

 

29. Fichte C, Steeten BW, Friedman AH. A histopathologic study of retinal arterial aneurysms. Am J Ophthalmol. 1978;85:509–18.

 

30. Brown DM, Sobol WM, Folk JC, Weingeist TA. Retinal arteriolar macroaneurysms: long term visual outcome. Br J Ophthalmol. 1994;78:534–8.

 

31. Russel SR, Folk JC. Branch retinal artery occlusion after dye yellow photocoagulation of an arterial macroaneurysm. Am J Ophthalmol. 1987;104:186–7.

 

32. Mainster MA, Whitacre MM. Dye yellow photocoagulation of retinal arterial macroaneurysms. Am J Ophthalmol. 1988;105:97–8.

 

33. Joondeph BC, Joondeph HC, Blair NP. Retinal macroaneurysms treated with the dye yellow laser. Retina. 1989;9:187–92.

 

34. Raymond LA. Neodymium:YAG laser treatment for hemorrhages under the internal limiting membrane and posterior hyaloid face in the macula. Ophthalmol. 1995;102:406–11.

 

35. Ijima H, Satoh S, Tsukahara S. Nd:YAG laser photodisruption for preretinal hemorrhage due to retinal macroaneurysm. Retina. 1998;18:430–4.

 

36. Ulbig MW, Mangouritsas G, Rothbacher HH, et al. Long-term results after drainage of premacular subhyaloid hemorrhage into the vitreous with a pulsed ND:YAG laser. Arch Ophthalmol. 1998;116:1465–9.

 

37. Ibanez HE, Williams DF, Thomas MA, et al. Surgical management of submacular hemorrhage: a series of 47 consecutive cases. Arch Ophthalmol. 1995;113:62–9.

 

38. Humayun M, Lewis H, Flynn HW, et al. Management of submacular hemorrhage associated with retinal arterial macroaneurysms. Am J Ophthalmol 1998;126:358–61.

 

39. McCabe CM, Flynn HW, McLean WC, et al. Nonsurgical management of macular hemorrhage secondary to retinal artery macroaneurysms. Arch Ophthalmol. 2000;118:780–5.

 

40. Heriot WJ. Intravitreal gas and tPA: an outpatient procedure for submacular hemorrhage. Paper presented at: American Academy of Ophthalmology Annual Vitreoretinal Update; Chicago; October 1996.

 

41. Hassan AS, Johnson MW, Schneiderman TE, et al. Management of submacular hemorrhage with intravitreous tissue plasminogen activator injection and pneumatic displacement. Ophthalmology. 1999;106:1900–7.

 

42. Ohji M, Saito Y, Hayashi A, et al. Pneumatic displacement of subretinal hemorrhage without tissue plasminogen activator. Arch Ophthalmol. 1998;116:1326–32.

Chapter 122 – Proliferative Retinopathies

Chapter 122 – Proliferative Retinopathies

 

DANIEL A. EBROON

SRILAXMI BEARELLY

LEE M. JAMPOL

 

 

 

 

 

DEFINITION

• A heterogeneous group of disorders that features preretinal and optic disc neovascularization.

 

KEY FEATURES

• Retinal new blood vessels.

• Optic disc new blood vessels.

 

ASSOCIATED FEATURES

• Retinal ischemia.

• Retinal capillary nonperfusion.

• Posterior segment inflammation.

• Neoplasia.

• Vitreous hemorrhage and fibrous proliferation.

• Retinal detachment.

 

 

 

INTRODUCTION

The proliferative retinopathies are defined as diseases associated with preretinal or disc neovascularization.[1] These diseases can be divided into two major categories ( Box 122-1 ), each with its own subset of hereditary disorders:

• Systemic diseases

• Retinal vascular and ocular inflammatory diseases

The topic of retinal angiogenesis is first reviewed, after which specific entities with retinal neovascularization are described, along with treatment options. Finally, an approach is suggested for the management of a patient who has neovascularization of unknown cause.

RETINAL ANGIOGENESIS

Current models of neovascularization of the retina are based on the concept of chemoattractants. The initiating event in the retina may be ischemic, inflammatory, or neoplastic.

A critical level of hypoxia or inflammation may stimulate retinal tissue to release potent chemical mediators, which have corresponding receptors in the retinal vasculature that initiate neovascularization. There are numerous chemical mediators, which may be stimulatory or inhibitory. Some stimulatory mediators act directly on endothelial cells to cause migration and proliferation. Other stimulatory mediators act indirectly by the release of sequestered direct-acting factors or by the activation of macrophages.

Factors that act directly on endothelial cells include fibroblast growth factor, transforming growth factor-a, platelet-derived endothelial cell growth factor, angiotropin, angiotensin II, insulin-like growth factor-1, and vascular endothelial growth factor (VEGF). Factors that act indirectly on endothelial cells include transforming growth factor-ß, tumor necrosis factor-a, and certain prostaglandins. Numerous animal and laboratory models have demonstrated that VEGF is a significant stimulant of retinal and choroidal neovascularization. In these models, increased expression of VEGF in the retina stimulates neovascularization within the retina, while antagonists of VEGF receptor signaling inhibit retinal and choroidal neovascularization.[7] VEGF has been shown to be upregulated by hypoxia, and its levels are elevated in the retina and vitreous of patients and laboratory animals with ischemic retinopathies. [8] Investigations of antiangiogenic agents such as pigment epithelium–derived factor may prove useful in curtailing aberrant growth of ocular endothelial cells. [9]

Neovascularization has the potential to cause loss of vision because the vessels are fragile and rupture more easily than do normal retinal vessels. Patients may develop vitreous hemorrhage, fibrovascular scarring, epiretinal membranes, retinal traction, and both rhegmatogenous and tractional retinal detachments. Early detection of neovascularization and appropriate treatment may help minimize the risks of such complications.

ENTITIES ASSOCIATED WITH RETINAL NEOVASCULARIZATION

Systemic Diseases

DIABETES MELLITUS.

The vast majority of neovascularization in diabetes occurs posterior to the equator ( Fig. 122-1 ), but peripheral neovascularization may occur also. Both panretinal and local scatter photocoagulation are effective in the regression of neovascular tissue. A program of tight blood sugar control helps to prevent the development of neovascular tissue. The extent of hyperglycemia and, therefore, blood sugar control, over both the short and long term, may be ascertained by the measurement of blood glucose levels and the hemoglobin A1c values, respectively. (For a more detailed description of diabetic retinopathy, see Chapter 117 .)

HYPERVISCOSITY SYNDROMES.

Patients who have disease processes such as chronic myelogenous leukemia, essential thrombocytosis, or polycythemia vera may have dramatic elevations in their leukocyte, platelet, or red blood cell counts, respectively. Elevations may increase blood viscosity, causing a sludging of blood flow in the peripheral retina. The consequences of this abnormal flow include venular dilation, perivenous sheathing, capillary dropout, and microaneurysm formation. Neovascularization develops at the border of perfused and nonperfused retina.[10]

AORTIC ARCH SYNDROMES AND OCULAR ISCHEMIC SYNDROMES.

Patients who have atherosclerosis that involves the carotid artery or aortic arch, arteritis (e.g., Takayasu’s disease), or syphilitic aortic involvement may develop disc or peripheral retinal neovascularization.[11] Such patients have in common extensive narrowing of the large arteries that supply blood to the eye. The resultant ischemia may cause neovascularization of the disc and iris, in addition to peripheral retinal neovascularization. Although both cryopexy and scatter photocoagulation are helpful, they are less successful in these syndromes than others, perhaps because the vasoproliferative stimulus is so intense and diffuse within the eye (see Chapter 118 ).

CAROTID–CAVERNOUS FISTULA.

In a carotid–cavernous fistula, carotid arterial blood enters the cavernous sinus venous system directly, bypassing the eye, and consequent ischemia may stimulate retinal neovascularization.[12] Panretinal photocoagulation

 

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Retinal Neovascularization

SYSTEMIC DISEASE

 

Diabetes mellitus**

 

Hyperviscosity syndromes**

 

Aortic arch syndromes and ocular ischemic syndromes**

 

Carotid–cavernous fistula**

 

Multiple sclerosis**

 

Retinal vasculitis† †

 

• Systemic lupus erythematosus

• Arteriolitis with SS-A autoantibody

• Acute multifocal hemorrhagic vasculitis

• Vasculitis resulting from infection

• Vasculitis resulting from Behçet’s disease

Sarcoidosis† †

 

Coagulopathies**

 

 

SYSTEMIC DISEASES WITH A STRONG HEREDITARY COMPONENT

Sickling hemoglobinopathies**

 

• SC, SS, Sß thalassemia, SO Arab

Other hemoglobinopathies**

 

• AC and C-ß thalassemia

Small vessel hyalinosis**

 

Incontinentia pigmenti‡ ‡

 

Familial telangiectasia, spondyloepiphyseal dysplasia, hypothyroidism, neovascularization, and tractional retinal detachment‡ ‡

 

 

RETINAL VASCULAR AND OCULAR INFLAMMATORY DISEASE

• Eales’ disease**

• Branch retinal artery or vein occlusion**

• Frosted branch angiitis*, * [2]

• Idiopathic retinal vasculitis, aneurysms, and neuroretinitis*, * †, † [3]

• Retinal embolization** (e.g., talc)

• Retinopathy of prematurity**

• Encircling buckling operation**

• Uveitis including pars planitis† †

• Acute retinal necrosis† †

• Birdshot retinochoroidopathy† †

• Long-standing retinal detachment**

• Choroidal melanoma, choroidal hemangioma‡ ‡

• Cocaine abuse‡ ‡

• Optic nerve aplasia,*, * [4] myelinated nerve fiber layer*, * [5]

• Radiation retinopathy*, * [6]

 

RETINAL DISEASES WITH A STRONG HEREDITARY COMPONENT

Familial exudative vitreoretinopathy**

 

Inherited retinal venous beading**

 

Retinoschisis‡ ‡

 

Retinitis pigmentosa‡ ‡

 

Autosomal dominant vitreoretinochoroidopathy‡ ‡

 

 

*Vascular disease with ischemia.

† Inflammatory disease with possible ischemia.

‡ Stimulus for neovascularization is unclear.

 

 

 

 

 

Figure 122-1 Diabetes mellitus. A large area of neovascularization of the disc seen in a patient who has long-standing insulin-dependent diabetes mellitus.

has been used effectively to cause regression of neovascular tissue in patients who have carotid–cavernous fistulas.

MULTIPLE SCLEROSIS.

Patients who have multiple sclerosis demonstrate focal neurological deficits such as optic neuritis. Neuroimaging reveals characteristic central nervous system plaques. Such patients may develop uveitis, peripheral retinal venous inflammatory sheathing (Rucker’s sign), or arteriolar sheathing, which occurs less frequently. If the vasculitis affects blood flow, ischemia and neovascularization may ensue. [13] Local scatter photocoagulation has been shown to halt neovascularization in these patients.

RETINAL VASCULITIS.

Neovascularization may result from ocular inflammation. The neovascular signal may be from ischemia, because blood flow is impaired, or may be the result of vasoproliferative factors induced by the inflammatory response. Specific vasculitic entities that cause retinal neovascularization include systemic lupus erythematosus (SLE),[14] arteriolitis with SS-A autoantibody, acute multifocal hemorrhagic vasculitis, and vasculitis that occurs with infection (e.g., herpes viruses, toxoplasmosis, and cytomegalovirus[15] ).

In SLE, vascular proliferation may occur despite normal antinuclear antibody (ANA) or complement levels. Patients who have a constellation of findings that resemble SLE, and whose blood studies are ANA negative and SS-A autoantibody positive, also may develop proliferative changes. Patients affected by acute multifocal hemorrhagic vasculitis have decreased visual acuity, retinal hemorrhages, posterior retinal infiltrates, vitritis, and papillitis, and they also may develop retinal neovascularization.[16] It is recommended that neovascularization in such conditions be treated with panretinal scatter photocoagulation. Treatment of the underlying vasculitis with anti-inflammatory agents or immune suppression also may be beneficial.

SARCOIDOSIS.

Sarcoidosis is an idiopathic granulomatous disorder that affects multiple organ systems. The ocular manifestations are disparate and include uveitis with periphlebitis. Inflammation may stimulate neovascularization either by the direct liberation of an angiogenic stimulus or indirectly by blocking blood flow, which results in ischemia.[17] Both anti-inflammatory therapy (e.g., corticosteroids) and scatter laser photocoagulation are recommended for the treatment of retinal neovascularization (see Chapter 175 ).

Systemic Diseases That Have a Strong Hereditary Component

HEMOGLOBINOPATHIES.

Sickle-cell disease has been studied extensively as a cause of retinal neovascularization. As a result of this and its relatively high prevalence, it may serve as a model by which to understand and treat the proliferative retinal vasculopathies (see Chapter 119 ).

The sickling hemoglobinopathies are blood diseases that share the characteristic of erythrocytes that can assume the shape of an elongated crescent or sickle. Point mutations result in amino acid

 

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substitutions within the hemoglobin molecule that change its tertiary structure under conditions of low oxygen tension, acidosis, or hypercapnia. These abnormally shaped erythrocytes become trapped in precapillary arterioles or capillaries and disrupt circulation. Common tissues affected are those of the spleen, bones, lungs, and eyes. African-Americans, as well as people from Mediterranean countries, Africa, India, and Saudi Arabia, have a high prevalence of the sickling hemoglobinopathies.

Proliferative changes in the retinal periphery account for much of the morbidity from sickle-cell disease. Sickling of erythrocytes and changes of the vascular endothelium in the retinal periphery result in capillary nonperfusion. Ischemic signals lead to peripheral neovascularization that takes the shape of a sea fan, a type of coral.[18] Although the term sea fan is associated with sickle-cell retinopathy most commonly, almost any type of peripheral retinal neovascularization may assume this configuration. Recent investigations of angiogenic factors in proliferative sickle-cell retinopathy have demonstrated VEGF and basic fibroblast growth factor to be associated with sea fan formations.[19]

The likelihood of neovascularization depends on the type of sickling hemoglobinopathy. For example, patients who have hemoglobin SC disease are 10 times more likely to develop peripheral neovascularization than patients affected by hemoglobin SS disease. This difference may be partly secondary to the higher hematocrit and blood viscosity in hemoglobin SC disease.

Peripheral retinal neovascularization leads to loss of vision if fragile neovascular tissue hemorrhages into the vitreous. With repeated hemorrhages and vitreous degeneration, fibrovascular elements of the vitreous may exert traction on the retina, and tractional or rhegmatogenous retinal detachment may ensue. Fibrovascular proliferation or nonvascular epiretinal membranes that affect the macula can further degrade vision by the formation of macular pucker or macular holes.

The treatment of peripheral ischemic retina with scatter photocoagulation results in the regression of sea fans in the majority of cases.[20] Rarely, vitrectomy may be necessary.

Hemoglobinopathies other than sickle-cell disease may be associated with peripheral retinal neovascularization. For example, patients who have hemoglobin AC and C-ß thalassemia have rarely been reported to develop peripheral neovascularization.

INCONTINENTIA PIGMENTI.

Incontinentia pigmenti is a rare X-linked dominant disorder that tends to be lethal for male fetuses in utero, so nearly all affected patients are female. Patients have dermatological, neurological, dental, and ophthalmologic findings.

One third of patients with incontinentia pigmenti have ophthalmologic findings including cataracts, strabismus, optic atrophy, and foveal hypoplasia. The peripheral retinal vasculature often is poorly developed ( Fig. 122-2 ), and at the junction of normal and abnormal vasculature, arteriovenous anastomoses, microvascular anomalies, and neovascularization may develop.[21] Vitreous hemorrhage, retinal tears, and retinal detachment may ensue. Although a predilection for peripheral involvement of vascular changes is well established, the posterior pole can be affected by similar findings. Neovascularization has been treated effectively in some cases using cryopexy or laser.

Retinal Vascular and Ocular Inflammatory Diseases

EALES’ DISEASE.

Strictly defined, Eales’ disease is a bilateral disorder of young (20–45 years old), otherwise healthy adults in developing countries (especially India). These patients have periphlebitis and develop peripheral retinal capillary nonperfusion, often superotemporally. The etiology remains unknown. The designation of Eales’ disease sometimes is used for any patient who has peripheral neovascularization and no clinical or laboratory features that identify another specific entity.

The general principle that neovascularization occurs at the border of perfused and nonperfused retina applies to Eales’ disease.[22] Scatter photocoagulation of ischemic retina has been

 

 

Figure 122-2 Incontinentia pigmenti. The peripheral retina of a patient who has incontinentia pigmenti demonstrates somewhat elevated vessels with white vessel walls. The majority of these vessels show nonperfusion. The more posterior retina was perfused and the anterior retina was ischemic.

shown to cause regression of neovascular tissue, presumably by a modulation of the ischemic signal for neovascularization. Direct feeder-vessel treatment also has been used.

Overall, the visual prognosis in Eales’ disease is good, although patients may develop complications such as vitreous hemorrhage, tractional or rhegmatogenous retinal detachment, rubeosis irides, secondary glaucoma, or cataract.

BRANCH RETINAL VEIN OCCLUSION.

Retinal neovascularization can occur with branch retinal vein occlusion.[23] Complications include vitreous hemorrhage, epiretinal membranes, and tractional or rhegmatogenous retinal detachments. Local scatter photocoagulation may cause regression of neovascular tissue and prevent vitreous hemorrhage (see Chapter 115 ).

RETINAL EMBOLIZATION.

Intravenous drug abusers who intravenously inject chopped pills that contain talc may develop retinal neovascularization.[24] The talc reaches the ocular arterial system after passage through capillaries or collaterals in the pulmonary vascular system. The talc wedges in smaller caliber arterioles, such as those found in the macula and retinal periphery. Ischemia and neovascularization may ensue ( Fig. 122-3 ). The neovascularization is responsive to either local scatter photocoagulation or cryopexy.

RETINOPATHY OF PREMATURITY.

Retinopathy of prematurity (ROP) affects the peripheral vasculature of the retina. Normal vascularization of the retina commences at 4 months of gestation and usually is completed by 9 months. In some instances of low birth weight, prematurity, and supplemental administration of oxygen, the normal process of vascularization is interrupted. How this occurs is understood poorly, but it is thought that hyperoxia from supplemental oxygen may further interrupt normal vascular development, and hypoxia associated with maturing avascular retina may result in liberation of angiogenic stimuli. Some infants progress to neovascularization and its complications, which include tractional, exudative, or rhegmatogenous retinal detachment.[25]

Treatment of ROP hinges on its recognition. Risk factors for ROP must trigger careful examination and follow-up. Treatment involves the use of cryotherapy or scatter laser photocoagulation to the avascular peripheral retina. The object is to arrest actively proliferative lesions by treatment of presumably ischemic avascular retina, which helps to preserve an attached macula (see Chapter 115 ).

UVEITIS.

Some patients who have uveitis, especially intermediate uveitis (pars planitis), may develop neovascularization of the disc or peripheral retina. Uveitic neovascularization appears

 

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Figure 122-3 Talc retinopathy. An area of sea-fan neovascularization, with a small overlying vitreous hemorrhage is shown, in an intravenous drug abuser. Talc retinopathy is demonstrated elsewhere in the fundus.

to be determined by the severity of inflammation and presence of retinal nonperfusion. A trial of systemic steroids may be attempted and if ineffective, local scatter photocoagulation can be considered[26] (see Chapter 181 ).

ACUTE RETINAL NECROSIS.

Both herpes simplex and herpes zoster cause the acute retinal necrosis syndrome, with findings that include anterior uveitis, vitritis, retinal vasculitis, necrotizing retinitis, and retinal detachment. The inflammation and ischemia may stimulate vascular proliferation[27] (see Chapter 173 ).

BIRDSHOT CHORIORETINOPATHY.

Birdshot chorioretinopathy is characterized by white lesions in the deep retina or retinal pigment epithelium, and by vitritis, papillitis, and macular edema. Closure of peripheral retinal vessels may lead to vasoproliferation.[28] Local scatter photocoagulation has been shown to be beneficial.

LONG-STANDING RETINAL DETACHMENT.

Retinal ischemia in a patient who has a prolonged retinal detachment may result from disruption of either the retinal or choroidal supply of oxygen or nutrients to the retina. The neovascularization may appear angiomatous or may take the shape of a sea fan. Surgical repair of a rhegmatogenous detachment can cause regression of the neovascularization.[29]

CHOROIDAL MELANOMA AND HEMANGIOMA.

Both choroidal melanoma[30] and hemangioma,[31] perhaps by the release of a tumor angiogenic factor or secondary to retinal detachment over the tumor, can promote neovascularization that overlies the tumor. Treatment of a choroidal melanoma with radiation or scatter photocoagulation can cause regression of the neovascularization. Ocular tumors are covered in Part 9 .

Hereditary Retinal Diseases

FAMILIAL EXUDATIVE VITREORETINOPATHY.

Familial (dominant or X-linked) exudative vitreoretinopathy (FEVR) is a group of vascular disorders of the peripheral retina with findings on retinal examination that are very similar to those of ROP. However, FEVR differs from ROP in that patients usually are born at full term, have normal birth weight, and have not had supplemental oxygenation. In addition, a positive family history often is found. A demarcation line that separates vascular from avascular retina may occur in the retinal periphery. Peripheral retinal vessels assume a characteristic straightened course.

Presumably, an ischemic signal from the avascular retina stimulates neovascularization. These vessels may leak, form intraretinal or subretinal exudates, and result in exudative retinal

 

 

Figure 122-4 Retinitis pigmentosa. This fundus view demonstrates neovascularization of the disc, neovascularization elsewhere, and a small vitreous hemorrhage in a patient who has autosomal dominant retinitis pigmentosa.

detachment. Some eyes develop cicatricial changes, which include straightened retinal vessels, foveal ectopia, meridional folds, tractional retinal detachment, or rhegmatogenous retinal detachment. Other complications include cataract, band keratopathy, rubeosis iridis, neovascular glaucoma and, in some eyes, phthisis bulbi.[32] Patients with the X-linked variety of FEVR may have abnormalities in the same gene that causes Norrie’s disease.

As in ROP, treatment depends on early recognition. Cryotherapy and panperipheral photocoagulation of avascular retina have been shown to halt vasoproliferation in some patients.

INHERITED RETINAL VENOUS BEADING.

This rare entity has an autosomal dominant inheritance pattern. Findings on retinal examination include venous beading, microaneurysms, hemorrhages, exudates, neovascularization, and vitreous hemorrhage.[33] Panretinal scatter photocoagulation is advocated as treatment for neovascularization.

RETINOSCHISIS.

Patients who have X-linked (juvenile) retinoschisis, degenerative retinoschisis, or acquired retinoschisis with shaken baby syndrome[34] can develop retinal neovascularization. In X-linked retinoschisis, whitish deposits may be seen at the point where peripheral vessels appear to be occluded. Consequent to vascular occlusion, ischemia may promote neovascularization.[35]

RETINITIS PIGMENTOSA.

Patients who have retinitis pigmentosa can have neovascularization of the disc and retina ( Fig. 122-4 ). [36] The pathogenesis of the neovascularization is unknown but may be related to the inflammation seen in this disorder. These patients have diffuse loss of retinal pigment epithelial cells, so laser photocoagulation burns are difficult to create. Cryopexy has proved beneficial. Full details are given in Chapter 108 .

AUTOSOMAL DOMINANT VITREORETINOCHOROIDOPATHY.

Autosomal dominant vitreoretinochoroidopathy is a rare disorder in which the ocular findings include abnormal peripheral chorioretinal pigmentation that has a characteristic sharp demarcation near the equator. Patients also may manifest cataract, macular edema, retinal neovascularization, vitreous hemorrhage, and selective b wave reduction on an electroretinogram.[37]

OVERVIEW ON DIAGNOSING AND TREATING NEOVASCULARIZATION

If retinal neovascularization is identified and the cause is unknown ( Fig. 122-5 ), the physician should obtain a detailed

 

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Figure 122-5 Idiopathic proliferative retinopathy. The temporal periphery of the left retina demonstrates an elevated fibrovascular lesion like a sea fan in an African-American who was otherwise completely healthy. Tests for sickle-cell disease were negative and no causative factor for the neovascularization could be determined. The other eye has no peripheral fundus abnormalities.

medical, family, birth, and social history. ROP, talc retinopathy, diabetes, and familial exudative vitreoretinopathy all are diagnoses that a thorough history will help to uncover. Furthermore, with a detailed review of systems and a family history, disorders can be grouped quickly into one of the categories outlined in Box 122-1 . Finally, laboratory tests can be directed toward specific disorders suggested by the history and examination. For example, a suspected diagnosis of a hemoglobinopathy may be confirmed by hemoglobin electrophoresis.

When retinal neovascularization is identified, treatment often is given to prevent complications such as vitreous hemorrhage and rhegmatogenous retinal detachment. In addition to treatment of the underlying systemic condition, the neovascular tissue itself should be treated, if possible, by photocoagulation, cryopexy, or vitreoretinal surgery.

The rationale of treatment is to alter ischemic or inflammatory tissues so that the neovascular stimulus is suppressed. The argon laser may be used to create retinal burns. When hemorrhage or dense nuclear sclerotic cataracts are present, a red or diode laser may be used because these wavelengths penetrate such media better, or the cataract may be removed. In general, laser spots are scattered about one burn-width apart in areas of the retina thought to be ischemic. The power and duration settings on the laser are adjusted so that the laser burn appears as a moderate-intensity gray–white lesion.

If the retinal ischemic process seems to affect the entire retina diffusely, such as in diabetes mellitus, scatter photocoagulation should be placed throughout the peripheral retina (panretinal photocoagulation). Direct treatment of vessels flat on the retina that feed or drain neovascular tissue (feeder-vessel coagulation) is effective. However, such treatment has a greater incidence of complications, which include retinal tears or breaks in Bruch’s membrane, than does scatter treatment. Direct treatment of elevated neovascular tissue is not effective.

If neovascular tissue cannot be treated with the laser (e.g., because of a media opacity), then cryopexy may be useful. Similar to the laser, it is applied to peripheral ischemic retina and affects the neovascular tissue indirectly. Alternatively, vitreoretinal surgery is indicated for long-standing vitreous hemorrhage, for repair of rhegmatogenous or tractional retinal detachment, and when epiretinal membrane removal is needed. Removal of the posterior vitreous face also removes the scaffolding for further neovascularization. Furthermore, vitrectomy may remove angiogenic factors affecting the retinal vasculature.

 

 

REFERENCES

 

1. Jampol LM, Ebroon DA, Goldbaum MH. Peripheral proliferative retinopathies: an update on angiogenesis, etiologies, and management. Surv Ophthalmol. 1994;38:519–40.

 

2. Borkowski LM, Jampol LM. Frosted branch angiitis complicated by retinal neovascularization. Retina. 1999;19:454–5.

 

3. Chang TS, Aylward GW, Davis JL, et al. Idiopathic retinal vasculitis, aneurysms, and neuro-retinitis. Ophthalmology. 1995;102:1089–97.

 

4. Lee BL, Bateman JB, Schwartz SD. Posterior segment neovascularization associated with optic nerve aplasia. Am J Ophthalmol. 1996;122:131–3.

 

5. Leys AM, Leys MJ, Hooymans JM, et al. Myelinated nerve fibers and retinal vascular abnormalities. Retina. 1996;16:89–96.

 

6. Kinyoun JL, Lawrence BS, Barlow WE. Proliferative radiation retinopathy. Arch Ophthalmol. 1996;114:1097–100.

 

7. Kwak N, Okamoto N, Wood JM, et al. VEGF is a major stimulator in model of choroidal neovascularization. Invest Ophthalmol Vis Sci. 2000;41:3158–64.

 

8. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480–7.

 

9. Stellmach V, Crawford SE, Zhou W, et al. Prevention of ischemia-induced retinopathy by the natural ocular antiangiogenic agent pigment epithelium-derived factor. Proc Natl Acad Sci U S A. 2001;98:2593–7.

 

10. Frank RN, Ryan SJ Jr. Peripheral retinal neovascularization with chronic myelogenous leukemia. Arch Ophthalmol. 1972;87:585–9.

 

11. Brown GC, Magargal LE, Simeone FA, et al. Arterial obstruction and ocular neovascularization. Ophthalmology. 1982;89:139–46.

 

12. Kalina RE, Kelly WA. Proliferative retinopathy after treatment of carotid–cavernous fistulas. Arch Ophthalmol. 1978;96:2058–60.

 

13. Vine AK. Severe periphlebitis, peripheral retinal ischemia, and preretinal neovascularization in patients with multiple sclerosis. Am J Ophthalmol. 1992;113:28–32.

 

14. Kayazawa F, Honda A. Severe retinal vascular lesions in systemic lupus erythematosus. Ann Ophthalmol. 1981;13:1291–4.

 

15. Bogie GJ, Nanda SK. Neovascularization associated with cytomegalovirus retinitis. Retina. 2001;21:85–7.

 

16. Blumenkranz MS, Kaplan HJ, Clarkson JG, et al. Acute multifocal hemorrhagic retinal vasculitis. Ophthalmology. 1988;95:1663–72.

 

17. Asdourian GK, Goldberg MF, Busse BJ. Peripheral retinal neovascularization in sarcoidosis. Arch Ophthalmol. 1975;93:787–91.

 

18. Goldberg MF. Classification and pathogenesis of proliferative sickle retinopathy. Am J Ophthalmol. 1971;71:649–65.

 

19. Cao J, Mathews MK, McLeod DS, et al. Angiogenic factors in human proliferative sickle cell retinopathy. Br J Ophthalmol. 1999;83:838–46.

 

20. Farber MD, Jampol LM, Fox P, et al. A randomized clinical trial of scatter photocoagulation of proliferative sickle cell retinopathy. Arch Ophthalmol. 1991;109:363–7.

 

21. Goldberg MF, Custis PH. Retinal and other manifestations of incontinentia pigmenti. Ophthalmology. 1993;100:1645–54.

 

22. Elliot AJ. 30-year observation of patients with Eales’ disease. Am J Ophthalmol. 1975;12:404–8.

 

23. Orth DH, Patz A. Retinal branch vein occlusion. Surv Ophthalmol. 1978;22: 357–76.

 

24. Tse DT, Ober RR. Talc retinopathy. Am J Ophthalmol. 1980;90:624–40.

 

25. Kingham JD. Acute retrolental fibroplasia. Arch Ophthalmol. 1977;95:39–47.

 

26. Kuo IC, Cunningham ET Jr. Ocular neovascularization in patients with uveitis. Int Ophthalmol Clin. 2000;40:111–26.

 

27. Wang CL, Kaplan HJ, Waldrep JC, et al. Retinal neovascularization associated with acute retinal necrosis. Retina. 1983;3:249–52.

 

28. Barondes MJ, Fastenberg DM, Schwartz PL, et al. Peripheral retinal neovascularization in birdshot retinochoroidopathy. Ann Ophthalmol. 1989;21:306–8.

 

29. Felder KS, Brockhurst RJ. Retinal neovascularization complicating rhegmatogenous retinal detachment of long duration. Am J Ophthalmol. 1982;93:773–6.

 

30. Lee J, Logani S, Lakosha H, et al. Preretinal neovascularization associated with choroidal melanoma. Br J Ophthalmol. 2001;85:1309–12.

 

31. Leys AM, Bonnet S. Case report: associated retinal neovascularization and choroidal hemangioma. Retina. 1993;13:22–5.

 

32. Ober RR, Bird AC, Hamilton AM, et al. Autosomal dominant exudative vitreoretinopathy. Br J Ophthalmol. 1980;64:112–20.

 

33. Stewart MW, Gitter KA. Inherited retinal venous beading. Am J Ophthalmol. 1988;106:675–81.

 

34. Brown SM, Shami M. Optic disc neovascularization following severe retinoschisis due to shaken baby syndrome. Arch Ophthalmol. 1999;117:838–9.

 

35. Pearson R, Jagger J. Sex linked juvenile retinoschisis with optic disc and peripheral retinal neovascularization. Br J Ophthalmol. 1989;73:311–3.

 

36. Uliss AE, Gregor ZJ, Bird AC. Retinitis pigmentosa and retinal neovascularization. Ophthalmology. 1986;93:1599–603.

 

37. Blair NP, Goldberg MF, Fishman GSA, et al. Autosomal dominant vitreoretinochoroidopathy (ADVIRC). Br J Ophthalmol. 1984;68:2–9.

 

 

Chapter 121 – Radiation Retinopathy and Papillopathy

Chapter 121 – Radiation Retinopathy and Papillopathy

 

DESMOND B. ARCHER

 

 

 

 

 

DEFINITION

• A chronic, progressive retinal and papillary vasculopathy induced by suprathreshold doses of ionizing radiation.

 

KEY FEATURES

• Retinal microaneurysms.

• Retinal hemorrhages.

• Retinal telangiectatic vessels.

• Retinal hard exudates.

• Macular edema.

• Cotton-wool spots.

• Optic disc swelling.

 

ASSOCIATED FEATURES

• Intraretinal microvascular abnormalities.

• Retinal neovascularization.

• Vitreous hemorrhage.

• Traction retinal detachment.

• Rubeosis iridis.

• Optic atrophy.

• Occlusive choroidal vasculopathy.

 

 

 

INTRODUCTION

Although Röntgen discovered X-rays more than a century ago, it was not until the mid-1930s that consistent reports of a retinal vasculopathy following radiotherapy began to emerge.[1] It was soon appreciated that the clinical retinopathy and the less frequent papillopathy were dose related and had a characteristic, although variable, latent period.[2]

In more recent years, a better understanding of the biological effects of ionizing radiation and more accurate targeting of radiation energy to the index tissue have reduced the incidence of collateral damage to the retina and optic nerve. Nevertheless, the posterior eye may be unavoidably exposed to excessive radiation in the treatment of cephalic malignancies by external beam irradiation (teletherapy) or in the treatment of retinal and choroidal tumors by teletherapy or plaque therapy (brachytherapy), and a sight-threatening vasculopathy can develop. [3] [4] Careful monitoring of the developing vasculopathy and institution of therapy when required often serve to preserve vision in patients who have established and severe retinopathy.

EPIDEMIOLOGY AND PATHOGENESIS

Radiation Dose

The key determinants in the development of radiation retinopathy are the total dose of radiation administered to the retina and the fraction size in the case of teletherapy. In brachytherapy for choroidal melanoma or retinoblastoma, local retinal and choroidal changes are universal and the severity of retinopathy is directly proportional to the dose of radiation. Brachytherapy for posterior melanomas, especially within 5?mm of the macula, carries a significant risk of maculopathy and loss of vision.[5] [6] The minimum dose of brachytherapy to induce maculopathy is unknown, although one study of brachytherapy for posteriorly located retinoblastomas recorded maculopathy in 7 of 18 eyes that received an estimated macular dose of 6000?rad (60?Gy) and in 9 of 10 eyes that received a macular dose of 7500?rad (75?Gy) or more.[7] The threshold dose of teletherapy for clinical retinopathy is also unknown; estimates fall in the range 1500–6000?rad (15–60?Gy). The incidence of radiation retinopathy steadily increases with doses greater than 4500?rad (45?Gy). [8] Dose fractions, the field design, and the type and rate of administration of radiation also have to be taken into account. A general rule is that patients whose eyes receive radiation doses of less than 2500?rad (25?Gy) in fractions of 200?rad (2?Gy) or less are unlikely to develop significant retinopathy.

The precise incidence of radiation retinopathy is not known but is probably underestimated because many patients with early or mild retinopathy have few or no symptoms and some patients with established disease are so gravely ill that the ocular pathology goes unreported. One study of patients who received cephalic radiation for orbital, paranasal, and nasopharyngeal malignancies showed that, despite modern radiotherapeutic screening techniques, 55% developed clinical retinopathy and of these almost 50% progressed to sight-threatening vascular complications. Roughly one third of patients who received treatment for midline tumors (e.g., nasopharyngeal carcinomas) developed bilateral retinopathy.[4]

Risk Factors

Several different chemotherapeutic drugs used in tumor therapy may potentiate the injurious effects of ionizing radiation on the retinal and papillary microvasculatures by their effects on DNA synthesis and vascular endothelial cell repair and division.[3] [9] Also experimental and clinical evidence suggests that coexisting diabetes mellitus is a risk factor for the development of radiation retinopathy and that patients who have diabetes are more likely to develop extensive retinal ischemia and neovascularization. [10] Patients who have systemic vascular disease (e.g., hypertension, collagen disease, and acute leukemias) also seem more vulnerable to radiation in terms of retinopathy. Concurrent chemotherapy is a risk factor for the development of optic neuropathy.

Latency

The length of time from radiotherapy to development of retinopathy is highly variable and unpredictable. Many patients who receive substantial radiotherapy develop only minor microvascular changes that do not materially affect vision—this

 

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probably accounts for the great variation in reported latencies, 1 month to 15 years. The most commonly reported latent intervals are from 6 months to 3 years; the latent period is shorter for eyes with severe ischemia and proliferative retinopathy.[11] The characteristic latent period to retinopathy is probably related to the turnover cycle of retinal vascular endothelial cells, which on average is about once every 2–3 years.[12]

Radiobiology

All retinal cells are relatively radioresistant, and the nonreplicating neural cells are highly radioresistant. The relative radiosensitivity of the retinal vascular cells seems to be related to the conformation of their nuclear chromatin. The heterochromatic nuclear DNA of retinal vascular endothelial cells and pericytes is less accessible to repair enzymes than the loosely arranged euchromatic DNA characteristic of neurons. Hence, the vascular cells are more vulnerable to ionizing radiation “hits,” which cause single- or double-stranded DNA breaks. Dividing retinal vascular cells are exquisitely sensitive to radiation as the chromatin of the mitotic cell is in the ultimate state of condensation. The differential sensitivity of retinal vascular endothelial cells with respect to pericyte and smooth muscle cells is probably a function of their particular exposure to high ambient oxygen and blood transition metals, such as iron, which induces free radical formation and cell membrane damage. [12]

Pathogenesis

Good histopathological and ultrastructural evidence indicates that the retinal vascular endothelial cell is the first and prime casualty of retinal irradiation and that its malfunction or demise is the starting point for the development of radiation retinopathy and its complications.[10] With each radiation insult, it is likely that a small and scattered population of vascular endothelial cells that are undergoing mitosis suffer mitotic death. A few cells that absorb sufficient radiation may also suffer immediate interphase death. The first wave of cell death initiates division and migration of adjacent cells to establish endothelial continuity; however, some of these cells will have suffered sufficient radiation damage to cause mitotic death when compelled to replicate. This initiates a further round of division, and so on, until the vascular endothelium is unable to maintain its integrity and the clotting cascade is initiated.

Capillary occlusion leads to the formation of small dilated collateral channels that bypass the area of ischemia and assume a telangiectatic-like form. Microvascular abnormalities, such as microaneurysms, intraretinal microvascular abnormalities, and incompetent capillaries, develop in response to hemodynamic events and alteration in the local metabolism. Where areas of capillary closure are extensive, preretinal and papillary new vessels may form. The events that lead to radiation papillopathy are less certain, although the superficial retinal capillaries probably suffer the same fate as the peripapillary retinal vasculature. High doses of radiation cause an occlusive vasculopathy of the choroidal circulation.[13] It is likely, but unproved, that the posterior ciliary-derived microcirculation of the optic nerve head is similarly compromised. The retinal ganglion cells are highly radioresistant and, although axoplasmic stasis is a feature of acute radiation papillopathy, it is probably secondary to ischemic changes at the optic nerve head.

OCULAR MANIFESTATIONS

The earliest clinical features of radiation retinopathy are discrete foci of occluded capillaries and irregular dilatation of the neighboring microvasculature at the posterior fundus. Fluorescein angiography confirms the extent of capillary dropout and the general capillary competence at this stage.[14] As the retinopathy develops, microaneurysms and telangiectatic channels appear,

 

 

Figure 121-1 Exudative radiation retinopathy of right posterior fundus. A 45-year-old patient who received 6400?rad (64?Gy) of radiation and chemotherapy for a nasopharyngeal tumor.

 

 

Figure 121-2 Fluorescein angiogram of fundus shown Figure 121-1 . Note the microaneurysms, capillary fallout, and hypofluorescent area of retinal hemorrhage and exudation.

particularly in areas of depleted capillaries, and with time become incompetent. Retinal exudation and small intraretinal or nerve fiber hemorrhages may be superimposed on the gradually evolving ischemic retinopathy; however, with modest radiation damage the retinopathy and vision may change little over a period of years.

More substantial radiation injury is associated with diffuse capillary closure and microvascular incompetence that leads to macular exudation, edema, and decline in vision ( Figs. 121-1 and 121-2 ). An acute form of ischemic retinopathy may follow intense retinal irradiation, as in the course of eradicating a nasopharyngeal or orbital tumor, during which eye protection is limited. The clinical picture is one of ischemic retinal necrosis with widespread arteriolar occlusion, cotton-wool spots, and superficial and deep retinal hemorrhages, which affect both central and peripheral neural retina[3] ( Figs. 121-3 and 121-4 ). Some resolution of hemorrhage and absorption of axoplasmic debris and edema typically occur, and a very limited reperfusion of ischemic areas may be evident. Intraretinal microvascular abnormalities are commonly observed in ischemic retinopathy, and, where vascular occlusion is extensive, preretinal and papillary neovascular membranes form. Most patients who have proliferative retinopathy develop the new vessels within 2 years of diagnosis of retinopathy.[11] Vitreous hemorrhage, traction detachment, rubeosis iridis, and phthisis bulbi are end-stage complications of severe radiation damage to the eye.

 

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Figure 121-3 Ischemic radiation retinopathy of left posterior fundus. Note the retinal hemorrhages, cotton-wool spots, and optic atrophy, which followed 5500?rad (55?Gy) of radiation for an anterior meningeal tumor.

 

 

Figure 121-4 Fluorescein angiogram of fundus shown in Figure 121-3 . Widespread capillary, arteriolar, and venular occlusion is seen, as well as staining of the vessels and nasal disc with dye.

The retinal pigment epithelium and choroid also display clinical and angiographic signs of radiation damage adjacent to radioactive plaques ( Fig. 121-5 ); this is also seen in patients who receive high-dosage teletherapy. These signs include scattered areas of hypo- and hyperpigmentation, evidence of choroidal vascular stasis and occlusion, serous detachment of the macula, and, very occasionally, choroidal neovascularization.[13]

Radiation optic neuropathy may complicate either brachytherapy or teletherapy—most patients who suffer neuropathy have accompanying retinopathy. In the acute phase disc hyperemia and swelling occur, usually in association with peripapillary edema, hard exudates, hemorrhage, and cotton-wool spots ( Fig. 121-6 ). Fluorescein angiography demonstrates microvascular incompetence, together with areas of capillary nonperfusion of the disc and nearby neural retina. Optic nerve-head swelling may persist for weeks or months but eventually leads to a severe and striking optic atrophy. Vision loss is characteristically severe. The dose of radiation and latent period for clinical optic neuropathy are similar to those for retinopathy; diabetes and concurrent chemotherapy are also risk factors. [15]

DIAGNOSIS

A history of cephalic radiotherapy and the presence of an ischemic retinopathy usually suffice to secure a diagnosis of radiation retinopathy. Macular telangiectatic vessels are a feature,

 

 

Figure 121-5 Proliferative and exudative radiation retinopathy following brachytherapy for retinoblastoma. Note the chorioretinal atrophy at a prior tumor site inferior to left optic disc. There is hemorrhage and exudation from new and incompetent vessels that border the scar.

 

 

Figure 121-6 Radiation papillopathy. Swollen ischemic right optic nerve head with peripapillary hemorrhage exudation and cotton-wool spots: 27 months following 64?Gy for nasopharyngeal tumor.

if not a hallmark, of radiation damage and all the microvascular alterations can be displayed vividly by fluorescein angiography. Indocyanine green angiography may identify areas of choroidal hypoperfusion, precapillary arteriolar occlusion, and abnormal staining of the affected choroid. Electroretinographic (ERG) responses are depressed following acute retinal radiation—pattern ERG and visual evoked response abnormalities confirm inner retinal damage or the presence of a maculopathy. Visual fields show a spectrum of changes, which depend on the extent of ischemic retinopathy and neuropathy and usually correlate with the area of retina exposed to radiotherapy.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis is given in Box 121-1 . The diagnosis of radiation retinopathy is usually self-evident, given the history of radiotherapy. However, for diabetic patients who receive radiotherapy for midline cephalic tumors it may be difficult to decide the exact nature of the retinopathy.

The presence of dilated telangiectatic channels at the macula and relative paucity of microaneurysms, venous beading, and vasoproliferative changes (despite sufficient inner neural retinal ischemia) suggest that radiation damage is predominant and may reflect relative sparing of pericytes and smooth muscle cells at the histological level.

 

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Differential Diagnosis of Radiation Retinopathy

Diabetic retinopathy

 

Branch retinal vein obstruction

 

Central retinal vein obstruction

 

Accelerated hypertensive retinopathy

 

Coats’ disease

 

Perifoveal telangiectasia

 

Ischemic optic neuropathy

 

Optic neuritis

 

Papilledema

 

 

 

 

Radiation optic neuropathy in the absence of retinopathy may mimic the clinical picture of anterior ischemic optic neuropathy but tends to occur in younger, normotensive patients and little or no involvement of the short posterior ciliary vessels is seen on angiography. Elderly patients who have ischemic optic neuropathy merit an erythrocyte sedimentation rate or C-reactive protein assessment, despite a history of radiotherapy, to rule out temporal arteritis.

The interpretation of continuing visual loss after neurosurgery and radiotherapy for tumors of the sellar region is often difficult. A diagnosis of radiation-induced optic neuropathy may be facilitated by magnetic resonance imaging with gadolinium–pentetic acid and the presence of altitudinal field defects. [16]

PATHOLOGY

Most histopathological studies show preferential preservation of the outer retina compared with the inner retina and alterations to the nerve fiber layer attributable to inner retinal ischemia. Trypsin digest preparations from irradiated eyes with vasculopathy show an early and unequivocal loss of retinal vascular endothelial cells with relative sparing of the pericyte population ( Fig. 121-7 ). Associated changes include microaneurysms and fusiform dilatation of capillaries, which predominate on the arterial side of the circulation. Acellular, nonperfused, and collapsed capillaries are a feature of ischemic retina and are associated with varying degrees of neuronal degeneration and gliosis. Large thin-walled channels with dense collagenous adventitia are the histopathological correlates of the telangiectatic-like vessels observed clinically.[17] With intense radiation, such as 6000?rad (60?Gy) for an orbital rhabdomyosarcoma, widespread loss of photoreceptors, retina pigment epithelial cells, and choriocapillaries and atrophy of the associated inner retina and optic nerve may occur.[18]

TREATMENT

Photocoagulation

Only a few patients develop advanced radiation retinopathy, and to date no randomized controlled study exists to assess properly the value of photocoagulation in either limiting macular edema or containing the vasoproliferative response. Anecdotal and small group studies suggest that focal or grid laser photocoagulation, given as for diabetic retinopathy, has a favorable effect on radiation macular edema, particularly in the absence of severe macular ischemia or cystoid degeneration and where vision remains 20/80 (6/24) or better. Cataract, vitreous hemorrhage, prior panretinal photocoagulation or detachment, and optic neuropathy are all factors that may limit visual recovery.[19] Focal photocoagulation may also prove beneficial for retinal and choroidal neovascularization that occurs at tumor sites following either plaque or external beam therapy.[14] Panretinal photocoagulation, given as for proliferative diabetic retinopathy, has been used to contain preretinal and papillary neovascularization

 

 

Figure 121-7 Vascular endothelial cell loss in irradiated retina—5000?rad (50?Gy). Note the severe depletion of capillary endothelial cells but preservation of pericytes, that is, most of the residual capillary nuclei.

and reduce the incidence of vitreous hemorrhage and neural retinal detachment. In general, less intense photocoagulation is required to contain radiation retinopathy compared with that required for diabetic retinopathy. Retinal cryoablation has also been used to contain neovascularization in the presence of dense vitreous hemorrhage. [20]

Vitrectomy—Retinal Detachment Surgery

Persistent vitreous hemorrhage and retinal traction that affect the macula respond to pars plana vitrectomy and rhegmatogenous retinal detachments yield to conventional detachment surgery.

COURSE AND OUTCOME

Clinically significant radiation retinopathy or papillopathy usually follows teletherapy for nasopharyngeal, paranasal sinus, or orbital tumors, during which only limited protection can be afforded during the eradication of the tumor. Plaque therapy for retinal and choroidal neoplasms causes severe damage to the immediate retina and choroid and secondary alterations to the surrounding tissues for a distance of several millimeters. With teletherapy it is often difficult to compute precisely how much radiation the retina and optic disc will receive or the exact dose of radiation that will precipitate clinical retinopathy. Doses in excess of 3400?rad (34?Gy) are likely to induce retinopathy, especially if fraction doses exceed 200?rad (2?Gy) and other risk factors are present. Minor degrees of retinopathy, characterized by subtle capillary fallout and occasional dilated channels and microaneurysms, may not affect vision and may remain stable for years. No treatment is required, but such patients merit annual follow-up as the disease is slowly progressive. Macular exudation that causes significant retinal thickening and visual symptoms requires prompt laser photocoagulation. Treatment reduces edema and, in the absence of severe macular ischemia, improves or stabilizes visual acuity. Recurrent treatment may be required if fresh leaking foci develop. Patients who have nonproliferative retinopathy, on average, can expect to retain a visual acuity of 20/50 (6/15) for at least 4 years.[19]

Severe ischemic retinopathy typically follows direct orbital irradiation for lymphoma, rhabdomyosarcoma, or lacrimal gland carcinomas; visual loss is attributable to macular or optic nerve ischemia. New vessels that may bleed profusely develop in some of these patients, who should be observed at regular intervals. Panretinal photocoagulation is effective in the long term in containing the vasoproliferative process. Patients who have proliferative radiation retinopathy have a poor prognosis for retaining good central vision, with a high proportion (86%) achieving only 20/200 (6/60) vision or worse after 6 years.[11]

It is important that the ophthalmologist and radiotherapist liaise closely when patients receive cephalic radiation that involves the eye in the treatment field. Careful monitoring of the patient and judicious photocoagulation can help preserve vision

 

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in patients who may otherwise be severely disabled for a variety of reasons.

 

REFERENCES

 

1. Stallard HB. Radiant energy as (a) a pathogenic (b) a therapeutic agent in ophthalmic disorders. Br J Ophthalmol Monogr Suppl. 1993;6:1–126.

 

2. Merriam GR, Szechter A, Focht EF. The effects of ionizing radiations on the eye. Front Radiat Ther Oncol. 1972;6:346–85.

 

3. Brown GC, Shields JA, Sanborn G, et al. Radiation retinopathy. Ophthalmology. 1982;89:1494–501.

 

4. Amoaku WMK, Archer DB. Cephalic radiation and retinal vasculopathy. Eye. 1990;4:195–203.

 

5. Char DH, Castro JR, Kroll SM, et al. Five year follow-up of helium ion therapy for uveal melanoma. Arch Ophthalmol. 1990;108:209–14.

 

6. Lommatzsch PK. Results after beta-irradiation (106Ru/106Rh) of choroidal melanomas: 20 years’ experience. Br J Ophthalmol. 1986;70:844–51.

 

7. Ehlers N, Kaae S. Effects of ionizing radiation on retinoblastoma and on the normal ocular fundus in infants: a photographic and fluorescein angiographic study. Acta Ophthalmol (Copenh). 1987;65(Suppl 181):1–84.

 

8. Parsons JT, Bova FJ, Fitzgerald CR, et al. Radiation retinopathy after external-beam irradiation: analysis of time-dose factors. Int J Radiat Oncol Biol Phys. 1994;30: 765–73.

 

9. Griffin JD, Garnick MB. Eye toxicity of cancer chemotherapy: a review of the literature. Cancer. 1981;48:1539–49.

 

10. Archer DB. Doyne lecture. Responses of retinal and choroidal vessels to ionising radiation. Eye. 1993;7:1–13.

 

11. Kinyoun JL, Lawrence BS, Barlow WE. Proliferative radiation retinopathy. Arch Ophthalmol. 1996;114:1097–100.

 

12. Archer DB, Gardiner TA. Ionizing radiation and the retina. Curr Opin Ophthalmol. 1994;5(111):59–65.

 

13. Midena E, Segato T, Valenti M, et al. The effect of external eye irradiation on choroidal circulation. Ophthalmology. 1996;103:1651–60.

 

14. Amoaku WMK, Archer DB. Fluorescein angiographic features, natural course and treatment of radiation retinopathy. Eye. 1990;4:657–67.

 

15. Brown GC, Shields JA, Sanborn G, et al. Radiation optic neuropathy. Ophthalmology. 1982;89:1489–93.

 

16. Guy J, Mancuso A, Beck R, et al. Radiation-induced optic neuropathy: a magnetic resonance imaging study. J Neurosurg. 1991;74:426–32.

 

17. Archer DB, Amoaku WMK, Gardiner TA. Radiation retinopathy: clinical, histopathological, ultrastructural and experimental correlations. Eye. 1991;5: 239–51.

 

18. Krebs IP, Krebs W, Merriam JC, et al. Radiation retinopathy: electron microscopy of retina and optic nerve. Histol Histopathol. 1992;7:101–10.

 

19. Kinyoun JL, Zamber RW, Lawrence BS, et al. Photocoagulation treatment for clinically significant radiation macular oedema. Br J Ophthalmol. 1995;79:144–9.

 

20. Kinyoun JL, Chittum ME, Wells CG. Photocoagulation treatment of radiation retinopathy. Am J Ophthalmol. 1988;105:470–8.

Chapter 120 – Coats’ Disease and Retinal Telangiectasia

Chapter 120 – Coats’ Disease and Retinal Telangiectasia

 

JULIA A. HALLER

 

 

 

 

 

DEFINITION

• A localized, congenital, retinal vascular disorder that consists of abnormal telangiectatic segments of blood vessels that result in leakage.

 

KEY FEATURES

• Retinal telangiectasia.

• Retinal capillary nonperfusion.

• Dilated intercapillary spaces.

• Lipid exudate.

• Subretinal fluid.

 

ASSOCIATED FEATURES

• Usually unilateral.

• Male predominance.

• Fibrovascular macular scars.

• Leukokoria.

 

 

 

INTRODUCTION

Retinal telangiectasia is found in a wide range of ocular disease processes. Most retinal telangiectases are acquired secondary to local or systemic conditions, as, for example, in branch retinal vein occlusion and diabetic retinopathy. These disorders should be considered in the differential diagnosis when alterations are seen in the retinal vasculature and should be excluded before primary retinal telangiectasia is diagnosed. Primary retinal telangiectasia is found in Coats’ disease, Leber’s miliary aneurysms (a localized, less severe form of Coats’ disease), idiopathic juxtafoveal telangiectasia, and other angiomatous diseases.

Coats’ disease, an idiopathic condition characterized by retinal vascular changes and exudation, was first described by Coats[1] in 1908. In 1912 Leber reported his series of patients who had multiple miliary aneurysms and retinal degeneration. In 1915 Leber wrote two more articles and concluded that the disease he had described in 1912 was a variant of Coats’ disease.[2]

EPIDEMIOLOGY

Coats’ disease is characterized by discrete zones of alteration in the retinal vascular structure with aneurysmal dilatation, capillary dropout, and leakage. Vision may decrease as a result of leakage from the abnormal vascular channels that are formed, with consequent edema, lipid deposition, and exudative retinal detachment. The disease affects men three times as often as women, has no reported racial or ethnic predilection, and is usually unilateral, although as many as 10–15% of cases may be bilateral. The average age at diagnosis is 8–16 years, although the disease has been described in patients as young as 4 months. About two thirds of juvenile cases present before age 10 years; approximately one third of patients are 30 years or older before symptoms begin.[3] Coats’ disease does not appear to be inherited.

OCULAR MANIFESTATIONS

The typical ophthalmoscopic picture of Coats’ disease is one of retinal vascular abnormalities associated with localized lipid deposition and varying degrees of subneural retinal exudate ( Fig. 120-1 ). Vessels may appear sheathed and telangiectatic, and they may have aneurysms that are grape-like, clustered, or lightbulb shaped; often, the vessels are adjacent to areas that lack normal capillaries ( Fig. 120-2 ). The severity of vascular malformation parallels the degree of surrounding neural retinal thickening, exudation, hemorrhage, and destruction of small vessels. Aberrant arteriovenous communicating channels are frequently present, and occasionally true retinal neovascularization occurs. Leakage from the abnormal vascular bed produces a cloudy subretinal exudate, which gravitates toward the posterior pole. As the serous component of the exudate is resorbed by retinal vessels, the lipid-rich yellowish component is left beneath and within the outer neural retinal layers.[4] Over long periods, this yellow exudate may stimulate the ingrowth of blood vessels and fibrous scar tissue ( Fig. 120-3 ). The vascular abnormalities occur more commonly superotemporally; they also are found in the macular and paramacular areas. On average, two quadrants of retina are found to be affected at the initial diagnosis in older patients, but young patients may have more serious disease and more extensive retinal involvement. In more advanced and severe cases

 

 

Figure 120-1 Coats’ disease. Note the typical vascular abnormalities with aneurysmal dilatation, telangiectasia, exudation, and severe lipid deposition in the macula.

 

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of Coats’ disease, exudative retinal detachment develops ( Fig. 120-4 ).[5] Cells in the vitreous are common.

The clinical course is variable but generally progressive. Acute exacerbations of the disease may be interspersed with more quiescent stages. Spontaneous remissions have been reported, with spontaneous occlusion of the vessels and resorption of the exudate, but these are the exception. Choroidal neovascularization may occur in areas of lipid deposition. Secondary complications include neovascularization, vitreous hemorrhage, cataract, rubeosis iridis, and neovascular glaucoma, with phthisis bulbi in severe cases.[3] [6] [7]

DIAGNOSIS

In children, Coats’ disease is typically diagnosed as a result of the recognition of poor vision, strabismus, or leukokoria. In patients with leukokoria, a white pupillary reflex on photographs may be the initially noted abnormality. (The disorder is picked up most frequently by parents or pediatricians or on routine school vision screening.) In these cases, the disease is usually advanced already, with extensive lipid deposition and retinal detachment (see Fig. 120-4 ). In adults, the most common presenting complaint with Coats’ disease is poor vision; in these cases, the disease may be much more limited in extent.

 

 

Figure 120-2 Vessels may appear sheathed, dilated, and telangiectatic or feature grape-like bunches of aneurysms. Vascular changes that are saccular and lightbulb shaped may be seen as well.

 

 

Figure 120-3 Long-standing submacular exudate. This may stimulate ingrowth of blood vessels or fibrous tissue, with retinal pigment epithelium migration and hyperplasia and the formation of fibrous scars.

The anterior segment examination findings are normal in all but the most advanced cases of Coats’ disease, in which rubeosis iridis, angle-closure glaucoma, and cataract may be present. The diagnosis is confirmed ophthalmoscopically when the typical vascular abnormalities are seen in association with lipid deposition and subretinal exudate. The retinal vascular abnormalities occur in small clusters and include kinked, looped, tortuous, and sheathed vessels of varied and irregular caliber.

Fluorescein angiography is a useful tool for delineating the nature and extent of the vascular abnormalities present in this disease. Most commonly, numerous areas of telangiectasia and micro- and macroaneurysm formation are seen, with beading of blood vessel walls and anomalous vascular communicating channels ( Fig. 120-5 ). Early and persistent dye leakage documents the source of exudation and hemorrhage.[4] [8] [9] The microvasculature may be diffusely absent, with areas of complete capillary nonperfusion.

DIFFERENTIAL DIAGNOSIS

The severe juvenile form of Coats’ disease, which presents with exudative retinal detachment, must be differentiated from other diseases that cause leukokoria in childhood, including retinoblastoma,

 

 

Figure 120-4 In children, Coats’ disease may present as leukokoria, with advanced lipid deposition and exudative retinal detachment. In this eye, the anterior chamber is shallowed slightly, and the retina is immediately behind the lens.

 

 

Figure 120-5 Fluorescein angiography of Coats’ disease. In this eye, extensive vascular changes are seen to extend temporally from the macula, with zones of telangiectasia and aneurysm formation adjacent to a large area of capillary nonperfusion. Beading of the blood vessel walls and anomalous vascular communicating channels are present.

 

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retinopathy of prematurity, retinal detachment, persistent hyperplastic primary vitreous, congenital cataract, toxocariasis, incontinentia pigmenti, Norrie’s disease, and familial exudative vitreoretinopathy. Gass[4] has pointed out that telangiectatic vessels may appear on the surface of both retinoblastomas and Coats’ disease lesions. In retinoblastoma, these dilated vessels are continuous with the large vascular trunks that extend into the tumor; in Coats’ disease, the dilated vessels do not extend into the subretinal mass.[4] Fluorescein angiography may help differentiate the two entities. The diagnostic modalities used most commonly are ultrasonography and computed tomography (CT), because of their ability to pick up calcium deposits in retinoblastomas.

Ultrasonography is a convenient, noninvasive test that may distinguish between Coats’ disease and retinoblastoma, as well as other entities. The retinal detachment in Coats’ disease typically is exudative in appearance, with an absence of the calcifications seen in retinoblastoma. CT may help characterize intraocular morphology, quantify subretinal densities, and identify vascularity within the subretinal space, through the use of contrast enhancement. Also, CT may help detect other abnormalities within the orbit or intracranial space. For optimal resolution, multiple thin slices before and after contrast induction are recommended. Magnetic resonance imaging (MRI) is a useful ancillary test because it permits multiplanar imaging and superior contrast resolution, and it may provide information about the biochemical makeup of tissues. However, MRI is less useful for the detection of calcium than either ultrasound or CT scanning, but it has been shown to help differentiate retinoblastoma from Coats’ disease, toxocariasis, and persistent hyperplastic primary vitreous. High-resolution Doppler ultrasonography occasionally may be of use as an adjunctive diagnostic modality. This technique provides real-time imaging; duplex pulse Doppler evaluation may delineate structural abnormalities that are not shown by other testing modalities. Serum lactate dehydrogenase and isoenzyme levels have not proved useful in distinguishing between Coats’ disease and retinoblastoma. Examination of subretinal fluid is used rarely, but it confirms the diagnosis of Coats’ disease on the basis of cholesterol crystals and pigment-laden macrophages in the absence of tumor cells.[3]

Less severe stages of Coats’ disease, especially in adults, must be differentiated from other disorders that produce vascular changes and exudation; these include inflammatory disorders such as Eales disease, vasculitis, and collagen vascular disease. Tumors accompanied by exudation may mimic Coats’ disease, as may diabetic vasculopathy with lipid deposition, branch retinal vein occlusion with vascular remodeling and edema, rhegmatogenous retinal detachment, radiation retinopathy, idiopathic juxtafoveal telangiectasia, von Hippel’s disease, angiomatosis of retina, exophytic capillary hemangioma, and sickle-cell retinopathy. In these cases, a thorough review of the systems and medical and family histories usually help differentiate primary from secondary disorders. Fluorescein angiography and, occasionally, echography also may be of use.[3] [4] [10]

Idiopathic Juxtafoveal Retinal Telangiectasia

Idiopathic juxtafoveal retinal telangiectasia is a group of disorders initially described by Gass and Oyakawa[11] in 1982. The disease is characterized by onset in adulthood and presentation with mild blurring of central acuity caused by exudate from ectatic retinal capillaries in the juxtafoveal region of one or both eyes. They divided these patients into four categories: groups 1A, 1B, 2, and 3.[11] [12]

GROUP 1A.

Group 1A disease consists of unilateral congenital parafoveal telangiectasia, which typically occurs in men and affects only one eye. Retinal vascular abnormalities are present in a small area, one to two disc areas in diameter, in the temporal half of the macula. Onset of symptoms, with visual loss in the 20/40 (6/12) or better range, typically develops at a mean age of 40 years. Photocoagulation of areas of leakage may help restore acuity.

GROUP 1B.

Group 1B disease consists of unilateral idiopathic parafoveal telangiectasia, usually found in middle-aged men who have blurring caused by a tiny area of capillary telangiectasia confined to one clock hour at the edge of the foveal avascular zone. Vision is usually 20/25 (6/7) or better. Photocoagulation usually is not considered for these eyes because of the proximity of the leakage to the fovea and the good prognosis without treatment. The lesion may be acquired or may simply be a very small focus of congenital telangiectasia.

GROUP 2.

Group 2 disease consists of bilateral, acquired, idiopathic parafoveal telangiectasia. This variant affects patients in the fifth and sixth decades; mild blurring of vision occurs in one or both eyes. The patients typically have small, symmetrical areas of capillary dilatation, usually the size of one disc area or less, in both eyes. The vascular changes may be temporal only or may include all or part of the parafoveolar nasal retina as well. No lipid is deposited, and minimal serous exudation is present. A hallmark is the characteristic gray appearance of the lesions on biomicroscopic examination, with occasional glistening white dots in the superficial retina. Red-free photography often highlights these findings best ( Figs. 120-6 and 120-7 ). These patients also commonly have right-angled retinal venules that drain the capillary abnormalities and are present in the deep or outer retinal layers. Retinal pigment epithelial hyperplasia eventually

 

 

Figure 120-6 Bilateral idiopathic parafoveal telangiectasia can often best be demonstrated with red-free photography. This eye features capillary abnormalities present for virtually 360° in the parafoveal area.

 

 

Figure 120-7 Early transit of the eye shown in Figure 120-6 demonstrates a plexus of capillary abnormalities ringing the fovea.

 

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tends to develop along these venules. In these patients, slow loss of visual acuity over many years is produced by atrophy of the central fovea; patients also may develop choroidal neovascularization, hemorrhagic macular detachment, and retinochoroidal anastomosis. Photocoagulation may be of benefit, but in most cases, the abnormal lesions are so close to the fovea that treatment is problematical, and choroidal neovascularization, if it develops, is often subfoveal.

GROUP 3.

Bilateral idiopathic perifoveal telangiectasia with capillary occlusion is a rare variant in which adults experience loss of vision because of progressive obliteration of the capillary network, which begins with telangiectasia. The capillaries’ aneurysmal malformations are more marked than in the other, milder forms of the disease; no leakage occurs from the capillary bed.

SYSTEMIC ASSOCIATIONS

Isolated case reports have described a number of other diseases that occurred simultaneously in patients with Coats’ disease. In many cases, it is doubtful that an actual causal association exists. These diseases include retinitis pigmentosa, muscular dystrophy, deafness, mental retardation, central nervous system dysfunction, Senior-Loken syndrome, the ichthyosis hystrix variant of epidermal nevus syndrome, and Turner’s syndrome. Gass[4] described a patient who had a facial angioma and typical retinal telangiectasia, and another who had bilateral retinal disease and progressive facial hemiatrophy. Bilateral telangiectasia and Coats’ syndrome have been reported in multiple family members who have facioscapulohumeral muscular dystrophy and deafness. No definite connection, however, has been made between other systemic or ocular conditions and Coats’ disease, and no clear evidence exists of genetic transmission. The adult form of the disease has been described as frequently associated with hypercholesterolemia, although such an association does not occur in the juvenile form.[2] [13]

PATHOLOGY

Histopathologically, Coats’ disease has been studied intensively because of the number of enucleations formerly performed for suspected intraocular tumors. Eyes with Coats’ disease demonstrate marked thickening of the basement membrane of the telangiectatic vessels, as demonstrated by deposition of periodic acid-Schiff (PAS)–positive material. Irregular dilatation of the retinal vessels is seen, often associated with massive exudation of PAS-positive material into the outer neural retinal layers ( Fig. 120-8 ). This exudate produces variable amounts of degeneration

 

 

Figure 120-8 Histopathological section of an eye with Coats’ disease. Note the marked neural retinal edema, dilated and aneurysmal vascular channels (with PAS-positive material in their walls), and intra- and subneural retinal exudate. (Courtesy of W. R. Green, MD.)

and disruption of the neural retinal architecture. Lipid-laden macrophages are present beneath and in the outer layers of the neural retina. Glial cells and retinal pigment epithelium cells may migrate in, surround, and wall off the lipid-laden subretinal exudate, which results in the formation of macular and subretinal nodules. Marked retinal endothelial proliferation and hemorrhagic infarction may occur.[3] [7]

TREATMENT

The major goal of treatment in Coats’ disease is to preserve or improve visual acuity or, when this is impossible, to preserve the anatomical integrity of the eye. Intervention is contemplated when exudation is extensive and progressive, threatens central acuity, or produces significant peripheral retinal detachment. In severe, untreated cases, total retinal detachment, iris neovascularization with glaucoma, and phthisis bulbi can result. Treatment of Coats’ disease is directed toward closure of the abnormal, leaking retinal vessels to allow resorption of exudate. Restoration of vision may be a difficult goal to achieve; in many cases, the visual results are poor even with successful treatment, especially when the macula is involved initially in the exudative process.[2] [6] [10] [14] [15]

Laser photocoagulation is the treatment of choice in mild to moderate cases of exudation from Coats’ disease. Fluorescein angiographic guidance allows precise, localized treatment of the leaking aneurysms and vessels. Early photocoagulation trials used the xenon arc laser to produce resolution of exudate. The most extensive clinical experience has been with the argon blue-green laser, but more recently, clinicians have employed wavelengths of light better absorbed by hemoglobin, such as the argon green-yellow and the diode green. Lesions that leak are treated directly with relatively large (200–500?µm) applications of moderate-intensity light ( Fig. 120-9 ).[3] Scatter photocoagulation to areas of extensive nonperfusion are of unproved value but may lessen the chance of secondary neovascularization. Peripheral lesions may be treated with the indirect laser if they are inaccessible via the contact lens and slit-lamp delivery system. The indirect laser is also a useful modality in children, who frequently need to be treated under general anesthesia.

Cryotherapy and diathermy are of use in the ablation of abnormal retinal vessels in Coats’ disease. In cases of exudative detachment, a trans-scleral mode of energy delivery is preferred; cryotherapy is the modality most commonly used. Where subretinal fluid is present, cryotherapy to the anomalous vessels is recommended using a single freeze or freeze-refreeze technique.

 

 

Figure 120-9 Initial photocoagulation of the eye shown in Figure 120-5 . Large, medium-intensity spots have been placed on leaking aneurysms, sparing the foveal avascular zone at first. More peripherally, photocoagulation covers temporal aneurysms and is also placed in a scatter pattern in zones of nonperfusion.

 

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Figure 120-10 Technique used for drainage of subretinal fluid in eyes with extensive exudative detachment. The pediatric infusion cannula is sutured into the anterior chamber through a limbal stab incision with a single Vicryl suture. This is placed in a convenient quadrant so that the eye can be rotated and a posterior draining sclerotomy fashioned. The infusion runs into the anterior chamber and around intact lens zonules, keeping the eye formed as voluminous quantities of thick, yellow subretinal fluid are drained; this subretinal fluid is speckled with cholesterol and lipid deposits.

If the retina is highly elevated, it may be necessary to drain subretinal fluid in order to flatten the retina and allow sufficient freeze to reach the retinal vessels. In these cases, the retina is flattened, the eye reformed, and cryotherapy or laser applied ( Fig. 120-10 ). Subretinal pigmentation and fibrosis usually ensue and follow the lipid resolution. If this involves the macula, visual return is commensurately poor.[3]

Another approach to eyes that have significant retinal detachment is to perform a scleral buckling procedure, which involves dissection of a scleral bed in the area of the abnormal vessels, application of diathermy with drainage of subretinal fluid in the bed, and silicone buckle implantation. In all four of the cases so treated, successful reattachment was achieved, and the exudation gradually resorbed as the abnormal vasculature disappeared, without, however, any return of vision.[2] Harris[14] reported that a scleral buckle sometimes aids the application of postoperative photocoagulation, because it can be oriented beneath the abnormal vessels, and anomalies at the apex of the buckle can be treated effectively, with residual subretinal fluid remaining elsewhere. Siliodor et al. [10] reported a series of 13 children (who had blind eyes and bullous exudative detachments) followed either after no treatment or after surgery that involved intraocular infusion, drainage of subretinal fluid, and cryotherapy on one or more occasions. Of the six untreated eyes, four developed painful neovascular glaucoma and underwent enucleation. The seven treated with surgery all remained cosmetically acceptable and comfortable; none developed neovascular glaucoma.

In selected cases of Coats’ disease with intravitreal proliferation and traction detachment, vitreous surgery may improve the clinical course. Machemer and Williams[16] reported successful results with surgical removal of vitreal and preretinal membranes and destruction of leaking vessels in a small series of patients. Other authors have also reported some success, again in end-stage eyes, with vitrectomy, transvitreal drainage of subretinal fluid, and extensive photocoagulation or cryotherapy to prevent neovascular glaucoma.

Repeated therapeutic laser or cryotherapy treatments may be required in eyes that have Coats’ disease. Most patients require at least two treatments. Exudate typically begins to resorb within 6 weeks of treatment, if the abnormal vasculature has been eliminated. Depending on the amount of lipid accumulation, in many cases, it takes months to more than a year for complete resolution. Successful treatment is accomplished more easily in eyes that have fewer quadrants with affected vasculature. Recurrence of exudate after initially successful treatment signals the development of new abnormal leaking vessels; these must be searched out meticulously. Contact lens biomicroscopy with a three-mirror lens sometimes is a useful adjunct to indirect ophthalmoscopy in these cases, as is fluorescein angiography with careful sweeps of the retinal periphery. Recurrences may occur years after initially successful treatment, so it is particularly important to follow juvenile patients who may develop significant problems if left unattended. Egerer et al. [2] recommended that all patients who have Coats’ disease should be examined at least twice a year to catch any early recurrent problems that may develop in a small percentage of these patients.

COMPLICATIONS OF TREATMENT

Complications of photocoagulation and cryotherapy for Coats’ disease include inflammation; hemorrhage; chorioretinal anastomosis formation; and retinal, chorioretinal, and subretinal fibrosis. Macular distortion secondary to epiretinal membrane formation and contraction has been reported following photocoagulation for Coats’ disease and may occur even if the disease is untreated. Gass[4] reported one adult patient who developed total retinal detachment and proliferative vitreoretinopathy after cryotherapy for peripheral retinal telangiectasia that was discovered late in life; the eye initially had 20/20 (6/6) acuity.

With intraocular surgical intervention, additional risks include cataract formation, choroidal hemorrhage, retinal detachment, endophthalmitis, glaucoma, and phthisis.

COURSE AND OUTCOME

The clinical course in Coats’ disease is variable, but it is usually progressive if left untreated. Continued exudation from abnormal vascular channels produces a gradual accumulation of lipid and serous retinal detachment. The downhill course is more rapid in eyes with more extensive vascular abnormalities. Acute exacerbations of the disease may occur, with intervening periods of relative stability. Occasional remissions, produced by spontaneous occlusion of the vessels, have been reported. The end stage of the exudative process, seen in eyes with severe Coats’ disease and particularly in young patients who have an early onset of symptoms, is total retinal detachment, which may be followed by rubeosis iridis, neovascular glaucoma, and eventually phthisis bulbi.

The ultimate prognosis for eyes with Coats’ diseases can be measured in terms of two end points: visual acuity and anatomical stability. Unfortunately, central visual acuity is frequently poor in eyes with Coats’ disease, because the disease is not diagnosed and treated until after significant macular lipid deposition is present. Even with good treatment and resolution of the macular deposits, significant subretinal fibrosis and macular impairment are present. Despite this, amblyopia therapy should be considered in young patients who have Coats’ disease. Optical penalization or occlusion of the better eye can result in significant visual improvement in the diseased eye, with gains in acuity to the 20/60–20/100 (6/18–6/30) range after resorption of macular exudate.

Visual acuity results may be quite good in patients who have very mild vascular anomalies that do not require treatment or are discovered and treated before the macula is involved by the exudative process. It is difficult to estimate the frequency with which this situation develops in the general population, because reported series discuss only more severe cases referred to tertiary treatment centers, and the disease is rare enough to have avoided scrutiny in population-based studies.

Eyes with severe exudation and retinal detachment rarely retain vision better than 20/400 (6/120), and many see much worse than this. Nevertheless, successful treatment of leaking vascular channels may salvage some vision, and this has the advantage of stabilizing the eye anatomically. Occasionally an eye may be saved structurally without light perception.[17]

 

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The prognosis for retaining anatomical integrity of the globe is much better. The worst outcomes are in juvenile cases of total retinal detachment. With modern diagnostic improvements, these eyes are now rarely removed when a tumor is suspected, but some cannot be rehabilitated and go on to phthisis or enucleation. Most eyes with Coats’ disease, however, can be saved. Despite chorioretinal scarring, most eyes are cosmetically acceptable, grow and develop otherwise normally, and in many cases have useful vision. Amblyopia therapy, strabismus surgery, and other types of ancillary rehabilitation may be useful and should not be neglected as part of the total treatment of these patients.

 

 

REFERENCES

 

1. Coats G. Forms of retinal dysplasia with massive exudation. Royal London Ophthalmol Hosp Rep. 1908;17:440–525.

 

2. Egerer I, Tasman W, Tomer TL. Coats’ disease. Arch Ophthalmol. 1974;92:109–12.

 

3. Haller JA. Coats’ disease. In: Ryan SJ, ed. Retina. St Louis: CV Mosby; 1989:1453–60.

 

4. Gass JDM. Stereoscopic atlas of macular diseases. St Louis: CV Mosby; 1987:384–9.

 

5. Reese AB. Telangiectasis of the retina and Coats’ disease. Am J Ophthalmol. 1956;42:1–8.

 

6. Morales AG. Coats’ disease. Natural history and results of treatment. Am J Ophthalmol. 1965;60:855–65.

 

7. Tarkkanen A, Laatikainen L. Coats’ disease: clinical angiographic, histopathological findings and clinical management. Br J Ophthalmol. 1983;67:766–76.

 

8. Yannuzzi LA, Gitter KA, Schatz H. The macula: a comprehensive text and atlas. Baltimore: Williams & Wilkins; 1979:118–26.

 

9. Theodossiadis GP. Some clinical, fluorescein-angiographic, and therapeutic aspects of Coats’ disease. J Pediatr Ophthalmol Strabismus. 1979;16:257–62.

 

10. Siliodor SW, Augsburger JJ, Shields JA, Tasman W. Natural history and management of advanced Coats’ disease. Ophthalmol Surg. 1988;19:89–93.

 

11. Gass JDM, Oyakawa RT. Idiopathic juxtafoveal retinal telangiectasis. Arch Ophthalmol. 1982;100:769–80.

 

12. Gass JDM. Stereoscopic atlas of macular diseases. St Louis: CV Mosby; 1987:390–7.

 

13. Woods AC, Duke J. Coats’ disease. 1. Review of the literature, diagnostic criteria, clinical findings, and plasma lipid studies. Br J Ophthalmol. 1963;47:385–412.

 

14. Harris GS. Coats’s disease, diagnosis and treatment. Can J Ophthalmol. 1970; 5:311–20.

 

15. Ridley ME, Shields JA, Brown GC, Tasman W. Coats’ disease. Evaluation of management. Ophthalmology. 1982;89:1381–7.

 

16. Machemer R, Williams JH Sr. Pathogenesis and therapy of traction detachments in various retinal vascular diseases. Am J Ophthalmol. 1988;105:173–81.

 

17. Shields JA, Shields CL, Honavar SG, et al. Classification and management of Coats’ disease: the 2000 Proctor Lecture. Am J Ophthalmol. 2001;131(5):572–83.

Chapter 119 – Hemoglobinopathies

Chapter 119 – Hemoglobinopathies

 

ALLEN C. HO

 

 

 

 

 

DEFINITION

• A spectrum of ocular abnormalities, including peripheral “sea fan” retinal neovascularization, that results from an inherited defect in the synthesis of the hemoglobin molecule.

 

KEY FEATURES

• Macular ischemia.

• Retinal vascular peripheral nonperfusion.

• Retinal hemorrhages: “salmon patches,” “iridescent spots,” and “black sunbursts.”

• Peripheral retinal neovascularization: “sea fans.”

 

ASSOCIATED FEATURES

• Conjunctival comma-shaped capillaries.

• Iris atrophy and posterior synechiae.

• Sickle disc sign.

• Macular depression sign.

• Arteriovenous anastomoses.

• Vitreous hemorrhage.

• Retinal detachment.

 

 

 

INTRODUCTION

Normal red blood cell hemoglobin comprises four polypeptide globin chains, each associated with a central heme ring (ferroprotoporphyrin).[1] The globin chains consist of an identical pair of ß polypeptide chains and an identical pair of ß polypeptide chains. The sickle-cell hemoglobinopathies are characterized by a genetic error in ß chain synthesis, which results in abnormal function of the hemoglobin molecule. Under certain circumstances, the imperfect globin chains induce pathological alterations in red blood cell morphology. These occur particularly in conditions of ischemia and metabolic stress. Owing to their crescent shape, the altered red blood cells are labeled “sickle cells.”

Systemic and ocular sequelae are well described. Interestingly, the severity of systemic symptoms does not typically correlate with the severity of ocular manifestations. The most severe systemic complications are observed in sickle SS disease, while severe ocular features are most commonly noted in patients with sickle SC or sickle thalassemia (S-Thal) disease. In general, vision-threatening sequelae of the sickle hemoglobinopathies are secondary to ischemia or peripheral retinal neovascularization.

EPIDEMIOLOGY AND PATHOGENESIS

Hemoglobinopathies can be characterized electrophoretically as well as by the genetic mutations that lead to abnormal amino acid substitutions in the ß globin chain. Normal adult hemoglobin with two normal a and ß chains is termed hemoglobin A. Sickle hemoglobin, known as S, was initially described by Pauling and others in 1949 as a single point mutation that results in substitution of the amino acid valine for glutamic acid at the sixth position. The substitution of lysine for glutamic acid at this position results in the manufacture of hemoglobin C. The sickle hemoglobinopathies are caused by qualitative errors in globin chain synthesis. Inadequate production of either normal or abnormal globin chains, a quantitative error in globin synthesis, is referred to as thalassemia (Thal).

Because these mutations are inherited, heterozygous and homozygous conditions exist. For example, normal hemoglobin comprises normal homozygous AA globin chains. Classic sickle cell anemia, or SS disease, usually arises when two parents who have sickle trait (AS) disease each pass on their single abnormal S globin chain mutation. If hemoglobin S is inherited from one parent and hemoglobin C from another, a double heterozygous form of hemoglobin, known as sickle SC disease, is created.

Thalassemia mutations can coexist with normal hemoglobin A or with various abnormal hemoglobin chains to produce double heterozygotes, such as those with S-Thal disease. In the United States, African-Americans account for the majority of patients afflicted by the hemoglobinopathies. In this population, the prevalence of sickle trait disease is estimated to be in the range of 5–10%. Clinical sickle AC disease is believed to afflict up to 5% of this group; double heterozygotes—such as those with SS (afflicting approximately 0.4%), SC (approximately 0.1–0.3%), and S-Thal (approximately 0.5–1.0%)—are all less common than those who have at least one normal globin A chain.[2]

Normal hemoglobin confers pliability to the oval-shaped red blood cells, which allows them to pass easily through the microvasculature, where they deliver oxygen. Sickle hemoglobins, such as hemoglobin SS, result in red blood cells with a crescentic, elongated shape, particularly under conditions of hypoxia or acidosis. This causes the blood cells to stack, which further exacerbates local ischemia. A vicious circle of ischemia, red blood cell sickling, tissue hypoxia, and necrosis is set in motion.

Although sickle SS disease has the most severe systemic manifestations, hemoglobin SC and S-Thal have the most severe ocular manifestations. The reasons for this discrepancy are not clear. The more severe anemia of SS disease is associated with red blood cell counts lower than those in hemoglobin SC and S-Thal disease. Relative anemia may leave the remaining red blood cells less disposed to sludging in the circulation.

Because many of the ocular complications of sickle disease are time dependent, their overall prevalence is unknown. From a cross-sectional study, the incidence of proliferative sickle retinopathy (PSR) has been estimated. Approximately 40% of hemoglobin SC patients and 20% of hemoglobin SS patients can be expected to develop PSR.[3]

The hemoglobinopathies described here constitute only a small sampling of the reported mutants of hemoglobin production. Originally, the abnormal hemoglobin chains were described with letters such as S and C. The subsequent explosion of descriptions of globin chain mutants has led to other names, including some that use the geographical location where the hemoglobin was discovered (e.g., hemoglobin Zurich).[1]

OCULAR MANIFESTATIONS

Nearly all ocular or periocular structures can be affected by the sickle hemoglobinopathies. Classic anterior segment findings

 

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include conjunctival comma-shaped capillaries that represent intravascular sludging of sickling red blood cells[4] ( Fig. 119-1 ). Sectorial iris atrophy represents areas of anterior uveal ischemia. Associated anterior or posterior synechiae may occur. A mild anterior chamber cell and flare reaction may be observed secondary to incompetence of the blood-ocular barrier. The anterior segment manifestations generally do not pose significant risks for vision loss.

Posterior segment manifestations of sickle hemoglobinopathies may be observed in the vitreous body, optic disc, retina, and subretinal structures. Vitreous hemorrhage secondary to peripheral retinal neovascularization may develop. The optic disc may demonstrate sludging red blood cells within prepapillary retinal capillaries, which appear as small, dark spots or vascular lines on the surface of the optic disc head.[5] The “macular depression sign” presumably represents atrophy and thinning of the neural macula, which results in an oval depression of the bright central reflex [6] ( Fig. 119-2, A ). Red-free illumination highlights the macular depression sign; this area of macular ischemia may be associated with a decrease in vision. More debilitating macular ischemia can result in frank macular infarction with an enlarged foveal avascular zone secondary to multiple retinal arteriolar occlusions. [7] [8] [9] This type of macular ischemia may have an insidious, progressive course. Fluorescein angiography reveals irregularity in or enlargement of the foveal avascular zone, with adjacent areas of retinal capillary nonperfusion and retinal vascular remodeling (see Fig. 119-2, B ). Retinal arterial microaneurysms are less commonly observed, although cotton-wool spots in the posterior segment are not uncommon.

Both nonproliferative and proliferative forms of sickle retinopathy may be observed, including nonspecific, nonproliferative retinal vascular changes, such as retinal arteriolar sclerosis and venous tortuosity. Retinal arteriolar sclerosis may be observed in areas where there is diffuse capillary nonperfusion that reflects prior retinal vascular occlusion. Venous tortuosity is observed in as many as half of all patients who have SS disease and in one third of patients who have SC disease. Neither of these retinal findings is pathognomonic of sickle retinopathy, since they are observed in a variety of other conditions. Angioid streaks are described in association with sickle-cell disease.

Other nonproliferative retinal findings are more characteristic of sickle hemoglobinopathies. [10] [11] [12] Salmon-colored retinal hemorrhages are preretinal or superficial intraretinal hemorrhages that occur adjacent to a retinal arteriole and are often found in the equatorial retina ( Fig. 119-3 ). Histopathologically, they dissect into the vitreous cavity or into the subretinal space.[13] The salmon hue is attributed to an evolution of color changes; the initial presentation is bright red. These hemorrhages are believed to result from the rupture of a medium-sized retinal arteriole

 

 

Figure 119-1 A classic anterior segment finding in sickle eye disease is comma- or S-shaped conjunctival capillaries. These vessels represent areas of red blood cell sickling or sludging within the capillary bed. (Courtesy of William Tasman, MD.)

due to ischemic vasculopathy. They usually resolve with few sequelae, although a retinoschisis cavity lined with iridescent refractile yellow particles may persist. The schisis cavity is created by resorption of the intraretinal hemorrhage, and the iridescent particles represent macrophages that have engulfed hemoglobin and blood breakdown products.[14]

If the intraretinal hemorrhage dissects into the subneural retinal space and disturbs the retinal pigment epithelium, a black sunburst lesion may result ( Fig. 119-4 ). These dark, irregularly shaped, spiculated or stellate lesions are the result of retinal pigment epithelial hyperplasia and intraretinal migration.[13] [14] Because they are secondary to equatorial retinal hemorrhages, they are located in the same area and generally do not result in significant visual symptoms.

Because PSR can lead to severe vision loss, it was classified into five stages by Goldberg.[2] [12] [15] This progression of retinopathy typically occurs in the third or fourth decade of life but has been noted as early as the second decade. The five stages are as follows:

 

1.

Peripheral arteriolar occlusions

 

2.

Arteriolar-venular anastomoses

 

3.

Neovascular proliferation

 

4.

Vitreous hemorrhage

 

5.

Retinal detachment

Peripheral retinal arteriolar occlusion can leave large areas of anterior retinal capillary nonperfusion, which is highlighted well by fluorescein angiography. Curiously, retinal venous occlusion is uncommon in patients who have sickle-cell disease. Occluded arterioles initially appear dark red but subsequently evolve into “silver wire” vessels. Peripheral arteriolar-venular

 

 

 

 

Figure 119-2 Sickle SC disease. A, Macular ischemia with the macular depression sign and perifoveal vascular remodeling. B, Fluorescein angiogram of the same patient demonstrating an irregular and moth-eaten perifoveal capillary network and vascular telangiectasia. (Courtesy of William Tasman, MD.)

 

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anastomoses evolve, so retinal arterial blood is shunted into retinal venules. These abnormal arteriolar-venular anastomoses can be seen at the junction of perfused and nonperfused retina, typically just peripheral to the equator. These changes often are difficult to observe ophthalmoscopically but are seen easily with fluorescein angiography.

Retinal neovascularization in a sea-fan configuration is the hallmark of PSR ( Fig. 119-5 ). The neovascularization extends from the border zone of perfused and nonperfused retinae ( Fig. 119-6 ). Initially, a sea fan is supplied by one major feeding retinal arteriole and one major draining retinal venule. Over the course of time, an arborization of the neovascular complex occurs in the peripheral retina. Growth typically is circumferential along the border of perfused and nonperfused retina, rather than radial. Sea fans most commonly are observed in patients who have SC disease or S-Thal disease and are rare in patients who have other hemoglobinopathies.[12] [15] Fluorescein angiography demonstrates massive leakage of dye into the vitreous. Generally, the sea fans represent a progressive proliferative retinopathy, which exposes the patient to the risks of vitreous

 

 

Figure 119-3 An equatorial “salmon patch” intraretinal hemorrhage with periarteriolar hemorrhage. These peripheral hemorrhages may lead to retinoschisis cavities lined with iridescent particles that comprise hemoglobin degradation products. The vision is 20/20 (6/6). (Courtesy of William Tasman, MD.)

 

 

Figure 119-4 A black “sunburst” retinal lesion. This is caused by a hemorrhage that dissected into the subneural retinal space and disrupted the retinal pigment epithelium, which culminated in pigmentary migration. Note the spiculated borders. (Courtesy of William Tasman, MD.)

hemorrhage and retinal detachment. Sea fans may spontaneously involute, resulting in areas of grayish white fibrovascular tissues that often have residual perfused retinal vessels at their base. About 40–50% of sea fans may undergo some degree of autoinfarction during their course.[3]

Vitreous hemorrhage is a common complication of retinal sea-fan formation; it may be spontaneous or induced by minor ocular trauma, and it may be limited or dense. Before this occurs, a patient who has PSR may be entirely visually asymptomatic. Patients who have limited vitreous hemorrhage experience floaters, while those who have dense vitreous hemorrhage have sudden severe vision loss. These hemorrhages may clear spontaneously with time or may persist to give ochre-colored vitreous membranes. It is not uncommon for a patient who has suffered one vitreous hemorrhage to experience recurrent vitreous hemorrhages.

Retinal sea fans may induce fibrovascular tissue on the surface of the retina that causes traction or rhegmatogenous retinal detachments ( Fig. 119-7 ). Circumferential sea-fan involvement can cause peripheral traction retinal detachment through areas of

 

 

Figure 119-5 Neural retina in a sickle SC patient. Note the partially regressed peripheral retinal neovascularization at the junction of the perfused retina (right) and the nonperfused retina (far left).

 

 

Figure 119-6 Fluorescein angiography. This demonstrates profound peripheral capillary nonperfusion (far left), retinal vascular remodeling, arteriovenous communications, and extensive leakage of fluorescein dye into the vitreous cavity from the sites of neovascularization.

 

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Figure 119-7 Traction-rhegmatogenous retinal detachment. A retinal tear has developed at the site of peripheral neovascularization and fibrosis, leading to a combined traction-rhegmatogenous retinal detachment. (Courtesy of William Tasman, MD.)

perfused and nonperfused retina. In the areas of thin, nonperfused retina, atrophic, stretched retinal holes can develop to create combined traction and rhegmatogenous retinal detachments.

DIAGNOSIS

Most patients who present with the ophthalmic complications of sickle hemoglobinopathies are aware of their underlying red blood cell abnormality. However, patients with SC and S-Thal disease who have milder anemias and minimal systemic manifestations may be completely unaware of their systemic diagnosis when the ocular complications flare. A history of multiple hospitalizations secondary to painful crises, chronic end-organ damage, multiple infections, and bony abnormalities may be absent. These findings are more characteristic of hemoglobin SS patients.

Hemoglobin electrophoresis is necessary to characterize the abnormal globin chain type. A positive test for sickling, such as the metabisulfite preparation (sickle preparation) or the solubility test, indicates the presence of hemoglobin S but does not distinguish among SS, AS, and double heterozygotes such as S-Thal and SC.[1]

Diagnosis of the ophthalmic manifestations of the sickle hemoglobinopathies is enhanced by careful examination of the conjunctiva, iris, anterior chamber, optic disc, and macula, with special attention paid to the subtle ocular manifestations of sickle-cell disease. Indirect ophthalmoscopy and peripheral retinal contact lens biomicroscopy are helpful to delineate retinal hemorrhages and proliferative changes.

Fluorescein angiography characterizes macular perfusion and peripheral retinal perfusion. Early sea-fan formation is highlighted well by fluorescein leakage. Diagnostic ultrasonography can characterize posterior segment anatomy when a media opacity occurs, such as from vitreous hemorrhage or ochre membranes.

DIFFERENTIAL DIAGNOSIS

Other causes of macular ischemia and peripheral retinal neovascularization, vitreous hemorrhage, and neural retinal detachment are given in Box 119-1 .

SYSTEMIC ASSOCIATIONS

Patients who have classic sickle SS disease manifest a variety of systemic abnormalities, including anemia, bone marrow infarcts, bony sclerosis (e.g., vertebral “fishmouthing”), aseptic necrosis of the femoral head, ischemia of visceral organs, shortness

 

 

Differential Diagnosis of Hemoglobinopathies

 

OTHER CAUSES OF MACULAR ISCHEMIA

Diabetic retinopathy

 

Retinal vascular obstruction

 

Embolic phenomena such as talc retinopathy

 

 

OTHER CAUSES OF PERIPHERAL RETINAL NEOVASCULARIZATION, VITREOUS HEMORRHAGE, AND RETINAL DETACHMENT

Proliferative diabetic retinopathy

 

Retinal vein obstruction

 

The ocular ischemic syndrome

 

Sarcoidosis

 

Pars planitis

 

Retinopathy of prematurity

 

Familial exudative vitreoretinopathy

 

Eales’ disease

 

 

 

 

of breath caused by pulmonary infarcts, and an increased susceptibility to bacterial infections, particularly salmonellosis caused by reticuloendothelial cell dysfunction.

Other hemoglobinopathies result in less severe systemic disease. In some, a mild anemia may be the only manifestation.

TREATMENT

Despite an understanding of the molecular pathogenesis of sickle hemoglobinopathies, there is currently no effective form of therapy that prevents the sickling of red blood cells or the ensuing ocular complications. For example, no intervention has been shown definitively to halt the progression of macular ischemia, although case reports exist of improvement after exchange transfusion and oxygenation [7] [9] [13] [16] or hyperbaric oxygenation.

Most treatment efforts focus on altering the course of PSR to reduce the chance of vitreous hemorrhage and retinal detachment.[11] Cryotherapy, diathermy, xenon arc photocoagulation, and argon laser photocoagulation have all been employed to treat peripheral retinal neovascularization. Cryotherapy has been used to treat peripheral retinal neovascularization in the presence of vitreous hemorrhage when the neovascular proliferation is visualized only partially and when vitreous hemorrhage precludes treatment with laser photocoagulation. Both single freeze-thaw and triple freeze-thaw techniques have been described. However, cryotherapy has been largely abandoned because of the significant complication rate. Ocular diathermy treatment to obliterate peripheral retinal neovascularization and associated feeder vessels has been reported, but it too is saddled with a high rate of complications.

Various methods of laser photocoagulation effectively induce regression of peripheral neovascularization.[9] [17] [18] [19] [20] [21] Feeder-vessel laser photocoagulation requires intensive treatment with high energy and is more likely to be complicated by chorioretinal or choriovitreal neovascularization, retinal detachment, and vitreous hemorrhage.[22]

Scatter laser photocoagulation of areas that surround sea-fan proliferation and associated areas of ischemic retina induces regression of these lesions. The rationale is to ablate areas of ischemic retina that are stimulating neovascular proliferation. Two laser techniques have been described, and both can induce successful regression of neovascularization. The first is a localized treatment confined to areas anterior to the patent neovascular fronds.[21] The second uses a 360° peripheral, circumferential retinal scatter technique to the anterior retina.[18] [20] The rationale of the 360° scatter treatment is to induce regression of existing peripheral retinal neovascularization and to prevent the formation of any future neovascularization. In general, these techniques can be performed with light- to moderate-intensity burns approximately 500?mm in diameter placed approximately one burn

 

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width apart. At this time, scatter laser photocoagulation, either localized or circumferential, is the treatment of choice to prevent complications secondary to peripheral sea-fan proliferation.

Vitreous hemorrhage secondary to PSR may be followed for up to 6 months to await spontaneous clearing. If areas of retinal neovascularization can be identified through the vitreous hemorrhage, the associated anterior retina should be treated with scatter laser photocoagulation. Fluorescein angiography or fluorescein angioscopy using an indirect ophthalmoscope and a blue light filter may be used to identify retinal neovascularization in cases of limited vitreous hemorrhage. When the retina is not well visualized, it is important to follow these eyes with ultrasonography to rule out retinal detachment. A minority of patients progress to retinal detachment with or without laser treatment.

Surgery on patients who have sickle hemoglobinopathies is fraught with ocular and systemic pitfalls. A preoperative work-up to assess the severity of anemia, hemoglobin electrophoretic status, and overall systemic condition is critical. Intraoperative and postoperative systemic complications include thromboembolic events such as pulmonary or cerebral embolism. The role of exchange transfusions in reducing the risk of a sickle-cell crisis precipitated by general anesthesia remains unclear. These exchange transfusions are performed to achieve 50–60% hemoglobin A, as indicated by electrophoresis, with a hematocrit of 35–40%. Exchange transfusions may reduce the rate of anterior segment ischemia and optic nerve and macular infarcts, which can occur with intraocular pressures (IOPs) as low as 25?mmHg. Currently, however, no compelling reason exists to perform transfusions.[23]

Although the role of exchange transfusions is in question, adequate hydration and supplemental oxygen are often administered during the perioperative and operative periods. If possible, surgery should be performed under monitored local anesthesia; vasoconstrictive agents, such as epinephrine (adrenaline) in the anesthetic block and pupillary dilating agents, should be avoided. Many advocate lowered IOP to both maximize intraocular perfusion and avoid hemoconcentration. Single doses of carbonic anhydrase inhibitors or intravenous mannitol may be administered to lower the IOP, but these agents should not be used repetitively. Even transient elevations in IOP should be avoided, particularly if a scleral buckle is used, to avert vitreous hemorrhage and macular ischemia.

The possibility of anterior segment ischemia is reduced by avoiding treatments in the horizontal meridians, which harbor the long posterior ciliary arteries. For the same reason, manipulation of horizontal and vertical rectus muscles should be performed with care; transection of these muscles should be avoided. Drainage of subretinal fluid is often desirable, since this may minimize the elevation of IOP if a scleral buckle is employed. With current vitrectomy instrumentation, fluctuations in IOP during vitrectomy surgery are less common. A current ultrasonogram to elucidate the intraocular anatomy is important in cases of vitreous hemorrhage. The peripheral vitreous may be firmly attached to shallow areas of traction retinal detachment at the sites of fibrovascular proliferation and may not be well visualized intraoperatively, particularly when ochre-colored membranes are present.

In cases of combined traction-rhegmatogenous retinal detachment, the surgical goals include the release of areas of traction that elevate the retina and the removal of fibrovascular proliferation that may prevent the retinal tear from settling flat. Once this is achieved, scatter endolaser photocoagulation is performed. Postoperatively, the patient’s IOP must be monitored closely, particularly if intraocular gas is used.

Anterior segment ischemia does not usually occur if care is taken to avoid elevations of IOP and if the anterior ciliary circulation is not violated. [24] Anterior segment necrosis results in persistent red eye, corneal decompensation, uveitis, and synechiae formation.

Patients who have sickle hemoglobinopathies and who develop postoperative or posttraumatic hyphema are at risk for posterior segment ischemia or infarction, even at mildly elevated IOPs. Low oxygen tension and high ascorbic acid levels in the anterior chamber promote sickling of red blood cells, which can obstruct the trabecular meshwork and lead to a greater elevation of IOP. Macular infarction has been reported with IOPs as low as 25?mmHg. Therefore, aggressive lowering of IOP to less than this level is indicated. Some authors recommend early paracentesis to reduce the IOP in acute situations.

COURSE AND OUTCOME

The course for patients who have ocular complications secondary to sickle hemoglobinopathies is variable.[25] [26] Untreated, the incidence of blindness from PSR is about 12%.[3] Clearly, with modern laser and vitrectomy techniques, the risk in treated eyes is less. Patients who require intraocular surgery for vitreous hemorrhage or retinal detachment have a higher risk of systemic and postoperative ocular complications, including anterior segment ischemia and optic disc or macular infarction. Patients whose PSR is rendered quiescent with laser photocoagulation may enjoy excellent vision in the long term. In one study of long-term follow-up following laser photocoagulation, only 4% of treated eyes had a repeat vitreous hemorrhage, versus 66% of untreated eyes. Fortunately, severe visual loss was rare in both groups.[26]

 

 

REFERENCES

 

1. Rifkind RA, Bank A, Marks PA, et al. Fundamentals of hematology. Chicago: Year Book Medical Publishers; 1980.

 

2. Goldberg MF. Sickle cell retinopathy. In: Duane TD, Jaeger EA, Goldberg MF, eds. Clinical ophthalmology. Philadelphia: JB Lippincott; 1989:1–45.

 

3. Condon PI, Serjeant GR. Behaviour of untreated proliferative sickle retinopathy. Br J Ophthalmol. 1980;64:404–11.

 

4. Paton D. Conjunctival sign of sickle cell disease. Arch Ophthalmol. 1961;66: 90–4.

 

5. Goldbaum MH, Jampol LM, Goldberg MF. The disc sign in sickling hemoglobinopathies. Arch Ophthalmol. 1978;96:1597–1600.

 

6. Goldbaum MH. Retinal depression sign indicating a small retinal infarct. Am J Ophthalmol. 1978;86:45–55.

 

7. Asdourian GK, Goldberg MF, Rabb MF. Macular infarction in sickle cell B+ thalassemia. Retina. 1982;2:155–8.

 

8. Merritt JC, Risco JM, Pantell JP. Bilateral macular infarction in SS disease. J Pediatr Ophthalmol Strabismus. 1982;19:275–8.

 

9. Sanders RJ, Brown GC, Rosenstein RB, Magargal L. Foveal avascular zone diameter and sickle cell disease. Arch Ophthalmol. 1991;109:812–5.

 

10. Goldberg MF. Retinal vaso-occlusion in sickling hemoglobinopathies [review]. Birth Defects: Original Article Ser. 1976;12:475–515.

 

11. Cohen SB, Fletcher ME, Goldberg MF, Jednock NJ. Diagnosis and management of ocular complications of sickle hemoglobinopathies: Part V [review]. Ophthalmic Surg. 1986;17:369–74.

 

12. Goldberg MF. Classification and pathogenesis of proliferative sickle retinopathy. Am J Ophthalmol. 1971;71:649–65.

 

13. Romayananda N, Goldberg MF, Green WR. Histopathology of sickle cell retinopathy. Trans Am Acad Ophthalmol Otolaryngol. 1973;77:642–76.

 

14. van Meurs JC. Evolution of a retinal hemorrhage in patient with sickle cell–hemoglobin C disease. Arch Ophthalmol. 1995;113:1074–5.

 

15. Goldberg MF, Charache S, Acacio I. Ophthalmologic manifestations of sickle cell thalassemia. Arch Intern Med. 1971;128:33–43.

 

16. Khwarg SG, Feldman S, Ligh J, Straatsma BR. Exchange transfusion in sickling maculopathy. Retina. 1985;5:227–9.

 

17. Jampol LM, Condon P, Farber M, et al. A randomized clinical trial of feeder vessel photocoagulation of proliferative sickle cell retinopathy. I. Preliminary results. Ophthalmology. 1983;90:540–5.

 

18. Kimmel AS, Magargal LE, Stephens RF, Cruess AF. Peripheral circumferential retinal scatter photocoagulation for the treatment of proliferative sickle retinopathy. An update. Ophthalmology. 1986;93:1429–34.

 

19. Fox PD, Minninger K, Forshaw ML, et al. Laser photocoagulation for proliferative retinopathy in sickle haemoglobin C disease. Eye. 1993;7:703–6.

 

20. Cruess AF, Stephens RF, Magargal LE, Brown GC. Peripheral circumferential retinal scatter photocoagulation for treatment of proliferative sickle retinopathy. Ophthalmology. 1983;90:272–8.

 

21. Rednam KR, Jampol LM, Goldberg MF. Scatter retinal photocoagulation for proliferative sickle cell retinopathy. A long-term follow-up. Ophthalmology. 1982;98:594–9.

 

22. Dizon-Moore RV, Jampol LM, Goldberg MF. Chorioretinal and choriovitreal neovascularization: their presence after photocoagulation of proliferative sickle retinopathy. Arch Ophthalmol. 1981;99:842–9.

 

23. Pulido JS, Flynn HW, Clarkson JG, Blankenship GW. Pars plana vitrectomy in the management of complications of proliferative sickle retinopathy. Arch Ophthalmol. 1988;106:1553–7.

 

24. Ryan SJ, Goldberg MF. Anterior segment ischemia following scleral buckling in sickle cell hemoglobinopathy. Am J Ophthalmol. 1971;72:35–50.

 

25. Goldberg MF. Natural history of untreated proliferative sickle retinopathy. Arch Ophthalmol. 1971;85:428–36.

 

26. Jacobson MS, Gagliano DA, Cohen SB, et al. A randomized clinical trial of feeder vessel photocoagulation of sickle cell retinopathy. Ophthalmology. 1991;98:581–5.

Chapter 118 – Ocular Ischemic Syndrome

Chapter 118 – Ocular Ischemic Syndrome

 

MATTHEW T.S. TENNANT

ARUNAN SIVALINGAM

GREGORY M. FOX

GARY C. BROWN

 

 

 

 

 

DEFINITION

• Ocular signs and symptoms secondary to severe, chronic arterial hypoperfusion.

 

KEY FEATURES

• Visual loss.

• Blot retinal hemorrhages.

• Dilated, beaded retinal veins.

• Decreased ocular perfusion pressure.

• Ocular neovascularization.

• Severe ipsilateral or bilateral carotid artery obstruction.

 

ASSOCIATED FEATURES

• Pain or ocular angina.

• Neovascular glaucoma.

• Corneal edema and striae.

• Mild anterior uveitis.

• Cherry-red spot in macula.

• Cotton-wool spots.

• Spontaneous pulsations of retinal arteries.

• Ischemic optic neuropathy.

 

 

 

INTRODUCTION

Ocular ischemic syndrome is a condition that has a variable spectrum of signs and symptoms that result from chronic ocular hypoperfusion, usually secondary to severe carotid artery obstruction. Ocular signs and symptoms secondary to severe carotid artery obstruction, described in 1963 by Kearns and Hollenhorst,[1] initially was called venous stasis retinopathy. Because other authors employed same the term to describe nonischemic central retinal vein occlusion,[2] an entirely different condition, this nomenclature is best avoided. Additional names given to this condition include hypoperfusion retinopathy, hypotensive retinopathy, ischemic ocular inflammation,[3] and ischemic oculopathy.[4]

EPIDEMIOLOGY AND PATHOGENESIS

The ocular ischemic syndrome occurs at a mean age of 65 years and generally does not develop before 50 years of age. Men who have this condition outnumber affected women by a ratio of 2:1, which reflects the higher incidence of atherosclerotic cardiovascular disease in men. No racial predilection exists. Bilateral involvement occurs in 20% of cases.[5] The incidence of ocular ischemic syndrome is not known precisely but is estimated at 7.5 cases per million population annually based on the work of Sturrock and Mueller. [6] Approximately 5% of patients who have hemodynamically significant carotid artery disease develop ocular ischemic syndrome.

The pathogenesis of the syndrome is decreased arterial inflow on a chronic basis. The period and extent of the impaired blood flow necessary to develop this syndrome still is not clear. Using color Doppler imaging, Ho et al.[7] were able to study blood flow velocity and vascular resistance in the ocular circulation. Reversal of ophthalmic artery flow was demonstrated in 12 of 16 eyes studied, and all the studied eyes that had ocular ischemic syndrome had decreased peak systolic flow velocities of the central retinal artery. Reversal of flow within the ophthalmic artery represents collateralization through the external carotid artery system in response to obstructions in the internal carotid artery system. Moreover, Ho et al.[7] were able to show that eyes that have significant visual loss demonstrate posterior ciliary artery hypoperfusion. Therefore, secondary ischemia of the optic nerve, choroid, retinal pigment epithelium, and outer segments of the photoreceptors is likely to result in the visual loss seen in ocular ischemic syndrome. Experimental blood flow studies of McFadzean et al.[8] corroborate these findings, which suggest that posterior ciliary arterial hypoperfusion results in visual loss in ocular ischemic syndrome. In rare cases, color Doppler imaging detects isolated ophthalmic artery stenosis in patients who have ocular ischemic syndrome but no carotid artery disease.

OCULAR MANIFESTATIONS

Symptoms

Loss of vision is present in over 90% of affected patients at the time of evaluation.[5] The visual loss generally occurs gradually, over a period of weeks to months, but can occur abruptly. Approximately 5% of patients have a previous history of amaurosis fugax.

The severity of the visual loss is variable.[5] About 35% of affected eyes at the time of evaluation have a visual acuity of 20/40 (6/12) or better, while 30% range from 20/50 (6/15) to 20/400 (6/120). In the remaining 35%, acuity is sufficient to count fingers or worse. The absence of light perception is an uncommon finding initially but may develop as a sequela of severe posterior segment ischemia, often in combination with neovascular glaucoma. A prolonged time for recovery of vision after exposure to bright lights may occur in patients who have posterior segment ischemia.

A dull ache over the eye or brow is reported by up to 40% of patients who have ocular ischemic syndrome.[5] The pain results from either ischemia of the globe or elevated intraocular pressure (IOP) caused by neovascular glaucoma. The pain associated with ocular ischemic syndrome, especially when IOP is normal, has been called ocular angina.

Anterior Segment

Anterior segment findings in ocular ischemic syndrome are common. Corneal edema and striae may not be present unless an increased pressure from neovascular glaucoma also is present. Approximately two thirds of eyes that have ocular ischemic syndrome have neovascularization of the iris at the time of initial examination by the ophthalmologist.[5] However, this percentage may be deceptively high, because those who have asymptomatic milder involvement may not visit the ophthalmologist. In severe cases, ectropion uvea may develop. Flare in the anterior chamber commonly accompanies iris neovascularization. Iris neovascularization

 

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Figure 118-1 Retinal vascular changes in ocular ischemic syndrome. Narrowed retinal arteries; dilated, minimally tortuous retinal veins; and blot retinal hemorrhages are present in an eye that is affected by ocular ischemic syndrome.

in the eye of a nondiabetic, with no evidence of venous occlusive disease or other predisposing cause, is suggestive of ocular ischemic syndrome.

Neovascular glaucoma, defined as neovascularization of the iris and an IOP greater than 22?mmHg, is seen in only one half of the patients with ocular ischemia who have neovascularization of the iris.[5] Some patients who have neovascularization of the iris may develop complete closure of the anterior chamber angle with fibrovascular tissue, but the IOP remains normal. This phenomenon probably results from impaired ciliary body perfusion and decreased aqueous humor production as a consequence of carotid stenosis.

Anterior uveitis in eyes that have ocular ischemic syndrome has been described well.[3] Iritis, present in 20% of these eyes, is generally mild. Flare is a more prominent feature than the cellular response, and keratitic precipitates are seen infrequently. In patients over 50 years of age who have new-onset iritis, the possibility of ocular ischemic syndrome must be considered.

Lens opacification, even formation of a mature cataract, may occur in the end stages of ocular ischemic syndrome. However, often at the time of evaluation little difference exists in the incidence of cataract between affected eyes and fellow eyes.[5]

Posterior Segment

Signs in the posterior segment provide important clinical clues that suggest this diagnosis. Numerous signs can be seen in the fundus, which include the following:

• Retinal arterial narrowing

• Retinal venous dilation without tortuosity

• Retinal hemorrhages and microaneurysms

• Neovascularization of the optic disc or retina

• Cherry-red spot

• Cotton-wool spots

• Spontaneous pulsations of the retinal arteries

Retinal arterial narrowing and straightening, commonly associated with areas of focal constriction, are seen in eyes that have ocular ischemic syndrome. These signs can be difficult to differentiate from the narrowed vessels commonly seen in the elderly. Dilated retinal veins are seen frequently in eyes that display ocular ischemic syndrome. In ocular ischemic syndrome retinal veins also may have significant beading, similar to eyes that have preproliferative or proliferative diabetic retinopathy. In contrast to eyes that have central retinal venous occlusion, retinal venous tortuosity is not a prominent feature ( Fig. 118-1 ). Retinal hemorrhages are seen in 80% of eyes, most characteristically of a dot and blot variety located in the midperiphery, but they can extend into the posterior pole ( Fig. 118-2 ). Microaneurysms also

 

 

Figure 118-2 Retinal hemorrhages in ocular ischemic syndrome. Dot and blot hemorrhages, as well as microaneurysms, are seen commonly in the midperiphery of eyes that are affected by ocular ischemic syndrome.

are seen in the same locations. Neovascularization, which ranges from mild to severe, may occur on the optic disc in over one third of patients who have ocular ischemic syndrome.[5] Retinal neovascularization has been described in 8% of eyes.

During examination, a cherry-red spot is seen in 12% of eyes that display ocular ischemic syndrome.[5] This finding most commonly occurs as the IOP from neovascular glaucoma exceeds the central retinal artery’s perfusion pressure. Cotton-wool spots and spontaneous pulsations of the retinal arteries are each found in 5% of eyes that have the syndrome.[5] When not present spontaneously, retinal arterial pulsations can be elicited easily by minimal pressure on the globe, because of the severe diminution in ocular perfusion pressure. In contrast, eyes that have nonischemic central retinal venous occlusion require a normal amount of digital pressure to induce retinal arterial pulsations. [9] In the past, ocular plethysmography was performed to assess ocular perfusion pressure quantitatively. It rarely is used now.

Ischemic optic neuropathy, which appears with acute, pale swelling of the disc, has been reported in an eye affected by ocular ischemic syndrome.[10] Otherwise, the optic disc tends to be normal in appearance, unlike the disc edema seen with central retinal vein obstruction.

DIAGNOSIS AND ANCILLARY TESTING

In addition to clinical examination, fluorescein angiography can help to establish the diagnosis of ocular ischemic syndrome. Ideally, a delay in arm-to-choroid and arm-to-retina circulation times is demonstrated by fluorescein angiography, but variation in the location and speed of injection may make these times difficult to assess. However, demonstration of a well-demarcated leading edge of fluorescein dye within a retinal artery is very unusual for a normal eye and suggests ocular hypoperfusion ( Fig. 118-3 ). Patchy filling of the choroid that lasts more than 5 seconds is seen in about 60% of eyes affected by ocular ischemic syndrome ( Fig. 118-4 ).[5]

Other findings on fluorescein angiography include an increased arteriovenous transit time, staining of the retinal vessels, macular edema, retinal capillary nonperfusion, and evidence of microaneurysms (especially in the periphery). The arteriovenous transit time exceeds 11 seconds in approximately 95% of affected eyes.[5] Late staining of retinal vessels, more prominent in arterioles than in venules, is present in about 85% of cases ( Fig. 118-5 ).[5]

Electroretinography demonstrates a decrease in both the a waves and b waves in eyes that are affected by ocular ischemic syndrome, in contrast to the sparing of the a wave found in central retinal artery occlusions.[11] The choroidal and outer retinal ischemia of eyes that have ocular ischemic syndrome accounts for this difference.

 

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Figure 118-3 Fluorescein angiography, ocular ischemic syndrome. A distinctly abnormal finding in a fluorescein angiogram of eyes that are affected by ocular ischemic syndrome is a well-demarcated leading edge of dye within the retinal arteries.

Color Doppler imaging is an excellent noninvasive means by which to assess the velocity of blood flow in the retrobulbar circulation. Diminution of blood flow velocities in the central retinal artery, choroidal vessels, and ophthalmic artery is typical. Reversal of flow in the ophthalmic artery is common, as well. Color Doppler imaging may be used to assess the carotid arteries simultaneously.

Carotid arteriography discloses generally a 90% or greater obstruction of the ipsilateral carotid artery in patients who have ocular ischemic syndrome. If noninvasive carotid artery evaluation is unremarkable in an eye that shows signs suggestive of ocular ischemia, conventional carotid arteriography or digital subtraction angiography may be required to demonstrate possible chronic obstruction of the ophthalmic artery. [11] [12] [13] Rarely, cases of ocular ischemia may be induced by a more distal obstruction in the ophthalmic artery itself.

DIFFERENTIAL DIAGNOSIS

Nonischemic central retinal venous occlusions and diabetic retinopathy are conditions most likely to be confused with ocular ischemic syndrome. Various ocular signs help to differentiate these conditions, as given in Table 118-1 . One particularly useful differentiating feature is a swollen optic disc, which typically is seen in nonischemic vein occlusions and not in ocular ischemic syndrome. In addition, central retinal vein occlusions typically have dilated and tortuous retinal veins. Although microaneurysms may occur in both diabetes and ocular ischemic syndrome, in diabetes they tend to involve the posterior pole preferentially. On rare occasions, giant cell arteritis may induce findings similar to those of ocular ischemic syndrome. In general, however, giant cell arteritis has a much more dramatic clinical picture, with ischemic optic neuropathy or retinal artery occlusion, or both.

Takayasu’s Arteritis

Takayasu’s arteritis, also known as aortic arch syndrome or pulseless disease, is an idiopathic inflammation of larger elastic and muscular arteries—the aorta is affected in particular. It is primarily a disease of young adults, especially women, and is most prevalent in the Far East. Constitutional symptoms are common, including fever, fatigue, and weight loss.

The ocular manifestations can mimic those of ocular ischemic syndrome. Retinal arterial narrowing, large arteriovenous anastomoses, and peripheral microaneurysms are common. Retinal neovascularization with vitreous hemorrhage may occur. Systemic corticosteroids are the treatment of choice.

 

 

Figure 118-4 Patchy choroidal filling, ocular ischemic syndrome. Patchy choroidal filling that lasts more than 5 seconds occurs in about 60% of eyes affected by ocular ischemic syndrome.

 

 

Figure 118-5 Staining of retinal arteries, ocular ischemic syndrome. Prominent staining of retinal arteries, rather than venules, can help to differentiate an eye that has ocular ischemic syndrome from an eye that is affected by a nonischemic central retinal vein occlusion (which shows more prominent staining of the venules).

SYSTEMIC ASSOCIATIONS

The atherosclerosis that affects the carotid artery sufficiently to cause ocular ischemic syndrome generally is widespread. Of patients who have ocular ischemic syndrome, 50% show evidence of ischemic heart disease; and 25% have a history of previous cerebrovascular accidents.[14]

Additional risk factors for both atherosclerosis and arteriosclerosis are found in these patients, such as systemic hypertension, which is found in two thirds of patients who have ocular ischemic syndrome, and diabetes mellitus, which is observed in more than 50% of these patients.[14]

A 5-year mortality of 40% in patients who have ocular ischemic syndrome reflects the severity of their systemic vascular disease. The main cause of death in these patients is ischemic heart disease, with stroke the second most common cause.

PATHOLOGY

In the early stage of the ocular ischemic syndrome, the neural retina shows coagulative necrosis of its inner layers, which are supplied by the retinal arterioles. If the area of coagulative necrosis is small and localized, it appears clinically as a cotton-wool spot, a microinfarct of the nerve fiber layer. Histologically, the

 

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TABLE 118-1 — FEATURES THAT DISTINGUISH OCULAR ISCHEMIC SYNDROME

Feature

Ocular Ischemic Syndrome

Nonischemic Central Retinal Vein Occlusion

Diabetic Retinopathy

Laterality

80% unilateral

Unilateral

Bilateral

Age (years)

50–80

50–80

Variable

FUNDUS SIGNS

Veins

Dilated, nontortuous

Dilated, tortuous

Dilated, beaded

Optic disc

Normal

Swollen

Normal

Retinal artery perfusion pressure

Decreased

Normal

Normal

Retinal hemorrhages

Mild

Mild to severe

Mild to moderate

Microaneurysms

Midperiphery

Variable

Posterior pole

Hard exudates

Absent unless in association with diabetes

Rare

Common

FLUORESCEIN ANGIOGRAPHY

Choroidal filling

Delayed, patchy

Normal

Normal

Arteriovenous transit time

Prolonged

Prolonged

Normal

Retinal vessel staining

Prominent arterial staining

Prominent venous staining

Absent (usually)

Clinical signs and fluorescein angiography that help differentiate ocular ischemic syndrome from nonischemic central retinal vein occlusions or diabetic retinopathy.

 

 

swollen end-bulbs of the infarcted nerve fiber layer superficially resemble cells, hence the term cytoid body. If the area of coagulative necrosis is extensive, it appears clinically as a gray neural retinal area, blotting out the background choroidal pattern. With complete coagulative necrosis of the posterior pole (e.g., after a central retinal artery occlusion), the red choroid shows through the central fovea as a cherry-red spot. The inner half of the neural retina becomes “homogenized” into a diffuse, relatively acellular zone. Generally, thick-walled retinal blood vessels are present.

TREATMENT, COURSE, AND OUTCOME

Patients who have mild ocular ischemic syndrome may maintain excellent vision, but the natural course of eyes that have the full-blown syndrome is quite poor.[15] Assessment of carotid artery function in patients with ocular ischemic syndrome is of utmost importance. The North American Symptomatic Carotid Endarterectomy Trial demonstrated that carotid endarterectomy was beneficial for patients with carotid stenosis of 70–99% with a recent history of amaurosis fugax, a hemispheric transient ischemic attack, or a nondisabling stroke. The cumulative risk of ipsilateral stroke was 26% after 2 years for patients receiving antiplatelet treatment, while the cumulative risk of stroke was 9% 2 years after endarterectomy.[16] The benefit of endarterectomy was tempered by a 2.1% risk of severe stroke or death during the immediate postoperative period in the patients who underwent surgery versus 0.9% in the antiplatelet group. In symptomatic patients with carotid artery stenosis of 50–69%, only a moderate reduction in risk of stroke was identified after carotid endarterectomy.[17]

Stabilization or improvement in vision has been reported in about 25% of eyes after endarterectomy.[15] Doppler color imaging has shown postoperative normalization of preoperative retrograde ophthalmic artery flow following endarterectomy.[18] Electroretinogram a waves and b waves have improved with increased amplitude following endarterectomy.[19] Occasionally, in eyes that have ciliary body hypoperfusion, complete angle closure, and normal IOP, carotid endarterectomy has resulted in severe glaucoma immediately after surgery. In cases in which 100% obstruction and distal propagation of a thrombus has occurred, bypass procedures, such as superficial temporal artery to middle cerebral artery, have been attempted. Although the vision improves transiently in 20% of such eyes, it usually deteriorates within 1 year of surgery.[15]

In cases that have iris neovascularization in which the anterior chamber angle is open, panretinal photocoagulation may induce regression of the rubeosis. Unfortunately, the regression is not as prominent as that seen in patients who have iris neovascularization after central retinal vein occlusion.[20] Elevated IOP from neovascular glaucoma may require cyclodestructive therapies or filtering procedures.

 

 

REFERENCES

 

1. Kearns TP, Hollenhorst RW. Venous stasis retinopathy of occlusive disease of the carotid artery. Mayo Clin Proc. 1963;38:304–12.

 

2. Hayreh SS. So-called “central retinal vein occlusion.” Venous stasis retinopathy. Ophthalmologica. 1976;172:14–37.

 

3. Knox DL. Ischemic ocular inflammation. Am J Ophthalmol. 1965;60:995–1002.

 

4. Young LHY, Appen RE. Ischemic oculopathy: a manifestation of carotid artery disease. Arch Neurol. 1981;38:358–61.

 

5. Brown GC, Magargal LE. The ocular ischemic syndrome: clinical, fluorescein angiographic and carotid angiographic features. Int Ophthalmol. 1988;11:239–51.

 

6. Sturrock GD, Mueller HR. Chronic ocular ischaemia. Br J Ophthalmol. 1984;68:716–23.

 

7. Ho AC, Lieb WE, Flaharty PM, et al. Color Doppler imaging of the ocular ischemic syndrome. Ophthalmology. 1992;99:1453–62.

 

8. McFadzean RM, Graham DI, Lee WR, Mendelow AD. Ocular blood flow in unilateral carotid stenosis and hypotension. Invest Ophthalmol Vis Sci. 1989;30:487–90.

 

9. Kearns TP. Differential diagnosis of central retinal vein obstruction. Ophthalmology. 1983;90:475–80.

 

10. Brown GC. Anterior ischemic optic neuropathy occurring in association with carotid artery obstruction. J Clin Neurol Ophthalmol. 1986;6:39–42.

 

11. Brown GC, Magargal LE, Simeone FA, et al. Arterial obstruction and ocular neovascularization. Ophthalmology. 1982;89:139–46.

 

12. Bullock JD, Falter RT, Downing JE, Snyder HE. Ischemic ophthalmia secondary to ophthalmic artery occlusion. 1972;74:486–93.

 

13. Madsen PH. Venous-stasis retinopathy insufficiency of the ophthalmic artery. Acta Ophthalmol. 1966;44:940–7.

 

14. Sivalingham A, Brown GC, Magargal LE, Menduke H. The ocular ischemic syndrome. II. Mortality and systemic morbidity. Int Ophthalmol. 1990;13:187–91.

 

15. Sivalingham A, Brown GC, Magargal LE. The ocular ischemic syndrome. III. Visual prognosis and the effect of treatment. Int Ophthalmol. 1991;15:15–20.

 

16. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991;325:445–53.

 

17. Barnett HJM, Taylor DW, Eliasziw M, et al. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med. 1998; 339:1415–25.

 

18. Kawaguchi S, Okuno S, Sakaki T, Nishikawa N. Effect of carotid endarterectomy on ocular ischemic syndrome due to internal carotid artery stenosis. Neurosurgery. 2001;48:328–33.

 

19. Story JL, Held KS, Harrison JM, et al. The ocular ischemic syndrome in carotid artery occlusive disease: ophthalmic color Doppler flow velocity and electroretinographic changes following carotid endarterectomy reconstruction. Surg Neurol. 1995;44:534–5.

 

20. Eggleston TF, Bohling CA, Eggleston HC, Hershey FB. Photocoagulation for ocular ischemia associated with carotid artery occlusion. Ann Ophthalmol. 1980;12:84–7.

Chapter 117 – Diabetic Retinopathy

Chapter 117 – Diabetic Retinopathy

 

BRETT J. ROSENBLATT

WILLIAM E. BENSON

 

 

 

 

 

DEFINITION

• Progressive dysfunction of the retinal vasculature caused by chronic hyperglycemia.

 

KEY FEATURES

• Microaneurysms.

• Retinal hemorrhages.

• Retinal lipid exudates.

• Cotton-wool spots.

• Capillary nonperfusion.

• Macular edema.

• Neovascularization.

 

ASSOCIATED FEATURES

• Vitreous hemorrhage.

• Retinal detachment.

• Neovascular glaucoma.

• Premature cataract.

• Cranial nerve palsies.

 

 

 

INTRODUCTION

Successful management of diabetic retinopathy via a combination of glucose control, laser therapy, and vitrectomy represents one of the most striking achievements of modern ophthalmology. If fundus examinations are initiated prior to the development of significant retinopathy and repeated periodically, and if the recommendations of the Early Treatment Diabetic Retinopathy Study (ETDRS) are followed with respect to the management of subsequent diabetic macular edema or neovascularization, the risk of severe visual loss is less than 5%. Despite this, diabetic retinopathy remains the number one cause of new blindness in most industrialized countries. The vast majority of diabetic individuals who lose vision do so, not because of an inability to treat their disease, but rather due to a delay in seeking medical attention. The key to sight preservation for diabetic patients is routine examinations to detect the earliest signs of retinopathy.

EPIDEMIOLOGY

The best predictor of diabetic retinopathy is the duration of the disease.[1] Patients who have had type 1 for 5 years or less rarely show any evidence of diabetic retinopathy. However, 27% of those who have had diabetes for 5–10 years and 71–90% of those who have had diabetes for longer than 10 years have diabetic retinopathy. [2] After 20–30 years, the incidence rises to 95%, and about 30–50% of these patients have proliferative diabetic retinopathy (PDR).

Yanko et al.[3] described the prevalence of retinopathy in patients with type 2 diabetes. They found that the prevalence of retinopathy 11–13 years after the onset of type 2 diabetes was 23%; after 16 or more years, it was 60%; and 11 or more years after the onset, 3% of the patients had PDR. Klein et al. [2] found that 10 years after the diagnosis of type 2 diabetes, 67% of patients had retinopathy and 10% had PDR.

The most important determinant of retinopathy is the duration of diabetes after the onset of puberty. For example, the risk of retinopathy is roughly the same for two 25-year-old patients, of whom one developed diabetes at the age of 6 and the other at the age of 12 years.[4]

The Diabetes Control and Complications Trial showed emphatically that patients with type 1 diabetes who closely monitored their blood glucose (four measurements per day = tight control) do far better than patients treated with conventional therapy (one measurement per day).[5] The former had a 76% reduction in the rate of development of any retinopathy (primary prevention cohort) and a 54% reduction in progression of established retinopathy (secondary intervention cohort) as compared with the conventional treatment group. For advanced retinopathy, however, even the most rigorous control of blood glucose may not prevent progression. The value of intensive treatment has been demonstrated for type 2 diabetes, as well. The United Kingdom Prospective Diabetes Study (UKPDS) revealed a 21% reduction in the 1-year rate of progression of retinopathy. [6]

Renal disease, as evidenced by proteinuria, elevated blood urea nitrogen levels, and elevated blood creatinine levels, is an excellent predictor of the presence of retinopathy.[1] Even patients with microalbuminuria are at high risk of developing retinopathy.[7] Similarly, 35% of patients with symptomatic retinopathy have proteinuria, elevated blood urea nitrogen values, or elevated creatinine levels. Systemic hypertension appears to be an independent risk factor for diabetic retinopathy.[1]

In women who begin a pregnancy without retinopathy, the risk of developing nonproliferative diabetic retinopathy (NPDR) is about 10%. Those with NPDR at the onset of pregnancy and those who have or who develop systemic hypertension tend to show progression, with increased hemorrhages, cotton-wool spots, and macular edema.[8] Fortunately, there is usually some regression after delivery. About 4% of pregnant women with NPDR progress to PDR. Those with untreated PDR at the onset of pregnancy frequently do poorly unless they are treated with panretinal photocoagulation (PRP). However, previously treated PDR usually does not worsen during pregnancy. There is no doubt that women who maintain good metabolic control during pregnancy have fewer spontaneous abortions and fewer children with birth defects. Therefore, obstetricians strive for strict control. Women who begin pregnancy with poorly controlled diabetes who are suddenly brought under strict control frequently have severe deterioration of their retinopathy and do not always recover after delivery.[8]

PATHOGENESIS

The final metabolic pathway that causes diabetic retinopathy is unknown. There are several theories.

 

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Aldose Reductase

Aldose reductase converts sugars into their alcohols. For example, glucose is converted to sorbitol and galactose is converted to galactitol. Because sorbitol and galactitol cannot easily diffuse out of cells, their intracellular concentration increases. Osmotic forces then cause water to diffuse into the cell, resulting in electrolyte imbalance. The resultant damage to lens epithelial cells, which have a high concentration of aldose reductase, is responsible for the cataract seen in children and in experimental animals with galactosemia and in animals with experimental diabetes mellitus.[9] Because aldose reductase is also found in high concentration in retinal pericytes and Schwann cells, some investigators suggest that diabetic retinopathy and neuropathy may be caused by aldose reductase–mediated damage. Despite all of these theoretical benefits, clinical trials have thus far failed to show a reduction in the incidence of diabetic retinopathy or of neuropathy by aldose reductase inhibitors, possibly because an effective aldose reductase inhibitor with few systemic side effects has yet to be developed.[9]

Vasoproliferative Factors

Currently intense interest exists in vasoproliferative factors released by the retina itself, retinal vessels, and the retinal pigment epithelium, which are felt to induce neovascularization. Vascular endothelial growth factor (VEGF), which inhibits the growth of the retinal endothelial cells in vitro, has been implicated in diabetic retinopathy. Considerable evidence suggests that VEGF has a direct role in the retinal vascular abnormalities that are found in diabetes. Animal models demonstrate that VEGF expression correlates with the development and regression of neovascularization.[10] The concentration of VEGF is higher in the vitreous of eyes with PDR as compared with eyes with NPDR.[11] Furthermore, inhibitors of VEGF have been successful in suppressing hypoxia-induced neovascularization in animal models.[12] Although the release of growth factors may explain the neovascular response to ischemia, growth factors themselves may or may not represent a direct link between hyperglycemia and retinal vasculopathy.

Platelets and Blood Viscosity

Diabetes is associated with abnormalities of platelet function. It has been postulated that platelet abnormalities or alterations in blood viscosity in diabetics may contribute to diabetic retinopathy by causing focal capillary occlusion and focal areas of ischemia in the retina which, in turn, contribute to the development of diabetic retinopathy.[13]

OCULAR MANIFESTATIONS

The earliest stage of diabetic retinopathy is nonproliferative (NPDR). In some patients, there is progression to proliferative retinopathy (PDR).

Early Nonproliferative Diabetic Retinopathy

Microaneurysms are the first ophthalmoscopically detectable change in diabetic retinopathy ( Fig. 117-1,A ), seen as small red dots in the middle retinal layers. When the wall of a capillary or microaneurysm is weakened enough, it may rupture, giving rise to an intraretinal hemorrhage. If the hemorrhage is deep (i.e., in the inner nuclear layer or outer plexiform layer), it usually is round or oval (“dot or blot”) (see Fig. 117-1, A ). It is very difficult to distinguish a small dot hemorrhage from a microaneurysm by ophthalmoscopy. Fluorescein angiography helps to distinguish patent microaneurysms because they leak dye ( Fig. 117-1, B ). However, angiography cannot distinguish a hemorrhage from a microaneurysm filled with clotted blood. If the

 

 

 

 

Figure 117-1 Nonproliferative diabetic retinopathy with microaneurysms. A, Small dot hemorrhages, microaneurysms, hard (lipid) exudates, circinate retinopathy, an intraretinal microvascular abnormality, and macular edema. B, Fluorescein angiography of the eye shown in A. Microaneurysms are seen as multiple dots of hyperfluorescence, but the dot hemorrhages do not fluoresce. The foveal avascular zone is minimally enlarged.

 

 

Figure 117-2 Nonproliferative retinopathy with some blot hemorrhages, splinter hemorrhages, and cotton-wool spots.

hemorrhage is superficial, in the nerve fiber layer, it takes a flame or splinter shape indistinguishable from a hemorrhage seen in hypertensive retinopathy ( Figs. 117-2 and 117-3 ). Diabetics who have normal blood pressure may have multiple splinter hemorrhages. Nevertheless, the presence of numerous splinter hemorrhages in a diabetic patient should prompt a blood pressure

 

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Figure 117-3 Nonproliferative retinopathy. A, With soft exudates. B, Fluorescein angiography shows capillary nonperfusion in the area of the superior cotton-wool spot and a larger area just inferonasal to the foveal avascular zone.

check, because a frequent complication of diabetes is systemic hypertension.

Macular edema, or retinal thickening (see Fig. 117-1, A ), is an important manifestation of NPDR and represents the leading cause of legal blindness in diabetics. The intercellular fluid comes from leaking microaneurysms or from diffuse capillary incompetence. Clinically, macular edema is best detected by biomicroscopy with a 60-diopter or contact macular lens. The edema causes scattering of light by the multiple interfaces it creates in the retina by separated retinal cells. This decreases the retina’s translucency such that the normal retinal pigment epithelial and choroidal background pattern is blurred (see Fig. 117-1, A ). Finally, the pockets of fluid in the outer plexiform layer, if large enough, can be seen as cystoid macular edema. Usually cystoid macular edema is seen in eyes that have other signs of severe NPDR such as numerous hemorrhages or exudates. In rare cases, cystoid macular edema due to generalized diffuse leakage from the entire capillary network can be seen in eyes that have very few other signs of diabetic retinopathy.

If the leakage of fluid is severe enough, lipid may accumulate in the retina (see Fig. 117-1, A ); again, the outer plexiform layer is first to be affected. In some cases, lipid is scattered through the macula. In others, it accumulates in a ring around a group of leaking microaneurysms, or around microaneurysms surrounding an area of capillary nonperfusion. This pattern is called circinate retinopathy (see Fig. 117-1, A ).

Advanced Nonproliferative Diabetic Retinopathy

In advanced NPDR, signs of increasing inner retinal hypoxia appear, including multiple retinal hemorrhages, cotton-wool spots

 

 

 

 

Figure 117-4 Severe nonproliferative retinopathy. A, With cotton-wool spots, intraretinal microvascular abnormalities, and venous beading. B, Fluorescein angiography shows severe capillary nonperfusion.

(see Fig. 117-3 ), venous beading and loops ( Fig. 117-4 ), intraretinal microvascular abnormalities (IRMA) (see Figs. 117-1, A and 117-4 ), and large areas of capillary nonperfusion depicted on fluorescein angiography.

Cotton-wool spots, also called soft exudates or nerve fiber infarcts, result from ischemia, not exudation. Local ischemia causes effective obstruction of axoplasmic flow in the normally transparent nerve fiber layer; the subsequent swelling of the nerve fibers gives cotton-wool spots their characteristic white fluffy appearance. Fluorescein angiography shows no capillary perfusion in the area corresponding to a cotton-wool spot. Microaneurysms frequently surround the hypoxic area (see Fig. 117-3 ).

Venous beading (see Fig. 117-4 ) is an important sign of sluggish retinal circulation. Venous loops nearly always are adjacent to large areas of capillary nonperfusion. IRMAs are dilated capillaries, which seem to function as collateral channels. They frequently are difficult to differentiate from surface retinal neovascularization. Fluorescein dye, however, does not leak from IRMAs but leaks profusely from neovascularization. Capillary hypoperfusion often surrounds IRMA (see Fig. 117-4 ).

The ETDRS found that IRMA, multiple retinal hemorrhages, venous beading and loops, widespread capillary nonperfusion, and widespread leakage on fluorescein angiography were all significant risk factors for the development of proliferative retinopathy. Interestingly, cotton-wool spots were not.[14]

Proliferative Diabetic Retinopathy

Although the macular edema, exudates, and capillary occlusions seen in NPDR often cause legal blindness, affected patients usually maintain at least ambulatory vision. PDR, on the other hand,

 

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Figure 117-5 Approximately one half the disc area shows neovascularization of the disc and initial, incomplete panretinal photocoagulation.

may result in severe vitreous hemorrhage or retinal detachment, with hand-movements vision or worse. Approximately 50% of patients with very severe NPDR progress to proliferative retinopathy within 1 year.[15] Proliferative vessels usually arise from retinal veins and often begin as a collection of multiple fine vessels. When they arise on or within one disc diameter of the optic nerve head they are referred to as NVD (neovascularization of the disc) ( Figs. 117-5 and 117-6 ). When they arise further than one disc diameter away, they are called NVE (neovascularization elsewhere) (see Fig. 117-6, B ). Unlike normal retinal vessels, NVD and NVE both leak fluorescein into the vitreous.

Once the stimulus for growth of new vessels is present, the path of subsequent growth taken by neovascularization is along the route of least resistance. For example, the absence of a true internal limiting membrane on the disc could explain the prevalence of new vessels at that location. Also, neovascularization seems to grow more easily on a preformed connective tissue framework. Thus, a shallowly detached posterior vitreous face is a frequent site of growth of new vessels.

The new vessels usually progress through a stage of further proliferation, with associated connective tissue formation. As PDR progresses, the fibrous component becomes more prominent, with the fibrotic tissue being either vascular or avascular. The fibrovascular variety usually is found in association with vessels that extend into the vitreous cavity or with abnormal new vessels on the surface of the retina or disc. The avascular variety usually results from organization or thickening of the posterior hyaloid face. Vitreous traction is transmitted to the retina along these proliferations and may lead to traction retinal detachment.

NVE nearly always grows toward and into zones of retinal ischemia until posterior vitreous detachment occurs (see Fig. 117-6 ). Then, the vessels are lifted into the vitreous cavity. The end stage is characterized by regression of the vascular systems. No further damage may take place, but there may be contraction of the connective tissue components, development of subhyaloid bands, thickening of the posterior vitreous face, and the appearance of retinoschisis, retinal detachment, or formation of retinal breaks.

Posterior vitreous detachment in diabetics is characterized by a slow, overall shrinkage of the entire formed vitreous rather than by the formation of cavities caused by vitreous destruction. Davis et al. [16] have stressed the role of the contracting vitreous in the production of vitreous hemorrhage, retinal breaks, and retinal detachment. Neovascular vessels do not “grow” forward into the vitreous cavity; they are pulled into it by the contracting vitreous to which they adhere. Confirmation of the importance of the vitreous in the development and progression of proliferative retinopathy comes from the long-term follow-up of eyes that have undergone successful vitrectomy. The existent neovascularization

 

 

 

 

Figure 117-6 Neovascularization. A, Neovascularization of the disc with some fibrous proliferation. B, Neovascularization elsewhere.

shrinks, leaks less fluorescein, and new areas of neovascularization rarely arise.

It has long been assumed that sudden vitreous contractions tear the fragile new vessels, causing vitreous hemorrhage. However, the majority of diabetic vitreous hemorrhages occur during sleep, possibly because of an increase in blood pressure secondary to early morning hypoglycemia or to rapid eye movement sleep. Because so few hemorrhages occur during exercise, it is not necessary to restrict the activity of patients with proliferative retinopathy. When a hemorrhage occurs, if the erythrocytes are all behind the posterior vitreous face, they usually quickly settle to the bottom of the eye and are absorbed. However, when erythrocytes break into the vitreous body, they adhere to the gel and clearing may take months or years.

A large superficial hemorrhage may separate the internal limiting membrane from the rest of the retina. Such hemorrhages usually are round or oval but also may be boat shaped. The blood may remain confined between the internal limiting membrane and the rest of the retina for weeks or months before breaking into the vitreous. Sub-internal limiting membrane hemorrhages were formerly thought to occur between the internal limiting membrane and the cortical vitreous and were called subhyaloid or preretinal hemorrhages. It is now felt that true subhyaloid hemorrhages probably are quite rare. Tight sub-internal limiting membrane hemorrhages are dangerous, because they may progress rapidly to traction retinal detachment.

As the vitreous contracts, it may pull on the optic disc, causing traction striae involving the macular area, or actually drag the macula itself, both of which contribute to decreased visual acuity.[17]

 

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Two types of diabetic retinal detachments occur, those which are caused by traction alone (nonrhegmatogenous) and those caused by retinal break formation (rhegmatogenous). Characteristics of nonrhegmatogenous (traction) detachment in PDR include the following:

• The detached retina usually is confined to the posterior fundus and infrequently extends more than two thirds of the distance to the equator.

• The detached retina has a taut and shiny surface.

• The detached retina is concave toward the pupil.

• No shifting of subretinal fluid occurs.

Occasionally, a spontaneous decrease in the extent of a traction detachment may occur, but this is the exception rather than the rule. Traction on the retina also may cause focal areas of retinoschisis, which may be difficult to distinguish from full-thickness retinal detachment; in retinoschisis the elevated layer is thinner and more translucent.

When a detachment is rhegmatogenous, the borders of the elevated retina usually extend to the ora serrata. The retinal surface is dull and grayish and undulates because of retinal mobility due to shifting of subretinal fluid. Retinal breaks are usually in the posterior pole near areas of fibrovascular change. The breaks are oval in shape and appear to be partly the result of tangential traction from the proliferative tissue, as well as being due to vitreous traction. Determination of the location of retinal holes may be complicated by many factors, particularly poor dilatation of the pupil, lens opacity, increased vitreous turbidity, vitreous hemorrhage, intraretinal hemorrhage, and obscuration of the breaks by overlying proliferative tissue.

OTHER OCULAR COMPLICATIONS OF DIABETES MELLITUS

Cornea

Corneal sensitivity is decreased in proportion to both the duration of the disease and the severity of the retinopathy.[18] Corneal abrasions are more common in people with diabetes, presumably because adhesion between the basement membrane of the corneal epithelium and the corneal stroma is not as firm as that found in normal corneas. Hyperglycemia and the aldose reductase pathway probably play a major role in epithelial abnormalities, because aldose reductase inhibitors may accelerate healing of corneal abrasions.[19] Following vitrectomy, recurrent corneal erosion, striate keratopathy, and corneal edema are more common in diabetics than in nondiabetics.

Glaucoma

The relationship between diabetes and primary open-angle glaucoma is unclear. Some population-based studies have found an association[20] but others have not.[21]

Neovascularization of the iris (NVI) usually is seen only in diabetics who have PDR. Panretinal photocoagulation not only has protective value against NVI, it also is an effective treatment against established NVI.[22] If the media are clear, PRP should be performed prior to any other treatment for NVI, even in advanced cases, because regression and permanent pressure control in patients who have extensive angle closure and intraocular pressures as high as 60?mm Hg have been documented.[22] If the media are too cloudy for PRP, trans-scleral laser or peripheral retinal cryoablation are alternative means of treatment (see below).

Lens

The risk of cataract is 2–4 times greater in diabetics than in non-diabetics and may be 15–25 times greater in diabetics under 40 years old.[23]

Patients with diabetes mellitus who have no retinopathy have excellent results from cataract surgery, with 90–95% having a final visual acuity of 20/40 or better, but chronic cystoid macular edema is about 14 times more common in diabetics than in nondiabetics.[24] The best-known predictor of postoperative success is the preoperative severity of retinopathy.[25] The most dreaded anterior complication is NVI. It was hoped that modern surgery, which leaves an intact posterior capsule, would protect the eye from NVI by reducing the diffusion of vasoproliferative factors into the anterior chamber, but several studies have shown that it does not. Furthermore, an Nd:YAG laser capsulotomy does not increase the risk.[26] Other anterior segment complications which are more common in diabetics than in non-diabetics are pupillary block, posterior synechiae, pigmented precipitates on the implant, and severe iritis.[24]

Posterior complications of cataract surgery include macular edema, proliferative retinopathy,[27] vitreous hemorrhage,[26] and traction retinal detachment. Studies from the early 1990s suggested that patients with NPDR were likely to develop or have worsening of macular edema. Recent reports suggest that modern, uncomplicated cataract surgery may not accelerate progression of diabetic retinopathy in type 2 diabetics with NPDR.[28] Caution should be observed when considering cataract surgery in patients who have diabetic retinopathy; however, up to 70% of these patients can attain a final visual acuity of 20/40 or better.[29]

Cataract surgery in patients with active PDR often results in still poorer postoperative visual outcome because of the high risk of both anterior and posterior segment complications. In one series, no patient with active PDR or preproliferative diabetic retinopathy achieved better than 20/80. Most experts recommend aggressive preoperative PRP.[24] [25]

Optic Neuropathy

As demonstrated by increased latency and decreased amplitude of the visual evoked potential, many diabetic patients without retinopathy have subclinical optic neuropathy. They have an increased risk for anterior ischemic optic neuropathy. In addition, diabetics are susceptible to diabetic papillopathy, which is characterized by acute disc edema without the pale swelling of anterior ischemic optic neuropathy. It is bilateral in one half of cases and may not show an afferent pupillary defect. [30] Macular edema is a common concurrent finding and is the most common cause of failure of visual recovery in these patients.[30] Visual fields may be normal or show an enlarged blind spot or other nerve fiber defects. The prognosis is excellent, because most patients recover to 20/50 or better.

Cranial Neuropathy

Extraocular muscle palsies may occur in diabetics secondary to neuropathy involving the third, fourth, or sixth cranial nerves. The mechanism is believed to be a localized demyelinization of the nerve secondary to focal ischemia. Pain may or may not be experienced, and not infrequently extraocular muscle palsy may be the initial clue to a latent diabetic condition. Recovery of extraocular muscle function in diabetic cranial nerve palsies generally takes place within 1–3 months.[31] When the third cranial nerve is involved, pupillary function is usually normal. This pupillary sparing in the diabetic third cranial nerve palsy is an important diagnostic feature, helping to distinguish it from an intracranial tumor or aneurysm.

DIAGNOSIS AND ANCILLARY TESTING

In nearly all instances, diabetic retinopathy is diagnosed easily via ophthalmoscopic examination. The hallmark lesions are microaneurysms, which usually develop in the posterior pole. Without microaneurysms, the diagnosis of diabetic retinopathy is in doubt. Fasting blood sugar testing, a glucose tolerance test, and hemoglobin A1c determinations all can be used to confirm the presence of systemic hyperglycemia.

 

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Although further diagnostic testing rarely is indicated, intravenous fluorescein angiography is a widely administered ancillary test. Fluorescein angiography is most helpful to assess the severity of diabetic retinopathy, to determine sites of leakage in macular edema, to judge the extent of capillary nonperfusion, and to confirm neovascularization. It is a useful preoperative test to evaluate the extent of retinopathy in patients who are to undergo cataract surgery and have media opacity. Optical coherence tomography is a noninvasive imaging technique that accurately measures retinal thickness. Diabetic patients often show psychophysical abnormalities. One of the early symptoms of diabetic retinopathy is poor night vision (dark adaptation) and poor recovery from bright lights (photostress).[32] Diabetics, even those without retinopathy, are more likely to have abnormal color vision than are nondiabetics matched for age.[33] Blue-yellow discrimination is affected earlier and more severely than is red-green discrimination. As retinopathy advances, color vision deteriorates.

One of the earliest electrophysiological abnormalities seen in diabetic patients without ophthalmoscopically visible retinopathy is diminution of the amplitude of the oscillatory potentials of the electroretinogram at a time when both the A and B waves are normal. This abnormality probably reflects ischemia in the inner nuclear layer of the retina. Diminished oscillatory potentials are a good predictor of progression of retinopathy.[34] As the severity of diabetic retinopathy increases, the amplitude of the B wave decreases.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis is listed in Box 117-1 .

PATHOLOGY

The earliest histopathological abnormalities in diabetic retinopathy are thickening of the capillary basement membrane and pericyte dropout. Microaneurysms begin as a dilatation in

 

 

Differential Diagnosis of Diabetic Retinopathy

Radiation retinopathy

 

Hypertensive retinopathy

 

Retinal venous obstruction (central retinal vein occlusion [CRVO], branch retinal vein occlusion [BRVO])

 

The ocular ischemic syndrome

 

Anemia

 

Leukemia

 

Coats’ disease

 

Idiopathic juxtafoveal retinal telangiectasia

 

Sickle cell retinopathy

 

 

 

 

 

 

Figure 117-7 Microaneurysms, pericyte dropout, and acellular capillaries are seen.

the capillary wall in areas where pericytes are absent; microaneurysms initially are thin walled. Later, endothelial cells proliferate and lay down layers of basement membrane material around themselves. Fibrin may accumulate within the aneurysm, and the lumen of the microaneurysm actually may be occluded ( Fig. 117-7 ). In early cases, microaneurysms are present mostly on the venous side of the capillaries, but later they are seen on the arterial side as well. Despite the multiple layers of basement membrane, they are permeable to water and large molecules, allowing the accumulation of water and lipid in the retina. Because fluorescein passes easily through them, many more microaneurysms are seen on fluorescein angiography than are apparent on ophthalmoscopy (see Figs. 117-1 and 117-3 ).

TREATMENT

Medical Therapy

ANTIPLATELET THERAPY.

The ETDRS reported that aspirin 650?mg daily does not influence the progression of retinopathy, affect visual acuity, or influence the incidence of vitreous hemorrhages. However, there was a significant decrease in cardiovascular morbidity in the aspirin-treated group compared with the placebo cohort.[35] Ticlopidine (Ticlid), like aspirin, inhibits adenosine diphosphate–induced platelet aggregation. It has been shown to decrease the risk of stroke in patients with transient ischemic attacks, but there is no clear evidence showing an impact on diabetic retinopathy.

ANTIHYPERTENSIVE AGENTS.

The Hypertension in Diabetes Study, part of the United Kingdom Prospective Diabetes Study, evaluated the effect blood pressure control on the progression of diabetic retinopathy. Patients were treated with angiotensin-converting enzyme inhibitors (ACEIs) or ß-blockers to achieve “tight” control of blood pressure (<150/85?mm Hg) or “less tight” control (<180/105?mm Hg). The group with better blood pressure control had a 37% risk reduction in microvascular changes. There was no differrence in effect between the two agents used.[36] Lisinopril, an ACEI, has been shown to decrease the progression of NPDR and PDR in normotensive diabetics, as well. The patients in this study with the better glycemic control benefited more from lisinopril.[37]

ANTIANGIOGENESIS AGENTS.

Novel approaches to the prevention and treatment of diabetic retinopathy are based on the hypothesis that local growth factors stimulate retinal vascular alterations. Inhibition of protein kinase C, a compound critical in the cascade that activates VEGF expression, is being pursued actively. An oral inhibitor of protein kinase C has been shown to suppress retinal neovascularization in animal models. [38] Currently a multicenter, randomized, placebo-controlled study is under way to evaluate this compound in diabetic patients.

Surgical Therapy

PANRETINAL PHOTOCOAGULATION.

The Diabetic Retinopathy Study proved that both xenon arc and argon laser PRP significantly decrease the likelihood that an eye with high-risk characteristics (HRC) will progress to severe visual loss.[39] Eyes with HRC are defined as those with NVD greater than one fourth to one third the disc area, those with any NVD and vitreous hemorrhage, or those with NVE greater than one half the disc area and vitreous or preretinal hemorrhage.

The exact mechanism by which PRP works remains unknown. Some investigators feel that PRP decreases the production of vasoproliferative factors by eliminating some of the hypoxic retina or by stimulating the release of antiangiogenic factors from the retinal pigment epithelium. An alternative hypothesis suggests that by thinning the retina, PRP increases oxygenation of the remaining retina by allowing increased diffusion of oxygen from the choroid. Yet another hypothesis is that PRP leads to an increase in vasoinhibitors by directly stimulating

 

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the retinal pigment epithelium to produce inhibitors of vasoproliferation.[40]

The goal of PRP is to arrest or to cause regression of the neovascularization. The recommended therapy is 1200–2000 burns 500?µm in diameter delivered through the Goldmann lens, or the same number of 200?µm burns delivered through the Rodenstock panfundoscope lens or Volk Superquad lens. The burns should be intense enough to whiten the overlying retina, which usually requires a power of 200–600?mW and duration of 0.1 second (see Fig. 117-5 ). Most ophthalmologists use the argon blue-green or green laser, but a large clinical trial has shown that krypton red is equally effective.[41]

The number of burns necessary to achieve these goals has not been established. Some retinal specialists feel that there is no upper limit to the total number of burns and that treatment should be continued until regression occurs.[42] The only prospective, controlled study found that eyes which received supplementary PRP treatment had no improved outcome over those which received standard PRP only. [43] About two thirds of eyes with HRC that receive PRP have regression of their HRC by 3 months after treatment.

The ETDRS found that PRP significantly retards the development of HRC in eyes with very severe NPDR and macular edema.[15] After 7 years of follow-up, 25% of eyes that received PRP developed HRC as compared with 75% of eyes in which PRP was deferred until HRC developed. Nevertheless, the ETDRS concluded that treatment of severe NPDR and PDR short of HRC was not indicated for three reasons. First, after 7 years of follow-up 25% of eyes assigned to deferral of PRP had not developed HRC. Second, when patients are closely monitored and PRP is given as soon as HRC develops, severe visual loss can be prevented. After 7 years of follow-up, 4.0% of eyes that did not receive PRP until HRC developed had a visual acuity of 5/200 or less, as compared with 2.5% of eyes assigned to immediate PRP. The difference was neither clinically nor statistically significant. Third, PRP has significant complications. It often causes decreased visual acuity by increasing macular edema or by causing macular pucker.[44] Fortunately, the edema frequently regresses spontaneously over 6 months, but the visual field usually is moderately, but permanently, decreased. Color vision and dark adaptation, which often are already impaired, also are worsened by PRP.[32]

PERIPHERAL RETINAL CRYOTHERAPY.

Peripheral retinal cryotherapy is used to treat HRC in eyes with media too hazy for PRP. Reported benefits include resorption of vitreous hemorrhages and regression of NVD, NVE, and NVI. The main complication is the development or acceleration of traction retinal detachment in 25–38% of eyes.[44] [45] Therefore, this treatment should be avoided in patients with known traction retinal detachment, and all patients must be monitored carefully.

TREATMENT OF MACULAR EDEMA.

Patz[46] was the first to show that argon laser photocoagulation decreases or stabilizes macular edema. Later, the ETDRS confirmed his results. The ETDRS defined clinically significant macular edema as:

• Retinal thickening involving the center of the macula

• Hard exudates within 500?µm of the center of the macula (if associated with retinal thickening)

• An area of macular edema greater than one disc area but within one disc diameter of the center of the macula

The treatment strategy is to photocoagulate all leaking microaneurysms further than 500?µm from the center of the macula (see Fig. 117-8 )

 

 

 

 

 

 

 

 

Figure 117-8 Macular edema. A, In an eye previously treated with panretinal photocoagulation. B, Midphase of fluorescein angiography showing microaneurysms, large areas of capillary nonperfusion, and slight enlargement of the foveal avascular zone. C, Late phase of fluorescein angiography showing diffuse capillary leakage. D, Grid pattern of focal macular photocoagulation in same eye.

 

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and to place a grid of 100–200?µm burns in areas of diffuse capillary leakage and in areas of capillary nonperfusion ( Fig. 117-8 ). After 3 years of follow-up, 15% of eyes with clinically significant macular edema had doubling of the visual angle as opposed to 32% of untreated control eyes.[47] The ETDRS also showed that PRP should not be given to eyes with clinically significant macular edema unless HRC are present.[15] Patients with macular edema who have the best prognosis for improved vision have circinate retinopathy of recent duration or focal, well-defined leaking areas and good capillary perfusion surrounding the avascular zone of the retina. Patients with an especially poor prognosis have dense lipid exudate in the center of the foveola ( Fig. 117-9 ). Other poor prognostic signs include diffuse edema with multiple leaking areas, extensive central capillary nonperfusion, increased blood pressure, and cystoid macular edema.[46] Nevertheless, the ETDRS found that even eyes with these adverse findings still benefited from treatment when compared with control eyes.[47] Small, uncontrolled studies have shown encouraging results with intravitreal injection of triamcinolone acetonide, a corticosteroid, in patients who have refractory diabetic edema.[48] [49] Long-term efficacy and potential side effects have yet to be clarified.

In summary, the Diabetic Retinopathy Study and the ETDRS conclusively proved that timely laser photocoagulation of diabetic retinopathy can reduce severe visual loss by 95%.[50] Such treatment makes sense, not only from the humanitarian point of view, but also from a cost-effectiveness view. It has been estimated that ETDRS-style therapy saves $250–500 million per year in the United States by enabling patients to avoid disability and welfare.[51] Nevertheless, fully one half of Americans with diabetes do not receive annual eye examinations that include dilatation.

VITRECTOMY IN DIABETIC PATIENTS.

Vitrectomy, introduced by Robert Machemer, plays a vital role in the management of severe complications of diabetic retinopathy. The major indications are nonclearing vitreous hemorrhage, macular-involving or macular-threatening traction retinal detachment, and combined traction–rhegmatogenous retinal detachment. Less common indications are macular edema with a thickened and taut posterior hyaloid, macular heterotopia, epiretinal membrane, severe preretinal macular hemorrhage, and neovascular glaucoma with cloudy media.[52]

To evaluate whether early vitrectomy (in the absence of vitreous hemorrhage) might improve the visual prognosis by eliminating the possibility of later traction macular detachment, the Diabetic Retinopathy Vitrectomy Study (DRVS) randomized 370 eyes with florid neovascularization and visual acuity of 20/400 or better to either early vitrectomy or to observation.[53] After 4 years of follow-up, approximately 50% of both groups had 20/60 or better, and approximately 20% of each group had light perception or worse. Thus, the results indicate that such patients probably do not benefit from early vitrectomy. They should be observed closely so that vitrectomy, when indicated, can be undertaken promptly.

If a patient has a vitreous hemorrhage severe enough to cause a visual acuity of 5/200 or less, the chances of visual recovery within 1 year are only about 17%.[54] The DRVS randomized patients who had a visual acuity of 5/200 or less for more than 6

 

 

Figure 117-9 Hard exudate plaque in the center of the macula.

months into two groups, those who received an immediate vitrectomy and those whose vitrectomy was deferred for a further 6 months.[54] The goals of surgery were to release all anterior–posterior vitreous traction and to perform a complete PRP to reduce the incidence of recurrent hemorrhage. Of those who had a deferred vitrectomy, 15% had a final visual acuity of 20/40 or better, as opposed to 25% of those who had an immediate vitrectomy. In patients with type 1 diabetes, 12% of those who had a deferred vitrectomy had a final visual acuity of 20/40 or better, as opposed to 36% of those who had an immediate vitrectomy. The reason for this discrepancy is thought to be excessive growth of fibrovascular proliferation during the waiting period. For this reason, the DRVS concluded that strong consideration should be given to immediate vitrectomy, especially in type 1 diabetics (in type 2 diabetics, the final visual results were similar). Nevertheless, many clinicians feel that in most cases vitrectomy should be deferred for about 6 months or longer if the retina is attached, to give a chance for spontaneous clearing to occur. Some patients will not need the surgery but, more importantly, 25% of the patients in the DRVS who received an immediate vitrectomy had a final visual acuity of no light perception. Exceptions to this general rule are patients who have bilateral visual loss because of vitreous hemorrhage, with chronically recurring hemorrhage, and known traction retinal detachment close to the macula. If surgery is deferred, ultrasonography and electroretinography should be performed at regular intervals to make sure that traction retinal detachment is not developing behind the hemorrhage.

The results of vitrectomy for nonclearing vitreous hemorrhage using this plan are excellent.

In patients who have recurrent vitreous hemorrhage after vitrectomy, a simple outpatient air–liquid exchange may restore vision without the need for a repeat vitrectomy.[55]

Traction retinal detachments are usually a much greater challenge. In general, unless the macula becomes involved, observation is the best therapy for these patients because, in most cases, the detachment does not progress into the macula. These patients should be counseled to consult their ophthalmologists without delay should macular vision suddenly be lost, because vitrectomy at that point becomes an urgent procedure. The surgical objectives are to clear the media, to release all anterior–posterior traction, to release tangential traction via delamination or segmentation (cutting the fibrotic bridges between areas of tractional detachment), and to perform endophotocoagulation to prevent NVI. The prognosis is best in patients who have small areas of traction. An alternative technique is to remove the vitreous and preretinal membranes by the “en bloc” technique.[56] The prognosis is poorest in eyes with table-top detachments, significant preoperative vitreous hemorrhage, no prior PRP, and advanced fibrovascular proliferation. If a lensectomy is required or if iatrogenic breaks are created, the results also are poorer.[57] Approximately 60–70% of patients have improved visual acuity and a final visual acuity of 20/800 or better, but 20–35% have decreased vision after vitrectomy. Cases with severe peripheral fibrovascular proliferation also may require a scleral buckling procedure.[58] Repeated operations are required in about 10% of patients, most commonly for rhegmatogenous retinal detachment and recurrent vitreous hemorrhage.[59]

In traction–rhegmatogenous retinal detachments, the objectives are to find all of the retinal breaks and to release all vitreous traction. After air–fluid exchange to flatten the retina, endolaser photocoagulation is used to treat retinal breaks. Approximately one half of such detachments can be cured. In severe cases, silicone oil is required to maintain reattachment of the retina.

The most common cause of failure following an otherwise successful vitrectomy is NVI resulting in neovascular glaucoma. The risk is higher if there is preoperative NVI (33% versus 17%), if there is persistent retinal detachment after surgery, if the lens is removed during surgery, and if there is florid NVD and retina. In

 

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eyes without these factors, the incidence of neovascular glaucoma is only about 2%. The pathogenesis of this complication is unknown. Some investigators feel that removal of the vitreous allows vasoproliferative factors produced in hypoxic retina to diffuse forward to the iris. Others feel that following vitrectomy increased oxygen diffusion occurs posteriorly out of the anterior chamber, thereby lowering its oxygen tension too far. Fortunately, if an eye does not develop iris neovascularization during the first 4–6 months after vitrectomy, it rarely does so later.[60]

Another vision-threatening complication is neovascularization that originates from the anterior retina and extends along the anterior hyaloid to the posterior lens surface (anterior hyaloidal fibrovascular proliferation).[61] This is more common in young, phakic diabetics who have extensive capillary nonperfusion.

CONCLUSIONS

The prognosis for diabetic retinopathy used to be dismal. Today, using timely laser photocoagulation as advocated by the Diabetic Retinopathy Study and the ETDRS, severe visual loss can be reduced by 95%. Nevertheless, many diabetics still become legally blind, because they are not examined regularly by an ophthalmologist. Prevention offers the most hope to diabetics. If blood glucose levels are controlled aggressively, both the onset of retinopathy and the pace of its progression are delayed significantly.

Although all agree that screening of asymptomatic diabetic patients is critical, the most cost-effective timing remains controversial. It generally is agreed that type 2 diabetics should be examined at the onset of their disease, then yearly thereafter. Type 1 diabetics do not have to be examined until 5 years into their disease course, but no sooner than puberty, then yearly thereafter. If retinopathy is detected, the frequency of examinations should be increased appropriately.

 

 

REFERENCES

 

1. Klein R, Klein B. Epidemiology of proliferative diabetic retinopathy. Diabetes Care. 1992;15:1875-91.

 

2. Klein R, Klein B, Moss S, et al. The Wisconsin epidemiologic study of diabetic retinopathy. XIV. Ten-year incidence and progression of diabetic retinopathy. Arch Ophthalmol. 1994;112:1217–28.

 

3. Yanko L, Goldbourt U, Michaelson C, et al. Prevalence and 15-year incidence of retinopathy and associated characteristics in middle-aged and elderly diabetic men. Br J Ophthalmol. 1983;67:759–65.

 

4. Kostraba JN, Dorman JS, Orchard TJ, et al. Contribution of diabetes duration before puberty to the development of microvascular complications in IDDM subjects. Diabetes Care. 1989;12:686–93.

 

5. Diabetes Control and Complications Trial Research Group. The effect of intensive diabetes treatment on the progression of diabetic retinopathy in insulin-dependent diabetes mellitus. Arch Ophthalmol. 1995;113:36–51.

 

6. United Kingdom Prospective Diabetes Study Group. Intensive blood-glucose control with sulfonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes. UKPDS 33. Lancet. 1998;352:837–53.

 

7. Klein R, Klein BEK, Moss SE,et al. The Wisconsin epidemiologic study of diabetic retinopathy. II. Prevalence and risk of diabetic retinopathy when age is less than 30 years. Arch Ophthalmol. 1984;102:520–6.

 

8. Rosenn B, Miodovnik M, Kranias G, et al. Progression of diabetic retinopathy in pregnancy: association with hypertension in pregnancy. Am J Obstet Gynecol. 1992;166:1214–8.

 

9. Frank RN. The aldose reductase controversy. Diabetes. 1994;43:169–72.

 

10. Pierce E, Foley E, Smith L. Regulation of vascular endothelial growth factor by oxygen in a model of retinopathy of prematurity. Ophthalmology. 1996;114: 1219–28.

 

11. Aiello L, Avery R, Arrigg P, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480–7.

 

12. Adamis A, Shima D, Tolentino M, et al. Inhibition of VEGF prevents retinal ischemia associated iris neovascularization in non-human primate. Arch Ophthalmol. 1996;114:66–71.

 

13. Colwell J, Winocour P, Halushka P. Do platelets have anything to do with diabetic microvascular disease? Diabetes. 1983;32(suppl):14–9.

 

14. Early Treatment Diabetic Retinopathy Study Research Group. Fundus photographic risk factors for progression of diabetic retinopathy. ETDRS Report No. 12. Ophthalmology. 1991;98:823–33.

 

15. Early Treatment Diabetic Retinopathy Study Research Group. Early photocoagulation for diabetic retinopathy. ETDRS Report No. 9. Ophthalmology. 1991;98: 766–85.

 

16. Davis M, Fisher M, Gangnon R. Vitreous contraction in proliferative diabetic retinopathy. Arch Ophthalmol. 1965;74:741–51.

 

17. Bresnick G, Haight B, deVenecia G. Retinal wrinkling and macular heterotopia in diabetic retinopathy. Arch Ophthalmol. 1979;97:1890–5.

 

18. Schwartz D. Corneal sensitivity in diabetics. Arch Ophthalmol. 1974;91:174–8.

 

19. Ohashi Y, Matsuda M, Hosotai H, et al. Aldose reductase inhibitor (CT-112) eye drops for diabetic corneal epitheliopathy. Am J Ophthalmol. 1988;105:223.

 

20. Klein B, Klein R, Jensen S. Open-angle glaucoma and older-onset diabetes: the Beaver Dam Eye Study. Ophthalmology. 1994;101:1173–7.

 

21. Tielsch J, Katz J, Quigley H,et al. Diabetes, intraocular pressure, and primary open-angle glaucoma in the Baltimore Eye Survey. Ophthalmology. 1995;102: 48–53.

 

22. Jacobson D, Murphy R, Rosenthal A. The treatment of angle neovascularization with panretinal photocoagulation. Ophthalmology. 1979;86:1270–5.

 

23. Bernth-Peterson P, Bach E. Epidemiologic aspects of cataract surgery. III: Frequencies of diabetes and glaucoma in a cataract population. Acta Ophthalmol. 1983;61:406–16.

 

24. Krupsky S, Zalish M, Oliver M,et al. Anterior segment complications in diabetic patients following extracapsular cataract extraction and posterior chamber intraocular lens implantation. Ophthalmic Surg. 1991;22:526–30.

 

25. Hykin P, Gregson R, Stevens J, et al. Extracapsular cataract extraction in proliferative diabetic retinopathy. Ophthalmology. 1993;100:394–9.

 

26. Benson W, Brown G, Tasman W,et al. Extracapsular cataract extraction with placement of a posterior chamber lens in patients with diabetic retinopathy. Ophthalmology. 1993;100:730–8.

 

27. Pollack A, Leiba H, Bukelman A, et al. The course of diabetic retinopathy following cataract surgery in eyes previously treated by laser photocoagulation. Br J Ophthalmol. 1992;76:228–31.

 

28. Squirrell D, Bhola R, Bush J, et al. A prospective, case controlled study of the natural history of diabetic retinopathy and maculopathy after uncomplicated phacoemulsification cataract surgery in patients with type 2 diabetes. Br J Ophthalmol. 2002;86(5):565–71.

 

29. Krepler K, Biowski R, Schrey S, et al. Cataract surgery in patients with diabetic retinopathy: visual outcome, progression of diabetic retinopathy, and incidence of diabetic macular oedema. Graefes Arch Clin Exp Ophthalmol. 2002;240(9): 735–8.

 

30. Regillo C, Brown G, Savino P, et al. Diabetic papillopathy: patient characteristics and fundus findings. Arch Ophthalmol. 1995;113:889–95.

 

31. Burde R. Neuro-ophthalmic associations and complications of diabetes mellitus. Am J Ophthalmol. 1992;114:498–501.

 

32. Pender P, Benson W, Compton H, et al. The effects of panretinal photocoagulation on dark adaptation in diabetics with proliferative retinopathy. Ophthalmology. 1981;88:635–8.

 

33. Kinnear P, Aspinall P, Lakowski R. The diabetic eye and colour vision. Trans Ophthalmol Soc U K. 1972;92:69–78.

 

34. Bresnick G, Palta M. Oscillatory potential amplitudes. Arch Ophthalmol. 1987;105:929–33.

 

35. Chew E, Klein M, Murphy R, et al. Effects of aspirin on vitreous/preretinal hemorrhage in patients with diabetes mellitus. ETDRS Report No. 20. Arch Ophthalmol. 1995;113:52–5.

 

36. United Kingdom Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes. UKPDS 38. BMJ. 1998;317:703–13.

 

37. Chaturvedi N, Sjolie A, Stephenson J, et al. Effect of lisinopril on progression of retinopathy in normotensive people with type 1 diabetes. The EUCLID Study Group. EURODIAB controlled trial of lisinopril in insulin-dependent diabetes mellitus. Lancet. 1998;351:28–31.

 

38. Danis R, Bingaman D, Jirousak M, et al. Inhibition of intraocular neovascularization caused by retinal ischemia in pigs by PKC with LY333531. Invest Ophthalmol Vis Sci. 1998;39:171–9.

 

39. Diabetic Retinopathy Study Research Group. Four risk factors for severe visual loss in diabetic retinopathy: the third report from the Diabetic Retinopathy Study. Arch Ophthalmol. 1979;97:654–65.

 

40. Stefansson E, Machemer R, de Juan E, et al. Retinal oxygenation and laser treatment in patients with diabetic retinopathy. Am J Ophthalmol. 1992;113:36–8.

 

41. Krypton Argon Regression Neovascularization Study Research Group. Randomized comparison of krypton versus argon scatter photocoagulation for diabetic disc neovascularization. Ophthalmology. 1993;100:1655–64.

 

42. Reddy V, Zamora R, Olk R. Quantification of retinal ablation in proliferative diabetic retinopathy. Am J Ophthalmol. 1995;119:760–6.

 

43. Doft B, Metz D, Kelsey S. Augmentation laser for proliferative diabetic retinopathy that fails to respond to initial panretinal photocoagulation. Ophthalmology. 1992;99:1728–35.

 

44. Ferris F, Podgor M, Davis M, et al. Macular edema in diabetic retinopathy study patients. Diabetic Retinopathy Study Report No. 12. Ophthalmology. 1987; 94:754–60.

 

45. Daily M, Gieser R. Treatment of proliferative diabetic retinopathy with panretinal cryotherapy. Ophthalmic Surg. 1984;15:741–5.

 

46. Patz A, Schatz H, Berkow J,et al. Macular edema: an overlooked complication of diabetic retinopathy. Trans Am Acad Ophthalmol Otolaryngol. 1973;77:34–42.

 

47. Early Treatment Diabetic Retinopathy Study Research Group. Focal photocoagulation treatment of diabetic macular edema. Relationship of treatment effect to fluorescein angiographic and other retinal characteristics at baseline: ETDRS Report No. 19. Arch Ophthalmol. 1995;113:1144–55.

 

48. Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology. 2002;109(5):920–7.

 

49. Jonas JB, Kreissig I, Sofker A, Degenring RF. Intravitreal injection of triamcinolone for diffuse diabetic macular edema. Arch Ophthalmol. 2003;121(1):57–61.

 

50. Ferris F. How effective are treatments for diabetic retinopathy? JAMA. 1993;269:1290–1.

 

51. Javitt J, Aiello L, Bassi L, et al. Detecting and treating retinopathy in patients with type I diabetes mellitus. Ophthalmology. 1991;98:1565–74.

 

52. Lewis H, Abrams G, Blumenkranz M, et al. Vitrectomy for diabetic macular traction and edema associated with posterior hyaloidal traction. Ophthalmology. 1992;99:753–9.

 

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53. Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe proliferative diabetic retinopathy in eyes with useful vision. Results of a randomized trial—diabetic retinopathy vitrectomy study report 3. Ophthalmology. 1988;95:1307–20.

 

54. Diabetic Retinopathy Vitrectomy Study Research Group. Early vitrectomy for severe vitreous hemorrhage in diabetic retinopathy. Two-year results of a randomized trial. Diabetic retinopathy vitrectomy study report 2. Arch Ophthalmol. 1985;103:1644–54.

 

55. Martin D, McCuen II B. Efficacy of fluid–air exchange for postvitrectomy diabetic vitreous hemorrhage. Am J Ophthalmol. 1992;114:457–63.

 

56. Williams D, Williams G, Hartz A. Results of vitrectomy for diabetic traction retinal detachments using the en bloc excision technique. Ophthalmology. 1989;96:752–8.

 

57. Thompson J, deBustros S, Michels R, et al. Results and prognostic factors in vitrectomy for diabetic vitreous hemorrhage. Arch Ophthalmol. 1987;105:191–5.

 

58. Han D, Pulido J, Mieler W, et al. Vitrectomy for proliferative diabetic retinopathy with severe equatorial fibrovascular proliferation. Am J Ophthalmol. 1995;119: 563–70.

 

59. Brown G, Tasman W, Benson W, et al. Reoperation following diabetic vitrectomy. Arch Ophthalmol. 1992;110:506–10.

 

60. Schachat A, Oyakawa R, Michels R,et al. Complications of vitreous surgery from diabetic retinopathy. II. Postoperative complications. Ophthalmology. 1983; 90:522.

 

61. Lewis H, Aarberg T, Abrams G. Causes of failures after repeat vitreoretinal surgery for recurrent proliferative vitreoretinopathy. Am J Ophthalmol. 1991;111:15–9.

Chapter 116 – Retinopathy of Prematurity

Chapter 116 – Retinopathy of Prematurity

 

FRANCO M. RECCHIA

ANTONIO CAPONE

 

 

 

 

 

DEFINITION

• A disorder of premature, low-birth-weight infants featuring abnormal proliferation of developing retinal blood vessels at the junction of vascularized and avascular retina.

 

KEY FEATURES

• Avascular, peripheral retina.

• A demarcation line lying within the plane of the retina between the vascular and avascular retina.

• Progression of the demarcation line into an elevated ridge or mesenchymal shunt.

• Extraretinal proliferation of blood vessels above the ridge, into the vitreous, with fibrous membrane development.

• Significant shunting of blood through the proliferative ridge (plus disease) with venous dilation adjacent to the optic nerve.

 

ASSOCIATED FEATURES

• Low birth weight.

• Low gestational age.

• Myopia.

• Macular dragging.

• Traction retinal detachment.

• Retinal fold.

• Retrolental fibroplasia.

• Glaucoma.

 

 

 

INTRODUCTION

First described in 1942,[1] retinopathy of prematurity (ROP) is a proliferative retinopathy affecting premature infants of low birth weight and young gestational age. Despite improvements in detection and treatment, ROP remains a leading cause of lifelong visual impairment among premature children in developed countries. Basic research into the pathogenesis of ROP continues to provide a greater understanding of retinal development, angiogenesis, and intraocular neovascularization.

CLINCAL FEATURES AND CLASSIFICATION

During normal retinal development, vessels migrate from the optic disc to the ora serrata beginning at about 16 weeks of gestation.[2] Vasculogenesis transforms precursor mesenchymal spindle cells into capillary networks. Mature vessels differentiate from these networks and extend to the nasal ora serrata by 36 weeks of gestation and to the temporal ora serrata by 39–41 weeks. The fundamental process underlying the development of ROP is incomplete vascularization of the retina, and the ophthalmoscopic findings stem from this arrested development. The

 

 

Figure 116-1 Stage I retinopathy of prematurity. The flat, white border between avascular and vascular retina seen superiorly is called a demarcation line. (Reproduced with permission of Earl A. Palmer, MD and the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity.)

location of the interruption of normal vasculogenesis is related to the time of premature birth.

The International Classification of Retinopathy of Prematurity (ICROP) was established in 1984, and revised in 1987, to provide standards for the clinical assessment of ROP on the basis of the severity (stage) and anatomical location (zone) of disease.[3] [4] According to this classification, the first sign of ROP (stage I) is the appearance of a thin, flat, white structure (termed a demarcation line) at the junction of vascularized retina posteriorly and avascular retina anteriorly ( Fig. 116-1 ). Stage II ROP occurs as the demarcation line develops into a pink or white elevation (ridge) of thickened tissue ( Fig. 116-2 ); small tufts of vessels may be seen posterior to the ridge. Vessel growth into and above the ridge (extraretinal fibrovascular proliferation) characterizes stage III ROP ( Figs. 116-3 and 116-4 ). This fibrovascular proliferation may extend into the overlying vitreous and cause vitreous hemorrhage. With progressive growth into the vitreous, contraction of fibrovascular proliferation exerts traction on the retina, leading to partial retinal detachment (stage IV ROP), either without foveal involvement (stage IVa) or with foveal involvement (stage IVb) ( Fig. 116-5 ). Stage V ROP denotes a total retinal detachment ( Fig. 116-6 ). Because stage V detachments are always funnel shaped, the configuration of such detachments can be further described as open or closed anteriorly and open or closed posteriorly. Leukokoria resulting from fibrovascular proliferation and advanced retinal detachment is termed retrolental fibroplasia.

During the acute phases of ROP, progressive vascular insufficiency at the edge of the abnormally developing vasculature may

 

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Figure 116-2 Stage II retinopathy of prematurity. The elevated mesenchymal ridge has height. Highly arborized blood vessels from the vascularized retina dive into the ridge. (Reproduced with permission of Earl A. Palmer, MD and the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity.)

 

 

Figure 116-3 Stage III retinopathy of prematurity. Vessels on top of the ridge project into the vitreous cavity. This extraretinal proliferation carries with it a fibrovascular membrane. Note the opalescent avascular retina anterior to the ridge.

 

 

Figure 116-4 Stage III retinopathy of prematurity. Note finger-like projections of extraretinal vessels into the vitreous cavity. Hemorrhage on the ridge is not uncommon.

 

 

Figure 116-5 Stage IV. A, Stage IVa detachment spares the fovea. B, Stage IVb detachment involves the fovea.

 

 

Figure 116-6 Stage V retinal detachment. Depiction of an open anterior configuration secondary to fibrovascular proliferation that pulls the peripheral retina anteriorly.

lead to increasing dilation and tortuosity of peripheral retinal vessels, engorgement of iris vessels, pupillary rigidity, and vitreous haze. These findings were defined by the ICROP as progressive vascular disease.[4] “Plus disease” occurs when the peripheral vascular shunting of blood is so overwhelming that it leads to marked venous dilation and arterial tortuosity in the posterior pole ( Fig. 116-7 ). Plus disease is the hallmark of rapidly progressive ROP and is notated by adding a plus sign after the number of the ROP stage.

ROP is also classified by anatomical location, by identifying the anterior extent of retinal vascularization ( Fig. 116-8 ). Because there is a direct correlation between severity of disease and amount of avascular retina, the location of the border between vascularized and avascular retina is an important prognostic sign. Zone 1 is defined as a circle, the center of which is the disc and the radius of which is twice the distance of the disc to the fovea. Zone 2 is a doughnut-shaped region that extends from the anterior border of zone 1 to within one disc diameter of the ora serrata nasally and to the anatomical equator temporally. Zone 3 encompasses the residual temporal retina. Appropriate description of an eye with ROP includes both a stage and the posteriormost zone containing disease.

 

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Figure 116-7 An example of moderate plus disease. Dilated retinal veins and tortuous arteries in the posterior pole may be seen.

The determination of “threshold ROP” in the Multicenter Trial of Cryotherapy for Retinopathy of Prematurity (Cryo-ROP) sought to define the severity of ROP for which a given eye had an equal chance of spontaneous regression or progression to untoward outcome.[5] Although initially based only on clinical estimation, threshold disease has become accepted as the point at which treatment should be administered. It is currently defined as stage III+ ROP in zone 1 or 2 occupying at least 5 contiguous clock hours or 8 noncontiguous clock hours of retina[5] ( Fig. 116-9 ). For eyes with zone 2 ROP, this estimation proved quite precise: 62% of untreated eyes with threshold ROP went on to an untoward visual outcome.[6] [7] However, the estimation of a 50-50 threshold for eyes with zone 1 ROP was off the mark: untreated threshold zone 1 eyes had a 90% chance of untoward outcome. [6]

EPIDEMIOLOGY

Valuable information regarding the incidence, clinical course, and natural history of ROP was gleaned from the CRYO-ROP trial.[8] This prospective trial, initiated in 1986, included 4009 infants weighing less than 1251?g (2?lb, 13?oz). These infants received an initial examination by an experienced examiner at 4 to 7 weeks after birth and at defined intervals thereafter. Overall, 65.8% of infants developed some degree of ROP and 6% reached threshold. Gender was not associated with progression to threshold disease, and African-American infants appeared less susceptible to progression (3.2% versus 7.8%). Multiple births and birth outside a study hospital were associated with an increased risk of severe disease.[8] [9]

The incidence and severity of disease were closely correlated with lower birth weights and earlier gestational (postconceptional) age. Whereas the incidence of ROP was 47% in infants with birth weights between 1000 and 1251?g (2?lb, 3?oz to 2?lb, 13?oz), it rose to 81.6% for infants weighing less than 1000?g (2?lb, 3?oz) at birth. Over 80% of infants born at less than 28 weeks’ gestational age developed ROP, but only 60% of infants born at 28–31 weeks developed ROP.[8] Similar findings were reported in a more recent study involving 2528 infants: no infant born after 32 weeks of gestation developed ROP, and stage III disease was not seen in infants with birth weights greater than 1500?g (3?lb, 5?oz).[10]

The CRYO-ROP investigators stressed that the timing of pathological vascular events correlated more closely with postconceptional age than chronological age, independent of birth

 

 

Figure 116-8 Classification of retinopathy of prematurity by zone. The temporal edge of zone 2 coincides with the equator.

 

 

Figure 116-9 Definition of “threshold” retinopathy of prematurity.

weight. The median onset of stage I ROP was 34 weeks after conception. The median onset of threshold disease was 37 weeks, with a range of 33.6 to 42 weeks, after conception.[8]

It has been estimated that ROP causes visual loss in 1300 children and severe visual impairment in 500 children born each year in the United States. [11] As technological advances have made possible increased survival for extremely premature infants, it seems likely that the number of infants with ROP will rise.[12] Several studies have suggested, however, that although there is increased survival of high-risk neonates, this is not associated with a universal increase in the incidence of ROP.[10] [13] [14] [15] This trend may reflect improvements in ventilation techniques and perinatal care, specifically the prophylactic use of surfactant[15] and the maternal use of antenatal steroids.[16]

SYSTEMIC FACTORS

Retinopathy is only one of many devastating complications of premature birth. Other systemic abnormalities that afflict these infants include bronchopulmonary dysplasia, anemia, cardiac defects, sepsis, necrotizing enterocolitis, intraventricular hemorrhage, cerebral palsy, and neurodevelopmental delay. [17] [18] [19] As with ROP, these associated conditions are more prevalent and more serious in infants of lower birth weight. Moreover, the severity of neonatal ROP is a marker for functional disability later in life.[19]

 

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A relationship between oxygen levels and ROP has been suspected for half a century.[1] In recent years, results of experiments with animal models and epidemiological studies have brought the complexity and paradox of this relationship to light. In 1948, Michaelson [20] proposed that a progressive oxygen deficit within the retina during normal differentiation can induce angiogenesis in neighboring vessels through secretion of a chemical messenger (so-called factor X). In the 1950s, therapeutic administration of supplemental oxygen to premature infants, in an effort to relieve the putative stimulus for retinal neovascularization, thus seemed rational. This practice was abandoned after the Cooperative Study of Retrolental Fibroplasia disclosed a threefold risk of ROP in neonates without lung disease who had been given prolonged oxygen supplementation.[21] However, the concept of a hypoxic stimulus for neovascularization remained biologically plausible, and the issue of supplementary oxygen regained attention. This renewed interest was based in part on several case-control studies in which infants who developed severe ROP had hospital courses complicated by lower arterial oxygenation and greater fluctuation in blood oxygen levels.[22] [23]

The Supplemental Therapeutic Oxygen for Prethreshold ROP (STOP-ROP) was a multicenter clinical trial begun in 1994 to determine the efficacy and safety of supplemental oxygen administered to premature infants to reduce the progression to threshold ROP.[24] Six hundred forty-nine premature infants with prethreshold ROP in at least one eye were randomly assigned to a “conventional” arm (with pulse oximetry targeted at 89–94% oxygen saturation) or to a “supplemental” arm (96–99% oxygen saturation). The progression to threshold ROP was lower in the supplemental arm (41% versus 48%) but not to a statistically significant degree. Subgroup analysis did show, however, that infants without plus disease and without severe lung disease may benefit from supplemental oxygen (32% progression in the supplemental arm versus 46% progression in the conventional arm).[24]

Several authors have suggested that candidemia may be independently associated with severe ROP in babies weighing less than 1000?g (2?lb, 3?oz).[25] [26] A large cohort study of 449 infants, however, failed to show a strong correlation and suggested instead that much of the observed association of these two clinical conditions is linked more to young postconceptional age.[27]

Hospital nursery lighting is an additional variable that has been suspected to contribute to ROP. In the Light Reduction in Retinopathy of Prematurity (LIGHT-ROP) study, involving 361 infants weighing less than 1251?g, a reduction in exposure to ambient light did not alter the incidence of ROP.[28]

Genetic factors may play a role in the development of severe ROP in a subset of premature infants. Prompted by the observation that some clinical features of ROP noted in near-term and full-term infants may resemble those seen in familial exudative vitreoretinopathy (FEVR), the X-linked form of which is associated with mutations in the Norrie disease (ND) gene,[29] Shastry et al.[30] investigated a cohort of 16 premature infants with ROP for mutations in the ND gene. Missense mutations were found in four, all of whom had advanced disease, and in none of the parents or 50 healthy control subjects.[30] A larger scale study demonstrated the presence of ND mutations in 2% of infants with ROP.[31]

PATHOLOGY AND PATHOPHYSIOLOGY

Histologically, stage I ROP is characterized by hyperplasia of the primitive spindle-shaped cells of the vanguard mesenchymal tissue at the demarcation line.[32] The ridge of stage II consists of further hyperplasia of the spindle cells, along with proliferation of the endothelial cells of the rearguard mesenchymal tissue. In stage III, extraretinal vascular tissue emanates from the ridge. Proliferation of endothelial cells and small, thin-walled vessels occurs. Equally important is the condensation of vitreous into sheets and strands oriented anteriorly toward the equator of the lens. Vitreous tractional forces draw the retina anteriorly and may lead to retinal detachment.

Hypoxia is a common precursor to the abnormal neovascularization seen in many retinal diseases. Michaelson’s hypothesis of an angiogenic chemical messenger secreted in response to tissue hypoxia has led to the identification of numerous angiogenic factors, among them basic fibroblast growth factor (bFGF),[33] transforming growth factor–a (TGF-a),[34] and tumor necrosis factor–a (TNF-a).[35] Increasing attention, however, has been focused on vascular endothelial growth factor (VEGF), formerly called vascular permeability factor (VPF).[36] Vitreous levels of VEGF are elevated in patients with a variety of proliferative retinopathies, including ROP, and vitreous fluid from these patients stimulates growth of endothelial cells in vitro. [37]

DIAGNOSIS

Ophthalmoscopic evaluation of the premature infant may be performed in the nursery or in the office. Two drops each of 2.5% phenylephrine and 0.5% tropicamide are applied, and a lid speculum is inserted between the lids. Examination of the anterior segment is performed with a hand light, with specific attention to the iris vessels, lens, and tunica vasculosa lentis. Funduscopy is performed with an indirect ophthalmoscope and a 28D or 30D condensing lens. The posterior pole is examined without depression for the presence of absence of plus disease. Scleral depression is then used to examine the temporal retina, followed by the nasal retina, to establish the proximity of retinal vessels to the ora serrata. Scleral depression is appropriate in all cases.

Given the progressive nature of ROP as well as the proven benefits of early diagnosis and timely intervention to minimize the risk of severe visual loss, a joint statement outlining the principles of a screening program for ROP has been set forth[38] :

 

1.

Screening for ROP should be performed in all infants with a birth weight less than 1500?g (3?lb, 4?oz) or a gestational age of 28 weeks or less, as well as in infants weighing between 1500 and 2000?g (4?lb, 6?oz) with an unstable clinical course and who are believed to be at high risk.

 

2.

In most cases, at least two examinations should be performed. One examination may suffice if it shows unequivocally that retinal vascularization is complete bilaterally. The first examination should be performed between 4 and 6 weeks of chronological (postnatal) age or between the 31st and 33rd weeks of postconceptional age (calculated as gestational age plus chronological age), whichever is later.

 

3.

Infants at high risk for progression to threshold disease should be examined weekly. Included are infants with any zone 1 disease, stage II+ or stage III disease in zone 2, or stage III+ disease occupying fewer clock hours than defined as threshold.

 

4.

Infants with less severe disease in zone 2 or disease restricted to zone 3 should be examined every 2 weeks until the fundus matures.

 

5.

Infants with threshold ROP should receive peripheral ablative therapy within 72 hours of diagnosis.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of ROP is given in Box 116-1 . In a premature infant of low birth weight with characteristic findings of immature retinal development, the diagnosis is often straightforward. On the other hand, if a premature infant has not been screened or treated appropriately, a white retrolental fibrous mass may develop, and the only presenting sign may be leukokoria. In such cases, the treating ophthalmologist must first suspect and evaluate for retinoblastoma, which often displays calcification on ultrasonography or computed tomography. Other causes of leukocoria in an infant include exudative retinal detachment, most commonly from Coats’ disease (usually unilateral and more common in boys) or diffuse choroidal hemangioma; persistent fetal vasculature syndrome, formerly called persistence of primary hyperplastic vitreous (usually unilateral

 

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Differential Diagnosis for Retinopathy of Prematurity

Retinoblastoma

 

Familial exudative vitreoretinopathy

 

Norrie’s disease

 

X-linked retinoschisis

 

Incontinentia pigmenti

 

 

 

 

and associated with microphthalmia and prominent ciliary processes); infectious causes such as endogenous endophthalmitis, toxocariasis, or toxoplasmosis (all of which may be diagnosed by appropriate microbiological and immunological testing); coloboma of the optic disc or choroid; cataract; and genetic syndromes, such as trisomy 13, Norrie disease, Warburg syndrome, and incontinentia pigmenti (all of which may be diagnosed by genetic testing and/or characteristic systemic physical findings). Finally, congenital retinoschisis and FEVR may be suggested by family history or examination of relatives.

TREATMENT

The ultimate goals of treatment of threshold ROP are prevention of any retinal detachment or scarring and optimization of visual outcome. Treatment involves ablation of avascular retina by either cryotherapy or laser photocoagulation.

The laser has become the instrument of choice of ophthalmologists throughout the world and has long been the standard of treatment in the management of other vasoproliferative retinopathies associated with diabetes, sickle cell disease, and retinal vascular occlusion. Few indications remain for utilizing cryopexy over the laser in the management of ROP: poor fundus visibility, lack of availability of a laser, and a treating physician’s unfamiliarity with indirect laser retinopexy techniques.

Cryotherapy

Cryotherapy has been used to treat ROP since 1972.[39] It may be performed under topical, local, or general anesthesia, either transconjunctivally or transsclerally following a conjunctival peritomy (as is necessary for posterior disease). The probe should be removed periodically for several minutes to avoid prolonged ocular hypertension. A favorable response usually occurs within 1 week.

The Cryo-ROP trial was a multicenter clinical trial in which eyes of premature infants (birth weight less than 1251?g) with threshold ROP were randomly assigned to either cryotherapy or observation to establish whether treatment reduced the occurrence of an unfavorable visual outcome (20/200 or worse) or unfavorable structural outcome (retinal fold, retinal detachment, or retrolental fibroplasia).[5] [6] At 10-year follow-up, eyes treated with cryotherapy were less likely to be legally blind (44% versus 62%), and were less likely to have an unfavorable structural outcome. Total retinal detachment still occurred in 22% of treated eyes, however.[40] Cryotherapy did not appear to cause a significant detriment to visual field or contrast sensitivity.[41] [42]

Laser Photocoagulation

Since the inception of the Cryo-ROP study, argon laser and diode laser indirect ophthalmoscope systems have been developed. Advantages of photocoagulation include ease of treatment, portability, and fewer systemic complications. Photocoagulation is delivered through a dilated pupil with a 20D or 28D condensing lens. The end point is near-confluent ablation, with burns spaced one-half burn width apart, from the ora serrata up to, but not including, the ridge for 360°.[43] The retina should be inspected for skip areas, and the infant should be reexamined within 1 week. Persistent plus disease and fibrovascular proliferation

 

 

Figure 116-10 Threshold retinopathy of prematurity. Immediate postoperative appearance of indirect laser photocoagulation.

are indications for additional treatment. Complications of laser treatment include anterior segment ischemia, cataract, and burns of the cornea, iris, or tunica vasculosa lentis.[44] [45]

Laser photocoagulation has been shown to be at least as effective as [46] [47] [48] if not more effective than[49] [50] cryotherapy for threshold disease. In one series of 61 eyes treated exclusively with a diode laser, only 3 eyes (5%) progressed to stage IV disease.[51] In another series of 120 eyes observed for at least 12 months, 91% had favorable structural outcomes ( Fig. 116-10 ). [49] In the largest, prospective, randomized comparison of laser photocoagulation with cryotherapy (25 infants observed for at least 4 years), eyes treated with cryotherapy were significantly more likely to have visual acuity of 20/50 or better and were significantly less myopic.[50] Laser photocoagulation is most effective for posterior (zone 1) disease: favorable anatomical results have been reported in 83–85% of eyes.[52] [53] Cryotherapy, by contrast, provided favorable outcomes in only 25% of eyes with zone 1 disease.[54]

Surgery

Although retinal ablation is effective in a majority of cases of threshold ROP, a significant number of these eyes progress to retinal detachment. Detachment is most commonly tractional, originating at the ridge in a circumferential, purse-string pattern that draws the retina anteriorly and centrally ( Fig. 116-11 ).

The advanced stages of ROP (stages IVa, IVb, and V) are poorly understood. Common misconceptions are that macula-sparing (stage IVa) partial retinal detachments are largely benign, that surgery should be deferred until the macula is detached, that scleral buckle is the preferred retinal reattachment procedure, and that useful vision cannot be obtained in eyes with total (stage V) detachments.

ROP-related detachments may appear stable in the first few weeks or months after peripheral retinal ablation. Yet neither the stability of partial detachment[6] nor visual acuity[55] is predictable from the retinal appearance in infants with ROP. This is particularly true for untreated eyes[6] or those with incomplete peripheral retinal ablation. Visual outcome of eyes with even partial ROP-related retinal detachment is generally poor by 4½ years of age: in the cohort of 61 eyes from the Cryo-ROP study with partial retinal detachment 3 months after threshold, only 6 eyes had vision of 20/200 or better at age 4½. [8] [56]

The goal of intervention for ROP-related retinal detachments varies with the severity of the detachment. The goal for extramacular retinal detachment (stage IVa ROP) is an undistorted or minimally distorted posterior pole, total retinal reattachment, and preservation of the lens and central fixation vision. Scleral buckling [57] [58] and vitrectomy[59] have been used to manage stage IVa ROP. Vitreous surgery can interrupt progression of ROP from

 

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Figure 116-11 “Purse-string” circumferential traction. This causes retinal detachment in retinopathy of prematurity.

stage IVa to stage 4b or 5 by directly addressing transvitreal traction resulting from fibrous proliferation.[60] Disadvantages of scleral buckling for stage IVa ROP are the dramatic anisometropic myopia and the second intervention required for transection or removal so that the eye may continue to grow.[61]

Surgery for tractional retinal detachments involving the macula (stage IVb ROP) is performed to minimize retinal distortion and prevent total detachment (stage V). The functional goal is ambulatory vision. In earlier studies, visual outcome for retinal detachment beyond stage IVa was quite poor. More recent reports demonstrate that form-vision can be obtained by vitrectomy for stage V ROP.[59] [62] Maximal recovery of vision following the insult of macula-off retinal detachment and interruption of visual development in infants may take years.

LONG-TERM COURSE

As infants afflicted with ROP have matured, the ophthalmic community has gained experience with “adult ROP.” Early nuclear sclerotic cataract, glaucoma,[63] exudative retinopathy,[64] and rhegmatogenous retinal detachment[65] are but a few of the sequelae of ROP prompting the need for lifelong ophthalmic monitoring of formerly premature adults.

 

 

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2. Ashton N. Retinal angiogenesis in the human embryo. Br Med Bull. 1970;26: 103–6.

 

3. Committee for the Classification of Retinopathy of Prematurity. An international classification of retinopathy of prematurity. Arch Ophthalmol. 1984;106:471–9.

 

4. 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. 1987;105:906–12.

 

5. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity. Preliminary results. Arch Ophthalmol. 1988;106:471–9.

 

6. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: 3½-year outcome—structure and function. Arch Ophthalmol. 1993;111:339–44.

 

7. Cryotherapy for Retinopathy of Prematurity Cooperative Group. The natural ocular outcome of premature birth and retinopathy. Status at 1 year. Arch Ophthalmol. 1994;112:903–12.

 

8. Palmer EA, Flynn JT, Hardy RJ, et al. Incidence and early course of retinopathy of prematurity. Ophthalmology. 1991;98:1628–40.

 

9. Schaffer DB, Palmer EA, Plotsky DF, et al. Prognostic factors in the natural course of retinopathy of prematurity. Ophthalmology. 1993;100:230–7.

 

10. Hussain N, Clive J, Bhandari V. Current incidence of retinopathy of prematurity, 1989–97. Pediatrics. 1999;104(3):e26.

 

11. Phelps DL. Retinopathy of prematurity: an estimate of vision loss in the United States—1979. Pediatrics. 1981;67:924–6.

 

12. Hack M, Fanaroff AA. Outcomes of extremely-low-birth-weight infants between 1982 and 1988. N Engl J Med. 1989;321:1642–7.

 

13. Vyas J, Field D, Draper ES, et al. Severe retinopathy of prematurity and its association with different rates of survival in infants less than 1251?g birth weight. Arch Dis Child Fetal Neonatal Ed. 2000;82:F145–9.

 

14. Rowlands E, Ionides ACW, Chinn S, et al. Reduced incidence of retinopathy of prematurity. Br J Ophthalmol. 2001;85:933–5.

 

15. Pennefather PM, Tin W, Clarke MP, et al. Retinopathy of prematurity in a controlled trial of prophylactic surfactant treatment. Br J Ophthalmol. 1996;80:420–4.

 

16. Bullard SR, Donahue SP, Feman SS, et al. The decreasing incidence and severity of retinopathy of prematurity. J AAPOS. 1999;3:46–52.

 

17. Wood NS, Marlow N, Costeloe K, et al. Neurologic and developmental disability after extremely preterm birth. EPICure Study Group. N Engl J Med. 2000;343:378–84.

 

18. O’Keefe M, Kafil-Hussain N, Flitcroft I, Lanigan B. Ocular significance of intraventricular hemorrhage in premature infants. Br J Ophthalmol. 2001;85:357–9.

 

19. Msall ME, Phelps DL, DiGaudio KM, et al. Severity of neonatal retinopathy of prematurity is predictive of neurodevelopmental functional outcome at age 5.5 years. Pediatrics. 2000;106:998–1005.

 

20. Michaelson IC. The mode of development of the vascular system of the retina: with some observations on its significance for certain retinal diseases. Trans Ophthalmol Soc UK. 1948;68:137–80.

 

21. Kinsey VE, Jacobus JT, Hemphill F. Retrolental fibroplasias: cooperative study of retrolental fibroplasia and the use of oxygen. Arch Ophthalmol. 1956;56: 481–547.

 

22. Kinsey VE, Arnold HJ, Kalina RE, et al. PaO2 levels and retrolental fibroplasia: a report of the cooperative study. Pediatrics. 1977;60:655–68.

 

23. Katzman G, Satish M, Krishnan V. Hypoxemia and retinopathy of prematurity. Pediatrics. 1987;80:972.

 

24. The STOP-ROP Multicenter Study Group. Supplemental therapeutic oxygen for prethreshold retinopathy of prematurity (STOP-ROP), a randomized, controlled trial. I: Primary outcomes. Pediatrics. 2000;105:295–310.

 

25. Mittal M, Dhanireddy R, Higgins R. Candida sepsis and association with retinopathy of prematurity. Pediatrics. 1998;101:654–7.

 

26. Noyola DE, Bohra L, Paysse EA, et al. Associations of candidemia and retinopathy of prematurity in very low birthweight infants. Ophthalmology. 2002;109:80–4.

 

27. Karlowicz MG, Giannone PJ, Pestian J, et al. Does candidemia predict threshold retinopathy of prematurity in extremely low birth weight (1000?g) neonates? Pediatrics. 2000;105:1036–40.

 

28. Reynolds JD, Hardy RJ, Kennedy KA, et al. Lack of efficacy of light reduction in preventing retinopathy of prematurity. Light reduction in retinopathy of prematurity (LIGHT-ROP) study group. N Engl J Med. 1998;338:1572–6.

 

29. Chen ZY, Battinelli EM, Fielder A, et al. A mutation in the Norrie disease gene (NDP) associated with X-linked familial exudative vitreoretinopathy. Nat Genet. 1993;5:180–3.

 

30. Shastry BS, Pendergast SD, Hartzer MK, et al. Identification of missense mutations in the Norrie disease gene associated with advanced retinopathy of prematurity. Arch Ophthalmol. 1997;115:651–5.

 

31. Hiraoka M, Berinstein DM, Trese MT, Shastry BS. Insertion and deletion mutations in the dinucleotide repeat region of the Norrie disease gene in patients with advanced retinopathy of prematurity. J Hum Genet. 2001;46:178–81.

 

32. Foos RY. Pathologic features of clinical stages of retinopathy of prematurity. In: Flynn JT, Tasman WS, eds. Retinopathy of prematurity. New York: Springer-Verlag; 1992:23–36.

 

33. Gospodarowicz D. Purification of a basic fibroblast growth factor from bovine pituitary. J Biol Chem. 1975;250:2505–10.

 

34. Schreiber AB, Winkler ME, Derynk R. Transforming growth factor alpha: a more potent angiogenic mediator than epidermal growth factor. Science. 1986;232: 1250–3.

 

35. Frater-Schroder M, Risau W, Hallman R, et al. Tumor necrosis factor alpha, a potent inhibitor of endothelial cell growth in vitro is angiogenic in vivo. Proc Natl Acad Sci U S A 1987;84:5277–81.

 

36. Shweki D, Itin A, Soffer D, Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature. 1992;358:843–5.

 

37. Aiello LP, Avery RL, Arrigg PG, et al. Vascular endothelial growth factor in ocular fluid of patients with diabetic retinopathy and other retinal disorders. N Engl J Med. 1994;331:1480–7.

 

38. Screening examination of premature infants for retinopathy of prematurity. Pediatrics. 2001;108:809–11.

 

39. Yamashita Y. Studies on retinopathy of prematurity: III. Cryocautery for retinopathy of prematurity. Jpn J Ophthalmol. 1972;26:385–93.

 

40. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity: ophthalmological outcomes at 10 years. Arch Ophthalmol. 2001;119:1110–8.

 

41. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Effect of retinal ablative therapy for threshold retinopathy of prematurity: results of Goldmann perimetry at the age of 10 years. Arch Ophthalmol. 2001;119:1120–5.

 

42. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Contrast sensitivity at age 10 years in children who had threshold retinopathy of prematurity. Arch Ophthalmol. 2001;119:1129–33.

 

43. Banach MJ, Ferrone PJ, Trese MT. A comparison of dense versus less dense diode laser photocoagulation patterns for threshold retinopathy of prematurity. Ophthalmology. 2000;107:324–8.

 

44. Lambert SR, Capone A Jr, Cingle KA, Drack AV. Cataract and phthisis bulbi after laser photoablation for threshold retinopathy of prematurity. Am J Ophthalmol. 2000;129:585–91.

 

45. Kaiser RS, Trese MT. Iris atrophy, cataracts, and hypotony following peripheral ablation for threshold retinopathy of prematurity. Arch Ophthalmol. 2001;119: 615–7.

 

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46. Shalev B, Farr A, Repka MX. Randomized comparison of diode laser photocoagulation versus cryotherapy for threshold retinopathy of prematurity: seven-year outcome. Am J Ophthalmol. 2001;132:76–80.

 

47. Pearce IA, Pennie FC, Gannon LM, et al. Three year visual outcome for treated stage 3 retinopathy of prematurity: cryotherapy versus laser. Br J Ophthalmol. 1998;82:1254–9.

 

48. O’Keefe M, O’Reilly J, Lanigan B. Longer term visual outcome of eyes with retinopathy treated with cryotherapy or diode laser. Br J Ophthalmol. 1998;82:1246–8.

 

49. Foroozan R, Connolly BP, Tasman WS. Outcomes after laser therapy for threshold retinopathy of prematurity. Ophthalmology. 2001;108:1644–6.

 

50. Connolly BP, McNamara JA, Sharma S, et al. A comparison of laser photocoagulation with trans-scleral cryotherapy in the treatment of threshold retinopathy of prematurity. Ophthalmology. 1998;105:1628–31.

 

51. DeJonge MH, Ferrone PJ, Trese MT. Diode laser ablation for threshold retinopathy of prematurity. Short-term structural outcome. Arch Ophthalmol. 2000;118: 365–7.

 

52. Capone A Jr, Diaz-Rohena R, Sternberg P Jr, et al. Diode-laser photocoagulation for zone 1 threshold retinopathy of prematurity. Am J Ophthalmol. 1993;116:444–50.

 

53. Axer-Siegel R, Snir M, Cotlear D, et al. Diode laser treatment of posterior retinopathy of prematurity. Br J Ophthalmol. 2000;84:1383–6.

 

54. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Multicenter trial of cryotherapy for retinopathy of prematurity. Three-month outcome. Arch Ophthalmol. 1990;108:195–204.

 

55. Reynolds J, Dobson V, Quinn GE, et al. Prediction of visual function in eyes with mild to moderate posterior pole residua of retinopathy of prematurity. Cryotherapy for Retinopathy of Prematurity Cooperative Group. Arch Ophthalmol. 1993;111:1050–6.

 

56. Gilbert WS, Quinn GE, Dobson V, et al. Partial retinal detachment at 3 months after threshold retinopathy of prematurity. Long-term structural and functional outcome. Arch Ophthalmol. 1996;114:1085–91.

 

57. Trese MT. Scleral buckling for retinopathy of prematurity. Ophthalmology. 1994; 101:23–6.

 

58. Greven C, Tasman W. Scleral buckling in stages 4B and 5 retinopathy of prematurity. Ophthalmology. 1990;97:817–20.

 

59. Trese MT, Droste PJ. Long-term postoperative results of a consecutive series of stages 4 and 5 retinopathy of prematurity. Ophthalmology. 1998;105:992–7.

 

60. Capone A Jr, Trese MT. Lens-sparing vitreous surgery for tractional stage 4A retinopathy of prematurity retinal detachments. Ophthalmology. 2001;108:2068–70.

 

61. Chow DR, Ferrone PJ, Trese MT. Refractive changes associated with scleral buckling and division in retinopathy of prematurity. Arch Ophthalmol. 1998;116:1446–8.

 

62. Mintz-Hittner HA, O’Malley RE, Kretzer FL. Long-term form identification vision after early, closed, lensectomy-vitrectomy for stage 5 retinopathy of prematurity. Ophthalmology. 1997;104:454–9.

 

63. Gallo JE, Holmstrom G, Kugelberg U, et al. Regressed retinopathy of prematurity and its sequelae in children aged 5–10 years. Br J Ophthalmol. 1991;75:527–31.

 

64. Brown MM, Brown GC, Duker JS, et al. Exudative retinopathy of adults: a late sequela of retinopathy of prematurity. Int Ophthalmol. 1994–95;18(5):281–5.

 

65. Kaiser RS, Trese MT, Williams GA, Cox MS Jr. Adult retinopathy of prematurity. Outcomes of rhegmatogenous retinal detachments and retinal tears. Ophthalmology. 2001;108:1647–53.

Chapter 115 – Venous Obstructive Disease of the Retina

Chapter 115 – Venous Obstructive Disease of the Retina

 

MICHAEL G. MORLEY

JEFFREY S. HEIER

 

 

 

 

Central Retinal Vein Obstruction

Branch Retinal Vein Obstruction

 

DEFINITION

• Obstruction of the central retinal vein at the lamina cribrosa.

 

KEY FEATURES

• Retinal hemorrhages in all four quadrants.

• Dilated, tortuous veins in all four quadrants.

 

ASSOCIATED FEATURES

• Optic disc edema.

• Macular edema.

• Cotton-wool spots.

• Capillary nonperfusion.

• Neovascularization of the iris, retina, or optic disc.

• Neovascular glaucoma.

• Optic disc venous–venous collateral vessels (opticociliary shunt vessels).

• Exudative retinal detachment in severe cases.

 

DEFINITION

• Obstruction of a branch retinal vein.

 

KEY FEATURE

• Retinal hemorrhages in the distribution of the obstructed branch retinal vein.

 

ASSOCIATED FEATURES

• Macular edema.

• Retinal neovascularization.

• Vitreous hemorrhage.

• Dilated, tortuous retinal vein.

• Capillary nonperfusion.

• Cotton-wool spots.

• Venous–venous retinal collateral vessels.

• Sheathing of vessel.

• Lipid exudates.

• Microvascular changes including microaneurysms and collateral vessels.

• Pigmentary macular disturbances.

• Subretinal fibrosis.

 

 

 

CENTRAL RETINAL VEIN OBSTRUCTION

INTRODUCTION

Venous obstructive disease of the retina is a relatively common retinal vascular disorder, second only to diabetic retinopathy in incidence. It typically affects patients who are 50 years of age or older. Usually, retinal vein obstructions are recognized easily and treatment options have been investigated thoroughly using large, multicenter, randomized clinical trials.

Retinal vein obstructions are classified according to whether the central retinal vein or one of its branches is obstructed. Central retinal vein obstruction and branch retinal vein obstruction differ with respect to pathophysiology, underlying systemic associations, average age of onset, clinical course, and therapy.

Central retinal vein obstructions can be divided further into ischemic and nonischemic varieties. This distinction among central retinal vein obstructions, although somewhat arbitrary, is important because up to two thirds of patients who have the ischemic variety develop iris neovascularization and neovascular glaucoma.

EPIDEMIOLOGY AND PATHOGENESIS

Central retinal vein obstruction is found most commonly in individuals over 50 years old. [1] [2] Diabetes mellitus, systemic arterial hypertension, and atherosclerotic cardiovascular disease are the most frequently associated underlying medical diseases; however, their direct relationship to pathogenesis remains speculative. [2] [3] [4] [5] Completely normal medical and laboratory evaluation results are found in about one fourth of patients.[3] [6] A significant inverse association with central retinal vein obstruction, which represents decreasing risk, is present with alcohol consumption, education, physical activity and, in women, exogenous estrogen use.[2]

Open-angle glaucoma is a relatively common finding in patients who have central retinal vein obstruction. Patients who have a history of glaucoma are about 5 times more likely to have central retinal vein obstruction than those who do not, presumably because of structural alterations of the lamina cribrosa induced by elevated intraocular pressure. Acute angle-closure glaucoma may precipitate central retinal vein obstruction.

The precise pathogenesis of central retinal vein obstruction remains obscure. The obstruction is believed to be the result of a thrombus in the central retinal vein at, or posterior to, the lamina cribrosa. Arteriosclerosis of the neighboring central retinal artery that causes turbulent venous flow and then endothelial damage often is implicated. Also, endothelial cell proliferation has been suggested. An alternative theory is that thrombosis of the central retinal vein is an end-stage phenomenon, induced by a variety of primary lesions. Such lesions could include compressive

 

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or inflammatory optic nerve or orbital problems, structural abnormalities in the lamina cribrosa, or hemodynamic changes.

Because the retinal venous circulation represents a relatively high-resistance, low-flow system it is particularly sensitive to hematological factors. Along with an elevated erythrocyte sedimentation rate and antithrombin III levels, other studies indicate that an elevated hematocrit level, elevated homocysteine level, elevated fibrinogen level, increased blood viscosity, the presence of a lupus anticoagulant or another antiphospholipid antibody, and a deficiency in activated protein C may be associated with retinal venous disease. [7] [8] [9] Whether these hematological factors alone can initiate a central retinal vein obstruction or whether their role is to function as cofactors remains unknown.

OCULAR MANIFESTATIONS

Both types of central retinal vein obstruction, ischemic and nonischemic, share similar findings—dilated, tortuous retinal veins and retinal hemorrhages in all four quadrants. The distinction between the two varieties is important, because it assists the clinician in the following:

• Prediction of the risk of subsequent ocular neovascularization

• Identification of patients who have poorer visual prognosis

• Determination of the likelihood of spontaneous visual improvement

• Decision as to appropriate follow-up intervals

The distinction between the two types of vein obstructions remains somewhat arbitrary and is based on the total area of nonperfusion on fluorescein angiography. Most investigators accept that nonischemic and ischemic central retinal vein obstructions represent varying severity of the same underlying disease continuum. Other investigators suggest, however, that these are two distinct clinical entities with different pathogenesis. The ischemic variety is associated with concurrent, severe retinal arterial disease, while the milder, nonischemic type results from a thrombosis located more distally, behind the lamina cribrosa.[10]

Nonischemic Central Retinal Vein Obstruction

Alternative names include partial, incomplete, imminent, threatened, incipient, or impending vein obstruction, as well as venous stasis retinopathy.[11] Of the patients who have central retinal vein obstruction, 75–80% can be classified as having this milder form. Patients usually have mild to moderate decreased visual acuity, although this can vary from normal to as poor as difficulty with finger counting. Intermittent blurring or transient visual obscuration also may be a complaint. Pain is rare.

 

 

Figure 115-1 Nonischemic central retinal vein obstruction. Fundus view of diffuse retinal hemorrhages, optic nerve head edema, dilated and tortuous veins, and a cotton-wool spot.

Pupillary testing rarely reveals an afferent defect which, if present, is only slight. Ophthalmoscopy reveals a variable number of dot and flame retinal hemorrhages, present in all four quadrants ( Fig. 115-1 ). Optic nerve head swelling is common, and engorgement and tortuosity of the retinal veins are characteristic. Cotton-wool spots, if present, are few in number and located posteriorly. When vision is decreased, this is usually the result of macular hemorrhage or edema, which may be in the form of cystoid macular edema, diffuse macular thickening, or both.

Neovascularization of either the anterior or posterior segment is rare in a true nonischemic central retinal vein obstruction (less than 2% incidence), although conversion from an initially nonischemic vein obstruction to the ischemic variety is fairly common. The Central Vein Occlusion Study Group noted that 34% of nonischemic central retinal vein occlusions (CRVOs) progressed to become ischemic within 3 years,[12] and 15% of the study group converted within the first 4 months.

Many or all of the pathological retinal findings may resolve over the 6–12 months following diagnosis. Retinal hemorrhages can resolve completely. The optic nerve may appear normal, but opticociliary collateral vessels are common. Macular edema also may resolve, to leave a normal appearance. However, persistent cystoid macular edema can linger and result in permanent visual loss, often leading to pigmentary changes, epiretinal membrane formation, or subretinal fibrosis.

Ischemic Central Retinal Vein Obstruction

Ischemic central retinal vein obstructions are referred to as severe, complete, or total vein obstruction, and hemorrhagic retinopathy[11] ; they account for 20–25% of all central retinal vein obstructions. Acute, markedly decreased visual acuity is the usual initial complaint. Vision usually ranges from 20/200 (6/60) to hand-motion acuity. A prominent afferent pupillary defect is typical. Pain at the time of evaluation may occur if neovascular glaucoma has developed.

The ophthalmoscopic picture of an ischemic central retinal vein obstruction may be confused with other entities, but rarely. It is characterized by extensive retinal hemorrhages in all four quadrants, most notably centered in the posterior pole ( Fig. 115-2 ). Hemorrhages can be so extensive that the retinal and choroidal details are obscured. Bleeding may break through the internal limiting membrane, which results in vitreous hemorrhage. The optic disc usually is edematous, and the retinal veins are markedly engorged and tortuous. Cotton-wool spots are usually present and may be numerous. Macular edema is often severe but may be obscured by hemorrhage. Massive lipid exudation in the

 

 

Figure 115-2 Ischemic central retinal vein obstruction. Fundus view of extensive retinal hemorrhages, venous dilation and tortuosity, and scattered cotton-wool spots.

 

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macular region can occur, especially in patients who have elevated triglyceride levels. Exudative retinal detachment may develop and is associated with a poor visual prognosis. Secondary, non-neovascular angle-closure glaucoma may occur.

The incidence of anterior segment neovascularization in ischemic central retinal vein obstruction is 60% or higher and has been documented as early as 9 weeks after onset.[3] [13] Neovascularization of the angle and neovascular glaucoma may occur within 3 months of disease onset (90-day glaucoma), and it can result in intractably elevated pressure. Neovascularization of the optic disc and retinal neovascularization may be seen as well, but they are less common. As with nonischemic central retinal vein obstruction, the findings may decrease or resolve 6–12 months after diagnosis.

During the resolution phase, the optic nerve shows pallor and opticociliary collateral vessels more often than it does in the mild form of central retinal vein obstruction. Permanent macular changes can develop that include pigmentary changes, epiretinal membrane formation, and subretinal fibrosis that resembles disciform scarring. Macular ischemia may be present, as well.

HEMICENTRAL RETINAL VEIN OBSTRUCTION.

In about 20% of eyes, the central retinal vein enters the optic nerve as two separate branches, the superior and inferior, prior to merging as a single trunk posterior to the lamina cribrosa. In these eyes, obstruction of one of the dual trunks within the substance of the optic nerve results in a hemicentral retinal vein obstruction. Although only one half of the retina is involved, these obstructions act more like central retinal vein obstructions than a branch retinal vein obstruction in terms of visual outcome, risk of neovascularization, and response to laser treatment.

Papillophlebitis or Optic Disc Vasculitis

Some mild central retinal vein obstructions in patients younger than 50 years have been referred to as papillophlebitis or optic disc vasculitis—terms that suggest a benign course. An inflammatory optic neuritis or vasculitis is hypothesized as the cause. These eyes tend to have optic disc edema out of proportion to the retinal findings, cotton-wool spots that ring the optic disc, and occasionally cilioretinal artery obstructions or even partial central retinal artery obstructions. Although spontaneous improvement is common, the course is not always benign. Up to 30% of these patients may develop the ischemic type of occlusion, a final visual acuity of 20/200 (6/60) or worse occurs in nearly 40%, and neovascular glaucoma has been reported.[14]

DIAGNOSIS AND ANCILLARY TESTING

The diagnosis of an ischemic central retinal vein obstruction is based on the characteristic fundus findings:

• Widespread retinal hemorrhages

• Retinal venous engorgement and tortuosity

• Cotton-wool spots

• Macular edema

• Optic disc edema

Rarely is this clinical picture confused with other entities. However, the clinical picture of a nonischemic central retinal vein obstruction can be far more subtle. Although retinal hemorrhages usually are present in all four quadrants, they may be scant. If the eye is observed several months after disease onset, the hemorrhages may have resolved. Cotton-wool spots, optic nerve edema, and macular edema tend to be absent. Venous engorgement and tortuosity, which may be mild, are usually present.

Fluorescein angiography is the most useful ancillary test for the evaluation of the two most serious, debilitating and, unfortunately, common complications of central retinal vein obstruction—anterior segment

 

 

Figure 115-3 Ischemic central retinal vein obstruction. Fluorescein angiography reveals marked hypofluorescence secondary to widespread capillary nonperfusion. The venous system shows marked dilation with focal areas of constriction, and the vessel walls stain in areas of ischemia.

neovascularization and macular edema. Studies suggest that eyes with 10 disc areas or greater of nonperfusion noted on fluorescein angiography are at increased risk for the development of anterior segment neovascularization and, therefore, should be classified as ischemic.[15] [16] The Central Vein Occlusion Study found the greatest risk was in patients with worse than 20/200 (6/60) visual acuity or 30 or more disc areas of nonperfusion. [12] Electroretinography is used occasionally to help determine the prognosis of a CRVO. [17] [18]

Fluorescein angiography in ischemic central retinal vein obstruction may show marked hypofluorescence ( Fig. 115-3 ), which may be secondary to blockage from extensive hemorrhages or to retinal capillary nonperfusion. When extensive hemorrhages are present, little information is gained from the angiogram. However, as the hemorrhages clear over several months, the degree of capillary nonperfusion may become apparent. Most eyes (80%) that have this degree of hemorrhage eventually are classified as ischemic.

Macular edema is the most common cause of visual loss in central retinal vein obstruction. It is present almost universally in ischemic cases and frequently is severe. It may manifest as large cystoid spaces or diffuse leakage on fluorescein angiography. Macular edema may be obscured by hemorrhage, but as the hemorrhage and edema resolve, macular ischemia may become apparent. Angiography also reveals optic nerve head leakage and perivenous staining. In the late stages of the disease, generalized extensive retinal capillary nonperfusion, arteriovenous collateral vessels, and microaneurysms are seen. The macular region shows persistent edema or pigmentary degeneration.

With a nonischemic central retinal vein obstruction, fluorescein angiography reveals staining along the retinal veins, microaneurysms, and dilated optic nerve head capillaries. Retinal capillary nonperfusion ( Fig. 115-4 ) is minimal or absent. As the nonischemic central retinal vein obstruction resolves, angiography may become normal. If macular edema persists, or if pigmentary changes occur, these become evident.

The Central Vein Occlusion Study Group reported that 37% of ischemic central retinal vein obstructions demonstrated anterior segment (iris or angle or both) neovascularization at or before the 4-month follow-up.[19] Although the results of fluorescein angiography help to differentiate patients at high risk for the development of neovascularization, visual acuity alone is a more powerful, less expensive, and less invasive measurement by which to determine the prognosis and appropriate follow-up.[12]

A general medical evaluation, to include extensive medical history and physical examination with blood pressure evaluation, is recommended ( Box 115-1 ). Laboratory evaluation may include a complete blood count, glucose tolerance test, lipid profile, serum protein electrophoresis, chemistry profile, and syphilis serology. Additional testing, based upon the above findings,

 

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Figure 115-4 Nonischemic central retinal vein obstruction. Fluorescein angiography shows marked venous dilation and tortuosity, optic nerve head edema, and staining of vessel walls. Capillary nonperfusion is absent.

 

 

 

Medical and Ophthalmic Work-Up for Central Retinal Vein Obstruction and Branch Retinal Vein Obstruction

 

CENTRAL RETINAL VEIN OBSTRUCTION

Complete history and physical examination

 

Complete ophthalmic examination

 

Fluorescein angiography

 

Gonioscopy to look for iris and/or angle neovascularization

 

Blood pressure

 

Complete blood count

 

Prothrombin time

 

Partial thromboplastin time

 

Antinuclear antibodies

 

Serum protein electrophoresis

 

Erythrocyte sedimentation rate

 

 

BRANCH RETINAL VEIN OBSTRUCTION

Complete history and physical examination

 

Complete ophthalmic examination

 

Fluorescein angiography

 

Blood pressure

 

 

 

 

may be necessary. If a history of systemic clotting diathesis exists, further hematological tests such as lupus anticoagulant level, anticardiolipin antibody, and protein S and protein C levels should be considered. Diagnosis and treatment of an associated disease is not expected to improve the visual outcome in the affected eye, but it may help to prevent subsequent obstruction in the fellow eye.

DIFFERENTIAL DIAGNOSIS

As stated above, rarely is the full-blown picture of an ischemic central retinal vein obstruction confused with other disease entities. However, nonischemic or long-standing central retinal vein obstructions can appear similar to the retinopathy of carotid occlusive disease—the ocular ischemic syndrome(s). A great deal of confusion existed in the past over these two entities, not only because of their similar clinical pictures, but also because each has been referred to in the literature as venous stasis retinopathy.[11] [20] Both conditions are associated with blurred vision, and both may have transient visual loss. Blurring of vision when a darker room is entered after being in a brighter area is suggestive of carotid artery disease.[21] Although disc edema always is present in ischemic central retinal vein obstruction, and may be present in nonischemic central retinal vein obstruction, it is quite rare in carotid occlusive disease. Although the veins are engorged in both diseases, they are generally not tortuous in the ocular ischemic syndrome. The retinal hemorrhages seen in carotid disease tend to localize to the midperiphery, instead of the posterior pole as seen in central retinal vein obstruction.

Hyperviscosity syndromes may produce a bilateral retinopathy similar to central retinal vein obstruction and may, in fact, induce a true central retinal vein obstruction with thrombus formation. Simultaneous bilateral disease is an unusual finding in central retinal vein obstructions but occurs more commonly in hypercoagulable and hyperviscous states. Diseases such as sickle cell disease, polycythemia vera, leukemia, and multiple myeloma are but a few of the possibilities. When a patient seeks treatment for bilateral central retinal vein obstructions, especially simultaneous, the medical and laboratory evaluation should include a search for evidence of hyperviscous and hypercoagulable syndromes. Improvement in the affected eye is possible when a hyperviscosity syndrome is responsible and plasmapheresis is performed.[22] Severe anemia with thrombocytopenia can masquerade as a central retinal vein obstruction, and it is differentiated from a central retinal vein obstruction by a complete blood count with platelets. In addition, acute hypertensive retinopathy with disc edema may resemble bilateral central retinal vein obstruction.

SYSTEMIC ASSOCIATIONS

Central retinal vein obstruction has been associated with systemic vascular disease such as hypertension, diabetes mellitus, and cardiovascular disease; blood dyscrasias such as polycythemia vera, lymphoma, and leukemia; paraproteinemias and dysproteinemias including multiple myeloma and cryoglobulinemia; vasculitis of syphilis and sarcoidosis; and autoimmune disease such as systemic lupus erythematosus. [23] Blood dyscrasias and dysproteinemias result in hyperviscosity syndromes, which may appear similar to central retinal vein obstruction but possibly represent curable disease (as discussed under differential diagnosis above). Oral contraceptive use in women may be associated with both thromboembolic disease and central retinal vein obstruction.[24]

PATHOLOGY

Green et al.[13] evaluated histological sections of 29 eyes in 28 patients who had central retinal vein obstruction. All 29 eyes had the formation of a fresh or recanalized thrombus at or just posterior to the lamina cribrosa. Within the thrombi, a mild lymphocytic infiltration with prominent endothelial cells was seen. Loss of the inner retinal layers consistent with inner retinal ischemia was a common finding.

Alterations in blood flow, hyperviscosity, and vessel wall abnormalities may produce central retinal vein obstructions by enabling a thrombus of the central retinal vein to form. Local factors can predispose to central retinal vein obstruction. Glaucoma has been associated with central retinal vein obstruction. It has been hypothesized that glaucoma causes stretching and compression of the lamina cribrosa, which results in vessel abnormalities, increased resistance to flow and, ultimately, thrombosis. [13]

 

TREATMENT

No treatment has been proven to reverse the pathology seen in central retinal vein obstruction. Aspirin; systemic anticoagulation with coumarin, heparin, and alteplase; local anticoagulation with intravitreal alteplase; corticosteroids; anti-inflammatory agents; isovolemic hemodilution; plasmapheresis; and optic nerve sheath decompression all have been advocated but without definitive proof of efficacy. Certain complications of central retinal

 

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Treatment Guidelines for Patients Who Have Central Retinal Vein Obstruction

 

NO PROVED EFFECTIVE TREATMENT

Panretinal photocoagulation if intraocular neovascularization present

 

Lower intraocular pressure if elevated

 

Treat underlying medical conditions

 

Macular edema generally does not respond to grid laser

 

 

 

 

vein obstruction may be preventable or reversible, however ( Box 115-2 ).

Neovascular Glaucoma

Neovascular glaucoma is a devastating complication of ischemic central retinal vein obstruction. Intractable glaucoma, blindness, and pain that culminates in enucleation can occur. The Central Vein Occlusion Study Group determined whether prophylactic panretinal photocoagulation (PRP) was an effective method with which to prevent the development of iris neovascularization or angle neovascularization in patients who had ischemic central retinal vein obstruction, or whether it was more appropriate to apply PRP after the development of anterior segment neovascularization. [25] The study found that prophylactically treated ischemic eyes developed iris neovascularization less frequently than ischemic eyes that were followed (20% in the early treatment group versus 35% in the no-early-treatment group), although the difference was not statistically significant. However, PRP is more likely to result in prompt regression of neovascularization of the iris in the previously untreated group versus the prophylactically treated group (56% versus 22%, respectively, after 1 month). As a result, for ischemic central retinal vein obstructions, frequent follow-up examinations during the early months and prompt PRP if iris neovascularization develops is the recommended treatment strategy.

Treatment should be applied in all four quadrants to give medium-white burns of diameter 400–500?µm (a total of 1000–2000 burns). Identification of early iris neovascularization at the pupillary border is critical—examination of the undilated pupil is recommended. Routine gonioscopy also is suggested, because angle neovascularization can occur without iris neovascularization.

Macular Edema

Macular edema and subsequent permanent macular dysfunction occur in virtually all patients with ischemic central retinal vein obstruction, and in many patients with nonischemic central retinal vein obstruction. The Central Vein Occlusion Study evaluated the efficacy of macular grid photocoagulation in patients with central retinal vein obstruction and macular edema.[26] Patients with both ischemic and nonischemic central retinal vein obstruction were studied. Although macular grid laser treatment conclusively reduced angiographic macular edema, the study did not find a difference in visual acuity between the treated and untreated eyes at any stage of the follow-up period. As a result, currently it is not recommended that macular grid photocoagulation be employed in the setting of central retinal vein obstruction. Intravitreal triamcinolone is being studied as a treatment for cystoid macular edema.

COURSE AND OUTCOME

The prognosis for visual recovery is highly dependent upon the subtype of central retinal vein obstruction. In general, the visual prognosis can be predicted from the visual acuity during evaluation. Patients who have nonischemic central retinal vein

 

 

Follow-Up for Patients Who Have Central Retinal Vein Obstruction

 

PRESENTING VISUAL ACUITY OF 20/40 (6/12) OR BETTER

Examinations every 1–2 months for 6 months after diagnosis

 

Annual examinations as the patient’s condition stabilizes

 

 

PRESENTING VISUAL ACUITY BETWEEN 20/50 (6/15) AND 20/200 (6/60)

Examinations monthly to bimonthly (at the physician’s discretion, based on which end of the spectrum the visual acuity lies) for the first 6 months after diagnosis

 

Examinations every 6 months to yearly afterward

 

 

PRESENTING VISUAL ACUITY OF 20/200 (6/60)

Examinations every month for the initial 6 months

 

Then every 2 months until 8 months after presentation

 

Then every 4 months until 2 years after presentation

 

 

 

 

obstructions may experience a complete recovery of vision, although this occurs in less than 10% of cases.[6] Although patients with nonischemic disease may retain acuity of 20/60 (6/18) or better, as many as 50% deteriorate to levels of 20/200 (6/60) or worse.[3] [6] Conversion of nonischemic to ischemic occlusions is seen in about one third of cases and typically occurs during the first 6–12 months after evaluation.[3] [6] [12] [28] Of the patients who have ischemic central retinal vein obstructions, more than 90% have a final visual acuity of 20/200 (6/60) or worse.

As many as 7% of patients with central retinal vein obstruction develop a nonsimultaneous venous occlusion of the fellow eye within 2 years.[29] Contralateral branch retinal vein and retinal arterial obstructions also may be seen. The risk of any vascular occlusion in the fellow eye is estimated to be 0.9% per year.[12]

Based on the Central Vein Occlusion Study, the recommended follow-up examinations in patients who have central retinal vein obstruction are given in Box 115-3 .[12] [19] [25]

If visual acuity deteriorates to less than 20/200 (6/60) at any time during the disease course, the patient should be treated as a patient with a new CRVO who has an acuity of that level and assessed monthly.

BRANCH RETINAL VEIN OBSTRUCTION

INTRODUCTION

Branch retinal vein obstruction is a common retinal vascular disorder of the elderly. Visual loss from a branch retinal vein occlusion usually is caused by macular edema, macular ischemia, or vitreous hemorrhage. In some patients, laser treatment can help stabilize or even improve vision.

EPIDEMIOLOGY AND PATHOGENESIS

Branch retinal vein obstructions occur approximately 3 times more commonly than central retinal vein obstructions. Men and women are affected equally, with the usual age of onset between 60 and 70 years. Most epidemiological and histopathological evidence implicates arteriolar disease as the underlying pathogenesis. Branch retinal vein obstruction almost always occurs at an arteriovenous crossing, where the artery and vein share a common adventitial sheath. The artery nearly always is anterior (innermost) to the vein.[30] It is postulated that a rigid, arteriosclerotic artery compresses the retinal vein, which results in turbulent blood flow and endothelial damage, followed by thrombosis and obstruction of the vein. Most branch retinal vein obstructions occur superotemporally, probably because this is where the highest concentration of arteriovenous crossings lie.

 

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Figure 115-5 Branch retinal vein obstruction. Fundus view of extensive retinal hemorrhages in segmental distribution of a superotemporal retinal vein. Dilated, tortuous veins, cotton-wool spots, and macular edema also can be seen.

Rarely, local ocular diseases, especially of an inflammatory nature, can result in a secondary branch retinal vein obstruction. This has been reported in diseases such as toxoplasmosis, Eales’ disease, Behçet’s syndrome, and ocular sarcoidosis. Also, macroaneurysms, Coats’ disease, retinal capillary hemangiomas, and optic disc drusen are linked to branch retinal vein obstruction. Glaucoma is also a risk factor for the development of branch retinal vein occlusion. Branch retinal vein occlusion is usually unilateral, with only 9% of patients having bilateral involvement.

OCULAR MANIFESTATIONS

Patients with branch retinal vein occlusion usually complain of sudden onset of blurred vision or a visual field defect. Retinal hemorrhages confined to the distribution of a retinal vein are characteristic for branch retinal vein obstruction ( Fig. 115-5 ). As a result of the distribution, the hemorrhages usually assume a triangular configuration with the apex at the site of blockage. Flame-shaped hemorrhages predominate. Mild obstructions are associated with a relatively small amount of hemorrhage. Complete obstructions result in extensive intraretinal hemorrhages, cotton-wool spot formation, and widespread capillary nonperfusion. If the macular region is involved, macular edema or hemorrhage occurs, which causes decreased visual acuity. Visual acuity may range from 20/20 (6/6) to counting fingers. If the macula is spared, a branch retinal vein obstruction may be asymptomatic, found only on routine examination of the fundus. Occasionally a partial branch retinal vein occlusion with little hemorrhage and edema may progress to a completely occluded vein, with an increase in hemorrhage and edema and a corresponding decrease in visual acuity. Retinal neovascularization occurs in approximately 20% of cases. The incidence of retinal neovascularization rises with increasing area of retinal nonperfusion. Retinal neovascularization typically develops within the first 6–12 months but may occur years later. Vitreous hemorrhage can ensue and may require vitrectomy. Anterior segment neovascularization rarely is seen in patients with branch retinal vein obstruction, unless other ischemic conditions co-exist (e.g., diabetes). With time, the dramatic picture of an acute branch retinal vein obstruction can become much more subtle. Hemorrhages fade with time so that the fundus can look almost normal. Collateral vessels and microvascular abnormalities develop to help drain the affected area. The collateral vessels often cross the horizontal raphe. Proximal to the site of blockage, the retinal vein may become sclerotic. The retinal

 

 

Figure 115-6 Branch retinal vein obstruction. Fluorescein angiography of the patient shown in Figure 115-4 . Marked hypofluorescence is present secondary to extensive hemorrhage in the distribution of a superotemporal branch vein. Vessel dilation, tortuosity, and staining is seen in the same distribution.

artery that feeds the affected zone may become narrowed and sheathed, as well. Microaneurysm formation occurs and lipid exudation may be present. Capillary nonperfusion is seen best in the later stages, after the hemorrhages have cleared. Epiretinal membrane and macular retinal pigment epithelial changes as a result of chronic cystoid macular edema sometimes are seen in the late phase of a branch retinal vein obstruction. Retinal detachment, either rhegmatogenous or tractional, is uncommon but may be seen. Exudative localized retinal detachment in the distribution of the branch retinal vein occlusion also is seen if there is severe ischemia.

DIAGNOSIS AND ANCILLARY TESTING

The diagnosis of an acute branch retinal vein obstruction is made by finding retinal hemorrhages in the distribution of an obstructed retinal vein. Usually the retinal vein is dilated and tortuous ( Fig. 115-6 ). The obstruction almost always occurs at an arteriovenous crossing site, with the artery anterior to the vein.[30]

Fluorescein angiography is a helpful adjunct for both establishment of the diagnosis and guidance for the treatment of branch retinal vein obstruction. Arteriolar filling is usually normal, but venous filling in the affected vessel usually is delayed in the acute phase. Hypofluorescence caused by hemorrhage and capillary nonperfusion are common findings, and dilated, tortuous capillaries are seen. Collateral vessels may cross the horizontal raphe. The retinal vessels, particularly the vein walls, may stain with fluorescein. Neovascular fronds may leak fluorescein profusely. In contrast, collateral vessels do not leak fluorescein. Retinal vessels, particularly the vein walls, may stain with fluorescein, especially at the site of the occlusion. Macular edema, which is noted clinically but not angiographically, may indicate ischemia. Classic petaloid cystoid macular edema may involve the entire fovea or just several clock hours, depending on the distribution of the obstruction.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of branch retinal vein obstructions is shown in Box 115-4 . Hypertensive retinopathy with marked arteriovenous crossing changes and retinal hemorrhages may look like a branch retinal vein occlusion. A chronic branch retinal vein obstruction with telangiectatic capillaries may be confused with juxtafoveal retinal telangiectasia. Asymmetrical diabetic retinopathy can have a picture similar to a branch vein obstruction or, conversely, obscure the diagnosis of a branch vein obstruction.

 

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SYSTEMIC ASSOCIATIONS

Hypertension is the condition most commonly associated with branch retinal vein obstruction. The Eye Disease Case Control Study clearly demonstrated the important association of hypertension with vein obstructions.[2] In that study, more than 50% of branch retinal vein obstructions were associated with hypertension. The study also found an association between vein obstructions and a history of cardiovascular disease, increased body mass index at 20 years of age, glaucoma, and higher serum levels of a2 -globulin. A reduced risk of branch retinal vein obstruction was found with alcohol consumption and increasing levels of high-density lipoprotein cholesterol levels.

PATHOLOGY

A histopathological study of nine branch vein occlusions showed a fresh or recanalized thrombus at the site of the vein occlusion in all eyes.[31] Ischemic atrophy of the retina was found in the distribution of the occlusion in most of the eyes. All eyes showed varied degrees of arteriosclerosis. No thrombus was noted in any of the arteries. Neovascularization of the disc and retina was noted in four eyes and cystoid macular edema was present in five.

TREATMENT

The Branch Vein Occlusion Study represented a major advance in the understanding of the treatments for two of the most significant complications of branch vein occlusions, namely macular edema and neovascularization.[27] [32] [33] The study found that a grid pattern laser treatment helped to reduce macular edema and improved visual acuity. In patients who have 20/40 (6/12) or worse vision and macular edema on fluorescein angiography,

 

 

Differential Diagnosis of Branch Retinal Vein Obstruction

Hypertensive retinopathy

 

Diabetic retinopathy

 

Ocular ischemic syndrome

 

Juxtafoveal retinal telangiectasia

 

Combined branch retinal artery and branch retinal vein occlusion

 

Radiation retinopathy

 

 

 

 

 

 

Figure 115-7 Branch retinal vein obstruction. Immediate posttreatment view of grid laser treatment for macular edema secondary to a branch retinal vein obstruction.

laser treatment improved the chances of a two-or-more–line improvement in vision on the Snellen chart when compared with untreated controls[32] [33] (65% versus 37%). Because visual acuity and macular edema may improve spontaneously, patients were not treated with laser for at least 3 months after the development of the vein obstruction, to allow for spontaneous improvement. Also, treatment was delayed if the intraretinal hemorrhage was too dense to allow either photocoagulation or adequate evaluation with fluorescein angiography. Patients who had hemorrhage directly in the fovea were excluded. A fluorescein angiogram less than 1 month old was used to guide treatment. A grid pattern of laser was applied to the area of capillary leakage ( Fig. 115-7 ).

Photocoagulation did not extend closer than the edge of the foveal avascular zone, nor did it extend peripherally beyond the major vascular arcades. The eyes were reevaluated with fluorescein angiography 4 months after treatment, and additional photocoagulation was applied if the vision remained poor and macular edema persisted. Most patients required only one treatment. Typically, a 100?µm spot size is used and medium-white burns, each of 0.1-second duration, are applied to the area of edema. In both treated and controlled groups, patients who had hypertension tended to respond less favorably to laser treatment.

The Branch Vein Occlusion Study Group also evaluated the efficacy and timing of sectorial PRP for retinal neovascularization and vitreous hemorrhage. [32] In patients with neovascularization treated with laser, only 29% developed vitreous hemorrhage, versus 61% of those untreated. The data showed no advantage with treatment before neovascularization occurred, even if extensive capillary nonperfusion existed. If laser is applied to all nonperfused branch retinal vein obstructions, a large percentage of patients will be treated unnecessarily ( Boxes 115-5 and 115-6 ). Fluorescein angiography can be helpful in guiding laser treatment, because it will help define areas of capillary nonperfusion. A scatter pattern of laser is performed in the affected sector. Typically, 500?µm–sized medium-white burns are applied, extending from the arcade out to the periphery. Fill-in PRP may be applied if neovascularization progresses or if vitreous hemorrhage

 

 

Treatment Guidelines for Branch Retinal Vein Occlusion and Macular Edema

 

FOR MACULAR EDEMA, VISUAL ACUITY OF 20/40 (6/12) OR WORSE

Wait for clearance of retinal hemorrhage to allow adequate fluorescein angiography

 

Determine if decreased visual acuity is caused by macular edema (versus macular nonperfusion)

 

If macular edema explains visual loss, and no spontaneous improvement has occurred by 3 months, grid macular photocoagulation is recommended

 

If capillary nonperfusion explains decreased visual acuity, laser treatment is not advised

 

 

 

 

 

 

 

Treatment Guidelines for Branch Retinal Vein Occlusion and Neovascularization

Good quality fluorescein angiography is obtained after retinal hemorrhages have cleared sufficiently.

 

If more than five disc diameters of nonperfusion are present, the patient should be followed at 4-month intervals to seek the development of neovascularization.

 

If neovascularization develops, panretinal photocoagulation to the involved retinal sector should be applied using argon laser to achieve “medium” white burns, 200–500?mm in diameter—one burn width apart to cover the entire involved segment.

 

 

 

 

 

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occurs. Vitreous surgery is employed occasionally for nonclearing vitreous hemorrhages, epiretinal membrane, or tractional retinal detachment with macular involvement. The outcomes are generally favorable, although preexisting pathology frequently limits recovery of good vision.[34]

COURSE AND OUTCOME

Without treatment, one third of patients who have branch retinal vein occlusion end up with visual acuity better than 20/40 (6/12). However, two thirds have decreased visual acuity secondary to macular edema, macular ischemia, macular hemorrhage, or vitreous hemorrhage. As noted above, laser treatment for macular edema significantly enhances the chance that the patient’s baseline visual acuity will improve by two lines (65% versus 37%). The mean number of lines of improvement in visual acuity averages 1.33 in treated patients versus 0.23 in the control group. Poor visual prognostic factors include advancing age, male sex, worse baseline visual acuity, and an increased number of risk factors.[35] Good prognosis is associated with a younger age, female sex, and fewer risk factors. Patients should be followed up every 3–4 months.

Approximately 20% of patients with branch retinal vein occlusion will develop neovascularization. Of these patients, about 60% will have episodic vitreous hemorrhages. Fortunately, laser treatment (sector PRP) can reduce this by one half to 30%.

NEW TREATMENTS FOR BRANCH RETINAL VEIN OCCLUSION

New treatments for branch retinal vein occlusion that are being evaluated include sheathotomy [36] [37] [38] and intravitreal steroid injection G triamcinolone for treatment of cystoid macular edema resulting from branch retinal vein occlusion.

 

 

REFERENCES

 

1. Hayreh SS, Zimmerman MB, Podhajsky P. Incidence of various types of retinal vein occlusion and their recurrence and demographic characteristics. Am J Ophthalmol. 1994;117:429–41.

 

2. The Eye Disease Case-Control Study Group. Risk factors for branch retinal vein occlusion. Am J Ophthalmol. 1993;116:286–96.

 

3. Zegarra H, Gutman FA, Conforto J. The natural course of central retinal vein occlusion. Ophthalmology. 1979;86:1931–8.

 

4. Rath EZ, Frank RN, Shin DH, Kim C. Risk factors for retinal vein occlusions. A case-control study. Ophthalmology. 1992;99:509–14.

 

5. Hayreh SS, Zimmerman B, McCarthy MJ, Podhajsky P. Systemic diseases associated with various types of retinal vein occlusion. Am J Ophthalmol. 2001;131:61–77.

 

6. Quinlan PM, Elman MJ, Bhatt AK, et al. The natural course of central retinal vein occlusion. Am J Ophthalmol. 1990;110:118–23.

 

7. Dhote R, Bachmeyer C, Orellou MH, et al. Central retinal vein thrombosis associated with resistance to activated protein C. Am J Ophthalmol. 1995;120:388–9.

 

8. Glacet-Bernard A, Chabanel A, Lelong F, et al. Elevated erythrocyte aggregation in patients with central retinal vein occlusion and without conventional risk factors. Ophthalmology. 1994;101:1483–7.

 

9. Vine, AK. Hyperhomocystinemia: a new risk factor for central retinal vein occlusion. Trans Am Ophthalmol Soc. 2000;98:453–503.

 

10. Hayreh SS. Retinal vein occlusion. Indian J Ophthalmol. 1994;42:109–32.

 

11. Hayreh SS. Classification of central retinal vein occlusion. Ophthalmology. 1983;90:458–74.

 

12. The Central Vein Occlusion Study Group. Natural history and clinical management of central retinal vein occlusion. Arch Ophthalmol. 1997;115:486–91.

 

13. Green WR, Chan CC, Hutchins GM, et al. Central retinal vein occlusion: a prospective histopathologic study of 29 eyes in 28 cases. Retina. 1981;1:27–55.

 

14. Fong ACO, Schatz H, McDonald HR, et al. Central retinal vein occlusion in young adults (papillophlebitis). Retina. 1991;11:3–11.

 

15. May DR, Klein ML, Peyman GA, et al. Xenon arc panretinal photocoagulation for central retinal vein occlusion: a randomized prospective study. Br J Ophthalmol. 1979;63:735–43.

 

16. Magargal LE, Brown GC, Augsburger JJ, et al. Neovascular glaucoma following central retinal vein obstruction. Ophthalmology. 1981;88:1095–101.

 

17. Sabates R, Hirose T, McMeel JW. Electroretinography in the prognosis and classification of central retinal vein occlusion. Arch Ophthalmol. 1983;101:232–5.

 

18. Barber C, Galloway NR, Reacher M, et al. The role of the electroretinogram in the management of central retinal vein occlusion. Doc Ophthalmol Proc Ser. 1984;40:149–59.

 

19. Central Vein Occlusion Study Group. Baseline and early natural history report: the Central Vein Occlusion Study. Arch Ophthalmol. 1993;11:1087–95.

 

20. Kearns TP. Differential diagnosis of central retinal vein obstruction. Ophthalmology. 1983;90:475–80.

 

21. Furlan AJ, Whisnant JP, Kearns TP. Unilateral visual loss in bright light; an unusual symptom of carotid artery occlusive disease. Arch Neurol. 1979;36:675–6.

 

22. Schwab PJ, Okun E, Fahey FL. Reversal of retinopathy in Waldenström’s macroglobulinemia by plasmapheresis. Arch Ophthalmol. 1960;64:515–21.

 

23. Gutman FA. Evaluation of a patient with central retinal vein occlusion. Ophthalmology. 1983;90:481–3.

 

24. Stowe GC, Zakov ZN, Albert DM. Central retinal vascular occlusion associated with oral contraceptives. Am J Ophthalmol. 1978;86:798–801.

 

25. The Central Vein Occlusion Study Group. A randomized clinical trial of early panretinal photocoagulation for ischemic central vein occlusion: the Central Vein Occlusion Study Group N Report. Ophthalmology. 1995;102:1434–44.

 

26. The Central Vein Occlusion Study Group. Evaluation of grid pattern photocoagulation for macular edema in central vein occlusion: the Central Vein Occlusion Study Group M Report. Ophthalmology. 1995;102:1425–33.

 

27. McAllister IL, Constable IJ. Laser-induced chorioretinal venous anastomosis for treatment of non-ischemic central retinal vein occlusion. Arch Ophthalmol. 1995;113:456–62.

 

28. Mitchell P, Smith W, Chang A. Prevalence and associations of retinal vein occlusion in Australia. Arch Ophthalmol. 1996;114:1243–7.

 

29. Hayreh SS, Zimmerman MMB, Podhajsky P. Incidence of various types of retinal vein occlusion and their recurrence in demographic characteristics. Am J Ophthalmol. 1994;117:429–41.

 

30. Duker JS, Brown GL. Anterior location of the crossing artery in branch retinal vein occlusion. Arch Ophthalmol. 1989;107:998–1000.

 

31. Frangieh GT, Green WR, Barraquer-Somers E, Finkelstein D. Histopathologic study of nine branch retinal vein occlusions. Arch Ophthalmol. 1982;100:1132–40.

 

32. Branch Vein Occlusion Study Group. Argon laser scatter photocoagulation for prevention of neovascularization and vitreous hemorrhage in branch vein occlusion. Arch Ophthalmol. 1986;104:34–41.

 

33. Finkelstein D. Argon laser photocoagulation for macular edema in branch vein occlusion. Ophthalmology. 1986;93:975–7.

 

34. Amirikia A, Sioh IV, Murray TG, et al. Outcomes of vitreoretinal surgery for complications of branch retinal vein occlusion. Ophthalmology. 2001;108:372–6.

 

35. Glacet-Bernard A, Coscas G, Chabanel A, et al. Prognostic factors for retinal vein occlusion. A prospective study of 175 cases. Ophthalmology. 1996;103:551–60.

 

36. Opremcak EM, Bruce RA. Surgical decompression of branch retinal vein occlusions via arteriovenous crossing sheathotomy: a prospective review of 15 cases. Retina. 1999;19:1–5.

 

37. Ostelah MD, Charles S. Surgical decompression of branch retinal vein occlusions. Arch Ophthalmol. 1998;106:1469–71.

 

38. Shah GK, Sharma S, Fineman MS, et al. Arteriovenous adventitial sheathotomy for the treatment of macular edema associated with branch retinal vein occlusion. Am J Ophthalmol. 2000;129:104–6.

Chapter 114 – Retinal Arterial Obstruction

Chapter 114 – Retinal Arterial Obstruction

 

JAY S. DUKER

 

 

 

 

Central Retinal Artery Obstruction

Branch Retinal Artery Obstruction

 

DEFINITION

• An abrupt diminution of blood flow through the central retinal artery severe enough to cause ischemia of the inner retina.

 

KEY FEATURES

• Abrupt, painless, severe loss of vision.

• Cherry-red spot.

• Box-carring of blood flow in the retinal vessels.

• Ischemic retinal whitening of the posterior pole.

 

ASSOCIATED FEATURES

• Amaurosis fugax.

• Visible embolus (25%).

• Carotid artery disease (33%).

• Giant cell arteritis (5%).

• Neovascularization of the iris (18%).

• Arterial collaterals on the optic disc.

 

DEFINITION

• An abrupt diminution of blood flow through a branch of the central retinal artery severe enough to cause ischemia of the inner retina in the territory of the affected vessel.

 

KEY FEATURES

• Retinal whitening in the territory of the obstructed vessel.

• Embolus (66%).

• Visual field defect that corresponds to the territory of the obstructed vessels.

 

ASSOCIATED FEATURES

• Carotid artery disease.

• Cardiac valvular disease.

• Cardiac myxoma, long-bone fracture, endocarditis, depot drug injection (rare).

• Systemic clotting disorder or vasculitis (rare).

 

 

 

CENTRAL RETINAL ARTERY OBSTRUCTION

INTRODUCTION

Retinal arterial obstructions are divided into the categories central and branch, depending on the precise site of obstruction. A central retinal artery obstruction occurs when the blockage is within the optic nerve substance itself and therefore the site of obstruction is generally not visible on ophthalmoscopy. A branch retinal artery obstruction occurs when the site of blockage is distal to the lamina cribrosa of the optic nerve.

Obstructions more proximal to the central retinal artery, in the ophthalmic artery, or even in the internal carotid artery may produce visual loss as well. Ophthalmic artery obstructions may be difficult to differentiate from central retinal artery obstruction. More proximal obstructions usually cause a more chronic form of visual problem—the ocular ischemic syndrome (see Chapter 118 ).

The majority of retinal arterial obstructions are either thrombotic or embolic in nature. The potential sources and various types of emboli generally do not differ between central retinal artery obstruction and branch retinal artery obstruction; however, a branch retinal artery obstruction is far more likely to be embolic than is a central retinal artery obstruction. It has been determined that over two thirds of branch retinal artery obstructions are caused by emboli, whereas probably less than one third of central retinal artery obstructions result from emboli.

The retina has a dual circulation with little to no anastomoses. The inner retina is supplied by the central retinal artery, which is an end artery. The outer retina receives its nourishment via diffusion from the choroidal circulation (see Chapter 101 ). Retinal artery obstructions selectively affect the inner retina only.

Because the accompanying visual loss tends to be severe and permanent, it is fortunate that retinal artery obstructions are rare occurrences. As there is a strong association with systemic disease, all patients who suffer retinal artery obstructions should undergo a systemic evaluation.

EPIDEMIOLOGY AND PATHOGENESIS

Central retinal artery obstruction is a rare event—it has been estimated to account for about 1 in 10,000 outpatient visits to the ophthalmologist. [1] Men are affected more commonly than women in the ratio 2:1. The mean age at onset is about 60 years, with a range of reported ages from the first to the ninth decade of life. Right eyes and left eyes appear affected with equal incidence. Bilateral involvement occurs in 1–2% of cases.

In central retinal artery obstruction, the site of obstruction is not usually visible on clinical examination and, in general, the central retinal artery is too small to image with most techniques; therefore, the precise cause is speculative. It is currently believed that the majority of central retinal artery obstructions are caused by thrombus formation at or just proximal to the lamina cribrosa. Atherosclerosis is implicated as the inciting event in most cases, although congenital anomalies of the central retinal artery, systemic coagulopathies, or low-flow states from more proximal arterial disease may also be present and render certain individuals more susceptible.

In only 20–25% of cases are emboli visible in the central retinal artery or one of its branches, suggesting that an embolic cause is not frequent. A more detailed discussion of embolus types is given later in the section on branch retinal artery obstruction.

 

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Further indirect evidence against emboli as a frequent cause of central retinal artery obstruction is the 40% or less probability of finding a definitive embolic source on systemic evaluation and the small incidence (approximately 10%) of confirmed associated ipsilateral cerebral emboli in affected patients.[2]

Inflammation in the form of vasculitis (e.g., varicella infection), optic neuritis, or even orbital disease (e.g., mucormycosis) may cause central retinal artery obstruction.[3] [4] Local trauma that results in direct damage to the optic nerve or blood vessels may lead to central retinal artery obstruction.[5] Arterial spasm or dissection rarely produces retinal arterial obstruction. In addition, systemic coagulopathies may be associated with both central and branch retinal artery obstructions.[6]

Other rare causes include radiation retinopathy,[7] emboli associated with depot medication injection around the eye,[8] optic disc drusen, and prepapillary arterial loops. Medical examinations and manipulations (e.g., carotid angiography, angioplasty, chiropractic neck manipulation) rarely result in emboli to the central retinal artery.[9] [10] Although elevated intraocular pressure has been implicated as a cause of central retinal artery obstruction, unless the underlying perfusion of the eye is impaired markedly or prolonged external pressure is placed on the globe, it is unlikely that intraocular pressure can be raised high enough to block arterial inflow to the eye.

OCULAR MANIFESTATIONS

The hallmark symptom of acute central retinal artery obstruction is abrupt, painless loss of vision.[11] Pain is unusual and suggests associated ocular ischemic syndrome. Amaurosis fugax precedes visual loss in about 10% of patients. Rarely, in cases associated with arterial spasm, a relapsing and remitting course of visual loss precedes central retinal artery obstruction.[12]

Examination typically reveals a visual acuity of 20/800 (6/240) or worse.[13] Hand motion or light perception vision can occur, but no light perception vision is uncommon except in the setting of an ophthalmic artery obstruction or temporal arteritis. If a patent cilioretinal artery is present and perfuses the fovea, normal central acuity may occur. An afferent pupillary defect on the affected side is the rule.

Anterior segment examination is normal except in the setting of concurrent ocular ischemic syndrome with neovascularization of the iris.

Within the first few minutes to hours after the obstruction, the fundus may appear relatively normal ( Fig. 114-1 , A and B). [1] Eventually, the decreased blood flow results in ischemic whitening of the retina in the territory of the obstructed artery, which is most pronounced in the posterior pole (where the nerve fiber

 

 

 

 

 

 

Figure 114-1 The left eye of a healthy 37-year-old man. The patient had a 3-hour history of visual loss and a visual acuity of 20/60 (6/18). A, Retinal whitening is very subtle and the retinal vessels appear normal. B, Fluorescein angiography reveals abnormal arterial filling with a leading edge of dye that confirms central retinal artery obstruction. C, The same eye 24 hours later. Despite intravenous urokinase, visual acuity dropped to hand movements, and intense retinal whitening with a cherry-red spot is present. Note the interruption in the blood column of the retinal arteries.

layer of the retina is thickest). Acutely, the arteries appear thin and attenuated. In severe blockages, both veins and arteries may manifest “box-carring” or segmentation of the blood flow ( Fig. 114-2 ).

A cherry-red spot of the macula is typical and arises in this area because the nerve fiber layer is thin. Transmission of the normal choroidal appearance, therefore, is not diminished, which contrasts distinctly with the surrounding area of intense retinal whitening that blocks transmission of the normal choroidal coloration. Although other conditions may be associated with a macular cherry-red spot ( Box 114-1 ), these are usually differentiated easily from central retinal artery obstruction. Splinter retinal hemorrhages on the disc are common, but more extensive retinal hemorrhaging suggests an alternative diagnosis. If pallid swelling is present, temporal arteritis must be suspected. A patent cilioretinal artery results in a small area of retina that appears normal ( Fig. 114-3 ).

By 4–6 weeks after obstruction, the retinal whitening is usually resolved, the optic disc develops pallor, and arterial collaterals may form on the optic disc. No foveolar light reflex is apparent, and fine changes in the retinal pigment epithelium may be visible.

Secondary ocular neovascularization is not uncommon after central retinal artery obstruction. Iris neovascularization occurs in about 18% of patients,[14] [15] with many of these eyes going on to neovascular glaucoma. Panretinal photocoagulation appears to reduce the risk of neovascular glaucoma moderately.[16] Neovascularization of the optic disc occurs after about 2% of

 

 

Figure 114-2 Central retinal artery obstruction. The right eye of a 68-year-old woman. Note box-carring of the blood column in the superotemporal arteries and superior veins. Cilioretinal artery sparing is apparent just temporal to the optic disc.

 

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Figure 114-3 A central retinal artery obstruction. A prominent cherry-red spot with cilioretinal artery sparing in the papillomacular bundle.

 

 

 

Other Causes of a Cherry-Red Spot

Tay–Sachs disease

 

Farber’s disease

 

Sandhoff’s disease

 

Niemann–Pick disease

 

Goldberg’s syndrome

 

Gaucher’s disease

 

Gangliosidase GM1, type 2

 

Hurler’s syndrome (mucopolysaccharidosis I H)

 

ß-Galactosidase deficiency (mucopolysaccharidosis VII)

 

Hallevorden-Spatz disease

 

Batten–Mayou–Vogt–Spielmeyer disease

 

 

 

 

central retinal artery obstruction ( Fig. 114-4 ).[17] Vitreous hemorrhage may ensue.

DIAGNOSIS AND ANCILLARY TESTING

Diagnosis of central retinal artery obstruction is straightforward when diffuse ischemic retinal whitening is present in the setting of abrupt, painless visual loss. Fluorescein angiography may help if the diagnosis is in doubt. A delayed arm-to-retina time with a leading edge of dye visible in the retinal arteries is typical (see Fig. 114-1 , B). In some cases, it may be minutes before the retinal arterial tree fills with fluorescein. Arteriovenous transit is delayed as well, and late staining of the disc is common.

Electroretinography characteristically reveals a decreased to absent b-wave with intact a-wave. Visual fields show a remaining temporal island of peripheral vision. If a patent cilioretinal artery is present, a small intact central island is found as well.

Color Doppler imaging is a form of ultrasonography that can help to determine the blood flow characteristics of the retrobulbar circulation. Color Doppler studies of acute central retinal artery obstruction show diminished to absent blood flow velocity in the central retinal artery, generally with intact flow in the ophthalmic and choroidal branches. Color Doppler imaging can be used to detect calcific emboli at the lamina cribrosa and also may be used to monitor blood flow changes induced by therapy. In addition, carotid artery studies may be carried out concurrently with ocular blood flow determinations to evaluate the possible causes of the central retinal artery obstruction.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of central retinal artery obstruction is given in Box 114-2 .

 

 

 

 

Figure 114-4 A 26-year-old diabetic man. A, Central retinal artery obstruction caused by a platelet-fibrin embolus. B, After 3 months, extensive neovascularization of the disc is present. (Courtesy of Larry Magargal, MD.)

 

 

 

Differential Diagnosis of Central Retinal Artery Obstruction

Single or multiple branch retinal artery obstruction

 

Cilioretinal artery obstruction

 

Severe commotio retinae

 

Necrotizing herpetic retinitis

 

 

 

 

SYSTEMIC ASSOCIATIONS

Although systemic diseases are found commonly in patients who suffer from retinal artery obstruction, the true cause and effect may not be clear. About 60% of patients have concurrent systemic arterial hypertension, and diabetes is present in 25%. Systemic evaluation reveals no definite cause for the obstruction in over 50% of affected patients. Potential embolic sources are found in less than 40% of cases.[1] [14] [18]

The most common pathogenetic association uncovered is hemodynamically significant ipsilateral carotid artery disease, which is present in about one third of affected patients.[1] [14] Carotid noninvasive testing should be considered for all patients who have central retinal artery obstruction, although disease in those younger than 50 years of age is quite rare ( Fig. 114-5 ). An embolic source from the heart is present in less than 10% of patients with central retinal artery obstruction; however, echocardiography and Holter monitoring should be performed, especially in younger patients. In some cases, transesophageal echocardiography is necessary to reveal embolic sources.[19]

Even though it is present in less than 5% of cases, it is of paramount importance that temporal arteritis be ruled out in all patients older than 50 years who have a central retinal artery obstruction.

 

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Figure 114-5 Acute central retinal artery obstruction. Secondary to an embolus at the lamina cribrosa. Note two other emboli in the superior retinal vessels. Ipsilateral carotid artery disease was present.

 

 

 

Systemic Conditions Associated with Retinal Artery Obstructions

 

ATHEROSCLEROTIC CARDIOVASCULAR DISEASE

Ophthalmic artery plaques, stenosis,

 

or dissection

 

Carotid artery plaques, stenosis,

 

or dissection

 

Aortic plaques, stenosis, or dissection

 

 

CARDIAC

Valvular disease (including

 

rheumatic fever)

 

Ventriculoseptal defects

 

Papillary fibroelastoma

 

Cardiac myxoma

 

Mural thrombus

 

Arrhythmias

 

Subacute bacterial endocarditis

 

 

COAGULOPATHIES

Antiphospholipid antibodies

 

Protein C deficiency

 

Protein S deficiency

 

Antithrombin III deficiency

 

Elevation of platelet factor 4

 

 

ONCOLOGIC

Metastatic tumors

 

Leukemia

 

Lymphoma

 

 

RADIOLOGIC AND MEDICAL PROCEDURES

Angiography

 

Angioplasty

 

Chiropractic neck manipulation

 

Depot corticosteroid injection

 

 

SYSTEMIC VASCULITIS

Susac’s disease

 

Systemic lupus erythematosus

 

Polyarteritis nodosa

 

Temporal arteritis

 

Sneddon–Wilkinson disease

 

Wegener’s granulomatosis

 

Inflammatory bowel disease

 

Kawasaki’s syndrome

 

 

SYSTEMIC INFECTIONS

Syphilis

 

Mediterranean spotted fever

 

Loiasis

 

 

LOCAL TRAUMA

Direct ocular compression

 

Penetrating injury

 

Retrobulbar injection

 

Orbital trauma

 

Retrobulbar hemorrhage

 

Purtscher’s disease

 

 

LOCAL OCULAR

Prepapillary arterial loops

 

Optic nerve drusen

 

Necrotizing herpetic retinitis

 

Orbital mucormycosis

 

Toxoplasmosis

 

 

MISCELLANEOUS

Amniotic fluid embolism

 

Pancreatitis

 

Migraine

 

Pregnancy

 

Oral contraceptives

 

Cocaine abuse

 

Intravenous drug use

 

 

 

 

An immediate erythrocyte sedimentation rate must be obtained, and if it is elevated or if clinical suspicion exists, corticosteroid therapy and a temporal artery biopsy should be considered.

Other rare associated systemic diseases include blood-clotting abnormalities such as antiphospholipid antibodies, protein S deficiency, protein C deficiency, and antithrombin III deficiency.[20] [21] A list of systemic associations for retinal artery obstructions is given in Box 114-3 .

 

 

 

 

Figure 114-6 Central retinal artery occlusion. A, A trichrome-stained section shows an organized thrombus (T) that occludes the central retinal artery within the optic nerve (V, vein). B, A histological section at the early stage shows edema of the inner neural retinal layers and ganglion cell nuclei pyknosis. Patient had a cherry-red spot in fovea at time of enucleation. IM, Internal limiting membrane; IN, inner nuclear layer; NG, swollen nerve fiber and ganglion layers; ON, outer nuclear layer; OP, outer plexiform layer; PR, photoreceptors. (From Yanoff M, Fine BS. Ocular pathology, ed 5. St. Louis: Mosby, 2002.)

PATHOLOGY

Histopathological examination shows coagulative necrosis of the inner retina. Acute, early, intracellular edema is followed by complete loss of the inner retinal tissue. Chronically, a diffuse acellular zone replaces the nerve fiber layer, ganglion cell layer, and inner plexiform layer. The outer retinal cells remain relatively intact. Sections of the obstructed central retinal artery may reveal a thrombus or embolus that is often recanalized ( Fig. 114-6 ).

TREATMENT

No proved treatment exists for central retinal artery obstruction, but treatment strategies center around the following goals:

• Increase retinal oxygenation

• Increase retinal arterial blood flow

• Reverse arterial obstruction,

• Prevent hypoxic retinal damage

Theoretically, retinal oxygenation can be increased by breathing carbogen (95% oxygen, 5% carbon dioxide). Investigationally, the high concentration of oxygen has been shown to elevate oxygen tension at the inner retina via diffusion through the intact choroidal circulation. The carbon dioxide prevents the normal retinal autoregulatory mechanisms from inducing constriction of the retinal arteries. No clinical study indicates efficacy for carbogen therapy, and one retrospective study suggests that it has no beneficial effect.[22] In most centers, it is no longer used.

 

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An increase in retinal arterial blood flow is attempted by lowering intraocular pressure. This is accomplished by ocular massage, paracentesis, and the administration of ocular antihypertensive medications. Medical attempts to dilate retinal arteries or block vascular spasm have been tried as well. Sublingual nitroglycerin, pentoxifylline (oxpentifylline), calcium channel blockers, and ß-blockers have all been used with no proof of efficacy.[11] [23]

Reversal of arterial obstruction through the use of anticoagulation and fibrinolytic mediations has been reported. To date, the utility of these mediations has not been proved by controlled clinical trials; however, anecdotal reports of success with intravenous heparin, tissue plasminogen activator, streptokinase, and urokinase exist. In addition, an intra-arterial injection of tissue plasminogen activator, streptokinase, or urokinase during selective catheterization of the ophthalmic artery has been attempted, with reported success in some selected cases.[24] [25]

At present, prevention of hypoxic damage to the retina is only theoretically possible.[26] Antioxidant medications (e.g., superoxide dismutase) and N-methyl-D-aspartate (NDMA) inhibitors are two classes of compounds that may accomplish retinal rescue pharmacologically and are under study.

Cases of central retinal artery obstruction associated with temporal arteritis are treated emergently with high-dose corticosteroids. Without therapy, the risk to the second eye is great. Although the first-affected eye rarely recovers, instances exist in which high-dose intravenous methylprednisolone induced visual recovery from central retinal artery obstruction associated with temporal arteritis. [27]

COURSE AND OUTCOME

Most central retinal artery obstructions result in severe, permanent loss of vision. About one third of patients experience some improvement in final vision in terms of presentation acuity, either with or without conventional treatment. Three or more Snellen lines of improved visual acuity occur in only about 10% of patients, whether treated by current methods or untreated. On occasion, some patients experience significant restoration of normal vision.

Experimentally, if an obstruction exists in the primate retina for more than 100 minutes, complete irreversible death of the inner retina occurs. [28] In practice, a rare patient has experienced total spontaneous recovery even after several days of documented visual loss.[29] Spontaneous recovery may be more common in young children.[6] [8]

BRANCH RETINAL ARTERY OBSTRUCTION

INTRODUCTION

Branch retinal artery obstruction represents a rarely encountered retinal vascular disorder. Although current treatments are not effective, in the majority of cases the source of the obstruction can be determined. As associated systemic implications occur, diagnosis and systemic evaluation of these patients are critical.

EPIDEMIOLOGY AND PATHOGENESIS

Branch retinal artery obstruction is a rare event, even less common than central retinal artery obstruction overall. The exception to this comparative incidence is with young patients, in whom branch retinal artery obstruction is the more common type of retinal artery obstruction.[30] Overall, men are more affected than women by a 2:1 ratio, which reflects the higher incidence of vasculopathic disease in men. In the subset of young patients (less than 50 years of age), women and men are affected equally. The mean age of affected patients is 60 years, with a range from the second decade of life to the tenth. The great majority of patients are in the sixth or seventh decade of life. The right eye (60%) is affected more commonly than the left (40%), which probably reflects the greater possibility of cardiac or aortic emboli traveling to the right carotid artery.[11] Branch retinal artery obstruction strikes the temporal retinal circulation far more frequently than the nasal, consistent with the greater blood flow to the macular retina.

Over two thirds of branch retinal artery obstructions are secondary to emboli to the retinal circulation.[1] [11] [31] In most cases, the emboli are clearly visible in the arterial tree. Emboli to the retinal circulation may originate at any point in the proximal circulation from the heart to the ophthalmic artery. Risk factors reflect the vasculopathic mechanisms that produce disease within the cardiovascular system. These include predisposing family history, hypertension, elevated lipid levels, cigarette smoking, and diabetes mellitus.

Three main types of retinal emboli have been identified:

• Cholesterol (Hollenhorst plaque)

• Platelet-fibrin

• Calcific.

Cholesterol emboli typically emanate from atheromatous plaques of the ipsilateral carotid artery system, although the aorta or heart valves may also be a source. They are yellow-orange in color, refractile, and globular or rectangular in shape. They may be small and do not always result in blockage of blood flow. Platelet-fibrin emboli are long, smooth, white-colored, intra-arterial plugs that may be mobile or break up over time. Usually, they are associated with carotid or cardiac thromboses. Calcific emboli are solid, white, nonrefractile plugs associated with calcification of heart valves or the aorta.

Less commonly seen embolic types include tumor cells from atrial myxoma[32] or a systemic metastasis, septic emboli associated with septicemia or endocarditis, fat emboli associated with large bone fractures, emboli dislodged during angioplasty or angiography, and depot drug preparations from intra-arterial injections around the eye or face.

Rarely, local ocular conditions produce branch retinal artery obstruction. These include inflammatory diseases, such as toxoplasmosis or acute retinal necrosis, or structural problems, such as optic disc drusen or prepapillary arterial loops.[1] [11]

Systemic hematological or clotting problems may induce isolated branch retinal artery obstruction or even multiple recurrent branch retinal artery obstruction.[33] [34] Systemic vasculitides, such as polyarteritis nodosa or local vasculitis associated with varicella infection, may be associated with branch retinal artery obstruction. Oral contraceptive use and cigarette smoking have been implicated as possible risk factors, especially in young, otherwise healthy women.[18] [30]

OCULAR MANIFESTATIONS

Abrupt, painless loss of vision in the visual field corresponding to the territory of the obstructed artery is the typical history of presentation. Unlike the situation in retinal venous obstruction, patients can typically define the time and extent of visual loss precisely. Amaurosis fugax occurs in about one fourth of patients prior to frank obstruction, especially in the setting of carotid disease. Rarely, patients develop bilateral simultaneous branch retinal artery obstruction, which can mimic homonymous field defects.

Acutely, examination reveals intact central acuity in about 50% of patients. A relative afferent pupillary defect is common, the presence of which is determined by the extent of retinal involvement.

Retinal whitening that corresponds to the areas of ischemia is the most notable finding. The whitening stops at adjacent retinal veins, as these vessels mark the extent of the territory of the retinal arteries ( Fig. 114-7 ). Retinal emboli are seen in over two thirds of branch retinal artery obstructions. Flame hemorrhages at the margins of the retinal ischemia are not uncommon, and

 

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Figure 114-7 Superior hemispheric branch retinal artery obstruction. The site of obstruction is probably within the optic nerve substance itself. Note that the dual trunk of the central retinal artery obstruction has separated proximal to the lamina. Only the superior trunk was affected.

 

 

 

Differential Diagnosis of Branch Retinal Artery Obstruction

Cotton-wool spot(s)

 

Central retinal artery obstruction

 

Cilioretinal artery obstruction

 

Retinal astrocytoma

 

Inflammatory or infectious retinitis

 

 

 

 

local areas of more intense inner retinal whitening that resemble scattered cotton-wool spots can develop.

A syndrome of multiple, recurrent, bilateral branch retinal artery obstruction in young, otherwise healthy patients has been reported. A few of the patients also manifest vestibuloauditory symptoms.[35] Although the underlying pathology in this subset of patients is probably heterogeneous, some probably have Susac’s syndrome, a rare disorder that manifests as a microangiopathy of the central nervous system. Others probably have various types of systemic clotting abnormalities.[36]

In the chronic phase, when the retinal whitening has diminished, a loss of the nerve fiber layer in the affected area may be apparent. In most instances, the affected retina appears normal. At the site of obstruction, localized sheathing of the arteriole is common. Arteriolar collaterals on the optic disc or at the site of obstruction may develop.

DIAGNOSIS AND ANCILLARY TESTING

Ancillary testing is not usually necessary to make the diagnosis. Fluorescein angiography reveals an abrupt diminution in dye at the site of the obstruction and distally. Filling in the adjacent retinal veins is slow to absent, and late staining or even leakage from the embolus site may occur.

Visual field testing can confirm the extent of visual loss and may pick up contralateral field loss from previous emboli or other associated conditions.

DIFFERENTIAL DIAGNOSIS

The differential diagnosis of branch retinal artery obstruction is given in Box 114-4 .

SYSTEMIC ASSOCIATIONS

Systemic evaluation of patients who have branch retinal artery obstruction discloses evidence of an embolic source from the carotid arteries or the heart in many cases. Other rare systemic conditions associated with branch retinal artery obstruction include

 

 

Figure 114-8 Cytoid body formation in neural retinal nerve fiber layer. Histological counterpart of the clinical cotton-wool spot. (From Yanoff M, Fine BS. Ocular pathology, ed 5. St. Louis: Mosby, 2002.)

amniotic fluid embolism, pancreatitis, sickle cell disease, homocystinuria, and Kawasaki disease. Young patients, especially those who have multiple or recurrent branch retinal artery obstruction, should be evaluated for systemic clotting abnormalities such as protein S deficiency, protein C deficiency, antithrombin III deficiency, platelet abnormalities (“sticky platelet syndrome”), and antiphospholipid antibodies.

Branch retinal artery obstruction associated with temporal arteritis is exceedingly uncommon.[37] It is not usually necessary to obtain an erythrocyte sedimentation rate unless other evidence of temporal arteritis exists. Box 114-3 lists the systemic conditions most commonly associated with retinal artery obstructions.

PATHOLOGY

Early, coagulative necrosis of the inner layers of the neural retina, which are supplied by the retinal arterioles, is manifest by edema of the neuronal cells during the first few hours after arterial occlusion and becomes maximal within 24 hours. The intracellular swelling accounts for the gray, retinal opacity seen clinically. If the area of coagulative necrosis is small and localized, it appears as a cotton-wool spot, the clinical manifestation of a microinfarct of the nerve fiber layer of the neural retina. The cytoid body observed microscopically ( Fig. 114-8 ) is a swollen, interrupted axon in the neural retinal nerve fiber layer. Histologically, the swollen end bulb superficially resembles a cell, hence the term cytoid body. A collection of many cytoid bodies, along with localized edema, marks the area of the microinfarct. A cotton-wool spot represents a localized accumulation of axoplasmic debris in the neural retinal nerve fiber layer and results from interruption of the orthograde or retrograde organelle transport in ganglion cell axons, that is, obstruction of axoplasmic flow.

The outer half of the neural retina is well preserved. The inner half of the neural retina, however, becomes “homogenized” into a diffuse, relatively acellular zone, which generally contains thick-walled retinal blood vessels. Because the glial cells die along with the other neural retinal elements, gliosis does not occur.

TREATMENT

No proved treatment exists for branch retinal artery obstruction. Because the visual prognosis is much better for branch retinal artery obstruction than for central retinal artery obstruction, invasive therapeutic maneuvers of dubious utility are not typically performed. On occasion, ocular massage or paracentesis is successful in dislodging an embolus. Laser photocoagulation has been employed to “melt” an embolus, without improvement in the vision.[38]

One report suggests that hyperbaric oxygen therapy may improve the visual loss associated with multiple branch retinal artery obstruction in Susac’s syndrome.[39]

 

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In the rare patient who has branch retinal artery obstruction accompanied by a systemic clotting disorder, systemic anticoagulation may prevent further events.

COURSE AND OUTCOME

Most patients remain with a fixed visual field defect but intact central acuity. About 80% of eyes recover to 20/40 (6/12) or better central acuity. Retinal neovascularization has been reported but is distinctly uncommon. Iris neovascularization does not occur.[11]

OPHTHALMIC ARTERY OBSTRUCTION

Acute simultaneous obstruction of both the retinal and choroidal circulations is referred to as an ophthalmic artery obstruction. In some cases a single site of blockage in the ophthalmic artery is present, and in others simultaneous interruption of the retinal and posterior choroidal circulations with multiple blockage sites is found.

Ophthalmic artery obstructions can be differentiated clinically from central retinal artery obstruction by the following features[40] :

• Severe visual loss—bare or no light perception;

• Intense ischemic retinal whitening that extends beyond the macular area;

• Little to no cherry-red spot;

• Marked choroidal perfusion defects on fluorescein angiography;

• Nonrecordable electroretinogram; and

• Late retinal pigment epithelium alterations.

Cases of ophthalmic artery obstruction usually have associated local orbital or systemic diseases, which include orbital mucormycosis, orbital trauma, retrobulbar anesthesia, depot corticosteroid injection, atrial myxoma, or carotid artery disease. Temporal arteritis usually does not produce ophthalmic artery obstruction in the absence of ipsilateral ischemic optic neuropathy.

As with central retinal artery obstruction, no proved therapy exists and significant visual recovery usually does not occur. In the absence of local causes, systemic evaluation must include testing for temporal arteritis, carotid artery disease, and cardiac disease.

CILIORETINAL ARTERY OBSTRUCTION

A cilioretinal artery exists in about 30% of individuals. It is a vessel that perfuses the retina and is derived directly from the posterior ciliary circulation rather than from the central retinal artery. For this reason, it may remain patent in the setting of a central retinal artery obstruction. Such vessels are usually observed to emanate from the temporal disc margin. They may be multiple and can also perfuse the nasal retina. On fluorescein angiography, they fill 1–3 seconds prior to the retinal circulation. Cilioretinal artery obstruction exists in three clinical variations:

• Isolated

• Cilioretinal artery obstruction combined with central retinal vein obstruction

• Cilioretinal artery obstruction combined with ischemic optic neuropathy

Isolated cilioretinal artery obstructions usually occur in young patients in the setting of collagen vascular disorders. They carry a good visual prognosis, with 90% of eyes left with 20/40 (6/12) or better vision.[41]

Cilioretinal artery obstruction combined with central retinal vein obstruction is not an uncommon variant in young patients ( Fig. 114-9 ). It generally behaves as a nonischemic central retinal vein obstruction with a good central visual prognosis. The scotoma from the artery obstruction is usually permanent. Although the mechanism of this association is unclear, it is hypothesized that some eyes harbor a primary optic disc vasculitis (papillophlebitis) that affects both the arterial and venous circulation.[42] It is more common in men than in women and patients

 

 

Figure 114-9 Cilioretinal artery obstruction. In conjunction with mild nonischemic central retinal vein obstruction. Note the retinal whitening just inferior to the fovea in the distribution of the cilioretinal artery.

 

 

Figure 114-10 Combined central retinal artery obstruction and central retinal vein obstruction. Visual acuity in this 21-year-old woman who had lupus was light perception, and neovascularization of the iris ensued.

are generally healthy; however, this entity has been seen in conjunction with inflammatory bowel disease and leukemia.

In contrast to the first two groups discussed before, cilioretinal artery obstruction with ischemic optic neuropathy carries a grim visual prognosis and a strong association with temporal arteritis.

COMBINED ARTERY AND VEIN OBSTRUCTIONS

Central retinal artery obstruction combined with simultaneous central retinal vein obstruction rarely occurs. Such patients present with acute, severe loss of vision, usually to bare or no light perception. Examination shows a cherry-red spot combined with features of a central retinal vein obstruction, which include dilated, tortuous veins that have retinal hemorrhages in all four quadrants ( Fig. 114-10 ).[43] Associated systemic or local disease is the rule—collagen vascular disorders, leukemia, orbital trauma, retrobulbar injections, and mucormycosis have been implicated. The visual prognosis is generally poor and the risk of neovascularization of the iris is about 75%. Exceptionally, a patient may manifest spontaneous improvement. [44]

Branch retinal artery obstruction combined with simultaneous central retinal vein obstruction has also been reported.[45] This rare entity behaves as a central retinal vein obstruction. Neovascularization of the iris is possible, but systemic associations other than hypertension and diabetes have not been confirmed.

 

 

REFERENCES

 

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