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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.

 

 

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

 

 

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