Retinitis Pigmentosa and Retinal Neovascularization ALAN E. ULISS, MD, ZDENEK J. GREGOR, FRCS, ALAN C. BIRD, MD, FRCS

Abstract: Four patients with retinitis pigmentosa and either disc or peripheral retinal neovascularization with recurrent vitreous hemorrhage are described. One patient with peripheral retinal neovascularization also had rubeosis and neovascular glaucoma. The effects of relative hyperoxia on the retinal micro­circulation in retinitis pigmentosa as well as intraocular inflammation may account for such changes. Laser photocoagulation appears effective in preventing vit­reous hemorrhage in these patients, but systemic administration of cortico­steroids did not cause the new vessels to regress. [Key words: retinal neovas­cularization, retinitis pigmentosa.] Ophthalmology 93:1599-1603,1986

Retinal vascular changes in association with retinitis pigmentosa has been previously reported including dis­ordered permeability of retinal capillaries, cystoid macular edema, and Coats'-like retinal vascular abnormalities with subretinal exudation and retinal detachment. 1-9 However, unlike typical Coats' syndrome, such vascular abnormal­ities are bilateral, show no sex predilection and appear to affect older individuals. Peripheral vascular retinopathy characterized by perivenous accumulation of fluorescein in the temporal periphery has also been reported, but iso­lated disc neovascularization, or peripheral retinal neo­vascularization, has not been reported. 7

We describe four patients who demonstrate an asso­ciation between disc neovascularization and/or peripheral retinal neovascularization with recurrent vitreous hem­orrhage and retinitis pigmentosa.

METHODS

Patients with retinitis pigmentosa who showed evidence of retinal and/or disc neovascularization on fluorescein angiography were reviewed from the records of the Ge­netic Clinic and Retinal Diagnostic Department at Moor­fields Eye Hospital. Four such patients were recalled for further examination.

From the Department of Oinical Ophthalmology, Institute of Ophthalmology, Moorfields Eye Hospital, London, England.

Alan Uliss was a Glorney-Raisbeck Fellow of the New York Acaderny of Medicine during this study.

Reprint requests to Alan E. Uliss, MD, Departrnent of Ophthalmology, Montefiore Medical Center, 111 East 210th Street, Bronx, NY 10467.

The diagnosis of retinitis pigmentosa was established by typical fundus changes and visual field constriction. Electroretinography was performed on all of our patients. The patients recalled were given a general ophthalmic examination, noting their visual acuity, visual field, vit­reous, and fundus changes. Systemic evaluation, including immunologic surveys and fluorescein angiography, was performed.

CASE REPORTS

CASE 1

A 23-year-old woman, whose autosomal dominantly inherited retinitis pigmentosa was diagnosed at age 7, first complained of blurred vision in the right eye in June 1980. She was found to have disc neovascularization and a preretinal hemorrhage, which broke through into the vitreous in that eye. New vessels devel­oped subsequently on the optic disc of the left eye, and she was referred to Moorfields Retinal Diagnostic Department in March 1981 for further evaluation and management.

At this time, her visual acuities were 6/18 with the right eye and 6/24 with the left eye. Both anterior segments were free of inflammatory activity, but the vitreous of each eye contained cells and there was bilateral intragel vitreous hemorrhage. Results from the funduscopic examination revealed arteriolar narrowing and 'bone corpuscular' pigmentation of both retinae. Focal areas of disc neovascularization extended towards the macular regions from the temporal discs in both eyes (Fig 1). Examination of the peripheral fundus showed no retinal holes, tears, retinal te­langiectasis, or subretinal exudation. There was no rubeosis nor peripheral retinal neovascularization present in either eye.

Biochemical, hematologic, and immunologic investigations were all unremarkable. Her affected mother was examined but she had neither disc nor peripheral retinal neovascularization.

She was treated initially with a short trial of systemic steroids

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(prednisolone 60 mg/day for 1 month), which had no observable effect on the disc neovascularization. Argon laser panretinal photocoagulation was performed in the right eye after a recurrent vitreous hemorrhage in that eye in 1982. No further hemorrhage has occurred after treatment of the right eye, and the disc neo­vascularization has regressed. She has recently undergone kryp­ton laser photocoagulation for the disc neovascularization in the left eye. Her visual acuities are maintained at pretreatment levels (6/18, right eye; 6/24, left eye).

CASE 2

This 34-year-old white housewife presented to the Retinal Diagnostic Department of Moorfields Eye Hospital in August 1984. Although nyctalopia first became apparent in childhood, the diagnosis of retinitis pigmentosa was not established until the age of 31 when typical visual field constriction and pigmen­tary degeneration were noticed. Progressive visual difficulty in both eyes had ensued. Only her two brothers had retinitis pig­mentosa, which was suggestive of a recessive multiplex inheri­tance pattern, but the specific mode of inheritance could not be ascertained.

At the time of presentation, her visual acuity was 6/9 with the right eye and 6/18 with the left. Both anterior segments were free of inflammation, but the vitreous of each eye contained erythrocytes and leukocytes. There was bilateral intragel vitreous hemorrhage, more pronounced in the left eye. On funduscopic examination, arteriolar narrowing and typical 'bone corpuscular' pigmentation involving both retinae were seen along with focal areas of neovascularization associated with vessel sheathing and fibrosis in the inferior mid-peripheral retina in both eyes. No retinal holes, tears, or localized exudative retinal detachments were present. There was no rubeosis nor disc new vessels present in either eye.

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Fig 1. Case 1. Fluorescein angiogram of the left poste­rior pole demonstrates dye leakage from new vessels ex­tending from the temporal margin of the optic disc.

Fluorescein angiography demonstrated marked peripheral retinal capillary nonperfusion. There was peripheral neovascu­larization (Fig 2, 1 arrow) in addition to Coats'-like telangiectasia (Fig 2, 2 arrows) with marked leakage of eye into the vitreous during the late stages of the angiogram.

Systemic investigation including biochemical, serological, he­matologic, and immunologic investigations were all unremark­able. Her affected siblings were examined and neither had retinal neovascularization.

She was treated initially with a one-month trial of systemic steroids (prednisolone 40 mg/day), which had no observable ef­fect on the peripheral neovascularization. Argon laser photo­coagulation of the retinal periphery surrounding the areas of neovascularization was begun but recurrent vitreous hemorrhage precluded further laser treatment. Therefore, peripheral cryopexy was performed to the areas of neovascularization. After treat­ment, no further hemorrhages have occurred, the peripheral neovascular complex has regressed and her visual acuities are maintained at the pre-treatment level.

CASE 3

In this 34-year-old white male with an autosomal dominant family history of retinitis pigmentosa, nyctalopia was noticed at the age of 14. His central vision had been maintained until July 1984 when an intragel vitreous hemorrhage developed in the right eye. At presentation, his visual acuity was 6/12 with the right eye and 6/9 with the left. On funduscopic examination, there were dilated peripheral retinal vessels and a surrounding intraretinal hemorrhage in the superotemporal quadrant of the right eye. Fluorescein angiography demonstrated peripheral capillary closure and new vessel formation with marked leakage of dye. The hemorrhage slowly cleared on bed rest, but the pe­ripheral neovascular complex persisted.

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Fig 2. Case 2. Fluorescein angiogram of the left eye demonstrates dye leakage from a frond of peripheral neovascularization (right ar­row). Notice peripheral cap­illary nonperfusion and reti­nal telangiectasis (2 arrows).

He returned in January 1985 with a second vitreous hemor­rhage in the right eye. Fluorescein angiography demonstrated early leakage from focal areas of peripheral neovascularization in the superotemporal quadrant as well as diffuse posterior pole edema. He was given a one-month trial of systemic steroids (prednisolone 60 mg/day) with SUbjective improvement of cen­tral vision (6/12, right eye; 6/9, left eye) and recently underwent krypton laser photocoagulation of the peripheral retinal neo­vascularization in the superotemporal quadrant of the right eye. However, to date, the peripheral neovascular complex has not regressed and recurrent vitreous hemorrhage has precluded fur­ther laser treatment.

CASE 4

In this 41-year-old white female from a family of autosomal dominantly inherited retinitis pigmentosa with incomplete pen­etrance, bilateral constriction of visual fields and nyctalopia were noticed at age 14. The diagnosis of retinitis pigmentosa was es­tablished at age 22 when progressive deterioration of both pe­ripheral and central vision was reported. At age 27, she under­went a right retinal detachment repair for holes in the inferior periphery. Bilateral lens opacities subsequently developed, and she required bilateral lens extraction at age 34. Thereafter, she experienced recurrent vitreous hemorrhage in both eyes due to peripheral retinal neovascularization associated with subretinal exudation and diffuse posterior pole edema. Short trials of sys­temic steroids provided dramatic changes in her macular edema and improvement of central vision in both eyes, but had no observable effect on the peripheral neovascularization. At age 39, she was admitted as an emergency for neovascular glaucoma in the left eye (Fig 3) and bilateral vitreous hemorrhage secondary to peripheral retinal neovascularization. She underwent bilateral peripheral retinal cryotherapy and argon laser pametinal pho­tocoagulation to the left eye and had a moderate reduction of intraocular pressure in the left eye. After treatment, no further hemorrhages have occurred, but her visual acuities have re­mained at light perception in both eyes.

SUMMARY OF CLINICAL PROFILES

Four patients with retinitis pigmentosa in various stages of the disease and either disc or peripheral retinal neo­vascularization were seen. One patient with peripheral retinal neovascularization also had rubeosis and neovas­cular glaucoma. Three patients had proven autosomal dominant inheritance and one had a family history suggestive of a recessive pattern (Table 1).

All patients had excessive numbers of pigmented erythrocytes and leukocytes in their vitreous as well as vitreous hemorrhage. All had evidence of retinal edema as manifest on fluorescein angiography by retinal vascular leakage and accumulation of dye at the macula and pos­terior pole.

Fig 3. Case 4. Ectropion uveae and rubeosis iridis of the right eye.

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Table 1. Clinical Details of Patients with Retinitis Pigmentosa and Retinal Neovascularization

Visual Acuity Fundus Appearance

Patient Vitreous Cells/ Posterior Pole Fluorescein No. Age/Sex R L Hemorrhage Edema Exudation Telangiectatic Noevascularization Nonperfusion Inheritance

1 23/F 6/18 6/24 + + DNV + AD 2 34/F 6/9 6/18 + + + PNV + Multiplex 3 34/M 6/12 6/9 + + PNV + AD 4 41/F LP LP + + + + PNV + AD

R = right; L = left; F = female; M = male; LP = light perception; DNV = disc new vessels; PNV = peripheral new vessels; AD = autosomal dominant.

In two patients, telangiectatic vessels were seen in the peripheral retina; in one, this was associated with intra­retinal and subretinal exudation similar to Coats' disease, but in the other no localized exudation was present. flu­orescein angiography demonstrated marked peripheral retinal capillary nonperfusion in all our patients.

Retinal and/or disc neovascularization, like retinal edema, was not restricted to one genetic type.

DISCUSSION

Narrowing of the retinal vascular system is a charac­teristic finding in retinitis pigmentosa; in a recent series, 96% of 192 patients showed this sign.s Although its pathogenesis is not entirely understood, clinical studies suggest that these vascular changes occur as a response to loss of neuroretina. In a selected group of patients with hereditary retinal degeneration studied by electroretin­ography and fluorescein angiography, it was shown that in the early stages of the degeneration, damage to the pho­toreceptor cell system anteceded any disturbance in retinal or choroidal circulations.9 In RCS rats, there is a close temporal relationship between thinning of the outer retinal layers and changes in retinal capillaries. 1O It was thought that vascular narrowing is the result of a relative increase in oxygen tension in the retina, which is itself due to tissue loss.

Although hyperoxia may provide a rational basis for the understanding of reduced perfusion in retinitis pig­mentosa, it does not explain retinal telangiectasia or the occurrence of neovascularization. Retinal telangiectasis in the outer retina has been shown to occur in rodents with retinal receptor dystrophies. I 1,12 The pathogenesis of these vascular changes was not identified although loss of receptor cells, approximation of the retinal vascular bed to the pigment epithelium, and pigment epithelial dys­function might predictably alter the metabolic environ­ment of the retinal vasculature and thereby cause these secondary changes. 13,14

Capillary nonperfusion with its associated ischemia may serve as a stimulus for retinal neovascularization in reti­nitis pigmentosa as it does with primary retinal vascular disease. It is significant that in this series, all patients had areas of marked peripheral capillary nonperfusion in ad-

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dition to the more usual vasoconstriction. It is possible that the process of vasoconstriction and subsequent clo­sure of retinal blood vessels once started may continue independent of oxygen tension. In addition, narrowing of blood vessels in the mid-periphery, where the atrophy is most marked, may induce closure of blood vessels in the far periphery where there is little tissue loss. In both cases, a state of relative hypoxia may be created. In three of our patients, retinal neovascularization developed peripherally and arose from those vessels located immediately adjacent to areas of non perfusion. Interestingly, it occurred at the same site (the equatorial zone) where both the earliest and most advanced retinal degenerative changes have been shown to occur histopathologically. 15

Intraocular inflammation is not an uncommon finding in retinal receptor dystrophies and may also contribute to the associated vascular abnormalities seen in retinitis pigmentosa.16 Many of the vascular changes in retinitis pigmentosa are found in other conditions of which in­flammation is thought to be the cause. Retinal vascular leakage and edema might represent a nonspecific response to inflammation consequent upon the degeneration of photoreceptors or pigment epithelium. Thus, longstanding intraocular inflammation might also play a role in the development of retinal neovascularization, although sys­temic corticosteroids had no observable effect on the neo­vascularization in our patients. However, corticosteroids did reverse some other retinal vascular abnormalities as­sociated with retinitis pigmentosa such as disordered per­meability of retinal capillaries and retinal edema. Perhaps longer durations of steroid therapy are required to affect a change in retinal neovascularization in retinitis pig­mentosa.

The rationale for laser photocoagulation was to ablate the areas of non perfusion, thereby eliminating any pos­sible stimulus for retinal neovascularization as a result of ischemia, an approach used in the management of primary emia, an approach used in the management of primary retinal vascular disease. When recurrent vitreous hem­orrhage precluded further laser treatment, peripheral cry­opexy was performed to complete the peripheral ablation as well as destroy any residual leaking telangiectatic ves­sels. No further vitreous hemorrhages have occurred to date after treatment of the neovascularization by laser photocoagulation and/or peripheral cryopexy in three of four patients, and the neovascular complex has regressed

ULlSS, et al • RETINITIS PIGMENTOSA

in these. Furthermore, amelioration of the ischemic stim­ulus by laser and/or peripheral cryopexy also caused regression of iris new vessels in one patient.

ACKNOWLEDGMENTS

The authors thank Mr. K. S. Sehmi for his photographic ex­pertise and Miss Deborah Hollingsworth for her secretarial as­sistance.

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