CHORIORETINOPATHY IN A CASE OF SYSTEMIC LUPUS ERYTHEMATOSUS*

BY Kenneth R. Diddie, MD (BY INVITATION),

Andrew J. Aronson, MD (BY INVITATION), ANDJ. Terry Ernest, MD

INTRODUCTION

SYSTEMIC LUPUS ERYTHEMATOSUS IS A GENERALIZED DISORDER AFFECTING YOUNG

women predominantly. The disease appears to arise from a hyper-reactive immunologic system causing the synthesis of anti-cell, anti-cytoplasmic, and anti-nuclear antibodies. Excessive immunoglobulin, IgG, is present, and there is an increased erythrocyte sedimentation rate, and a positive floculation test. The most common ophthalmoscopic findings in systemic lupus erythematosus are cotton-wool spots and retinal hemorrhages.' Rarely there is secondary optic atrophy, superficial and deep hemorrhages, and arteriole and venous occlusion. Postmortem histologic study of a woman with systemic lupus erythematosus indicated subretinal fluid accumulation, and immunofluorescent immunoglobulins localized in uveal blood vessels.
CASE REPORT

A 19-year-old black woman (67-89-61) with systemic lupus erythematosus, confirmed by renal biopsy (Type III lupus nephritis) was followed for five years. In May 1976 she complained of blurred vision of two weeks duration. Medications included prednisone 20 mg daily and furosemide (Lasix) 160 mg daily. Blood pressure with antihypertensive medications was 130/100. Corrected visual acuity was 20/20, 4 point in each eye; the external examination and the anterior segments were normal. Ophthalmoscopy showed discrete, round areas of elevation of the posterior sensory retina with multiple greyish-yellow spots at the level of the outer retina (Fig 1). The fluorescein angiogram showed hyper*From the Eye Research Laboratories, Department of Ophthalmology, University of Chicago, Chicago, Illinois. This study was supported in part by Public Health Service grant EY-00523 from the National Eye Institute, National Institutes of Health.
TR. ANm. OPHTH. Soc., vol. LXXV, 1977

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FIGURE 1

Ocular fundus photographs from May 1976. A: right eye. B: left eye. The arterioles and venules are normal. There are multiple foci of subretinal fluid and diffuse, circular, yellowish-white areas located at the level of the outer retina consistent with localized areas of intraretinal edema.

FIGURE

Flourescein angiogram of right eye May 1976. A: mid-venous phase showing scattered retinal pigment epithelium transmission defects and localized areas of hypofluorescence due to obstruction of fluorescence fromn the underlying choroid. B: late venous phase showing normal retinal capillary filling. c: after 1 minute there is diffuse leakage of dye into the subretinal space. D: late phase showing leakage of dve inito the macula.

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fluorescence of the grey-yellow spots with slow leakage of fluorescein into circumscribed descrete accumulations of subretinal fluid. (Fig 2) In July 1976, vision was 20/30 in each eye and the ophthalmoscopic picture remiainied the same. Blood pressure was controlled at 120/90 with the addition of hydrochlorothiazide and reserpine (Hydralazine) 100 ing daily and spironolactone (Aldactone) 100 mg daily plus furosemide (Lasix) and methyldopa (Aldomet). In August 1976, the patient complained of blurred vision and intermittenit headaches. Her visioIn was 20/60 in each eye and an electro-oculogram lightto-dark ratio was 1.42 and 1.75 in the right and left eyes respectively (normnal greater than 1.8). Because of the persistence of pockets of subretinal fluid and the development of headaches and ascites, she was hospitalized. On admission, blood pressure was 120/100; electrolytes, blood urea nitrogeni, and creatininie were niormal. Urinialysis showed 2+ albumini and hvaline casts. Cholesterol was 300 mg/100 ml (norinal = 170 - 280) and triglycerides were 1940 mg/100 ml (normiial = 45 - 155). Resuilts of serum proteins electrophoresis were: total protein 7.6 mg/100 ml; albumnin 3.59/100 inl; globulins 4.01/100 ml, with alpha 1 fraction, 0.22 ing/100 ml, alpha 2, 1.20 mg/100 ml, beta, 0.74 mg/100 ml and gammlua

FIG(URE 3

with lipemnia retinalis. There are focal areas of retinal pigment epithelium proliferation in the macula consistent with Elschnig spots.

Octular findus photograph from August 1976. The arteries and veins look similar consistent

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glob)ulin fraction, 1.85 mg/100 ml, showing an inverted A/G ratio and increased gamma globulin. Sedimnenitationi rate was 45 mm/hour (normal for age and sex less than 22 mm/hr). Most serological tests indicative of systemic lupus erythematosus were abnormal: antinuclear immunofluorescence (ANIF) positive in 1:25 dilution (normnal less than or equal to 1:1 dilution), complemnent levels -CHL = 10 mg/100 ml (normal 180 - 350), C3 = 35 ml/100 ml (normal 55 - 120) and C4 = 3 mg/100 ml (normal 20 - 40). A lumbar puncture revealed an opening pressure of 180 mm of water, no cells but an abnormal protein electrophoresis: total protein 420 mg/100 ml (normal less than 400 mg/100 ml) of which 20% was gamma globulini (normiial percentage of gamma globulin 12 - 18%). Computerized axial tomography showed cerebral and brain stein atrophv. The cenitral niervous system and retinal findings, together with her abdominal ascites, suggestedl active lupus ervthematosus and prednisone was increased to 60 img daily. Propraniolol 80 mg dailv was also started. After three weeks of treatmenit, visioIn was right eye 20/25 and left eye 20/20.

FIGURE 4

Fluorescein angiogram of right eye August 1976. A: mid-venous phase showing scattered areas of hyperfluorescence suggesting retinial pigmenit epitheliullm atrophy anld other areas of descrete hypofluiorescenice conisistent with aggregations of pigmelt. B, C: venious phases in which there were no large significant areas of failure of perfuisioni of the choriocapillaris. ): late phase in which the retinal pigmenit epithelium appeared intact with nio detectable leakage into the subretinial space.

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The subretinal fluid could not be detected ophthalmoscopically (Fig 3) and the yellow spots had become darkly pigmented, blocking fluorescence and no longer leaking (Fig 4). We also noted lipemia retinalis which corresponded with the patient's new metabolic status. Despite up to 100 units of insulin daily, fasting blood glucose was 380 mg/100 ml; cholesterol had risen to 700 mg/100 ml, triglycerides to 6640 mg/100 ml, lipoprotein electrophoresis showed: alpha = 6.8, (normal 3 - 35%); pre-beta = 28.5 (normal = 10 - 25%); beta 41.4% (ml 40 - 65%); chylomicrons 23.3% (normal = 0 in fasting blood). Thus the patient had a Type V hyperlipoproteinemia, commonly seen in secondary diabetes mellitus. The patient died two weeks later with a pneumococcal septicemia.

We obtained both eyes at autopsy and fixed one in formalin after sending specimens of uvea and conjunctiva for immunofluoresence studies. Histologically there were accumulations of eosinophillic material beneath the epithelium of the ciliary body and the sensory retina (Fig 5). The walls of the choroidal blood vessels appeared thick and there was an increased number of mononuclear cells in the choroid. Some of the smaller vessels showed what appeared to be fibrinoid necrosis. The choriocapillaris appeared to be reasonably intact (Fig 6). Immunofluorescence studies showed positive results in uveal blood vessels for all immunoglobulins; especially IgG (Fig 7).

FIGURE

Photomicrograph showing extensive accumulation of eosinophilic substance in the subretinal space (hematoxylin and eosin, x 120).

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FIGURE 6

Photomicrograph of the choroid with diffuse thickening of medium-sized vessels and multiple foci of lymphocytes.

FIGURE 7

Photomicrograph of the uvea prepared for immunofluorescence. The white indicates immune complexes deposited in the walls of blood vesses.

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DISCUSSION

Systemic lupus erythematosus (SLE) is a disease with widespread involvement. The joints, skin, kidneys, cardiac and pulmonary systems are most commonly affected. The "autoimmune" or "collagen" disease is characterized by anti-cell antibodies and disseminated vascular inflammation and obliteration. The most common ophthalmoscopic findings in SLE are cotton-wool spots and retinal hemorrhages.' Papilledema,2 retinal arteriolar narrowing,3 retinal venous occulsion,4 and retinal arteriolar occlusion5 have been described. Henkind stressed that these abnormalities were independent of any co-existing systemic hypertension.3 Grey-white patches thought to be choroidal degeneration,6 exudates at the level of choriocapillaris,7 and choroiditis8 have been seen at the posterior pole. There are no previous descriptions of loculated areas of sensory retinal elevation associated with fluorescein leakage from the choroid. We believe that the primary process in our patient was an occlusive choroidal vasculitis with a transudate which broke through Bruch's membrane and the retinal pigment epithelium. There are several pieces of data supporting this. First, the fluorescein leakage stopped and subretinal fluid disappeared with corticosteroid therapy. Second, the extremely high cerebrospinal fluid protein level most probably represented diffuse central nervous system vasculitis, 59 and the eye might be expected to be involved. Third, a number of authors have described mononuclear cell infiltration of the choroid in SLE by light microscopy.8"10'11'12 The walls of the uveal vasculature were infiltrated with immune complexes marking this as a site of inflammation. Immunofluorescence has demonstrated immunoglobulin and complement in renal and splenic blood vessels of humans with SLE. 13 Moreover, Levine and Ward'4 localized antinuclear antibodies by immunofluorescence in retinal vessels of rabbits after they were sensitized to bovine serum albumin and challenged. The prognostic value of ophthalmoscopic lesions in SLE is questionable. The overall frequency of retinal lesions has been reported to be over 25%. 15 Some have found the incidence much lower, however, and attribute the difference to good control with retinopathy reserved for the more acutely ill patient.3 In retrospect it appears that our patient's ophthalmoscopic lesions heralded a stormy systemic course.
SUMMARY

A 19-year-old woman with systemic lupus erythematosus had choroidal fluorescein leakage into discreet areas of subretinal fluid. The findings

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were abolished with corticosteroids. A choroidal vasculitis was suggested by mononuclear infiltration and immunofluorescent demonstration of immunoglobulin.
REFERENCES
1. Henkind P, Gold DH: Oculocutaneous manifestations of rheumatic diseases: Rheumnatology, Vol. 4, Basel, Karger, 1973, pp 13-59. 2. Spaeth GL: Corneal staining in systemic lupus erythematosus. N EnglJ Med 276:1168, 1976 3. Gold DH, Morris DA, Henkind P: Ocular findings in systemic lupus erythematosus. BrJ Ophthalmol 56:800, 1972. 4. Harvey A, McG Schulman LE, Tumulty PA, et al: Systemic lupus erthematosus: Review of the literature and clinical analysis of 138 cases. Medicine 33:291, 1954. 5. Pfaffenbach DD, Hollenhorst RW: Microangiopathy of the retinal arterioles. JAMA 225:480, 1973. 6. Rose E, Pillsbury DM: Acute disseminated lupus erythematosus - a systemic disease. Ann Intern Med 12:951, 1939. 7. Koch FL, McGuire WP: Intraocular manifestations of acute disseminated lupus erythematosus. Amiz J Ophthalinol 29:1243, 1946. 8. Sermon HC, Wolff E: Acute lupus erythematosus with fundus lesions. Proc R Soc Med 27:153, 1934. 9. Johnson RT, Richardson EP: The neurological manifestations of systemic lupus erythematosus. Medicine 47:337, 1968 10. Cordes FC, Aiken SD: Ocular changes in acute disseminated lupus erythematosus. Aim J Ophthalmol 30:1541, 1947. 11. Maumanee AE: Retinal lesions in lupus erythematosus. Amn J Ophthalmol 23:971, 1940. 12. Clifton F, Greer CH: Ocular changes in acute systemic lupus erythematosus. Br J Ophthalmol 3:1, 1955. 13. Svec KH, Blair JD, Kaplan MH: Immunopathologic studies of systemic lupus erythematosus (SLE). I. Tissue-bound immunoglobulins in relation to serum antinuclear immunoglobulins in systemic lupus and in chronic liver disease with LE cell factor. J Clin Invest 46:558, 1967. 14. Levine RA, Ward DA: Experimental acute immunologic ocular vasculitis. Am J Ophthalhnol 69:1023, 1970. 15. Shearn MA, Pirofsky B: Disseminated lupus erythematosus; analysis of thirty-four cases. Arch Intern Med 90:790, 1952.

DISCUSSION DR WILLIA\M TASMAN. I would like to thank Drs Diddie, Aronson, and Ernest for allowing me to read their paper well in advance of the meetinig and I should like to congratulate them on this very interesting case report. In this presentation the authors designate a primary process in the choroid which they feel was a choroiditis associated with transudate that penetrated Bruch's memnbran-e and the retinal pigment epithelium to give rise to discrete serous detachments of the sensory retina in the posterior pole. Certainlv the fluorescein angiogramns, while not demonstratinig dramatic leakage, do suggest dysfunctioni of the retinal pigment epithelium barrier which has permnitted fluid

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to accumulate in focal areas beneath the sensory retina. The authors also were able to demonstrate with immunofluorescence studies immunoglobulins in the uveal tract, particularly in association with the uveal blood vessels. Undoubtedly the most commoni ophthalmoscopic findings in systemic lupus ervthematosis are cotton-wool spots and retinal hemorrhages. As stressed by the authors as well as Henkind and others, these abnormalities may be independent of any coexisting systemic hypertension. Gray-white patches thought to be choroidal degenerationi have previously also been described. It is interesting that in the case report presented today there was evidence of a mild inflammatory process within the choroid. The findiings described are sometimes simnulated in other acquired connective tissue dlisorders, particularly scleroderma and necrotizing arteritis. Cotton-wool spots and retinal hemorrhages may occur in scleroderma (progressive systemic sclerosis) and in such cases mayvbe secondary to associated hypertension. In a recenit article, Coppeto anid Lessell described bilateral retinal vasculitis in a case of systemiiic lupus erythematosis anid postulated a total arrest of the retinal circtulationi dtie to thrombosis of most of the retinal vasculature including major arterioles. Pfaffenbach anid Hollenhorst have also nioted retinal arteriolar thrombosis in systemic lupus erythemncatosis in patients with central nervous system involvement. In a recent severe case ofnecrotizing arteritis we had the opportunity to examinie the octular fundi and noted severe vascular involvement of the choroidal circulationi. In certain areas there was inarked leakage from the choroid while in other locations the choroidal vessels could niot be identified presumably because of infarction. Bilateral serous retinal detachments of the retina were also present anid in our experienice have proved a bacl prognostic sign for survival. This latter experienice parallels to some degree that of the authors in that the patient did expire after dleveloping choroidal involvement and serous detachmenits of the retinia despite the fact that in both cases, there was resolution of the serous dletachlmilenits following the adminiistrationi of systemnic steroids. I should like to ask the authors if thev have been able to identifv with imnIntunofluiorescenice studies any iimmunoglobulins in the retinal blood vessels anid whether they have had anly opportunity to do any ftirther studies of this case utilizinig electronmicroscopy. I shouild like to againi congratulate the authors andl want also to thank the progr-amn commiiiiittee for allowinig me the privilage of discussing this paper.

DRi MYRON YANOFF. Dr Harringtoni, Dr Hollenhorst, Members and Gtmests. The authors have presented a most interestinig case stuidy. We are now studyinig the eves of a 26-year-old black woinan who died of the effects of svstem-ic lupus ervthlematosus. The funidus of 1oth eyes showed cotton wool spots presenit in the distribution of the peripapillary capillaries. The retina in onie eve was serially sectioned andl showed typical inicroinifarcts of the nerve fiber layer, containinlg cvtoidl bodies. The retinia in the other eve Was digested with trypsin and a whole imounlt preparationi was imade. Many areas of discrete fibrinoid necrosis of retinal arterioles were seen, correspondinig to the cotton wool spots seen grossly. In

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some areas, major arterioles underwent a sudden change from relative normality to an acellular structure with fibrinoid necrosis in its wall. In other areas the precapillary arterioles showed similar changes. The fibrinoid necrosis often extended for a short distance down contiguous retinal capillaries. Both proximal and distal to the areas of fibrinoid necrosis the retinal blood vessels (arterioles and capillaries) appeared normal. I wish to congratulate the authors on their study and to thank you for allowing me to discuss their paper.
DR J. TERRY ERNEST. Depending on the series, as high as 25% of patients with lupus have retinal changes with cotton wool spots. There have been previous reports of immnune complexes in the brain and there were immune complexes in the walls of the retinal vessels in our case. However, the retinal vessels were not occluded and there was very little edema and I don't know why our case was different. We could not interpret the ultrastructural changes from our material because there was too much autolysis. I would like to thank Dr. Tasman and Dr Yanoff for their discussion.