Acute Retinal Necrosis B. DAVID GORMAN, MD, ALFRED J. NADEL, MD, ROBERT S. COLES, MD

Abstract: Acute retinal necrosis represents a distinct, recently recog­nized clinical syndrome. Four patients who presented with rapid visual loss associated with uveitis and coalescent areas of retinal necrosis, followed by development of retinal detachments were examined. This paper emphasizes the following: (1) unilateral involvement does occur, (2) the distribution of lesions can be peripheral or central, and (3) early lesions are not associated with retinal vascular abnormalities either clinically or angiographically. Signs and symptoms are suggestive of an infectious process, possibly viral. [Key words: bilateral acute retinal ne­crosis, herpes virus group, immunocompetence, Kirisawa's uveitis, reti­nal detachment, retinal necrosis, retinitis, uveitis.] Ophthalmology 89:809-814, 1982

Reports have appeared in the literature describing a clinically distinct inflammatory disorder characterized by extensive damage to the retina, known as necrotiz­ing vaso-occlusive retinitis,l bilateral acute retinal ne­crosis,2-4 or, in the Japanese literature, as Kirisawa's uveitis.5 Common features of this recently recognized syndrome have included: (1) an anterior uveitis fre­quently preceding other signs, (2) vitreous cellular in­filtration, and (3) the progressive development of in­tensely opaque white patches within the retina. Optic nerve involvement, vascular sheathing, and retinal hemorrhages have occurred. Upon resolution of the inflammatory process most eyes have developed reti­nal holes, usually at the margin of the involved and uninvolved zones, leading to the development of a de­tachment. Therapeutic regimens, as well as surgical attempts to repair the detachments, frequently have failed to restore useful vision to these eyes.

Our experience with this disorder has spanned ten years. We have encountered four patients, three women and one man, whose ages have ranged from 35 to 67 years. In describing their case histories, we would like to emphasize the following points:

1. Unilateral involvement does occur.

From the Department of Ophthalmology, Lenox Hill Hospital. New York, New York.

Presented at the Eighty-sixth Annual Meeting of the American Academy of Ophthalmology, Atlanta, Georgia, November 1-6, 1981.

Reprint requests to B. David Gorman, 125 East 72nd Street, New York, NY 10021.

0161-6420/82/0700/0809/$1.10 © American Academy of Ophthalmology

2. The distribution of the retinal lesions may be predominately central or peripheral.

3. The earliest lesions were not associated with retinal vascular abnormalities, either clinically or an­giographically. Treatment in our hands has proved unsuccessful, and our diagnostic studies have failed to give clues re­garding etiology.

CASE REPORTS

Case 1. A 52-year-old white woman was referred in 1970 for evaluation of uveitis in her left eye of one month's dura­tion. Her visual acuity was recorded as 6/6 right eye and 6/30 left eye. Examination of the left eye showed "mutton-fat" KPs on the corneal endothelium, cells in the anterior chamber, fibrillar condensations and cells in the vitreous, and some opaque retinal patches. The latter were distributed anterior to the equator over 3600

, except for an isolated patch involving the inferior portion of the macular region. Retinal vessels were narrowed irregularly. The patient was treated with steroids by her referring ophthalmologist. Two months after the onset of her symptoms, she developed a retinal detachment in this eye. A scleral buckling procedure was performed in September 1970, and the retina was reattached until the spring of 1971 when irreparable vitreoretinal organi­zation ensued.

In December 1970, following a similar inflammatory episode in the right eye, she developed a retinal detachment. Three procedures over the next 16 months resulted in flat­tening of the nasal retina. A prominent fold persisted tem­porally. When last seen in 1976, her vision was 6/240 right eye and no light perception left eye.

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Case 2. A 35-year-old woman was referred in April 1974 with a two-week history of pain, redness, and decreased vision in her right eye following a febrile illness. When ex­amined, her acuity was limited to counting fingers right eye and was 6/6 left eye. There were "mutton-fat" KPs on the corneal endothelium and a heavy flare in the anterior chamber of the right eye. Cells were present in the vitreous. Fundus examination showed an edematous optic disc and retina in the macular region. The major retinal arteries were irregular in caliber. There were scattered hemorrhages at the posterior pole and in the equatorial region. III-defined white patches could be seen throughout the periphery anterior to the equator. (Fig I). Basic hematologic studies were normal. LE prep, ANA titer, and sedimentation rate were normal.

The patient was placed on 100 mg of prednisone per day. Within four weeks, the inflammatory reaction had di­minished and vision in this eye was 6/9. Prednisone was tapered gradually to 20 mg per day. Fundus examination showed irregular pigmentary changes throughout the entire periphery. The retinal arteries were narrowed and, in some places, were "silver-wired."

On June 20, two months after the onset of symptoms. the patient noted a sudden loss of vision in the affected right eye. Acuity was limited to light perception, and she was found to have a total retinal detachment with some preretinal organi-

Fig 1. Case 2. Right eye .

zation inferiorly. A scleral buckling procedure was per­formed and the retina was reattached. In September 1974, her acuity in this eye was 6/30. The anterior segment was relatively quiet. Posterior synechiae limited the pupillary re­sponse to light. There were numerous cells in the vitreous. A high buckle was present, and the retina appeared flat. The patient was not seen again until October 1976. At that time, the eye was atrophic and demonstrated bare light perception. A dense cataract was present precluding visualization of the posterior segment. An ultrasonogram was not performed. Vision in the left eye was 6/6. This eye was entirely normal. The patient was subsequently lost to follow-up.

Case 3. A 67-year-old white man was referred with a three-week history of blurred vision in his left eye, dating from July 1977. Examination showed a visual acuity of 6/9. KPs were present on the cornea, and there was a cellular reaction in the aqueous and vitreous. Fundus examination of this eye showed sheathing of the superior temporal artery. The retina around this vessel was white and opaque (Fig 2). The fundus periphery was normal. The patient was started on topical mydriatics and steroids as well as prednisone, 30 mg per day. During the next month, despite an increase in prednisone to 60 mg per day, there was a more pronounced cellular infiltration in the vitreous, and there was contiguous spread of the opaque areas from the superior vascular arcade

Fig 2. Case 3. Left eye.

Fig 3. Case 4. Left eye. Nasal retina (left) and posterior pole (right).

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Fig 4. Case 4. Left eye

Fig 6. Case 4. Right eye. Angiogram of early lesion.

into the macular region. Vision was limited to counting fin­gers. Fluorescein angiography showed narrowing of the su­perior temporal artery near the disc with complete occlusion toward the equatorial zone. There was some narrowing of other retinal arterioles. A histoplasma agglutination test was negative and an ELISA test for Toxocara was negative. However, the toxoplasma antibody titer was reported as 1:16,384.

The patient was seen by several other consultants who suggested that a malignant form of toxoplasmosis was re­sponsible for the clinical findings. As a consequence, the patient was started on c1indamycin in addition to systemic steroids. During the next two months, vision in the affected eye decreased slowly. There was no diminution in the cellu­lar infiltration of the vitreous. Ill-defined white lesions began

Fig S. Case 4. Right eye. Early posterior lesion.

Fig 7. Case 4. Right eye.

to appear in the fundus periphery. Initially, these varied in size, but gradually, they began to coalesce. Some hemor­rhages could be seen at the posterior pole. The large lesion near the arcade and in the macular region remained white. More condensations began to appear in the vitreous but pig­mentary changes could be seen at the fundus periphery as the white, opaque lesions faded. Finally, in February 1978, seven months after the onset of symptoms, the patient de­veloped a total retinal detachment with fixed folds. In addi­tion, there was membrane formation in the vitreous. The eye was deemed inoperable, and all medication gradually was discontinued. Vision was limited to light perception but, within two months, the eye became hypotonous, a cataract developed, and all light discrimination was lost.

The chest x-ray in February 1978 showed changes in the

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right apex, not seen at the time of initial work-up. Reactiva­tion of TB was presumed to be on the basis of steroid ther­apy. The patient was placed on a course of INH and Rifam­pin for one year, during which time the pulmonary findings cleared.

The patient has been followed regularly and was seen last on June 1, 1981. At that time, there was no light perception in the left eye. It was soft to palpatation but not grossly at­rophic. A dense cataract precluded visualization of the pos­terior segment. Ultrasonography showed a total, funnel­shaped retinal detachment. During the past 3yz years, vision in the right eye has remained 6/9. Except for some folds in Descemet's membrane, known to have been present since childhood, this eye has been entirely normal in appearance.

Case 4. A 60-year-old white woman was referred in Oc­tober 1980 with a two-week history of redness and floaters in her left eye following an ear infection. She had been exam­ined previously, found to have uveitis, and placed on 50 mg of prednisone per day. Despite therapy, her vision de­creased. When we first examined her, the acuity was 6/6 right eye, and this eye was normal. Vision in the affected left eye was limited to counting fingers. There were cells in the aqueous and vitreous. The disc was hemorrhagic. Most of the nasal hemisphere, the posterior pole (with the exception of the macular region), and the temporal periphery showed a white, opaque appearance. The retinal vessels were very irregular in caliber (Fig 3). The prednisone was increased to 125 mg per day. During the next two weeks, white material belonging to the retina in the left eye peeled from its surface creating debris in the vitreous and leaving some irregular pigmentary changes throughout the fundus. The disc became pale, and the retinal vessels became sheathed or silver­wired (Fig 4). Vision remained counting fingers, and there were cells in the anterior chamber as well as in the vitreous.

On November 11, 1980, a routine follow-up examination revealed retinal lesions in the previously normal right eye. Initially, seven ill-defined opaque sites could be seen, three nasally (including the largest), two superiorly, and two tem­porally. All were anterior to the equator with the exception of one, about the size of the disc, that was located temporal to the foveal region (Fig 5). Fluorescein angiography was performed, and the opaque lesion demonstrated blockage of the background. There was no retinal vascular disturbance in the region of the lesion or at the posterior pole (Fig 6). Dur­ing the next three weeks, more lesions appeared in the right eye in "clusters" and the older ones began to spread and coalesce. The entire nasal and superior retina anterior to the equator became densely white, although the optic nerve head and retinal vasculature posteriorly remained normal (Fig 7). There were a few hemorrhages in the region of the lesions. Some cells began to appear in the vitreous and vision in this eye decreased to 6/9.

At this time, vision in the left eye improved to 6/60. There were fewer cells in the vitreous but more condensations and more pigmentary changes at the posterior pole outside the macular region. On December 2, 1980, the patient noted a sudden decrease in the vision of her left eye. She was found to have a retinal detachment involving the superior temporal quadrant related to multiple holes at the junction of involved and uninvolved areas superiorly. A scleral buckling proce­dure was performed but was complicated by a choroidal hemorrhage in the inferior nasal quadrant. After operation the pupil was deformed, and blood diffused gradually into the vitreous, obscuring the fundus. Ultrasonography showed the retina to be detached. Subretinal fluid from the surgical procedure was frozen in Hank's solution and taken to the

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virology laboratory. There, it was diluted with Eagle's solu­tion and inoculated onto Rhesus monkey kidney, W1381ung fibroblasts, and human embryonic kidney cell plates. All cultures were negative.

During December 1980 and January 1981, the opaque white areas in the right fundus faded gradually and pig­mentary changes could be seen throughout the periphery. There were no lesions more posterior than the one temporal to the foveal region. Vision in this eye remained 6/9 as the prednisone was tapered to 20 mg per day. In late January, vision decreased to 6118 because of cystoid macular edema. The prednisone was increased to 75 mg per day, and the edema resolved. On February 3, the acuity was 6/9. Some cells could be seen in the anterior chamber and condensa­tions were present in the mid vitreous. On February 12, the patient noted a sudden loss of vision in this eye. Her acuity was 6/30, and she was found to have an inferior retinal de­tachment with holes in an area of thinning nasally. There was retinal wrinkling in the macular region emanating from the site of the most posterior original lesion. Within one week, the detachment became total, and additional holes could be seen superiorly. A scleral buckling procedure was performed on February 26, 1981 (at the Bascom Palmer Eye Institute). This was complicated by a choroidal hemorrhage in the in­ferior nasal quadrant. However, the retina was reattached, and the patient recovered an acuity of 6/21. She did well until April when examination showed elevation of the retina pos­terior to the buckle temporally. A second scleral buckling procedure and a pars plana vitrectomy were performed on April 16, 1981. The retina was reattached. In September 1981, vision in this eye was 6/60 with correction, and there was no sign of residual inflammation. The left eye retained light perception despite massive preretinal organization.

DISCUSSION

The clinical features and course of these four patients are identical with previously reported cases and dem­onstrate clearly the syndrome of nontraumatic acute retinal necrosis. 1- 9 Half of our patients had unilateral involvement, and this proportion holds true for the total number described in the ophthalmic literature. Among the bilateral cases, involvement of the fellow eye usually appears within two months. There has been a report, however, documenting delays of 13 to 22 months. 4 The inflammation begins as an anterior uveitis associated with keratitic precipitates, either fine or "mutton-fat." Vitreous cellular infiltration ap­pears shortly thereafter. This is followed by a retinitis in which opaque white lesions and vascular sheathing occur. The inflammation subsides within several weeks, and pigmentary changes become visible in the fundus. Retinal holes develop leading to the formation of rhegmatogenous detachments, some of which are complicated by gross preretinal organization.

There may be some variation in the distribution of the retinitis. In our third patient, for example, the posterior pole was primarily involved while, in others, the zone anterior to the equator was most affected. In our fourth patient, the disc as well as the nasal hemi-

GORMAN, et al • ACUTE RETINAL NECROSIS

sphere of her left eye was involved but, in her right, the posterior pole was spared.

Although vascular involvement is a prominent fea­ture in many cases, we have observed white lesions in areas with normal retinal circulation. In our fourth case, the earliest lesion we could identify in an asymptomatic eye was not oriented along a major reti­nal vessel and was not associated with a localized oc­clusion or with increased vascular permeability. Fluorescein angiography concentrated upon this lesion revealed blockage of the background and no vascular leakage. This leads us to suspect that the vascular leakage, sheathing, and attenuation seen in eyes during the course of the disorder may be the consequence of the same factor(s) that produces the opaque white reti­nallesions.

Some authors2 have suggested that the rapid resolu­tion of the white lesions is due to sloughing of the necrotic retina into the vitreous. In case four, we had the opportunity to observe white material peeling from the retinal surface like an eschar, revealing pigmentary changes in the underlying tissue. To us, the rapid dis­appearance of the retinal lesions is compatible with liquefaction and dissolution into the vitreous. This finding is consistent with the pathology described by Urayama5 where thinned retina revealed loss of inner layers but some retention of outer ones.

With rare exception,6-8 retinal detachments develop as the inflammation resolves. The presence of multiple holes in proximity to the affected retinal areas has been implicated as the cause for the detachments. However, traction from vitreous bands has been a prominent feature in other instances. Of our patients, case 3 showed extensive vitreous organization with the rapid formation of a funnel-shaped detachment. In case 4, although numerous holes were present and the vitreous was relatively clear, a second scleral buckling procedure combined with a pars plana vitrectomy was required to reattach the retina. This suggests to us that both vitreous and retinal pathology are factors in the formation of the detachments.

In our four patients we were not able to establish an etiology. Laboratory tests performed were nondiag­nostic. In case 3, a high toxoplasmosis titer was noted. Severe retinitis and retinal detachments can occur in patients with toxoplasmosis. However, clinical and angiographic features in this case are identical to those of other acute retinal necrosis cases we reviewed. Furthermore, the patient's disease progressed quite characteristically for ARN. At this time, we cannot determine the significance of this toxoplasmosis labo­ratory finding. The retinitis of Behcet's syndrome bears a resemblance to some of the fundus findings in acute retinal necrosis. However, differences in the clinical features of the two disorders remain consider­able. In Behcet's syndrome, there is a hypopyon, mu­cous membrane involvement, and a lengthy course with exacerbations and remissions. These features do not characterize cases of acute retinal necrosis.

The occurrence of prodromata and the pattern that

comprises an initial uveitis, retinal lesions that enlarge and coalesce, and resolution of the inflammation sug­gest an infectious etiology. To us, the appearance of the necrotic fundus lesions and the vasculitis is most like viral retinal infections due to the herpes group (cytomegalovirus, herpes zoster/varicella, and herpes simplex). Indeed, retinal detachments have been re­ported complicating documented cytomegalovirus ret­initis.lO.l1 However, these viral retinal infections have occurred almost exclusively in immuno-incompetent patients, including infants, those with malignancies, and those taking immunosuppressive agents. 12.13 Thus far, the reported cases of acute retinal necrosis have not included patients in these categories of gross im­munodeficiency. In addition, cultures from the sub­retinal fluid and vitreous taken on several occasions at different institutions4 •5 have been negative for viruses. Pathologic studies of two eyes enucleated during the early course of acute retinal necrosis4•5 have failed to demonstrate virus particles. Recently, however, the Bascom Palmer Eye Institute reported a positive cul­ture for a herpes group virus in another enucleated eye. 9 Viral inclusions were demonstrated in the retina on microscopic examination. Should this finding be confirmed in subsequent cases, the factors that characterize the immune system of these otherwise healthy patients permitting virus proliferation within the eye deserve elucidation.

Treatment of acute retinal necrosis with antibiotics and antituberculosis agents has proved ineffective. Steroids in high doses have been given in an attempt to control the inflammatory signs but appear to have no influence on the ultimate course. Regression of the opaque peripheral lesions has been observed rapidly upon withdrawal of steroids as well as during the course of therapy. Antimetabolites, such as chloram­bucil and cyclophosphamide, have been used without success and often with severe complications. In one instance, pooled transfer factor was tried but did not appear to affect the pathologic process.! On the basis of our limited experience with these four patients, we have no recommendations regarding systemic therapy.

ACKNOWLEDGMENTS

We would like to thank Drs. Robert Brockhurst and Per­cyvaldo Wendler for allowing us to use their slides. and Samuel Potthoff, Norman Roman, and Diane Clauss for their help with preparation of the photographic material.

REFERENCES

1. Willerson D Jr. Aaberg TM, Reeser FH. Necrotizing vaso­occlusive retinitis. Am J Ophthalmol 1977; 84:209-19.

2. Young NJA, Bird AC. Bilateral acute retinal necrosis. Br J Ophthalmol 1978; 62:581-90.

3. Price FW Jr., Schlaegel TF Jr. Bilateral acute retinal necrosis. Am J Ophthalmol 1980; 89:419-24.

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4. Sternberg P, Knox DL, Finkelstein D, et al. Bilateral acute reti­nal necrosis. (In preparation.)

5. Urayama A, Yamada N, Sasaki T, et al. Unilateral acute uveitis with retinal periarteritis and detachment. Jpn J Clin Ophthal­mol 1971; 25:607-19.

6. Okinami S, Tsukahara I. Acute severe uveitis with retinal vas­culitis and retinal detachment. Ophthalmologica 1979; 179:276-85.

7. Kometani J, Asayama T. A case of specific uveitis occurring acutely in the right eye. Folia Ophthalmol Jpn 1978; 29: 1397 -401.

8. Hayreh MMS, Kreiger AE, Straatsma BR, et al. Acute retinal necrosis. ARVO Abstracts. Invest Ophthalmol Vis Sci 1980; 19(5uppl):48.

9. Fisher JP, et al. Syndrome of acute necrosis. I. Clinical man-

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ifestations, natural history, etiology and management. Pre­sented at Cornell University, New York Hospital-Manhattan Eye, Ear and Throat Hospital. June 1981.

10. Broughton WL, Cupples HP, Parver LM. Bilateral retinal de­tachment following cytomegalovirus retinitis. Arch Ophthalmol 1978; 96:618-9.

11. Meredith TA, Aaberg TM, Reeser FH. Rhegmatogenous retinal detachment complicating cytomegalovirus retinitis. Am J Ophthalmol 1979; 87:793-6.

12. Egbert PR, Pollard RB, Gallagher JG, Merigan TC. Cytomeg­alovirus retinitis in immunosuppressed hosts. II. Ocular Man­ifestations. Ann Intern Med 1980; 93:664-70.

13. Cogan DG. Immunosuppression and eye disease. Am J Ophthalmol 1977; 83:777 -88.