Author Affiliations: Emory Eye Center, Emory University School of Medicine, Atlanta, Georgia (Dr Yeh); Department of Laboratory Medicine, National Institutes of Health, Bethesda, Maryland (Mr Fahle); and Casey Eye Institute, Oregon Health and Science University, Portland (Drs Flaxel and Francis).
Acute retinal necrosis (ARN) is a viral syndrome characterized by necrotizing retinitis and severe panuveitis due to the varicella zoster virus or the herpes simplex virus type 1 or type 2. Although peripheral occlusive vasculitis is frequently observed and considered one of the diagnostic features of ARN,1 central retinal vasculature occlusion has rarely been reported.2,3 We describe 3 patients who developed central retinal vascular occlusions associated with ARN. All patients were elderly, received systemic corticosteroids prior to their referral, and 2 patients had preexisting cardiovascular disease. The combination of central retinal vascular occlusion and panuveitis should prompt the physician to consider ARN as a diagnosis.
A 66-year-old man complained of 6 days of headaches and visual loss in the left eye (OS). He presented to an outside physician with a visual acuity of hand motions and optic disc edema OS. Because of possible giant cell arteritis, 1 g of intravenous solumedrol was given. Two days later, the patient was referred to our institution for continued decline in visual acuity.
Visual acuities were 20/25 OD and bare hand motions OS. A dense relative afferent pupillary defect OS and severely constricted visual fields were observed. Slitlamp examination showed trace cells OS. Dilated funduscopic examination showed 2+ vitreous haze and vitreous hemorrhage. There was a cherry-red spot with diffuse retinal hemorrhages and marked arteriolar attenuation with venous engorgement. The results of an ophthalmic examination of the right eye (OD) were unremarkable. Fluorescein angiography showed extremely delayed arterial perfusion OS and absent venous filling during the recirculation phase, consistent with a combined central retinal artery occlusion (CRAO) and central retinal vein occlusion (Figure 1).
Figure 1. Fundus photographs of the left eye of a 66-year-old man (case 1) that show hazy media secondary to vitreous hemorrhage. There was diffuse retinal pallor and a cherry-red spot, as well as diffuse retinal hemorrhages within the major vascular arcades (A) and in the midretinal and far-retinal periphery (B). No focal retinal necrosis was discernible. Fluorescein angiographic images show poor arterial perfusion (C) and impaired arterial and venous filling at 5 minutes and 39 seconds (D). There was also diffuse leakage from the optic nerve with masking defects corresponding to retinal hemorrhage. Following a diagnostic pars plana vitrectomy, widespread retinal necrosis with central retinal whitening, as well as peripheral retinal necrosis and diffuse hemorrhages, are more apparent (E). Results of quantitative polymerase chain reaction showed more than 25 × 106 copies/mL of varicella zoster virus DNA.
The results of a rapid plasma reagin test, a microhemagglutination– Treponema pallidum test, an angiotensin-converting enzyme test, a purified protein derivative (tuberculin) test, protein C and protein S tests, an antithrombin III test, a chest radiograph, and magnetic resonance imaging of the brain and orbits were normal. Two days later, the patient returned with bare light perception vision. Ophthalmic examination showed a fibrinous anterior chamber reaction (ie, 3+ vitreous cells/haze with worsening vitreous hemorrhage).
Pars plana vitrectomy was performed, and widespread retinal necrosis with hemorrhage was observed intraoperatively. Intravenous acyclovir sodium (10 mg/kg) and intravitreal foscarnet sodium (2.4 mg/0.1 cm3) were administered, and treatment with 2 g of valacyclovir hydrochloride 3 times a day was started. The results of vitreous polymerase chain reaction showed varicella zoster virus DNA with a copy number of 25 625 000 viral genome equivalents/mL. Following 3 weeks of treatment with 2 g of valacyclovir 3 times a day, the patient was given 1 g of valacyclovir 3 times a day for 4 weeks, which was subsequently reduced to twice a day. A retinal detachment developed, but additional surgery was deferred because of the poor prognosis.
A subsequent cardiac workup showed severe coronary artery disease with near-complete occlusion of the left anterior descending and left circumflex arteries. The patient subsequently underwent percutaneous transluminal coronary angioplasty with stent and aggressive hypertension and hyperlipidemia treatment. At 9-month follow-up, visual acuities were 20/25 OD and no light perception OS.
A 64-year-old woman with phthisis bulbi OS of unknown etiology presented with blurred vision OD that she had for 1 month. Initial ophthalmic examination showed visual acuity of 20/200 OD, 2+ vitritis, and peripheral pigmented chorioretinal lesions with adjacent retinal whitening. Treatment with trimethoprim sulfate and sulphamethoxazole (Bactrim DS; Roche) twice daily and prednisone (60 mg/d) were started for presumptive toxoplasmosis. The vision loss progressed over the next month, prompting referral to our institution.
Visual acuity was hand motions OD. Slitlamp examination showed keratic precipitates, trace anterior chamber cells, and 2+ vitreous cells OD. Dilated funduscopic examination showed 3+ vitreous haze, optic nerve pallor, and retinal whitening associated with pigment scarring. The left globe was phthisical.
Using polymerase chain reaction, we found that the vitreous was positive for herpes simplex virus type 2. The results of serum toxoplasmosis IgM and IgG, a rapid plasma reagin test, a fluorescent treponemal antibody absorption test, a purified protein derivative (tuberculin) test, and a chest radiograph were negative. Treatment with oral valacyclovir 3 times a day was initiated, and serial intravitreal foscarnet injections were administered every 3 days for a total of 4 injections. Visual acuity declined to light perception, secondary to worsening vitreous hemorrhage. Two areas of focal traction retinal detachment were identified by using B-scan ultrasonography, prompting a pars plana vitrectomy, membrane peel, endolaser, and silicone oil instillation. Optic nerve pallor, severely attenuated retinal arterioles, and peripheral neovascularization were observed intraoperatively.
The patient's vision improved to counting fingers at 3 ft postoperatively. The findings from a fluorescein angiography confirmed severe retinal ischemia (Figure 2). She was stable at 9-month follow-up.
Figure 2. A, Fundus photograph of the right eye of a 64-year-old woman (case 2) that shows 2+ vitreous haze, optic nerve pallor, and an ellipse-shaped area of retinal whitening superotemporal to the optic nerve (white arrow). Result of polymerase chain reaction was positive for herpes simplex virus type 2 DNA. Following pars plana vitrectomy, membrane peel, endolaser, and silicone oil instillation for a vitreous hemorrhage and tractional retinal detachment, a fundus photograph showed extremely sclerotic retinal arterioles and optic nerve pallor (B). Fluorescein angiographic images show a global delay in arterial perfusion with arterial filling at 21 seconds (C) and delayed venous filling, which was consistent with a central retinal artery occlusion (D).
An 87-year-old man with coronary artery disease after percutaneous transluminal coronary angioplasty developed blurred vision and eye redness OD, prompting treatment with topical corticosteroids for iritis. Two weeks later, he developed severe visual loss to hand motions OD. Ophthalmic examination showed a quiet anterior chamber, trace vitreous cells, and a CRAO. A therapeutic anterior chamber paracentesis was performed because of concern for a thromboembolic CRAO, and oral prednisone (60 mg/d) was prescribed, resulting in minimal improvement in visual acuity.
Three weeks later, the patient was referred for an evaluation. Visual acuity was counting fingers at 3 ft OD and 20/25 OS. Slitlamp examination showed granulomatous keratic precipitates, 1+ anterior chamber cell/flare, and 1+ vitreous cell. Dilated funduscopic examination showed optic nerve pallor and severe retinal arteriolar attenuation. Inferotemporally, there was approximately 2 to 3 clock hours of retinal necrosis. The findings from a fluorescein angiography confirmed poor arterial perfusion consistent with a CRAO (Figure 3).
Figure 3. Fundus photographs of the right eye of an 87-year-old man (case 3) that show 1+ vitreous haze, optic nerve pallor, punctate intraretinal hemorrhage, and extremely sclerotic-appearing retinal arterioles (A) with areas of vascular dropout (B). In the peripheral retina anterior to the equator, there was a 2 to 3 clock-hour zone of retinitis with villiform projections (C), all of which resolved following antiviral therapy. Fluorescein angiographic images show absent perfusion at 37 seconds (D), poor arterial blood flow at 2 minutes and 30 seconds (E), and poor venous filling in the late recirculation phase (F).
Polymerase chain reaction testing of aqueous fluid was positive for varicella zoster virus DNA. Treatment with oral valacyclovir was initiated at 1 g twice a day secondary to kidney dysfunction, and intravitreal foscarnet injections were administered every 3 days for a total of 6 injections. The patient is still being treated with valacyclovir (1 g daily) for ARN prophylaxis. Results of ultrasonography of the patient's carotid showed some plaque but no frank stenosis. At 6-month follow-up, the patient's symptoms were unchanged.
Central retinal vascular occlusion in association with ARN is extremely rare, with only 2 reported cases in the literature.2,3 In one patient, central retinal venous occlusion progressed to a combination CRAO and central retinal vein occlusion and no light perception vision prior to the diagnosis of varicella zoster virus–related ARN.2 In another patient, CRAO with cilioretinal sparing and peripheral necrotizing retinitis were observed.3 The 3 patients described herein further emphasize the relevance of this disease association in both varicella zoster virus–related ARN and herpes simplex virus–related ARN (Table). Although other infectious (eg, Bartonella, tuberculosis, and syphilis) and noninfectious entities (eg, Behçet syndrome, sarcoidosis, and Wegener granulomatosis) may also be present with retinal vaso-occlusive sequelae and uveitis, the clinical features and laboratory findings of each patient excluded these possibilities. Interestingly, 2 of the 3 patients also had comorbid coronary artery disease, and all 3 patients were elderly, which suggests that prior vasculopathy may predispose patients to a central retinovascular event in the setting of ARN. All 3 patients were also treated with systemic corticosteroids prior to presentation to our institutions; for 2 of these patients, the administration of corticosteroids before antiviral therapy was associated with a decline in visual acuity.
The precise mechanism of occlusive vasculopathy in ARN is unknown. The histology of ocular specimens has demonstrated chronic granulomatous inflammation,4 and electron microscopy has shown herpesvirus in multiple retinal layers with retinal arteritis.5 The recent description of Kyrieleis' vasculitis in ARN suggests an immune-mediated phenomena.6 Hayreh7 described widespread pathologic vasculitis involving the iris, choroid, retina, and optic nerve and suggested that “acute ocular panvasculitis syndrome” may be preferred to “acute retinal necrosis.” Increased awareness that ARN-related vasculitis may affect multiple ocular vascular structures including central retinal vessels is helpful clinically. Specifically, recognition of the association of central retinal vascular occlusion with panuveitis should prompt consideration of a workup for herpetic retinitis given the potential for severe visual loss in these challenging cases.
Correspondence: Dr Francis, Casey Eye Institute, 3375 SW Terwilliger Blvd, Portland, OR 97239 (firstname.lastname@example.org).
Financial Disclosure: None reported.
Funding/Support: This work was supported in part by an unrestricted grant from Research to Prevent Blindness (to Casey Eye Institute, Oregon Health and Science University, Portland, Oregon, and Emory Eye Center, Emory University, Atlanta, Georgia). Dr Yeh has received support from the Ronald G. Michels Fellowship Foundation.
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