From the National Eye Institute (SY, WTW, EDW, JCL, EYC, RBN), National Institutes of Health, Bethesda, Maryland; and the Department of Ophthalmology (EDW), Walter Reed Army Medical Center, Washington, DC.
Presented at the American Society of Retina Specialists Annual Meeting, December 2007, Palm Springs, California.
The views expressed herein are those of the authors and do not necessarily reflect those of the National Institutes of Health or the U.S. Army.
The authors have no financial or proprietary interest in the materials presented herein.
Address correspondence to Robert B. Nussenblatt, MD, MPH, National Eye Institute, Laboratory of Immunology, Building 10, 10S-219, 10 Center Dr., Bethesda, MD 20892-1857.
Progressive outer retinal necrosis is a clinical entity in the spectrum of herpetic viral retinitides. Initially described by Forster et al. in two patients with acquired immunodeficiency syndrome, progressive outer retinal necrosis is primarily found in immunosuppressed individuals1 but has been rarely reported in immunocompetent patients.2 Clinical features of progressive outer retinal necrosis include multiple areas of yellow-white, deep retinal opacification, which become confluent. Following acute infection, large areas of outer retinal necrosis predispose patients to rhegmatogenous retinal detachment in up to 70% of cases.3 One prior report described the utility of OCT for the diagnosis of progressive outer retinal necrosis. In this report, an area of decreased reflectivity within the outer retina was suggestive of outer retinal necrosis in the acute phase of the disease.4 Subsequent reports on OCT findings in progressive outer retinal necrosis have described retinal edema in the acute phase of disease with diffuse retinal thinning observed later in the clinical course.5,6 We report the OCT and fundus autofluorescence findings in a patient with progressive outer retinal necrosis, both in the acute phase of disease and following therapy, and correlate anatomic findings on OCT with fundus autofluorescence abnormalities.
A 41-year-old woman with a history of HIV/AIDS and oral candidiasis presented with a 3-day history of decreasing visual field in her right eye. Her CD4 count was 14 cells/μL. She was not receiving highly active anti-retroviral therapy.
Visual acuity was 20/20 in the right eye and 20/16 in the left eye. Pupillary examination revealed sluggish light reactivity in the right eye, brisk reactivity in the left eye, and a 1+ relative afferent pupillary defect in the right eye. Humphrey visual field 24-2 testing in the right eye revealed a dense superior and inferior nasal visual field defect, which extended to involve the superotemporal quadrant. Slit-lamp examination showed 1+ anterior chamber inflammation with trace anterior vitreous cells in the right eye.
Fundus examination in the right eye revealed mild optic disc edema and multiple, deep white retinal opacities involving the posterior pole and retinal periphery. In the temporal retina, the areas of retinal opacification were confluent and associated with areas of perivascular hemorrhage. In the perifoveal region, a crescent-shaped band of retinal opacification extended from the inferonasal to the superotemporal perifoveal retina, sparing the central fovea (Figs. 1A and 2). Results of fundus examination of the left eye were normal. OCT in a vertical plane demonstrated increased thickness corresponding to the area of perifoveal opacification (Fig. 1B). Inner retinal hyperreflectivity in the region of perifoveal opacification and decreased reflectivity in the outer retina, suggestive of outer retinal edema, were also seen. Progressive outer retinal necrosis was confirmed with polymerase chain reaction of an aqueous specimen, which was positive for varicella zoster virus DNA.
Figure 1. (A) Fundus Photograph of the Right Eye at Initial Presentation Shows Widespread Retinal Opacification and Heme. (B) Corresponding Optical Coherence Tomography (OCT) Shows Hyperreflectivity of the Inner Retina (asterisk) and Outer Retinal Edema (arrows), Whereas (C) Fundus Autofluorescence Shows Subtle Hypofluorescence (arrows). At 1 Week, Fundus Lesions Remain Prominent (D) and OCT Shows Outer Retinal Disorganization (arrow) with Persistent Inner Retinal Hyperreflectivity (asterisk, E). (F) Fundus Autofluorescence now Shows an Area of Stippled Hyperfluorescence in an Area of Hypofluorescence (arrowheads). At 1 Month, Atrophic Changes Are Seen with Resolution of Opacities (G) but OCT Shows Schisis Cavity (asterisk) and Irregular Retinal Pigment Epithelium (arrows, H). Fundus Autofluorescence Shows Multiple Areas of Hypofluorescence and Hyperfluorescence (black Arrowheads, White Arrow), Which Correspond to Large Areas of Retinal Pigment Epithelium Atrophy and Necrosis (I).
Figure 2. Photo Montage Demonstrating Widespread Retinal Opacification and Perivascular Hemorrhage at Initial Visit (A). Widespread Retinal Pigment Epithelium Atrophy and Necrosis Is Seen at the 1-Month Follow-Up (B) with Multiple Regions of Stippled Hyperfluorescence or Hypofluorescence on the Fundus Autofluorescence Image Corresponding to Widespread Retinal Pigment Epithelium Atrophy (C).
The patient was given intravenous acyclovir and ganciclovir induction therapy. Intravitreal ganciclovir therapy was also instituted biweekly (2 mg/0.05 mL/injection). At 1 week of follow-up, intravitreal foscarnet (1.25 mg/0.05 mL/injection) was added because of disease progression. The patient’s intravenous regimen was changed to ganciclovir and foscarnet following consultation with the Infectious Disease service.
At 1 week of follow-up, visual acuity in the right eye was 20/32. Areas of retinal opacification were more prominent both peripherally and in the perifoveal region (Fig. 1D). OCT through the fovea showed increased foveal thickness with cystoid spaces of low reflectivity in the outer retina (Fig. 1E). At 1 month of follow-up, visual acuity was 20/40 in the right eye. In the inferior perifoveal region, the area of previous retinal opacification had progressed to an atrophic, translucent, schisis-like cavity (Fig. 1G). On OCT, loss of reflectivity of both the middle and outer retinal lamina was observed inferiorly, consistent with the atrophic changes appreciated clinically. In addition, the hyperreflective outer retinal band corresponding to the retinal pigment epithelial (RPE) layer appeared discontinuous and irregular (Fig. 1H).
Fundus autofluorescence images using a Topcon fundus camera (excitation filter 580 nm, barrier filter of 695 nm) (Topcon, Paramus, NJ) were also obtained during follow-up. At the initial visit, subtle areas of hypofluorescence were observed in the posterior pole (Fig. 1C). At 1 week of follow-up, fundus autofluorescence images showed a region of hypofluorescence with interspersed stippled, hyperfluorescent signal in the superotemporal macula, which had not been appreciated initially (Fig. 1F). This region corresponded to an area of retina in which confluent opacification was appreciated. At 1 month of follow-up, an additional area of similarly stippled, hyperfluorescent signal was also observed inferior to the fovea, corresponding to the translucent area of outer retinal necrosis and schisis seen clinically and on OCT (Fig. 1I). In addition, widespread regions of hypofluorescence with interspersed, stippled hyperfluorescent signal appeared throughout the retinal periphery (Fig. 2C). These findings corresponded to areas of previous peripheral retinal opacification, which appeared atrophic at 1 month post-treatment.
Two months after the initiation of therapy, the patient returned for follow-up with a visual acuity of hand motions and a macula-off rhegmatogenous retinal detachment with multiple retinal breaks. Following pars plana vitrectomy, retinectomy, and silicone oil tamponade, retinal attachment was achieved. Visual acuity at the 10-month follow-up remained counting fingers at 1 foot despite anatomic reattachment.
Our case report demonstrates the progression of structural changes of the retina by OCT and fundus autofluorescence during the management of progressive outer retinal necrosis. In the early stages of progressive outer retinal necrosis, areas of retinal opacification were increased in overall thickness. At this stage, the inner retina appeared hyperreflective and the outer retina showed mild decreased reflectivity and disorganization indicative of early inflammation and tissue damage. Following therapy, OCT showed an overall reduction in retinal thickness; clinically, large atrophic areas of retina were observed. In some areas (eg, foveal center), cystoid macular edema had resolved with restoration of normal architecture. However, in adjacent areas where atrophy could be seen clinically, prominent tissue disorganization and loss, greater in the outer than the inner retina, were observed on OCT.
The staged progression of fundus autofluorescence changes was also observed in this patient. Early in the course of the disease, when retinal opacification was first observed, abnormalities in fundus autofluorescence were subtle and limited in extent. Changes in fundus autofluorescence appeared to follow retinal opacification and were correlated with areas where retinal necrosis and tissue breakdown were seen on OCT. It is possible that these fundus autofluorescence changes occur subsequent to photoreceptor death and outer retinal injury and inflammation by varicella zoster virus. The subsequent accumulation of lipofuscin or its photoreactive degradative components from tissue breakdown by RPE cells may then give rise to the appearance of multiple areas of stippled hyperfluorescence and hypofluorescence.
This case of polymerase chain reaction-confirmed progressive outer retinal necrosis correlates early and subacute clinical changes to the progression of OCT appearance and fundus autofluorescence imaging. Although late histologic changes of progressive outer retinal necrosis have been described as a full-thickness breakdown of the retina,7 the sequence of pathologic events in different levels of the retina in progressive outer retinal necrosis is still incompletely understood.
The observations in this case indicate that the early events in progressive outer retinal necrosis take the form of outer retinal inflammation, opacification, and swelling. With continuing tissue breakdown and necrosis in the outer retina, lipofuscin from cellular debris accumulates in the RPE, resulting in patchy stippled fundus autofluorescence patterns. In the late phase, recovery of normal retinal thickness and lamination is seen in less affected areas, whereas full-thickness loss of retinal tissue is seen in other more affected areas, resulting in atrophy, formation of schisis cavities in some areas, and eventually attenuation and loss of the RPE layer. Future concurrent use of OCT and fundus autofluorescence imaging modalities with clinical examination may provide further insight into the nature of progression of progressive outer retinal necrosis and the effect of intervention in the course of the disease.
- Forster DJ, Dugel PU, Frangieh GT, Liggett PE, Rao NA. Rapidly progressive outer retinal necrosis in the acquired immunodeficiency syndrome. Am J Ophthalmol. 1990;110:341–348.
- Benz MS, Glaser JS, Davis JL. Progressive outer retinal necrosis in immunocompetent patients treated initially for optic neuropathy with systemic corticosteroids. Am J Ophthalmol. 2003;135:551–553. doi:10.1016/S0002-9394(02)01978-5 [CrossRef]
- Engstrom RE Jr, Holland GN, Margolis TP, et al. The progressive outer retinal necrosis syndrome: a variant of necrotizing herpetic retinopathy in patients with AIDS. Ophthalmology. 1994;101:1488–1502.
- Narayanan R, Kuppermann BD. Optical coherence tomography in progressive outer retinal necrosis. Ophthalmic Surg Lasers Imaging. 2006;37:506–507.
- Almony A, Dhalla MS, Feiner L, Shah GK. Macular optical coherence tomography findings in progressive outer retinal necrosis. Can J Ophthalmol. 2007;42:881. doi:10.3129/i07-171 [CrossRef]
- Blair MP, Goldstein DA, Shapiro MJ. Optical coherence tomography of progressive outer retinal necrosis. Retina. 2007;27:1313–1314. doi:10.1097/IAE.0b013e3180cc2630 [CrossRef]
- Kashiwase M, Sata T, Yamauchi Y, et al. Progressive outer retinal necrosis caused by herpes simplex virus type 1 in a patient with acquired immunodeficiency syndrome. Ophthalmology. 2000;107:790–794. doi:10.1016/S0161-6420(99)00143-8 [CrossRef]