ACUTE CENTRAL SEROUS CHORIORETINOPATHY AND FUNDUS AUTOFLUORESCENCE

ACUTE CENTRAL SEROUS CHORIORETINOPATHY AND FUNDUS AUTOFLUORESCENCE CHIARA M. EANDI, MD,*† MICHAEL OBER, MD,* REZA IRANMANESH, MD,* ENRICO PEIRETTI, MD,* LAWRENCE A. YANNUZZI, MD* Objectives: To describe fundus autofluorescence (FAF) in a series of patients with acute central serous chorioretinopathy (CSC). Methods: Nine eyes of six patients with acute CSC were evaluated with fluorescein angiography (FA) and FAF imaging to evaluate the nature of the focal retinal pigment epithelial (RPE) leak evident with FA. Results: All nine eyes in this series demonstrated hypoautofluorescence corresponding precisely to the site of the focal RPE leak seen on FA. Conclusions: In this group of patients, the acute focal RPE leaks seen with FA corresponded precisely to an area of hypoautofluorescence imaged with FAF. This observation supports the concept that a mechanical defect or absence of the RPE accounts for the leakage from the inner choroid to the subneurosensory space in CSC. FAF is also a useful noninvasive diagnostic adjunct to identify the focal RPE leak in patients with acute CSC. RETINA 25:989 –993, 2005

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or more than a century, central serous chorioretinopathy (CSC) has been well known to ophthalmologists as a distinct clinical entity.1 Numerous clinical studies have described its demographic features, risk factors, clinical manifestations, and course1–5; however, its pathogenesis and treatment are still unclear.6 – 8 In the acute stage, fluorescein angiography reveals a focal leak at the level of the retinal pigment epithelium (RPE) beneath a macular neurosensory retinal detachment. Indocyanine green (ICG) angiography demonstrates multifocal islands of inner choroidal

staining even in eyes where focal RPE leaks are not evident on FA.8,9 This form of imaging is also useful in differentiating CSC from masquerading syndromes such as polypoidal choroidal vasculopathy.10 The advent of optical coherence tomography (OCT) allows the detection of shallow neurosensory retinal detachments not apparent by clinical biomicroscopic examination.11 This novel imaging technology also records other features of CSC, including detachments of the RPE, as well as chronic exudation and cystic change within the retina itself.10 Recently, fundus autofluorescence (FAF) imaging has been used to study the macula in CSC.12,13 This noninvasive technique has documented the intensity and spatial distribution of autofluorescence in the acute and chronic stages of the disorder. In other studies, hyperautofluorescence was described at the site of the focal RPE leak seen with FA in acute CSC.12,13 We studied nine eyes with acute CSC to determine the nature of the focal RPE leak identified with FA when studied with FAF.

From *The LuEsther T. Mertz Retina Research Center of Manhattan Eye, Ear and Throat Hospital, New York, and VitreousRetina-Macula Consultants of New York, New York; and †Department of Clinical Physiopathology, Eye Clinic, University of Torino, Italy. Supported by the Macula Foundation, Inc., New York, New York. Reprint requests: Lawrence A. Yannuzzi, MD, LuEsther T. Mertz Retinal Research Center of Manhattan Eye, Ear and Throat Hospital, 210 East 64th Street, New York, NY 10021.

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Fig. 1. A, B, The early phase of fluorescein angiograms (FA) shows bilateral focal retinal pigment epithelial (RPE) leak (arrow). C, D, The late phase FA images reveal the area of the RPE detachment (arrowheads) in both eyes. E, F, The corresponding fundus autofluorescence images show hypoautofluorescence at the site of the acute RPE leak (arrow).

Methods We used FAF imaging to study nine eyes with acute CSC and the focal RPE leaks. We defined acute CSC as symptoms and neurosensory macular detachment of less than 6 months duration with focal RPE leak on FA. The patients were seen at a tertiary retina referral practice in New York City. Each patient underwent a complete ophthalmic examination including slit-lamp biomicroscopy and indirect ophthalmoscopy. Bestcorrected visual acuity (Snellen) and intraocular pressure were measured. Digital fundus photographs and digital FA were performed with a Topcon TRC 50IX fundus camera (Topcon, Tokyo, Japan). The FAF was performed with special filters to avoid imaging the autofluorescence of the lens, as previously described.14 We compared the acute RPE leaks detected on FA with FAF using ImageNet 2000 software, Version 2.16 for Windows, Topcon American Corporation (TAC), Paramus, NJ. Results In this study, nine eyes of six patients were analyzed. The mean age was 39.5 years (range 30 to 53

years). There were four male and two female patients. In three patients, both eyes were affected. The clinical examination showed manifestations typical of patients with CSC, including zonal or patchy RPE atrophy and pigmentary degeneration, neurosensory retinal detachment, and serous pigment epithelial detachments (PEDs). The FA demonstrated a focal RPE leak beneath the acute neurosensory detachment seen on clinical biomicroscopic examination. In all nine eyes in our series, the FAF study revealed a focal area of hypoautofluorescence corresponding precisely to the site of the focal RPE leak evident with FA (Figures 1 and 2). FAF also revealed well demarcated zones of patchy hypo- and hyperautofluorescence, which corresponded to areas of RPE atrophy and pigment deposition. Discussion FAF is an imaging technique that is designed to document the presence of lipofuscin in the RPE.15 Lipofuscin is a mixture of proteins, lipids, and small chromophores generated as by-products of the retinoid cycle. N-retinyl-N-retinylidene ethanolamine (A2E) is Fig. 2. A, The early phase of fluorescein angiogram (FA) shows focal retinal pigment epithelial (RPE) leak (arrow) long the superior temporal vascular arcade. B, The late phase FA reveals the area of the RPE detachment (arrowheads). C, The corresponding fundus autofluorescence image shows hypoautofluorescence at the site of the acute RPE leak (arrow).

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a crucial component of lipofuscin, and it is formed in the RPE only after outer segments phagocytosis where A2E precursors are localized. The RPE is intimately involved in the phagocytic uptake and degradation of the constantly shedding photoreceptors, actively transporting multiple products between the outer retina and the choroidal circulation. The accumulation of lipofuscin in the RPE is due to impaired or overwhelmed lysosomal activity, leading to incompletely digested cellular debris.16,17 The presence of FAF is thought to correspond to the accumulation or dispersion of lipofuscin in the subretinal space or RPE. Hyperautofluorescence is also known to occur beneath a chronic detachment of the retina. In patients with chronic CSC and persistent detachment, there is a time-dependent progressive increase in the intensity of the FAF.12,13 This is believed to be due to normal shedding of the outer segments, which disperses the chromophores into the subneurosensory retinal space. Another contributing factor may be an intrinsic genetic abnormality which inhibits the disposal of lipofuscin by the RPE in certain heredo-familial diseases such as Stargardt’s18 disease, Best’s vitelliform dystrophy,19 and even age-related macular degeneration.20 In any macular diseased state, there may be an increase in the intensity of FAF from variations in the metabolism of the involved tissue layers, specifically the photoreceptors and the RPE itself. Reduced autofluorescence or hypoautofluorescence Fig. 3. Diagrammatic representation of a proposed pathophysiology mechanism for central serous chorioretinopathy. A, Initially, there is a little leak of the indocyanine green (ICG) dye from the choroidal vessels. B, With time, more dye leaks, diffuses through the choroid, and accumulates in the subretinal pigment epithelium (RPE) space. This is evident on ICG angiogram as hyperfluorescent areas and predisposes to the formation of focal pigment epithelium detachments (PED). C, Sequentially, a break in the PED referred to as a “blow out” may occur at the edge or near the junction of the attached and detached pigment epithelium. D, This mechanical disruption then provides a pathway or access for the exudative changes to leak beneath the neurosensory retina space producing a clinical detachment of the neurosensory retina.

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is also a function of the lipofuscin content of the RPE and the metabolic activity of the photoreceptor renewal system. Areas of photoreceptor and/or RPE atrophy do not produce lipofuscin and therefore appear hypoautofluorescent. Furthermore, a rip or break in the RPE would also result in a hypoautofluorescent image. Normal FAF or isoautofluorescence will vary, dependent on age and spatial locations in the fundus.20 von Ruckmann and collegues12,13 described hyperautofluorescence at the site of the focal RPE leak in patients with CSC. Loss of photoreceptors and enhanced outer segment turnover, along with RPE lipofuscin accumulation, were the factors cited by the authors to explain their observations in hyperautofluorescence. Their conclusions were based on an assumption that an increase in metabolic activity in the vicinity of the focal RPE leak produced lipofuscin accumulation and hyperautofluorescence in the involved RPE. Diametrically opposite findings were noted in our study when we examined the acute focal RPE leak on FA and compared it to the FAF. In all cases, the acute focal RPE leak was associated with hypoautofluorescence. Contiguous areas surrounding the focal RPE leak revealed a zone of mottled hypo- and hyperautofluorescence consistent with antecedent neurosensory detachment. Although our findings on CSC and AF differ from what has been previously reported by

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von Ruckmann et al,12,13 our observations are not absolutely contradictory because their report involved patients with chronic disease. None of the images in their report depict a pinpoint fluorescein leak.12,13 The present study included only patients with symptoms and detachment of fewer than 6 months duration and focal fluorescein leaks. Over time, acute focal RPE defects like those present in CSC are remodeled, often resulting in spontaneous resolution of neurosensory detachment, which may result in a loss of the focal hypoautofluorescent spot. All of our patients had pinpoint expanding leak, so called “ink blot” in nature. The clinical and fluorescein findings in chronic CSC are different and result in a different autofluorescence pattern. Furthermore, persistent exudative detachments of extended duration regardless of etiology are associated with a gradual increase in hyperautofluorescence. The FAF of the neurosensory retinal detachment in all of our cases, however, was isoautofluorescent, indicative of their acute nature. Further evidence supporting our findings is the report of Karadimas et al,21 who found that the leaking point was present in AF imaging as a dark spot or as a target lesion using a scanning laser ophthalmoscope. In addition, Spaide and Klancnik22 recently reported on fundus autofluoresence and CSC using the fundus camera technique and also found hypoautofluorescence at the point of RPE leak. Our explanation for the hypoautofluorescence observed at the site of the RPE leak is speculative but consistent with our previous hypothesis on the pathophysiology of CSC. We believe that the sequence of events leading to neurosensory detachment begins with exudative changes within the inner choroid. This is best demonstrated with ICG angiography, which shows choroidal vascular hyperpermeability in the mid stages of the study. This finding is present even in asymptomatic eyes and precedes detachment of the neurosensory retina9,23 (Figure 3). The accumulation of exudate in the inner choroid in association with a relatively loosely adherent RPE leads to serous detachment of the pigment epithelium (PED). As a result of pressure from the serous elevation of the RPE, a “blow out” may develop at or near the junction of the attached and detached pigment epithelium.3,8,24 This mechanical disruption, essentially a micro pigment epithelial rip or dehiscence, then provides a pathway or access for the exudates to enter the subretinal space. If the micro RPE rip is large there tends to be a “smokestack leak” as the fluorescein dye flows readily into the subretinal serous detachment. As the RPE defect compensates with RPE cellular proliferation, the nature of the leak converts to a pinpoint or expanding “ink blot.” Convex currents induced by the

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warmer choroidal circulation and molecular weight differences between the fluorescein molecule and the subretinal exudate also contribute to the nature of the leak. However, we believe the permeability state of the RPE at the site of the leak plays a predominant mechanical role. As large protein molecules such as fibrinogen, fibrin, and their breakdown products pass into the subneurosensory retina space, they draw fluid via osmosis from adjacent vasculature to produce a clinical detachment of the neurosensory retina.8 So, we believe that the blow-out of the RPE likely represents the focal RPE leak seen with FA as well as the hypoautofluorescent counterpart evident with FAF imaging. The absence of the RPE at this location results in the absence of FAF. In short, the blow-out is devoid of RPE; accordingly, there is no tissue to accumulate and display lipofuscin at that site. In summary, a focal RPE leak in acute CSC can be identified noninvasively with autofluorescence photographs. FAF may therefore prove useful in guiding laser treatment without resorting to the more interventional diagnostic FA standard. This may be especially beneficial in pregnant patients who are prone to CSC exacerbation,25 and in those with fluorescein allergy. Key words: central serous chorioretinopathy, fundus autofluorescence, retinal pigment epithelium. References 1. 2.

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Fundus autofluorescence in Stargardt macular dystrophy– fundus flavimaculatus. Am J Ophthalmol 2004;138:55–63. Jarc-Vidmar M, Kraut A, Hawlina M. Fundus autofluorescence imaging in Best’s vitelliform dystrophy. Klin Monatsbl Augenheilkd 2003;220:861–867. Delori FC, Goger DG, Dorey CK. Age-related accumulation and spatial distribution of lipofuscin in RPE of normal subjects. Invest Ophthalmol Vis Sci 2001;42:1855–1866. Karadimas P, Goritsa A, Paleokastritis GP, et al. Autofluorescence imaging in central serous chorioretinopathy and correlation with Fluorescein angiography and indocyanine green angiography. Invest Ophthalmol Vis Sci 2005;46: EAbstract 3463. Spaide RF, Klancnik JM Jr. Fundus autofluorescence and central serous chorioretinopathy. Ophthalmology 2005;112: 825–833. Spaide RF, Hall L, Hass A, et al. Indocyanine green videoangiography of older patients with central serous chorioretinopathy. Retina 1996;16:203–213. Goldstein BG, Pavan PR. ’Blow-outs’ in the retinal pigment epithelium. Br J Ophthalmol 1987;71:676–681. Quillen DA, Gass DM, Brod RD, Gardner TW, Blankenship GW, Gottlieb JL. Central serous chorioretinopathy in women. Ophthalmology 1996;103:72–79.