Near-Infrared and Short-Wavelength Autofluorescence Imaging in Central Serous. Ahmet Hamdi Bilge, MD 1

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1 BJO Online First, published on October 17, 2008 as /bjo Near-Infrared and Short-Wavelength Autofluorescence Imaging in Central Serous Chorioretinopathy Ali Ayata, MD 1, Sinan Tatlipinar, MD 2, Taner Kar, MD 1, Melih Unal,MD 1, Dilaver Ersanli MD 1, Ahmet Hamdi Bilge, MD 1 1 Department of Ophthalmology, Gulhane Military Medical Academy, Haydarpasa Training Hospital, 34668, Uskudar, Istanbul, Turkey 2 Department of Ophthalmology, Yeditepe School of Medicine, Istanbul, Turkey From the Department of Ophthalmology, Gulhane Military Medical Academy, Haydarpasa Training Hospital, 34668, Uskdar, Istanbul, Turkey Corresponding author: Dr.Ali Ayata Goz Hastaliklari Servisi GATA Haydarpasa Egitim Hastanesi 34668, Uskudar, Istanbul, Turkey ali_ayata@yahoo.com Tel: Fax: Ethics committee approval: Haydarpaşa Numune Egitim ve Arastirma Hastanesi Etik Kurulu, Istanbul, Turkey. Tel: date: prot no: Copyright Article author (or their employer) Produced by BMJ Publishing Group Ltd under licence.

2 Abstract Purpose: To document short-wavelength (SW) and near-infrared (NIR) autofluorescence properties of acute central serous chorioretinopathy (CSC). Methods: Twenty six eyes of the 26 patients diagnosed with CSC (mean age 37.4 years) were included in this retrospective study. Autofluorescence (AF) images were evaluated and compared with angiographic and ophthalmoscopic findings. Fluorescein angiography and AF imaging were performed using a confocal scanning laser ophthalmoscope. Results: Focally decreased AF at leakage site was seen in most of the cases with acute CSC (20 of 26 eyes in SW-AF; 20 of 20 eyes in NIR-AF). Twenty four of the 26 cases had the decreased SW-AF corresponding to the area of the serous retinal detachment while 19 of the available 20 cases had the decreased NIR-AF corresponding to the area of the serous retinal detachment. Increased granular AF corresponding to the extent of the former retinal detachment was seen earlier in SW-AF mode, and disappears later in the course of disease with NIR-AF imaging. Conclusions: AF imaging of CSC demonstrates different patterns according to the course of the disease reflecting RPE and outer retinal changes. Combining two different AF imaging might predict recent or former CSC episodes and may be a non-invasive technique for monitoring CSC and performing differential diagnosis. Keywords: Short wavelength autofluorescence; near infrared autofluorescence; central serous chorioretinopathy; retinal pigment epithelium. Introduction Central serous chorioretinopathy (CSC) is characterized by serous detachment of the neurosensory retina and or the retinal pigment epithelium (RPE). CSC typically affects young and middle-aged adults and frequently causes mild to moderate visual impairment. Patients usually complain of blurred or decreased vision, central-paracentral scotoma, micropsia or metamorphopsia. Acute CSC is commonly healed with spontaneous resolution with monofocal or paucifocal RPE changes. Widespread alterations in the RPE can be seen in patients with recurrent or chronic CSC with or without persistent neurosensorial retinal detachment. [1] Imaging of fundus autofluorescence (FAF) with a confocal scanning laser ophthalmoscope (cslo) is a relatively new technique that shows level and distribution of lipofuscin in the retinal pigment epithelium (RPE) in vivo.[2,3] Lipofuscin is main source of the short-wavelength fundus autofluorescence (SW-AF), and it is a byproduct of the photoreceptor outer segment and accumulates with age and retinal disease within lysosomes of RPE.[4,5] Thus, AF imaging of the RPE with a cslo can be used as a non-invasive diagnostic tool to evaluate changes in the level of the RPE. [6-8] As it has been reported previously, near infrared reflectance and autofluorescence (NIR- R and NIR-AF) is derived from pigmented lesions and melanin is a possible source of increased NIR-AF.[9,10] Hence, high NIR-R and NIR-AF of these lesions acquired with cslo results from backscattered light from the highly refractile melanin granules. 2

3 Recently, near-infrared fundus autofluorescence (NIR-AF) has been introduced to measure the autofluorescence of the melanin in the RPE and the choroid. Kellner et al. and Theelen et al. recently reported NIR-AF and SW-AF in chloroquine retinopathy and inherited retinal diseases, respectively.[11,12] They both observed characteristic AF patterns, which differed between excitation wavelengths and concluded that both wavelengths provided additional information for description in these diseases. Although SW-AF properties of acute and chronic CSC have been described previously in a few reports [13-17], NIR-AF properties of the CSC has been mentioned briefly in a single paper.[9] In this study, we analyzed SW-AF and NIR-AF properties of CSC and compared the findings of these two imaging modalities. Methods We retrospectively analyzed the medical data of 26 patients with CSC examined between September 2006 and February One eye of the patients with a follow-up of at least 4 months was included. The clinical examination included best-corrected Snellen visual acuity determination, slit-lamp biomicroscopy using a 78-diopter non contact lens, and applanation tonometry. Digital fundus photography with infrared and red-free illumination, SW-AF, NIR-AF and intravenous fluorescein angiography were performed using a cslo. The diagnosis of CSC was based on the characteristic appearance of the fundi and fluorescein angiography. Laser photocoagulation was not applied in any subject. Image Acquisition SW-AF and NIR-AF imaging was performed with a cslo (Heidelberg Retina Angiograph 2, HRA2, Heidelberg Engineering, Heidelberg, Germany). Thirty and 55 degree view modes were used. For SW-AF imaging 488 nm wavelength was used for excitation and emitted light was detected above 500 nm with a barrier filter. NIR-AF images of ocular fundi were obtained at 787 nm excitation wavelength using a barrier filter for detection of emitted light above 810 nm. For both SW-AF and NIR-AF, 32 single images were averaged (8.7 frame/s) using the HRA mean-art algorithm to obtain a high quality mean image. Results We conducted a retrospective study in 26 eyes of the 26 consecutive patients (21 men, six women) with CSC. The patients ages ranged from 23 to 58 years (mean ± SD, 37.1 ± 7.9 years). In all 26 eyes, the SW-AF images obtained during the acute phase were compared with those obtained in follow up examination or after resolution of the retinal detachment. NIR-AF images were available during the initial and late examinations in 20 of the 26 eyes. All 26 eyes had a serous retinal detachment that involved the center of the fovea, and fluorescein angiography showed fluorescein leakage from the retinal pigment epithelium. Twenty of the 26 cases were diagnosed as acute CSC and 6 cases were classified as acute episode of the recurrent CSC due to the presence of the former RPE lesions and/or patient history. In the initial examination, 24 of the 26 cases had the decreased SW-AF corresponding to the area of the serous retinal detachment while 20 of the 26 cases had the decreased SW-AF corresponding to the 3

4 leaking point (Figure 1). Nineteen of the available 20 cases had the decreased NIR-AF corresponding to the area of the serous retinal detachment, and all 20 cases had decreased NIR-AF corresponding to the leaking point (Figure 1). Interestingly, leaking point-related hyponir-af was observed in four of the cases without associated remarkable hypoaf spot in SW-AF imaging (Figure2). Spontaneous resolution was observed in all cases within 3 to 6 months. Leaking pointassociated decreased SW and NIR-AF was still visible after resolution of the serous detachment (Figure 1-2). Diffuse and/or granular increased SW-AF was observed in the previously detached or residual retinal detachment areas, especially in extended cases. Increased diffuse and/or granular NIR-AF was also observed in all cases in the later examinations corresponding to the previously detached retinal area. Appearance of the hypernir-af was delayed but more prominent compared to increased SW-AF (Figure 3). In summary, focally decreased AF at leakage site was seen in most of the cases with acute CSC. Increased granular AF corresponding to the extent of the former retinal detachment was seen earlier in SW-AF mode, and disappears later in the course of disease with NIR-AF imaging. Discussion SW and NIR-AF imaging of ocular fundus with a cslo is a relatively new, noninvasive technique and is a diagnostic tool that is designed to document the presence of lipofuscin and melanin, respectively. In normal AF images, optic disk and vessels appear dark due to the absence of autofluorescent fluorophores. Macular area appears hypoautofluorescent in SW-AF mode (being minimum in the fovea) because the macular pigments absorb blue light. Contrary to the SW excitation, macular area appears hyperautofluorescent in the NIR-AF mode due to the high melanin content of RPE in the macula. Abnormal AF is defined as an increased or decreased AF signal compared to AF outside the lesion, latter being labeled as normal AF.[15] Decreased AF (hypoaf) is either due to the RPE atrophy or blockage (eg, retinal hemorrhage or exudate). On the other hand, increased AF (hyperaf) is derived from RPE reaction or increased visibility of RPE (eg, macular hole).[18] Decreased SW-AF corresponding to both serous retinal detachment and the leaking point in acute CSC cases has been reported in previous studies.[14-17] Blockage of the SW-AF due to the presence of the subretinal fluid is the explanation for the hypoaf of the detached retinal area early in the course of the disease. It is thought that hypoaf observed at the leakage point is either due to RPE defect or the presence of dense subretinal fluid containing fibrin.[14,15] Framme et al. reported that three fourth of the patients with acute CSC demonstrated a clear hyposw-af corresponding to the leakage point and most of their patients showed hypo SW-AF over the area of detached retina.[15] Our results are quite similar to their findings. Additionally, in four cases with fibrinous exudate in fundoscopic examination, leaking pointassociated hypo-sw-af spot became considerably smaller at follow up examinations indicating that fibrin accumulation is responsible from the large area of the hypoaf initially (Figure 1). 4

5 NIR-AF properties of acute CSC are largely similar to those of SW-AF imaging. However, rate of hypoaf spot at leakage point was found to be higher in NIR-AF imaging. Moreover, NIR-AF was able to demonstrate hypoautofluorescencent leaking spot in four patients in whom SW-AF imaging did not reveal such a finding. Additionally, in one of the patients, NIR- AF imaging reveals several other hypoaf spots which are not actively leaking on angiogram (figure 2). This observation may be explained by pathological site of the chorioretinal disturbance being more extensive than expected/usual in this case. This patient was not one of the acute episode of the recurrent cases. Depending on the size and location of the RPE defect (particularly true for lesions adjacent to the fovea), observation of a clear leaking spot was not possible in some cases with SW-AF imaging. However, due to the bright luminescence of the macula in NIR-AF imaging, detecting hypoautofluorescencent leaking spot was more possible owing to the contrast difference. Peculiarity of the wavelength used in the NIR-AF imaging may also contribute to the visibility of the leaking spot. In the normal retina, the photoreceptors continuously renew and shed fragments of their outer segments, and the fragments are phagocytized by the RPE. Separation of the neurosensory retina from the RPE reduces the photoreceptor outer segments renewal, but does not completely disrupt the process.[19, 20] Photoreceptors continue to elongate and shed their outer segments in to the subretinal space.[21, 22] By time, fragments of the photoreceptor outer segments scatter into the subretinal space and form aggregates. In CSC, the autofluorescence originates not only from the RPE but also from the detached retina. Spaide and Klancnik theorized that the origin of the hypersw-af is the accumulated photoreceptor outer segments that are not phagocytized by the RPE or macrophages with a phagocytized outer segment, because the outer segments of the photoreceptors contain a precursor of lipofuscin displaying autofluorescence.[17, 23] These subretinal aggregates are source of the granular pattern hyper-sw-af corresponding to former or residual detached retinal area. During the resolution period, resorbtion of the subretinal fluid through the healthy RPE will be rapid for water and salts, but not for macromolecules, and they will precipitate. Hence, subretinal protein concentration will gradually increase, potentially reaching saturation and causing precipitation. This may also be a contributing factor to hyperaf appearance of former or residual detached retinal area. Appearance of this pattern in the NIR-AF mode was quite similar to the SW-AF mode. However, formation of this pattern on AF imaging was not simultaneous in SW and NIR-AF. Not all of the hypersw-af granules demonstrated hyper NIR-AF at the beginning, i.e., appearance of the hyper NIR-AF was delayed compared to SW-AF indicating a phase difference. It is known that lipofuscin does not show NIR-AF properties and melanin is the main source of the NIR-AF.[9] We speculate three possible mechanisms to explain the dual autofluorescence behavior (both SW-AF and NIR-AF) of these subretinal granules and phase difference. First, in a case of the anterior uveitis; corneal endothelial keratic precipitates seem yellowish, light gray initially and their appearance turns in to dark due to the pigment incorporation with time. Similar to this scenario, in longstanding CSC cases, subretinal aggregates may be coated by the melanin from damaged RPE cells and may acquire hypernir- AF property. Second, aggregates may be covered by the fibrin within time and fibrin coating may cause NIR-AF behaviour. Third, in analogy to hypernir-af from degraded blood in the case of 5

6 subretinal hemorrhage [10], aggregation of the photoreceptor outer segment membrane remnants may be source of the NIR-AF property of these granules through an undetermined flourophore. Also, Keilhauer and Delori previously reported that melanin and/or melanin compounds (e.g. oxidized melanin, melanolipofuscin) was in large part responsible of the observed NIR-AF and that small contributions from other fluorophores could not be excluded. [24] Additionally, one who is evaluating AF image should be aware of the limitation of AF imaging. Quality of the AF image is dependent on ocular media transparency and on the variable features of the different capture devices that limits the reproducibility and consistency of many AF studies. The confocal scanning laser ophthalmoscope used has a depth of field of only abot 300 µm, so fluorescence from deeper layers can not be detected. Increased retinal thickness, intraretinal oedema, or presence of subretinal fluid may then affect the AF signal. Another limitation of the AF capture method is that an optimal AF image can only be obtained when the studied surface is in focus, so AF areas wich are not in focus can be underestimated. To the best of our knowledge, NIR-AF characteristics of CSC have not been reported in detail before. SW-AF and NIR-AF imaging provide valuable information regarding the course of the CSC. Leaking point was observed as hypoaf spot in nearly all of our cases with NIR-AF imaging. Granular hyperaf pattern may support diagnosis of previous CSC and therefore AF can be used as a noninvasive diagnostic tool for diagnosis of former CSC. Figure Legends: Figure 1: A 45-year-old man complained of decreased vision for about 2 weeks. (A) Redfree image of a case with acute CSC. (B) Pinpoint leakage site is seen temporal to the fovea. (C) HypoSW-AF spot is seen corresponding to the leakage site (arrow). Serous detachment area (arrowheads) is also observed hyposw-af (acute phase). (D) NIR-AF imaging corresponds to SW-AF imaging (acute phase). (E) SW-AF picture after resolution: note that leaking point-associated hypo-sw-af spot became considerably smaller due to resorbtion of fibrin. (F) NIR-AF picture after resolution: macular AF is restored, and visibility of the leaking point hypoaf is more prominent than SW-AF image. Figure 2: A 32-year-old woman presented with acute visual loss in her left eye of 2 weeks duration. (A) Fluorescein angiogram obtained in acute phase reveals leaking spot. Although, no leaking site related hypoaf spot is seen in SW-AF clearly (B), NIR-AF imaging demonstrates leakage site. Additionally NIR-AF imaging reveals several other hypoaf spots which are not actively leaking on angiogram (arrows). (C). Fluorescein angiogram performed after resolution of the subretinal fluid revealed no leakage but several additional RPE lesions were visible corresponding to the NIR-AF imaging (D). Although, no remarkable leakage site related hyposw-af spot is seen (E), NIR-AF 6

7 imaging still demonstrates leakage site clearly after resolution of the serous retinal detachment (arrows) (F). Figure 3: A 35-year-old woman complained of blurred and decreased vision in her right eye of 3 weeks duration. (A) Infrared reflectance image of a case with acute CSC indicating serous detachment. (B) Pinpoint leakage site is seen superior to the fovea. (C) Six months after beginning of the symptoms and two months after resolution, SW-AF image appears near normal except the hypoaf spot at leakage site(arrow). (D) NIR-AF imaging obtained the same day as SW-AF image depicts granular hyperaf pattern corresponding to former retinal detachment area (arrowheads). Licence to BMJ Publishing Group Limited ( BMJ Group ) for Publication The Corresponding Author (Ali AYATA, MD) has the right to grant on behalf of all authors and does grant on behalf of all authors, a non exclusive licence on a worldwide basis to the BMJ Publishing Group Ltd and its licencees, to permit this article (if accepted) to be published in BJO and any other BMJ Group products and to exploit all subsidiary rights, as set out in our licence ( Competing interest: None. Funding: None References 1. Wang M, Munch IC, Hasler PW, Prünte C, Larsen M. Central serous chorioretinopathy. Acta Ophthalmol Scand. 2007;28; Delori FC, Dorey CK, Staurenghi G, et al. In vivo fluorescence of the ocular fundus exhibits retinal pigment epithelium lipofuscin characteristics. Invest Ophthalmol Vis Sci 1995;36: von Rückmann A, Fitzke FW, Bird AC. Distribution of fundus autofluorescence with a scanning laser ophthalmoscope. Br J Ophthalmol. 1995:79: Feeney-Burns L, Berman ER, Rothman H. Lipofuscin of human retinal pigment epithelium. Am] Ophthalmol. 1980;90: 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: Robson AG, Saihan Z, Jenkins SA, Fitzke FW, Bird AC, Webster AR, Holder GE. Functional characterisation and serial imaging of abnormal fundus autofluorescence in patients with retinitis pigmentosa and normal visual acuity. Br 7

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10 Near-Infrared and Short-Wavelength Autofluorescence Imaging in Central Serous Chorioretinopathy Ali Ayata, Sinan Tatlipinar, Taner Kar, Resident, Melih Unal, Dilaver Ersanli and Ahmet H Bilge Br J Ophthalmol published online October 1, 2008 Updated information and services can be found at: alerting service These include: Receive free alerts when new articles cite this article. Sign up in the box at the top right corner of the online article. Topic Collections Articles on similar topics can be found in the following collections Retina (1590) Notes To request permissions go to: To order reprints go to: To subscribe to BMJ go to: