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i ■ m a g c l i n i c a l i n g s c i e n c e ■ Ultra-Wide–Field Green-Light (532-nm) Autofluorescence Imaging in Chronic Vogt-Koyanagi-Harada Disease Florian M. Heussen, MD; Daniel V. Vasconcelos-Santos, MD, PhD; Rajeev R. Pappuru, MD; Alexander C. Walsh, MD; Narsing A. Rao, MD; Srinivas R. Sadda, MD n BACKGROUND AND OBJECTIVE: To assess the prevalence of peripheral fundus autofluorescence (FAF) abnormalities in chronic Vogt-Koyanagi-Harada disease (VKH). n PATIENTS AND METHODS: A retrospective review of cases at the Doheny Eye Institute between December 2009 and April 2010. Patients with chronic VKH who had ultra-wide–field FAF and pseudo-color imaging performed were included. All images were reviewed independently by two reading center certified retina specialists. ed in this analysis. Fourteen eyes of 7 patients (70%) showed peripheral changes on FAF images outside the posterior pole. Three different patterns were observed: multifocal hypofluorescent spots (n = 11 eyes), hyperfluorescent spots (n = 8 eyes), and a unique lattice-like pattern in both eyes of one patient. There were noticeable disparities between FAF and color images. n CONCLUSION: Peripheral FAF abnormalities are frequent in chronic VKH and are readily revealed by widefield FAF imaging and manifesting with distinct patterns. Further investigation in prospective studies is warranted. n RESULTS: Twenty eyes of 10 patients were includ- [Ophthalmic Surg Lasers Imaging 2011;42:272-277.] INTRODUCTION sive clinical stages.1-3 In the acute uveitic stage, leakage at the level of the retinal pigment epithelium (RPE) leads to bilateral exudative retinal detachments, which usually resolve after adequate high-dose steroid thera- Vogt-Koyanagi-Harada disease (VKH) is a bilateral granulomatous panuveitis characterized by succes- From the Doheny Eye Institute and the Department of Ophthalmology, Keck School of Medicine, University of Southern California, Los Angeles, California. Originally submitted January 11, 2011. Accepted for publication March 24, 2011. Posted online May 12, 2011. Supported in part by NIH Grant EY03040 and NEI Grant R01 EY014375. Drs. Sadda and Walsh share in royalties from intellectual property licensed to Topcon Medical Systems by the Doheny Eye Institute. Dr. Sadda serves on the scientific advisory board for Heidelberg Engineering and receives research support from Carl Zeiss Meditec and Optovue Inc. This is not related to the article’s subject matter. The remaining authors have no financial or proprietary interest in the materials presented herein. Address correspondence to Srinivas R. Sadda, MD, Doheny Eye Institute, 1450 San Pablo Street, Los Angeles, CA 90033. E-mail: [email protected] doi: 10.3928/15428877-20110505-01 272 Copyright © SLACK Incorporated i m a g py. Patients then enter a convalescent stage, but some may present recurrences (chronic recurrent stage)1-4 and progressive chorioretinal damage mainly associated with RPE changes.1,5 Such RPE changes can lead to vision-threatening complications, subretinal fibrosis, and choroidal neovascularization.1,5 New advances in imaging of the outer retina and RPE may aid in better characterizing and monitoring the retinal changes in VKH, with a possible impact on the optimal management of the disease.5 Fundus autofluorescence (FAF) is based on excitation of inherent fluorophores by light of a certain wavelength (typically between 488 and 585 nm) and recording the emitted light to create a brightness map. The nature of excited fluorophores greatly depends on the excitation wavelength used. A prevalent fluorophore is lipofuscin6 and its composites, such as N-retinyl-N-retinylidene ethanolamine (A2E), the accumulation of which is seen as an indicator for metabolic stress on RPE cells. Therefore, an increase or decrease in FAF has been shown to correlate with integrity and functional status of the photoreceptor–RPE complex, and FAF imaging is increasingly being used for qualitative assessment of RPE pathology, also due in part to its noninvasive nature.7 Frequently, inflammatory diseases of the posterior segment directly or indirectly involve the RPE and underlying choriocapillaris, and as such many investigators have suggested that FAF imaging may be useful in evaluating these diseases. Some studies have demonstrated that FAF imaging may be superior to ophthalmoscopy for the clinical assessment of RPE damage in these inflammatory entities,8 including in VKH.5 However, in VKH many of these changes manifest in the periphery, which may be beyond the field of view of traditional FAF imaging techniques that tend to focus on the posterior pole. As a result, more peripheral FAF abnormalities in VKH have not been characterized or compared with the ophthalmoscopic findings. Recently, a prototype wide-field green-light (532-nm) autofluorescence imaging system (Optos P200CAF; Optos, Dunfermline, UK) has been developed, allowing assessment of more peripheral FAF abnormalities. In this report, we identify the frequency and morphology of these peripheral FAF changes in a series of patients with chronic VKH. PATIENTS AND METHODS A retrospective review was conducted of all patients with VKH consecutively seen at Doheny Eye Ophthalmic Surgery, Lasers & Imaging · Vol. 42, No. 4, 2011 i n g Institute from December 2009 to April 2010. The diagnosis of VKH established by one of the authors (NAR) according to the most recently revised criteria4,9 and chronic disease was defined based on a duration of intraocular inflammation longer than 3 months. Additionally, for inclusion in the study these patients had to have been imaged with the P200CAF Wide-field-Autofluorescence scanning laser ophthalmoscope prototype (532-nm; Optos). All patients underwent both FAF imaging and pseudo-color (red and green only) imaging by the same machine, in addition to color fundus photographs in a regular fundus camera. Ten cases met the aforementioned criteria and were included in this analysis. For all 10 subjects, a detailed medical chart review was performed and anonymous demographic and clinical data were recorded in a separate database, including gender, age, ethnicity, disease duration, visual acuity, and findings for slit-lamp biomicroscopy and mydriatic ophthalmoscopy. The research protocol was approved by the Institutional Review Board of the University of Southern California and was in accordance with tenets set forth in the Declaration of Helsinki. All subjects signed a written informed consent form. All FAF images were reviewed and graded by two retina specialists (SRS and ACW), who are certified graders and investigators at the Doheny Image Reading Center. Regions of increased, decreased, or isointense FAF relative to background fluorescence were noted and compared with corresponding locations on the pseudo-color images. Similarly, abnormalities noted on the pseudo-color images were compared and correlated with corresponding locations on the FAF images. Particular care was taken to compare areas of sunset glow fundus, evident on the color images, with the FAF images. Common patterns of peripheral FAF abnormalities were identified. Pseudo-color images were also compared and validated against regular color photographs. RESULTS Of the 10 patients included in this study, 9 were women and 1 was a man. The ages ranged from 25 to 57 years (mean: 40.0 ± 8.7 years; median: 40.0 years). Three patients were in the convalescent stage of VKH and were not receiving any anti-inflammatory therapy at the time of evaluation. Three patients 273 i m a g i n g Table Clinical Features of a Series of Patients With Chronica Vogt-Koyanagi-Harada Disease and Peripheral FAF Changes Case No. BCVA Sex Age (Y) Disease Duration (Mo) Disease Status Current Treatment OD OS 1 F 43 137 Inactive Prednisonec 20/20 20/40 OD/OS multifocal hypofluorescent spots (< 20), solitary hyperfluorescent spots (< 20) 2 F 25 34 Inactive MFM, prednisonec 20/30 20/30 OD/OS multifocal hypofluorescent spots (> 100), solitary hyperfluorescent spots (< 20) 3 F 32 36 Inactive None 20/20 20/20 None 4 F 42 7 Inactive MFM, prednisone 20/40 20/25 None 5 M 37 240 Inactive 20/30 20/300 OD/OS multifocal hypofluorescent spots (> 20 and < 100) 6 F 36 218 Inactive None 20/20 20/25 OD/OS multifocal hypofluorescent spots (> 20 and < 100), solitary hyperfluorescent spots (< 20) 7 F 47 24 Active Prednisonec 20/25 20/200 OD hyperfluorescent spots (+), OS multifocal hypofluorescent spots (< 20), solitary hyperfluorescent spots (< 20) 8 F 57 4 Inactive CSA, prednisone 20/50 20/25 OD/OS lattice-like pattern 9 F 43 90 Inactive Prednisonec 20/20 20/25 OD/OS multifocal hypofluorescent spots (> 20 and < 100) 10 F 38 51 Inactive None 20/20 20/20 Topical prednisone Peripheral FAF Abnormalitiesb None FAF = fundus autofluorescence; BCVA = best-corrected visual acuity; OD = right eye; OS = left eye; MFM = mycophenolate mofetil; CSA = cyclosporine A. a Defined as during > 3 months. b Number of observed lesions in parentheses. c Dose < 5 mg/day. were receiving a low oral dose (< 5 mg/day) of prednisone alone, two patients were receiving oral prednisone and mycophenolate mofetil, and one patient was receiving a combination of oral prednisone and cyclosporine-A. Disease duration ranged widely from 4 to 240 months (median: 43.5 months) and active intraocular inflammation was noted in only 1 patient at the time of wide-field FAF imaging. Best-corrected visual acuity (BCVA) ranged from 20/300 to 20/20 (Table). On ophthalmoscopy, all eyes were noted to have varying degrees of sunset glow fundus. Peripheral FAF changes were seen in 14 eyes of 7 274 patients, whereas 3 patients had no FAF abnormalities in either eye. The predominant FAF abnormality was the presence of multifocal, nummular foci of decreased autofluorescence signal in 11 eyes of 6 patients, which could be correlated to chorioretinal scars on the pseudo-color images in most instances (Fig. 1). Eight of the 14 eyes with FAF abnormalities also showed focal spots of increased autofluorescence signal, which were generally far fewer in number than the hypofluorescent foci and did not appear to correlate with abnormalities on the pseudo-color images (Figs. 1 and 2). One patient presented distinc- Copyright © SLACK Incorporated i m a g i n g Figure 2. Right eye of case 1. Few sharply demarcated hypofluorescent spots are visible on the fundus autofluorescence image (A), which correlate to scars on the pseudo-color image (B). In this case, a hyperfluorescent spot marked with an arrow on A shows no correlate on B. Similarly, a small group of hypofluorescent spots is clearly visible on A (arrow with asterisk), yet more difficult to spot on image B. Figure 1. Fundus autofluorescence (FAF) (A and B), pseudo-color (C and D), and color images (E and F) of case 2 showing both eyes. Multifocal hypofluorescent foci are clearly visible on both FAF images, which correlate well with the chorioretinal scars in C and D. In addition, few hyperfluorescent spots are seen. Interestingly, hyperpigmentation does not reliably show up on FAF images (arrows) and other disparities are clearly seen (arrows with asterisk). The sunset glow fundus changes seen on the pseudo-color and the color images show no correlate on the FAF images. tive changes on FAF, namely a striking lattice-like pattern of increased autofluorescence signal (Fig. 3). On closer inspection of the pseudo-color images (and regular color photographs), many of these streaks correlated with linear bands of hyperpigmentation. No correlation was observed between the pattern or extent of FAF abnormalities and current disease activity or treatment regimen. A summary of these findings is shown in the table. The sunset glow fundus changes were apparent on regular color fundus photographs and less so on the wide-field pseudo-color images. Interestingly no direct correlate for the sunset glow changes could be seen on the FAF images, independent of the degree of changes. Overall, there was good agreement between the chorioretinal lesions on regular color fundus photographs and their aspect on wide-field pseudo-color imaging, although the latter was able to show more peripheral lesions. Ophthalmic Surgery, Lasers & Imaging · Vol. 42, No. 4, 2011 Figure 3. Both eyes of case 8. The fundus autofluorescence images (A and B) demonstrate a lattice-like pattern of hyperfluorescence along the vascular arcades. Some streaks can be correlated to pigmented lines seen on the color images (C and D) as indicated by the arrows (B and D). DISCUSSION In the current study, we report the frequency and pattern of peripheral FAF abnormalities in a series of patients with chronic VKH in southern California. The functional assessment of the RPE layer through FAF imaging may be valuable in these patients5 because RPE changes have been associated with severe vision-threatening complications in chronic VKH.1 The peripheral changes reported in the current study were documented by a wide-field FAF scanning laser ophthalmoscope prototype, which allows for a more thorough assessment of the retinal periphery than conventional FAF instruments. Not unexpectedly in this disease population, 7 of 10 cases (14 of 20 eyes) showed peripheral FAF changes and common patterns of FAF abnormalities could be identified. 275 i m a The most prevalent FAF changes were multifocal sharply demarcated foci of decreased autofluorescent signal (in 11 eyes of 6 patients). These hypofluorescent foci appeared to have a stereotypic appearance across cases and were easy to identify due to the high contrast of wide-field FAF images. On pseudo-color (and regular color) images, these foci corresponded to nummular atrophic scars with various degrees of pigmentation, which have been shown in both opticalcoherence-tomography–based5 and histopathological studies10,11 of patients with chronic VKH. In these areas, the decreased autofluorescence signal is associated with disruption in the outer retina, RPE atrophy, and subsequent loss of fluorophores.5,11 Eight eyes also demonstrated focal spots of increased autofluorescence signal, but the morphology of these lesions was more variable, with spots varying in both size and brightness. Some foci of increased autofluorescence signal did not correlate to any fundus findings seen on pseudo-color imaging (and regular color fundus photographs). It is possible that these lesions represent areas of subclinical disease that may eventually develop into zones of RPE atrophy, similar to the progression of hyperfluorescent abnormalities in macular diseases such as atrophic age-related macular degeneration.12 Interestingly, one patient also presented with a lattice-like pattern of hyperfluorescent streaks in both eyes (Fig. 3). Only after careful comparison were some of the streaks found to match faint pigmented lines in the corresponding color image. Even within our database of more than 400 imaged patients with more than 20 different posterior uveitides, we did not see another case with this lattice-like FAF pattern. The clinical significance of this unique finding and whether it is only associated with chronic VKH remains unclear. Based on our previous fundus autofluorescence and spectraldomain optical coherence tomography (SD-OCT) studies in VKH, these areas likely correspond to foci of RPE proliferation with a possibly spared outer retinal architecture.5 However, the precise histologic correlate is still speculative, because the far peripheral location of some of these abnormalities precluded obtaining SDOCT scans through these lesions. One should bear in mind that hyperpigmentation does not necessarily contribute to an increased autofluorescence signal, which is rather due to an increased level of fluorophores.13 Although there are pigmented 276 g i n g fluorophore compounds such as melanolipofuscin, the dominant fluorophores do not seem to have a close relation to the level of pigmentation. However, in areas where the RPE has proliferated, an increase in the total amount of fluorophores or their accumulation in the outer retina might still be associated with an increased autofluorescence signal.5 Particularly in inflammatory diseases, a high fluorophore content might also be associated with a local pro-oxidative environment, although the nature and exact localization of these specific fluorophores are largely unknown.14 Of note, some spots of decreased autofluorescence signal could not be clearly correlated to respective sites on the pseudo-color images, and similarly some findings on the pseudo-color images were not associated with any abnormality on FAF imaging. Underlying reasons for this phenomenon are manifold. Heavily depigmented spots on the pseudo-color images might mimic RPE atrophy and even atrophic areas might still show a level of autofluorescence due to choroidal and scleral autofluorescent properties. In addition, the autofluorescent signal can be blocked by structures/pigment anterior to the source of emission.7 All of our patients exhibited varying degrees of sunset glow fundus on clinical examination. This fundus change is associated with depigmentation of the choroid10,11 and has been regarded as a distinctive clinical feature of chronic VKH.3 One aim of our study was to seek a correlation between FAF changes and the sunset glow fundus. However, in concordance with previous reports,5 the autofluorescence signal was preserved in these areas and undistinguishable from normal background autofluorescence. This is presumably because choroidal changes do not contribute significantly to the green-light autofluorescence signal, which largely originates from the lipofuscin content of the RPE.6 Thus, even a heavily depigmented choroid is not detectable via fundus autofluorescence alone in the presence of vital RPE. This shows that although the autofluorescence signal carries additional clinical information, it should be regarded as adjunctive imaging in combination with color fundus photographs. Also of note, regular color fundus photographs more easily demonstrated the sunset glow fundus when compared with pseudo-color images in this study. We did not find any association between the number and type of FAF changes and disease duration or inflammatory activity. However, this is a small series Copyright © SLACK Incorporated i m a g and FAF imaging was only reported at a single time point. Therefore, we cannot rule out the influence of therapy and recurrences in the prevalence of these FAF changes. There are limitations to our study, mainly the small sample size with a variable duration of disease and the lack of longitudinal data. It is not yet known how these FAF patterns evolve over time and whether changes in FAF patterns may be used as a reliable marker of disease progression. In addition, the abnormalities identified in this study are based on scanning laser ophthalmoscope green-light autofluorescence. As such, the patterns may not correspond to findings from flash-based FAF approaches or other wavelengths, such as blue or near-infrared. Finally, the use of pseudo-color widefield images (which are based on a reconstructed color map of only two color channels: red and green but not blue) might not provide images as accurate as regular color fundus photography. Although it is known that little information is carried in the blue channel, we also compared the pseudo-color images with regular color fundus photographs to attenuate this possible bias. We observed that peripheral FAF abnormalities are frequent in patients with chronic VKH and may be readily detected using wide-field FAF imaging. These FAF abnormalities do not always correlate with abnormalities visible on ophthalmoscopy or color photography. At the same time, ophthalmoscopic findings do not necessarily have a correlate on FAF images, as is the case with sunset glow fundus changes that are not apparent on FAF images. Still, we believe that wide-field FAF imaging might be useful to assess peripheral RPE Ophthalmic Surgery, Lasers & Imaging · Vol. 42, No. 4, 2011 i n g changes in patients with chronic VKH. However, the exact clinical relevance of these FAF changes needs to be investigated in future prospective studies. REFERENCES 1. Moorthy RS, Inomata H, Rao NA. Vogt-Koyanagi-Harada syndrome. Surv Ophthalmol. 1995;39:265-292. 2. Sugiura S. Vogt–Koyanagi–Harada disease. Jpn J Ophthalmol. 1978;22:9-35. 3. Rao NA, Gupta A, Dustin L, et al. Frequency of distinguishing clinical features in Vogt-Koyanagi-Harada disease. Ophthalmology. 2010;117:591-599. 4. Read RW, Holland GN, Rao NA, et al. Revised diagnostic criteria for Vogt-Koyanagi-Harada disease: report of an international committee on nomenclature. Am J Ophthalmol. 2001;131:647-652. 5. Vasconcelos-Santos DV, Sohn EH, Sadda S, Rao NA. Retinal pigment epithelial changes in chronic Vogt-Koyanagi-Harada disease: fundus autofluorescence and spectral domain-optical coherence tomography findings. Retina. 2010;30:33-41. 6. 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;36:718-729. 7. Schmitz-Valckenberg S, Holz FG, Bird AC, Spaide RF. Fundus autofluorescence imaging: review and perspectives. Retina. 2008;28:385409. 8. Haen SP, Spaide RF. Fundus autofluorescence in multifocal choroiditis and panuveitis. Am J Ophthalmol. 2008;145:847-853. 9. Rao NA, Sukavatcharin S, Tsai JH. Vogt-Koyanagi-Harada disease diagnostic criteria. Int Ophthalmol. 2007;27:195-199. 10. Inomata H, Rao NA. Depigmented atrophic lesions in sunset glow fundi of Vogt-Koyanagi-Harada disease. Am J Ophthalmol. 2001;131:607-614. 11. Rao NA. Pathology of Vogt-Koyanagi-Harada disease. Int Ophthalmol. 2007;27:81-85. 12. Schmitz-Valckenberg S, Fleckenstein M, Scholl HP, Holz FG. Fundus autofluorescence and progression of age-related macular degeneration. Surv Ophthalmol. 2009;54:96-117. 13. Bindewald A, Bird AC, Dandekar SS, et al. Classification of fundus autofluorescence patterns in early age-related macular disease. Invest Ophthalmol Vis Sci. 2005;46:3309-3314. 14. Spaide RF. Chorioretinal inflammatory disorders. In: Holz FG, Schmitz-Valckenberg S, Spaide RF, Bird AC, eds. Atlas of Fundus Autofluorescence Imaging. Berlin: Springer; 2007:207-239. 277