Fundus Autofluorescence and Progression of Age-related Macular Degeneration

Fundus autofluorescence imaging is an imaging method that provides additional information compared to conventional imaging techniques. It permits to topographically map lipofuscin distribution of the retinal pigment epithelial cell monolayer. Excessive accumulation of lipofuscin granules in the lysosomal compartment of retinal pigment epithelium cells represents a common downstream pathogenetic pathway in various hereditary and complex retinal diseases including age-related macular degeneration (AMD). This comprehensive review contains an introduction in fundus autofluorescence imaging, including basic considerations, the origin of the signal, different imaging methods, and a brief overview of fundus autofluorescence findings in normal subjects. Furthermore, it summarizes cross-sectional and longitudinal fundus autofluorescence findings in patients with AMD, addresses the pathophysiological significance of increased fundus autofluorescence, and characterizes different fundus autofluorescence phenotypes as well as fundus autofluorescence alterations with disease progression.     

Choroideremia Carriers: Dark-Adapted Perimetry and Retinal Structures

PurposeIn choroideremia (CHM) carriers, scotopic sensitivity was assessed by dark adapted chromatic perimetry (DACP) and outer retinal structure was evaluated by multimodal imaging.MethodsNine carriers (18 eyes) and 13 healthy controls (13 eyes) underwent DACP testing with cyan and red stimuli. Analysis addressed peripapillary (4 test locations closest to the optic disc), macular (52 locations), and peripheral (60 locations outside the macula) regions. Responses were considered to be rod-mediated when cyan relative to red sensitivity was >5 dB. Fundus imaging included spectral domain optical coherence tomography (SD-OCT), short-wavelength (SW-AF), near-infrared (NIR-AF), ultrawide-field (200 degrees) pseudocolor fundus imaging, and quantitative (qAF) fundus autofluorescence.ResultsDetection of the cyan stimulus was rod mediated in essentially all test locations (99.7%). In the macular and peripheral areas, DACP sensitivity values were not significantly different from healthy eyes. In the peripapillary area, sensitivities were significantly decreased (P < 0.05). SD-OCT imaging ranged from hyper-reflective lesions and discontinuities of the outer retinal bands to hypertransmission of signal. SW-AF and NIR-AF images presented with peripapillary atrophy in seven patients (14 eyes). Mosaicism was detectable in SW-AF images in seven patients and in NIR-AF images in five patients. Frank hypo-autofluorescence was visible in eight patients with distinct chorioretinopathy in seven patients. The qAF values were below the 95% confidence interval (CI) of healthy age-matched individuals in 12 eyes.ConclusionsRod mediated scotopic sensitivity was comparable to that in control eyes in macular and peripheral areas but was decreased in the peripapillary area where changes in retinal structure were also most severe.     

眼底自发荧光技术在眼科中的应用

眼底自发荧光是一种新近发展的眼底成像技术,它能显示RPE的分布情况。观察自发荧光的分布及其强度,有助于确定某些视网膜疾病的诊断及其预后评价。本文就自发荧光的基本原理及其在各种视网膜疾病中的表现作一综述。     

Lipofuscin and the Principles of Fundus Autofluorescence: A Review

Fundus autofluorescence is a non-invasive imaging modality that measures lipofuscin that has accumulated in the retinal pigment epithelium (RPE). Excessive lipofuscin in the RPE is a common pathway found in several diseases including Stargardt’s disease and age-related macular degeneration. This review discusses the role of photooxidative damage in the development of lipofuscin and the principles of fundus autofluorescence.     

Fundus autofluorescence in children and teenagers with hereditary retinal diseases

Introduction In adults, evaluation of fundus autofluorescence (AF) plays an important role in the differential diagnosis of retinal diseases. The aim of this study was to evaluate the feasibility of recording AF in children and teenagers and to define typical AF findings of various hereditary retinal diseases during childhood. Methods Fifty patients aged 2 to 16 years with hereditary retinal diseases were analysed using the HRA (Heidelberg Retina Angiograph). To enhance the AF signal, a mean of up to 16 single images was calculated. Twenty healthy children (aged 4–16 years) served as controls. Results In many children as young as 5 years of age and even in one 2-year-old child good AF images could be obtained. To achieve high quality images, larger image series (about 50 single images) were taken and appropriate single images were chosen manually to calculate the mean. Characteristically, Stargardt disease shows a central oval area of reduced AF, often surrounded by more irregular AF. In patients with Best disease, a central round structure with regular or irregular intense AF is visualised. Some patients with X-linked retinoschisis show central radial structures. In many patients with rod-cone dystrophies, a central oval ring-shaped area of increased AF is present. In early-onset severe retinal dystrophy (EOSRD) with RPE65 mutations AF is completely absent, whereas in other forms of Leber congenital amaurosis, AF is normal. Discussion Fundus autofluorescence may visualise disease-specific distributions of lipofuscin in the retinal pigment epithelium, often not (yet) visible on ophthalmoscopy. AF images can be used in children to differentiate hereditary retinal diseases and to facilitate follow-up controls. In many cases, four single images are sufficient to analyse the AF pattern. Presented in part at the 102nd Meeting of the German Ophthalmological Society (DOG)     

Chloroquine retinopathy: lipofuscin- and melanin-related fundus autofluorescence,optical coherence tomography and multifocal electroretinography

Purpose To evaluate melanin-related near-infrared fundus autofluorescence (NIA, excitation 787 nm, emission > 800 nm), lipofuscin-related fundus autofluorescence (FAF, excitation 488 nm, emission >500 nm), optical coherence tomography (OCT), and multifocal electroretinography (mfERG) in patients with chloroquine (CQ) retinopathy. Methods Two patients with progressed CQ retinopathy underwent clinical examination, ISCEV mfERG evaluation, and FAF and NIA imaging using a confocal scanning laser ophthalmoscope (Heidelberg Retina Angiograph 2) with either a 30° or wide-angle field-of-view. OCT3 imaging was performed in one of these patients. Results In the foveola, FAF and NIA were relatively normal. Parafoveal loss of retinal pigment epithelium (RPE) was indicated by absent FAF and NIA. An area of reduced FAF and NIA surrounded the parafoveal region of RPE loss. In the adjacent area, FAF was increased and increased NIA marked the peripheral border of increased FAF. Wide-field imaging revealed increased FAF in association with retinal vessels. Retinal thickness was markedly reduced in the OCT predominantly in the parafoveal region. Visual field loss and mfERG amplitude reduction corresponded to areas with increased or reduced FAF and NIA. Conclusion Patterns of FAF and NIA indicate different stages of pathophysiologic processes involving lipofuscin and melanin in the RPE. Combined retinal imaging and functional testing provides further insights in the pathogenesis and development of retinal degenerative disease. An association of CQ retinopathy with retinal vessels architecture is hypothesized.     

The Role of Fundus Autofluorescence in Late-Onset Retinitis Pigmentosa (LORP) Diagnosis

Abstract

Purpose: To demonstrate the utility and characteristics of fundus autofluorescence in late-onset retinitis pigmentosa.

Methods: Observational case series. Patients diagnosed with late-onset retinitis pigmentosa were identified retrospectively in an institutional setting. Twelve eyes of six patients were identified and medical records were reviewed.

Results: All patients presented with slowly progressive peripheral field loss and initial clinical examination revealed only subtle retinal changes. There was a notable lack of intraretinal pigment migration in all patients. Five out of six patients underwent magnetic resonance imaging of the brain to rule out intracranial processes and all were referred from another ophthalmologist for further evaluation. Fundus autofluorescence was ultimately employed in all patients and revealed more extensive retinal pathology than initially appreciated on clinical examination. Fundus autofluorescence directed the workup toward a retinal etiology in all cases and led to the eventual diagnosis of late-onset retinitis pigmentosa through electroretinogram testing.

Conclusion: Fundus autofluorescence may be a more sensitive marker for retinal pathology than stereo fundus biomicroscopy alone in late-onset retinitis pigmentosa. Early use of fundus autofluorescence imaging in the evaluation of patients with subtle retinal lesions and complaints of peripheral field loss may be an effective strategy for timely and cost-efficient diagnosis.     

Fluorescence lifetime imaging ophthalmoscopy

Imaging techniques based on retinal autofluorescence have found broad applications in ophthalmology because they are extremely sensitive and noninvasive. Conventional fundus autofluorescence imaging measures fluorescence intensity of endogenous retinal fluorophores. It mainly derives its signal from lipofuscin at the level of the retinal pigment epithelium. Fundus autofluorescence, however, can not only be characterized by the spatial distribution of the fluorescence intensity or emission spectrum, but also by a characteristic fluorescence lifetime function. The fluorescence lifetime is the average amount of time a fluorophore remains in the excited state following excitation. Fluorescence lifetime imaging ophthalmoscopy (FLIO) is an emerging imaging modality for in vivo measurement of lifetimes of endogenous retinal fluorophores. Recent reports in this field have contributed to our understanding of the pathophysiology of various macular and retinal diseases.Within this review, the basic concept of fluorescence lifetime imaging is provided. It includes technical background information and correlation with in vitro measurements of individual retinal metabolites. In a second part, clinical applications of fluorescence lifetime imaging and fluorescence lifetime features of selected retinal diseases such as Stargardt disease, age-related macular degeneration, choroideremia, central serous chorioretinopathy, macular holes, diabetic retinopathy, and retinal artery occlusion are discussed. Potential areas of use for fluorescence lifetime imaging ophthalmoscopy will be outlined at the end of this review.     

Fundus autofluorescence imaging: Fundamentals and clinical relevance

Fundus autofluorescence (FAF), a relatively new imaging modality, focuses on the fluorescent properties of pigments in the retina to generate images that help us view various disease processes from a different perspective. It aids us in the understanding of the pathophysiology of different retinal disorders. Recently, FAF imaging is being used commonly to help us in the diagnosis, prognosis as well as in determining the treatment response of various retinal disorders. It generates an image based on the distribution pattern of a fluorescent pigment called lipofuscin. Knowing the distribution pattern of lipofuscin in the normal retina is key to understanding an FAF image representing a retinal pathology. Like most other imaging modalities, FAF comes with its own limitations, taking steps to overcome these limitations will be of utmost importance in using this imaging modality to its fullest potential.     

Fundus autofluorescence imaging of retinal dystrophies

Fundus autofluorescence (FAF) is a non-invasive imaging technique that enables the visualization of lipofuscin changes in the retinal pigment epithelium. This study aims to illustrate the spectrum of FAF changes in a variety of retinal dystrophies. For this purpose, we examined patients with retinal dystrophies such as Stargardt disease, Best vitelliform macular dystrophy, and retinal dystrophies associated with mutations in the peripherin/RDS gene. All retinal dystrophies were confirmed by molecular genetic analysis. A broad range of characteristic FAF patterns was observed. Our results indicate that FAF imaging constitutes a useful additive tool in the diagnosis and follow-up of various retinal dystrophies.     

Macular autofluorescence in eyes with cystoid macula edema,detected with 488 nm-excitation but not with 580 nm-excitation

Background  Fundus autofluorescence (AF) derives from lipofuscin in the retinal pigment epithelium (RPE). Because lipofuscin is a by-product of phagocytosis of photoreceptors by RPE, AF imaging is expected to describe some functional aspect of the retina. In this study we report distribution of AF in patients showing macular edema. Methods  Three eyes with diabetic macular edema (DME) and 11 with retinal vein occlusion (RVO), associated with macular edema (ME) were examined. ME was determined by standard fundus examination, fluorescein angiography (FA) and optical coherence tomography (OCT). AF was recorded using a Heidelberg confocal scanning laser ophthalmoscope (cSLO) with 488 nm laser exciter (488 nm-AF), and a conventional Topcon fundus camera with halogen lamp exciter and 580 nm band-pass filter (580 nm-AF). Color fundus picture, FA image and these two AF images were analyzed by superimposing all images. Results  All subjects presented cystoid macular edema (CME) with petaloid pattern hyperfluorescence in FA. In 488 nm-AF, all eyes (100%) showed macular autofluorescence of a similar shape to that of the CME in FA. In contrast, in 580 nm-AF only one eye (7%) presented this corresponding petaloid-shaped autofluorescence. In all cases, peripheral retinal edemas did not show autofluorescence corresponding to the leakage in FA. Conclusions  In eyes with CME, analogous hyperautofluorescence to the CME was always observed in 488 nm-AF, while it was rarely observed in 580 nm-AF. Moreover, this CME hyperautofluorescence was only seen in the macular area. We hypothesize that autofluorescence from CME may be considered as a “pseudo” or “relative” autofluorescence, due to macular stretching following CME that may result in lateral displacement of macular pigments (MPs) and subsequent reduction of MPs density, as MPs block 488 nm-AF more intensely than 580 nm-AF. Although this phenomenon may not directly indicate change of RPE function, it may be used as a method to assess or track CME non-invasively. No author has financial relationship for this research. Kenichiro Bessho and Fumi Gomi have full control of all primary data. The authors agree to allow Graefe’s Archive for Clinical and Experimental Ophthalmology to review their data upon request.     

Fundus Autofluorescence Imaging in Punctate Inner Choroidopathy with Blind Spot Enlargement

Purpose: To present a case report in which fundus autofluorescence (FAF) helped to diagnose and monitor the clinical course of a patient diagnosed with punctate inner choroidopathy (PIC).

Methods: Retrospective chart review of patient data.

Results: FAF showed multiple hypoautofluorescent spots in the posterior pole.It also showed an area of hypoautofluorescence surrounded by a ring of hyperautofluorescence, which corresponded to a larger lesion seen clinically. As the disease became inactive, the number of hypoautofluorescent spots decreased. The rim of hyperautofluorescence surrounding the macular lesion became attenuated.Persistent hypofluorescent areas grew in size.

Conclusions: FAF is a useful imaging modality to better visualize and delineate the extent of damaged retinal pigment epithelium (RPE) in PIC. FAF also helps the clinician to assess the resolution of the disease by the appearance of the RPE.     

Fundus autofluorescence applications in retinal imaging

Fundus autofluorescence (FAF) is a relatively new imaging technique that can be used to study retinal diseases. It provides information on retinal metabolism and health. Several different pathologies can be detected. Peculiar AF alterations can help the clinician to monitor disease progression and to better understand its pathogenesis. In the present article, we review FAF principles and clinical applications.     

以临床前期糖尿病视网膜病变为例分析医学图像人工智能系统在自发荧光图像识别中的应用

目的：以临床前期糖尿病视网膜病变为例分析医学图像人工智能系统对于自发荧光图像识别的能力，为早期诊断治疗提供技术支持。方法：连续收集2017年8月至2018年5月在温州医科大学附属第三医院眼科门诊就诊患者的眼底自发荧光图像，按是否患有糖尿病标准，纳入正常组102例（200 眼），糖尿病组105例（200眼）。受检者均行裂隙灯显微镜、前置镜、裸眼视力或矫正视力、眼底自发荧光影像等检查。采用基于二维格子复杂性度量的医学图像特征提取和识别系统对糖尿病组及正常组图像进行分析。结果：该系统分析临床前期糖尿病视网膜病变眼底自发荧光图像与正常视网膜自发荧光图像具有可识别差异，提取出具有比较意义的25个特征。针对25个特征进行单个特征及多个特征的10折交叉检验以及5折交叉检验，准确率为82.47%。结论：复杂性分析医学图像人工智能系统可用于识别临床前期糖尿病视网膜病变的眼底自发荧光改变，准确率高。     

七种眼底形态的红外线扫描和自发荧光图像的分析

目的解析7种眼底形态的红外线（IR）扫描和自发荧光图像（AF）。方法使用Heidelberg公司HRA-Spectralis眼底检查系统,对537例患者（1023只眼）进行眼底IR和AF检查。结果从中选出8例（8只眼）具有典型特征的眼底图像。结论IR分辨率较一般眼底照相高,可用于眼底浅层疾病的检查诊断;AF在诊断视网膜色素上皮（RPE）病变上有无可比拟的优势,它反映的是RPE代谢的变化,且视网膜色素变性（RP）患者的AF图像有极其明显的特征,是检查诊断RP病的金指标。     

Fundus autofluorescence in patients with macular holes imaged with a laser scanning ophthalmoscope

AIM—To demonstrate the usefulness of a recently developed technique of imaging fundus autofluorescence and to compare it with the results of fluorescein angiography in the diagnosis and staging of macular holes.
METHODS—The intensity and distribution of fundus autofluorescence was studied in 51 patients with idiopathic macular holes and pseudoholes using a confocal laser scanning ophthalmoscope (cLSO) and the images were compared with those obtained by fundus fluorescein angiography.
RESULTS—Autofluorescence imaging demonstrated bright fluorescence of macular holes with appearance similar to that obtained by fluorescein angiography. In contrast macular pseuodoholes showed no such autofluorescence. The attached operculum in stage 2 macular holes and the preretinal operculum in stage 3 macular holes showed focal decreased autofluorescence. The associated retinal elevation and the cuff of subretinal fluid were less fluorescent compared with the background autofluorescence of the normal fellow eyes. Following successful surgical treatment the autofluorescence of the macular holes was no longer visible.
CONCLUSION—Autofluorescence imaging with the cLSO makes the assessment of macular holes possible with an accuracy comparable with that of fluorescein angiography. Being non-invasive and rapid, autofluorescence imaging may become a useful alternative to fluorescein angiography in the assessment and the differential diagnosis of full thickness macular holes.

Keywords: fundus autofluorescence; macular hole; lipofuscin; retinal pigment epithelium; laser scanning ophthalmoscope     

非增生型糖尿病视网膜病变超广角眼底彩色照相与眼底自发荧光图像特征分析

目的　分析非增生型糖尿病视网膜病变（non-proliferative diabetic retinopathy，NPDR）超广角眼底彩色照相与眼底自发荧光（fudus autofluorescence，FAF）的图像特征。方法　使用欧堡全景200激光扫描检眼镜对40例（80眼）NPDR患者进行免散瞳模式下的超广角眼底彩色照相及FAF检查，对所有图像进行分析，得出两种模式下NPDR眼底改变的图像特征及阳性率。结果　超广角眼底彩色照相和FAF的图像质量基本一致，均能反映周边部视网膜的情况。在各种典型的眼底病变中，极其微小的血管瘤以及点片状视网膜出血的显影在FAF上有增强，有助于细微病变的诊断。渗出在FAF上的显影并不明显，分辨率不够。视网膜新鲜性光凝斑在两种模式检查上均显影清晰，陈旧性光凝斑在FAF上易与出血混淆，应谨慎诊断。结论　超广角眼底彩色照相图像清晰，周边部显示好，可以提供直观的视网膜图像；FAF可以观察到组织结构的细微改变及视网膜色素上皮细胞的代谢情况。两种模式相辅相成，能为NPDR的诊断、分期和治疗提供更好的帮助。     

Abnormal fundus autofluorescence in relation to retinal function in patients with retinitis pigmentosa

Background Fundus autofluorescence (AF) in some patients with retinitis pigmentosa is characterized by a parafoveal ring of increased AF which surrounds the centre as hypofluorescent changes appear at the periphery. The aim of this study was to evaluate the AF patterns in relation to retinal function measured by electroretinography and visual fields. Methods Thirty-two patients with RP were included in the study. AF imaging of the macular area was performed with the scanning laser ophthalmoscope. Patients were divided in two groups according to their fundus AF patterns. All patients from group 1 had a ring of increased AF of different size but no atrophic areas inside vascular arcades. Patients with a ring of increased AF and round atrophic changes at different eccentricities from their fovea were selected in group 2. Visual fields were tested with kinetic, automated perimetry and microperimetry; the radius of the hyperfluorescent ring and the smallest distance of hypofluorescent areas from the fovea were compared to visual fields, PERG P50 and N95 and mfERG P1 amplitudes of the inner three rings. Results A linear relationship was found in group 1 between the radius of the ring of increased AF and both the automated (r=0.82) and kinetic perimetry (r=0.80). The radius of the AF ring correlated highly with the PERG P50 (r=0.72) and N95 (r=0.74) amplitudes. In all patients, mfERG responses were reduced at all retinal locations, more pronounced at periphery. There was a good correlation between the ring of increased AF and the P1 amplitude of ring 2 of mfERG (r=0.62). Patients from group 2 had significantly reduced or non-recordable PERGs and mfERGs. The eccentricities of hypofluorescent changes did not correlate with any type of perimetry. Conclusions Our results show that in stages of retinitis pigmentosa, before atrophic lesions spread inside the vascular arcades, the pattern of fundus autofluorescence correlates well with functional tests such as perimetry and electroretinography. The ring of increased AF appears to represent the border between functional and dysfunctional retina. This shows that autofluorescence, as a quick and non-invasive imaging tool, may be related to retinal function as well.     

Fundus Autofluorescence Imaging in Age-Related Macular Degeneration

Abstract

Fundus autofluorescence (FAF) is a noninvasive imaging technology that provides information on the distribution of lipofuscin within the retinal pigment epithelial cells. Progressive accumulation of lipofuscin within retinal pigment epithelial cells is involved in the pathogenesis of age-related macular degeneration (AMD). Fundus autofluorescence imaging using a confocal scanning laser ophthalmoscope is a useful technique to identify high-risk characteristics in patients with nonexudative AMD. It gives also some valuable knowledge and clues in differantial diagnosis of exudative age-related macular degeneration. This review comprises an introduction to fundus autofluorescence, a review of FAF imaging in AMD, and the recent classification of geographic atrophy (GA) and early AMD phenotypes by the Fundus Autofluorescence in Age-related Macular Degeneration Study. The association of phenotype and atrophy progression and choroidal neovascularization development are also summarized.     

Fundus autofluorescence related to retinal morphological and functional changes in idiopathic macular holes

Purpose: To investigate fundus autofluorescence (FAF) characteristics in relation to morphological and functional features of idiopathic macular hole (IMH). Methods: Twenty eyes of 20 consecutive patients with stage 3 or 4 macular holes were included. Fundus autofluorescence images were obtained using the Heidelberg retina angiograph 2, retinal structure was evaluated with 3‐dimensional (3‐D) imaging of Fourier‐domain optical coherence tomography (FD‐OCT), and retinal function was assessed with microperimetry‐1 (MP‐1). Results: Markedly increased FAF in the foveal centre corresponding to the macular hole, confirmed with FD‐OCT, was demonstrated in all eyes. A surrounding hypoautofluorescent ring corresponded to the subretinal fluid cuff. The area of relatively reduced FAF around the ring corresponded precisely to retinal oedema. In 15 eyes (75%), a stellate appearance with dark radiating striae was seen in the relatively reduced FAF and was correlated with intraretinal cystic changes in the outer plexiform layer, observed by FD‐OCT. Mean preoperative visual acuity was significantly poorer in eyes without a stellate appearance than in those with a stellate appearance (p = 0.023). The MP‐1 study confirmed impaired retinal function in the macular hole bed and in the area of the fluid cuff and retinal oedema. Conclusions: Fundus autofluorescence imaging reflects anatomic changes and represents the dysfunctional retinal area in IMH. The technique provides 2‐D images with 3‐D information on the retinal morphology of this disease.