Fundus Autofluorescence in Retinal Disease: A Review and Perspectives

The second of a two-part series

Fundus Autofluorescence in Retinal Disease: A Review and Perspectives

The second of a two-part series


In the first part of this series, which appeared in the last issue of Retinal Physician, we provided an overview of fundus autofluorescence (FAF) imaging technologies (Table), and we reviewed the factors that produce and can affect fluorescence. In this second part, we apply these concepts to specific retinal conditions.

Table. Fundus Autofluorescence Imaging Modalities
Fundus camera Better for visualizing exudative retinal disease, red-shifted wavelengths decrease absorption by macular pigments, can be used with FA, color imaging, decreased motion artifact, more comfortable for patient No real-time averaging, poor contrast, capture more reflected and scattered light, prone to pseudoautofluorescence
Topcon TRC-50DX 535-585 nm 615-715 nm 20, 35, 50 Nonmydriatic, also offers FA, ICG
Zeiss Visucam 224/524 510-580 nm 650-735 nm 30, 45 Nonmydriatic. Visucam 524 with FA and optional ICG
Canon CR-2 plus AF (nonmydriatic) 530-580 640 nm 35, 45 Nonmydriatic, also offers cobalt setting
Confocal scanning laser ophthalmoscope (cSLO) Confocal optics reduces interference from the lens, real-time averaging, high contrast, high resolution, decreased scattered light Excitation beam is absorbed by macular pigments, cannot be preceded by FA, fixation loss, monochromatic, patient discomfort
Heidelberg Retinal Angiograph (HRA 2) 488 nm 500 nm 20, 30, 55 No longer commercially available
Heidelberg Spectralis 488 nm 500 nm 20, 30, 55 Also offers red-free, FA, ICG, simultaneous FA/ICG, infrared reflectance, multicolor imaging; dual wavelength technology can calculate macular pigment density, spectral-domain OCT
Zeiss prototype SM 30 4024 (ZcSLO) 488 nm 521 nm 20, 40 No longer commercially available
Rodenstock (RcSLO) 488 nm 515 nm 20, 40 No longer commercially available
Nidek F-10 490 nm 510 nm 40, 60 Also offers multicolor imaging, retro-mode, FA, ICG
Widefield cSLOs Detects peripheral findings, nonmydriatic, brief image acquisition time, can be used with FA Disadvantages vary by system and lens
Optos Ultra-Widefield 532 nm, 633 nm 540 nm 200 Decreased absorption by macular pigments, also offers color fundus, red-free, FA, ICG No real-time averaging, poor contrast, distortion of peripheral retina, view limited in superior and inferior quadrants, lid/lash artifact
Staurenghi lens N/A N/A 150 Lens attaches to cSLO Requires placement of contact lens
Heidelberg Ultra-widefield lens N/A N/A 105 Lens attaches to HRA or Spectralis. High contrast, non-distorted images, no lid/lash artifact, can be used with FA Smaller field of view, view limited in nasal and temporal quadrants


Age-related Macular Degeneration

Age-related macular degeneration has been characterized by FAF, and unique FAF findings not otherwise seen with funduscopy or other imaging systems are valuable in determining the diagnosis, management, and prognosis of the disease.

In early, non-neovascular AMD, FAF can show both hyper- and hypoautofluorescent foci, often revealing more widespread disease than identified with clinical examination. In 2005, an international FAF classification group designated eight FAF patterns seen in early AMD: normal, minimal change, focal increase, lace-like, speckled, patchy, linear, and reticular. The patchy phenotype, as well as linear and reticular patterns, is associated with increased risk for the development of choroidal neovascularization.1

Madeline Yung, MD, is an intern at Olive View-UCLA Medical Center in Los Angeles, CA. David Sarraf, MD, is on the faculty of the Stein Eye Institute at UCLA. Dr. Sarraf has received research grants from Allergan, Genentech, Optovue, and Regeneron, and he is a consultant to Genentech and Optovue. Dr. Yung reports no financial interests. Dr. Sarraf can be reached via e-mail at

The FAF appearance of drusen varies substantially depending on drusen size and type, as well as the health of the overlying retinal pigment epithelium. Small drusen show minimal changes.2 Intermediate drusen (65-125 nm) show central hypoautofluorescence from RPE atrophy and a hyperautofluorescent border representing abnormal RPE cells.3 Large drusen and drusenoid pigment epithelial detachments (PEDs) are hyperautofluorescent.2

Cuticular and crystalline drusen are hypoautofluorescent.4,5 Reticular pseudodrusen, referring to deposits above the RPE, present as small, round, hypoautofluorescent foci with interspersed reticular hyperautofluorescence.6 Of these entities, drusenoid pigment epithelial detachments and reticular pseudodrusen confer the greatest risk for disease progression.7,8

On FAF, geographic atrophy manifests as sharply demarcated areas of hypoautofluorescence due to RPE atrophy. Holz et al identified five different patterns of perilesional hyperautofluorescence that can surround areas of geographic atrophy — none, focal, banded, patchy, and diffuse — with the diffuse pattern further subdivided into reticular, branching, trickling, fine granular, and fine granular with peripheral punctate spots.9 The banded and diffuse trickling patterns have been associated with high risk for disease progression.

Early CNV can cause minimal FAF changes due to intact RPE and photoreceptor layers10 or hypoautofluorescence due to atrophy of the overlying RPE or a blocking effect.11 Retinal hemorrhage or exudates initially absorb light, resulting in decreased autofluorescence, but they become hyperautofluorescent after degradation.12,13 Patients may also have a hyperautofluorescent ring of RPE especially encircling type 2 neovascularization and in association with subretinal fluid and photoreceptor degeneration.14

As a well-known complication of AMD, RPE tears present as a wedge- or crescent-shaped area of remarkable hypoautofluorescence with sharp, irregular borders representing the zone of denuded RPE, and adjacent hyperautofluorescence at the site of rolled retracted RPE (Figure 1). Over time, RPE tears undergo resurfacing, with recovery of autofluorescence and associated visual function occurring centripetally toward the center of the lesion (Figure 2).15-18

Figure 1. Sequential FAF of RPE tear. RPE tears (a) appear as well-demarcated central hypoautofluorescence due to absent RPE with adjacent irregular hyperautofluorescence corresponding to the retracted edges of RPE. Serial images obtained three weeks (b) and one year (c) later show resurfacing and remodeling of the lesion, with centripetal recovery of autofluorescence extending from the borders.

Figure 2. Sequential FAF of RPE tear treated with aflibercept. RPE tears (a) appear as a well-demarcated central hypoautofluorescence due to absent RPE with adjacent irregular hyperautofluorescence corresponding to the retracted edges of RPE. The patient received anti-VEGF therapy with half-dose aflibercept. Over time (b), the lesion shows evidence of remodeling and resurfacing, with centripetal recovery of autofluorescence.

Central Serous Chorioretinopathy

In central serous chorioretinopathy, RPE and choroidal dysfunction results in accumulation of subretinal fluid and serous retinal detachment. Near-infrared (NI)-FAF has superior sensitivity over short-wavelength (SW)-FAF in detecting abnormalities,19 and ultrawidefield FAF is an essential component of imaging evaluation because 57% of CSC cases involve the peripheral retina.20,21

The initial formation of serous retinal detachment causes hypoautofluorescence due to blockage by subretinal fluid.22-24 As photoreceptor debris and macrophages accumulate in the form of subretinal precipitates, the serous detachment develops a granular or stippled hyperautofluorescence, most notably at the margins (Figure 3). With time, there is gravitation of the fluid and the autofluorescent findings inferiorly.24,25 Chronic cases lasting more than six months are associated with hypoautofluorescent, atrophic gravitational tracts.23,25

Figure 3. FAF in central serous chorioretinopathy. FAF (a) of a patient with acute exacerbation of CSC shows macular detachment, with hyperautofluorescent material at the margin and inferior region of the detachment. SD-OCT (b) of the lesion shows a serous retinal detachment associated with a small pigment epithelial detachment. FAF of the patient’s asymptomatic father (c) incidentally revealed an atrophic hypoautofluorescent gravitational tract from chronic inactive CSC with hyperautofluorescent margins.

Stargardt Macular Dystrophy

Stargardt disease is a hereditary juvenile macular dystrophy resulting from autosomal recessive mutations in the ABCA4 gene and, in rare cases, autosomal dominant mutations in the ELOVL4 gene. The salient retinal findings include central macular atrophy (hypoautofluorescent on FAF) in a bull’s eye or geographic pattern and surrounding yellow flecks that exhibit peripapillary sparing.26,27 Active flecks are hyperautofluorescent, while resorbed flecks are hypoautofluorescent (Figure 4).

Figure 4. Fundus autofluorescence of Stargardt disease. While fundus photography (a,b) and clinical examination may have nonspecific findings, fundus autofluorescence (c,d) shows hyperautofluorescent flecks with peripapillary sparing characteristic of the disease. The flecks surround a hypoautofluorescent central macula corresponding to significant chorioretinal atrophy on SD-OCT (e).

FAF is sensitive for abnormalities early in the disease course and can be used in the diagnostic evaluation for Stargardt disease.28

Cideciyan et al proposed a six-stage disease model that correlates well with FAF findings, in which early stages involve a general increase in lipofuscin and hyperautofluorescence, intermediate stages involve broad variation in the mean intensity and texture of autofluorescence, and late stages involve hypoautofluorescent chorioretinal atrophy in the macula with hyperautofluorescent flecks in the midperiphery.27-30

Best Macular Dystrophy

Autosomal dominant mutations in the BEST1 gene cause early-onset, bilateral vitelliform lesions in the macula with associated vision loss.31,32 FAF findings have been defined for the five clinical stages of disease progression.33 Previtelliform lesions have zero to minimally increased autofluorescence, vitelliform lesions are hyperautofluorescent, the pseudohypopyon stage shows a hyperautofluorescent layer gravitating inferiorly, the vitelliruptive lesion is hypoautofluorescent and bordered by hyperautofluorescent condensations, and the atrophic stage appears as diffuse hypoautofluorescence.33

Pattern Dystrophies

Pattern dystrophies encompass a collection of late-onset macular dystrophies with a stable, benign course, primarily resulting from autosomal dominant mutations in the PRPH2 gene (formerly the RDS gene).34 These dystrophies display a wide range of phenotypic variability, and FAF can be useful in disease diagnosis.35

Adult onset vitelliform dystrophy (AOVD) manifests as small, bilateral, hyperautofluorescent vitelliform lesions that are usually subfoveal but can be multifocal.36 As the disease progresses, RPE atrophy causes regions of hypoautofluorescence.37

Parodi et al found that AOVD progressed through normal, then focal, and finally patchy SW-FAF patterns, which correlate with deteriorating visual function.38 NI-FAF is more sensitive than SW-FAF for the detection of abnormalities.

As suggested by its name, multifocal pattern dystrophy simulating fundus flavimaculatus presents as a flecked retina syndrome, with hyperautofluorescent flecks at the posterior pole and vascular arcades. However, unlike Stargardt, this disease has an autosomal dominant inheritance, late onset, normal appearance of the choroid, and absence of hypoautofluorescent atrophy of the central macula.39

Other pattern dystrophies, including butterfly pigment dystrophy, fundus pulverulentus, and reticular dystrophy, are not yet well characterized by FAF. However, FAF can be used to identify more sensitively the remarkable hyperautofluorescent butterfly or reticular patterns characteristic of these diseases.

Retinitis Pigmentosa

Retinitis pigmentosa (RP) refers to a genetically heterogeneous spectrum of diseases that result in rod photoreceptor degeneration. Common autosomal dominant mutations include the RHO gene, autosomal recessive mutations include the USH2A gene, and X-linked mutations include the RPGR and RP2 genes. Although electroretinography remains the gold standard for the diagnosis and monitoring of RP, it becomes less reliable in advanced stages of disease.40 FAF can be used in lieu of electroretinography to monitor disease progression.41

On FAF, a large subset of patients with RP demonstrates a hyperautofluorescent Robson-Holder ring, which represents the border of active outer segment dysgenesis and abnormal lipofuscin production (Figure 5).42-45

Figure 5. Robson-Holder ring in retinitis pigmentosa. FAF (left) of retinitis pigmentosa shows an area of normal preserved retina at the posterior fundus bordered by a hyperautofluorescent Robson-Holder ring, a characteristic finding visible on FAF but not on fundus photography (right).

Optical coherence tomography studies have shown photoreceptor loss outside the ring and normal retina within. In addition, the diameter of the ring corresponds with retinal sensitivity and visual field constriction — the more the ring encroaches centrally, the more constricted the visual field is.46

Serial FAF imaging of the Robson-Holder ring provides an accurate measurement of disease progression.43 Similar rings are also seen in other retinal dystrophies, including Leber congenital amaurosis, Best macular dystrophy, and cone dystrophy.47


Arising from an X-linked mutation in the CHM gene, choroideremia is associated with choroidal, RPE, and photoreceptor atrophy with macular sparing, leading to night blindness and visual field constriction.48,49 FAF shows bilateral midperipheral zones of hypoautofluorescence with scalloped edges bordering a central stellate area of preserved autofluorescence (Figure 6).50

Figure 6. Fundus autofluorescence of choroideremia. Fundus photography (a, b) shows a pale fundus with zones of choroidal atrophy in the midperiphery, revealing the sclera underneath. Fundus autofluorescence (c, d) demonstrates corresponding zones of hyperautofluorescence given the autofluorescent properties of the sclera. Note the central stellate island of preserved choriocapillaris and retinal pigment epithelium in each eye, which is very characteristic of choroideremia.

Interestingly, female carriers of the CHM mutation are asymptomatic but may demonstrate a peripheral speckled pattern of hyper- and hypoautofluorescence, underscoring the value of FAF in evaluating the female relatives of affected patients.49,51

Fundus Albipunctatus

Due to an autosomal recessive mutation in the RDH5 gene causing defective rhodopsin recycling and delayed regeneration of visual pigments, fundus albipunctatus is associated with delayed dark adaptation and stationary night blindness.52,53 Decreased lipofuscin production results in severely attenuated background autofluorescence and grainy FAF images (Figure 7).54,55

Figure 7. Fundus autofluorescence of fundus albipunctatus. Fundus photography (a) demonstrates multifocal white flecks in the midperiphery with macular sparing. FAF (b) shows profoundly decreased background autofluorescence and a grainy resolution.

The white spots seen on funduscopy correlate with the foci of relatively enhanced autofluorescent signals, although these foci are often not visible on FAF given the overall decreased background autofluorescence.56 Other flecked retina syndromes not associated with an RDH5 mutation produce hyperautofluorescent dots with FAF. Hyperautofluorescent crescents and concentric parafoveal rings have also been reported with fundus albipunctatus.

Other retinal diseases involving mutations in the same visual cycle pathway include retinitis punctata albescens and RPE65 mutations. Retinitis punctata albescens arises from an autosomal recessive mutation in the RLBP1 gene, causing white, hyperautofluorescent, punctate retinal lesions and severe progressive night blindness.57 RPE65 mutations also decrease background autofluorescence, but they perpetrate more severe disease than fundus albipunctatus.58,59

White Dot Syndromes

White dot syndromes include a diverse collection of inflammatory chorioretinopathies with the common phenotype of multifocal white or yellow spots in the posterior pole and peripheral fundus. White dot syndromes vary significantly in pathogenesis, treatment, and prognosis.60 FAF and widefield FAF are sensitive tools for detecting lesions and differentiating diseases.61,62

Multiple evanescent white dot syndrome (MEWDS) is a self-limited, unilateral disorder that affects young, healthy women. Funduscopy shows multifocal 100- to 200-µm white spots in the paramacular and midperipheral fundus, which are hyperautofluorescent due to a window defect from photoreceptor loss (Figure 8).63 FAF can show hypoautofluorescence at the fovea, and it is more sensitive than clinical exam or fluorescein angiography for detecting lesions.64

Figure 8. Ultra-widefield imaging of multiple evanescent white dot syndrome (MEWDS). Ultra-widefield FAF of active disease (a) with multifocal hyperautofluorescence and resolution (b) six weeks later.

Punctate inner choroidopathy occurs in young, myopic female subjects and is a diagnosis of exclusion, occurring in the absence of uveitis or presumed ocular histoplasmosis. The white dots represent sub-RPE nodules that can have minimal hyperautofluorescence.65

Widefield FAF has been used to detect clinically occult hyperautofluorescent lesions indicative of active or recurrent disease, and it can be used to guide management.66 As the nodules break through the RPE, the lesions may become hypoautofluorescent with a hyperautofluorescent margin.67

Punctate inner choroidopathy may be associated with CNV, which has similar FAF findings to the CNV in AMD.65 Ninety percent of patients with diffuse hyperautofluorescent patches were found to have concurrent MEWDS on multimodal imaging.67

Hydroxychloroquine Toxicity

Hydroxychloroquine (Plaquenil, Sanofi, Bridgewater, NJ) is an inexpensive, well-tolerated agent to treat systemic rheumatological diseases, but its risk for ocular toxicity rises sharply with cumulative doses greater than 1,000 g.

In Caucasians, toxicity manifests as parafoveal photoreceptor loss with foveal sparing, resulting in a hyperautofluorescent parafoveal ring due to the window defect, with decreasing autofluorescence over time as the RPE progressively atrophies, and in advanced cases, progression to a characteristic bull’s eye maculopathy.68

Recent studies have found that Asians tend to have a more eccentric pericentral pattern of toxicity (a pericentral hyperautofluorescent ring is identified with FAF), with a hazard ratio of 27.1, which is more difficult to recognize on standard screening.69

The 2016 guidelines from the American Academy of Ophthalmology recommend a baseline examination and then annual screening with spectral-domain optical coherence tomography and perimetry starting after five years of standard use.70 FAF can be used as a supplemental imaging modality to detect early photoreceptor degeneration, to provide a topographic map of retinal toxicity, and to show extramacular patterns in Asian eyes.70


FAF is a noninvasive retinal imaging modality with rapid acquisition that detects the natural autofluorescence of ocular fluorophores. SW-FAF reflects the topography of lipofuscin and can be visualized using several imaging systems, including fundus cameras, confocal scanning laser ophthalmoscopes, and ultrawidefield systems.

FAF can detect abnormalities not otherwise identified with clinical examination, color fundus photography, FA, spectral-domain optical coherence tomography, and other techniques, and it can identify signature phenotypes facilitating the diagnosis of a wide variety of retinal disorders. In short, FAF has become a rapidly evolving and valuable tool in the evaluation and management of retinal disease. RP


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