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Retinal Physician

Article

Fundus Autofluorescence Update and Clinical Applications

Detect abnormalities that may be missed on clinical examination.

By: Rohan Jalalizadeh, MD, Alia K. Durrani, MD
Retinal Physician January 1, 2021 Vol 18, Issue January/February 2021 Page(s): 24-26, 28, 30, 31

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Fundus autofluorescence (FAF) is a noninvasive tool to characterize the structure and function of the retinal pigment epithelium (RPE)/RPE complex. As an imaging modality, it may often detect abnormalities not seen on clinical examination. Clinical applications of FAF continue to expand, and this article provides an overview of the basics, some prominent clinical uses, and recent developments for FAF.

PRINCIPLES AND BASIS FOR IMAGING

Fundus autofluorescence relies on the property of the RPE to emit certain wavelengths in response to excitation by short-wavelength light, with the dominant fluorophore being RPE lipofuscin, which contains the fluorescent pigment A2E.1 Accumulation of lipofuscin within the RPE is most likely a byproduct of the phagocytosis of discs shed by retinal photoreceptor outer segments, a process integral to the vision cycle.2-4

The major categories of devices used to obtain FAF images are confocal scanning laser ophthalmoscopy (cSLO), modified conventional fundus camera (mFC), and ultrawidefield ophthalmoscopic devices.5 The 3 devices use a variety of excitation wavelengths and record autofluorescence (AF) emissions in a certain range.2,5-7 The mFC uses a single bright flash of light to image the entire retinal field, which can lead to an inferior signal-to-noise ratio and autofluorescence signal originating from extraretinal structures (ie, the lens), which may make diagnostic interpretation difficult.8,9 The cSLO uses a low excitation intensity and records the average of several emission images, for an improved signal-to-noise ratio.9

In the normal fundus, the center of the macula shows decreased AF due to blockage by the light-absorbing pigments lutein and zeaxanthin, which are abundant in the fovea. The optic disc appears dark because of the absence of lipofuscin, and blood vessels appear dark because light is absorbed by blood. The remainder of the macula shows a homogeneous signal, which tends to increase with age due to gradual accumulation of RPE lipofuscin.2

In addition to increased signal associated with aging, lipofuscin accumulation caused by RPE dysfunction can lead to increased AF. Reduced AF can be caused by pigment or reduced lipofuscin density, as discussed above, as well as fibrosis, intraretinal fluid, and RPE loss or atrophy.

FUNDUS AUTOFLUORESCENCE IN VARIOUS DISEASE CONDITIONS

Below is a review of some common and important conditions for which FAF has been demonstrated to be useful diagnostically and prognostically.

DRUG TOXICITY AND MONITORING

Hydroxychloroquine and Chloroquine

Retinopathy due to toxicity from chloroquine and hydroxychloroquine has been well recognized and can lead to severe and irreversible vision loss. These medications, most commonly hydroxychloroquine, are used in the treatment of systemic inflammatory disorders, such as systemic lupus erythematosus, rheumatoid arthritis, dermatologic conditions, malaria, and, most recently, experimentally in the acute setting for treatment or postexposure prophylaxis of coronavirus disease (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).10,11

Screening guidelines for toxic retinopathy due to chloroquine and hydroxychloroquine have changed in recent years as a result of evolving data, but they involve evaluation of the visual field, spectral-domain optical coherence tomography (SD-OCT), FAF, and multifocal electroretinogram (mfERG). Risk of toxicity increases with increased daily dose, total duration of use, concomitant renal disease, and use of tamoxifen. Recommended dosage to reduce the risk of retinopathy is <5.0 mg/kg/day based on real body weight.12

Damage from hydroxychloroquine and chloroquine toxicity appears to primarily affect the perifoveal photoreceptors, with secondary damage to the RPE. Early on, changes are noted on SD-OCT and mfERG, and increased AF is seen with FAF, likely due to early RPE dysfunction. Late findings include atrophy and decreased AF. In Asian patients, toxicity may show extramacular findings; thus, for these patients, wide-angle FAF may be useful (Figure 1).12

Figure 1. Fundus autofluorescence (A) and color fundus (B) photos of a patient with hydroxychloroquine toxicity.
Figure 1. Fundus autofluorescence (A) and color fundus (B) photos of a patient with hydroxychloroquine toxicity.

Pentosan Polysulfate Sodium

In 2018, a pigmentary maculopathy was described in the setting of chronic exposure to the drug pentosan polysulfate sodium (PPS), which is used in the treatment of interstitial cystitis. Visual acuity appeared to be preserved initially, with patients reporting difficulty reading and prolonged dark adaptation.13,14 This toxic maculopathy has been thought to progress after discontinuation of PPS (Figure 2).15 On fundus examination, there are often subtle hyperpigmented macular spots with interspersed pale yellow deposits. Fundus autofluorescence images may demonstrate large confluent areas of mottled increased and decreased AF spots, in most cases involving the fovea.16 Spectral-domain OCT shows elevation and thickening of the RPE. These RPE findings have been noted to be dynamic over time.16 Some reports have demonstrated more widespread changes correlating to the cumulative dose of PPS, with attempts to quantify the imaging changes.17 With increased awareness of this likely drug toxicity, we can expect to continue to learn more about the natural history, risk factors, and management of this condition. Recent data have led some urologists to question the role of PPS in treating interstitial cystitis: a randomized, double-blind controlled trial showed no benefit of the drug over placebo in controlling symptoms of interstitial cystitis.18

Figure 2. Fundus autofluorescence images of a patient with pentosan polysulfate sodium toxicity (A, right eye; B, left eye). Note the symmetric, speckled increased and decreased autofluorescence in a large zone centered on the fovea.
Figure 2. Fundus autofluorescence images of a patient with pentosan polysulfate sodium toxicity (A, right eye; B, left eye). Note the symmetric, speckled increased and decreased autofluorescence in a large zone centered on the fovea.

AGE-RELATED MACULAR DEGENERATION

Fundus autofluorescence has been used to detect changes in eyes that have age-related macular degeneration (AMD), including identification of intermediate and large drusen, reticular pseudodrusen, cuticular drusen, and geographic atrophy (GA).8,9,19 Intermediate (63 µm to 125 µm diameter) and large (>125 µm diameter) drusen appear as foci of increased AF (Figure 3), and drusenoid pigment epithelial detachments (PEDs) appear as increased AF lesions surrounded by a halo of decreased AF. A higher risk of disease progression has been associated with drusenoid PEDs and increased number and size of drusen.

Figure 3. Age-related macular degeneration. Note increased autofluorescence, which correspond to macular drusen, and decreased autofluorescence, corresponding to pigment clumping.
Figure 3. Age-related macular degeneration. Note increased autofluorescence, which correspond to macular drusen, and decreased autofluorescence, corresponding to pigment clumping.

Cuticular drusen appear as foci of decreased AF. Reticular pseudodrusen, which are accumulations of material above the RPE, appear as round foci of decreased AF with interspersed areas of increased AF.19 Reticular pseudodrusen are also associated with a high risk of progression to advanced AMD.

GEOGRAPHIC ATROPHY

Geographic atrophy, sharply delineated round areas of hypopigmentation or depigmentation measuring at least 175 µm in diameter, is a manifestation of late-stage non-neovascular AMD, as well as other retinal degenerations and inherited retinal dystrophies.20 These atrophic lesions of RPE, choroid, and outer neurosensory retina tend to enlarge over time and cause absolute scotomas in the corresponding visual field, eventually leading to profound vision loss if the fovea becomes involved.21-24 On FAF, GA appears as decreased AF, often with increased AF at the borders of atrophy in a variety of different phenotypes. Classification of these distinct hyperautofluorescent patterns has been done by the Fundus Autofluorescence in Age-related Macular Degeneration (FAM) study group, among others, and suggests that different phenotypic FAF patterns are associated with different rates of GA progression.25 Thus, FAF may serve a prognostic role in the future management of patients who have GA. Changes in FAF may be observable prior to visual acuity changes, allowing for monitoring of disease progression (Figure 4).26

Figure 4. Geographic atrophy. Decreased AF in areas of atrophy of the retinal pigment epithelium (RPE) and RPE/photoreceptor outer segment complex.
Figure 4. Geographic atrophy. Decreased AF in areas of atrophy of the retinal pigment epithelium (RPE) and RPE/photoreceptor outer segment complex.

PATTERN DYSTROPHIES

A number of retinal dystrophies were classically described by Gass as pattern dystrophies and include adult-onset foveomacular vitelliform dystrophy (AFVD), butterfly macular dystrophy, reticular dystrophy, multifocal pattern dystrophy simulating fundus flavimaculatus, and fundus pulverulentus. These are bilateral, symmetric, and associated with autosomal dominant mutations in PRPH2 on chromosome 6.27 In AFVD, early subfoveal vitelliform lesions demonstrate increased AF, and progression of possible atrophic disease demonstrates decreased AF (Figure 5). In multifocal pattern dystrophy simulating fundus flavimaculatus, a “dot and halo” pattern of AF is seen with yellowish flecks, demonstrating decreased AF surrounded by a halo of increased AF.27 The other pattern dystrophies demonstrate a variety of FAF morphologies, including ring-like, spoke-like, and reticular changes in the macula and posterior pole. Fundus autofluorescence findings in these subtypes have not been as well characterized.

Figure 5. Adult foveomacular vitelliform dystrophy toxicity (A, right eye; B, left eye). Increased autofluorescence is seen corresponding to the vitelliform deposits, along with mottled increased and decreased autofluorescence, which is typical of pattern dystrophies.
Figure 5. Adult foveomacular vitelliform dystrophy toxicity (A, right eye; B, left eye). Increased autofluorescence is seen corresponding to the vitelliform deposits, along with mottled increased and decreased autofluorescence, which is typical of pattern dystrophies.

OTHER INHERITED RETINAL DISEASES

Fundus autofluorescence may be used to monitor progression of a variety of inherited retinal diseases. For example, in retinitis pigmentosa, a disease predominantly of rod dysfunction, FAF may demonstrate a parafoveal ring of increased AF correlating to rod photoreceptor outer segment and secondary RPE dysfunction.28,29 Cone dystrophies may demonstrate increased AF of the fovea or a ring of increased AF similar to that seen in retinitis pigmentosa, and these patterns may be seen in rod dystrophies with cone involvement as well.30,31 The areas of abnormal AF correspond to areas of decreased visual function as measured on perimetry and electroretinogram (Figure 6).32

Figure 6. Progressive cone-rod dystrophy shown with fundus autofluorescence (A) and color fundus (B) photos. Prominent features of the fundus autofluorescence image include decreased autofluorescence corresponding to central atrophy, surrounded by a ring of increased autofluorescence, and patchy areas of decreased autofluorescence in regions of atrophy and pigment clumping.
Figure 6. Progressive cone-rod dystrophy shown with fundus autofluorescence (A) and color fundus (B) photos. Prominent features of the fundus autofluorescence image include decreased autofluorescence corresponding to central atrophy, surrounded by a ring of increased autofluorescence, and patchy areas of decreased autofluorescence in regions of atrophy and pigment clumping.

Maculopathies such as Stargardt disease may manifest with initial increased AF and progressive decreased AF over areas of classic “yellow flecks” that may be present. These classic fleck lesions expand centrifugally with time, sparing the peripapillary area.33 Several recent prospective studies evaluating FAF in Stargardt disease demonstrated the utility of serial FAF in following disease progression.34,35

Best disease, which classically presents at a young age with bilateral yolk-like submacular deposits, is thought to be caused by RPE dysfunction, which leads to accumulation of photoreceptors, lipofuscin, and debris in the submacular space.

The disease classically progresses through 5 stages, as initially described, based on biomicroscopic appearance, and FAF demonstrates unique findings at each stage.36-38 In the vitelliform, or second stage, there is homogeneously increased AF. The pseudohypopyon stage demonstrates increased AF in the inferior portion of the lesion. In the scrambled-egg stage, the lesion’s border typically has increased AF, while the center may have decreased AF (Figure 7), and in the atrophic stage, AF signal is significantly decreased.38

Figure 7. Multifocal Best disease. This patient developed several yolk-like submacular deposits, which appear as increased AF here on a background of decreased AF.
Figure 7. Multifocal Best disease. This patient developed several yolk-like submacular deposits, which appear as increased AF here on a background of decreased AF.

CENTRAL SEROUS CHORIORETINOPATHY

Central serous chorioretinopathy (CSCR) is a condition characterized by RPE and serous retinal detachment, often in the posterior pole. The pathophysiology is unclear, but hyperpermeability of the choroid is thought to lead to leakage of fluid through the RPE and into the subretinal space, and the strongest known associated risk factor is exogenous glucocorticoid.39,40 On FAF, areas of serous retinal detachment demonstrate increased AF, particularly at the borders of the detachment. In acute CSCR, small punctate areas of increased AF correspond to punctate subretinal precipitates seen on funduscopic examination. Diffuse RPE and outer retinal atrophy, which can be seen in chronic CSCR, appears as decreased AF.41,42 In some cases, gravitational tracking, or “guttering,” is seen in areas of atrophy secondary to chronic subretinal fluid (Figure 8).43

Figure 8. Bilateral central serous chorioretinopathy (A, right eye; B, left eye). Note the guttering phenomenon, with increased AF at the edges of chronic subretinal fluid, decreased AF in areas of retinal pigment epithelium atrophy, and punctate increased AF corresponding to subretinal precipitates.
Figure 8. Bilateral central serous chorioretinopathy (A, right eye; B, left eye). Note the guttering phenomenon, with increased AF at the edges of chronic subretinal fluid, decreased AF in areas of retinal pigment epithelium atrophy, and punctate increased AF corresponding to subretinal precipitates.

RECENT DEVELOPMENTS IN FAF IMAGING

In recent years, procedures for quantitative FAF (qFAF) have been developed using cSLO. Measurements of FAF intensity and spatial information are used. This provides the advantages of discerning truly abnormal signal intensity from normal age-related increases in AF, directly comparing FAF imaging of an eye with subsequent images over time, and allowing for interpatient comparisons of AF.7,44 With a quantitative approach, differences in lesion size, distribution, and patterns will be able to be objectively analyzed.

Initial research utilizing qFAF has been seen in conditions such as AMD, Stargardt disease, Best disease, retinitis pigmentosa, acute zonal occult outer retinopathy, and pseudoxanthoma elasticum, as well as in basic and translational animal studies.7

LIMITATIONS OF FAF

The limitations of fundus autofluorescence may relate to image quality and acquisition. As discussed, autofluorescence artifacts from the ocular media reduce the signal-to-noise ratio. The phenomenon of photoreceptor bleaching, due to rhodopsin absorption and photoisomerization, limits the ability of examiners to obtain reliable FAF and fluorescein angiography in the same sitting, because recently excited photoreceptors demonstrate relatively increased AF.45,46 RP

Rohan Jalalizadeh, MD, is a vitreoretinal surgery fellow at The Retina Institute in St. Louis, Missouri. Alia K. Durrani, MD, is a retina specialist at The Retina Institute. The authors report no related disclosures. Reach Dr. Durrani at mddurrani.aliak@rc-stl.com.

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