Retinal Pigment Epithelial Cell Loss Assessed by Fundus Autofluorescence Imaging in Neovascular Age-related Macular Degeneration

doi:10.1016/j.ophtha.2012.07.076

Ophthalmology

Volume 120, Issue 2, February 2013, Pages 334-341

https://doi.org/10.1016/j.ophtha.2012.07.076 Get rights and content

Purpose

To characterize retinal pigment epithelial (RPE) cell loss as evidenced by autofluorescence imaging in patients with neovascular age-related macular degeneration (AMD).

Design

Retrospective cohort study.

Participants

There were 162 eyes of 116 consecutive patients with neovascular AMD examined in a retinal practice.

Methods

Each patient underwent a complete examination including autofluorescence imaging. Areas of confluent absence of autofluorescence signal of at least 0.5 mm in greatest linear diameter were measured within the macular area. Patient demographic and examination data were evaluated in relation to the autofluorescence data.

Main Outcome Measures

Prevalence and progression of confluent areas of absent autofluorescence and the relationship these areas had with visual acuity.

Results

The mean age of the patients was 82.9 years, and the mean visual acuity was 20/71 (logarithm minimum angle of resolution [logMAR], 0.55). Confluent loss of autofluorescence was seen in 58.6% of eyes at baseline, and the median area of absent autofluorescence among those was 1.57 mm² (interquartile range [IQR], 0.62–4.32 mm²). Using generalized estimation equation modeling, the significant predictors for area of confluent absent autofluorescence at baseline were duration of disease and any previous treatment with photodynamic therapy. The significant predictor of baseline visual acuity was baseline area of confluent absent autofluorescence. Follow-up was available for 124 (76.5%) eyes, with a mean follow-up of 2.9 years. By then, the mean visual acuity was 20/90 (logMAR, 0.65), and 79% of eyes had confluent areas of absent autofluorescence, the large majority of which affected the central macula. The median area of absent autofluorescence was 3.61 mm² (IQR, 1.16–7.11 mm²). The best predictor of final visual acuity was the area of absent autofluorescence at the final follow-up.

Conclusions

Confluent absence of autofluorescence, a measure signifying RPE loss, was a significant predictor of visual acuity both at baseline and at final follow-up. This is the first study to document the prevalence, rate of progression, and factors associated with measures of confluent RPE loss in patients with neovascular AMD. Application of strategies to limit RPE cell loss may prove useful in eyes with neovascular AMD.

Financial Disclosure(s)

Proprietary or commercial disclosure may be found after the references.

Section snippets

Patients and Methods

The study had institutional review board approval by the Western Institutional Review Board, Olympia, Washington, complied with the Health Insurance Portability and Accountability Act of 1996, and adhered to the tenets of the Declaration of Helsinki. Patients with neovascular AMD examined in the month of September 2011 at Vitreous Retina and Macula Consultants New York (under the care of RFS) were eligible. All patients had signed an informed consent for study participation. All patients

Results

There were 162 eyes of 116 patients with a mean age±standard deviation of 82.9±7.9 years at baseline, 72 (62.1%) of whom were female. The mean duration of disease to the first autofluorescence imaging was 2.1±2.4 years. Of the 162 eyes, 38 were evaluated once and follow-up was available for 124 (76.5%) of eyes that had a mean follow-up time of 3.0±1.8 years. The mean visual acuity at baseline was 20/71 (logMAR, 0.55). At baseline, 95 (58.6%) eyes had an area of confluent RPE cell loss of 0.5 mm

Discussion

The RPE phagocytizes outer segments of the photoreceptors and recycles the contained polyunsaturated fatty acids and retinoids.19, 20 Damaged and cross-linked molecules are processed, and the indigestible material is sequestered into liposomes as lipofuscin. Because lipofuscin in RPE cells contains retinoids, it can be made to fluoresce with the wavelengths used in the present study.¹⁹ Because RPE cells contain lipofuscin as a fundamental part of being alive and functional, autofluorescence

References (46)

R.F. Spaide
Fundus autofluorescence and age-related macular degeneration
Ophthalmology
(2003)
P.J. Rosenfeld et al.
Characteristics of patients losing vision after 2 years of monthly dosing in the phase III ranibizumab clinical trials
Ophthalmology
(2011)
Z. Yehoshua et al.
Progression of geographic atrophy in age-related macular degeneration imaged with spectral domain optical coherence tomography
Ophthalmology
(2011)
S. Schmitz-Valckenberg et al.
Fundus autofluorescence and progression of age-related macular degeneration
Surv Ophthalmol
(2009)
B. Lorenz et al.
Lack of fundus autofluorescence to 488 nanometers from childhood on in patients with early-onset severe retinal dystrophy associated with mutations in RPE65
Ophthalmology
(2004)
Y. Imamura et al.
Fundus autofluorescence and visual acuity in central serous chorioretinopathy
Ophthalmology
(2011)
W. Smith et al.
Risk factors for age-related macular degeneration: pooled findings from three continents
Ophthalmology
(2001)
S.J. Bakri et al.
Absence of histologic retinal toxicity of intravitreal bevacizumab in a rabbit model
Am J Ophthalmol
(2006)
A.C. Bird et al.
An international classification and grading system for age-related maculopathy and age-related macular degeneration
Surv Ophthalmol
(1995)
J.M. Seddon et al.
Evaluation of the clinical age-related maculopathy staging system
Ophthalmology
(2006)

Prevalence of age-related macular degeneration in the United States

Arch Ophthalmol

(2004)

J.P. Sarks et al.

Evolution of geographic atrophy of the retinal pigment epithelium

Eye (Lond)

(1988)

J.S. Sunness et al.

Measuring geographic atrophy in advanced age-related macular degeneration

Invest Ophthalmol Vis Sci

(1999)

A.P. Göbel et al.

Imaging geographic atrophy in age-related macular degeneration

Ophthalmologica

(2011)

J.S. Sunness et al.

Issues in quantifying atrophic macular disease using retinal autofluorescence

Retina

(2006)

S. Schmitz-Valckenberg et al.

Fundus autofluorescence imaging: review and perspectives

Retina

(2008)

S. Bearelly et al.

Fundus autofluorescence imaging in age-related macular degeneration and geographic atrophy

Adv Exp Med Biol

(2010)

R.F. Spaide et al.

Continuing medical education review: choroidal neovascularization in age-related macular degeneration—what is the cause?

Retina

(2003)

M.A. Zarbin

Current concepts in the pathogenesis of age-related macular degeneration

Arch Ophthalmol

(2004)

H.P. Scholl et al.

An update on the genetics of age-related macular degeneration

Mol Vis [serial online]

(2007)

H. Kaneko et al.

DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration

Nature

(2011)

J. Sarks et al.

Development of atrophy of the retinal pigment epithelium around disciform scars

Br J Ophthalmol

(2006)

D.M. Brown et al.

Ranibizumab versus verteporfin for neovascular age-related macular degeneration

N Engl J Med

(2006)

Cited by (43)

Fundus Autofluorescence in Neovascular Age-Related Macular Degeneration: A Clinicopathologic Correlation Relevant to Macular Atrophy
2021, Ophthalmology Retina
Macular atrophy (MA) of retinal pigment epithelium (RPE) and photoreceptors leads to vision loss in neovascular age-related macular degeneration (nAMD) despite successful treatment with antiangiogenic agents. To enhance understanding of MA, fortify the cellular basis of fundus autofluorescence (FAF) imaging, and inform management of nAMD, we performed histologic analysis of an eye with multimodal clinical imaging and apparent prior exudation due to nAMD.
Case study and clinicopathologic correlation.
A White woman in whom age-related macular degeneration (AMD) findings of inactive subretinal fibrosis (right eye) were followed for 9 years using FAF and OCT, with no detectable subretinal fluid or other recurrent exudation and no intravitreal injections before her death at age 90 years.
The right eye was preserved 6.25 hours after death, postfixed in osmium tannic acid paraphenylenediamine, and prepared for submicrometer epoxy resin sections (n = 115), with 19 matched to clinical OCT B-scans.
Light microscopic morphology of a hyperautofluorescent (hyperFAF) area due to prior exudation (“floodplain” hyperFAF), hypoautofluorescent (hypoFAF) spots of MA, and areas of unremarkable FAF.
Floodplain hyperFAF was visible throughout the 9 years of follow-up, with several hypoFAF atrophic spots expanding within it over time. The hyperFAF pattern corresponded to outer retinal atrophy (ORA) on OCT and photoreceptor loss over dysmorphic yet continuous RPE in histology. The hypoFAF spots inside the floodplain corresponded to complete RPE and outer retinal atrophy (cRORA) on OCT and loss of both photoreceptors and RPE in histology. In contrast, areas of unremarkable FAF showed continuous RPE accompanied by full-length photoreceptors and a thick outer nuclear layer.
This direct clinicopathologic correlation for FAF imaging is the first for nAMD. Fundus autofluorescence is a projection image that involves optical signal modulation by photoreceptors as well as emission signal sources in RPE. Hyperautofluorescence due to an exudative floodplain signifies loss of photoreceptors over continuous RPE. Hypoautofluorescence in MA signifies loss of both cell layers. For maximal value, fundus autofluorescence imaging should be interpreted with the multilayer perspective provided by OCT. Prevention of exudation in nAMD may preserve photoreceptors.
Fundus autofluorescence imaging
2021, Progress in Retinal and Eye Research
Fundus autofluorescence (FAF) imaging is an in vivo imaging method that allows for topographic mapping of naturally or pathologically occurring intrinsic fluorophores of the ocular fundus. The dominant sources are fluorophores accumulating as lipofuscin in lysosomal storage bodies in postmitotic retinal pigment epithelium cells as well as other fluorophores that may occur with disease in the outer retina and subretinal space. Photopigments of the photoreceptor outer segments as well as macular pigment and melanin at the fovea and parafovea may act as filters of the excitation light. FAF imaging has been shown to be useful with regard to understanding of pathophysiological mechanisms, diagnostics, phenotype-genotype correlation, identification of prognostic markers for disease progression, and novel outcome parameters to assess efficacy of interventional strategies in chorio-retinal diseases. More recently, the spectrum of FAF imaging has been expanded with increasing use of green in addition to blue FAF, introduction of spectrally-resolved FAF, near-infrared FAF, quantitative FAF imaging and fluorescence life time imaging (FLIO). This article gives an overview of basic principles, FAF findings in various retinal diseases and an update on recent developments.
Angiogenesis in gynecological cancers and the options for anti-angiogenesis therapy
2021, Biochimica et Biophysica Acta - Reviews on Cancer
Citation Excerpt :
Anti-angiogenic therapies are tested in gynecological cancers because of the importance of angiogenesis in gynecological cancers and the need for new treatment strategies [152,217]. VEGF has emerged as a major therapeutic target in several types of cancers [156,157,218,219] and other pathological conditions [35,220–222]. Currently, three VEGF-targeting monoclonal antibodies, bevacizumab, ramucirumab, and aflibercept, have been approved for the treatment of various types of cancer [223,224].
Angiogenesis is required in cancer, including gynecological cancers, for the growth of primary tumors and secondary metastases. Development of anti-angiogenesis therapy in gynecological cancers and improvement of its efficacy have been a major focus of fundamental and clinical research. However, survival benefits of current anti-angiogenic agents, such as bevacizumab, in patients with gynecological cancer, are modest. Therefore, a better understanding of angiogenesis and the tumor microenvironment in gynecological cancers is urgently needed to develop more effective anti-angiogenic therapies, either or not in combination with other therapeutic approaches. We describe the molecular aspects of (tumor) blood vessel formation and the tumor microenvironment and provide an extensive clinical overview of current anti-angiogenic therapies for gynecological cancers. We discuss the different phenotypes of angiogenic endothelial cells as potential therapeutic targets, strategies aimed at intervention in their metabolism, and approaches targeting their (inflammatory) tumor microenvironment.
Retinal biomarkers provide “insight” into cortical pharmacology and disease
2017, Pharmacology and Therapeutics
The retina is an easily accessible out-pouching of the central nervous system (CNS) and thus lends itself to being a biomarker of the brain. More specifically, the presence of neuronal, vascular and blood-neural barrier parallels in the eye and brain coupled with fast and inexpensive methods to quantify retinal changes make ocular biomarkers an attractive option. This includes its utility as a biomarker for a number of cerebrovascular diseases as well as a drug pharmacology and safety biomarker for the CNS. It is a rapidly emerging field, with some areas well established, such as stroke risk and multiple sclerosis, whereas others are still in development (Alzheimer's, Parkinson's, psychological disease and cortical diabetic dysfunction). The current applications and future potential of retinal biomarkers, including potential ways to improve their sensitivity and specificity are discussed. This review summarises the existing literature and provides a perspective on the strength of current retinal biomarkers and their future potential.
Imaging Protocols in Clinical Studies in Advanced Age-Related Macular Degeneration: Recommendations from Classification of Atrophy Consensus Meetings
2017, Ophthalmology
Citation Excerpt :
In eyes with neovascular AMD, the correlation between reduced FAF and presence of scotomas may be less pronounced. Yet, it could be shown that the area of confluent autofluorescence loss in the central macula is highly correlated to visual acuity, contrast sensitivity, and reading speed in eyes treated with anti-VEGF agents for neovascular AMD.7,31 In addition, FAF has proved useful in the differential diagnosis of disease entities that cause atrophy and in classifying GA lesions according to distinct progression rates.12,32–34
To summarize the results of 2 consensus meetings (Classification of Atrophy Meeting [CAM]) on conventional and advanced imaging modalities used to detect and quantify atrophy due to late-stage non-neovascular and neovascular age-related macular degeneration (AMD) and to provide recommendations on the use of these modalities in natural history studies and interventional clinical trials.
Systematic debate on the relevance of distinct imaging modalities held in 2 consensus meetings.
A panel of retina specialists.
During the CAM, a consortium of international experts evaluated the advantages and disadvantages of various imaging modalities on the basis of the collective analysis of a large series of clinical cases. A systematic discussion on the role of each modality in future studies in non-neovascular and neovascular AMD was held.
Advantages and disadvantages of current retinal imaging technologies and recommendations for their use in advanced AMD trials.
Imaging protocols to detect, quantify, and monitor progression of atrophy should include color fundus photography (CFP), confocal fundus autofluorescence (FAF), confocal near-infrared reflectance (NIR), and high-resolution optical coherence tomography volume scans. These images should be acquired at regular intervals throughout the study. In studies of non-neovascular AMD (without evident signs of active or regressed neovascularization [NV] at baseline), CFP may be sufficient at baseline and end-of-study visit. Fluorescein angiography (FA) may become necessary to evaluate for NV at any visit during the study. Indocyanine-green angiography (ICG-A) may be considered at baseline under certain conditions. For studies in patients with neovascular AMD, increased need for visualization of the vasculature must be taken into account. Accordingly, these studies should include FA (recommended at baseline and selected follow-up visits) and ICG-A under certain conditions.
A multimodal imaging approach is recommended in clinical studies for the optimal detection and measurement of atrophy and its associated features. Specific validation studies will be necessary to determine the best combination of imaging modalities, and these recommendations will need to be updated as new imaging technologies become available in the future.
Fellow Eye Comparisons for 7-Year Outcomes in Ranibizumab-Treated AMD Subjects from ANCHOR, MARINA, and HORIZON (SEVEN-UP Study)
2016, Ophthalmology
To compare study and fellow eyes in subjects with age-related macular degeneration (AMD) for 7-year outcomes arising from contrasting treatment histories and disease statuses.
Multicenter cohort study, predetermined secondary analysis.
A total of 65 participants from the ranibizumab-treatment arms of the Anti-VEGF Antibody for the Treatment of Predominantly Classic Choroidal Neovascularization in Age-Related Macular Degeneration (ANCHOR), Minimally Classic/Occult Trial of the Anti-VEGF Antibody Ranibizumab In the Treatment of Neovascular AMD (MARINA), and Open-Label Extension Trial of Ranibizumab for Choroidal Neovascularization Secondary to Age-Related Macular Degeneration (HORIZON) trials, recruited for an update evaluation from 14 study sites.
Seven-year visual outcomes and retinal imaging data were compared with the ANCHOR, MARINA, and HORIZON databases. Under the ANCHOR and MARINA protocols, study eyes had received monthly ranibizumab injections for the initial 2 years, during which fellow eyes were prohibited from anti–vascular endothelial growth factor (VEGF) treatments.
Percentage of subjects with study eye vision better than fellow eye, vision change from baseline to year 7, and mean area of macular atrophy (MA) were predetermined secondary end points.
Fellow eyes with exudative AMD had received a mean 7.3 total injections of anti-VEGF agents in the mean 3.4 years off-study. For the 35% of subjects with exudative AMD in both eyes at baseline, within-patient comparisons at year 7 showed better vision in the study eye in 82%, with better mean final vision in study eyes (54.7 vs. 27.3 letters in fellow eyes, P < 0.001). Also in this subgroup, study eyes, which had received 2 years of high-frequency ranibizumab, had less severe MA than the respective fellow eye at year 7 in 88% of patients (mean area ± standard deviation 2.8±2.2 mm² vs. 5.8±2.5 mm² in the fellow eyes, P = 0.0013). Final fellow eye vision outcome was significantly correlated with MA severity (coefficient −6.95, P < 0.001), and patients' inter-eye vision difference corresponded to the degree of MA asymmetry.
Exudative fellow eyes remained at risk for further vision decline in later years under management with low-frequency anti-VEGF therapy. In patients with bilateral exudative AMD at baseline, final vision at year 7 was significantly better in study eyes than in fellow eyes, and MA was less severe. Macular atrophy area correlated with final visual outcomes, determined inter-eye vision differences, and was not attributable to high-frequency ranibizumab therapy.

View all citing articles on Scopus

: Manuscript no. 2012-432.

Financial Disclosure(s): The author(s) have made the following disclosure(s):

Richard F. Spaide: Royalty payments—Topcon Medical Systems, Inc.

The remaining authors have no potential conflicting relationships to report.

: Supported by the Macula Foundation, New York, New York.

View full text

Original articleRetinal Pigment Epithelial Cell Loss Assessed by Fundus Autofluorescence Imaging in Neovascular Age-related Macular Degeneration

Purpose

Design

Participants

Methods

Main Outcome Measures

Results

Conclusions

Financial Disclosure(s)

Section snippets

Patients and Methods

Results

Discussion

Ophthalmology

Ophthalmology

Ophthalmology

Surv Ophthalmol

Ophthalmology

Ophthalmology

Ophthalmology

Am J Ophthalmol

Surv Ophthalmol

Ophthalmology

Prevalence of age-related macular degeneration in the United States

Arch Ophthalmol

Evolution of geographic atrophy of the retinal pigment epithelium

Eye (Lond)

Measuring geographic atrophy in advanced age-related macular degeneration

Invest Ophthalmol Vis Sci

Imaging geographic atrophy in age-related macular degeneration

Ophthalmologica

Issues in quantifying atrophic macular disease using retinal autofluorescence

Retina

Fundus autofluorescence imaging: review and perspectives

Retina

Fundus autofluorescence imaging in age-related macular degeneration and geographic atrophy

Adv Exp Med Biol

Continuing medical education review: choroidal neovascularization in age-related macular degeneration—what is the cause?

Retina

Current concepts in the pathogenesis of age-related macular degeneration

Arch Ophthalmol

An update on the genetics of age-related macular degeneration

Mol Vis [serial online]

DICER1 deficit induces Alu RNA toxicity in age-related macular degeneration

Nature

Development of atrophy of the retinal pigment epithelium around disciform scars

Br J Ophthalmol

Ranibizumab versus verteporfin for neovascular age-related macular degeneration

N Engl J Med

Original article
Retinal Pigment Epithelial Cell Loss Assessed by Fundus Autofluorescence Imaging in Neovascular Age-related Macular Degeneration