Abstract
purpose. To describe morphologic variations in outer retinal layers in eyes with atrophic age-related macular degeneration (AMD) using high-resolution, spectral-domain optical coherence tomography (SD-OCT).
methods. SD-OCT scans were obtained with a combined confocal scanning laser ophthalmoscope (cSLO) and SD-OCT for simultaneous tomographic and topographic in vivo imaging. A total of 81 eyes of 56 patients (mean age, 77.8 ± 7.4 years) with geographic atrophy (GA) were examined. Morphologic alterations were analyzed and classified in the perilesional zone, at the junction between GA and nonatrophic retina, and in the atrophic area itself.
results. In the perilesional zone, distinct morphologic alterations included elevations of the outer retinal layers, thickening, and spikes of the outer hyperreflective band as well as clumps at different neurosensory retinal levels. At the junction, highly variable transitions of the outer retinal layers were present with different degrees of loss of the normal hyperreflective bands. Within the actual GA, hyperreflective clumps at different retinal levels, segmented plaques of the outer band and elevations with variable reflectivity were visualized.
conclusions. SD-OCT imaging in eyes with GA revealed a wide spectrum of morphologic alterations, both in the surrounding retinal tissue and in the atrophic area. These alterations may reflect different disease stages or, alternatively, heterogeneity on a cellular and molecular level. Longitudinal studies using in vivo SD-OCT imaging may allow evaluation of the relevance of these phenotypic changes as potential predictive markers for the progression of disease (i.e., enlargement rates of GA over time) and may be used for monitoring of future therapeutic interventions.
Age-related macular degeneration (AMD) is a complex disease with both genetic and environmental factors that has become the most common cause of legal blindness in industrialized countries.
1 2 3 4 5 6 7 8 It represents a chronic, progressive disease with various phenotypic manifestations, different disease stages, and variable rates of progression over time. Early manifestations of AMD include focal hypo- and hyperpigmentation and soft drusen with extracellular material accumulating in the inner aspects of Bruch’s membrane. Geographic atrophy (GA) and choroidal neovascularization (CNV) represent the late stages of AMD. Although the incidence of neovascular AMD is higher overall than of GA, pure GA has recently been found to occur four times more often than neovascular AMD in individuals ≥85 years of age.
4 Natural history studies of GA, including the pivotal investigations by Sunness et al.
9 10 11 12 13 have identified various disease characteristics, including progression rates and functional consequences.
9 10 11 12 13 14 15 16 Current data reflect not only the public health impact of advanced atrophic AMD, but are also being used in the design of interventional trials.
Despite a recent breakthrough with anti-VEGF-therapy for neovascular AMD, there is as yet no treatment available for patients with GA. To identify potential targets for intervention, a better understanding of the pathogenesis of late atrophic AMD appears mandatory.
Recent developments in retinal imaging technologies have enabled more accurate phenotyping and provided further insights in the diseases process. Abnormal fundus autofluorescence patterns in atrophic AMD and their impact on disease progression has been intently studied with confocal scanning laser ophthalmoscopy (cSLO) imaging (Bindewald A, et al.
IOVS 2004;45:ARVO E-Abstract 2960).
14 15 16 17 18 19 20 21 22 23 The findings implicate a role of excessive lipofuscin accumulation in the retinal pigment epithelium (RPE) and toxic fluorophores such as A2-E in the pathogenesis of outer retinal atrophy in the context of late AMD. With the advent of optical coherence tomography (OCT), vertical sections of the retina can be obtained in vivo with visualization of microstructural alterations in retinal diseases such as AMD. Recently, spectral-domain (SD) OCT technology has been introduced with further improvements in resolution and imaging speed compared with previous time-domain OCT imaging instruments.
24 25 26 27 28 29 30 31 32
The combination of the two technologies (i.e., cSLO and SD-OCT) in one instrument, together with real-time eye tracking, now allows accurate orientation of vertical OCT scans at anatomic sites of interest with a pixel-to-pixel correlation and therefore provides three dimensional mapping of pathologic alterations within the retinal layers (Helb H-M, et al. IOVS 2007;48:ARVO E-Abstract 129). We used this imaging method to identify morphologic alterations in outer retinal layers in a systemic approach in eyes with GA due to AMD.
In a cross-sectional study, 81 eyes of 56 patients with late atrophic AMD (mean age, 77.8 ± 7.4) were examined by simultaneous cSLO SD-OCT imaging. Patients (42 women and 14 men) with uni- or multifocal GA and overall clear media were enrolled. Exclusion criteria included the presence of signs of CNV or subretinal fibrosis and other retinal diseases in the study eye, such as diabetic retinopathy or hereditary retinal dystrophies, as well as any history of retinal surgery, laser photocoagulation, and radiation therapy. Before examination, the pupil of the study eye was dilated with 1% tropicamide eye drops.
Simultaneous recordings of SD-OCT and cSLO digital infrared or fundus autofluorescence (FAF) images were obtained with a novel combined imaging system (Spectralis HRA+OCT; Heidelberg Engineering, Heidelberg, Germany). The cSLO system provides fundus autofluorescence imaging (excitation wavelength: 488 nm, barrier filter; 500 nm), as well as infrared reflectance (IR; 820 nm) and blue (488 nm) reflectance imaging. The size of the field of view was 30° × 30°. Image acquisition was performed in high-speed mode. Images with 30° field of view are digitized in frames of 768 × 768 pixels with a resolution of approximately 11 μm per pixel. Optical resolution is approximately 10 μm. Image acquisition speed for a 30° field of view is nine images/s.
The SD-OCT runs simultaneously with the cSLO imaging system, using a second, independent pair of scanning mirrors. The wavelength of the SD-OCT imaging system is 870 nm. Optical resolution is approximately 7 μm in depth and 14 μm transversely. Acquisition speed is 40,000 A-scans per second. The scan depth is 1.8 mm. Each A-scan consists of 512 pixels, providing a digital depth resolution of 3.5 μm per pixels. Live B-scans can be acquired and observed simultaneously with a cSLO reference image that can be a confocal infrared or blue reflectance image, a fluorescein angiography image, or a fundus autofluorescence image. A B-scan covers a transverse range of 30° and consists of 768 A-scans in high-speed mode, which provides a digital transverse resolution of approximately 11 μm. B-scan acquisition speed for 30° scan width is 48 B-scans per second in high-speed mode. In high-speed mode, the vertical presentation of the OCT scan is magnified twice; therefore, morphologic alterations are presented disproportionately high in the vertical dimension.
The presence of atrophic areas was confirmed on cSLO FAF images with corresponding dark-appearing areas in the absence of the RPE cell monolayer and thus absence of fluorophores relevant for the FAF signal. Vertical and horizontal OCT scans were placed in the area of interest. Three different areas were analyzed with respect to alterations in the OCT scans: (1) the perilesional zone, which compasses retinal areas with visible abnormalities on fundus photograph, cSLO image, or OCT outside atrophic patches; (2) the junction between atrophic patches and nonatrophic retina, and (3) the atrophic patch itself
(Fig. 1) . Alterations within the SD-OCT scan were proportionally magnified for better visualization of alterations
(Fig. 2) .
The study adhered to the tenets of the Declaration of Helsinki. Informed consent was obtained from each patient after explanation of the nature and possible consequences of the study.
Examination by high-resolution OCT allows for visualization of microstructural alterations of the inner and outer retinal layers in vivo. With the advent of high-resolution OCT imaging new insights in phenotypic variations in the disease can now be obtained. While the clinical presentation of GA associated with AMD on funduscopy or two-dimensional images such as fundus photography appears relatively uniform, a wide, complex spectrum of heterogeneous alterations can be identified in SD-OCT scans.
Previous reports not specifically focusing on atrophic AMD have recently addressed some findings on SD-OCT images.
25 35 36 37 38 39 The goal of the present study was to identify and demonstrate the broad spectrum of morphologic alterations that can be visualized by high-resolution OCT imaging and to allocate these changes to the different zones in eyes with late atrophic AMD.
By applying the morphologic substrates proposed by Pircher et al.,
33 alterations of the different bands in the OCT scans can be correlated with findings reported in histologic studies in eyes with AMD
(Fig. 8) .
40 41 42 43 44 In the perilesional zone of primary GA, RPE cells are irregular in shape, some being enlarged and others attenuated; closer to the junction, the RPE becomes increasingly disorganized. Cells that are packed with pigment granules are shed into more inner retinal layers. Photoreceptor outer segments may terminate in rounded collections of membranes lying on the internal surface of the RPE, each partly surrounded by broad apical extensions from the RPE cells. Sub-RPE deposits and hyalinization and densification of Bruch’s membrane can be observed. The closer to the junction of GA, the more grossly abnormal the photoreceptors become.
Although ultrastructural changes cannot be visualized by OCT imaging so far, alterations of the outer retinal layers including the RPE layer can be observed that may be in accordance with histopathologic findings. Thinning or thickening of the RPE band (band 4) in the OCT scan may indeed reflect boundaries of enlarged or attenuated RPE cells. Hyperreflective clumps at different retinal layers can be visualized that correlate with funduscopically visible hyperpigmentary changes; these findings are in accordance with recently reported RPE changes imaged by ultrahigh resolution OCT in eyes with nonexudative AMD by Pieroni et al.
38
Besides soft drusen that present as dome-shaped elevations of the RPE band in OCT, more elongated elevations can be observed that may be consistent with sub-RPE deposits (e.g., basement membrane deposits)
45 ; however, the localization with respect to the basement membrane of the RPE cannot be clearly determined by OCT. Variations in reflectivity of such sub-RPE deposits detected in our study may reflect different compositions of the underlying material. The thin line that was seen in some sections at the former RPE level in the area of such elevations may indeed represent Bruch’s membrane
35 ; hyperreflective plaques at this level may represent histologically described densification.
41 42 Attenuation or disappearance of the IPRL in the OCT scans seems to be in accordance with morphologic alterations of the photoreceptors in the perilesional zone.
Above soft drusen, alterations of the RPE, IPRL (band 2), ELM (band 1) and ONL, respectively, can be observed by OCT imaging; this observation is in accordance with the histologic findings in drusen-related atrophy, where the degeneration of the RPE preferentially occurs over drusen and photoreceptors and the ONL subsequently disappear.
In areas with a reticular drusen pattern in the cSLO image, small elevations of the IPRL band were noted along with a mottled irregular appearance of the RPE band; however, the exact origin of the reticular signal could not be determined. Thus, the exact location of reticular drusen, at this stage, remains unclear.
Increased distance between the IPRL and RPE band with the impression of accumulating material between the RPE and the photoreceptors could be consistent with debris lying in the subretinal space which has been described in histologic sections in eyes with GA. It has been discussed that this debris may represent outer segment material that has not been phagocytosed.
42
Funduscopically visible abnormalities surrounding atrophy in GA resemble typical changes seen in early dry AMD, such as various types of drusen or hyper- or hypopigmentations. It is conceivable that the structural alterations revealed by SD-OCT at the perilesional zone of the patients with GA in this study may also represent general AMD changes and may therefore not be specific for GA.
At the junction of GA, histologic sections have revealed that the termination of the RPE may be characterized by a double layer of cells. The overlying photoreceptors may disappear for some distance beyond the edge or together with the RPE, and the ELM ends in a curved line; the ONL disappears and an attenuated OPL rests directly on Bruch’s membrane or the remaining sub-RPE deposits; the INL is reported to be less affected.
42 In the OCT sections, similar alterations are visualized. However, different variations of this “regular” edge are observed that may reflect different patterns of development and/or progression of GA (e.g., primary atrophy, drusen-related atrophy, or atrophy after RPE detachments as described by Sarks and Sarks).
40
Within the atrophic area, occasional whorls of persisting photoreceptors converging on a cluster of degenerating pigment cells have been reported by histopathology. Elsewhere, the photoreceptors disappear, but a few grossly abnormal RPE cells or membrane-bound bodies containing pigment commonly remain scattered throughout the area.
42 Accordingly, by OCT imaging, islands with preserved layers (i.e., RPE-, IPRL-band, ELM, ONL, and OPL) are noted that correlate with a preserved FAF signal in the cSLO image. Within other sections, hyperreflective clumps at different retinal levels can be visualized, but the outer retinal layers are not present.
Elevations or accumulations of highly reflective material within the atrophic area as well as plaques at the former RPE level can be observed by OCT imaging. These alterations may represent residual sub-RPE deposits and may reflect various stages of regressing drusen, which become calcified and increasingly irregular.
41 42 It has been postulated that regressing drusen material may remain in the atrophic area for many years. Its presence may refer to drusen-related evolution of the atrophic lesion.
Various limitations of this study must be considered. First, alterations of reflectivity are yet not readily correlated with physiological anatomic layers in normal eyes. Interpretation becomes even more difficult in the presence of complex pathologic alterations.
34 Therefore, misinterpretations of hyperreflective bands, especially in outer retinal layers, become an obstacle. Second, various morphologic alterations may be present in different vertical scans of the same eye. However, the goal of this study was to describe for the first time the spectrum of morphologic variations seen on SD-OCT in the different zones in eyes with GA, in an attempt to classify these alterations. By scrutinizing all vertical layers, future studies will address, to what extent the described alterations may be specific to individual eyes. Longitudinal observations over a longer period will help in understanding the evolution of the changes seen in this cross-sectional review. Furthermore, it would be helpful in future studies to correlate SD-OCT findings in images obtained in vivo with the histopathologic findings postmortem in donor eyes with atrophic AMD.
SD-OCT imaging in eyes with late atrophic AMD revealed highly variable morphologic alterations in the atrophic area and in the surrounding retinal tissue. These alterations may reflect both different stages of the disease and heterogeneity on a cellular and molecular level. Longitudinal studies using in vivo SD-OCT imaging will allow evaluation of the relevance of distinct phenotypic changes as potential predictive markers for the progression of disease (i.e., enlargement rates of atrophic areas).
Supported by the DFG (German Research Council), Research Priority Program Age-Related Macular Degeneration SPP 1088, Ho 1926/1-3; European Union FP6, Integrated Project Grant EVI-GENORET (LSHG-CT-2005-512036); and a DOG (German Society of Ophthalmology) research grant.
Submitted for publication March 3, 2008; revised April 9, 2008; accepted July 23, 2008.
Disclosure:
M. Fleckenstein, Heidelberg Engineering (F);
P. Charbel Issa, Heidelberg Engineering (F);
H.-M. Helb, Heidelberg Engineering (F);
S. Schmitz-Valckenberg, Heidelberg Engineering (F);
R.P. Finger, Heidelberg Engineering (F);
H.P.N. Scholl, Heidelberg Engineering (F);
K.U. Loeffler, Heidelberg Engineering (F);
F.G. Holz, Heidelberg Engineering (C, F)
The publication costs of this article were defrayed in part by page charge payment. This article must therefore be marked “
advertisement” in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Corresponding author: Frank G. Holz, Department of Ophthalmology, University of Bonn, Ernst-Abbe-Strasse 2, D-53127 Bonn, Germany;
[email protected].
AmbatiJ, AmbatiBK, YooSH, IanchulevS, AdamisAP. Age-related macular degeneration: etiology, pathogenesis, and therapeutic strategies. Surv Ophthalmol. 2003;48:257–293.
[CrossRef] [PubMed]ChakravarthyU, AugoodC, BenthamGC, et al. Cigarette smoking and age-related macular degeneration in the EUREYE Study. Ophthalmology. 2007;114:1157–1163.
[CrossRef] [PubMed]KlaverCC, WolfsRC, VingerlingJR, HofmanA, de JongPT. Age-specific prevalence and causes of blindness and visual impairment in an older population: The Rotterdam Study. Arch Ophthalmol. 1998;116:653–658.
[CrossRef] [PubMed]KleinR, KleinBE, KnudtsonMD, MeuerSM, SwiftM, GangnonRE. Fifteen-year cumulative incidence of age-related macular degeneration: The Beaver Dam Eye Study. Ophthalmology. 2007;114:253–262.
[CrossRef] [PubMed]TomanySC, WangJJ, VanLR, et al. Risk factors for incident age-related macular degeneration: pooled findings from 3 continents. Ophthalmology. 2004;111:1280–1287.
[CrossRef] [PubMed]van LeeuwenR, KlaverCC, VingerlingJR, HofmanA, de JongPT. Epidemiology of age-related maculopathy: a review. Eur J Epidemiol. 2003;18:845–854.
[CrossRef] [PubMed]WangJJ, RochtchinaE, LeeAJ, et al. Ten-year incidence and progression of age-related maculopathy: the blue Mountains Eye Study. Ophthalmology. 2007;114:92–98.
[CrossRef] [PubMed]AugoodCA, VingerlingJR, de JongPT, et al. Prevalence of age-related maculopathy in older Europeans: the European Eye Study (EUREYE). Arch Ophthalmol. 2006;124:529–535.
[CrossRef] [PubMed]SunnessJS, RubinGS, ApplegateCA, et al. Visual function abnormalities and prognosis in eyes with age-related geographic atrophy of the macula and good visual acuity. Ophthalmology. 1997;104:1677–1691.
[CrossRef] [PubMed]SunnessJS. The natural history of geographic atrophy, the advanced atrophic form of age-related macular degeneration. Mol Vis. 1999;5:25.
[PubMed]SunnessJS, Gonzalez-BaronJ, ApplegateCA, et al. Enlargement of atrophy and visual acuity loss in the geographic atrophy form of age-related macular degeneration. Ophthalmology. 1999;106:1768–1779.
[CrossRef] [PubMed]SunnessJS, ApplegateCA, BresslerNM, HawkinsBS. Designing clinical trials for age-related geographic atrophy of the macula: enrollment data from the geographic atrophy natural history study. Retina. 2007;27:204–210.
[CrossRef] [PubMed]SunnessJS, MargalitE, SrikumaranD, et al. The long-term natural history of geographic atrophy from age-related macular degeneration: enlargement of atrophy and implications for interventional clinical trials. Ophthalmology. 2007;114:271–277.
[CrossRef] [PubMed]HolzFG, Bindewald-WittichA, FleckensteinM, DreyhauptJ, SchollHPN, Schmitz-ValckenbergS. Progression of geographic atrophy and impact of fundus autofluorescence patterns in age-related macular degeneration. Am J Ophthalmol. 2007;143:463–472.
[CrossRef] [PubMed]Schmitz-ValckenbergS, BultmannS, DreyhauptJ, BindewaldA, HolzFG, RohrschneiderK. Fundus autofluorescence and fundus perimetry in the junctional zone of geographic atrophy in patients with age-related macular degeneration. Invest Ophthalmol Vis Sci. 2004;45:4470–4476.
[CrossRef] [PubMed]Schmitz-ValckenbergS, Bindewald-WittichA, Dolar-SzczasnyJ, et al. Correlation between the area of increased autofluorescence surrounding geographic atrophy and disease progression in patients with AMD. Invest Ophthalmol Vis Sci. 2006;47:2648–2654.
[CrossRef] [PubMed]BindewaldA, Schmitz-ValckenbergS, JorzikJJ, et al. Classification of abnormal fundus autofluorescence patterns in the junctional zone of geographic atrophy in patients with age related macular degeneration. Br J Ophthalmol. 2005;89:874–878.
[CrossRef] [PubMed]HolzFG, BellmannC, StaudtS, SchüttF, VölckerHE. Fundus autofluorescence and development of geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2001;42:1051–1056.
[PubMed]HolzFG, BellmannC, MargaritidisM, SchuttF, OttoTP, VolckerHE. Patterns of increased in vivo fundus autofluorescence in the junctional zone of geographic atrophy of the retinal pigment epithelium associated with age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol. 1999;237:145–152.
[CrossRef] [PubMed]HolzFG, PauleikhoffD, KleinR, BirdAC. Pathogenesis of lesions in late age-related macular disease. Am J Ophthalmol. 2004;137:504–510.
[CrossRef] [PubMed]BellmannC, HolzFG, SchappO, VolckerHE, OttoTP. Topographie der Fundusautofluoreszenz mit einem neuen konfokalen Scanning-Laser-Ophthalmoskop. Ophthalmologe. 1997;94:385–391.
[CrossRef] [PubMed]LoisN, OwensSL, CocoR, HopkinsJ, FitzkeFW, BirdAC. Fundus autofluorescence in patients with age-related macular degeneration and high risk of visual loss. Am J Ophthalmol. 2002;133:341–349.
[CrossRef] [PubMed]SmithRT, ChanJK, BusuoicM, SivagnanavelV, BirdAC, ChongNV. Autofluorescence characteristics of early, atrophic, and high-risk fellow eyes in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2006;47:5495–5504.
[CrossRef] [PubMed]DrexlerW, MorgnerU, GhantaRK, KartnerFX, SchumanJS, FujimotoJG. Ultrahigh-resolution ophthalmic optical coherence tomography. Nat Med. 2001;7:502–507.
[CrossRef] [PubMed]DrexlerW, SattmannH, HermannB, et al. Enhanced visualization of macular pathology with the use of ultrahigh-resolution optical coherence tomography. Arch Ophthalmol. 2003;121:695–706.
[CrossRef] [PubMed]DrexlerW, MorgnerU, KartnerFX, et al. In vivo ultrahigh-resolution optical coherence tomography. Opt Lett. 1999;24:1221–1223.
[CrossRef] [PubMed]DrexlerW. Ultrahigh-resolution optical coherence tomography. J Biomed Opt. 2004;9:47–74.
[CrossRef] [PubMed]CenseB, ChenTC, NassifN, et al. Ultra-high speed and ultra-high resolution spectral-domain optical coherence tomography and optical Doppler tomography in ophthalmology. Bull Soc Belge Ophtalmol. 2006.123–132.
WojtkowskiM, BajraszewskiT, GorczynskaI, et al. Ophthalmic imaging by spectral optical coherence tomography. Am J Ophthalmol. 2004;138:412–419.
[CrossRef] [PubMed]WojtkowskiM, BajraszewskiT, TargowskiP, KowalczykA. Real-time in vivo imaging by high-speed spectral optical coherence tomography. Opt Lett. 2003;28:1745–1747.
[CrossRef] [PubMed]NassifN, CenseB, ParkBH, et al. In vivo human retinal imaging by ultrahigh-speed spectral domain optical coherence tomography. Opt Lett. 2004;29:480–482.
[CrossRef] [PubMed]de BoerJF, CenseB, ParkBH, PierceMC, TearneyGJ, BoumaBE. Improved signal-to-noise ratio in spectral-domain compared with time-domain optical coherence tomography. Opt Lett. 2003;28:2067–2069.
[CrossRef] [PubMed]PircherM, GotzingerE, FindlO, et al. Human macula investigated in vivo with polarization-sensitive optical coherence tomography. Invest Ophthalmol Vis Sci. 2006;47:5487–5494.
[CrossRef] [PubMed]DrexlerW. Cellular and functional optical coherence tomography of the human retina: the Cogan lecture 1. Invest Ophthalmol Vis Sci. 2007;48:5339–5351.
[CrossRef] [PubMed]MichelsS, PircherM, GeitzenauerW, et al. Value of polarisation-sensitive optical coherence tomography in diseases affecting the retinal pigment epithelium 13. Br J Ophthalmol. 2008;92:204–209.
[CrossRef] [PubMed]AhlersC, MichelsS, ElsnerH, BirngruberR, PruenteC, Schmidt-ErfurthU. Topographic angiography and optical coherence tomography: a correlation of imaging characteristics. Eur J Ophthalmol. 2005;15:774–781.
[PubMed]Schmidt-ErfurthU, LeitgebRA, MichelsS, et al. Three-dimensional ultrahigh-resolution optical coherence tomography of macular diseases. Invest Ophthalmol Vis Sci. 2005;46:3393–3402.
[CrossRef] [PubMed]PieroniCG, WitkinAJ, KoTH, et al. Ultrahigh resolution optical coherence tomography in non-exudative age related macular degeneration. Br J Ophthalmol. 2006;90:191–197.
[CrossRef] [PubMed]KoTH, FujimotoJG, SchumanJS, et al. Comparison of ultrahigh- and standard-resolution optical coherence tomography for imaging macular pathology. Ophthalmology. 2005;112:1922–1935.
[PubMed]SarksSH, SarksJP. Age-related macular degeneration: atrophic form.RyanSJ SchachatAP MurphyRM eds. Retina. 1994;1071–1102.Mosby St. Louis.
GreenWR, KeySN, III. Senile macular degeneration: a histopathologic study. Trans Am Ophthalmol Soc. 1977;75:180–254.
[PubMed]SarksJP, SarksSH, KillingsworthMC. Evolution of geographic atrophy of the retinal pigment epithelium. Eye. 1988;2:552–577.
[CrossRef] [PubMed]MessmerEP, RuggliGH, AppleDJ, NaumannGOH. Spezielle Pathologie der Retina.NaumannGOH eds. Pathologie des Auges. 1997;1089–1099.Springer-Verlag Berlin.
BresslerSB, BresslerNM, SarksSH, SarksJP. Age-related macular degeneration: nonneovascular early AMD, intermediate AMD, and geographic atrophy.RyanSJ eds. Retina. 2006; 4th ed. 1041–1074.Elsevier Inc Philadelphia.
LoefflerKU, LeeWR. Terminology of sub-RPE deposits: do we all speak the same language?. Br J Ophthalmol. 1998;82:1104–1105.
[CrossRef] [PubMed]