- Email: [email protected]
Pseudodrusen Subtypes as Delineated by Multimodal Imaging of the Fundus
Pseudodrusen Subtypes as Delineated by Multimodal Imaging of the Fundus MIHOKO SUZUKI, TAKU SATO, AND RICHARD F. SPAIDE PURPOSE:
To subclassify pseudodrusen based on their appearance in multimodal imaging. DESIGN: Retrospective, observational series. METHODS: The color fundus photographs and infrared scanning laser ophthalmoscope (IR-SLO) images of patients with pseudodrusen were evaluated along with spectral-domain optical coherence tomography (SD OCT) by masked readers. Distinct types of pseudodrusen could be differentiated. RESULTS: There were 140 eyes of 93 patients with a mean age of 82.4 years. Multimodal imaging analysis showed 3 subtypes of pseudodrusen. One principal type was an orderly array of whitish discrete accumulations principally located in the perifovea, termed dot pseudodrusen. They appeared as hyporeflective spots, often with a target configuration, in IR-SLO images. The second type was interconnected bands of yellowish-white material forming a reticular pattern, called ribbon pseudodrusen, which were located in the perifovea. This subtype was faintly hyporeflective in IR-SLO imaging. Dot pseudodrusen were detected more commonly with IR-SLO imaging than in color photography (P [ .014) and ribbon pseudodrusen were seen more frequently in color than in IR-SLO images (P < .001). An uncommon third type of pseudodrusen, yellow-white globules primarily located peripheral to the perifoveal region, appeared hyperreflective in IR-SLO and were called peripheral pseudodrusen. All 3 types were seen as subretinal drusenoid deposits by SD OCT. CONCLUSION: Pseudodrusen may be classified into at least 3 categories, each with optimal methods of detection and only 1 that formed a reticular pattern. These findings suggest pseudodrusen could contain differing constituents and therefore may vary in conferred risk for progression to advanced age-related macular disease. (Am J Ophthalmol 2014;157:1005–1012. Ó 2014 by Elsevier Inc. All rights reserved.)
Accepted for publication Jan 29, 2014. From the Vitreous Retina Macula Consultants of New York; and the LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Hospital, New York, New York. Inquiries to Richard F. Spaide, Vitreous Retina Macula Consultants of New York, 460 Park Avenue, Fifth Floor, New York, NY 10022; e-mail: [email protected]
0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2014.01.025
Ó
2014 BY
N
UMEROUS STUDIES HAVE SHOWN AN ASSOCIA-
tion between pseudodrusen and manifestations of advanced forms of age-related macular degeneration (AMD), including geographic atrophy, choroidal neovascularization (CNV), and outer retinal atrophy.1–15 Population-based studies have classified pseudodrusen as soft drusen and therefore do not provide an opportunity to evaluate the independent risk pseudodrusen confer.1 Review of clinic-based studies has shown a remarkable variation in the proportion of eyes demonstrating pseudodrusen, and consequently the estimates of risk also vary.2 While the large range of reported prevalence may be attributable in part to differing patient samples and to improved recognition of pseudodrusen during clinical examination and in fundus imaging, there may be a larger problem with phenotype recognition. In the first publication by Mimoun and associates in 1990,3 pseudodrusen were described as being a yellowish interlacing network that was best recorded with bluelight fundus photography. Arnold and associates modified the name in 1995 to ‘‘reticular pseudodrusen.’’4 The pseudodrusen they visualized could be round or oval yellow spots that could join to form branches and an ill-defined interlacing network—hence the name reticular, which was derived from the Latin rete, or net. The use of infrared confocal scanning laser ophthalmoscopy for detecting pseudodrusen was introduced by Schmitz-Valckenberg and associates, but they described pseudodrusen as an array of round or oval irregularities approximately 150–250 mm in diameter showing decreased near-infrared reflectance.5 The lesions were single or could be clumped, but areas between these discrete lesions were said to exhibit no marked changes. In a subsequent publication Schmitz-Valckenberg and associates diagnosed the presence of pseudodrusen in infrared scanning laser ophthalmoscopic images if there was a regular complex of uniform round or oval irregularities with a diameter ranging between 50 and 400 mm.6 On the other hand, they made the diagnosis in color images if there were ‘‘yellow-pale or pale light ill-defined networks of broad, interlacing ribbons.’’6 This raises the question: are the lesions imaged in color (or its subset, blue channel photography) the same as those imaged by infrared light, or is there more than 1 phenotype of pseudodrusen, each with differing imaging characteristics? To answer this question, we reviewed patients with the known diagnosis of pseudodrusen who were part of previous Institutional Review Board (IRB)-approved studies, most
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of which have already been published.7–10 The color and infrared scanning laser ophthalmoscopic images of the patients within the region subtended by the Early Treatment Diabetic Retinopathy Study (ETDRS) grid overlay were evaluated. Along the way we realized that there was another presentation of pseudodrusen located outside of the ETDRS grid. From this investigation it appears that there are at least 3 different forms of pseudodrusen and all 3 types appear as subretinal deposits when imaged by spectral-domain optical coherence tomography (SD OCT).
PATIENTS AND METHODS THIS STUDY RETROSPECTIVELY REVIEWED A COMPILATION
of patients with the diagnosis of pseudodrusen who were part of previous IRB-approved studies conducted by the senior author (R.F.S.), most of which have already been published; the present study was approved by the Western IRB and complied with the Health Insurance Portability and Accountability Act of 1996.7–10 The patients could have no history of laser photocoagulation of the macula, rhegmatogenous or tractional retinal detachment, high myopia, acquired vitelliform detachment,16 or any retinal dystrophy or tapetoretinal degeneration. IMAGE CAPTURE:
Color fundus photographs were obtained with a Topcon ImageNet camera (Topcon America, Paramus, New Jersey, USA) and were viewed in Topcon ImageNet (version 2.55; Topcon America). Histogram stretching was used to standardize the images. To fully evaluate the color photographic information the blue channel was evaluated. This same viewing module was used to view the blue channel of the color fundus photographs by selecting the commands Utilities>RGB channels. The 3 principal channels (red, green, and blue) comprising the color image were then displayed along with the original color photograph and histogram stretching to standardize the blue color channel. An Early Treatment Diabetic Retinopathy Study (ETDRS) grid was overlaid on the color fundus photograph centered on the geometric center of the macula. The SD OCTs of the eyes were obtained with the Heidelberg Spectralis (version 1.6.1) as viewed with the contained Heidelberg software (Spectralis Viewing Module 4.0.0.0; Heidelberg Engineering, Heidelberg, Germany). Coincident with the OCT imaging was the capture of an infrared scanning laser ophthalmoscope (IR-SLO) image (820 nm highresolution mode: 1536 3 1536 pixels) that was evaluated by deselecting the option ‘‘Show Scan Positions’’ under ‘‘HRA Image.’’ In each patient of the case group, 31 B-scans were obtained within a 20 3 25-degree rectangle to encompass the macula, including the area to the temporal arcades. The distance between scans was 240 mm. 1006
The number of averaged images per section was dictated by image quality and the ability of the patient to maintain fixation, but typically was at least 10. IMAGE GRADING:
Each class of imaging was reviewed by 2 reviewers masked to the outcome of each other, and if there were discrepancies there was open adjudication with the senior author. Nonexudative AMD was diagnosed if the patient had 1 or more soft drusen _63 and >125 mm or more than 5 intermediate drusen (> <125 mm) or any focal hyperpigmentation but did not have evidence of either geographic atrophy or choroidal neovascularization.17 The diagnosis of neovascular AMD was based on fluorescein angiography. Because of the nature of the study, eyes were graded for pseudodrusen on a per-modality basis as opposed to a per-eye basis. In color imaging pseudodrusen were considered to be present if they were visible in the color photograph and if 5 or more drusen were brighter in the blue than in the green channel of the color photograph.18 In the infrared imaging pseudodrusen were thought to be present if there were 5 or more hyporeflective spots unrelated to the presence of an alternate ocular pathologic process. OCT was used in a confirmatory sense and was not primarily evaluated as a diagnostic testing modality in this study. Subretinal drusenoid deposits, the histologic and OCT visualization of subretinal material, was considered to be consistent with the diagnosis of pseudodrusen if there were 5 or more collections visible. Enhanced depth imaging OCT was performed for the choroidal thickness measurements. Digital calipers were placed at the outer edge of the hyper-reflective retinal pigment epithelium (RPE) line and the inner border of the hyper-reflective surface located behind the large choroidal vessels, which is the scleral/choroidal interface.
DEFINITIONS AND DATA ANALYSIS:
Pseudodrusen distribution was evaluated according to the ETDRS grid. The presence of pseudodrusen in the center circle and the 4 sectors (superior, temporal, inferior, and nasal) was recorded. Separate categories were created to summarize these data. The term ‘‘Any Subfield’’ was considered to be true if any 1 of the 5 regions contained pseudodrusen. The term ‘‘Preponderance of Subfields’’ was considered to be true if 3 or more of the 5 subfields contained pseudodrusen. Since there is no accepted gold-standard fundus photographic method to detect pseudodrusen, their presence, and that of their phenotypic subtypes, was considered to be true in any given eye if they were detected by either color photography or IR-SLO. The data obtained were analyzed with frequency and descriptive statistics. x2 testing was used for categorical analysis. The statistical analyses were performed with IBM SPSS software version 20 (IBM SPSS, Inc, Chicago, Illinois, USA). For all tests a P value less than .05 was considered significant.
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TABLE. Characteristics of Pseudodrusen Subtypes Found in the Fundus Pseudodrusen Subtype Dot
Color photography (when visible)
Discrete dots, can be confluent
IR-SLO (when visible)
Discrete hyporeflective dots, often with target configuration Subretinal accumulation of material, typically forming sharp peaks Perifoveal with decreasing size in the more central parafoveal areas Bilateral symmetry
OCT
Distribution
Ocular correspondence
Ribbon
Midperipheral
Interlocking ribbons, can be confluent Faint hyporeflective ribbons
Small individual globules, can be subconfluent Hyper-reflective spots
Subretinal accumulation of material, typically forming broad, rounded elevations Perifoveal with decreasing visibility in the more central parafoveal areas Bilateral symmetry
Subretinal accumulation of material, typically forming rounded elevations Zone peripheral to the perifovea extending to outside the vascular arcades Too few cases to make definitive statement; appears bilaterally symmetrical
IR-SLO ¼ infrared scanning laser ophthalmoscope image; OCT ¼ optical coherence tomography.
RESULTS THERE WERE 93 PATIENTS WITH A MEAN AGE OF 82.4 YEARS
(median 83.7, interquartile range [IQR] 78.1–87.5 years); 23 were male and 70 were female. Forty-six of 186 eyes were excluded because there were no pseudodrusen in the evaluated eye (12 eyes), scarring and atrophy occupying the ETDRS grid (18 eyes), or inadequate color photographs (16 eyes). Of the remaining 140 eyes, 132 had involvement principally within the ETDRS grid and 8 outside the grid; 63 eyes had a history of CNV, all of which were treated. The mean visual acuity of the eyes with no CNV was 20/36 (logMAR 0.255) as compared with those with CNV, 20/64 (logMAR 0.507). Pseudodrusen detected in the ETDRS grid by any means were present in all eyes, consistent with the entry criteria. Pseudodrusen detected by color fundus photography were found in Any [ETDRS] Subfield in 101 of 132 eyes (76.5%) and by IR-SLO imaging in Any Subfield in 115 (87.1%). Pseudodrusen detected in the Preponderance of Subfields occurred in 56 of 132 eyes (42.4%) using color fundus photography and 78 eyes (59.1%) using IR-SLO imaging. The difference in correlated proportions was not significant for the designation Any Subfield (P ¼ .059), but the difference was significant for the classification Preponderance of Subfields (P ¼ .005, McNemar test). Detailed review of the multimodal imaging information showed 3 subtypes of appearance of pseudodrusen (Table). The most common were seen as an orderly array of discrete dot-like accumulations principally located in the perifoveal area. For the purposes of this study this type of pseudodrusen was termed ‘‘dot’’ pseudodrusen. Dot pseudodrusen were considered to be relatively white spots in a color photograph. In IR-SLO imaging the dot pseudodrusen appeared as hyporeflective structures that sometimes had a central VOL. 157, NO. 5
round area of slightly greater reflectivity, giving a target appearance (Figure 1). Among eyes with dot pseudodrusen, they were more commonly detected using IR-SLO imaging than with color fundus photography for both the designations Any Subfield and Preponderance of Subfields (P ¼ .014 and P ¼ .044, respectively, x2 test). Dot pseudodrusen were seen in 127 of the evaluated eyes (96.1%). A second phenotype appeared as interconnected ribbons or bands of material located most prominently in the perifoveal region. For the purposes of this study this phenotype was termed ribbon pseudodrusen, although the pattern caused by the interlocking bands did suggest a reticular pattern, a sweeping term sometimes applied to all appearances of pseudodrusen (Figure 2). Ribbon pseudodrusen were considered to be an interconnected network of material that creates the appearance of broad interlacing ribbons in a color photograph. This form was seen in 53 eyes (40.2%). The ribbon pseudodrusen was much more commonly seen in color photographs than in IR-SLO images for both the designations Any Subfield and Preponderance of Subfields (P < .001 each, x2 test). Both the dot and ribbon patterns were seen together in 48 eyes. Representative images of the appearance of dot and ribbon pseudodrusen using fundus photographs, infrared scanning laser ophthalmoscopy, and spectral-domain OCT are shown in Figure 3. Sector representation of the percentage of detection of dot and ribbon pseudodrusen in color and infrared images can be seen in Figure 4. Along the way we realized that there was another presentation of pseudodrusen located outside of the ETDRS grid. The third phenotype of pseudodrusen was small, irregularly spaced, and frequently confluent globules principally located peripheral to the perifoveal region and therefore located outside of the ETDRS grid (Figures 5 and 6). The third phenotype of pseudodrusen, considered to be yellow, small individual globules, can be
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FIGURE 1. Dot pseudodrusen in the fundus. (Top) The color photograph shows the superior macula of an 88-year-old patient with dot pseudodrusen. (Middle) An optical coherence tomography (OCT) scan shows discrete subretinal drusenoid deposits corresponding to dot pseudodrusen. Subretinal accumulation of material forms sharp peaks. (Bottom) Infrared scanning laser ophthalmoscope (IR-SLO) image in the same region as Top. Dot pseudodrusen appear as dots, can be confluent, and in the IR-SLO image are discrete hyporeflective dots, often with a target appearance.
FIGURE 2. Ribbon pseudodrusen in the fundus. (Top) The color photograph shows the superior macula of an 83-year-old patient with ribbon pseudodrusen. (Middle) An optical coherence tomography (OCT) scan shows subretinal drusenoid deposits corresponding to ribbon pseudodrusen. Subretinal accumulation of material forms broad, rounded elevations. (Bottom) Infrared scanning laser ophthalmoscope (IR-SLO) image in the same region as Top. The ribbons are not particularly visible in the IR-SLO image.
subconfluent in a color photograph. The third phenotype of pseudodrusen was seen in 8 eyes. The majority of the deposits were located outside of the vascular arcades. The material was easily visualized in both color and IR-SLO images. Unlike other forms of pseudodrusen, these deposits were hyper-reflective in the IR-SLO images. The material was seen to be situated in the subretinal space in OCT images. This presentation is not to be confused with the more common conventional drusen found in the periphery, which are below the RPE and are not hyper-reflective in IR-SLO images. In addition, the representative case of this type showed regression of pseudodrusen, which was reported recently.10 There was a high degree of bilateral symmetry of pseudodrusen appearance. In color imaging the presence of the ribbon appearance showed significant symmetry (P ¼ .001, x2 test), as did the dot appearance with IR-SLO imaging (P ¼ .006). The presence of ribbons seen in color imaging was not associated with the dot configuration as seen by IR-SLO in the fellow eye (P ¼ .663). The peripheral form of pseudodrusen was seen bilaterally in every case. The subfoveal choroidal thickness for the group had a mean of 153.9 (median 137.5, IQR 90–195) mm. The subfoveal choroidal thickness was 153.5 6 98.4 mm for dot
pseudodrusen and 172.8 6 117.6 mm for ribbon pseudodrusen. Using 1-way analysis of variance testing, no difference in the subfoveal choroidal thickness was found among the dot, ribbon, or mixed groups.
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DISCUSSION IN THE CURRENT STUDY WE FOUND THAT PSEUDODRUSEN
could be classified into at least 3 types, dot and ribbon pseudodrusen in the macular area and peripheral pseudodrusen. They were delineated by differently colored fundus photographs and IR-SLO, although all 3 types showed subretinal deposits on SD OCT. The differing multimodal imaging characteristics of each type of pseudodrusen suggest that they might be composed of different constituent elements. These findings suggest there may be a corresponding dissimilarity in pathophysiologic events leading to their accumulation and also a potential for variability in the conferred risk of progression to late AMD. In describing pseudodrusen, previous papers used diverging phraseology that appeared to vary with the imaging modality being used.6 The current results showed 2 different types of
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FIGURE 3. A combination of dot and ribbon pseudodrusen in the fundus. (Top left) A 78-year-old woman had both conventional drusen (cyan arrow) and dot (yellow arrow) and ribbon (black arrow) pseudodrusen. She had no choroidal neovascularization or geographic atrophy. The central choroidal thickness was 115 mm and her visual acuity was 20/25. (Top right) Infrared scanning laser ophthalmoscope image. Of note was that the ribbon-like pattern was difficult to see. (Bottom left) Color photograph in the same lesion as Top right. The locations of the optical coherence tomography (OCT) slices (Bottom right) show as green lines. (Bottom right, top) A top OCT scan shows subretinal drusenoid deposits with broad, rounded elevations (black arrows) corresponding to ribbon pseudodrusen. Cyan arrow corresponds to conventional drusen. (Bottom right, middle) A middle OCT scan shows subretinal drusenoid deposits corresponding to ribbon pseudodrusen (black arrow) and to dot pseudodrusen (yellow arrows). (Bottom right, bottom) A bottom OCT scan shows subretinal drusenoid deposits with sharp peaks corresponding to dot pseudodrusen.
pseudodrusen in the macular region, each best detected by one modality over another, be it color fundus photography or IR-SLO. This raises the question whether previous reports11,17–20 in which only 1 modality was used to detect pseudodrusen, such as only infrared imaging or only color photography, could have missed specific subtypes of pseudodrusen. Since dot and ribbon pseudodrusen have differing multimodal imaging characteristics and often occur singly and together, one form is probably not a more advanced version of the other. Therefore, it is possible that dot pseudodrusen and ribbon pseudodrusen respectively confer varying risk for late age-related macular diseases, including choroidal neovascularization, geographic atrophy, and outer retinal atrophy. Investigating the risk that pseudodrusen confer for more advanced forms of age-related macular disease would require recognition of all forms of pseudodrusen. The cause of pseudodrusen formation is not known, but there are some interesting possibilities. Retinitis punctata albescens is caused by mutation in the gene encoding retinaldehyde binding protein 1 (RLBP1),21 VOL. 157, NO. 5
which is a water-soluble protein that carries 11-cisretinal as a ligand.22 Less commonly, mutations in the gene encoding lecithin retinol acyltransferase, an enzyme that catalyzes the esterification of retinol, can cause the same phenotype. Mutation in the gene encoding retinol dehydrogenase 5 (RDH5),23–27 an enzyme catalyzing the synthesis of 11-cis-retinal, and rarely compound heterozygous mutation of RPE65 gene,28 the product of which is also involved in the production of 11-cis retinal, are both associated with fundus albipunctatus. In both retinitis punctata albescens and fundus albipunctatus, numerous punctate outer retinal spots occur surrounding, but generally not including, the central macula and extend out toward the equator.29,30 Curiously, the SD OCT imaging of these conditions is nearly indistinguishable from the dot pseudodrusen phenotype described in this series.31 Vitamin A deficiency can cause subretinal flecks suggestive of the ribbon pattern of pseudodrusen,32,33 along with histologic findings of foamy material between the retina and RPE that forms aggregates.34 Cases of retinitis punctata albescens, fundus
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FIGURE 4. The percentage of detection of dot and ribbon pseudodrusen in the fundus. Sector representation of the percentage of detection of dot and ribbon pseudodrusen in color and infrared scanning laser ophthalmoscope (IR-SLO) imaging. Of note was that dot pseudodrusen seem to be more detectable in IR-SLO and ribbon pseudodrusen are seen more in color image.
albipunctatus, and vitamin A deficiency show white spots on IR-SLO images.31,33 Even though all of these conditions involve defects in metabolism or deficiencies of retinoid in the visual cycle, the actual material accumulating in the subretinal space is not known. Although retinitis punctata albescens, fundus albipunctatus, or pure vitamin A deficiency would not likely be confused with pseudodrusen seen in older patients, they serve as examples of how varying defects involving stages of the visual cycle can lead to punctate accumulation of subretinal material. It is conceivable that through aging, genetic susceptibility, or a combination of both, material could accumulate in the subretinal space in older adults as a consequence of an abnormality of the visual cycle. It is also possible that widespread deposition of material in the subretinal space could influence vitamin A and retinoid trafficking and recycling. Given their phenotypic variability, it is possible that 1 or more abnormalities may contribute to the formation of what is referred to, generically, as pseudodrusen. The association with late AMD may be attributable directly to local perturbations in outer retinal physiology induced by the pseudodrusen themselves or may be related principally to an underlying defect that also causes pseudodrusen. 1010
FIGURE 5. Color fundus image of peripheral pseudodrusen. (Top) Panoramic montage of an 84-year-old patient with subretinal drusenoid deposits (yellow accumulations) principally concentrated from just outside the macula to the midperiphery. (Bottom) When examined 5 years later, regression of the pseudodrusen appearance was noted (white arrows and arrowheads).
There are important limitations to this study. It was a retrospective study of patients who participated in previous studies and therefore does not represent a random sampling of patients with pseudodrusen. The patients were seen in a retinal referral practice, and this may have introduced biases in the ocular conditions, such as late AMD. The present patient group may not represent all types of pseudodrusen; however, the current results show that multimodal imaging can optimize detection strategies. Although SD OCT is reported to be the most useful among the other modalities, pseudodrusen detection should be performed
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FIGURE 6. Subretinal location of the material seen in the same patient as in Figure 5. (Top left) Infrared scanning laser ophthalmoscope (IR-SLO) image showing that the pseudodrusen are hyper-reflective, which is different from pseudodrusen principally found in the macula. The green line shows the location of the optical coherence tomography slice. (Bottom left) Subretinal accumulation of material forms rounded elevations. (Right, top and bottom) The regression of the pseudodrusen appearance is seen (cyan arrowheads).
using at least 2 imaging modalities for a more accurate diagnosis.35 It would be interesting to examine the detection rates for autofluorescence imaging for the subtypes of pseudodrusen detected in this study. The results of the present study can be used as a guide to design future clinic- and
population-based studies, which could help define risk characteristics for each subtype of pseudodrusen. In particular, reliance on one form of fundus photographic imaging may lead to an underdiagnosis of the prevalence of pseudodrusen.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. Dr Spaide receives consultant and royalty payment support from Topcon Inc, Tokyo, Japan, and receives consultant payment support from Bausch and Lomb, Rochester, New York, USA. Publication of this article was supported in part by the LuEsther T. Mertz Retinal Research Foundation, New York, New York. Contributions of authors: involved in design and conduct of study (R.F.S.), collection and management of data (M.S., T.S., R.F.S.), analysis (M.S., R.F.S.) and interpretation of data, and preparation and final approval of the manuscript (M.S., T.S., R.F.S.).
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10. Spaide RF. Outer retinal atrophy after regression of subretinal drusenoid deposits as a newly recognized form of late agerelated macular degeneration. Retina 2013;33:1800–1808. 11. Cohen SY, Dubois L, Tadayoni R, Delahaye-Mazza C, Debibie C, Quentel G. Prevalence of reticular pseudodrusen in age-related macular degeneration with newly diagnosed choroidal neovascularisation. Br J Ophthalmol 2007;91(3): 354–359. 12. Hamel CP, Meunier I, Arndt C, et al. Extensive macular atrophy with pseudodrusen-like appearance: a new clinical entity. Am J Ophthalmol 2009;147(4):609–620. 13. Lee MY, Yoon J, Ham DI. Clinical characteristics of reticular pseudodrusen in Korean patients. Am J Ophthalmol 2012; 153(3):530–535. 14. Steinberg JS, Auge J, Jaffe GJ, Fleckenstein M, Holz FG, Schmitz-Valckenberg S. Longitudinal analysis of reticular drusen associated with geographic atrophy in age-related macular degeneration. Invest Ophthalmol Vis Sci 2013;54(6): 4054–4060. 15. Querques G, Massamba N, Srour M, Boulanger E, Georges A, Souied EH. Impact of reticular pseudodrusen on macular function. Retina 2014;34(2):321–329. 16. Zweifel SA, Spaide RF, Yannuzzi LA. Acquired vitelliform detachment in patients with subretinal drusenoid deposits (reticular pseudodrusen). Retina 2011;31(2):229–234. 17. Ferris FL 3rd, Wilkinson CP, Bird A, et al. Clinical classification of age-related macular degeneration. Ophthalmology 2013;120(4):844–851. 18. Spaide RF, Curcio CA. Drusen characterization with multimodal imaging. Retina 2010;30(9):1441–1454. 19. Smith RT, Chan JK, Busuoic M, Sivagnanavel V, Bird AC, Chong NV. Autofluorescence characteristics of early, atrophic, and high-risk fellow eyes in age-related macular degeneration. Invest Ophthalmol Vis Sci 2006;47(12):5495–5504. 20. Wang JJ, Rochtchina E, Lee AJ, et al. Ten-year incidence and progression of age-related maculopathy: the Blue Mountains Eye Study. Ophthalmology 2007;114(1):92–98. 21. Fishman GA, Roberts MF, Derlacki DJ, et al. Novel mutations in the cellular retinaldehyde-binding protein gene (RLBP1) associated with retinitis punctata albescens: evidence of interfamilial genetic heterogeneity and fundus changes in heterozygotes. Arch Ophthalmol 2004;122(1): 70–75. 22. Dessalces E, Bocquet B, Bourien J, et al. Early-onset foveal involvement in retinitis punctata albescens with mutations in RLBP1. JAMA Ophthalmology 2013;131(10):1314–1323.
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23. Yamamoto H, Simon A, Eriksson U, Harris E, Berson EL, Dryja TP. Mutations in the gene encoding 11-cis retinol dehydrogenase cause delayed dark adaptation and fundus albipunctatus. Nat Genet 1999;22(2):188–191. 24. Sergouniotis PI, Sohn EH, Li Z, et al. Phenotypic variability in RDH5 retinopathy (Fundus Albipunctatus). Ophthalmology 2011;118(8):1661–1670. 25. Farjo KM, Moiseyev G, Takahashi Y, Crouch RK, Ma JX. The 11-cis-retinol dehydrogenase activity of RDH10 and its interaction with visual cycle proteins. Invest Ophthalmol Vis Sci 2009;50(11):5089–5097. 26. Ajmal M, Khan MI, Neveling K, et al. Novel mutations in RDH5 cause fundus albipunctatus in two consanguineous Pakistani families. Mol Vis 2012;18:1558–1571. 27. Wang NK, Chuang LH, Lai CC, et al. Multimodal fundus imaging in fundus albipunctatus with RDH5 mutation: a newly identified compound heterozygous mutation and review of the literature. Doc Ophthalmol 2012;125(1):51–62. 28. Schatz P, Preising M, Lorenz B, Sander B, Larsen M, Rosenberg T. Fundus albipunctatus associated with compound heterozygous mutations in RPE65. Ophthalmology 2011;118(5):888–894. 29. Pichi F, Morara M, Veronese C, Nucci P, Ciardella AP. Multimodal imaging in hereditary retinal diseases. J Ophthalmol 2013;2013:634351. 30. Pras E, Pras E, Reznik-Wolf H, et al. Fundus albipunctatus: novel mutations and phenotypic description of Israeli patients. Mol Vis 2012;18:1712–1718. 31. Genead MA, Fishman GA, Lindeman M. Spectral-domain optical coherence tomography and fundus autofluorescence characteristics in patients with fundus albipunctatus and retinitis punctata albescens. Ophthalmic Genet 2010;31(2): 66–72. 32. Elison JR, Friedman AH, Brodie SE. Acquired subretinal flecks secondary to hypovitaminosis A in a patient with hepatitis C. Doc Ophthalmol 2004;109(3):279–281. 33. Aleman TS, Garrity ST, Brucker AJ. Retinal structure in vitamin A deficiency as explored with multimodal imaging. Doc Ophthalmol 2013;127(3):239–243. 34. Sorsby A, Reading HW, Bunyan J. Effect of vitamin A deficiency on the retina of the experimental rabbit. Nature 1966;210(5040):1011–1015. 35. Ueda-Arakawa N, Ooto S, Tsujikawa A, Yamashiro K, Oishi A, Yoshimura N. Sensitivity and specificity of detecting reticular pseudodrusen in multimodal imaging in Japanese patients. Retina 2013;33(3):490–497.
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To subclassify pseudodrusen based on their appearance in multimodal imaging. DESIGN: Retrospective, observational series. METHODS: The color fundus photographs and infrared scanning laser ophthalmoscope (IR-SLO) images of patients with pseudodrusen were evaluated along with spectral-domain optical coherence tomography (SD OCT) by masked readers. Distinct types of pseudodrusen could be differentiated. RESULTS: There were 140 eyes of 93 patients with a mean age of 82.4 years. Multimodal imaging analysis showed 3 subtypes of pseudodrusen. One principal type was an orderly array of whitish discrete accumulations principally located in the perifovea, termed dot pseudodrusen. They appeared as hyporeflective spots, often with a target configuration, in IR-SLO images. The second type was interconnected bands of yellowish-white material forming a reticular pattern, called ribbon pseudodrusen, which were located in the perifovea. This subtype was faintly hyporeflective in IR-SLO imaging. Dot pseudodrusen were detected more commonly with IR-SLO imaging than in color photography (P [ .014) and ribbon pseudodrusen were seen more frequently in color than in IR-SLO images (P < .001). An uncommon third type of pseudodrusen, yellow-white globules primarily located peripheral to the perifoveal region, appeared hyperreflective in IR-SLO and were called peripheral pseudodrusen. All 3 types were seen as subretinal drusenoid deposits by SD OCT. CONCLUSION: Pseudodrusen may be classified into at least 3 categories, each with optimal methods of detection and only 1 that formed a reticular pattern. These findings suggest pseudodrusen could contain differing constituents and therefore may vary in conferred risk for progression to advanced age-related macular disease. (Am J Ophthalmol 2014;157:1005–1012. Ó 2014 by Elsevier Inc. All rights reserved.)
Accepted for publication Jan 29, 2014. From the Vitreous Retina Macula Consultants of New York; and the LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear, and Throat Hospital, New York, New York. Inquiries to Richard F. Spaide, Vitreous Retina Macula Consultants of New York, 460 Park Avenue, Fifth Floor, New York, NY 10022; e-mail: [email protected]
0002-9394/$36.00 http://dx.doi.org/10.1016/j.ajo.2014.01.025
Ó
2014 BY
N
UMEROUS STUDIES HAVE SHOWN AN ASSOCIA-
tion between pseudodrusen and manifestations of advanced forms of age-related macular degeneration (AMD), including geographic atrophy, choroidal neovascularization (CNV), and outer retinal atrophy.1–15 Population-based studies have classified pseudodrusen as soft drusen and therefore do not provide an opportunity to evaluate the independent risk pseudodrusen confer.1 Review of clinic-based studies has shown a remarkable variation in the proportion of eyes demonstrating pseudodrusen, and consequently the estimates of risk also vary.2 While the large range of reported prevalence may be attributable in part to differing patient samples and to improved recognition of pseudodrusen during clinical examination and in fundus imaging, there may be a larger problem with phenotype recognition. In the first publication by Mimoun and associates in 1990,3 pseudodrusen were described as being a yellowish interlacing network that was best recorded with bluelight fundus photography. Arnold and associates modified the name in 1995 to ‘‘reticular pseudodrusen.’’4 The pseudodrusen they visualized could be round or oval yellow spots that could join to form branches and an ill-defined interlacing network—hence the name reticular, which was derived from the Latin rete, or net. The use of infrared confocal scanning laser ophthalmoscopy for detecting pseudodrusen was introduced by Schmitz-Valckenberg and associates, but they described pseudodrusen as an array of round or oval irregularities approximately 150–250 mm in diameter showing decreased near-infrared reflectance.5 The lesions were single or could be clumped, but areas between these discrete lesions were said to exhibit no marked changes. In a subsequent publication Schmitz-Valckenberg and associates diagnosed the presence of pseudodrusen in infrared scanning laser ophthalmoscopic images if there was a regular complex of uniform round or oval irregularities with a diameter ranging between 50 and 400 mm.6 On the other hand, they made the diagnosis in color images if there were ‘‘yellow-pale or pale light ill-defined networks of broad, interlacing ribbons.’’6 This raises the question: are the lesions imaged in color (or its subset, blue channel photography) the same as those imaged by infrared light, or is there more than 1 phenotype of pseudodrusen, each with differing imaging characteristics? To answer this question, we reviewed patients with the known diagnosis of pseudodrusen who were part of previous Institutional Review Board (IRB)-approved studies, most
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of which have already been published.7–10 The color and infrared scanning laser ophthalmoscopic images of the patients within the region subtended by the Early Treatment Diabetic Retinopathy Study (ETDRS) grid overlay were evaluated. Along the way we realized that there was another presentation of pseudodrusen located outside of the ETDRS grid. From this investigation it appears that there are at least 3 different forms of pseudodrusen and all 3 types appear as subretinal deposits when imaged by spectral-domain optical coherence tomography (SD OCT).
PATIENTS AND METHODS THIS STUDY RETROSPECTIVELY REVIEWED A COMPILATION
of patients with the diagnosis of pseudodrusen who were part of previous IRB-approved studies conducted by the senior author (R.F.S.), most of which have already been published; the present study was approved by the Western IRB and complied with the Health Insurance Portability and Accountability Act of 1996.7–10 The patients could have no history of laser photocoagulation of the macula, rhegmatogenous or tractional retinal detachment, high myopia, acquired vitelliform detachment,16 or any retinal dystrophy or tapetoretinal degeneration. IMAGE CAPTURE:
Color fundus photographs were obtained with a Topcon ImageNet camera (Topcon America, Paramus, New Jersey, USA) and were viewed in Topcon ImageNet (version 2.55; Topcon America). Histogram stretching was used to standardize the images. To fully evaluate the color photographic information the blue channel was evaluated. This same viewing module was used to view the blue channel of the color fundus photographs by selecting the commands Utilities>RGB channels. The 3 principal channels (red, green, and blue) comprising the color image were then displayed along with the original color photograph and histogram stretching to standardize the blue color channel. An Early Treatment Diabetic Retinopathy Study (ETDRS) grid was overlaid on the color fundus photograph centered on the geometric center of the macula. The SD OCTs of the eyes were obtained with the Heidelberg Spectralis (version 1.6.1) as viewed with the contained Heidelberg software (Spectralis Viewing Module 4.0.0.0; Heidelberg Engineering, Heidelberg, Germany). Coincident with the OCT imaging was the capture of an infrared scanning laser ophthalmoscope (IR-SLO) image (820 nm highresolution mode: 1536 3 1536 pixels) that was evaluated by deselecting the option ‘‘Show Scan Positions’’ under ‘‘HRA Image.’’ In each patient of the case group, 31 B-scans were obtained within a 20 3 25-degree rectangle to encompass the macula, including the area to the temporal arcades. The distance between scans was 240 mm. 1006
The number of averaged images per section was dictated by image quality and the ability of the patient to maintain fixation, but typically was at least 10. IMAGE GRADING:
Each class of imaging was reviewed by 2 reviewers masked to the outcome of each other, and if there were discrepancies there was open adjudication with the senior author. Nonexudative AMD was diagnosed if the patient had 1 or more soft drusen _63 and >125 mm or more than 5 intermediate drusen (> <125 mm) or any focal hyperpigmentation but did not have evidence of either geographic atrophy or choroidal neovascularization.17 The diagnosis of neovascular AMD was based on fluorescein angiography. Because of the nature of the study, eyes were graded for pseudodrusen on a per-modality basis as opposed to a per-eye basis. In color imaging pseudodrusen were considered to be present if they were visible in the color photograph and if 5 or more drusen were brighter in the blue than in the green channel of the color photograph.18 In the infrared imaging pseudodrusen were thought to be present if there were 5 or more hyporeflective spots unrelated to the presence of an alternate ocular pathologic process. OCT was used in a confirmatory sense and was not primarily evaluated as a diagnostic testing modality in this study. Subretinal drusenoid deposits, the histologic and OCT visualization of subretinal material, was considered to be consistent with the diagnosis of pseudodrusen if there were 5 or more collections visible. Enhanced depth imaging OCT was performed for the choroidal thickness measurements. Digital calipers were placed at the outer edge of the hyper-reflective retinal pigment epithelium (RPE) line and the inner border of the hyper-reflective surface located behind the large choroidal vessels, which is the scleral/choroidal interface.
DEFINITIONS AND DATA ANALYSIS:
Pseudodrusen distribution was evaluated according to the ETDRS grid. The presence of pseudodrusen in the center circle and the 4 sectors (superior, temporal, inferior, and nasal) was recorded. Separate categories were created to summarize these data. The term ‘‘Any Subfield’’ was considered to be true if any 1 of the 5 regions contained pseudodrusen. The term ‘‘Preponderance of Subfields’’ was considered to be true if 3 or more of the 5 subfields contained pseudodrusen. Since there is no accepted gold-standard fundus photographic method to detect pseudodrusen, their presence, and that of their phenotypic subtypes, was considered to be true in any given eye if they were detected by either color photography or IR-SLO. The data obtained were analyzed with frequency and descriptive statistics. x2 testing was used for categorical analysis. The statistical analyses were performed with IBM SPSS software version 20 (IBM SPSS, Inc, Chicago, Illinois, USA). For all tests a P value less than .05 was considered significant.
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TABLE. Characteristics of Pseudodrusen Subtypes Found in the Fundus Pseudodrusen Subtype Dot
Color photography (when visible)
Discrete dots, can be confluent
IR-SLO (when visible)
Discrete hyporeflective dots, often with target configuration Subretinal accumulation of material, typically forming sharp peaks Perifoveal with decreasing size in the more central parafoveal areas Bilateral symmetry
OCT
Distribution
Ocular correspondence
Ribbon
Midperipheral
Interlocking ribbons, can be confluent Faint hyporeflective ribbons
Small individual globules, can be subconfluent Hyper-reflective spots
Subretinal accumulation of material, typically forming broad, rounded elevations Perifoveal with decreasing visibility in the more central parafoveal areas Bilateral symmetry
Subretinal accumulation of material, typically forming rounded elevations Zone peripheral to the perifovea extending to outside the vascular arcades Too few cases to make definitive statement; appears bilaterally symmetrical
IR-SLO ¼ infrared scanning laser ophthalmoscope image; OCT ¼ optical coherence tomography.
RESULTS THERE WERE 93 PATIENTS WITH A MEAN AGE OF 82.4 YEARS
(median 83.7, interquartile range [IQR] 78.1–87.5 years); 23 were male and 70 were female. Forty-six of 186 eyes were excluded because there were no pseudodrusen in the evaluated eye (12 eyes), scarring and atrophy occupying the ETDRS grid (18 eyes), or inadequate color photographs (16 eyes). Of the remaining 140 eyes, 132 had involvement principally within the ETDRS grid and 8 outside the grid; 63 eyes had a history of CNV, all of which were treated. The mean visual acuity of the eyes with no CNV was 20/36 (logMAR 0.255) as compared with those with CNV, 20/64 (logMAR 0.507). Pseudodrusen detected in the ETDRS grid by any means were present in all eyes, consistent with the entry criteria. Pseudodrusen detected by color fundus photography were found in Any [ETDRS] Subfield in 101 of 132 eyes (76.5%) and by IR-SLO imaging in Any Subfield in 115 (87.1%). Pseudodrusen detected in the Preponderance of Subfields occurred in 56 of 132 eyes (42.4%) using color fundus photography and 78 eyes (59.1%) using IR-SLO imaging. The difference in correlated proportions was not significant for the designation Any Subfield (P ¼ .059), but the difference was significant for the classification Preponderance of Subfields (P ¼ .005, McNemar test). Detailed review of the multimodal imaging information showed 3 subtypes of appearance of pseudodrusen (Table). The most common were seen as an orderly array of discrete dot-like accumulations principally located in the perifoveal area. For the purposes of this study this type of pseudodrusen was termed ‘‘dot’’ pseudodrusen. Dot pseudodrusen were considered to be relatively white spots in a color photograph. In IR-SLO imaging the dot pseudodrusen appeared as hyporeflective structures that sometimes had a central VOL. 157, NO. 5
round area of slightly greater reflectivity, giving a target appearance (Figure 1). Among eyes with dot pseudodrusen, they were more commonly detected using IR-SLO imaging than with color fundus photography for both the designations Any Subfield and Preponderance of Subfields (P ¼ .014 and P ¼ .044, respectively, x2 test). Dot pseudodrusen were seen in 127 of the evaluated eyes (96.1%). A second phenotype appeared as interconnected ribbons or bands of material located most prominently in the perifoveal region. For the purposes of this study this phenotype was termed ribbon pseudodrusen, although the pattern caused by the interlocking bands did suggest a reticular pattern, a sweeping term sometimes applied to all appearances of pseudodrusen (Figure 2). Ribbon pseudodrusen were considered to be an interconnected network of material that creates the appearance of broad interlacing ribbons in a color photograph. This form was seen in 53 eyes (40.2%). The ribbon pseudodrusen was much more commonly seen in color photographs than in IR-SLO images for both the designations Any Subfield and Preponderance of Subfields (P < .001 each, x2 test). Both the dot and ribbon patterns were seen together in 48 eyes. Representative images of the appearance of dot and ribbon pseudodrusen using fundus photographs, infrared scanning laser ophthalmoscopy, and spectral-domain OCT are shown in Figure 3. Sector representation of the percentage of detection of dot and ribbon pseudodrusen in color and infrared images can be seen in Figure 4. Along the way we realized that there was another presentation of pseudodrusen located outside of the ETDRS grid. The third phenotype of pseudodrusen was small, irregularly spaced, and frequently confluent globules principally located peripheral to the perifoveal region and therefore located outside of the ETDRS grid (Figures 5 and 6). The third phenotype of pseudodrusen, considered to be yellow, small individual globules, can be
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FIGURE 1. Dot pseudodrusen in the fundus. (Top) The color photograph shows the superior macula of an 88-year-old patient with dot pseudodrusen. (Middle) An optical coherence tomography (OCT) scan shows discrete subretinal drusenoid deposits corresponding to dot pseudodrusen. Subretinal accumulation of material forms sharp peaks. (Bottom) Infrared scanning laser ophthalmoscope (IR-SLO) image in the same region as Top. Dot pseudodrusen appear as dots, can be confluent, and in the IR-SLO image are discrete hyporeflective dots, often with a target appearance.
FIGURE 2. Ribbon pseudodrusen in the fundus. (Top) The color photograph shows the superior macula of an 83-year-old patient with ribbon pseudodrusen. (Middle) An optical coherence tomography (OCT) scan shows subretinal drusenoid deposits corresponding to ribbon pseudodrusen. Subretinal accumulation of material forms broad, rounded elevations. (Bottom) Infrared scanning laser ophthalmoscope (IR-SLO) image in the same region as Top. The ribbons are not particularly visible in the IR-SLO image.
subconfluent in a color photograph. The third phenotype of pseudodrusen was seen in 8 eyes. The majority of the deposits were located outside of the vascular arcades. The material was easily visualized in both color and IR-SLO images. Unlike other forms of pseudodrusen, these deposits were hyper-reflective in the IR-SLO images. The material was seen to be situated in the subretinal space in OCT images. This presentation is not to be confused with the more common conventional drusen found in the periphery, which are below the RPE and are not hyper-reflective in IR-SLO images. In addition, the representative case of this type showed regression of pseudodrusen, which was reported recently.10 There was a high degree of bilateral symmetry of pseudodrusen appearance. In color imaging the presence of the ribbon appearance showed significant symmetry (P ¼ .001, x2 test), as did the dot appearance with IR-SLO imaging (P ¼ .006). The presence of ribbons seen in color imaging was not associated with the dot configuration as seen by IR-SLO in the fellow eye (P ¼ .663). The peripheral form of pseudodrusen was seen bilaterally in every case. The subfoveal choroidal thickness for the group had a mean of 153.9 (median 137.5, IQR 90–195) mm. The subfoveal choroidal thickness was 153.5 6 98.4 mm for dot
pseudodrusen and 172.8 6 117.6 mm for ribbon pseudodrusen. Using 1-way analysis of variance testing, no difference in the subfoveal choroidal thickness was found among the dot, ribbon, or mixed groups.
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DISCUSSION IN THE CURRENT STUDY WE FOUND THAT PSEUDODRUSEN
could be classified into at least 3 types, dot and ribbon pseudodrusen in the macular area and peripheral pseudodrusen. They were delineated by differently colored fundus photographs and IR-SLO, although all 3 types showed subretinal deposits on SD OCT. The differing multimodal imaging characteristics of each type of pseudodrusen suggest that they might be composed of different constituent elements. These findings suggest there may be a corresponding dissimilarity in pathophysiologic events leading to their accumulation and also a potential for variability in the conferred risk of progression to late AMD. In describing pseudodrusen, previous papers used diverging phraseology that appeared to vary with the imaging modality being used.6 The current results showed 2 different types of
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FIGURE 3. A combination of dot and ribbon pseudodrusen in the fundus. (Top left) A 78-year-old woman had both conventional drusen (cyan arrow) and dot (yellow arrow) and ribbon (black arrow) pseudodrusen. She had no choroidal neovascularization or geographic atrophy. The central choroidal thickness was 115 mm and her visual acuity was 20/25. (Top right) Infrared scanning laser ophthalmoscope image. Of note was that the ribbon-like pattern was difficult to see. (Bottom left) Color photograph in the same lesion as Top right. The locations of the optical coherence tomography (OCT) slices (Bottom right) show as green lines. (Bottom right, top) A top OCT scan shows subretinal drusenoid deposits with broad, rounded elevations (black arrows) corresponding to ribbon pseudodrusen. Cyan arrow corresponds to conventional drusen. (Bottom right, middle) A middle OCT scan shows subretinal drusenoid deposits corresponding to ribbon pseudodrusen (black arrow) and to dot pseudodrusen (yellow arrows). (Bottom right, bottom) A bottom OCT scan shows subretinal drusenoid deposits with sharp peaks corresponding to dot pseudodrusen.
pseudodrusen in the macular region, each best detected by one modality over another, be it color fundus photography or IR-SLO. This raises the question whether previous reports11,17–20 in which only 1 modality was used to detect pseudodrusen, such as only infrared imaging or only color photography, could have missed specific subtypes of pseudodrusen. Since dot and ribbon pseudodrusen have differing multimodal imaging characteristics and often occur singly and together, one form is probably not a more advanced version of the other. Therefore, it is possible that dot pseudodrusen and ribbon pseudodrusen respectively confer varying risk for late age-related macular diseases, including choroidal neovascularization, geographic atrophy, and outer retinal atrophy. Investigating the risk that pseudodrusen confer for more advanced forms of age-related macular disease would require recognition of all forms of pseudodrusen. The cause of pseudodrusen formation is not known, but there are some interesting possibilities. Retinitis punctata albescens is caused by mutation in the gene encoding retinaldehyde binding protein 1 (RLBP1),21 VOL. 157, NO. 5
which is a water-soluble protein that carries 11-cisretinal as a ligand.22 Less commonly, mutations in the gene encoding lecithin retinol acyltransferase, an enzyme that catalyzes the esterification of retinol, can cause the same phenotype. Mutation in the gene encoding retinol dehydrogenase 5 (RDH5),23–27 an enzyme catalyzing the synthesis of 11-cis-retinal, and rarely compound heterozygous mutation of RPE65 gene,28 the product of which is also involved in the production of 11-cis retinal, are both associated with fundus albipunctatus. In both retinitis punctata albescens and fundus albipunctatus, numerous punctate outer retinal spots occur surrounding, but generally not including, the central macula and extend out toward the equator.29,30 Curiously, the SD OCT imaging of these conditions is nearly indistinguishable from the dot pseudodrusen phenotype described in this series.31 Vitamin A deficiency can cause subretinal flecks suggestive of the ribbon pattern of pseudodrusen,32,33 along with histologic findings of foamy material between the retina and RPE that forms aggregates.34 Cases of retinitis punctata albescens, fundus
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FIGURE 4. The percentage of detection of dot and ribbon pseudodrusen in the fundus. Sector representation of the percentage of detection of dot and ribbon pseudodrusen in color and infrared scanning laser ophthalmoscope (IR-SLO) imaging. Of note was that dot pseudodrusen seem to be more detectable in IR-SLO and ribbon pseudodrusen are seen more in color image.
albipunctatus, and vitamin A deficiency show white spots on IR-SLO images.31,33 Even though all of these conditions involve defects in metabolism or deficiencies of retinoid in the visual cycle, the actual material accumulating in the subretinal space is not known. Although retinitis punctata albescens, fundus albipunctatus, or pure vitamin A deficiency would not likely be confused with pseudodrusen seen in older patients, they serve as examples of how varying defects involving stages of the visual cycle can lead to punctate accumulation of subretinal material. It is conceivable that through aging, genetic susceptibility, or a combination of both, material could accumulate in the subretinal space in older adults as a consequence of an abnormality of the visual cycle. It is also possible that widespread deposition of material in the subretinal space could influence vitamin A and retinoid trafficking and recycling. Given their phenotypic variability, it is possible that 1 or more abnormalities may contribute to the formation of what is referred to, generically, as pseudodrusen. The association with late AMD may be attributable directly to local perturbations in outer retinal physiology induced by the pseudodrusen themselves or may be related principally to an underlying defect that also causes pseudodrusen. 1010
FIGURE 5. Color fundus image of peripheral pseudodrusen. (Top) Panoramic montage of an 84-year-old patient with subretinal drusenoid deposits (yellow accumulations) principally concentrated from just outside the macula to the midperiphery. (Bottom) When examined 5 years later, regression of the pseudodrusen appearance was noted (white arrows and arrowheads).
There are important limitations to this study. It was a retrospective study of patients who participated in previous studies and therefore does not represent a random sampling of patients with pseudodrusen. The patients were seen in a retinal referral practice, and this may have introduced biases in the ocular conditions, such as late AMD. The present patient group may not represent all types of pseudodrusen; however, the current results show that multimodal imaging can optimize detection strategies. Although SD OCT is reported to be the most useful among the other modalities, pseudodrusen detection should be performed
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FIGURE 6. Subretinal location of the material seen in the same patient as in Figure 5. (Top left) Infrared scanning laser ophthalmoscope (IR-SLO) image showing that the pseudodrusen are hyper-reflective, which is different from pseudodrusen principally found in the macula. The green line shows the location of the optical coherence tomography slice. (Bottom left) Subretinal accumulation of material forms rounded elevations. (Right, top and bottom) The regression of the pseudodrusen appearance is seen (cyan arrowheads).
using at least 2 imaging modalities for a more accurate diagnosis.35 It would be interesting to examine the detection rates for autofluorescence imaging for the subtypes of pseudodrusen detected in this study. The results of the present study can be used as a guide to design future clinic- and
population-based studies, which could help define risk characteristics for each subtype of pseudodrusen. In particular, reliance on one form of fundus photographic imaging may lead to an underdiagnosis of the prevalence of pseudodrusen.
ALL AUTHORS HAVE COMPLETED AND SUBMITTED THE ICMJE FORM FOR DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST. Dr Spaide receives consultant and royalty payment support from Topcon Inc, Tokyo, Japan, and receives consultant payment support from Bausch and Lomb, Rochester, New York, USA. Publication of this article was supported in part by the LuEsther T. Mertz Retinal Research Foundation, New York, New York. Contributions of authors: involved in design and conduct of study (R.F.S.), collection and management of data (M.S., T.S., R.F.S.), analysis (M.S., R.F.S.) and interpretation of data, and preparation and final approval of the manuscript (M.S., T.S., R.F.S.).
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AMERICAN JOURNAL OF OPHTHALMOLOGY
MAY 2014