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Unique optical coherence tomographic features in age-related macular degeneration
Journal Pre-proof Unique optical coherence tomographic features in age-related macular degeneration Sumit Randhir Singh, Marco Lupidi, Sai Bhakti Mishra, Manuel Paez-Escamilla, Giuseppe Querques, Jay Chhablani PII:
S0039-6257(20)30006-0
DOI:
https://doi.org/10.1016/j.survophthal.2020.01.001
Reference:
SOP 6924
To appear in:
Survey of Ophthalmology
Received Date: 8 October 2019 Revised Date:
10 January 2020
Accepted Date: 13 January 2020
Please cite this article as: Singh SR, Lupidi M, Mishra SB, Paez-Escamilla M, Querques G, Chhablani J, Unique optical coherence tomographic features in age-related macular degeneration, Survey of Ophthalmology (2020), doi: https://doi.org/10.1016/j.survophthal.2020.01.001. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
1 Title: Unique optical coherence tomographic features in age-related macular degeneration Running title: Unique optical coherence tomographic features in AMD Authors: Sumit Randhir Singh1,2, Marco Lupidi3, Sai Bhakti Mishra1,2, Manuel Paez-Escamilla4, Giuseppe Querques5, Jay Chhablani1,6 Affiliations: 1. Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye Institute, Hyderabad, India 2. Retina and Uveitis Department, GMR Varalakshmi Campus, LV Prasad Eye Institute, Visakhapatnam, India 3. Section of Ophthalmology, Department of Surgical and Biomedical Sciences, S. Maria della Misericordia Hospital, University of Perugia, Perugia, Italy. 4. University of Texas Southwestern Medical Center, Dallas, Texas. 5. Department of Ophthalmology, University Vita-Salute, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. 6. University of Pittsburgh, UPMC Eye Center, Pittsburgh, PA 15213. Corresponding Author: Dr Jay Chhablani Faculty – Clinician, University of Pittsburgh, UPMC Eye Center, 203 Lothrop Street, Pittsburgh, PA 15213 Phone: 412-377-1943, Fax: 412-647-5119 Email: [email protected]
2 Keywords: Outer retinal tubulations, onion sign, prechoroidal cleft, intraretinal pseudocyst, subretinal pseudocyst, cystoid degeneration, choroidal caverns, activated RPE, hyperreflective crystalline deposits.
Abbreviations: Age-related macular degeneration, AMD; retinal pigment epithelium, RPE; optical coherence tomography, OCT; neovascular AMD, n-AMD; choroidal neovascularization (CNV); intraretinal/ subretinal fluid , IRF/SRF; outer retinal tubulations, ORT; comparison of agerelated macular degeneration treatments trials (CATT); inner segment-outer segments (IS-OS); external limiting membrane, ELM; ellipsoid zone, EZ; vascular endothelial growth factors, VEGF; pigment epithelial detachment, PED; red-free, RF; near infrared, NIR.
3 Abstract Age-related macular degeneration (AMD) is a leading cause of blindness worldwide characterized by presence of drusen, leading to retinal pigment epithelium (RPE) and outer retinal changes in advanced stages. Approximately 10% of eyes with AMD develop neovascular complications and present with subretinal or sub-RPE exudation, hemorrhage, or both. Recent advances in imaging techniques, especially optical coherence tomography (OCT), help in early identification of disease and guide various treatment decisions; however, not all signs are suggestive of ongoing exudation or neovascular activity. Though uncommon, multiple OCTbased signs are reported that may be difficult to appreciate clinically. Prompt identification of these signs such as outer retinal tubulation, cystoid degeneration, or pseudocysts may avoid unnecessary interventions. Moreover, certain OCT-based features involving the choroid, such as prechoridal cleft, choroidal cavern, have also been found in eyes with AMD. We discuss these unique OCT-based signs, their pathogenesis, clinical relevance, and management.
4 1. Introduction Age-related macular degeneration (AMD) is a leading cause of visual loss in the elderly.17, 49 Neovascular AMD (nAMD) forms a small subset (less than 10%) of total AMD cases; however, the neovascular variant is responsible for the majority of severe visual loss in eyes with AMD.2 Optical coherence tomography (OCT) provides in-vivo high-resolution information about chorioretinal anatomy and vasculature. These modalities aid in diagnosis of AMD, help in treatment decisions, identify the disease recurrence, and establish the visual prognosis.49, 46 Literature search shows multiple signs based on cross-sectional or en-face OCT-B scans that are suggestive of choroidal neovascularization (CNV) in nAMD eyes.46, 49, 31 The evaluation of these criteria that include presence of intraretinal or subretinal fluid (IRF/SRF), ill-defined boundaries of the neovascular lesion, and, increase of central retinal thickness provide information about disease activity for retreatment decisions;31, 19 however, not all structural changes on OCT suggest either active CNV or exudation. These signs are multifactorial in origin, including degenerative changes (cystoid degeneration– pseudocysts, outer retinal tubulation), unique choroidal features directly associated with type 1 CNV, and retinal angiomatous proliferation (RAP) lesions (pre-choroidal clefts) or atrophic changes (choroidal caverns), and may not require treatment. We review the literature and analyze these unique OCT-based signs in AMD. Treating physicians need to be aware of these signs, thus avoiding overtreatment of the disease and reducing the economic burden on patients. 2. Outer retinal tubulation (ORT) Zweifel and coworkers in 2009 provided the first OCT description of ORTs using enface or C scans which are formed from rearrangement of photoreceptors after retinal injury.54, 41The terminology “outer retinal tubulations” is self-explanatory, where outer signifies the consistent
5 outer nuclear layer location and tubulations refer to their tubule-like morphology seen on en face OCT scans.48, 54 The reported prevalence rate of ORTs remains high, varying from 8.2% to 38.1%.12, 13, 54, 32, 52 Moreover, the incidence of ORT also increases with duration of disease. ORTs are reported in a small proportion at baseline (2.5%),increasing up to 28-35% at 2-3 years, and present in more than 40% of eyes with nAMD at 4 years.9 These lesions have been associated more commonly with classic CNV than occult lesions.13 Although initially described in eyes with nAMD, ORT has been reported in various other chorioretinal degenerative disorders (including retinitis pigmentosa (RP), Bietti crystalline dystrophy, choroidermia, gyrate atrophy, Stargardt disease, pattern dystrophy), central serous chorioretinopathy , CNV from other causes or geographic atrophy where outer retina including photoreceptors and retinal pigment epithelium (RPE) are affected.24, 20, 53, 54 Eyes with diabetic macular edema, retinal vein occlusion, or diseases with complete loss of photoreceptors such as advanced RP fail to show any ORT.54 Lee and coworkers analyzed patients enrolled in Comparison of Age-related Macular Degeneration Treatments Trials (CATT) and concluded that poor baseline visual acuity, geographic atrophy, large CNV size, blocked fluorescence, and subretinal hyper-reflective material were independently predictive of ORT formation at 2 years.32
Curcio and coworkers first described the histopathological features of ORT as interconnecting tubes in outer retina. Red-green cones formed the major constituents of ORT as shown by carbonic-anhydrase histochemistry.7 Loss of interdigitations between outer segments (OS) of photoreceptors and RPE may be initial triggering event in formation of ORT. This may be followed by simultaneous or sequential loss of neural attachments of photoreceptors with adjacent structures. Outward folding of photoreceptors ensues, leading to formation of tubular structure of ORT.54, 11 Litts and coworkers have shown that external limiting membrane (ELM)
6 and mitochondria within inner segments (IS) form the hyper-reflective outer border of ORT.33 Schaal and coworkers have described different phases of photoreceptor degeneration in the outer walls of ORT. Nascent phase (both IS and OS present), mature (IS only), degenerate (no or minimal remnants of IS which may be retracted from ELM), and end-stage phase (only ELM forms the hyper-reflective border with no IS) are the different phases described.48 The lumen of ORT may not always be hyporeflective and constituents within ORT can vary from degenerate photoreceptors to RPE or lipofuscin deposits.48, 54, 9 High resolution OCT images provide in-depth information regarding ORT and their subtypes, shapes and other differential diagnosis. They appear as hyper-reflective round or ovoid structures with a hypo- or hyperreflective lumen and can be identified on structural OCT B scan. ORT was more commonly seen in areas with loss of outer retinal layers and relatively preserved ellipsoid zone (EZ);54 however, the more complex tubular structure can be more delineated on en-face scans within close proximity of the RPE. These ORTs can be located above the fibrovascular scars, at sites of previous IRF, or adjacent to areas of geographic atrophy.48, 51, 54, 9 Closed or open ORT can be defined on the basis of their boundaries on OCT scans. ORTs that have 360 degree welldefined hyper-reflective borders are termed closed, whereas ORTs with deficient hyperreflective border are termed open ORTs.48 The presence of a branching pattern is not a prerequisite for identification of ORTs, as a sizeable number of ORT fail to show branching. Though the intraretinal outer nuclear layer location is constant, there is a significant variation of length of ORT varying from few microns to millimeters with width ranging from 70 to 509 µ.48, 28 The presence of ORTs confers a worse visual prognosis as compared to eyes without ORTs.32 The treatment with anti-VEGF agents may not halt the formation of newer ORTs or regression of pre-existing ORTs.9, 54 Moreover, the treatment protocol based on treat or extend, pro-re-nata
7 or monthly injections failed to show any difference in architecture or regression pattern of ORTs.9, 32 A representative case of nAMD showing multiple ORTs is shown as Figure 1.
3. Onion Sign Initially described by Mukkamala and coworkers in eyes with nAMD, the onion sign was reported in eyes with vascularized pigmented epithelial detachment (PED). This novel finding was seen between RPE and Bruch membrane in the form of multilayered hyper-reflective bands similar to multiple layers seen in an onion.37 The reported prevalence of onion sign is 5-7% in eyes with n-AMD.40 Pang and coworkers have also proposed a possible association with systemic hyper-cholesterolemia, though this has not been substantiated in their report.40 While Coscas and coworkers described this as fibrovascular tissue, Mukkamala and coworkers proposed that these sub-RPE bands could be sub-RPE lipids formed by chronic exudation and become trapped within these fibrovascular tissue, as confirmed on fundus photography in the form of deep yellow-gray deposits.6, 37A possible role of endothelial fenestrations of type 1 CNV leading to chronic, intermittent exudation which remains limited by RPE was initially proposed. These deposits may over time crystallize leading to formation of these hype-reflective bands. Pang and coworkers have provided the histological confirmation of these deposits as crystalline cholesterol deposits.40 Christakopoulos and coworkers have also reported similar findings of multilayered, hyperreflective lines in a case of polypoidal choroidal vasculopathy (PCV).3 Other groups have proposed mechanical stress on Bruch’s membrane or fibrovascular scar as the key constituents of histological correlates of onion sign.6 The location, shape, extent, orientation of hyper-reflective bands and presence of posterior shadowing are the variables used to describe this sign on OCT. These hyper-reflective bands usually extend along the PED. Quantitative assessment of these bands may be difficult at
8 present in view of closely packed layers and the limited resolution of OCT machines, especially underneath the RPE. The absence of any posterior shadowing ruled out any calcification in these bands. Red-free (RF) and near infrared (NIR) imaging showed these lesions as hyper-reflective entities and the reflectivity was higher with large area on NIR compared to RF. This finding can be explained due to deposition of fibrin and collagen in type 1 CNV which appears brighter on NIR; however, there was no obvious change in autofluorescence pattern.23 There is, however, a contrary evidence demonstrating the absence of fibrin in sub-RPE bands from excised CNV specimens.30 Pang and coworkershave shows that onion sign persists even with treatment with anti VEGF injections. This was seen in all 16 eyes in their study cohort over a mean follow up of 3.7 years.40 Figure 2 shows OCT of a case with fibrovascular PED and sub-RPE hyperreflective bands (white arrow) suggestive of onion sign.
4. Pre-choroidal cleft Pre-choroidal clefts are defined as hyporeflective spaces sandwiched between two hyperreflective lines on OCT, the RPE, and Bruch membrane and are characterized by posterior bowing of Bruch membrane.27, 35 Prechoroidal clefts are reported in 8.1-22.3% of treated nAMD eyes.35, 27, 26 Moreover, a higher incidence of clefts is seen in cases with retinal angiomatous proliferation and typical AMD compared to PCV.27 Khan and coworkers described a “triple layer sign” in cases with polypoidal choroidal vasculopathy. There was presence of two hyporeflective spaces separated by RPE, thickened, vascularized Bruch membrane and the rest of the choroid.25 Here, the proposed location of cleft was intra-choroidal rather than pre-choroidal. Mrejen and coworkers in their description have labeled the second hyper-reflective band as dense lamellar portion of CNV in contrast to
9 vascularized Bruch membrane by Khan and coworkers34, 25 Nagiel and coworkers described pre-choroidal cleft in 6 out of 8 eyes with nAMD and adherent neovascular complex to the undersurface of RPE.39 These eyes developed RPE rip post intravitreal anti-VEGF injections, and these clefts were seen to resolve post formation of RPE rip.39 Some have therefore proposed that these clefts may act as an independent risk factor for development of RPE rip.39, 36, 34
The presence of sub-RPE neovascular tissue leading to contractile and hydrostatic forces predispose to the development of these clefts. Histopathology reveals that neovascular tissue is associated with additional presence of inflammatory cells, glial cells and myofibroblasts.21 The treatment with anti-VEGF agents leads to regression of neovascular component. Moreover, contraction of the remaining fibrous tissue leads to a split in RPE-Bruch complex with the formation of pre-choroidal clefts. There are conflicting reports regarding the influence of clefts on visual acuity mostly due to differences in incidence of clefts in various types of AMD, variability in study population and duration.45, 27, 35 Kim and coworkers found a poor visual prognosis with presence of clefts, whereas Rahimy and coworkers showed no influence of clefts on visual acuity.27, 45, 26 Clefts which formed within six months of treatment were associated with worse visual acuity. Causes of poor visual outcomes can be multifactorial such as suboptimal response to treatment, subretinal fibrosis, and other complications including RPE rip.26 Moreover, the majority of clefts form within the first 24 months, and almost half of them were associated with RPE rip or subretinal heme.26 Interestingly, eyes with cleft with no complications fared equally well when compared to eyes without cleft.26 Figure 3 shows a prechoroidal cleft on OCT in an eye with nAMD. To conclude, pre-choroidal clefts may rarely be seen in eyes with nAMD and can be a potential harbinger of complications such as RPE rip or subretinal hemorrhage. Though not conclusive,
10 clefts may be associated with a worse visual acuity especially when associated with complications.
5. Cystoid degeneration / Pseudocysts – Intraretinal and Subretinal Cohen and coworkers found intraretinal pseudocysts in eyes with geographic atrophy in AMD with no obvious exudative CNV or retinal thickening.4 Pseudocysts can also be seen in nAMD eyes with fibroatrophic scars. Though most commonly reported in inner nuclear layers, these can be present below internal limiting membrane (ILM), within outer or all retinal layers.4, 42, 1 OCT showed optically empty spaces without the presence of any hyper-reflectivity at their borders, hence the term “pseudocyst”. In contrast to cystic spaces from CNV that are usually associated with retinal thickening and/ or focal disruption and irregularity of RPE and outer retinal layers, pseudocysts show absence of retinal thickening.4 This suggests that these changes are non-exudative in nature and don’t merit any intervention or treatment. Hypothetically, these cysts in either non-exudative or exudative AMD may be related to Müller cell degeneration.4, 42 Similar to these changes, Querques and coworkers found cystoid macular degeneration or degenerative pseudocysts in eyes with nAMD that had similarities with cystoid degeneration seen in central serous chorioretinopathy.42 Degenerated cysts showed at least one concave or straight border whereas exudative cysts show biconvex and rounded borders. Moreover, these cysts were associated with a worse visual acuity.42 Fluid in the exudative cysts start accumulating after the disruption of tight junctions of external limiting membrane.50, 16 Sacconi and coworkers described the term subretinal pseudocyst in an eye with type 1 nAMD which persisted despite multiple anti VEGF injections. They hypothesized that either migration of Müller cells to subretinal space or compression of outer nuclear layer due to accumulation of
11 subretinal fluid or blood can lead to formation of subretinal pseudocyst.47 These are quite uncommon with literature search showing only a single case report till date. They appear as a distinct entity compared to intraretinal pseudocyst, and whether these represent non-exudative or exudative process is not clearly understood at present. Figure 4 and 5 show examples of geographic atrophy with intraretinal and subretinal pseudocyst respectively.
6. Caverns - choroidal and sub-retinal pigment epithelium Originally described by Querques and coworkers as choroidal caverns, these were reported as choroidal hypo-reflective spaces in eyes with geographic atrophy secondary to AMD.43 Further detailed work expanded the clinical spectrum and their prevalence in nAMD and other disorders as well.10 Choroidal caverns were hypothesized to form at sites of pre-existing choroidal vessels with non perfused ghost vessels and preserved stromal pillars. The authors correlated the formation of choriocapillaris ghost vessel with the formation of caverns at level of Haller and Sattler layers.38 These eyes, however, had relatively preserved choriocapillaris and lumen either empty or with few internal hyper-reflectivity, presumably due to macrophage like cells or migration of calcified material from Bruch membrane. These were differentiated from choroidal vessel by the absence of hyper-reflective border (lack of vessel wall) and hyporeflective lumen (lack of blood) with a tail of hypertransmission; however, recent reports suggest their presence in sub-RPE space as well.10 Both en-face and cross-sectional OCT help in detection of these caverns as highlighted in figure 6. IR images provide a higher detection rates compared to color fundus photographs, red-free, autofluorescence, fluorescein angiography, and indocyanine green angiography. Caverns were seen as hyper-reflective on NIR images. Indocyanine green angiography and OCT angiography
12 (OCTA) have shown these areas as empty or devoid of any blood supply. Another possibility is the rate of blood flow below the detectable threshold in OCTA.10, 43 Choroidal hyporeflectivities manifesting as round or oval structures with hyper-reflective border could be a precursor lesion of choroidal caverns or lipid globules formed due to fatty degeneration probably in large, single celled tissue macrophages.5, 18, 29 Dolz-Marco and coworkers have shown histologic correlation (Friedman lipid-rich globules) with the choroidal cavern.10 They have also described a hypertransmission tail due to loss of RPE layer leading to increased transmission. There is limited information on the prognostic significance of caverns at either choroidal or sub-RPE level and by itself don’t merit any intervention.
7. Activated RPE, Hyperreflective Crystalline Deposits Curcio and coworkers have shown that RPE activation and migration may occur prior to onset of RPE atrophy. These changes occur in the form of intraretinal hyper-reflective foci which are histologically shown as filled with organelles.8 These are of presumably RPE or macrophages or microglial origin. Similarly, vitelliform deposits also were considered to be one of the stress responses of RPE via organelle expulsion.8 Initially described by Fleckenstein and coworkers, hyperreflective crystalline deposits were reported as hyper-reflective plaques at the level of RPE-Bruch complex.14 Other authors have similarly described hyper-reflective lines related to calcification in areas of drusen progression and location between RPE and Bruch membrane.44, 22 These were co-related histologically with densification. NIR imaging showed mirror like reflectivity of these deposits which over time was replaced by areas of atrophy. These deposits are not directly linked to exudation; however, vision loss can occur in these eyes due to macular complications such as complete RPE and outer retinal atrophy or development of neovascularization.15
13 8. Conclusions: These OCT based non-exudative or non-neovascular signs are not uncommon in AMD eyes. Their overall understanding is essential for decision making for treatment and follow-up. 9. Literature search: A literature search of medline/pubmed database (www.ncbi.nlm.nih.gov/pubmed) was done through August 2019. The following keywords were used: “outer retinal tubulations”, “onion sign”, “prechoroidal cleft”, “intraretinal pseudocyst”,“subretinal pseudocyst”, “cystoid degeneration”, “choroidal caverns”, “activated RPE”, “hyperreflective crystalline deposits”, “non exudative signs age related macular degenration”. The literature review included only english publications. The reference list of the searched publications were also reviewed for a more comprehensive review and analysis.
Funding/Support: None Financial Disclosure: No financial disclosures Acknowledgments: None Conflict of Interest: The authors report no commercial or proprietary interest in any product or concept discussed in this article.
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15 20. Goldberg NR, Greenberg JP, Laud K, Tsang S, Freund KB. Outer retinal tubulation in degenerative retinal disorders. Retina 2013;33:1871-6. 21. Green WR, Enger C. Age-related macular degeneration histopathologic studies. The 1992 Lorenz E. Zimmerman Lecture. Ophthalmology 1993;100:1519-35. 22. Heiferman MJ, Fawzi AA. DISCORDANCE BETWEEN BLUE-LIGHT AUTOFLUORESCENCE AND NEAR-INFRARED AUTOFLUORESCENCE IN AGE-RELATED MACULAR DEGENERATION. Retina 2016;36 Suppl 1:S137-s146. 23. Holz F, Spaide R. Medical Retina: Focus on Retinal Imaging. Heidelberg, Germany: Springer Medizin Verlag; 2010. 24. Iriyama A, Aihara Y, Yanagi Y. Outer retinal tubulation in inherited retinal degenerative disease. Retina 2013;33:1462-5. 25. Khan S, Engelbert M, Imamura Y, Freund KB. Polypoidal choroidal vasculopathy: simultaneous indocyanine green angiography and eye-tracked spectral domain optical coherence tomography findings. Retina 2012;32:1057-68. 26. Kim JH, Chang YS, Kim JW, Kim CG, Lee DW. Prechoroidal Cleft in Type 3 Neovascularization: Incidence, Timing, and Its Association with Visual Outcome. Journal of Ophthalmology 2018;2018:8. 27. Kim JM, Kang SW, Son DY, Bae K. Risk factors and clinical significance of prechoroidal cleft in neovascular age-related macular degeneration. Retina 2017;37:2047-2055. 28. King BJ, Sapoznik KA, Elsner AE, et al. SD-OCT and Adaptive Optics Imaging of Outer Retinal Tubulation. Optom Vis Sci 2017;94:411-422. 29. Krombach F, Münzing S, Allmeling AM, Gerlach JT, Behr J, Dörger M. Cell size of alveolar macrophages: an interspecies comparison. Environ Health Perspect 1997;105 Suppl 5:1261-3. 30. Lafaut BA, Bartz-Schmidt KU, Vanden Broecke C, Aisenbrey S, De Laey JJ, Heimann K. Clinicopathological correlation in exudative age related macular degeneration: histological differentiation between classic and occult choroidal neovascularisation. Br J Ophthalmol 2000;84:23943. 31. Lalwani GA, Rosenfeld PJ, Fung AE, et al. A variable-dosing regimen with intravitreal ranibizumab for neovascular age-related macular degeneration: year 2 of the PrONTO Study. Am J Ophthalmol 2009;148:43-58.e1. 32. Lee JY, Folgar FA, Maguire MG, et al. Outer retinal tubulation in the comparison of age-related macular degeneration treatments trials (CATT). Ophthalmology 2014;121:2423-31. 33. Litts KM, Messinger JD, Dellatorre K, Yannuzzi LA, Freund KB, Curcio CA. Clinicopathological correlation of outer retinal tubulation in age-related macular degeneration. JAMA Ophthalmol 2015;133:609-12. 34. Mrejen S, Sarraf D, Mukkamala SK, Freund KB. Multimodal imaging of pigment epithelial detachment: a guide to evaluation. Retina 2013;33:1735-62. 35. Mukai R, Sato T, Kishi S. A hyporeflective space between hyperreflective materials in pigment epithelial detachment and Bruch's membrane in neovascular age-related macular degeneration. BMC Ophthalmol 2014;14:159. 36. Mukai R, Sato T, Kishi S. Precursor stage of retinal pigment epithelial tear in age-related macular degeneration. Acta Ophthalmologica 2014;92:e407-e408. 37. Mukkamala SK, Costa RA, Fung A, Sarraf D, Gallego-Pinazo R, Freund KB. Optical coherence tomographic imaging of sub-retinal pigment epithelium lipid. Arch Ophthalmol 2012;130:1547-53. 38. Mullins RF, Johnson MN, Faidley EA, Skeie JM, Huang J. Choriocapillaris vascular dropout related to density of drusen in human eyes with early age-related macular degeneration. Invest Ophthalmol Vis Sci 2011;52:1606-12.
16 39. Nagiel A, Freund KB, Spaide RF, Munch IC, Larsen M, Sarraf D. Mechanism of retinal pigment epithelium tear formation following intravitreal anti-vascular endothelial growth factor therapy revealed by spectral-domain optical coherence tomography. Am J Ophthalmol 2013;156:981-988.e2. 40. Pang CE, Messinger JD, Zanzottera EC, Freund KB, Curcio CA. The Onion Sign in Neovascular AgeRelated Macular Degeneration Represents Cholesterol Crystals. Ophthalmology 2015;122:2316-26. 41. Preti RC, Govetto A, Filho RGA, et al. OPTICAL COHERENCE TOMOGRAPHY ANALYSIS OF OUTER RETINAL TUBULATIONS: Sequential Evolution and Pathophysiological Insights. Retina 2018;38:15181525. 42. Querques G, Coscas F, Forte R, Massamba N, Sterkers M, Souied EH. Cystoid macular degeneration in exudative age-related macular degeneration. Am J Ophthalmol 2011;152:100-107.e2. 43. Querques G, Costanzo E, Miere A, Capuano V, Souied EH. Choroidal Caverns: A Novel Optical Coherence Tomography Finding in Geographic Atrophy. Invest Ophthalmol Vis Sci 2016;57:2578-82. 44. Querques G, Georges A, Ben Moussa N, Sterkers M, Souied EH. Appearance of regressing drusen on optical coherence tomography in age-related macular degeneration. Ophthalmology 2014;121:173179. 45. Rahimy E, Freund KB, Larsen M, et al. Multilayered pigment epithelial detachment in neovascular age-related macular degeneration. Retina 2014;34:1289-95. 46. Regatieri CV, Branchini L, Duker JS. The role of spectral-domain OCT in the diagnosis and management of neovascular age-related macular degeneration. Ophthalmic Surg Lasers Imaging 2011;42 Suppl:S56-66. 47. Sacconi R, Mullins RF, Lutty GA, Borrelli E, Bandello F, Querques G. Subretinal pseudocyst: A novel optical coherence tomography finding in age-related macular degeneration. Eur J Ophthalmol 2019:1120672119846437. 48. Schaal KB, Freund KB, Litts KM, Zhang Y, Messinger JD, Curcio CA. OUTER RETINAL TUBULATION IN ADVANCED AGE-RELATED MACULAR DEGENERATION: Optical Coherence Tomographic Findings Correspond to Histology. Retina 2015;35:1339-50. 49. Schmidt-Erfurth U, Chong V, Loewenstein A, et al. Guidelines for the management of neovascular age-related macular degeneration by the European Society of Retina Specialists (EURETINA). British Journal of Ophthalmology 2014;98:1144-1167. 50. Schmidt-Erfurth U, Waldstein SM, Deak GG, Kundi M, Simader C. Pigment epithelial detachment followed by retinal cystoid degeneration leads to vision loss in treatment of neovascular age-related macular degeneration. Ophthalmology 2015;122:822-32. 51. Sergouniotis PI, Davidson AE, Lenassi E, Devery SR, Moore AT, Webster AR. Retinal structure, function, and molecular pathologic features in gyrate atrophy. Ophthalmology 2012;119:596-605. 52. Wolff B, Maftouhi MQ-E, Mateo-Montoya A, sahel J-a, Mauget-Faÿsse M. Outer retinal cysts in age-related macular degeneration. Acta Ophthalmologica 2011;89:e496-e499. 53. Wolff B, Matet A, Vasseur V, Sahel JA, Mauget-Faysse M. En Face OCT Imaging for the Diagnosis of Outer Retinal Tubulations in Age-Related Macular Degeneration. J Ophthalmol 2012;2012:542417. 54. Zweifel SA, Engelbert M, Laud K, Margolis R, Spaide RF, Freund KB. Outer retinal tubulation: a novel optical coherence tomography finding. Arch Ophthalmol 2009;127:1596-602.
17 Figure legends: Figure 1 shows near infrared image (left) of a patient with nAMD treated with multiple anti-VEGF injections. Cross-sectional optical coherence tomography (right) shows fibrovascular pigment epithelial detachment, subretinal scarring and multiple ovoid, tubular structures with central hyper-reflectivity at the level of outer nuclear layers (arrow) suggestive of outer retinal tubulations. The outer retinal layers are not clearly delineated. Figure 2. Cross-sectional OCT of a male with nAMD showing fibrovascular pigment epithelial detachment (FVPED) and multiple sub-RPE hyper-reflective lines (white arrow) suggestive of onion sign. Figure 3. Cross-sectional OCT of a patient with n-AMD showing hyporeflective space between fibrovascular pigment epithelial detachment (sub RPE) and Bruch membrane suggestive of prechoroidal cleft (arrows). Figure 4. Cross-sectional OCT of a patient with geographic atrophy from AMD. There is loss of outer retinal layers with collapse of inner retinal layers. Note the presence of degenerated cyst (intraretinal pseudocyst) in the inner retina (at level of inner plexifrom layer/ ganglion cell layer). Figure 5. Cross-sectional OCT scan through the macula of a patient with neovascular exudative AMD demonstrates the presence of a subretinal pseudocyst (white arrow). Figure 6. Structural OCT scan through the macula displays the presence of a choroidal cavern (white arrow).
S0039-6257(20)30006-0
DOI:
https://doi.org/10.1016/j.survophthal.2020.01.001
Reference:
SOP 6924
To appear in:
Survey of Ophthalmology
Received Date: 8 October 2019 Revised Date:
10 January 2020
Accepted Date: 13 January 2020
Please cite this article as: Singh SR, Lupidi M, Mishra SB, Paez-Escamilla M, Querques G, Chhablani J, Unique optical coherence tomographic features in age-related macular degeneration, Survey of Ophthalmology (2020), doi: https://doi.org/10.1016/j.survophthal.2020.01.001. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2020 Elsevier Inc. All rights reserved.
1 Title: Unique optical coherence tomographic features in age-related macular degeneration Running title: Unique optical coherence tomographic features in AMD Authors: Sumit Randhir Singh1,2, Marco Lupidi3, Sai Bhakti Mishra1,2, Manuel Paez-Escamilla4, Giuseppe Querques5, Jay Chhablani1,6 Affiliations: 1. Smt. Kanuri Santhamma Centre for Vitreo-Retinal Diseases, L V Prasad Eye Institute, Hyderabad, India 2. Retina and Uveitis Department, GMR Varalakshmi Campus, LV Prasad Eye Institute, Visakhapatnam, India 3. Section of Ophthalmology, Department of Surgical and Biomedical Sciences, S. Maria della Misericordia Hospital, University of Perugia, Perugia, Italy. 4. University of Texas Southwestern Medical Center, Dallas, Texas. 5. Department of Ophthalmology, University Vita-Salute, IRCCS Ospedale San Raffaele, Via Olgettina 60, 20132 Milan, Italy. 6. University of Pittsburgh, UPMC Eye Center, Pittsburgh, PA 15213. Corresponding Author: Dr Jay Chhablani Faculty – Clinician, University of Pittsburgh, UPMC Eye Center, 203 Lothrop Street, Pittsburgh, PA 15213 Phone: 412-377-1943, Fax: 412-647-5119 Email: [email protected]
2 Keywords: Outer retinal tubulations, onion sign, prechoroidal cleft, intraretinal pseudocyst, subretinal pseudocyst, cystoid degeneration, choroidal caverns, activated RPE, hyperreflective crystalline deposits.
Abbreviations: Age-related macular degeneration, AMD; retinal pigment epithelium, RPE; optical coherence tomography, OCT; neovascular AMD, n-AMD; choroidal neovascularization (CNV); intraretinal/ subretinal fluid , IRF/SRF; outer retinal tubulations, ORT; comparison of agerelated macular degeneration treatments trials (CATT); inner segment-outer segments (IS-OS); external limiting membrane, ELM; ellipsoid zone, EZ; vascular endothelial growth factors, VEGF; pigment epithelial detachment, PED; red-free, RF; near infrared, NIR.
3 Abstract Age-related macular degeneration (AMD) is a leading cause of blindness worldwide characterized by presence of drusen, leading to retinal pigment epithelium (RPE) and outer retinal changes in advanced stages. Approximately 10% of eyes with AMD develop neovascular complications and present with subretinal or sub-RPE exudation, hemorrhage, or both. Recent advances in imaging techniques, especially optical coherence tomography (OCT), help in early identification of disease and guide various treatment decisions; however, not all signs are suggestive of ongoing exudation or neovascular activity. Though uncommon, multiple OCTbased signs are reported that may be difficult to appreciate clinically. Prompt identification of these signs such as outer retinal tubulation, cystoid degeneration, or pseudocysts may avoid unnecessary interventions. Moreover, certain OCT-based features involving the choroid, such as prechoridal cleft, choroidal cavern, have also been found in eyes with AMD. We discuss these unique OCT-based signs, their pathogenesis, clinical relevance, and management.
4 1. Introduction Age-related macular degeneration (AMD) is a leading cause of visual loss in the elderly.17, 49 Neovascular AMD (nAMD) forms a small subset (less than 10%) of total AMD cases; however, the neovascular variant is responsible for the majority of severe visual loss in eyes with AMD.2 Optical coherence tomography (OCT) provides in-vivo high-resolution information about chorioretinal anatomy and vasculature. These modalities aid in diagnosis of AMD, help in treatment decisions, identify the disease recurrence, and establish the visual prognosis.49, 46 Literature search shows multiple signs based on cross-sectional or en-face OCT-B scans that are suggestive of choroidal neovascularization (CNV) in nAMD eyes.46, 49, 31 The evaluation of these criteria that include presence of intraretinal or subretinal fluid (IRF/SRF), ill-defined boundaries of the neovascular lesion, and, increase of central retinal thickness provide information about disease activity for retreatment decisions;31, 19 however, not all structural changes on OCT suggest either active CNV or exudation. These signs are multifactorial in origin, including degenerative changes (cystoid degeneration– pseudocysts, outer retinal tubulation), unique choroidal features directly associated with type 1 CNV, and retinal angiomatous proliferation (RAP) lesions (pre-choroidal clefts) or atrophic changes (choroidal caverns), and may not require treatment. We review the literature and analyze these unique OCT-based signs in AMD. Treating physicians need to be aware of these signs, thus avoiding overtreatment of the disease and reducing the economic burden on patients. 2. Outer retinal tubulation (ORT) Zweifel and coworkers in 2009 provided the first OCT description of ORTs using enface or C scans which are formed from rearrangement of photoreceptors after retinal injury.54, 41The terminology “outer retinal tubulations” is self-explanatory, where outer signifies the consistent
5 outer nuclear layer location and tubulations refer to their tubule-like morphology seen on en face OCT scans.48, 54 The reported prevalence rate of ORTs remains high, varying from 8.2% to 38.1%.12, 13, 54, 32, 52 Moreover, the incidence of ORT also increases with duration of disease. ORTs are reported in a small proportion at baseline (2.5%),increasing up to 28-35% at 2-3 years, and present in more than 40% of eyes with nAMD at 4 years.9 These lesions have been associated more commonly with classic CNV than occult lesions.13 Although initially described in eyes with nAMD, ORT has been reported in various other chorioretinal degenerative disorders (including retinitis pigmentosa (RP), Bietti crystalline dystrophy, choroidermia, gyrate atrophy, Stargardt disease, pattern dystrophy), central serous chorioretinopathy , CNV from other causes or geographic atrophy where outer retina including photoreceptors and retinal pigment epithelium (RPE) are affected.24, 20, 53, 54 Eyes with diabetic macular edema, retinal vein occlusion, or diseases with complete loss of photoreceptors such as advanced RP fail to show any ORT.54 Lee and coworkers analyzed patients enrolled in Comparison of Age-related Macular Degeneration Treatments Trials (CATT) and concluded that poor baseline visual acuity, geographic atrophy, large CNV size, blocked fluorescence, and subretinal hyper-reflective material were independently predictive of ORT formation at 2 years.32
Curcio and coworkers first described the histopathological features of ORT as interconnecting tubes in outer retina. Red-green cones formed the major constituents of ORT as shown by carbonic-anhydrase histochemistry.7 Loss of interdigitations between outer segments (OS) of photoreceptors and RPE may be initial triggering event in formation of ORT. This may be followed by simultaneous or sequential loss of neural attachments of photoreceptors with adjacent structures. Outward folding of photoreceptors ensues, leading to formation of tubular structure of ORT.54, 11 Litts and coworkers have shown that external limiting membrane (ELM)
6 and mitochondria within inner segments (IS) form the hyper-reflective outer border of ORT.33 Schaal and coworkers have described different phases of photoreceptor degeneration in the outer walls of ORT. Nascent phase (both IS and OS present), mature (IS only), degenerate (no or minimal remnants of IS which may be retracted from ELM), and end-stage phase (only ELM forms the hyper-reflective border with no IS) are the different phases described.48 The lumen of ORT may not always be hyporeflective and constituents within ORT can vary from degenerate photoreceptors to RPE or lipofuscin deposits.48, 54, 9 High resolution OCT images provide in-depth information regarding ORT and their subtypes, shapes and other differential diagnosis. They appear as hyper-reflective round or ovoid structures with a hypo- or hyperreflective lumen and can be identified on structural OCT B scan. ORT was more commonly seen in areas with loss of outer retinal layers and relatively preserved ellipsoid zone (EZ);54 however, the more complex tubular structure can be more delineated on en-face scans within close proximity of the RPE. These ORTs can be located above the fibrovascular scars, at sites of previous IRF, or adjacent to areas of geographic atrophy.48, 51, 54, 9 Closed or open ORT can be defined on the basis of their boundaries on OCT scans. ORTs that have 360 degree welldefined hyper-reflective borders are termed closed, whereas ORTs with deficient hyperreflective border are termed open ORTs.48 The presence of a branching pattern is not a prerequisite for identification of ORTs, as a sizeable number of ORT fail to show branching. Though the intraretinal outer nuclear layer location is constant, there is a significant variation of length of ORT varying from few microns to millimeters with width ranging from 70 to 509 µ.48, 28 The presence of ORTs confers a worse visual prognosis as compared to eyes without ORTs.32 The treatment with anti-VEGF agents may not halt the formation of newer ORTs or regression of pre-existing ORTs.9, 54 Moreover, the treatment protocol based on treat or extend, pro-re-nata
7 or monthly injections failed to show any difference in architecture or regression pattern of ORTs.9, 32 A representative case of nAMD showing multiple ORTs is shown as Figure 1.
3. Onion Sign Initially described by Mukkamala and coworkers in eyes with nAMD, the onion sign was reported in eyes with vascularized pigmented epithelial detachment (PED). This novel finding was seen between RPE and Bruch membrane in the form of multilayered hyper-reflective bands similar to multiple layers seen in an onion.37 The reported prevalence of onion sign is 5-7% in eyes with n-AMD.40 Pang and coworkers have also proposed a possible association with systemic hyper-cholesterolemia, though this has not been substantiated in their report.40 While Coscas and coworkers described this as fibrovascular tissue, Mukkamala and coworkers proposed that these sub-RPE bands could be sub-RPE lipids formed by chronic exudation and become trapped within these fibrovascular tissue, as confirmed on fundus photography in the form of deep yellow-gray deposits.6, 37A possible role of endothelial fenestrations of type 1 CNV leading to chronic, intermittent exudation which remains limited by RPE was initially proposed. These deposits may over time crystallize leading to formation of these hype-reflective bands. Pang and coworkers have provided the histological confirmation of these deposits as crystalline cholesterol deposits.40 Christakopoulos and coworkers have also reported similar findings of multilayered, hyperreflective lines in a case of polypoidal choroidal vasculopathy (PCV).3 Other groups have proposed mechanical stress on Bruch’s membrane or fibrovascular scar as the key constituents of histological correlates of onion sign.6 The location, shape, extent, orientation of hyper-reflective bands and presence of posterior shadowing are the variables used to describe this sign on OCT. These hyper-reflective bands usually extend along the PED. Quantitative assessment of these bands may be difficult at
8 present in view of closely packed layers and the limited resolution of OCT machines, especially underneath the RPE. The absence of any posterior shadowing ruled out any calcification in these bands. Red-free (RF) and near infrared (NIR) imaging showed these lesions as hyper-reflective entities and the reflectivity was higher with large area on NIR compared to RF. This finding can be explained due to deposition of fibrin and collagen in type 1 CNV which appears brighter on NIR; however, there was no obvious change in autofluorescence pattern.23 There is, however, a contrary evidence demonstrating the absence of fibrin in sub-RPE bands from excised CNV specimens.30 Pang and coworkershave shows that onion sign persists even with treatment with anti VEGF injections. This was seen in all 16 eyes in their study cohort over a mean follow up of 3.7 years.40 Figure 2 shows OCT of a case with fibrovascular PED and sub-RPE hyperreflective bands (white arrow) suggestive of onion sign.
4. Pre-choroidal cleft Pre-choroidal clefts are defined as hyporeflective spaces sandwiched between two hyperreflective lines on OCT, the RPE, and Bruch membrane and are characterized by posterior bowing of Bruch membrane.27, 35 Prechoroidal clefts are reported in 8.1-22.3% of treated nAMD eyes.35, 27, 26 Moreover, a higher incidence of clefts is seen in cases with retinal angiomatous proliferation and typical AMD compared to PCV.27 Khan and coworkers described a “triple layer sign” in cases with polypoidal choroidal vasculopathy. There was presence of two hyporeflective spaces separated by RPE, thickened, vascularized Bruch membrane and the rest of the choroid.25 Here, the proposed location of cleft was intra-choroidal rather than pre-choroidal. Mrejen and coworkers in their description have labeled the second hyper-reflective band as dense lamellar portion of CNV in contrast to
9 vascularized Bruch membrane by Khan and coworkers34, 25 Nagiel and coworkers described pre-choroidal cleft in 6 out of 8 eyes with nAMD and adherent neovascular complex to the undersurface of RPE.39 These eyes developed RPE rip post intravitreal anti-VEGF injections, and these clefts were seen to resolve post formation of RPE rip.39 Some have therefore proposed that these clefts may act as an independent risk factor for development of RPE rip.39, 36, 34
The presence of sub-RPE neovascular tissue leading to contractile and hydrostatic forces predispose to the development of these clefts. Histopathology reveals that neovascular tissue is associated with additional presence of inflammatory cells, glial cells and myofibroblasts.21 The treatment with anti-VEGF agents leads to regression of neovascular component. Moreover, contraction of the remaining fibrous tissue leads to a split in RPE-Bruch complex with the formation of pre-choroidal clefts. There are conflicting reports regarding the influence of clefts on visual acuity mostly due to differences in incidence of clefts in various types of AMD, variability in study population and duration.45, 27, 35 Kim and coworkers found a poor visual prognosis with presence of clefts, whereas Rahimy and coworkers showed no influence of clefts on visual acuity.27, 45, 26 Clefts which formed within six months of treatment were associated with worse visual acuity. Causes of poor visual outcomes can be multifactorial such as suboptimal response to treatment, subretinal fibrosis, and other complications including RPE rip.26 Moreover, the majority of clefts form within the first 24 months, and almost half of them were associated with RPE rip or subretinal heme.26 Interestingly, eyes with cleft with no complications fared equally well when compared to eyes without cleft.26 Figure 3 shows a prechoroidal cleft on OCT in an eye with nAMD. To conclude, pre-choroidal clefts may rarely be seen in eyes with nAMD and can be a potential harbinger of complications such as RPE rip or subretinal hemorrhage. Though not conclusive,
10 clefts may be associated with a worse visual acuity especially when associated with complications.
5. Cystoid degeneration / Pseudocysts – Intraretinal and Subretinal Cohen and coworkers found intraretinal pseudocysts in eyes with geographic atrophy in AMD with no obvious exudative CNV or retinal thickening.4 Pseudocysts can also be seen in nAMD eyes with fibroatrophic scars. Though most commonly reported in inner nuclear layers, these can be present below internal limiting membrane (ILM), within outer or all retinal layers.4, 42, 1 OCT showed optically empty spaces without the presence of any hyper-reflectivity at their borders, hence the term “pseudocyst”. In contrast to cystic spaces from CNV that are usually associated with retinal thickening and/ or focal disruption and irregularity of RPE and outer retinal layers, pseudocysts show absence of retinal thickening.4 This suggests that these changes are non-exudative in nature and don’t merit any intervention or treatment. Hypothetically, these cysts in either non-exudative or exudative AMD may be related to Müller cell degeneration.4, 42 Similar to these changes, Querques and coworkers found cystoid macular degeneration or degenerative pseudocysts in eyes with nAMD that had similarities with cystoid degeneration seen in central serous chorioretinopathy.42 Degenerated cysts showed at least one concave or straight border whereas exudative cysts show biconvex and rounded borders. Moreover, these cysts were associated with a worse visual acuity.42 Fluid in the exudative cysts start accumulating after the disruption of tight junctions of external limiting membrane.50, 16 Sacconi and coworkers described the term subretinal pseudocyst in an eye with type 1 nAMD which persisted despite multiple anti VEGF injections. They hypothesized that either migration of Müller cells to subretinal space or compression of outer nuclear layer due to accumulation of
11 subretinal fluid or blood can lead to formation of subretinal pseudocyst.47 These are quite uncommon with literature search showing only a single case report till date. They appear as a distinct entity compared to intraretinal pseudocyst, and whether these represent non-exudative or exudative process is not clearly understood at present. Figure 4 and 5 show examples of geographic atrophy with intraretinal and subretinal pseudocyst respectively.
6. Caverns - choroidal and sub-retinal pigment epithelium Originally described by Querques and coworkers as choroidal caverns, these were reported as choroidal hypo-reflective spaces in eyes with geographic atrophy secondary to AMD.43 Further detailed work expanded the clinical spectrum and their prevalence in nAMD and other disorders as well.10 Choroidal caverns were hypothesized to form at sites of pre-existing choroidal vessels with non perfused ghost vessels and preserved stromal pillars. The authors correlated the formation of choriocapillaris ghost vessel with the formation of caverns at level of Haller and Sattler layers.38 These eyes, however, had relatively preserved choriocapillaris and lumen either empty or with few internal hyper-reflectivity, presumably due to macrophage like cells or migration of calcified material from Bruch membrane. These were differentiated from choroidal vessel by the absence of hyper-reflective border (lack of vessel wall) and hyporeflective lumen (lack of blood) with a tail of hypertransmission; however, recent reports suggest their presence in sub-RPE space as well.10 Both en-face and cross-sectional OCT help in detection of these caverns as highlighted in figure 6. IR images provide a higher detection rates compared to color fundus photographs, red-free, autofluorescence, fluorescein angiography, and indocyanine green angiography. Caverns were seen as hyper-reflective on NIR images. Indocyanine green angiography and OCT angiography
12 (OCTA) have shown these areas as empty or devoid of any blood supply. Another possibility is the rate of blood flow below the detectable threshold in OCTA.10, 43 Choroidal hyporeflectivities manifesting as round or oval structures with hyper-reflective border could be a precursor lesion of choroidal caverns or lipid globules formed due to fatty degeneration probably in large, single celled tissue macrophages.5, 18, 29 Dolz-Marco and coworkers have shown histologic correlation (Friedman lipid-rich globules) with the choroidal cavern.10 They have also described a hypertransmission tail due to loss of RPE layer leading to increased transmission. There is limited information on the prognostic significance of caverns at either choroidal or sub-RPE level and by itself don’t merit any intervention.
7. Activated RPE, Hyperreflective Crystalline Deposits Curcio and coworkers have shown that RPE activation and migration may occur prior to onset of RPE atrophy. These changes occur in the form of intraretinal hyper-reflective foci which are histologically shown as filled with organelles.8 These are of presumably RPE or macrophages or microglial origin. Similarly, vitelliform deposits also were considered to be one of the stress responses of RPE via organelle expulsion.8 Initially described by Fleckenstein and coworkers, hyperreflective crystalline deposits were reported as hyper-reflective plaques at the level of RPE-Bruch complex.14 Other authors have similarly described hyper-reflective lines related to calcification in areas of drusen progression and location between RPE and Bruch membrane.44, 22 These were co-related histologically with densification. NIR imaging showed mirror like reflectivity of these deposits which over time was replaced by areas of atrophy. These deposits are not directly linked to exudation; however, vision loss can occur in these eyes due to macular complications such as complete RPE and outer retinal atrophy or development of neovascularization.15
13 8. Conclusions: These OCT based non-exudative or non-neovascular signs are not uncommon in AMD eyes. Their overall understanding is essential for decision making for treatment and follow-up. 9. Literature search: A literature search of medline/pubmed database (www.ncbi.nlm.nih.gov/pubmed) was done through August 2019. The following keywords were used: “outer retinal tubulations”, “onion sign”, “prechoroidal cleft”, “intraretinal pseudocyst”,“subretinal pseudocyst”, “cystoid degeneration”, “choroidal caverns”, “activated RPE”, “hyperreflective crystalline deposits”, “non exudative signs age related macular degenration”. The literature review included only english publications. The reference list of the searched publications were also reviewed for a more comprehensive review and analysis.
Funding/Support: None Financial Disclosure: No financial disclosures Acknowledgments: None Conflict of Interest: The authors report no commercial or proprietary interest in any product or concept discussed in this article.
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17 Figure legends: Figure 1 shows near infrared image (left) of a patient with nAMD treated with multiple anti-VEGF injections. Cross-sectional optical coherence tomography (right) shows fibrovascular pigment epithelial detachment, subretinal scarring and multiple ovoid, tubular structures with central hyper-reflectivity at the level of outer nuclear layers (arrow) suggestive of outer retinal tubulations. The outer retinal layers are not clearly delineated. Figure 2. Cross-sectional OCT of a male with nAMD showing fibrovascular pigment epithelial detachment (FVPED) and multiple sub-RPE hyper-reflective lines (white arrow) suggestive of onion sign. Figure 3. Cross-sectional OCT of a patient with n-AMD showing hyporeflective space between fibrovascular pigment epithelial detachment (sub RPE) and Bruch membrane suggestive of prechoroidal cleft (arrows). Figure 4. Cross-sectional OCT of a patient with geographic atrophy from AMD. There is loss of outer retinal layers with collapse of inner retinal layers. Note the presence of degenerated cyst (intraretinal pseudocyst) in the inner retina (at level of inner plexifrom layer/ ganglion cell layer). Figure 5. Cross-sectional OCT scan through the macula of a patient with neovascular exudative AMD demonstrates the presence of a subretinal pseudocyst (white arrow). Figure 6. Structural OCT scan through the macula displays the presence of a choroidal cavern (white arrow).