Pachychoroid Disease

C H A P T E R

2 Pachychoroid Disease Kunal K. Dansingani⁎,b, Serena Fragiotta†,‡,§,¶,b, K. Bailey Freund†,‡,§,a ⁎

Department of Ophthalmology, University of Pittsburgh Medical Center, Pittsburgh, PA, United States †Vitreous Retina Macula Consultants of New York, New York, NY, United States ‡LuEsther T. Mertz Retinal Research Center, Manhattan Eye, Ear and Throat Hospital, New York, NY, United States §Department of Ophthalmology, New York University School of Medicine, New York, NY, United States ¶Department of Medical–Surgical Sciences and Biotechnologies, Sapienza University of Rome, Rome, Italy

Although central serous chorioretinopathy (CSCR) originally was recognized and described as an idiopathic retinopathy featuring neurosensory detachment, the choroidal origin of subretinal fluid in CSCR was postulated first by Klein and Maumenee, who suggested that fluid extravasated from the choriocapillaris leaked through retinal pigment epithelium (RPE) defects.1, 2 This hypothesis was supported by fluorescein angiographic findings. Indocyanine green angiography (ICGA) studies showed diffuse choroidal hyperpermeability and choroidal venous dilatation, suggesting that, in eyes with CSCR, a diffuse alteration of the choroidal vasculature had occurred to which the manifestations at the level of the RPE and outer retina were secondary.3–9 Historically, advances in the accumulated knowledge on CSCR occurred in line with developments in multimodal imaging, particularly optical coherence tomography (OCT), which images ocular tissues with depth resolution and allows pigment epithelial detachments and RPE defects to be visualized in cross-section. The introduction of enhanced depth imaging (EDI) OCT allowed vascular details of the choroid to be imaged in unprecedented detail and, in many cases, the delineation of the choroid-scleral junction at the posterior pole. Several investigators observed that the subfoveal choroid appeared thickened in eyes with CSCR, leading to the idea that hydrostatic effects from choroidal congestion might be primarily responsible.10–12 a

K. Bailey Freund receives research funding from Genentech/Roche. Serena Fragiotta and Kunal K. Dansingani have no disclosures.

b

Central Serous Chorioretinopathy https://doi.org/10.1016/B978-0-12-816800-4.00002-4

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© 2019 Elsevier Inc. All rights reserved.

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In studying the choroid, EDI upgraded OCT from a topographic tool to a morphological one. The subsequent development of swept-source OCT enabled better visualization of deep structures without frame averaging. Higher scan speeds meant that the posterior pole could be imaged with denser raster patterns, enabling en face and volumetric analysis.13–15 The term pachychoroid (παχύ- [Greek prefix]: thick) was coined to describe the phenotype dominated by a focally thickened choroid and associated with a spectrum of macular diseases of which CSCR is one of the most representative.16 Pachychoroid disease, as originally described, includes a multitude of clinical presentations along a spectrum that includes central serous chorioretinopathy. The set of clinical features that defines pachychoroid has evolved to include focal or diffuse choroidal thickening attributable to dilated outer choroidal/Haller’s layer vessels (pachyvessels) and thinning of the choriocapillaris and Sattler’s layers. Fundus tessellation often is reduced and drusen are absent or scarce. The relative emphasis of each of these features in defining pachychoroid continues to undergo refinement as new data are incorporated.

PACHYCHOROID PIGMENT EPITHELIOPATHY In 2013, Warrow and colleagues employed the term pachychoroid when describing a form of retinal pigment epitheliopathy that can occur in patients with choroidal findings resembling those of CSCR.16 While these RPE changes occur in the unaffected fellow eyes of patients with unilateral CSCR, the authors noted that certain patients without documented or detectable neurosensory detachment exhibit a pigment epitheliopathy in one or both eyes, in areas where ICGA shows choroidal hyperpermeability. The RPE changes consist of foci of apparent RPE thickening or hyperplasia on OCT, with fundus autofluorescence showing alternating hyperand hypoautofluorescence, sometimes in a granular pattern (Fig. 1). Ersoz and colleagues have observed outer nuclear layer thinning in eyes with pachychoroid pigment epitheliopathy (PPE) and suggested that the pigment epitheliopathy leads to some photoreceptor atrophy.17 Small pigment epithelial detachments might be present. The pigment epithelial changes are located mostly in the macular region with a variable involvement of the ellipsoid and external limiting membrane. In patients with unilateral CSCR, the prevalence of PPE has been estimated at 61%.18 As in CSCR, the choroid in these patients is thickened, particularly at the site of RPE change.16,19 At these locations, choroidal thickening is attributable to dilatation of vessels of the outer choroid, and the inner choroid is often paradoxically thinned, resulting in approximation of the pathologically dilated outer choroidal vessels to Bruch’s membrane. The fundus, as seen ophthalmoscopically and on color photographs, is noted in both PPE and CSCR to have a reddish orange appearance with reduced tessellation.16,20,21 PPE, therefore, has been described as a forme fruste of CSCR, which has the potential to be misdiagnosed as pigmentary age-related macular degeneration (AMD) or pattern dystrophy, if certain choroidal findings and RPE details are overlooked.16,22

PACHYCHOROID NEOVASCULOPATHY Type 1 neovascularization can complicate various macular diseases including AMD, vitelliform disease, and chronic CSCR. The term pachychoroid neovasculopathy (PNV) was

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Pachychoroid Neovasculopathy

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FIG.  1  Pachychoroid pigment epitheliopathy (PPE). (A) Color photograph; (B) fundus autofluorescence (FAF) demonstrating irregularities of the retinal pigment epithelium (white arrowheads); (C) SD-OCT B-scan passing through these areas confirms the presence of subtle RPE changes; and (D) enhanced-depth imaging OCT B-scan demonstrates a diffuse increase in choroidal thickness.

introduced to acknowledge that neovascularization can occur on a background of PPE without antecedent neurosensory detachment, and that several of the characteristics of neovascularization arising from PPE and CSCR distinguish it from neovascularization seen in other contexts (Table 1).23 In pachychoroid disease, the onset of neovascularization often is insidious, and the neovascular tissue can remain quiescent.24,25 Patients with PNV are on average a decade younger that those with AMD at the time neovascularization is first detected.26 Drusen are absent or scarce and, when present, have a morphology and distribution that differs from that of AMD.27 The site of neovascularization in PNV often is extrafoveal and can be peripapillary. The choroid usually is thicker than in patients in AMD, especially so at the site where neovascular growth originates. At such sites, the inner choroidal layers are thinned, bringing pachyvessels into close proximity to Bruch’s membrane.

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TABLE 1  Clinical and Imaging Features of Type 1 Neovascularization in Age-Related Macular Degeneration and Pachychoroid Neovasculopathy Type 1 Neovascularization in AMD

Pachychoroid Neovasculopathy (Type 1 NV in Pachychoroid Disease)

Demograhics

- Age at diagnosis typically >70 years - Typically, white

- Age at diagnosis typically 50–70 years - All races

Ocular history

- Age-related macular degeneration

- Nil, PPE, CSCR, or AT1

Fellow eye

- Any stage of AMD

- Normal, PPE, CSCR, or AT1

Fundus

- - - - -

Nonspecific signs Soft drusen Pigmentary changes Macular atrophy Macular fluid and hemorrhage are common

- - - - -

OCT

- - - - - -

Soft drusen Drusenoid PED Subretinal fluid Intraretinal cystic changes Subretinal hyperreflective material Thin or normal choroidal thickness

- - - -

FA

- Poorly defined “occult” pattern of leakage - Staining of drusen

- Poorly defined “occult” pattern of staining or leakage

ICGA

- Late hyperfluorescent plaque staining (type 1 NV) - Late hypofluorescence of drusen and/or atrophy

- Areas of early filling delay - Dilated choroidal veins (pachyvessels) - Late hyperfluorescent plaque of staining (type 1 NV) - Late staining of drusenoid RPE changes (pachydrusen) - Choroidal hyperpermeability (patchy or diffuse) - Choroidal hyperpermeability might obscure type 1 NV

Red-orange fundus appearance Reduced fundus tessellation RPE abnormalities Drusenoid RPE changes (pachydrusen) Hemorrhage uncommon

Shallow irregular PED Absence of soft drusen +/− subretinal fluid Dilated choroidal vessels (pachyvessels) with inner choroidal thinning beneath neovascular tissue - Focal or diffuse choroidal thickening

AMD, age-related macular degeneration; AT1, aneurysmal type 1 neovascularization; CSCR, central serous chorioretinopathy; FA, fluorescein angiography; ICGA, indocyanine green angiography; PED, pigment epithelial detachment; PPE, pachychoroid pigment epitheliopathy.

The vascularized PEDs of PNV typically are shallower than those seen in AMD, presumably because there is minimal drusenoid material or basal laminar deposit in the sub-RPE space (Fig. 2). Additionally, because of the insidious indolent nature of PNV, the neovascular tissue can be quite mature at the time of diagnosis, consisting of trunk vessels and established loops that are visualized well by OCT angiography, within the shallow irregular PEDs.25,28

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Aneurysmal Type 1 Neovascularization (Polypoidal Choroidal Vasculopathy)

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FIG. 2  Pachychoroid neovasculopathy (PNV). Optical coherence tomography angiography (OCTA). (A) En face OCTA (6 × 6 mm) shows a mature type 1 neovascular lesion; (B) OCT B-scan with flow overlay (red and green) shows customized segmentation (RPE-RPEfit) passing through the neovascular lesion; (C) En face OCTA slab and (D) En face OCT structural slab demonstrate the presence of large choroidal vessels (pachyvessels) corresponding to the overlying shallow irregular retinal pigment epithelium detachment; and (E) OCT B-scan showing the segmentation boundaries within the choroid.

ANEURYSMAL TYPE 1 NEOVASCULARIZATION (POLYPOIDAL CHOROIDAL VASCULOPATHY) The term polypoidal choroidal vasculopathy, henceforth referred to as aneurysmal type 1 neovascularization (AT1), was introduced in the 1980s to refer to a series of patients who exhibited spontaneous exudative and hemorrhagic complications in the fundus, arising from vascular lesions with a saccular morphology, resembling aneurysms.29 Early studies of AT1 reported the condition as most prevalent in patients of African ancestry.30,31 Subsequently, it was observed that AT1 could occur in patients of other ethnicities, including white patients, but has a predilection for more pigmented individuals.32,33 ICGA demonstrated that these lesions were vascular, perfused, and associated with branching vascular networks; fluorescein angiography showed that they were external to the

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RPE, but their precise location with respect to the tissue lamellae was difficult to determine.34 Efforts to localize the lesions by histopathology in postmortem eyes were confounded by maturation and fibrosis, which had altered the normal tissue architecture.35,36 After the development of OCT, Sato and colleagues performed a depth-resolved study of AT1 and concluded that the polypoidal lesions were located in the sub-RPE compartment where they had arisen from branching vascular networks.37 The volume of literature on AT1 has grown exponentially over the decades, and the classification of AT1 has become complex.38 In patients of African descent, AT1 traditionally is recognized as a distinct entity, while in Southeast Asia and the Far East, it is considered a variant of neovascular AMD. Furthermore, lesions resembling those of AT1 have been identified in patients with neovascular complications of CSCR, myopic staphyloma, and dome-shaped maculopathy, and space-occupying choroidal lesions such as choroidal nevi.25,39,40 Taken together, these observations support the view that the lesions that characterize polypoidal choroidal vasculopathy actually represent an aneurysmal variant of type 1 neovascularization that can manifest in a number of seemingly disparate contexts.41 In the earliest publications on PNV, investigators noted that AT1 lesions appeared to be over-represented in patients with pachychoroid features.19,23 These patients had thicker choroids than are typically seen in AMD, choriocapillaris thinning at the site of neovascularization, and absent or minimal drusen. In a prospective study of single nucleotide polymorphism ­distributions in patients with pachychoroid and AMD, aneurysmal (polypoidal) lesions were detected in the PNV cohort but not in the neovascular AMD cohort.26 It was proposed, therefore, that certain cases of AT1 shared greater similarity with CSCR than with AMD and should be classified as pachychoroid disorders. This hypothesis was addressed and supported quantitatively in two imaging papers, in which it was shown that a cohort of Korean patients with AT1 exhibited focal choroidal thickening with inner choroidal thinning in areas of neovascularization, and that the alteration in the thickness ratio of outer:inner choroid occurred consistently, even in eyes with thinner choroids and in eyes with extrafoveal/peripapillary lesions.42,43

CONCLUSIONS The factors that underlie the development of pachychoroid features, and the mechanisms that link these features to the manifestations seen at the level of the RPE and outer retina, remain unknown. While cross-sectional OCT allows the detection of pachyvessels, and the inner choroidal attenuation that accompanies them, en face visualization demonstrates that these vessels are venous, coursing toward the vortex ampullae, as seen also on ICGA.44 Simultaneous cross-sectional and en face OCT facilitates point-to-point correlation between pachyvessels and topological features such as PED, neurosensory detachment, and RPE hyperplasia.19 Unlike normal Haller’s layer venules that have a small to medium caliber at the posterior pole and increase in caliber as they course toward the vortex ampullae, pachyvessels have an exaggerated diameter at the posterior pole where they also can appear densely packed in bundles (Fig. 3). This raises the question as to whether pachyvessel formation is a primary or secondary event with respect to inner choroidal attenuation. The latter appears to be more likely, considering OCT angiography findings that show that eyes with CSCR exhibit m ­ ultiple

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Conclusions

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FIG. 3  Chronic central serous chorioretinopathy. (A) Magnification of color ultra-widefield photograph displays multiple RPE changes with an irregular area of hypopigmentation along the inferotemporal vascular arcade; (B) ultra-widefield FAF confirms multiple RPE alterations showing hypoautofluorescent mottling in the macula and a homogenous hypoautofluorescent area surrounded by a hyperfluorescent halo along the inferotemporal vascular arcade; (C) en face structural OCT of the choroid; (D) early (1 min) indocyanince green angiography (ICGA) demonstrate dilated choroidal veins (pachyvessels) beneath the macula; (E) mid-phase (11 min) ICGA shows choroidal hyperpermeabilty posteriorly and hypofluorescence in the area of inferotemporal RPE atrophy; and (F) SD-OCT B-scan shows loss of the outer retinal bands overlying irregular choroidal thickening. There are dilated outer choroidal vessels (pachyvessels) with attenuation of the inner choroidal layers (choriocapillaris and Sattler’s layer).

foci of reduced choriocapillaris flow signal intensity, even when structural pachymetric and vascular morphological changes have not yet occurred.45 However, there are clinical situations in which choriocapillaris thinning and RPE changes occur along the course of a dilated choroidal vessel, suggesting that a dilated choroidal vessel might be a contributor to changes in the choriocapillaris, perhaps through mechanical stress, and not just a consequence of choriocapillaris loss.19,42,46

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CSCR remains an enigmatic disease about which little is known, even though it has been the subject of decades worth of literature. The description of pachychoroid is a relatively recent step in the endeavor of distinguishing CSCR from its related entities. Pachychoroid also represents an attempt to explain the manifestations of CSCR in hemodynamic terms. Incidentally, this has resulted in an appreciation that certain forms of neovascularization, such as AT1 and certain cases of idiopathic neovascularization, might be described better as pachychoroid neovasculopathies. This hemodynamic approach, however, also has raised new questions regarding the causal relationships between the variety of structural and angiographic findings now documented in the literature.

References 1. Klien BA. Macular lesions of vascular origin. II. Functional vascular conditions leading to damage of the macula lutea. Am J Ophthalmol. 1953;36:1–13. 2. Maumenee AE. Serous and hemorrhagic disciform detachment of the macula. Trans Pac Coast Otoophthalmol Soc Annu Meet. 1959;40:139–160. 3. Guyer DR, Yannuzzi LA, Slakter JS, Sorenson JA, Ho A, Orlock D. Digital indocyanine green videoangiography of central serous chorioretinopathy. Arch Ophthalmol. 1994;112:1057–1062. 4. Spaide  RF, Campeas  L, Haas  A, et  al. Central serous chorioretinopathy in younger and older adults. Ophthalmology. 1996;103:2070–2079 [discussion 2079–80]. 5. Spaide RF, Hall L, Haas A, et al. Indocyanine green videoangiography of older patients with central serous chorioretinopathy. Retina. 1996;16:203–213. 6. Iida T, Kishi S, Hagimura N, Shimizu K. Persistent and bilateral choroidal vascular abnormalities in central serous chorioretinopathy. Retina. 1999;19:508–512. 7. Prünte  C, Flammer  J. Choroidal capillary and venous congestion in central serous chorioretinopathy. Am J Ophthalmol. 1996;121:26–34. 8. Giovannini A, Scassellati-Sforzolini B, D’Altobrando E, Mariotti C, Rutili T, Tittarelli R. Choroidal findings in the course of idiopathic serous pigment epithelium detachment detected by indocyanine green videoangiography. Retina. 1997;17:286–293. 9. Spaide RF, Goldbaum M, Wong DWK, Tang KC, Iida T. Serous detachment of the retina. Retina. 2003;23:820–846 [quiz 895–6]. 10. Margolis R, Spaide RF. A pilot study of enhanced depth imaging optical coherence tomography of the choroid in normal eyes. Am J Ophthalmol. 2009;147:811–815. 11. Imamura Y, Fujiwara T, Margolis R, Spaide RF. Enhanced depth imaging optical coherence tomography of the choroid in central serous chorioretinopathy. Retina. 2009;29:1469–1473. 12. Maruko I, Iida T, Sugano Y, Ojima A, Sekiryu T. Subfoveal choroidal thickness in fellow eyes of patients with central serous chorioretinopathy. Retina. 2011;31:1603–1608. 13. Yasuno  Y, Miura  M, Kawana  K, et  al. Visualization of sub-retinal pigment epithelium morphologies of exudative macular diseases by high-penetration optical coherence tomography. Invest Ophthalmol Vis Sci. 2009;50:405–413. 14. Srinivasan VJ, Adler DC, Chen Y, et al. Ultrahigh-speed optical coherence tomography for three-dimensional and en face imaging of the retina and optic nerve head. Invest Ophthalmol Vis Sci. 2008;49:5103–5110. 15. Waldstein SM, Faatz H, Szimacsek M, et al. Comparison of penetration depth in choroidal imaging using swept source vs spectral domain optical coherence tomography. Eye. 2015; https://doi.org/10.1038/eye.2014.319. 16. Warrow DJ, Hoang QV, Freund KB. Pachychoroid pigment epitheliopathy. Retina. 2013;33:1659–1672. 17. Ersoz MG, Karacorlu M, Arf S, Hocaoglu M, Sayman MI. Outer nuclear layer thinning in pachychoroid pigment epitheliopathy. Retina. 2018;38:957–961. 18. Ersoz MG, Karacorlu M, Arf S, Hocaoglu M, Sayman MI. Pachychoroid pigment epitheliopathy in fellow eyes of patients with unilateral central serous chorioretinopathy. Br J Ophthalmol. 2018;102:473–478. 19. Dansingani KK, Balaratnasingam C, Naysan J, Freund KB. En face imaging of pachychoroid spectrum disorders with swept-source optical coherence tomography. Retina. 2016;36:499–516.

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REFERENCES 19

20. Ersoz MG, Arf S, Hocaoglu M, Sayman Muslubas I, Karacorlu M. Indocyanine green angiography of pachychoroid pigment epitheliopathy. Retina. 2017; https://doi.org/10.1097/IAE.0000000000001773. 21. Lee JH, Kim JY, Jung BJ, Lee WK. Focal disruptions in ellipsoid zone and interdigitation zone on spectral-domain optical coherence tomography in pachychoroid pigment epitheliopathy. Retina. 2018; https://doi.org/10.1097/ IAE.0000000000002187. 22. Pang CE, Freund KB. Pachychoroid pigment epitheliopathy may masquerade as acute retinal pigment epitheliitis. Invest Ophthalmol Vis Sci. 2014;55:5252. 23. Pang CE, Freund KB. Pachychoroid neovasculopathy. Retina. 2015;35:1–9. 24. Querques G, Srour M, Massamba N, et al. Functional characterization and multimodal imaging of treatment-­ naive “quiescent” choroidal neovascularization. Invest Ophthalmol Vis Sci. 2013;54:6886–6892. 25. Dansingani KK, Balaratnasingam C, Klufas MA, Sarraf D, Freund KB. Optical coherence tomography angiography of shallow irregular pigment epithelial detachments in pachychoroid spectrum disease. Am J Ophthalmol. 2015;160:1243–1254.e2. 26. Dansingani KK, Perlee LT, Hamon S, et al. Risk alleles associated with neovascularization in a pachychoroid phenotype. Ophthalmology. 2016;123:2628–2630. 27. Spaide RF. Disease expression in nonexudative age-related macular degeneration varies with choroidal thickness. Retina. 2017; https://doi.org/10.1097/IAE.0000000000001689. 28. Bousquet E, Bonnin S, Mrejen S, Krivosic V, Tadayoni R, Gaudric A. Optical coherence tomography angiography of flat irregular pigment epithelium detachment in chronic central serous chorioretinopathy. Retina. 2017; https://doi.org/10.1097/IAE.0000000000001580. 29. Yannuzzi LA, Sorenson J, Spaide RF, Lipson B. Idiopathic polypoidal choroidal vasculopathy (IPCV). Retina. 1990;10:1–8. 30. Capone Jr. A, Wallace RT, Meredith TA. Symptomatic choroidal neovascularization in blacks. Arch Ophthalmol. 1994;112:1091–1097. 31. Ross RD, Gitter KA, Cohen G, Schomaker KS. Idiopathic polypoidal choroidal vasculopathy associated with retinal arterial macroaneurysm and hypertensive retinopathy. Retina. 1996;16:105–111. 32. Yannuzzi  LA, Ciardella  A, Spaide  RF, Rabb  M, Freund  KB, Orlock  DA. The expanding clinical spectrum of idiopathic polypoidal choroidal vasculopathy. Arch Ophthalmol. 1997;115:478–485. 33. Imamura Y, Engelbert M, Iida T, Freund KB, Yannuzzi LA. Polypoidal choroidal vasculopathy: a review. Surv Ophthalmol. 2010;55:501–515. 34. Otani A, Sasahara M, Yodoi Y, et al. Indocyanine green angiography: guided photodynamic therapy for polypoidal choroidal vasculopathy. Am J Ophthalmol. 2007;144:7–14. 35. Tso  MOM, Suarez  MJ, Eberhart  CG. Pathologic study of early manifestations of polypoidal choroidal vasculopathy and pathogenesis of choroidal neo-vascularization. Am J Ophthalmol Case Rep. 2017; https://doi. org/10.1016/j.ajoc.2017.10.012. 36. Nakajima M, Yuzawa M, Shimada H, Mori R. Correlation between indocyanine green angiographic findings and histopathology of polypoidal choroidal vasculopathy. Jpn J Ophthalmol. 2004;48:249–255. 37. Sato T, Kishi S, Watanabe G, Matsumoto H, Mukai R. Tomographic features of branching vascular networks in polypoidal choroidal vasculopathy. Retina. 2007;27:589–594. 38. Wong CW, Yanagi Y, Lee W-K, et al. Age-related macular degeneration and polypoidal choroidal vasculopathy in Asians. Prog Retin Eye Res. 2016;53:107–139. 39. Naysan J, Dansingani KK, Balaratnasingam C, Freund KB. Type 1 neovascularization with polypoidal lesions complicating dome shaped macula. Int J Retina Vitreous. 2015;1:909. 40. Tan ACS, Yzer S, Freund KB, Dansingani KK, Phasukkijwatana N, Sarraf D. Choroidal changes associated with serous macular detachment in eyes with staphyloma, dome-shaped macula or tilted disk syndrome. Retina. 2017;37:1544–1554. 41. Dansingani KK, Gal-Or O, Sadda SR, Yannuzzi LA, Freund KB. Understanding aneurysmal type 1 neovascularization (polypoidal choroidal vasculopathy): a lesson in the taxonomy of “expanded spectra”—a review. Clin Exp Ophthalmol. 2018;46:189–200. 42. Lee WK, Baek J, Dansingani KK, Lee JH, Freund KB. Choroidal morphology in eyes with polypoidal choroidal vasculopathy and normal or subnormal subfoveal choroidal thickness. Retina. 2016;36(Suppl 1):S73–S82. 43. Baek J, Dansingani KK, Lee JH, Lee WK, Freund KB. Choroidal morphology in eyes with peripapillary polypoidal choroidal vasculopathy. Retina. 2018; https://doi.org/10.1097/IAE.0000000000002188.

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44. Pang CE, Shah VP, Sarraf D, Freund KB. Ultra-widefield imaging with autofluorescence and indocyanine green angiography in central serous chorioretinopathy. Am J Ophthalmol. 2014;158:362–371. e2. 45. Gal-Or O, Dansingani KK, Sebrow D, Dolz-Marco R, Freund KB. Inner choroidal flow signal attenuation in pachychoroid disease: optical coherence tomography angiography. Retina. 2018. Available: https://europepmc. org/abstract/med/29384997. 46. Inoue M, Dansingani KK, Freund KB. Progression of age-related macular degeneration overlying a large choroidal vessel. Retin Cases Brief Rep. 2016;10:22–25.

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