July 2014, Issue 71

Retinal Angiomatous Proliferation

Mary Elizabeth Hartnett, MD Moran Eye Center University of Utah Salt Lake City, UT

Richard F. Spaide, MD Vitreous-Retina-Macula Consultants of New York New York, NY

Giovanni Staurenghi, MD Department of Biomedical and Clinical Sciences Luigi Sacco Hospital University of Milan Milan, Italy

Retinal angiomatous proliferation (RAP), also known as retinal vascular anomalous complex (RVAC) or type 3 choroidal neovascularization (CNV), was first described as “angiomatous retinal vascular abnormality” in 1992 in association with pigment epithelial detachments (PED).¹ Prior to that time, retinal vascular changes had not been associated with age-related macular degeneration (AMD).

Subsequently, using scanning laser ophthalmoscopy, infrared imaging and indocyanine green angiography, members of the same investigative group reported findings that predated the formation of RAP lesions. Extensive Bruch’s membrane disease and drusen, along with intraretinal vascular telangiectasia and hemorrhages, and areas consistent with occult CNV were identified as findings that predated RAP lesions, while PED and chorioretinal anastomosis were observed in the late stages of RAP.² With scanning laser ophthalmoscopy and video angiography, these lesions were identified as having feeding retinal arterioles, intraretinal proliferation, and draining venules in many but not all cases. Therefore, the terminology “deep retinal vascular anomalous complex (RVAC)” was coined. At that time, it was appreciated that certain models of rats with loss of photoreceptors (phototoxic retinopathy and spontaneously hypertensive rats) also manifested retinal vascular growth in the outer retina.²

Based on clinical features and animal models, the group proposed a hypothesis as to the cause of the RVAC in advanced AMD. Extensive Bruch’s membrane deposits and changes in the choriocapillaris were proposed to lead to outer retinal hypoxia, which stimulated the release of angiogenic factors and created a chemotactic and angiogenic gradient for endothelial cell proliferation into the normally avascular outer retina.² Loss of retinal photoreceptors may also have resulted in a loss of factors that would normally inhibit vascular growth into the outer retina, but now permitted growth. The investigators speculated that Muller cells and/or cells of the retinal pigment epithelium (RPE) were involved in angiogenic factor expression in advanced AMD and suggested vascular endothelial growth factor (VEGF) as one factor. Since the RVAC publication in 1996 and with advancements in technology, other studies provide evidence for some of the findings speculated upon previously,² including that Muller cells can overexpress VEGF⁴ and lead to retinal vascular changes.⁵ Muller cells are also speculated to play a role in macular telangiectasia, another condition in which inner retinal blood vessels grow into the outer retina to proliferate.⁶ Further, the presence of outer retinal atrophy hypothesized to be associated with extensive pseudodrusen may lead to hypoxia predisposing to geographic atrophy.⁷ Some transgenic animals, specifically the vldlr-/- mouse, also develop outer retinal vascular proliferation.⁸ In addition, it is being recognized that a number of compounds in the outer retina may deflect blood vessel growth from the outer retina and open up the possibility that dysregulation of these “guidance” proteins may lead to a permissive environment allowing inner retinal blood vessels to grow into the outer retina.⁹

The terminology “RAP” was described later along with stages of RAP lesions proposed based on intraretinal (stage 1) or subretinal (stage 2) proliferation, and presence of PED (can occur in stage 3).¹⁰ Knowledge of the pathophysiology underlying RAP is still evolving, but improved detection of RAP lesions is possible with commercially available high-speed fluorescein and indocyanine angiography.¹¹

There is general consensus that early treatment of RAP lesions is associated with the best outcomes.¹² Treatments for RAP lesions include steroids, laser ablation of the feeding arteriole, anti-VEGF therapy, and photodynamic therapy.^13,14 Most studies reporting outcomes after treatment of RAP lesions have been small or uncontrolled. A larger clinical trial testing different treatment modalities is underway.

References
1. Hartnett ME, Weiter JJ, Garsd A, Jalkh AE.Classification of retinal pigment epithelial detachments associated with drusen. Graefes Arch Clin Exp Ophthalmol. 1992;230(1):11-9.
2. Hartnett ME, Weiter JJ, Staurenghi G, Elsner AE. Deep retinal vascular anomalous complexes in advanced age-related macular degeneration. Ophthalmology. 1996 Dec;103(12):2042-53.
3. Querques G, Querques L, Forte R, Massamba N, Blanco R, Souied EH.
Precursors of type 3 neovascularization: a multimodal imaging analysis. Retina. 2013 Jun;33(6):1241-8. doi: 10.1097/IAE.0b013e31827b639e.
4. Wang H, Smith GW, Yang Z, Jiang Y, McCloskey M, Greenberg K, Geisen P, Culp WD, Flannery J, Kafri T, Hammond S, Hartnett ME. Short hairpin RNA-mediated knockdown of VEGFA in Müller cells reduces intravitreal neovascularization in a rat model of retinopathy of prematurity. Am J Pathol. 2013 Sep;183(3):964-74.
5. Shen W, Fruttiger M, Zhu L, Chung SH, Barnett NL, Kirk JK, Lee S, Coorey NJ, Killingsworth M, Sherman LS, Gillies MC. Conditional Müllercell ablation causes independent neuronal and vascular pathologies in a novel transgenic model. J Neurosci. 2012 Nov 7;32(45):15715-27. doi: 10.1523/JNEUROSCI.2841-12.2012.
6. Powner MB, Gillies MC, Zhu M, Vevis K, Hunyor AP, Fruttiger M.
Loss of Müller's cells and photoreceptors in macular telangiectasia type 2. Ophthalmology. 2013 Nov;120(11):2344-52. doi: 10.1016/j.ophtha.2013.04.013. Epub 2013 Jun 12.
7. Grunwald JE, Daniel E, Huang J, Ying GS, Maguire MG, Toth CA, Jaffe GJ, Fine SL, Blodi B, Klein ML, Martin AA, Hagstrom SA, Martin DF; CATT Research Group. Risk of Geographic Atrophy in the Comparison of Age-related Macular Degeneration Treatments Trials. Ophthalmology 2014;121;150-161.
8. Heckenlively JR, Hawes NL, Friedlander M, Nusinowitz S,Hurd R, Davisson M, Chang B. Mouse model of subretinal neovascularization with choroidal anastomosis. Retina. 2003 Aug;23(4):518-22.
9. Buehler A, Sitaras N, Favret S, Bucher F, Berger S, Pielen A, Joyal JS, Juan AM, Martin G, Schlunck G, Agostini HT, Klagsbrun M, Smith LE, Sapieha P, Stahl A. Semaphorin 3F forms an anti-angiogenic barrier in outer retina. FEBS Lett.2013 Jun 5;587(11):1650-5. doi: 10.1016/j.febslet.2013.04.008. Epub 2013 Apr 18.
10. Yannuzzi LA, Negrão S, Iida T, Carvalho C, Rodriguez-Coleman H, Slakter J, Freund KB, Sorenson J, Orlock D, Borodoker N. Retinal angiomatous proliferation in age-related macular degeneration. Retina. 2001;21(5):416-34.
11. Parravano M, Pilotto E, Musicco I, Varano M,Introini U, Staurenghi G, Menchini U, Virgili G. Reproducibility of fluorescein and indocyanine green angiographic assessment for RAP diagnosis: a multicenter study. Eur J Ophthalmol. 2012 Jul-Aug;22(4):598-606. doi: 10.5301/ejo.5000087.
12. Viola F, Massacesi A, Orzalesi N, Ratiglia R, Staurenghi G. Retinal angiomatous proliferation: natural history and progression of visual loss. Retina. 2009 Jun;29(6):732-9. doi: 10.1097/IAE.0b013e3181a395cb.
13. Meyerle CB, Freund KB, Iturralde D, Spaide RF, Sorenson JA, Slakter JS, Klancnik JM Jr, Fisher YL, Cooney MJ, Yannuzzi LA. Intravitreal bevacizumab (Avastin) for retinal angiomatous proliferation. Retina. 2007 Apr-May;27(4):451-7.
14. Rouvas AA, Chatziralli IP, Theodossiadis PG, Moschos MM, Kotsolis AI, Ladas ID. Long-term results of intravitreal ranibizumab, intravitreal ranibizumab with photodynamic therapy, and intravitreal triamcinolone with photodynamic therapy for the treatment of retinal angiomatous proliferation. Retina. 2012 Jun;32(6):1181-9. doi: 10.1097/IAE.0b013e318235d8ce.