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.