AMD Update is a monthly e-newsletter from Ophthalmology Management dedicated to the latest and most useful clinical information and literature reviews on the management of age-related macular degeneration (AMD) in a quick, easy to review format. The leading retina subspecialists from around the world provide their insights.

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Ophthalmology Management | AMD Update

March 2022

Non-exudative Macular Neovascularization in AMD

Stephanie Choi, MD, and Nitish Mehta, MD

Eyes with intermediate to advanced non-exudative age-related macular degeneration (AMD) may harbor subclinical, non-exudative neovascular complexes before clinical progression to exudative AMD. Among recent studies, Hanutsaha et al identified patients with plaques or hot spots on indocyanine green angiography (ICGA) without leakage on fluorescein angiography that progressed to neovascular AMD.1 Spraul and Grossniklaus showed sub-retinal pigment epithelium (RPE) fibrovascular lesions occasionally appeared in autopsy specimens from patients with non-exudative AMD.2 Due to its ability to non-invasively provide depth-resolved flow information, optical coherence tomography angiography (OCTA) has helped further the understanding of the natural history and management of non-exudative macular neovascularization (MNV).     
 
The prevalence of non-exudative MNV, identified on OCTA as positive flow signal above Bruch’s membrane and below the RPE, has been estimated to be between 6.25% and 27% in fellow eyes of patients with contralateral unilateral exudative AMD.3-6 Similar rates were noted in patients with geographic atrophy.7 OCT may also be used with some confidence to identify non-exudative MNV. The presence of the double-layer sign on OCT, a shallow, irregular pigment epithelial detachment, carries good sensitivity and specificity (88% and 87%, respectively) for detecting non-exudative type 1 MNV.8  
 
The findings are of high clinical importance due to evidence of a 15.2-fold increased risk of conversion to exudative AMD in eyes with non-exudative MNV compared to those without.7 Cohort studies have reported cumulative incidence rates of conversion to exudative AMD in eyes with non-exudative MNV from 20% to 34.5% with follow-up ranging from 6 to 24 months.9-11 These results are consistent with post-hoc analysis of fellow eye conversion in pivotal neovascular AMD trials.12-13 Non-exudative MNV has also been noted to enlarge, but it is unclear if this enlargement increases the rate of conversion to exudative AMD.9-11,14 Unfortunately, no OCTA or OCT biomarker has been validated as a predictor of conversion.
 
Although no randomized clinical trial data exist to guide the management of non-exudative MNV, close monitoring of these lesions is considered essential because early detection and treatment of exudation is believed to result in a better long-term visual prognosis.15 Whether to treat non-exudative AMD to prevent exudation is a question that has become more complicated by recent data suggesting that non-exudative MNV may be protective against the development and enlargement of geographic atrophy.6,10
 
Given the asymptomatic and potentially protective nature of non-exudative MNV, it has been recommended to follow these patients at close intervals and treat with anti-vascular endothelial growth factor therapy only at the first sign of symptomatic exudation.14 There appear to be beneficial features of non-exudative MNV that lie outside our full understanding. Further research needs to be conducted to elucidate the pathogenesis and optimal management of this entity.
Reference(s):
  1. Hanutsaha P, Guyer DR, Yannuzzi LA, et al. Indocyanine-green videoangiography of drusen as a possible predictive indicator of exudative maculopathy. Ophthalmology. 1998;105(9):1632-1636. 
  2. Spraul CW, Grossniklaus HE. Characteristics of drusen and Bruch's membrane in postmortem eyes with age-related macular degeneration. Arch Ophthalmol.1997;115(2):267-273. 
  3. Palejwala NV, Jia Y, Gao SS, et al. Detection of nonexudative choroidal neovascularization in age-related macular degeneration with optical coherence tomography angiography. Retina. 2015;35(11):2204-2211. 
  4. Yanagi Y, Mohla A, Lee W-K, et al. Prevalence and risk factors for nonexudative neovascularization in fellow eyes of patients with unilateral age-related macular degeneration and polypoidal choroidal vasculopathy. Invest Ophthalmol Vis Sci. 2017;58(9):3488-3495. 
  5. Roisman L, Zhang Q, Wang RK, et al. Optical coherence tomography angiography of asymptomatic neovascularization in intermediate age-related macular degeneration. Ophthalmology. 2016;123(6):1309-1319. 
  6. Capuano V, Miere A, Querques L, et al. Treatment-naïve quiescent choroidal neovascularization in geographic atrophy secondary to nonexudative age-related macular degeneration. Am J Ophthalmol. 2017;182:45-55.
  7. de Oliveira Dias JR, Zhang Q, Garcia JMB, et al. Natural history of subclinical neovascularization in nonexudative age-related macular degeneration using swept-source OCT angiography. Ophthalmology. 2018;125(2):255-266. 
  8. Shi Y, Motulsky EH, Goldhardt R, et al. Predictive value of the OCT double-layer sign for identifying subclinical neovascularization in age-related macular degeneration. Ophthalmol Retina. 2019;3(3):211-219. 
  9. Yang J, Zhang Q, Motulsky EH, et al. Two-year risk of exudation in eyes with nonexudative age-related macular degeneration and subclinical neovascularization detected with swept source optical coherence tomography angiography. Am J Ophthalmol. 2019;208:1-11. 
  10. Heiferman MJ, Fawzi AA. Progression of subclinical choroidal neovascularization in age-related macular degeneration. PLoS One. 2019;14(6):e0217805.
  11. Yanagi Y, Mohla A, Lee SY, et al. Incidence of fellow eye involvement in patients with unilateral exudative age-related macular degeneration. JAMA Ophthalmol. 2018;136(8):905-911. 
  12. Parikh R, Avery RL, Saroj N, Thompson D, Freund KB. Incidence of new choroidal neovascularization in fellow eyes of patients with age-related macular degeneration treated with intravitreal aflibercept or ranibizumab. JAMA Ophthalmol. 2019;137(8):914-920.
  13. Barbazetto IA, Saroj N, Shapiro H, Wong P, Ho AC, Freund KB. Incidence of new choroidal neovascularization in fellow eyes of patients treated in the MARINA and ANCHOR trials. Am J Ophthalmol. 2010;149(6):939-946.e1. 
  14. Laiginhas R., Yang J., Rosenfeld PJ, Falcão M. Nonexudative macular neovascularization - A systematic review of prevalence, natural history, and recent insights from OCT angiography. Ophthalmol Retina. 2020;4(7):651-661. 
  15. Rauch R, Weingessel B, Maca SM, Vecsei-Marlovits PV. Time to first treatment: The significance of early treatment of exudative age-related macular degeneration. Retina. 2012;32(7):1260-1264.
About our author(s):

Author Dr. Choi is a PGY-3 ophthalmology resident at New York University (NYU). She obtained her medical degree from Harvard Medical School.
Author Dr. Mehta is a vitreoretinal surgeon and assistant professor of ophthalmology at NYU Langone Health in New York, NY.
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