Macular Neovascularization Secondary to Subclinical Angioid Streaks in Age-Related Macular Degeneration: Treatment Response to Anti-VEGF at 2-Year Follow-up

Age-related macular degeneration (AMD) is a complex disease with a multifactorial background involving genetic and environmental influences. AMD pathogenesis is not completely understood, even though three main structures are primarily involved: photoreceptors, retinal pigment epithelium (RPE) cells, and the choroidal circulation (especially the choriocapillaris) [1‐6]. Recently, our group described a new AMD phenotype, namely subclinical angioid streaks (AS). Subclinical AS are characterized by structural OCT findings typical of AS [Bruch’s membrane (BM) undulations, BM breaks, and large dehiscences of BM] but with the absence of AS employing fundus examination (for this reason “subclinical”) in patients with landmarks of AMD [i.e., drusen and reticular pseudodrusen (RPD)] [7]. The primary involvement of the BM using structural OCT and the concomitant high prevalence of RPD suggested the predominant involvement of BM as a driving factor of this new phenotype.

The development of macular neovascularization (MNV) represents a landmark of advanced AMD development, characterizing the neovascular form of the disease [8]. However, the development of choroidal neovascularization (CNV) was reported in several other macular diseases, such as in angioid streaks [9, 10]. The main therapy of MNV/CNV is based on intravitreal antivascular endothelial growth factor (VEGF) injections. Nevertheless, the treatment response of neovessels (i.e., number of injections needed, treatment regimen, development of fibrosis and/or atrophy) is different based on the background disease [11‐13]. The pathogenesis of subclinical AS phenotype showed several differences compared to other AMD phenotypes because of the greater involvement of the BM. For this reason, the response of MNV to the anti-VEGF treatment could be different in AMD patients with subclinical AS phenotype compared to MNV complicating other AMD phenotypes.

This study aimed to characterize the response to anti-VEGF treatment of treatment-naïve MNV secondary to AMD and subclinical AS phenotype during a 2-year follow-up. We compared their response to AMD eyes with treatment-naïve MNV but without AS treated with the same regimen.

In this study, we reported that treatment-naïve MNVs secondary to AMD with subclinical AS are characterized by a different response to anti-VEGF treatment (i.e., number of injections, anatomical and functional outcomes) during a 2-year follow-up compared to treatment-naïve MNV secondary to AMD without subclinical AS.

Subclinical AS is a recently reported phenotype of AMD that affects about 13.4% of patients with AMD [7]. This new phenotype is characterized by a predominant involvement of BM as a driving factor. Indeed, almost all cases displayed Bruch’s membrane alterations using structural OCT and the presence of RPD. These features are very close to pathophysiological mechanisms involved in the “typical” AS (i.e., visible on fundus examination). The development of CNV is a frequent scenario in patients affected by AS, facilitated by the locus minoris resistentiae of the BM interruption. However, CNVs secondary to AS are usually characterized by a worse prognosis due to the predominance of type 2 CNV, a high number of injections needed, and development of fibrosis and/or atrophy with worse visual outcomes [9‐13]. Different molecules showed efficacy in stabilization of BCVA up to 4-year follow-up in CNV secondary to AS [11, 12, 14‐18]. Recently, a few studies have shown promising results in terms of BCVA improvement and a low number of recurrences in CNVs secondary to AS treated by aflibercept [11, 18]. However, all studies were performed on small series (< 35 eyes), with variable follow-up, and all with PRN regimens. For this reason, a comparison between a PRN or proactive regimen (i.e., treat and extend) or between different molecules is not available.

Interestingly, in the present study, we found several differences in MNV secondary to AMD with subclinical AS and the control group (i.e., MNV secondary to AMD without AS), with several common features between CNV/MNV secondary to subclinical AS and typical AS. Indeed, in our series, MNV secondary to AMD with subclinical AS showed a greater proportion of type 2 MNV compared to MNV secondary to AMD but without subclinical AS (24% vs 7% of cases, p < 0.001). Furthermore, MNV secondary to AMD with subclinical AS needed more injections during the 2-year follow-up (10.6 ± 3.2 vs 8.3 ± 3.1 anti-VEGF injections in the AMD eyes with subclinical AS and without subclinical AS, respectively, p < 0.001). Despite the greater number of injections, MNV secondary to AMD with subclinical AS developed a higher rate of macular atrophy during the treatment, leading to worse visual outcomes. Indeed, MNV secondary to AMD with subclinical AS displayed a significant worsening of BCVA during the 2 years of treatment (p = 0.044), differently from the control group (i.e., MNV secondary to AMD without subclinical AS), which showed stable BCVA during the treatment. This could be due to the higher rate of atrophy development in the AMD with subclinical AS group (74% vs 29% in the AMD eyes with subclinical AS and without subclinical AS, respectively, p < 0.001). The development of macular atrophy is one of the worst events in the treatment of exudative MNV secondary to AMD [19‐22]. The rate of atrophy development is very variable, depending also on the AMD phenotype. However, in our series, the higher percentage of macular atrophy development could also be associated with the PRN treatment. Indeed, it is well known that a greater fluctuation of the macular thickness is associated with higher development of macular atrophy during the treatment [23, 24]. In this way, a “proactive” treatment (like the treat and extend regimen) should reduce the fluctuation of macular thickness compared to a “reactive” treatment (as the PRN regimen). However, we need to keep in mind that both groups (i.e., MNV secondary to AMD with and without subclinical AS) were treated with the same anti-VEGF regimen, the same drug, and by the same teams. Therefore, we supported that the different percentage of macular atrophy development between the two groups was due to the different phenotypes of the disease, reflecting a different pathogenetic background. As previously reported, subclinical AS was supposed to be characterized by a predominant involvement of the Bruch’s membrane, in contrast to the supposed choriocapillaris and RPE/photoreceptor loss of the other phenotype of AMD [3‐7, 25]. Furthermore, the group of AMD with subliclinical AS was characterized by the presence of RPD in almost all cases and a significantly thinner choroidal thickness compared to the control group. Both these two features are known to be significant risk factors for the development of atrophy [26‐28].

One can argue that differences in MNV subtypes and responses to anti-VEGF were due to the greater prevalence of RPD in the subclinical AS group compared to the control group (100% vs 56%, respectively). However, all these differences were confirmed when we compared only the 38 eyes displaying RPD in the control group.

The present study has several limitations. First, even if we included 102 eyes, this is a relatively small sample size for patients with neovascular AMD. However, we selected only eyes treated by a rigorous PRN regimen and with the same drug in both groups. Another limitation could be due to the PRN regiment that was adopted in the treatment of MNV. However, the same regimen and same criteria of re-treatment were used in both groups, leading to results comparable between groups. Of course, prospective studies with larger sample sizes are needed to confirm our conclusions and to possibly gather more insights into the pathogenesis of these different AMD phenotypes.

In conclusion, we reported the characteristics of MNV secondary to AMD with subclinical AS, defining its treatment response to anti-VEGF therapy compared to MNV secondary to AMD without subclinical AS. We highlighted that MNV secondary to AMD with subclinical AS showed a higher percentage of macular atrophy development and worse visual outcomes after 2 years of treatment, despite the greater number of injections needed. This was probably due to the greater proportion of type 2 MNVs and the greater aggressivity of MNVs secondary to this AMD phenotype. All these features should be kept in mind during the treatment of MNV secondary to AMD for the different prognoses with different phenotypes and to better personalize the treatment of patients affected by this recently reported AMD phenotype.