Subclinical Angioid Streaks with Pseudodrusen: A New Phenotype of Age-Related Macular Degeneration

Age-related macular degeneration (AMD) is a multifactorial disease characterized by a genetic and environmental background. AMD is classified into three different stages (i.e. early, intermediate, and late disease) based on different findings [1, 2]. In the early and intermediate stages of the disease, the macular area is characterized by the presence of drusen, reticular pseudodrusen (RPD), and AMD pigmentation abnormalities [2, 3]. Even if drusen are peculiar findings of AMD, the presence of RPD may also be associated with diseases characterized by primary alteration of Bruch’s membrane (BM), such as Sorsby fundus dystrophy or pseudoxanthoma elasticum (PXE) with angioid streaks (AS) [4‐6]. The pathogenesis of AMD is not completely understood. Histological and in vivo imaging studies indicate that important structural changes include the retinal pigment epithelium (RPE) cells, BM, and/or the choriocapillaris [7‐12].

Angioid streaks (AS) are characterized by breaks in BM, as firstly proposed by Kofler in 1917 and subsequently demonstrated by histological studies [13‐15]. BM breaks are not initially associated with alterations of RPE and choriocapillaris [16]. The pathogenesis of AS is complex but usually related to alterations in calcium homeostasis. The most frequent systemic disease associated with AS is PXE, an inherited disease related to ABCC6 gene mutation [17]. Patients with PXE have lower plasma levels of inorganic pyrophosphate, a factor thought to inhibit calcification of elastic fibers [18, 19]. The systemic alterations in calcium homeostasis promote extracellular matrix mineralization, including in BM [20, 21]. While the diagnosis of AS may be based on fundus examination, more in-depth information is available due to findings from structural optical coherence tomography (OCT) [21, 22]. The usual finding on OCT imaging associated with AS is a break in BM with variable dehiscence [16, 22, 23].

The aim of this study was to characterize demographic, clinical, and multimodal imaging features of patients diagnosed with AMD who presented with AS visible on OCT but not on fundus examination. For this reason, we named this phenotype subclinical AS in AMD. We compared features of subclinical AS in AMD eyes with AMD eyes without AS.

All 274 screened patients affected by AMD were Caucasian. Of the 543 screened eyes of these 274 patients with AMD(188 females, 86 males; mean [± SD] age 81 ± 7 years), 73 eyes of 46 patients (34 females, 12 males; mean age 82 ± 7 years) showed sub-clinical AS features using structural OCT and were included in the analysis (Figs. 2, 3, 4, 5). Therefore, estimated prevalence of subclinical age-related AS in our study cohort was 13.4% (95% confidence interval [CI] 10.3–16.3%). Absence of AS was confirmed by two graders (RS, IZ) on fundus examination, multicolor imaging, IR, and fundus autofluorescence [19]. No statistically significant difference in age and sex was found between patients with other phenotypes of AMD and subclinical AS (P = 0.432 and P = 0.231, respectively) (Table 1). Among the 46 patients included in the study, the fellow eyes of 19 patients were not included for absence of AS breaks/dehiscence (15 patients), the presence of macular hole (2 patients), presence of low-quality images (1 patient), and presence of only one eye (1 patient was monocle due to a childhood trauma).

Mean (± SD) BCVA was about 20/63 Snellen equivalent (0.57 ± 0.44 LogMAR), mean CMT was 330 ± 125 μm, and mean subfoveal ChT was 162 ± 64 μm. Of the 73 eyes with AMD and subclinical AS, 55 (73%) showed peripapillary atrophy, which in several cases (36%) was characterized by a “petaloid-like” pattern of atrophy, characterized by a multilobular hypoautofluorescence around the peripapillary area.

Of the 73 eyes with AMD and features of subclinical AS, 57 (78%) were affected by MNV (Figs. 4, 5), 14 eyes (19%) were affected by GA (Fig. 2), and two eyes (3%) were not affected by either MNV or GA (diagnosed as intermediate AMD) (Fig. 3). Interestingly, the distribution among these three stages was significantly different in comparison with eyes with AMD but without OCT features of subclinical AS (Exp(B) = 0.204; P < 0.001) (Table 1); eyes with subclinical AS were usually characterized by a more advanced stage of AMD (i.e., presence of MNV or GA) (P < 0.001). Among the 57 eyes with subclinical AS and MNV, 70% (38/54) displayed a type 1 MNV, 24% (13 eyes) displayed a type 2 MNV, 9% (5 eyes) displayed a mixed type 1 and 2 MNV, and 2% (1 eyes) displayed a type 3 MNV. Furthermore, 49 of the MNVs (86%) were located in the macular area, whereas eight MNVs (14%) were located in the peripapillary area.

Analyzing the phenotype (presence of drusen, RPD, or both), almost all cases of subclinical AS (71/73 cases, 97%) were affected by RPD, in combination with drusen (29/71 cases, 41%) or without drusen (42/71 cases, 59%); the remaining two cases (3%) displayed only drusen without RPD. The distribution of RPD and drusen was significantly different in eyes with AMD and features of subclinical AS compared to eyes with AMD but without OCT features of subclinical AS (P < 0.001) (Table 1). In particular, the presence of RPD was significantly higher in patients with subclinical AS in eyes with AMD (Exp(B) = 2.589, P < 0.001).

In this study, we report a specific phenotype of AMD with subclinical angioid streaks and describe associated demographic, clinical, and structural OCT features. Even though AS are not visible using fundus examination/photography (for this reason the name is “subclinical”), AMD patients with this phenotype displayed the OCT findings typically seen in eyes with AS [16, 22]. Another common feature between AS seen in patients with, for example, PXE and those with subclinical AS in AMD is the frequent involvement of the peripapillary area as the location of the BM alterations and atrophy development [23]. Indeed, peripapillary atrophy developed in 73% of subclinical AS in AMD cases in our series, and in > 50% in a previously reported series of AS secondary to PXE [24]. Interestingly, 36% of cases in our series showed a peculiar “petaloid-like” pattern of atrophy. This pattern was previously described by Marchese et al. [24] as a typical pattern of atrophy in AS patients secondary to PXE (affecting 34% of patients in that series). Finally, AS and subclinical AS in AMD showed a high prevalence of choroidal neovascularization (CNV) development. CNV is a well-known and frequent complication of AS, with a predominance of type 2 CNV [25]. In the present study, we found a similar rate of MNV prevalence (70%), with no predilection for the type of neovascularization. These above-mentioned aspects might suggest a partial common pathophysiological mechanism of onset, which could mainly be related more to BM alterations than to dysfunction of RPE and choriocapillaris. This assumption proposes BM pathology as the key factor for the development of RPE atrophy development and consequent choriocapillaris thinning and ingrowth of fibrous tissue through BM ruptures. The involvement of the BM with its conversion from an elastic structure to a calcified and brittle one is a well-known feature predisposing to developing AS. Due to its reduced elasticity, a brittle BM may be more vulnerable to mechanical stresses and thus to ruptures, even after physiological tension. This process is often located in the peripapillary area, which is a “locus minoris resistentiae” due to the interruption of BM in the papillary area. Due to the similar BM alterations and peripapillary involvement of subclinical AS in AMD, we suggest the predominant involvement of BM as a driving factor of this phenotype.

Interestingly, several differences characterize subclinical AS in AMD in comparison to AS. First, we excluded from our series all patients with systemic AS-related disease (e.g., PXE). Secondary, subclinical AS occurred in AMD patients who were older (mean ± SD: 82 ± 7 years in our series) than patients with conventional AS reported in a previous series (65.8 ± 13.9 years old) [22]. On the other hand, several features were shared between patients with subclinical AS and those with AMD. Even if patients with subclinical AS showed a higher prevalence of RPD (almost all cases), 42% of cases also showed drusen, the hallmark of AMD. Furthermore, our series did not provide significant differences in terms of median age between patients with the subclinical AS phenotype and other phenotypes of AMD (82 ± 7 years vs. 81 ± 8 years; P = 0.432). For these reasons, we speculate that subclinical AS could be the result of abnormal aging involving mainly the BM. In this scenario, this phenotype may represent an alternative form of chorioretinal aging with predominant involvement of BM, in contrast to supposed choriocapillaris loss (“vascular” hypothesis) or RPE cell death (“toxic” hypothesis) in AMD etiology [7, 26]. This speculation is supported mainly by the OCT findings and by the higher occurrence of RPD (97%) compared to drusen (42%) in these patients. To date, there is some evidence of lesions resembling RPD in PXE-associated AS, suggesting a possible role of the BM in the pathophysiology of RPD [5]. The frequency of RPD in patients with AMD is estimated to be approximately 30–50% depending on the phenotypes included in the analysis and the sensitivity of the imaging modalities used [4, 27]. Thus, the different ages at the onset of RPD in patients with AMD and AS might reflect a continuum of BM pathologic changes, with a minimal late-onset phenotype due to aging and pronounced early alterations associated with AS [5].

Due to the possible differences in the pathogenesis of subclinical AS and AMD, it can be speculated that subclinical age-related AS may be considered as a separate clinical entity. However, based on the common features between typical AMD and subclinical AS and the high prevalence of this phenotype in the AMD population (the estimated prevalence has been assessed at approximately 13.4% in our series), we propose that subclinical AS should be considered as a peculiar phenotype in the AMD spectrum. Interestingly, in an earlier study by Ellabban et al. [28], OCT undulations in patients with AMD were estimated to occur at a frequency similar to that of subclinical AS prevalence in our cohort of AMD patients. To explain this result, we could hypothesize that subclinical AS was misdiagnosed as “classic” AMD. In our case series, we excluded patients with only BM undulations because they did not show AS-related OCT findings (BM breaks and/or dehiscences). However, we did determine that 22 eyes in our AMD cohort had only BM undulations. This finding could represent a precursor of subclinical AS, as a sign of the first BM alteration. On the other hand, BM undulations may only be a sign of decreased elasticity of the BM-choroid complex associated with aging, as previously reported by Ugarte et al. [29]

It is possible to speculate that BM breaks are due to the passage of MNV from the choroidal circulation to the RPE/sub-RPE space; however, we reported BM breaks also in patients with intermediate AMD and in those with GA without MNV. Furthermore, also in eyes affected by neovascular AMD, the number of BM breaks was higher than those expected to be caused by the MNV passage through the BM.

Interestingly, patients with monoallelic ABCC6 mutations or with frequent hypomorphic variants in combination with a null variant in trans may show retinal changes overlapping certain phenotypic features of AMD (i.e., RPD, GA, and MNV), similar to the cohort in the present study with subclinical age-related AS [30, 31]. Hence, with an estimated carrier frequency in the general population of 1:30–1:200 [32], we can speculate that at least in some patients, the retinal disease is driven by increased soft tissue calcification due to ABCC6 dysfunction. Furthermore, some patients with hemochromatosis were previously reported with angioid-like streaks [33, 34]. For this reason, we cannot exclude the possibility that some of the patients in our series were affected by subclinical hemochromatosis.

We suggest that subclinical AS should be considered to be a different phenotype in the AMD population, particularly with respect to possible new therapies. Indeed, since BM likely plays a significant role in subclinical AS etiology, therapeutical approaches can be different from those for AMD. In particular, anti-complement treatments may not be as effective in this group of patients as in other drusen-driven “classic” AMD phenotypes. An important future target is to identify which structure is predominantly involved in chorioretinal aging, since this as yet unidentified structure could variably affect different anatomical sites.

The present study has several limitations, mainly due to the relatively small number of included eyes, its retrospective design, and the short interval of recruitment. However, our analysis is the first characterization of this novel age-related BM degeneration phenotype in the context of AMD. Of note, the prevalence of advanced stages of AMD (i.e., neovascular AMD and GA) could be overestimated in our population because our center is a tertiary referral center for macular diseases. Prospective studies with larger sample sizes are needed to reach more concrete conclusions and possibly gather more insights into their pathogenesis and progression. Furthermore, longitudinal studies are needed to understand if the response to the treatment in case of MNV is comparable to that of other phenotypes of AMD. Finally, dye angiographies (FA and ICGA) were not available for all included eyes; however, the absence of AS was based on fundus examination and different imaging analyses (multicolor, IR, and FAF) by two retinal experts.

In conclusion, we described the characteristics of subclinical AS in AMD by multimodal imaging approach, defining its prevalence in a cohort of AMD patients. We highlighted that patients with AS in AMD are characterized by different clinical presentation, imaging features, and pathogenesis, in comparison to eyes with AMD but without AS, and thus these eyes could represent a distinct group of the AMD population.