Abstract
Purpose
To provide an analysis of structural optical coherence tomography (OCT) and enface infrared reflectance (IR) differences between non-exudative macular neovascularizations (NE MNVs) secondary to age-related macular degeneration (AMD) and NE MNVs secondary to pachychoroid spectrum.
Methods
Patients diagnosed with NE-MNV documented by OCTA and dye angiography in the context of either AMD or pachychoroid spectrum were retrospectively included in AMD group and PACHY group respectively. Only treatment-naïve NE MNVs showing persistence of non-exudative status for at least 1 year after diagnosis were considered. Availability of good quality structural OCT B scan and IR enface acquisitions both at baseline and at 1 year follow up was also required.
Results
The study population included 15 eyes of 15 patients in AMD group and 13 eyes of 13 patients in PACHY group. AMD group showed at baseline a significantly wider pigment epithelium detachment (PED) apex angle (p = 0.02), higher homogeneity of the PED (p = 0.015), higher PED shadowing(p = 0.03). Both groups experienced a widening of apex angle (flattening of the PED) during follow-up. Ten (76.9%) patients in PACHY group showed a hyporeflective halo at the margins of the PED at baseline compared to 3/15 (20.0%) patients in AMD group (0.007), with no significant changes at 1 year follow up (p = 0.47).
Conclusion
NE-MNVs in pachychoroid eyes are characterized by sharper and more inhomogeneous PEDs with a lighter choroidal shadowing compared to NE-MNVs in AMD eyes. Moreover, they often show a hyporeflective halo around the lesion with IR imaging.
Subject terms: Predictive markers, Education
Introduction
Non exudative macular neovascularizations (NE MNVs) are new neovascular networks developing from choriocapillaris and/or the retina without evidence of exudation [1–3]. The presence of NE MNVs was first described in the setting of AMD and can be found in 6.25% to 27% fellow eyes of patients diagnosed with the exudative form of the disease [1]. A multimodal imaging characterization of NE MNVs in AMD was first provided by Querques et al. [2], that described them as late ICGA plaques whose area expanded over time despite the absence of exudation, visible with structural optical coherence tomography (OCT) as irregular elevations in the retinal pigment epithelium (RPE) with collections of moderately reflective material in the sub-RPE space, showing a major axis in the horizontal plane. The advent of optical coherence tomography angiography (OCTA) allowed a better comprehension of the phenomenon both on a clinical and on a pathogenetic point of view [3, 4]. In particular, OCTA became determinant in differential diagnosis between drusenoid pigment epithelium detachments (PEDs), consisting in confluent large and medium sized drusen without the presence of a vascularized network, and fibrovascular PEDs, that can be considered as MNVs [5]. Moreover, it allowed to study the structure and the growth pattern of the neovascular network within the NE MNV, which made it possible to document dimensional growth of the lesion over time despite the absence of exudation [6]. NE MNVs have been documented in a variety of retinal diseases, including pachychoroid spectrum disease, in which our group reported a prevalence of 10.9% [6, 7], Nevertheless, the ambiguity of the definition of pachychoroid spectrum makes it difficult to determine their exact prevalence and characteristics [8]. The pathogenetic hypothesis is that, similarly to what occurs in AMD, NE MNVs in the setting of pachychoroid could serve a “compensatory” role to choriocapillaris impairment and hypoxia of the RPE that develops in chronic forms of the disease [9]. Moreover, patients with pachychoroid are usually affected by long-standing PED that could result in a disruption of Bruch’s membrane and stimulation of the growth of the neovascular network. However, the natural course and triggers of choriocapillaris damage in AMD and in pachychoroid spectrum are different. We hypothesize that these differences might lead to a different structural morphology of the MNV in the two conditions, especially in its earliest phases of development such as in the case of NE MNVs. In particular, differences in internal reflectivity of the MNV are to be expected as a consequence of the different vascular structure reported in literature [10]. The aim of this study is to provide an analysis of structural OCT and enface infrared reflectance (IR) differences at baseline between NE MNVs secondary to AMD disease and NE MNVs secondary to pachychoroid disease. We also aim to analyze changes in NE MNV morphology that occurred during the course of 1 year follow up in the two conditions.
Materials and methods
Patients diagnosed with either non-exudative AMD or pachychoroid spectrum disease were retrospectively searched in the files of Medical Retina and Imaging Unit, IRCCS San Raffaele Scientific Institute, University Vita-Salute San Raffaele in Milan, Italy, from January 2018 to March 2023. Pachychoroid spectrum was defined as the simultaneous presence of a subfoveal choroidal thickness (SCT) > 270 μm and pachyvessels on indocyanine green angiography (ICGA) at baseline [8, 11]. Pachyvessels were defined as large outer choroidal vessels extending into the macula within the region of maximal choroidal thickness that showed choroidal vascular hyperpermeability on ICGA [12]. All AMD and pachychoroid eyes affected by NE MNV documented with both OCTA and dye angiography (including fluorescein angiography and ICGA) were included. On structural OCT, NE MNV was defined as an elevation of the RPE with moderately reflective material in the sub-RPE space and no intraretinal or subretinal hyporeflective fluid. On dye angiography, NE MNV was defined as a an ill-defined hyperfluorescent lesion distinguishable in the late-phase of fluorescein angiography without leakage or pooling of dye, and as a hyperfluorescent neovascular network appearing in the early-mid phases of ICGA [11]. Only NE MNVs showing persistence of non-exudative status for at least 1 year after diagnosis were considered in the analysis. This was done to analyze variations in shape and dimensions of the lesion over the course of the follow up focusing only on persistent clinically quiescent (i.e., absence of exudation) NE MNVs [10]. Moreover, only eyes that were naïve to anti-VEGF treatment were considered. An additional inclusion criterion was availability of good quality structural OCT B scan and IR enface acquisitions both at the baseline (moment of NE MNV diagnosis) and after 1 year of follow-up. Exclusion criteria were poor quality of the images (defined as Q score<15) due to dioptric media opacities or low compliance of the patient, high myopia (axial length>26 mm and/or spherical equivalent < -6 D) and history of ocular trauma and other simultaneous retinal and choroidal conditions predisposing to the development of a MNV (such as history of posterior uveitis, angioid streaks, intraocular tumors and hereditary chorioretinal dystrophies). Cases of overlap of AMD and pachychoroid spectrum were also excluded. The aim of the study was to detect OCT imaging differences in baseline characteristics between NE MNVs diagnosed in the context of AMD and those diagnosed in the context of pachychoroid spectrum disease. Moreover, we aimed to investigate changes in NE MNV characteristics occurred during the course of 1 year follow up in the 2 diseases. We divided the study population in 2 groups: AMD group and PACHY group, including respectively patients diagnosed with NE MNV secondary to AMD and patients diagnosed with NE MNV secondary to pachychoroid spectrum disease. The study was conducted in accordance with the Declaration of Helsinki and Italian legislation. A written informed consent for retrospective studies was collected from each patient. The study and the consent form were approved by Ethics Committee of IRCCS San Raffaele Scientific Institute (n of protocol 3201).
Image analysis and structural OCT parameters
Baseline and 1-year follow up images were acquired using Spectralis HRA + OCT (Heidelberg Eye Explorer, Version 1.10.4.0, Heidelberg Engineering, Heidelberg, Germany). B-scan raster acquisitions of a minimum size of 15° × 15° were examined for measurement of OCT variables of interest. We analyzed different structural OCT parameters at baseline and after 1 year: SCT, greatest linear diameter (GLD) of the NE MNV, maximum pigment epithelium detachment (PED) height, PED apex angle, PED homogeneity and PED shadowing.
SCT, GLD, and PED height were measured using Matlab software (Mathworks, Natick, MA) for pixel-length conversion using as a reference the 200 μm calliper provided within each OCT acquisition. SCT was measured as the linear distance between subfoveal outer margin of the Bruch membrane and inner margin of the sclera and was calculated on fovea crossing OCT B-scan acquisitions. GLD was defined as the maximum distance between two opposite points at the margin of the NE MNV and was calculated on mid phase ICGA angiograms.
SCT and GLD were assessed by two independent graders. The same cases were analyzed once again after a 1-month interval by the same graders to assess intra-grader variability and avoid anchoring bias. The other parameters were assessed with an automated method subjected to human control of segmentation errors. PED height was measured as the maximum value of the linear distance between Bruch membrane and the outer margin of the RPE within the PED region. To detect the highest peak in the PED, a tangential line to each point of the inner surface of the PED was automatically drawn. The line standing the farthest from the Bruch membrane was detected and the corresponding surface point was chosen as the point of highest peak. PED height was calculated as the mean of the highest peak distance from the Bruch membrane for each PED acquisition. After identification of the highest peak for each PED acquisition, the angle for each peak was calculated using ImageJ software (NIH, Bethesda, MD) as the angle formed at the intersection between lines drawn tangentially to the points of inflection of PED inner surface symmetric to the peak. Finally, PED apex angle value for each patient was the result of the mean of angle value for each acquisition.
Shadowing was measured as the percentage reduction in mean luminance of choroidal pixels underneath the PED compared to those immediately at the margins of the PED shadow. PED homogeneity was measured as the percentage of pixels showing a luminance within 1 standard. Deviation of the mean luminance of the pixels contained within the PED region (Fig. 1).
Fig. 1. Process of PED homogeneity and PED shadowing calculation.
A segmentation of the PED region (left image) and tridimensional plot distribution of pixel luminance for each pixel in the PED. B Choroidal luminance before (left image) and after (right image) removal of the shadowing.
Finally, IR enface images were analyzed and the presence of an hyporeflective halo at the border of the PED was registered for each image at both baseline and follow up. Also, for this analysis, two expert graders (EC and AC) independently evaluated the presence the halo and, in case of disagreement, a third senior retinal expert (GQ) graded the images.
Statistical analysis
Statistical analysis was conducted using SPSS v.26 (IBM, SPSS statistics). Normality of the distribution for quantitative variables was tested using Shapiro Wilk test. Sample size calculation was performed based on the estimated prevalence of NE-MNV in AMD and setting power of the study to 80% and α error to 5%. Differences in baseline qualitative variables between groups were compared using Chi square test of Fisher’s exact test when appropriate. Between groups comparison of quantitative variables was performed using two-tailed T test for independent samples. The analysis of the variation during the follow up of quantitative variables within the same group was performed using two tailed T test for dependent samples. Variations in the two groups were compared using two tailed T test for independent samples. Variation of qualitative variables was assessed using Chi square or Fisher’s exact test when appropriate. Inter-grader and intra-grader agreement in quantitative values were assessed using intraclass correlation coefficient. Agreement concerning qualitative variables was assessed using Cohen’s kappa analysis. A p value < 0.005 was considered as statistically significant and Bonferroni correction for multiple comparisons was applied.
Results
Twenty-five [25] NE MNV cases diagnosed with AMD and 16 cases diagnosed with pachychoroid disease met inclusion criteria. Among them, 10 cases in AMD group (40.0%) and 3 cases in PACHY group (18.7%) were excluded due to the development of exudation earlier than 1 year follow up. As a result, the study population included 15 eyes of 15 patients in AMD group and 13 eyes of 13 patients in PACHY group. Mean duration of available follow up for included cases was 3.8 ± 1.1 years. During this period, 3/15 cases (20.0%) in AMD group and 1/13 (7.8%) cases in PACHY group developed exudation.
Mean age of the total population was 74.0 ± 5.8 years and male sex had a prevalence of 14/28 (50.0%) The two groups showed no significant difference in sex composition: male sex prevalence was 40.0% in AMD group (6/15) and 61.5% in pachy group (8/13) (p = 0.449). AMD group patients were significantly older than PACHY group patients, with mean ages of 77.5 ± 5.1 years and 70.0 ± 3.5 years respectively (p < 0.001). Best corrected visual acuity was 0.08 ± 0.23 and 0.10 ± 0.25 in PACHY and AMD groups respectively. Both inter-grader and intra-grader agreement in SCT measurement were good (respectively 0.82 (0.78–0.85) and 0.86 (0.82–0.89)). Mean absolute variation of SCT from baseline to 1 year follow up was significantly higher in PACHY group compared to AMD group, with a mean variation of −38.2 ± 7.0 μm and −10.1 ± 4.7 μm respectively. GLD at baseline was 1918 ± 433 μm in AMD group and 1878 ± 482 μm in PACHY group, a difference that was borderline to statistical significance (p = 0.071, see Fig. 1 and Table 1). No significant differences in terms of variations in GLD over the course of the follow up were detected between groups (p = 0.617, see Table 2). Also, agreement in GLD measurement was good both between graders (ICC = 0.80 (CI 0.78–0.82) and within grader (ICC = 0.82 (0.80–0.84). PED apex angle was significantly higher at baseline in AMD group (p = 0.02, see Table 1 and Fig. 2), but no significant differences in variation of PED apex angle were found during the follow up (p = 0.812). Notably, both groups showed an increase in PED apex angle from baseline to follow up (see Table 2). No significant differences in terms of baseline PED height and variation in PED height from baseline to follow up were found (respectively p = 0.066 and p = 0.533). AMD group showed a significantly higher degree of homogeneity of the PED at baseline compared to PACHY group, corresponding to baseline values of 79.0 ± 10.3% and 58.5 ± 12.1% respectively (p = 0.015). No significant differences in variation of PED homogeneity between baseline and follow up examination were detected (Table 2). Similarly, PED shadowing was significantly higher in AMD group at baseline (24.8 ± 5.8%) compared to PACHY group (13.7 ± 4.4%)(p = 0.03), but no significant differences were found between baseline and follow up examination(see Table 2). PED homogeneity and PED shadowing both increased during the follow up. Lastly, 10/13 (76.9%) patients in PACHY group showed a hyporeflective halo at the margins of the PED at baseline compared to 3/15 (20.0%) patients in AMD group (0.007) (see Fig. 3). No significant differences in variation of this sign were detected at 1 year follow up (p = 0.47, see Table 2). Specifically, in two patients from PACHY group the hyporeflective halo disappeared after 12 months follow up but the majority of those manifesting this sign at baseline (6/8, 75.0%) still showed it after 12 months follow up (see Fig. 3). In AMD group, the three patients that presented with the halo at baseline still showed it after 12 months of follow up. Inter-grader and intra-grader agreement in halo assessment were substantial (respectively 0.66 (0.64–0.69) and 0.69 (0.67–0.71)).
Table 1.
Comparison of OCT B-scan and IR enface variables between the two study groups at baseline.
| AMD group | PACHY group | p | ||
|---|---|---|---|---|
| OCT B scan | SCT (μm) | 161.3 ± 22.8 | 236.2 ± 30.7 | <0.001 |
| GLD (μm) | 1918.10 ± 433.2 | 1878.04 ± 482.4 | 0.071 | |
| PED height (μm) | 123.5 ± 56.2 | 106.8 ± 22.1 | 0.066 | |
| PED apex angle (°) | 122.8° ± 15.1° | 90.7° ± 16.6° | 0.02 | |
| PED homogeneity (%) | 79.0 ± 10.3 | 58.5 ± 12.1 | 0.015 | |
| PED shadowing (%) | 24.8 ± 5.8 | 13.7 ± 4.4 | 0.03 | |
| IR enface | Hyporeflective halo | 3/15 (20.0%) | 10/13 (76.9%) | 0.007 |
AMD age related macular degeneration, GLD greatest linear diameter, IR infrared, PED pigment epithelial detachment, SCT subfoveal choroidal thickness.
Table 2.
Variation of OCT B-scan and IR enface variables between baseline and 1 year follow up. Each value corresponds to the changes that occurred during the follow up concerning each variable within the indicated group.
| AMD group | PACHY group | p | ||
|---|---|---|---|---|
| OCT B scan | Δ SCT (μm) | −10.1 ± 4.7 | −38.2 ± 7.0 | 0.045 |
| Δ GLD (μm) | +122.8 ± 16.5 | +119.7 ± 18.1 | 0.617 | |
| Δ PED height (μm) | 20.3 ± 6.7 | 15.2 ± 8.1 | 0.533 | |
| Δ PED apex angle (°) | 10.3° ± 8.3° | 8.1° ± 5.9° | 0.812 | |
| Δ PED homogeneity (%) | 6.9 ± 2.3 | 8.1 ± 1.8 | 0.679 | |
| Δ PED shadowing (%) | 3.5 ± 1.4 | 2.4 ± 1.9 | 0.733 | |
| IR enface | Hyporeflective halo | 0/15 (0.0%) | 2/13 (15.4%) | 0.47 |
AMD age-related macular degeneration, GLD greatest linear diameter, IR infrared, OCT optical coherence tomography, PED pigment epithelial detachment, SCT subfoveal choroidal thickness.
Fig. 2. Differences in PED apex angle between groups.
Lower angles correspond to sharper profiles of the PED. AMD age-related macular degeneration; PACHY pachychoroid disease.
Fig. 3. Hyporeflective halo.
Example of hyporeflective halo surrounding the PED at baseline and follow up examination in PACHY group (yellow dotted arrows). In the case from AMD group, no hyporeflective ring was visible both at baseline and follow up examination.
Discussion
Choriocapillaris impairment has been postulated to represent a trigger for the onset of neovascularization [13]. Despite choriocapillaris thinning and rarefaction represents a common characteristic for AMD and pachychoroid spectrum diseases, the pathogenesis of choriocapillaris impairment in the two conditions follows a different natural course [10, 14]. This led us to hypothesize that a different structural OCT morphology could characterize the early phases of MNV onset according to the different process of choriocapillaris damage. As concerns OCTA, literature describes NE MNV secondary to pachychoroid to be characterized by large-caliber vessels with a paucity of capillaries within the lesions, suggesting that the genesis of the MNV may be more related to arteriogenesis rather than angiogenesis [15]. Considering the possible overlap of the two conditions and the different clinical implications of the two types of MNV after the onset of exudation, the possibility to detect distinctive OCT signs for the two entities is of relevant clinical interest. In fact, MNV associated to central serous chorioretinopathy and polypoidal choroidal vasculopathy are associated to a resistance to anti-VEGF treatment compared to AMD cases [16–18], which could be due to the contribution of arteriogenesis to the growth of these lesions as postulated by Sacconi et al [15]. To the best of our knowledge, this is the first study in literature addressing this issue and offering an overview of relevant signs allowing to distinguish the origin of the lesion using a routine exam such as structural OCT and enface IR imaging. In fact, although past literature has already stressed the importance of structural OCT in suggesting the presence of NE MNVs [19, 20], no previous report focused on OCT differences between AMD and pachychoroid associated NE MNVs. According to our findings, 20% of cases of NE MNV in AMD and 7.8% of cases of NE MNV in pachychoroid disease developed exudation after 1 year follow up. Considering a mean duration of the follow up of around 4 years, this data could suggest a higher predisposition of NE MNVs developed in the context of AMD to faster exudation. However, the retrospective nature of the study and the small sample size do not allow to draw decisive conclusions on the matter. As concerns imaging findings, pachychoroid patients were characterized by a higher decrease in SCT during the first follow up year. This is coherent with the findings from Carnevali et al. [5]., which reported a decrease in SCT in patients with pachychoroid spectrum disease showing NE MNV. Nevertheless, despite being reported also by other authors [21], this finding could also be considered as the result of a regression to the mean bias. Moreover, pachychoroid patients are characterized by sharper PEDs at baseline, a characteristic that is represented by the lower apex angle compared to AMD patients. Nevertheless, NE MNVs in pachychoroid disease undergo a progressive process of flattening during the course of the follow up, a phenomenon that can be detected also in AMD patients according to our analysis. Moreover, the lower homogeneity of the PED in pachychoroid disease suggests a speckled appearance of the PED compared to a more homogeneous appearance of the PED in AMD patients at baseline. This could be a consequence of the different internal composition of the PED. In fact, angiogenesis is characterized by the presence of small leaking disorganized vessels that might confer more homogeneous reflectivity to the MNV structure due to the small size of the hyporeflective vessel lumen. By contrast, large vessels deriving from arteriogenesis could result in wider hyporeflective areas within the PED, thus conferring a more inhomogeneous aspect due to the contrast with fibrous material of the PED architecture. At the same time, NE MNVs deriving from AMD are characterized by a more intense shadowing effect on the underlying choroid, which, coherently to the previous hypothesis, could be the result of a dense fibrovascular net composed of small, numerous vessels immersed in a fibrotic medium. Lastly, we detected the presence of a hyporeflective margin of the NE MNV to be a sign more specific to pachychoroid disease rather than to AMD. A similar finding is described by Cheung et al. [22], according to which the identification of sharp-peaked PED (i.e., a thumb-shaped PED) and a sub-RPE ring like structure on OCT combined with an orange nodule evident on color fundus photography can distinguish PCV from typical neovascular AMD in treatment naïve cases. In the absence of ICGA, the combination of the three major OCT criteria (sub-RPE ring-like structure, complex RPE elevation on en-face OCT, and sharp-peaked PED) achieved an AUC of 0.90 for the accurate diagnosis of PCV. The presence of the halo could be due to a possible shadowing effect in the presence of sharp-peaked PED in PACHY group.
The limitations of our study include the small sample size, the retrospective nature of the study implying different conditions of acquisition and the absence of available dye-based method during the follow up examination, that could have been useful to implement the description of our findings. We therefore encourage to confirm our findings which we believe could be of particular interest when facing the clinical challenge of a NE MNV in real life experience. In particular, elements that should suggest pachychoroid disease as the original stimulus to NE MNV onset are sharp profile and inhomogeneous internal composition of the PED, the presence of a hyporeflective halo surrounding the PED at enface IR imaging and a light shadowing effect on the choroid underneath. However, it is important to clarify that the lack of a common definition of pachychoroid spectrum and the evolution of the consensus on the entities within could lead to the need of a redefinition of the characteristics of NE MNV associated to these conditions. Moreover, newly described parameters from this study such as PED apex angle will need further validation from the scientific community to be recognized as a suitable method for comparison of PED morphology. Lastly, intrinsic age differences in the two populations could also be responsible for the different morphology of the PED in the two study groups. Despite no such differences have been reported in literature as associated with aging, it would be interesting to analyze the contribution of aging to the morphology of PEDs in a future study.
Summary
What was known before
Non-exudative macular neovascularizations (NE-MNVs) can be detected in around 10% of eyes with pachychoroid spectrum disease and 15% of fellow eyes of wet age-related macular disease patients.
What this study adds
NE-MNVs developing in AMD show flatter profile, higher degree of internal homogeneity and higher choroidal shadowing compared to NE-MNVs associated to pachychoroid. NE-MNVs diagnosed in pachychoroid eyes show a hyporeflective halo around the lesion which is rarely present in NE-MNVs associated to AMD.
Author contributions
Conceptualization, AC, EC, FC, GQ; Methodology, AC, EC, FC; Software, EC, FC; Validation, FB, GQ, RS; Formal analysis, AC, EC, FC; Investigation, AC, EC, GQ, RS; Resources, AC, GQ, FB; Data curation, AC, EC, FC; Writing—original draft preparation, EC, FC; Writing—review and editing, AC, FB, GQ, RS; Supervision, FB, GQ; Project administration, GQ. All authors have read and agreed to the published version of the manuscript.
Data availability
Data are available upon reasonable request to the corresponding author.
Competing interests
The authors declare no competing interests.
Ethics approval
All procedures performed were in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments. Informed consent was obtained from all individual participants included in the study.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
These authors contributed equally: Emanuele Crincoli, Adriano Carnevali.
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Associated Data
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Data Availability Statement
Data are available upon reasonable request to the corresponding author.