Abstract
Purpose. The aim of the study is to analyze the swept source-optical coherence tomography angiography (SS-OCTA) characteristics of polypoidal lesions in Caucasian patients. Methods. In this retrospective observational case series, 43 polypoidal lesions in 32 eyes of 32 patients were diagnosed using indocyanine green angiography (ICGA) and compared to SS-OCTA at a tertiary medical retina center (Clinic Landstraße, Vienna Healthcare Group, Austria) between June 2017 and March 2020. Vascularity was identified by color-coded B-scan SS-OCTA while morphology was described as revealed by en face SS-OCTA after alignment with ICGA-confirmed findings. Results. In total, SS-OCTA detected all polypoidal lesions, as identified by ICGA. On B-scan SS-OCTA, circumscribed flow was detected in 33 (76.7%) polypoidal lesions and diffuse flow in 10 (23.3%) lesions. On en face SS-OCTA, polypoidal lesions appeared morphologically as 19 tangled vessel balls (44.2%), 6 tangled vessel balls next to dilated vessels (13.9%), 8 vascular dilatations (18.6%), and 8 ill-defined vascular networks (18.6%), leaving 2 lesions (4.6%) undetected. Circumscribed flow was significantly associated with tangled vessel balls (). Conclusion. This study highlights the importance of a multimodal imaging approach, including SS-OCTA, for the evaluation of polypoidal lesions. Our findings suggest a morphological heterogeneity of vascular patterns in Caucasian patients with polypoidal lesions, as pictured by SS-OCTA.
1. Introduction
Polypoidal lesions were first described as a distinct macular disorder characterized by nodular excrescences with interconnecting vascular channels more than 30 years ago [1]. Later on, two basic choroidal vascular changes were identified with the help of indocyanine green angiography (ICGA): a branching neovascular network (BNVN) in the inner choroid and vascular dilations at the border of the vascular network [2]. Since then, ICGA has been considered the gold standard for the diagnostic evaluation of polypoidal lesions independent of their origin. More recently, optical coherence tomography (OCT) has become valuable as a dye-independent diagnostic tool [3]. However, OCT is limited to structural findings as it is unable to illustrate the vascular flow. The era of OCT angiography (OCTA)—commencing with the spectral domain (SD) technology—enabled the visualization of different vascular patterns such as round-shaped or cluster-like structures attributed to polypoidal lesions in a noninvasive setting [4, 5]. The introduction of swept source OCT angiography (SS-OCTA) with a deeper penetration and lower sensitivity roll-off facilitated further insights into the morphology [6–8]. Recently described in an Asian population, B-scan SS-OCTA demonstrated a high diagnostic accuracy of specific flow signals in polypoidal lesions inside or adjacent to pigment epithelial detachments (PED) [9]. In another study, polypoidal lesions appeared as tangled vascular structures in en face SS-OCTA [10]. In Caucasians, polypoidal lesions are most commonly associated with age-related macular degeneration (AMD) and the pachychoroid disease spectrum besides having an idiopathic appearance [11]. The observed features were reported to be similar to those in Asians using multimodal imaging without OCTA [12].
In the light of the above, this study investigated the detection of ICGA-confirmed polypoidal lesions by combining B-scan SS-OCTA and en face SS-OCTA-based characteristics in a Caucasian patient cohort.
2. Materials and Methods
2.1. Study Population
This retrospective observational case series included 32 eyes of 32 patients diagnosed with polypoidal lesions of different origins, independent of any prior treatment at our tertiary medical retina center (Medical Retina Unit, Department of Ophthalmology; Clinic Landstraße, Vienna Healthcare Group, Karl Landsteiner Institute for Retinal Research and Imaging, Austria) between June 2017 and March 2020. All patients underwent comprehensive ophthalmic examinations including dilated fundoscopy and multimodal imaging with SD-OCT, fluorescein angiography and ICGA (SPECTRALIS HRA-OCT Confocal Scanning Laser Ophthalmoscope and Angiography; Heidelberg Engineering, Heidelberg, Germany), SS-OCT, and SS-OCTA (DRI OCT Triton Plus; Topcon Corporation, Tokyo, Japan) as baseline standards of care on the day of admission. The best corrected visual acuity (BCVA) was measured using the Early Treatment Diabetic Retinopathy Study (ETDRS) letter score (4 m) and converted to Snellen (Sn). The SS-OCTA device works at a wavelength of 1050 nanometers under an acquisition rate of 100.000 A-scans per second with a motion contrast algorithm called OCTARA™ [13]. It operates on 1 mW input power with a digital axial resolution of 2.6 µm and a transverse digital resolution range of 9.4 to 18.8 µm, depending on the selected cube. Two trained operators captured SS-OCTA B-scans and standardized 4.5 × 4.5 mm, 6 × 6 mm2, and 9 × 9 mm2 en face SS-OCTA macular cubes with a scan resolution of 320 × 320 or 512 × 512 B-scans for each eye. The study adhered to the tenets of the Declaration of Helsinki. All subjects provided informed consent to analyze their data retrospectively and, hence, to participate in the study at the first presentation. The Federal Hospitals Act §15a Abs. 3a states that approval from the Viennese ethics committee is not needed for this study design.
2.2. Imaging and Grading
Polypoidal lesions and the BNVN were diagnosed based on the EVEREST criteria and termed as suggested by medical retina experts [3, 14]. Two independent graders who were blinded to the angiographic findings evaluated all acquired SS-OCTA images for flow detection in B-scans and the structural morphology in en face scans by using the integrated OCTA analysis software IMAGEnet 6 (Version 1.24.1.15742, Topcon Corporation, Tokyo, Japan). The SS-OCTA grading approach was based on qualitative parameters for feasible reproducibility in clinical settings. In cases of grading disagreement, the images were independently reevaluated. If a grading disagreement existed, a senior clinical advisor was consulted. The final grade was determined by the majority vote of all three retinal specialists. The segmentation protocol defined the retinal pigment epithelium (RPE) as the inner line and Bruch’s membrane (BM) as the outer segmentation boundary. In the case of segmentation artifacts, resegmentation was performed either semi-automatically by altering the predefined sections or by drawing the lines manually. First, SS-OCTA B-scans were investigated to identify flow inside various configurated PEDs [15]. Color-coded flow signals were either found to be circumscribed with a focal increase of density existing in various shapes and forms within the PED (Figures 1 and 2) or diffuse as scattered flow along the PED or as complete flow within the PED (Figure 3). Circumscribed flow was defined by the presence of increased flow signals within a focal area inside the PED, while every other abnormal flow without precise localization was determined to be diffuse.
The corresponding en face SS-OCTA images were superimposed with the hypercyanescent spots in ICGA by an alignment of the inner retinal vasculature to confirm the topography of the respective structures. After locating the vascular complex as the lesion of interest correctly, a number of different en face SS-OCTA patterns were elaborated: First, the previously described tangled vessel ball type (Figure 1), a neovascularization with convoluted vessels in a ball-like formation. Second, a tangled vessel ball adjacent to dilated vessels inconsistent with the BNVN (Figure 2) was detected. Third, single vascular dilatations were defined by the presence of larger vessel calibers exceeding the size of other pathologic vessel formations (Figures 3(a)–3(c)). Fourth, neovascular lesions without a tangled ball-shaped appearance or abnormal dilatations but unclear demarcation from the BNVN were termed as ill-defined vascular networks (Figures 3(d)–3(f)). More than 50% of the polypoidal lesion area had to be consistent with the respective morphological pattern for valid grading. On structural OCT B-scans, the PED height, configuration, and the localization of the polypoidal lesion inside the PED were analyzed as covariables. In addition, subfoveal choroidal thickness (SFCT) was measured as the greatest vertical distance between the BM and sclerochoroidal interface to differentiate the pachychoroid.
2.3. Statistics
The sensitivity of each investigated SS-OCTA imaging modality was calculated in comparison to ICGA. Due to the small numbers, the differentiation between scattered flow along the PED and complete flow within the PED was set in contrast to circumscribed flow on B-scan SS-OCTA. The relationship between B-scan SS-OCTA and en face SS-OCTA was evaluated using the chi-square test. Age, sex, laterality, underlying disease, BCVA, SFCT, PED height, PED configuration, lesion localization inside the PED, presence of hemorrhage, and previous treatment with intravitreal antivascular endothelial growth factor (anti-VEGF) were investigated as potential influencing factors using generalized mixed-effect regression analyses for the binary dependent variable B-scan SS-OCTA (comparing the probability for diffuse flow vs. circumscribed flow) as well as for the binary dependent variable en face SS-OCTA (comparing the probability for tangled vessel balls vs. other results). All models were accounted for with random factors for patients. Statistical significance was set at . Intergrader variability was calculated using Cohen’s kappa coefficient (K) and corresponding 95% confidence intervals (CI). All analyses were performed using R, release 4.0.3, and SAS 9.4 software (SAS Institute Inc., Cary, NC, USA). The tables were illustrated using Microsoft Excel 2019 (Microsoft Corporation, Redmond, WA, USA). Figures were composed using Photoshop CC 14.0 (Adobe Systems Incorporated, San Jose, USA).
3. Results
In total, 43 polypoidal lesions were identified by the ICGA and were hence eligible for enrollment. The descriptive data and patient information summary are displayed in Tables 1 and 2.
All polypoidal lesions in ICGA were also displayed by color-coded flow signals (100%). In detail, circumscribed flow within the PED was found in 33 (76.7%) polypoidal lesions (Figures 1(d), 2(d)–2(h) and 3(i)), while diffuse flow was observed in 10 (23.3%) lesions (Figures 3(c) and 3(f)). Vascular morphology was captured by en face SS-OCTA in 41 (95.3%) polypoidal lesions (Figures 1(c), 2(c), 3(b), and 3(e)), leaving 2 (4.6%) undetected (Figure 3(h)). Out of these, 19 (44.2%) were shaped as tangled vessel balls (Figure 1(c)), 6 (13.9%) as tangled vessel balls in addition to dilated vessels (Figure 2(c)), 8 (18.6%) as vascular dilatations only (Figure 3(b)) and 8 (18.6%) as ill-defined vascular networks (Figure 3(e)). A significant relationship between circumscribed flow in B-scan SS-OCTA and tangled vessel balls in en face SS-OCTA was evaluated () (Figure 4 and Table 3).
No multivariate analysis for potentially influencing cofactors was performed, as the univariate analysis showed no statistical significance (Table 3). Nonetheless, a statistical tendency of male sex () and better BCVA () were related to diffuse flow in B-scan SS-OCTA. In general, 37 of 43 (86%) flow patterns in B-scan SS-OCTA and 32 of 43 (80%) morphological patterns in en face SS-OCTA were graded equally. Good initial intergrader agreement was observed in both B-scan SS-OCTA (Κ = 0.65; CI = 0.40–0.91) and en face SS-OCTA (Κ = 0.68; CI = 0.52–0.85).
4. Discussion
In this study, the diagnostic value of SS-OCTA in polypoidal lesions regarding functional characteristics of flow signals and morphology was investigated and set in contrast to the invasive imaging modality ICGA. All lesions seen in ICGA were identified using color-coded B-scan SS-OCTA. Fujita and colleagues primarily focused on the analysis of B-scan SS-OCTA and presented a detection rate of 94.7% with typical flow characteristics in Asians [9]. They described polypoidal lesions in B-scans as complete or incomplete round/ring-like or flow signals adjacent to a PED notch. While the authors emphasized on a detailed description of the distributed flow, this study attached less importance to the morphology of flow patterns in B-scan SS-OCTA. Instead, flow density was described as an expression of functionality, either circumscribed by a focal area of high flow or diffuse without exact localization within the PED. Interestingly, a statistical tendency for male preponderance and better BCVA was related to a diffuse distribution, suggesting a heterogenic variability in the respective characteristics.
Circumscribed flow in B-scan SS-OCTA was significantly related to the appearance of tangled vessels balls in en face SS-OCTA (Figure 4 and Table 3). In fact, all tangled vessel balls observed in this study were visualized as circumscribed flow in B-scan SS-OCTA, which was attributed to the densely packed multiple vascular branches in tangled vessel ball formations. In total, en face SS-OCTA was inferior to color-coded B-scan SS-OCTA as it was not able to visualize the morphology of all ICGA-confirmed spots. Tangled vascular structures with or without dilatations besides ill-defined vascular structures were observed. These findings partly coincide with the observation of Bo and colleagues who first reported that polypoidal lesions in ICGA correspond to tangled vessel balls using en face SS-OCTA [10]. In their Asian study population, all confirmed polypoidal lesions were pictured as tangled vascular structures by en-face SS-OCTA. The authors concluded that polypoidal lesions are a distinct form of neovascularization rather than an aneurysmal structure. On the other hand, the BNVN was considered a variant of MNV type 1 and the term “aneurysmal” was found to be more appropriate than “polypoidal” to describe the vascular dilatations observed by multimodal imaging [16]. While retinal experts widely agree upon the vascular—some even refer to as arterial – origin rather than solid fleshy polyps, consensus has not been reached whether polypoidal lesions are simple aneurysms or more complex vascular structures [17]. A Japanese study group detected tangled vascular structures in 58 of 72 (80.5%) polypoidal lesions using en-face SS-OCTA as a secondary outcome measure [9]. Nevertheless, they reported difficulties in determining detailed structural findings in the remaining polypoidal lesions, which were attributed to image resolution limits or low quality. In our cohort of Caucasian patients, a variety of morphological appearances besides tangled vessels balls were expressed such as vascular dilatations in connection with tangled vessels, mere findings, and even ill-defined vascularity without a specific pattern. This complexity suggests a more heterogenic structure of polypoidal lesions and could very well be the manifestation of the same disease in a different stage—treated or treatment-naive p.e.—or a distinct subtype. One hypothesis is based on the transformation of neovascular patterns following repeated intravitreal antiVEGF injections. Therefore, prior antiVEGF treatment was analyzed as an influencing factor without significant findings. Other reasons including higher luminal pressure, focal vessel wall weakness, and genetic variability could be responsible for the differing appearances. The question remains as to whether dilated vessels are possibly aneurysmal neovascularizations as polypoidal lesions typically but not solely arise secondary to the pachychoroid disease spectrum.
The presence of hemorrhage had no impact on the appearance of polypoidal lesions. It is well known that polypoidal lesions pose a risk of extended subretinal hemorrhage as frequently seen in our study cohort (Figure 1(a)). ICGA, as a validated method, has a limited capability to detect polypoidal lesions underneath blood due to its attributes in the blood circulation. The noninvasive SS-OCTA technique highlights blood flow as void signals below the RPE in B-scans but also as vascular structures in en face scans. The herein detected relation between circumscribed high flow signals and tangled vessel balls could be useful to narrow the topographic localization of polypoidal lesions and might be preferential in the presence of subretinal hemorrhage, in the case of a strategical therapeutic change, for example. A prior anti-VEGF treatment was also investigated as a cofactor for the occurrence of morphologic patterns, but it showed neither a significant influence nor a tendency at the time of observation. The transformation of a polypoidal lesion into a MNV type 1 after previous antiVEGF treatment was not investigated in this study [18]. Structural OCT demonstrated a high diagnostic accuracy by applying a combination of 3 OCT-based criteria: sub-RPE ring-like lesions, en face OCT complex RPE elevation, and a sharp-peaked PED [3]. In our study, the identified polypoidal lesions were set in relation to the PED height and PED formation as pictured by OCT B-scans. All polypoidal lesions were elucidated below the RPE in B-scan OCTA. They were either located within a sharp-peaked PED (Figure 3(c)), below the top of a PED (Figures 2(e), 2(f), and 2(h)) or adjacent to a PED notch (Figures 1(d), 2(d), and 2(g)). However, the univariate analysis of coexisting OCT B-scan features showed no significance to either of the OCTA findings. Other OCT-based criteria such as the subfoveal choroidal thickness of the affected and the contralateral eye were also investigated without significant relation. Attributes such as age or origin were separately investigated as cofactors without statistically significant results (Tables 2 and 3). This does not automatically imply that the different characteristics are independent of the etiologic nature of the underlying disease. It simply states that the herein applied covariables had no influence on the appearance of polypoidal lesions in SS-OCTA.
The limitations of this study are attributed to its retrospective nature. The majority of polypoidal lesions were found to be solitary while only 6 eyes showed multiple lesions. Arguably, the cluster-like appearances in the same eye were likely to demonstrate similar SS-OCTA characteristics as described by Bo when in fact they showed a heterogenic picture as displayed in Figure 2 [10]. Nonetheless, no conclusion could be drawn as only two eyes were affected by this multiplicity of polypoidal lesions. The consensual descriptions of morphological appearances were partially extracted from previous studies, which could lead to a grader’s bias. Another limitation is the description of qualitative flow parameters in B-scans, namely, focal or diffuse flow. This lack of diversity was partially driven by the low image resolution and the number of investigated eyes. However, good initial grader agreement underlines the predefined morphological expressions of flow signals and vascular patterns. To the best of our knowledge, this is the first study investigating the feasibility of SS-OCTA in Caucasian patients diagnosed with polypoidal lesions by combining flow signals in B-scan OCTA and vascular patterns in en face SS-OCTA.
In conclusion, this study elucidates the value of SS-OCTA and contributes to the noninvasive ICGA-independent diagnostic characteristics of polypoidal lesions. Our findings suggest a more diverse appearance of vascular patterns as a spectrum of the disease in Caucasians.
Data Availability
DAB and SAS had full access to all the data in the study and took responsibility for the integrity of the data and the accuracy of the data analysis. The datasets used and/or analyzed to support the findings of this study are available from the corresponding author on reasonable request.
Ethical Approval
All procedures performed in studies involving human participants 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 or comparable ethical standards. The Federal Hospitals Act §15a Abs. 3a states that a vote from the Viennese ethics committee is not obligatory for this study design.
Consent
Informed consent was obtained from all participants. Publication is approved by all authors as well as the responsible authorities. The statistical analysis was carried out by Alexandra Graf, an independent professional without affiliations to our department or the institute.
Disclosure
The abstract of the paper was presented at the annual meetings of the Austrian ophthalmological society in May 2022, Villach, Austria and at the 22nd EURETINA meeting in September 2022, Hamburg, Germany.
Conflicts of Interest
The authors declare that there are no conflicts of interest.
Authors’ Contributions
DAB is the lead author and guarantor and is responsible for conceptualization, design, data acquisition, interpretation of data, and drafting the article. AG performed statistical analysis and interpreted the data, prepared the draft of the article, and reviewed and edited the article. MS, AMH, SK, MJ, and CZ performed data acquisition, analysis, and interpretation; prepared draft of the article; and reviewed and edited the paper. KK supervised the study and thoroughly revised the paper. SAS was responsible for conception, methodology, supervision, and critical revision. All authors read and approved the final version of the manuscript. DAB and AG contributed equally to the content of this paper.