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. 2020 Oct 23;15(10):e0241230. doi: 10.1371/journal.pone.0241230

Flow signal change in polyps after anti-vascular endothelial growth factor therapy

Chia-Jui Chang 1,#, Yi-Ming Huang 1,#, Ming-Hung Hsieh 2,#, An-Fei Li 1,3,4,#, Shih-Jen Chen 1,3,*,#
Editor: Alfred S Lewin5
PMCID: PMC7584188  PMID: 33095843

Abstract

Optical coherence tomography angiography (OCTA) is a novel, non-invasive imaging tool used to detect vascular flow. The absence of a flow signal in OCTA in polyps revealed by indocyanine green angiography (ICGA) in patients with polypoidal choroidal vasculopathy (PCV) may indicate slow or compromised filling of blood flow from choroidal vessels. Naïve patients with PCV treated with intravitreal injections of aflibercept (IVI-A) were enrolled in this study to validate the hypothesis that baseline flow may affect the outcome of polyp regression in ICGA. The flow signal of polyps in OCTA was detected by manual segmentation in the corresponding location by ICGA. Polyps were defined as high-flow if both OCTA and ICGA showed positive findings, and low-flow if OCTA showed a negative flow signal in 3 consecutive horizontal scans at the polyp area shown in ICGA. A total of 24 polyps were identified in 13 PCV patients at baseline. Of these 24 polyps, 22 (91.7%) were high-flow and 2 (8.3%) were low-flow. After 3 monthly IVI-A, all low-flow polyps had complete regression in ICGA. Among 17 (77%) high-flow polyps at baseline that had regression after treatment, 10 (58.8%) became low-flow, while 5 (22.7%) persistent polyps remained high-flow. Flow signal of polyps as detected by OCTA could be a predictive factor for treatment response in patients with PCV. Monitoring changes in flow signal after treatment is clinically relevant.

Introduction

Optical coherence tomography angiography (OCTA) is a new and non-invasive imaging tool used to detect vascular flow by computing signal decorrelation from moving blood in vessels between consecutive cross-sectional scans. Compared to the gold standard of indocyanine green angiography (ICGA) [1], OCTA has a greater branching vascular network (BVN) detection rate of 80~100% but lower polyp detection rate of 45~85% [2–10]. Applying OCTA in addition to fundus color imaging, fluorescein angiography and structural OCT has been shown to increase the sensitivity but not the specificity of diagnosing polypoidal choroidal vasculopathy (PCV) [11]. This may be due to the over diagnosis of occult choroidal neovascularization (CNV) as PCV caused by the low polyp detection rate of OCTA.

Potential reasons for the low detection rate of polyps in OCTA include the extra-macular location of polyps outside the central 6x6 mm area, segmentation errors, especially when there is highly elevated retinal pigment epithelium (RPE) detachment, and low vascular flow within the polyps [12]. Several studies have reported that the polyp detection rate of OCTA can be improved by adjusting the segmentation manually [5–7, 9, 10]. OCTA can detect flow with a velocity as low as 0.2~0.3 mm/s using a 70k-Hz A-scan within seconds [13–15]. In contrast, ICGA takes at least 5 minutes to identify polyps from the first 30 seconds of video recorded by a confocal scanning laser ophthalmoscope in the filling phase of the polyps, and 5 minutes to picture hyper-fluorescent polyps in the early phase [16, 17]. Rebhun et al. found that the flow velocity not only varied from patient-to-patient but also polyp-to-polyp [10]. Huang et al. used OCTA to characterize the morphology of BVN, and found that different BVN patterns had different recurrence and response rates to the treatment [8]. Since different polyps may have different flow velocities and filling times as reflected by the detection ability of OCTA in comparison to ICGA, we hypothesized that polyps with different flow rates may have different responses and outcomes to anti-vascular endothelial growth factor (anti-VEGF) treatment. Based on this hypothesis, this study first aimed to categorize polyps into high flow, which could be detected by both ICGA and OCTA, and low flow, which could only be detected by ICGA. The second aim was to evaluate the outcomes of the polyps after anti-VEGF treatment based on their flow type.

Materials and methods

This study was reviewed and approved by the Institutional Review Board of Taipei Veterans General Hospital (Taipei, Taiwan, approval ID: 2018-09-006BC), and it was performed according to the relevant guidelines and regulations. Informed consent was obtained from all participants in this study. Patients with naïve PCV diagnosed by ICGA were consecutively enrolled from September 2018 to August 2019 at a tertiary medical center in Taiwan. Patients who had ever received treatment including intravitreal anti-VEGF injections or photodynamic therapy (PDT) before enrollment were excluded. In addition, patients with poor image quality due to fixation loss, medium opacity, massive hemorrhagic PED or submacular hemorrhage obscuring the polyp were also excluded. ICGA (Heidelberg Engineering Inc., Heidelberg, Germany) was performed at baseline and after 3 monthly intravitreal injections of aflibercept (IVI-A). Early and mid-phase ICGA were read by two retinal specialists separately (AFL and SJC), who were blinded to each other’s diagnosis and the clinical information of the patients. Lesions were enrolled only when they were considered to be polyps by both retinal specialists. The response after three IVI-A were determined only when there was consensus between the two retinal specialists. The response in ICGA was classified as complete regression when the nodular hyperfluorescence of the polyp disappeared, partial regression when the polyp shrunk in size, and persistent when the polyp remained at the pre-treatment size. If there was any disagreement on the diagnosis or response of the polyps in ICGA, the 2 retinal specialists discussed and if a consensus could not be reached, the polyp was excluded for the OCTA study. Polyps beyond the central 6x6 mm image of ICGA were also excluded.

The patients underwent spectral domain-OCT (SD-OCT) (Optovue, Fremont, CA) to evaluate double layer signs of BVN, bumps or notches of pigment epithelium detachment (PED) for the polyps, and subretinal fluid (SRF) at baseline and after treatment. OCTA (Avanti; Optovue, Fremont, CA) was performed after the structural OCT to evaluate the polyps and BVN. Polyps within 3x3 or 6x6 mm of the central macula were counted and compared to the flow signal beneath the RPE by OCTA. The flow signal was detected by manual segmentation from the superficial retinal layer to choriocapillaries in the corresponding location appearing in ICGA. Projection artifacts from the retinal vessels were carefully examined and excluded. The OCTA manual segmentation of each polyp was then done by a third specialist (YMH). This third specialist interpret the signal of OCTA at the polyps where the 2 specialists agreed on. The En-face OCTA and horizontal OCTA scans were both used for flow signal detection. The signal of En- face OCTA was studied for flow signal at areas of polyps and BVN shown in ICGA. To confirm the flow signal, especially in equivocal signal after anti-VEGF, horizontal OCTA scan were used line by line at polyps for confirmation. Three sequential horizontal scans at the center of the corresponding area of the polyps in ICGA were performed for all polyps. These 3 horizontal scans covered a vertical size of 30 μm in 3x3 mm and 45 μm in 6x6 mm OCTA. The flows were categorized into high flow (presence of flow signal in at least 3 consecutive horizontal scans), low flow (absence of flow signal in all 3 consecutive horizontal scans) (Fig 1), and equivocal flow (presence of flow signal in 1 or 2 of 3 consecutive horizontal scans). The area of the post-treatment OCTA was evaluated according to the same area and size (either 3x3 mm or 6x6 mm) at baseline, e.g., 3x3 mm at both baseline and after treatment. Polyps accompanied with or without PED were also assessed.

Fig 1. ICGA and OCTA of high-flow polyp and low-flow polyp.

Fig 1

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(A) ICGA revealed one polyp (arrow). (B~D) The polyp (arrow) was identified by en face flow OCTA, and flow signal (arrow) was identified by en face flow OCTA, and flow signal was detectable in all 3 consecutive horizontal scans at the center of the polyp. The polyp was then defined as “high flow.” (E) Two polyps identified on ICGA (arrow and dotted arrow). (F~H) En face OCTA and 3 consecutive horizontal scan of the 2 types of polyps. The flow signal of “high flow” polyp (arrow) was detectable in en face and all 3 consecutive horizontal scans, while the flow signal of the “low flow” polyp (dotted arrow) could not be detected in en face and all 3 horizontal scans.

Snellen visual acuity (VA) was transformed to logMAR for analysis. Statistical analyses were performed using SPSS software version 12.0 (SPSS Inc., Chicago, IL, USA), using the Student’s t-test. A p value < 0.05 was considered to be statistically significant.

Results

During this study time period, a total of 62 patients with PCV were initially enrolled. Twenty-four of them were excluded because of the history of previous treatment with intravitreal anti-VEGF injections and PDT. Twenty-five patients were further excluded due to poor image quality by massive hemorrhage, hemorrhagic PED, or poor fixation. In the end, 13 patients (8 males and 5 females) were enrolled with an average age of 66.69±9.22 years and average visual acuity of 0.37±0.16 logMAR (Snellen equivalent of 0.45±0.176). A total of 24 polyps were identified by ICGA before IVI-A. The number of polyps ranged from 1 to 4 for each patient, with an average of 1.84 polyps per case. All patients had SRF at the fovea as detected by SD-OCT before treatment (Table 1).

Table 1. Demographic data and clinical profile of the 24 polyps in 13 patients before and after treatment.

Before Treatment After Treatment
Case Sex Age VA SRF Polyp ICGA Flow in OCTA PED BVN (size, DA) VA SRF Outcome in ICGA Flow in OCTA PED BVN (size, DA)
1 F 73 6/7.5 + 1 + Positive + 1.0 6/6 - Complete Equivocal + 0.75
2 + Positive + - Partial Positive +
3 + Positive + - Complete Positive +
2 M 78 6/30 + 4 + Positive + - 6/7.5 - Complete Negative + -
3 M 75 6/15 + 5 + Negative + - 6/15 + Complete Negative - -
6 + Positive + + Partial Negative +
4 M 69 6/15 + 7 + Positive + 2.0 6/8.6 - Partial Equivocal + 2.0
5 M 64 6/8.6 + 8 + Positive + 2.0 6/7.5 - Partial Equivocal + 2.0
6 F 57 6/15 + 9 + Positive + 1.0 6/8.6 - Complete Negative + 1.0
10 + Positive + - Persistent Positive +
11 + Positive + - Persistent Positive +
12 + Positive + - Complete Negative -
7 M 57 6/15 + 13 + Positive + 1.0 6/6.7 - Persistent Positive + 1.0
8 M 62 6/20 + 14 + Positive + - 6/20 + Persistent Positive + -
15 + Positive + + Partial Positive +
9 F 61 6/20 + 16 + Positive + 1.0 6/10 - Complete Negative + 0.75
17 + Negative - - Complete Negative -
10 M 58 6/10 + 18 + Positive + 3.0 6/6.7 - Persistent Positive + 3.0
11 F 86 6/15 + 19 + Positive + - 6/10 - Complete Negative + -
12 M 69 6/10 + 20 + Positive + 1.0 6/7.5 - Partial Positive + 1.0
21 + Positive + + Partial Positive +
22 + Positive + - Partial Positive +
13 F 58 6/15 + 23 + Positive + 0.75 6/8.6 - Complete Negative + 0.75
24 + Positive + - Partial Positive +
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BVN: branching vascular networks; DA: disc area; ICGA: indocyanine green angiography; OCTA: optical coherence tomography angiography; PED: pigment epithelium detachment; SRF: subretinal fluid; VA: visual acuity.

At baseline, among the 24 polyps identified by ICGA, 22 (91.7%) which had a detectable flow in at least three horizontal scans were categorized as being high flow by OCTA. In addition, two (8.3%) polyps which had undetectable flow in all horizontal scans were categorized as being low flow. None of the polyps were classified into the equivocal-flow group at baseline (Fig 2).

Fig 2. Outcomes of the 24 polyps detected in ICGA and flow signal changes in OCTA before and after 3 monthly loading of intra-vitreal injections of aflibercept (IVI-A).

Fig 2

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All polyps were located beneath the RPE. All polyps had accompanying PED, except for 1 low-flow polyp (polyp 17). Nine among 13 patients had BVN before the treatment. The size of BVN ranged from 0.75 to 3.0 disc area(DA) in ICGA (average of 1.42±0.75 DA).

After 3 consecutive intravitreal injections of aflibercept, the average visual acuity improved to 0.17±0.15 logMAR (Snellen equivalent of 0.71±0.20) (p<0.001). In the structural OCT, 19 (79.2%) polyps showed no SRF after treatment on OCT, while 5 (20.8%) had persistent SRF. For the 23 polyps with PED at the baseline, 21 (91.3%) showed persisted but smaller PED and 2 (8.7%) showed complete resolution of the PED after treatment. After treatment, the size of the BVN remained unchanged (1.36±0.79 DA, p = 0.88) in our short term 3 months follow up.

As shown in Fig 2, ICGA revealed that 10 (41.7%) of the 24 polyps had complete regression, 9 (37.5%) had partial regression, and 5 (20.8%) remained persistent after treatment. While OCTA revealed that 12 (50.0%) polyps showed high flow, 3 (12.5%) showed equivocal flow, and 9 (37.5%) showed no flow signal (Figs 3–5).

Fig 3. ICGA and OCTA of case 1.

Fig 3

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(A) ICGA before treatment showed 3 polyps, labeled as polyp 1 (long arrow), polyp 2 (short arrow), and polyp 3 (arrowhead). (B) ICGA after treatment showed complete regression of polyp 1 and 3, but partial regression in the size of polyp 2 (short arrow). (C) OCTA of polyp 1 before and (D) after treatment showed the presence of flow signal (long arrow). (E) OCTA of polyp 2 before and (F) after treatment showed the presence of flow signal (short arrow). (G) OCTA of polyp 3 before and (H) after treatment showed the presence of flow signal (arrowhead).

Fig 5. ICGA and OCTA of case 6.

Fig 5

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(A) ICGA before treatment showed 4 polyps, labeled as polyp 9 (long arrow), polyp 10 (short arrow), polyp 11 (dotted arrow) and polyp 12 (arrowhead). (B) ICGA after the treatment showed complete regression of polyp 9 and 12, but the persistence of polyp 10 (short arrow) and polyp 11 (dotted arrow). (C) OCTA of polyp 9 before treatment showed the presence of flow signal (arrow) but (D) the absence of flow signal (arrow) after treatment. Note that the adjacent signal was projection artifacts from the retinal vessels. (E) OCTA of polyp 10 before and (F) after treatment showed the presence of flow signal (short arrow). (G) OCTA of polyp 11 before and (H) after treatment showed the presence of flow signal (dotted arrow). (I) OCTA of polyp 12 before treatment showed the presence of flow signal (arrowhead) but (J) the absence of flow signal (arrowhead) after treatment.

Fig 4. ICGA and OCTA of case 3.

Fig 4

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(A) ICGA before treatment showed 2 polyps, labeled as polyp 5 (arrowhead) and polyp 6 (arrow). (B) ICGA after treatment showed complete regression of polyp 5, but partial regression of polyp 6 (arrow). (C) OCTA of polyp 5 before and (D) after treatment showed the absence of flow signal (arrowhead) in this low-flow polyp. (E) OCTA of polyp 6 before treatment showed the presence of flow signal (arrow) but (F) the absence of flow signal (arrow) after treatment. Note the decrease in subretinal fluid and height of pigment epithelial detachment after treatment.

Both of the low-flow polyps at baseline had complete regression in ICGA and the flow remained undetectable in OCTA. For the 22 high-flow polyps at baseline, 8 (36.4%) had complete regression, 9 (40.9%) had partial regression, and 5 (22.7%) remained persistent in ICGA. Of these 22 high-flow polyps, 12 (54.5%) remained high-flow, 3 (13.6%) became equivocal-flow, and 7 (31.8%) became low-flow in OCTA after treatment.

Among the 17 polyps that showed complete or partial regression in ICGA, the flow could still be detected in 58.8% (10/17) in OCTA.

For the 12 polyps that remained high flow after treatment, 9 (75.0%) showed resolved SRF and 3 (25.0%) showed persistent SRF. Although PED persisted in all 12 polyps, 10 (83.3%) showed an improvement in the size of the PED.

SRF resolved in all 3 polyps that changed from high flow to equivocal flow after treatment. Although PED persisted in all 3 polyps, all of them became smaller after treatment.

Of the 7 polyps that changed from high to low flow after treatment, SRF resolved in 6 (85.7%) but persisted in 1 (14.3%). PED persisted but improved in all 7 of these polyps.

Discussion

Our results showed that the presence or absence of a flow signal in the polyps in OCTA may have been associated with different treatment responses after intravitreal anti-VEGF injections. Both of the 2 low-flow polyps in OCTA had complete regression in ICGA after treatment, while 77.3% of the 22 high-flow polyps had complete or partial regression in ICGA. Among these polyps with complete or partial regression, 58.8% had no detectable or equivocal flow signal in OCTA. All of the 5 (22.7%) persistent polyps in ICGA had a detectable flow, although SRF resolved in 4 (80%) of them. Differences in flow rate between polyps may indicate the heterogeneity of polyps in response to anti-VEGF or even to photodynamic therapy. Furthermore, our study also found that the size of the BVN in ICGA remained unchanged after treatment in our short term 3 months follow up. This was in accordance with previous studies that the BVN had poorer response to anti-VEGF than the polyps did [16, 18–22].

Polyps regression as a treatment goal for PCV management remained controversial since recent clinical trials had shown improved visual acuity with inactive but persisted polyps [18, 22]. A recent study with up to 11 years of follow-up showed that the long-term risk for massive submacular hemorrhage was significantly higher in patients with persistent polyps than those without [23]. The 2 years EVEREST II and the 2 years PLANET studies reported that the percentage of complete polyp regression as assessed by ICGA was around 34.7% after intravitreal injections of ranibizumab and 38.9% after aflibercept monotherapy at 12 months [18, 22]. The number of injections in the monotherapy arm ranged from 3 to 12, indicating that a high variety of polyps responded to anti-VEGF treatment. Even with combination therapy, 30% of the polyps remained present at 12 months [18]. Although several studies reported that single polyps, a smaller polyp area, and non-cluster type polyps had a better response after anti-VEGF monotherapy [19–21], it remained unknown whether the flow rate played a role in the treatment response. Our study showed that flow signal in OCTA, which may be attributed to the blood flow rate from the choroid to the polyps [12], could be a possible reason for the variable response to anti-VEGF treatment.

The presence of flow signal in OCTA could also be associated with clinical signs. Of the polyps with no flow signal or with an equivocal flow signal in OCTA after treatment, 83% (10/12) had complete polyp regression and anatomical improvement with disappearance of the SRF and decreased height of the PED. Moreover, of the polyps that still had high-flow in OCTA, 42% (5/12) persisted without becoming smaller, and 25% (3/12) had persisted SRF at the fovea. In addition to the activity of the polyps as revealed by the presence of SRF after 3 initial loading injections of anti-VEGF, a change in flow signal from high to low in OCTA may have predicted a better response with regards to polyp regression and clinical improvement. Moreover, the responses of the naïve polyps with no flow signal at baseline were even better. Our results suggest that flow signal of individual polyps in OCTA at baseline and follow-up after anti-VEGF treatment could be a prognostic factor for treatment outcomes and may alleviate the need for frequent ICGA studies.

It should be noted that 2 among 8 completely regressed polyps in ICGA after treatment still had flow signal in OCTA. Theoretically, the OCTA scan could detect very slow flow signal with velocity of 0.2 to 3 mm/s [13–15]. Therefore, though the ICGA after the treatment revealed complete regression of the polyp, there might be slow flow remaining in the area that could be defected by the OCTA but not visualized in ICGA.

There are several limitations to this study. First, the numbers of patients and polyps were small, especially for the low flow polyps, and the follow-up time was short. Because of the wide detection of flow signal by OCTA, the low flow polyps may indeed the polyps with very low filling flow of the polyps and the number may be quite few in symptomatic patients with PCV. It will be interesting to see if there are more low flow polyps in asymptomatic patients with PCV. Second, inaccuracies in flow signal detection were possible due to the manual measurements. However, by excluding the polyps with an equivocal diagnosis, meaning that suspicious lesions were considered to be polyps by one retinal specialist but not by another retinal specialist who interpreted the same ICGA separately, we believe that the rate of inaccurate detection was decreased. Third, we only recorded the presence or absence of flow signal in the polyps, but we did not quantify the flow intensity in the polyps or BVN in OCTA as this would have involved more sophisticated analysis of a 3-D structure of the lesions. And lastly, this classification of flow and response of polyps might not be applied to all kinds of patients with PCV due to the exclusion of patients with previous treatment of anti-VEGF or PDT or patients without good image quality of OCTA such as massive hemorrhage or poor fixation.

In conclusion, flow signal in polyps as revealed by OCTA could be associated with the response to anti-VEGF treatment in patients with PCV, and a low flow signal in polyps may indicate a good response. In addition, monitoring changes in the signal after treatment is clinically relevant and could be considered in the management of patients with PCV in the future.

Data Availability

All relevant data are within the manuscript.

Funding Statement

The authors received no specific funding for this work.

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Decision Letter 0

Pukhraj Rishi

11 May 2020

PONE-D-20-09993

Flow Signal Change in Polyps After Anti-Vascular Endothelial Growth Factor Therapy

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5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: 1. Kindly explain why horizontal OCTA scans have been preferred over En-face OCTA scan.

2. Presence of Branching vascular network (BVN) complex has not been recorded. Any correlation between polyps and BVN complex could also have been identified.

3. Fig 1 (F, G, H) showing En-face OCTA of low flow polyp, could not be considered a proper scan. The manual segmentation is not at the appropriate level to be able to visualise the polyp.

4. Figure 2 is incomplete. No details of high flow polyps given.

5. Figure 3 depicting ICGA after treatment, shows complete remission of polyp 1 and 3. However, flow signals in the polyps still persist on OCTA after treatment. How can it be explained?

6. A sample of 2 low flow polyps is clearly inadequate to conclude the relevance or to predict clinical response to anti-VEGF.

Reviewer #2: Comments:

The authors of this manuscript are interested to study the dynamic change of blood flow within polypoidal lesions and whether it is a predictive factor for PCV response to intravitreal anti-VEGF treatment. Regression and inactivity of polypoidal lesions are considered as important clinical outcomes in multicentre randomized controlled trials of intravitreal anti-VEGF in PCV eyes. Hence, the authors had picked a highly relevant research topic with a sound hypothesis.

OCTA may not be as sensitive as ICGA for the detection of polyopidal lesions, and the authors had already acknowledged a number of intrinsic limitations of current OCTA imaging technology. The examination of 3 sequential OCTA scans in this study had somewhat reduced the error rate in imaging analyses. Nevertheless, segmentation error could be commonly encountered in PCV eyes due to irregularities at the level of retinal pigment epithelium and large, tall pigment epithelial detachments. A large amount of macular haemorrhage and exudation may also block OCT signals. PCV eyes with poor visual acuity may not be able to fixate well during OCTA scan leading to motion artefacts. Were there any eyes excluded from the study and what were the reason for their exclusion? I believe providing details on the exclusion criteria and the number of patients that were excluded from the consecutive recruitment process is very important as it conveys to the readers how practical it would be to examine PCV eyes with OCTA and under which circumstances the examination of flow within polypoidal lesions would be feasible.

The authors defined high flow lesions as those that with the presence of polyps on both ICGA and OCTA as determined by the examiners, on the other hand, low flow polyps were only detected on ICGA. Where the examiners for ICGA and OCTA blinded from each other? How many image graders were there? In case the examiners of ICGA and OCTA were not independent, would there be any bias ?

I suggest the authors to enhance the research methodology of the manuscript, and to provide more details on the intrinsic limitations of the qualitative study design. Furthermore, it would be interesting to know what would be the author’s point of view on the clinical implication of polyp regression. Both polyp regression and polyp inactivity had been reported in large, prospective clinical trials of PCV. Recurrence or persistence of polyp activity (e.g. exudation on scans) may influence on treatment decision. It seems that the definition of high/low flow signal OCTA in this manuscript is associated with partial or complete polyp ‘remission’. Please clarity if remission’ is regarding to the regression of polyp (i.e. change in size) and/or polyp activity (i.e. leakage)? Although polyp regression rate has been a reported outcome in a number of clinical trials, it may not be equivalent to disease activity. It would be intriguing to discuss the current evidence based practice with regard to polyp regression/activity, and to review the prognostic implication of polyp regression. To my knowledge, PLANET and EVEREST II had only published 2-year results. Please review any updated information on longer term PCV outcomes in the context of polyp remission.

Reviewer #3: The article is an excellent effort at bringing attention to the potential role of OCT Angiography flow signals in PCV polyps as a non-invasive predictive biomarker of its response to therapy. The authors have done a commendable job in endeavouring to correlate OCTA flow signals in PCV polyps to their ICGA behaviour, structural OCT features like PED height and subretinal fluid. While there are several limitations, that the authors have acknowledged, the study has numerous strengths as mentioned above and therefore merits a place in literature after the below stated minor errors are corrected.

Line 106 - µm should be used instead of um

Line 211 – PLANET study needs to be in caps.

Line 236 – spelling of polyps

Figure 2 – Lots of the boxes are blank.. needs to be clearly formatted

Case 2 in Table 1- mentions the location of the OCTA flow signal as Outer retina? That does not qualify for a PCV polyp OCTA flow signal and raises doubt as to whether it was a projected artefact. This is a critical error that needs to be corrected. Infact, the location of all OCTA PCV polyps needs to be beneath RPE ( All the other polyps here ,except this, have that). Ideally, the depth of the signal below the RPE could be specified. If that is not possible this aspect of the table may be omitted altogether as it adds no useful information.

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Reviewer #1: Yes: Dr. Atul Kumar

Reviewer #2: No

Reviewer #3: Yes: Anand Rajendran

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email us at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Oct 23;15(10):e0241230. doi: 10.1371/journal.pone.0241230.r002

Author response to Decision Letter 0

23 Jun 2020

Dear Reviewer 1:

Comment 1: Kindly explain why horizontal OCTA scans have been preferred over En-face OCTA scan

Response: The En-face OCTA and horizontal OCTA scans were both used for flow signal detection. The signal of En- face OCTA was studied for flow signal at areas of polyps and BVN shown in ICGA. To confirm the flow signal, especially in equivocal signal after anti-VEGF, horizontal OCTA scan were used across the polyps line by line for confirmation. This is why we set the definition of positive flow signal in 3 consecutive horizontal scans on the polyps.

(This was further clarified in Page 5 line 108)

Comment 2: Presence of Branching vascular network (BVN) complex has not been recorded. Any correlation between polyps and BVN complex could also have been identified

Response: Thank you for the constructive advice. We had evaluated the presence of BVN in OCTA and ICGA, and found that 9 among 13 patients had BVN before the treatment. The size of BVN ranged from 0.75 to 3.0 disc area(DA) (average of 1.42±0.75 DA). After treatment, the size of the BVN remained unchanged in this short term 3 months follow up. This was in accordance with previous studies that the BVN had poorer response to anti-VEGF than the polyps did.

(This was further clarified in Table 1, Page 8 line 159, Page 9 line 167, Page 11 line 225)

Comment 3: Fig 1 (F, G, H) showing En-face OCTA of low flow polyp, could not be considered a proper scan. The manual segmentation is not at the appropriate level to be able to visualise the polyp.

Response: Since the case had prominent SRF, it was hard to visualize the polyp on the En-face OCTA even with manual segmentation. Fig 1 (F, G, H) explained the definition of low flow polyps in our study, of which no flow signal in 3 consecutive horizontal OCTA scan in the corresponding polyp location of the ICGA. There was an adjacent high flow polyp pointed out by arrow for comparison.

(New figure 1 (revised F, G, H) had been submitted, and figure legends had been revised in Page 6 line 129.)

Comment 4: Figure 2 is incomplete. No details of high flow polyps given.

Response: Figure 2 is the flow chart of all the outcomes of polyps. The blanks might be due to format converting error and was probably incompletely uploaded. We will re-submit and upload again and will check with the editor office to ensure the completeness of the figure. Figure 2 had been re-submitted.

Comment 5: Figure 3 depicting ICGA after treatment, shows complete remission of polyp 1 and 3. However, flow signals in the polyps still persist on OCTA after treatment. How can it be explained?

Response: This is a very interesting point. We did see 2 among 8 polyps had completely regressed in ICGA without fluorescence after treatment yet still had flow signal in OCTA. Theoretically, the OCTA scan could detect very slow flow signal with velocity of 0.2 to 3 mm/s. Therefore, though the ICGA after the treatment revealed complete regression of the polyp, there might be slow flow remaining in the area that could be defected by the OCTA but not visualized in ICGA.

This was further clarified in Page 13 line 258

Comment 6: A sample of 2 low flow polyps is clearly inadequate to conclude the relevance or to predict clinical response to anti-VEGF

Response: Thank you and we agreed with you that this is the limitation of our study with small numbers of cases. However, on the other hand, because of the wide detection of flow signal by OCTA (theoretically 0.2 to 3mm/second), the low flow polyps may indeed the polyps with very low filling flow of the polyps and the number may be quite few in symptomatic patients with PCV. It will be interesting to see if there are more low flow polyps in asymptomatic patients with PCV.

This was further clarified in Page 13 line 265

Dear Reviewer 2:

Comment 1: PCV eyes with poor visual acuity may not be able to fixate well during OCTA scan leading to motion artefacts. Were there any eyes excluded from the study and what were the reason for their exclusion? I believe providing details on the exclusion criteria and the number of patients that were excluded from the consecutive recruitment process is very important as it conveys to the readers how practical it would be to examine PCV eyes with OCTA and under which circumstances the examination of flow within polypoidal lesions would be feasible.

Response: The visual acuity of our naïve patients in this study ranged from 6/30~6/7.5. Patients with poor image quality due to poor fixation even with good visual acuity were exclude from the study. During this study period, there were 49 patients who met the exclusion criteria and were not enrolled in this study. These exclusion criteria included history of previous treatment with IVI or PDT, poor image quality due to fixation loss, medium opacity, massive hemorrhagic PED or submacular hemorrhage obscuring the polyps.

(The exclusion criteria had been revised in line 81 and line 134)

Comment 2: The authors defined high flow lesions as those that with the presence of polyps on both ICGA and OCTA as determined by the examiners, on the other hand, low flow polyps were only detected on ICGA. Were the examiners for ICGA and OCTA blinded from each other? How many image graders were there?

Response: There were 2 retinal specialists to interpret each color, OCT and ICGA images separately. They were blind to each other’s results. Lesions were enrolled only when they were considered to be polyps by both retinal specialists. The en face OCTA and manual segmentation of each polyp was then studied by a third specialist. This third specialist interpret the signal of OCTA at the polyps where the 2 specialists agreed on.

This was further clarified in line 85, and line 105

Comment 3: Please clarity if remission’ is regarding to the regression of polyp (i.e. change in size) and/or polyp activity (i.e. leakage)?

Response: The term “remission” in the study referred to regression of the polyp in ICGA whether it was completely disappeared or decreased in size. This had been defined at the Materials & Methods, line 90. The decreased activity with decreased subretinal fluid or no fluid was not regarded as remission. The activity change, e.g., SRF, PED, had been described in Table 1. However, considering that regression was more commonly used and to avoid misunderstanding, we had revised by replacing “remission” with “regression”. Thank you.

(The “remission” and been revised to “regression” in the text in line 29, 35, 36, 90, 91, 170, 176, 183, 190, 199, 201, 205, 219, 221, 229, 234, 247, 253.)

Comment 4: Please review any updated information on longer term PCV outcomes in the context of polyp remission.

Response: A recent study with up to 11 years of follow-up showed that the long-term risk for massive submacular hemorrhage was significantly higher in patients with persistent polyps than patients without. (Chou et al, Retina 2020; 40:468-476.)

This long term FU study of PCV had been added and discussed in line 229.

Dear Reviewer 3:

Comment 1: Line 106 - µm should be used instead of um

Response: Thank you for pointing out our error. The correction had been made in page 6, line 114.

Comment 2: Line 211 – PLANET study needs to be in caps.

Response: Thank you for pointing out our error. The correction had been made at page 12, line 234.

Comment 3: Line 236 – spelling of polyps

Response: Thank you for pointing out our error. The correction had been made at page 13, line 264.

Comment 4: Figure 2 – Lots of the boxes are blank needs to be clearly formatted.

Response: Figure 2 is the flow chart of all the outcomes of polyps. The blanks might be due to format converting error and was probably incompletely uploaded. We will re-submit and upload again and will check with the editor office to ensure the completeness of the figure. Figure 2 would be re-submitted.

Comment 5: Case 2 in Table 1- mentions the location of the OCTA flow signal as Outer retina? That does not qualify for a PCV polyp OCTA flow signal and raises doubt as to whether it was a projected artefact. This is a critical error that needs to be corrected. In fact, the location of all OCTA PCV polyps needs to be beneath RPE (All the other polyps here ,except this, have that). Ideally, the depth of the signal below the RPE could be specified. If that is not possible this aspect of the table may be omitted altogether as it adds no useful information.

Response: We apologize for such error. The OCTA of the case was reviewed, and confirmed that the polyp was still beneath the RPE. Thank you for pointing out our mistake.

(Table 1 and page 8 line 158 had been revised.)

Attachment

Submitted filename: Response to Reviewers.docx

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Decision Letter 1

Pukhraj Rishi

26 Aug 2020

PONE-D-20-09993R1

Flow Signal Change in Polyps After Anti-Vascular Endothelial Growth Factor Therapy

PLOS ONE

Dear Dr. Chen,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

==============================

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==============================

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Additional Editor Comments (if provided):

One of the reviewers have raised some persisting concerns; please address them

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

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Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

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6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Figure 1 (F, G, H) images are not showing the segmentation line. The en-face OCTA scans do not show any part of vasculature. Even the adjacent high flow polyp is not showing flow signal on en-face OCTA. Can the authors provide any other representative ICGA and OCTA images of low flow polyp?

Reviewer #2: I would accept the revised version. The revised version had adequately answered my previous comments.

**********

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Reviewer #1: Yes: Atul Kumar

Reviewer #2: No

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While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

PLoS One. 2020 Oct 23;15(10):e0241230. doi: 10.1371/journal.pone.0241230.r004

Author response to Decision Letter 1

1 Sep 2020

We thank the reviewer’s comments and suggestion. We had revised and provide the en-face image in figure 1 (F,G,H). The revised segmentation line with widened slab allow us to visualize the high flow and low flow polyps on en-face OCTA even they are at different height beneath the RPE with prominent subretinal fluid above. The 3 consecutive horizontal scan of the low flow polyp showed no flow signal comparing to the adjacent high flow polyp.

The figure legend of figure 1 were also revised accordingly.

Attachment

Submitted filename: Response to Reviewers (second revision).docx

Click here for additional data file. (17.8KB, docx)

Decision Letter 2

Alfred S Lewin

12 Oct 2020

Flow Signal Change in Polyps After Anti-Vascular Endothelial Growth Factor Therapy

PONE-D-20-09993R2

Dear Dr. Chen,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Alfred S Lewin, Ph.D.

Section Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Acceptance letter

Alfred S Lewin

14 Oct 2020

PONE-D-20-09993R2

Flow signal change in polyps after anti-vascular endothelial growth factor therapy

Dear Dr. Chen:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

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on behalf of

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