Abstract
Objectives
To detect retinal neovascularization elsewhere (NVE), of the optic disc (NVD) and intraretinal microvascular abnormalities (IRMA) in treatment naive diabetic retinopathy (DR) and compare these findings by using 90° Wide-Field Colour Fundus Photography (WF CFP), Wide-Field Spectral-Domain Optical Coherence Tomography Angiography (OCTA) and the combination of WF CFP and OCTA through overlay software.
Methods
Patients with treatment naive severe non-proliferative DR or proliferative DR were prospectively enrolled. All patients underwent WF-CFP and OCTA in the same day. Two readers independently analysed WF-CFP, SD-OCTA and the overlay of the two techniques. The degree of agreement between the two raters and between different techniques (WF CFP, OCTA, WF CFP combined to OCTA) were measured with Cohen’s Kappa coefficient.
Results
Thirty-one eyes from 21 patients (10 males, mean age 63 ± 15 years) were included. Inter-rater agreement by using WF-CFP in detection of NVE, NVD and IRMA was respectively 0.62, 0.22 and 0.55. OCTA scored values of inter-rater agreement of 0.86, 0.87 and 0.92 in detection of NVE, NVD and IRMA, respectively. By combining WF-CFP and SD-OCTA, inter-rater agreement in detection of NVE, NVD and IRMA was 0.93, 0.94 and 0.89, respectively.
Conclusion
Inter-rater agreement in detection of NVE, NVD and IRMA was substantial, fair and moderate, respectively. OCTA provided almost perfect values of inter-rater agreement in NVE, NVD and IRMA detection. Combining WF-CFP and OCTA further empowered concordance values in detection of NVE and NVD. Combining OCTA and WF-CFP is the best performance to detect NVE and NVD.
Subject terms: Retinal diseases, Prognostic markers
Introduction
Early detection and treatment of different grades of diabetic retinopathy (DR) are widely recognized as fundamental goals to reduce visual impairment in patients with diabetes [1, 2]. Consequently, a standardized and systematic classification for severity grading of DR is essential for therapeutic decisional process. According to the Early Treatment Diabetic Retinopathy Study (ETDRS) findings and the International Clinical Disease Severity Scale for DR, severity grading is univocally established based on colour fundus photography (CFP) and direct fundus examination [3]. Although this international DR scale is widely recognized and simple to use in common clinical practice, there is an increasing need to implement fundus findings with multimodal imaging examinations for therapeutic decision-making and DR severity grading [4–6].
Among the landscape of lesions and findings of diabetic retinopathy, intraretinal microvascular abnormalities (IRMA) showed a fair inter-rater agreement at colour fundus photography [7]. The complete agreement in IRMA detection between two independent ophthalmologists has been assessed at 51.5% (weighted kappa statistics = 0.49) [7]. Concurrently, the agreement in the detection at CFP of retinal neovascularization elsewhere (NVE) was considered as substantial, while the agreement in the detection of retinal neovascularization of the optic disc (NVD) yielded less satisfactory results and has been ranked as moderate (weighted kappa statistics = 0.48) [7].
As the severity of IRMA and retinal neovascularization is considered by ETDRS as an important factor for photocoagulation treatment strategy choice, it is fundamental to supplement these findings with multimodal imaging techniques [8]. Particularly, spectral domain optical coherence tomography angiography (SD-OCTA) showed a higher detection rate of IRMA, compared to colour fundus photography grading. In addition, structural spectral-domain optical coherence tomography (SD-OCT) allowed to a better characterization and differentiation of IRMA and NVE [9].
An overlay between CFP and angiographic data (SD-OCTA) allows a more comprehensive analysis of the landscape of pathological findings in DR. Matching anatomical (CFP) and functional (SD-OCTA) data could improve both the detection rate and the inter-rater agreement of IRMA and retinal neovascularization indeed.
Purpose of the study is to detect intraretinal microvascular abnormalities, retinal neovascularization elsewhere and retinal neovascularization of the optic disc in treatment naive diabetic retinopathy and to compare these findings by using 90° Wide-Field Colour Fundus Photography (WF-CFP), Wide-Field Spectral-Domain Optical Coherence Tomography Angiography (UWF SD-OCTA) and the combination of WF-CFP and UWF SD-OCTA through overlay software.
Methods
This was a prospective observational monocentric study of patients affected by treatment naive diabetic retinopathy enrolled at the Retina Medica and Imaging Unit of Department of Ophthalmology of San Raffaele Scientific Institute, Milan (Italy) from September 2021 to February 2022. This study was conducted under the tenets of the Declaration of Helsinki (1964). Written patients’ informed consent was obtained.
We included eyes with severe non-proliferative diabetic retinopathy (SNPDR) or proliferative diabetic retinopathy (PDR), according to the International Clinical Diabetic Retinopathy and Diabetic Macular Edema Disease Severity Scales.3 Both patients with type 1 and type 2 diabetes mellitus were enrolled in the study. Exclusion criteria were prior laser or intravitreal treatments in the included eye, any retinal disease than diabetic retinopathy, DR related complications impeding retinal imaging (vitreous haemorrhage, retinal detachment, corneal oedema) and optic media opacities limiting image quality.
We collected age, gender, medical and ocular history. Each included eye underwent WF-CFP centred on the fovea and SD-OCTA, with a scan field of 12 × 12 mm2 centred on the fovea.
WF-CFP was performed with Clarus® (ZEISS, Oberkochen, Germany). At fundus colour photography, we defined NVE as neovascularization that are on the surface of the retina or further forward in the vitreous cavity, except for those on the disc or within 1 optic disc diameter of its margin [7] (Fig. 1A) Conversely, a neovascularization that fulfil the abovementioned criteria, located on the optic disc or within 1 optic disc diameter, was indicated as NVD. (Fig. 2A) IRMA were defined as tortuous intraretinal vascular segments of variable diameter (within ¼ the width of a major vein at the disc margin) [7] (Fig. 3A).
Fig. 1. Detection of neovascularization elsewhere (NVE) (yellow circled areas) with three different techniques.
A 12 × 12 mm area of 90° Wide-Field Colour Fundus Photography. B Vitreoretinal interface slab at Enface Wide-Field Spectral-Domain Optical Coherence Tomography Angiography (12 × 12 mm scans) C Overlay between Colour Fundus Photography and vitreoretinal interface slab at Enface Wide-Field Spectral-Domain Optical Coherence Tomography Angiography (12 × 12 mm scans).
Fig. 2. Detection of neovascularization of the optic disc (NVD) (yellow circled areas) with three different techniques.
A 12 × 12 mm area of 90° Wide-Field Colour Fundus Photography. B Vitreoretinal interface slab at Enface Wide-Field Spectral-Domain Optical Coherence Tomography Angiography (12 × 12mm scans). C Overlay between Colour Fundus Photography and vitreoretinal interface slab at Enface Wide-Field Spectral-Domain Optical Coherence Tomography Angiography (12 × 12 mm scans).
Fig. 3. Detection of intraretinal microvascular abnormalities (IRMA) (yellow circled areas) with three different techniques.
A 12 × 12mm area of 90°Wide-Field Colour Fundus Photography. B Superficial Capillary Plexus (SCP) slab at Enface Wide-Field Spectral-Domain Optical Coherence Tomography Angiography (12 × 12 mm scans). C Overlay between Colour Fundus Photography and SCP slab at Enface Wide-Field Spectral-Domain Optical Coherence Tomography Angiography (12 × 12 mm scans).
SD-OCTA was performed with Cirrus 6000® (ZEISS, Oberkochen, Germany) and examined with Angioplex ® OCTA software (ver. 11.5.2, ZEISS, Oberkochen, Germany). SD-OCTA slabs were automatically segmented by SD-OCTA software and independently manually adjusted by two ophthalmologists (MM and RS). Vitreoretinal interface (VRI) slab, defined as the region 10–300 µm above the internal limiting membrane (ILM), was selected to detect NVE and NVD (Figs. 1B and 2B). Each suspected neovascularization was confirmed at B-scan as extraretinal proliferation. Superficial capillary plexus (SCP) slab was defined as the region between the inner nuclear layer (INL) and the ILM and selected to detect IRMA, identified as dilated terminal vessels adjacent to areas of capillary loss [10] (Fig. 3B).
Both VRI and SCP slabs were combined to WF-CFP through the overlay software (ZEISS Forum Viewer®, Carl Zeiss Meditec, Inc, Dublin, California, Usa) to detect NVE, NVD and IRMA. (Figs. 1C, 2C and 3C). The software created an overlay of the WF-CFP and en-face OCTA of VRI and SCP slabs, and B-scan OCTA was concurrently provided as well.
Two readers expert in medical retina (MM and BT) independently analysed WF-CFP, SD-OCTA and the overlay of the two techniques to detect and record the number and location of NVE, NVD and IRMA. Statistical analyses were performed using SPSS Statistics Software version 27.0 (IBM, Armonk, New York, USA). We summarized continuous variables as their mean ± standard deviation (SD). We summarized categorical variables as their absolute and relative prevalence. The degree of agreement in detecting NVE, NV and IRMA between the two readers and between different imaging techniques (WF CFP, UWF SD-OCTA, WF CFP combined to UWF SD-OCTA) were measured with Cohen’s Kappa (k) coefficient. Cohen’s Kappa (k) values were interpreted as slight when between 0.00 and 0.20, as fair when 0.21–0.40, as moderate when 0.41–0.60, as substantial when 0.61–0.80. Statistical significance values have been provided for each measurement. Cohen’s Kappa (k) values indicated almost perfect agreement when 0.81–1.00, while values <0.00 disclosed no agreement [11].
Results
Thirty-one eyes from 21 patients were included in the study. Patients’ mean age was 63 ± 15 years. Ten (48%) out of 21 patients were male. Best-corrected visual acuity was 6/12 Snellen Equivalent (IQR 6/6–6/15). Two eyes (6.5%) presented with severe proliferative diabetic retinopathy, 21 eyes (67.7%) were affected by proliferative diabetic retinopathy and 8 eyes (25.8%) by severe non-proliferative diabetic retinopathy. Demographic and clinical features of patients enrolled were reported in Table 1.
Table 1.
Demographic and clinical features of patients enrolled.
| Eyes (n) | 31 |
| Patients (n) | 21 |
| Age (mean ± SD, years-old) | 63 ± 15 years old |
| Sex (n, %) | |
| Male | 10 (48%) |
| Female | 11 (52%) |
| BCVA (IQR, LogMAR) | 0.30 (0.00–0.43) |
| DR severity (n, %) | |
| Severe non proliferative DR | 2 (6.5%) |
| Proliferative DR | 21 (67.7%) |
| Severe proliferative DR | 8 (25.8%) |
n number, SD standard deviation, BCVA best-corrected visual acuity, IQR Inter-quartile range, DR diabetic retinopath, LogMAR Logarithm of the Minimum Angle of Resolution.
Inter-rater agreement by using WF-CFP in detection of NVE, (Fig. 1A) NVD (Fig. 2A) and IRMA (Fig. 3A) was respectively 0.62 (p < 0.001), 0.22 (p = 0.101) and 0.55 (p = 0.002). SD-OCTA disclosed values of inter-rater agreement of 0.86 (p < 0.001), 0.87 (p < 0.001) and 0.92 (p < 0.001) in detection of NVE, (Fig. 1B) NVD (Fig. 2B) and IRMA, (Fig. 3B), respectively. By combining WF-CFP and SD-OCTA through overlay software, inter-rater agreement in detection of NVE, (Fig. 1C) NVD (Fig. 2C) and IRMA (Fig. 3C) was 0.93 (p < 0.001), 0.94 (p < 0.001) and 0.89 (p < 0.01), respectively.
WF-CFP and SD-OCTA showed concordance values of 0.15 (p = 0.376), 0.26 (p = 0.127) and 0.17 (p = 0.269) in detection of NVE, NVD and IRMA, respectively. In detection of NVE, NVD and IRMA, combination of WF-CFP and SD-OCTA through overlay software compared to CFP scored concordance values of 0.35 (p = 0.015), 0.13 (0.131) and 0.17 (p = 0.085), respectively. Combination of WF-CFP and SD-OCTA through overlay software compared to SD-OCTA showed concordance values of 0.59 (p = 0.002), 0.74 (p < 0.01) and 0.57 (p = 0.001), in detection of NVE, NVD and IRMA, respectively. Inter-rater agreement between readers and concordance between techniques were summarized in Table 2A and 2B, respectively.
Table 2.
A Inter-rater agreement between two readers by using WP-CFP, SD-OCTA, and WF-CFP and SD-OCTA through overlay software in detection of IRMA, NVE and ND. B Inter-rater agreement between two readers by using WP-CFP, SD-OCTA, and WF-CFP and SD-OCTA through overlay software in detection of IRMA, NVE and ND.
| IRMA | NVE | NVD | |
|---|---|---|---|
| (A) | |||
| Inter-rater agreement | |||
| WF-CFP | 0.55 | 0.62 | 0.22 |
| SD-OCTA | 0.92 | 0.86 | 0.87 |
| WF-CFP + SD-OCTA (overlay software) | 0.89 | 0.93 | 0.94 |
| (B) | |||
| Concordance | |||
| WF-CFP vs SD-OCTA | 0.17 | 0.15 | 0.26 |
| WF-CFP + SD-OCTA (overlay software) vs WF-CFP | 0.17 | 0.35 | 0.13 |
| WF-CFP + SD-OCTA (overlay software) vs SD-OCTA | 0.57 | 0.59 | 0.74 |
WF-CFP wide-field colour fundus photography, SD-OCTA spectral-domain optical coherence tomography, IRMA intraretinal microvascular abnormality, NVE neovascularization of elsewhere, NVD neovascularization of optic disc.
Discussion
Grading DR is an essential step for therapeutic decisional process [1]. Determining the presence of neovascularization and IRMA is still a challenge, since inter-rater agreement values in detection of these lesions do not provide adequate results [7]. OCTA could contribute in better characterization and detection of IRMA and neovascularization. We investigated whether combining anatomical data from WF-CFP and functional flow data from OCTA could improve the rate and the inter-rater agreement in detection of IRMA, NVE and NVD.
We found substantial (0.62), fair (0.22) and moderate (0.55) inter-rater agreement at WF-CFP in detection of NVE, NVD and IRMA, respectively. OCTA provided better values of inter-rater agreement. Particularly, Cohen’s kappa significantly improved in NVD detection, displaying almost perfect inter-rater agreement (0.87), as well as in NVE (0.86) and IRMA (0.92) detection. Combining WF-CFP and OCTA through overlay software further empowered concordance values in detection of NVE (0.93) and NVD (0.94), while concordance values in IRMA detection were slightly lower compared to OCTA but almost perfect (0.89).
WF-CFP and OCTA scored slight (0.26) and fair (0.15, 0.17) concordance values in detection of NVD, NVE and IRMA, respectively. Concordance values between WF-CFP and WF-CFP combined to OCTA were poor, as well. However, OCTA and WF-CFP combined to OCTA scored moderate (0.59, 0.57) or substantial (0.74) values in detection of NVE, IRMA and NVD respectively.
Distinguishing neovascularization from other findings related to DR represents a challenge for non-retina specialists [12]. Vascular abnormalities or haemorrhages are often confused with neovascularization, and concurrently neovascularization is thin, slightly coloured and is frequently missed when examined from a non-retina specialist ophthalmologist. Particularly, NVD detection could represent a challenge due to the underlying vascular network in the optic disc and explain the low value of inter-rater agreement at WF-CFP [13]. A-scan and B-scan OCTA helps in detection of NVE and NVD; ophthalmologists are able to localize whether the lesion is inside the vitreoretinal interface or not, distinguishing neovascularization from IRMA, and to characterize the presence of flow inside the abovementioned lesions. In our experience, this tool has improved inter-rater agreement in detection of both NVE and NVD. On the other hand, OCTA alone does not provide anatomical data and wrong segmented layers or artefacts could lead to misinterpreted data. Combining OCTA and WF-CFP with the overlay software allows better characterization of the lesions, since complementary data are merged. Most importantly, flow signal at B-scan OCTA can be analysed in the counterpart WF-CFP: artefacts or wrongly segmented layers can be better highlighted, and fundus findings (haemorrhages, suspected neovascularisations and suspected IRMA) can be deeply investigated and confirmed by functional flow characterization by OCTA. As a matter of fact, WF-CFP combined with OCTA provided better values of inter-rater agreement in NVE and NVD detection. Our results suggest a potential benefit by combining morphological (WF-CFP) and functional (OCTA) data in the detection of NVE and NVD, and thus in grading DR.
IRMA detection at WF-CFP disclosed poor inter-rater agreement (0.22). Since IRMA appear as abnormal branching or dilation of existing blood vessels in low-blood supply retinal area, they can be often confused with neovascularization or misinterpreted. OCTA highlights their tortuosity and their location in non-perfusion areas, and most importantly they can be easily distinguished from neovascularization, since IRMA localize in the superficial capillary plexus [14]. According to our results, the combination of OCTA and WF-CFP did not improve inter-rater agreement.
The main limitations of the study are the relatively small sample size and the scan protocol. Particularly, a disc-centred imaging could have provided more benefits and insights in detecting NVD, which constitute a common complication in DR and are often undiagnosed. Particularly, different scan protocols could affect the detection rate of diabetic retinopathy findings [15], and disc-centred OCTA could better characterize the nasal retina: further studies are required to investigate the potential benefit of combined wide-field imaging with different scan protocols detecting diabetic retinopathy lesions. In addition, inter-rater agreement of the considered imaging techniques could have been explored between ophthalmologists of different level of experience. Indeed, young ophthalmologists could eventually benefit the most from combining OCTA and WF-CFP.
In conclusion, combining OCTA and WF-CFP displayed good concordance values in detection of NVD and NVE, compared to OCTA. In addition, the overlay between the two techniques has shown better concordance values, particularly in NVE and NVD detection, as previously discussed. Thus, this tool could help ophthalmologists improving detection of clinical findings of diabetic retinopathy, particularly NVD and NVE. Further studies are required to confirm whether combining OCTA and WF-CFP could help detecting other findings (i.e. microaneurysms), and whether even retina specialists could improve their skills.
Summary
What was known before
Intraretinal microvascular abnormalities (IRMA) and neovascularization’s (NV) detection rate by using colour fundus photography is still unsatisfactory -IRMA and NV detection rate should be improved|||
Intraretinal microvascular abnormalities (IRMA) and neovascularization’s (NV) detection rate by using colour fundus photography is still unsatisfactory -IRMA and NV detection rate should be improved
What this study adds
OCTA improve NV and IRMA detection rate -Combining OCTA and colour fundus photography though overlay software improve detection rate of NVE and NVD|||
OCTA improve NV and IRMA detection rate
Combining OCTA and colour fundus photography though overlay software improve detection rate of NVE and NVD
Author contributions
All the authors contributed to the conception or design of the work, the acquisition, analysis, and interpretation of data, drafting the work, and revising it critically for important intellectual content. Each coauthor has seen and agrees with how his name is listed.
Data availability
The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at IRCCS Ospedale San Raffaele.
Competing interests
MM, BT, FF have nothing to disclose. RS has the following disclosures: Allergan Inc, Bayer Shering-Pharma, Medivis, Novartis, Zeiss. FB has the following disclosures: Allergan Inc, Bayer Shering-Pharma, Boehringer-Ingelheim, Fidia Sooft, Hofmann La Roche, Novartis, NTC Pharma, Oxurion NV, Sifi. GQ has the following disclosures: Alimera Sciences, Allergan Inc, Amgen, Bayer Shering-Pharma, Heidelberg, KBH, LEH Pharma, Lumithera, Novartis, Sandoz, Sifi, Sooft-Fidea, Zeiss. The authors have no competing interest in publishing the present work.
Footnotes
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
The data that support the findings of this study are not openly available due to reasons of sensitivity and are available from the corresponding author upon reasonable request. Data are located in controlled access data storage at IRCCS Ospedale San Raffaele.