Blue Widefield Images of Scanning Laser Ophthalmoscope Can Detect Retinal Ischemic Areas in Eyes With Diabetic Retinopathy

Abstract

Diabetic retinopathy (DR) is one of the leading causes of blindness worldwide. The retinal ischemic changes in DR need to be detected and treated appropriately to prevent further progression. At present, fluorescein angiography (FA) is the most commonly used method to detect the ischemic areas.　

We present our results that showed a practical method of detecting retinal ischemic area covering mid-peripheral retina by multicolor widefield scanning laser ophthalmoscopy (SLO) without fluorescein. Ninety patients with and 50 patients without diabetes mellitus were studied retrospectively. All had undergone multicolor widefield SLO imaging.

Hyporeflective areas in blue image of SLO were found in the incidence of 76.6% in eyes with proliferative DR eyes.　In a comparison of the hyporeflective areas of the blue SLO images to the non-perfused areas in the FA images, the appearance and the correspondence in the locations of these findings in the two types of images were found, and the incidence were highly concordant with Cohen kappa value of 0.785.

The high concordance between the hyporeflective areas in the wide-field blue SLO images and the NPAs in the FA images indicates that this method can be clinically useful to identify ischemic retinal areas in DR.

Introduction

Diabetic retinopathy (DR) is a leading cause of blindness worldwide ^1–3, and a further increase in the number of diabetic patients is anticipated in the future. The increase in the incidence of DR is not only in developed but also in undeveloped countries, and it is a consequence of urbanization, population aging, and changing lifestyle ^4–7. Accordingly, DR and its vision-threatening complications such as macular edema, proliferative DR (PDR) and neovascular glaucoma are emerging problems in ophthalmology throughout the world ^8,9.

The lesions in eyes with DR are most likely caused by chronic retinal ischemia in the non-perfused retinal areas (NPAs). The ischemia also causes the release of vascular endothelial growth factor (VEGF) from the cells surrounding the NPAs, and the additional VEGF induces a progression of the DR to PDR ^10,11. Once NPAs are identified, they are treated by photocoagulation to prevent the development of neovascularization and the progression of nonproliferative DR (NPDR) to PDR.

Fluorescein angiography (FA) has been the gold standard technique to detect the NPAs, but the recent introduction of widefield FA has been shown to be more helpful for detecting the NPAs that are widely distributed throughout the retina ^12,13. However, FA is an invasive technique because it requires an intravenous injection of fluorescein, and it cannot be performed on all patients.

OCT angiography (OCTA) is a relatively new technique that can detect retinal blood vessels including capillaries without requiring intravenous dye injections ^14–16. The advent of widefield OCTA has allowed clinicians to examine wider areas of the fundus ¹⁷. However, obtaining clear OCTA images of the periphery by conventional OCT devices is difficult especially in eyes with media opacities.

The advantages of widefield image compared to conventional devices are not only its ease in obtaining wide areas of the fundus but it also allows the acquisition of seamless images avoiding the absence of some areas of the far periphery. This is especially critical in finding all of the retinal ischemic areas in eyes with DR or RVO. At present, widefield imaging and multicolor SLO imaging can be performed by the Optos® and Mirante® (NIDEK, Aichi, Japan) devices. The Mirante® device is a multimodal imaging ophthalmic instrument whose image covers a field of view of 163 degrees. The color images are obtained by red, green, and blue confocal lasers. Although the field of view of this instrument is narrower than Optos® which has a 200 degree field of view, the Mirante® has an additional blue laser with the green and red lasers. Thus, the characteristics of the images obtained by SLO are different. When a widefield color image is recorded, the original single blue, green, and red SLO images are obtained simultaneously. In the multicolor SLO, the appearance of the lesion is different for each color image because the penetration of the different colors of laser is different ^18,19.

Shin et al. reported that the hyporeflective areas in the red-free blue SLO images corresponded with the NPAs in eyes with DR and retinal vein occlusion (RVO) ²⁰. However, they used an SLO with the conventional field of view, and the smaller visual field of view was a limitation because NPAs in DR or RVO are frequently seen in the mid-periphery of the fundus. Recent availability of widefield image in blue SLO by has allowed us to examine a wider area of the retina.

Thus, the purpose of this study was to investigate the concordance of widefield blue SLO and FA findings throughout fundus and to evaluate the usefulness of new method in detecting vast NPAs of DR in this non-invasive and relatively easy method.

Methods

Results

Discussion

The blue widefield images showed hyporeflective areas in a high percentage of patients with PDR. Among the 92 eyes with NPAs in the FA images due to PDR or moderate/severe NPDR, 52 eyes with PDR and 21 eyes with moderate/severe NPDR had hyporeflective areas in the blue SLO images (79.3%). A high concordance of the incidence of hyporeflective areas in the blue SLO and the NPAs in the FA images was confirmed with a kappa = 0.785. In addition, a direct comparison between the FA and blue SLO images showed that the location of the hyporeflective areas seen in the blue SLO images were also found within the location of the NPAs identified in the FA images in patients with PDR and moderate to severe NPDR.

The concordance between hyporeflective areas found in blue SLO image and NPAs in FA was comparable to the findings of Shin et al ²⁰. However, our findings were made in almost entire continuous fundus images while the previous study examined a relatively segmented narrower field. Our findings should be especially helpful in the management of DR because the ischemia of retina in DR is not limited to only the posterior pole but throughout fundus including the periphery. Additionally, we examined the retinal structure in the ultra-widefield OCT images corresponding to the hyporeflective areas in blue SLO, and we found morphological change including a thinning and disorganization of the retina indicating secondary ischemic degeneration of the retina.

The widefield images obtained by multicolor SLO (Mirante®) cover up to the equator (163 degree field of view), which give us comprehensive information of retinal ischemia of DR in a single image. Compared to the widefield OCTA images, the blue SLO images can be easily obtained with a single shot as in the conventional fundus photographs. Blue, green, and red images are instantly recorded separately. Thus, once multicolor images are obtained, the detection of hyporeflective areas in the blue images is possible. This correspondence was also found in eyes with BRVO although the number of eyes was small. These findings suggest that the hyporeflective areas in the blue widefield SLO images are good indicators of the presence of NPAs regardless of the disease.

Despite the high concordance between the number and locations of the hyporeflective areas and the NPAs, approximately 20% of DR eyes with NPAs did not have hyporeflective areas in the blue SLO images. One of the reasons for this was that the SLO images were not taken on or around the same day as the FA examinations in some eyes. In most cases, the SLO images were taken after the targeted photocoagulation of the NPAs or after PRP, while the FA images were taken before the photocoagulation. The chorioretinal scars of photocoagulation are occasionally seen as hyperreflective areas in the blue SLO images, and this brightness often makes it difficult to detect the hyporeflective areas in the blue SLO images especially in the areas with a large number of photocoagulation scars. In some cases, media opacities such as mild vitreous hemorrhages of onset after the FA examination also reduced the resolution of the SLO images.

Recent advances in OCT technology has allowed recordings that can reveal a disorganization of the inner retinal layer in the areas where the NPAs are located in eyes with DR ^21,22. In addition, a thinning of the inner retina in the areas of the NPAs has been reported ²². Despite the limited number of cases examined, ultra-widefield OCT was able to show the thinning and disorganization of the inner retina in the areas where the NPAs were located. Thus, it is highly likely that the hyporeflective areas in the blue SLO images represent morphological changes of the retina caused by non-perfusion in the retinal capillaries.

This study has several limitations. The study was conducted at a single tertiary eye center thus the results may not be applied to the general DR population. A second limitation is that the SLO and FA images were not always taken on the same day. Thus, an interval between the two examinations may have affected the findings.

In conclusion, these results indicate that widefield blue SLO can be used as a non-invasive and easy method to detect NPAs, and thus determine the severity of the DR. As automated screening for DR has been and will be more widely used ^23,24, this technique of detecting NPAs by just one fundus photograph is considered an important and easy technique for the clinical management and screening for DR. We also conclude that these findings will not only allow clinicians to detect NPAs accurately and easily, but will also allow a monitoring of the effectiveness of therapy in slowing or halting the progress of DR.

Declarations

Acknowledgements

We thanks to Professor Emeritus Duco Hamasaki of the Bascom Palmer Eye Institute for discussions and corrections of this manuscript.

Author Contributions

Figure and manuscript preparation: SH, KOM, Concept/Rationale: SH, KOM, Study design: SH, KOM, Data collection: SH, NK, Data analysis: SH, NK, Interpretation: SH, NK, KOM, Critical review on manuscript: All authors

Competing interest

S.H. and T.Y. belong to department of Advanced Ophthalmic Imaging in Tokyo Medical and Dental University, which is funded by NIDEK Corporation. There is no other conflict of interest. The other authors: NK., KK, TIY. KOM. have no competing interest related to this submission.

Data availability

The data in this study are subject to restrictions and are not being made publicly available. Data are available only on reasonable request and with permission of ethics committee of our institution.

References

1. Yau, J. W. Y. et al. Global prevalence and major risk factors of diabetic retinopathy. Diabetes Care 35, 556–564 (2012).
2. Flaxman, S. R. et al. Global causes of blindness and distance vision impairment 1990-2020: a systematic review and meta-analysis. Lancet Glob Health 5, e1221–e1234 (2017).
3. Zhang, X. et al. Prevalence of diabetic retinopathy in the United States, 2005-2008. JAMA 304, 649–656 (2010).
4. Sabanayagam, C., Yip, W., Ting, D. S. W., Tan, G. & Wong, T. Y. Ten Emerging Trends in the Epidemiology of Diabetic Retinopathy. Ophthalmic Epidemiol 23, 209–222 (2016).
5. Wang, L. Z. et al. Availability and variability in guidelines on diabetic retinopathy screening in Asian countries. Br J Ophthalmol 101, 1352–1360 (2017).
6. Ruta, L. M. et al. Prevalence of diabetic retinopathy in Type 2 diabetes in developing and developed countries. Diabet Med 30, 387–398 (2013).
7. Guariguata, L. et al. Global estimates of diabetes prevalence for 2013 and projections for 2035. Diabetes Res Clin Pract 103, 137–149 (2014).
8. Kume, A. & Kashiwagi, K. Recent epidemiological status of ocular and other major complications related to diabetes mellitus in Japan. Ophthalmologica (2020) Epub ahead of print.
9. Miyazaki, M. et al. Comparison of diagnostic methods for diabetes mellitus based on prevalence of retinopathy in a Japanese population: the Hisayama Study. Diabetologia 47, 1411–1415 (2004).
10. Adamiec-Mroczek, J. & Oficjalska-Młyńczak, J. Assessment of selected adhesion molecule and proinflammatory cytokine levels in the vitreous body of patients with type 2 diabetes--role of the inflammatory-immune process in the pathogenesis of proliferative diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 246, 1665–1670 (2008).
11. Nawaz, I. M. et al. Human vitreous in proliferative diabetic retinopathy: Characterization and translational implications. Prog Retin Eye Res 72, 100756 (2019).
12. Mustafi, D., Saraf, S. S., Shang, Q. & Olmos de Koo, L. C. New developments in angiography for the diagnosis and management of diabetic retinopathy. Diabetes Res Clin Pract 167, 108361 (2020).
13. Nicholson, L. et al. Retinal Nonperfusion Characteristics on Ultra-Widefield Angiography in Eyes With Severe Nonproliferative Diabetic Retinopathy and Proliferative Diabetic Retinopathy. JAMA Ophthalmol 137, 626–631 (2019).
14. Tey, K. Y. et al. Optical coherence tomography angiography in diabetic retinopathy: a review of current applications. Eye Vis (Lond) 6, 37 (2019).
15. Ashraf, M. et al. Vascular Density of Deep, Intermediate and Superficial Vascular Plexuses Are Differentially Affected by Diabetic Retinopathy Severity. Invest. Ophthalmol. Vis. Sci. 61, 53 (2020).
16. Samara, W. A. et al. Quantification of Diabetic Macular Ischemia Using Optical Coherence Tomography Angiography and Its Relationship with Visual Acuity. Ophthalmology 124, 235–244 (2017).
17. Sawada, O. et al. Comparison between wide-angle OCT angiography and ultra-wide field fluorescein angiography for detecting non-perfusion areas and retinal neovascularization in eyes with diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol 256, 1275–1280 (2018).
18. Terasaki, H. et al. Ability of MultiColor scanning laser ophthalmoscope to detect non-glaucomatous retinal nerve fiber layer defects in eyes with retinal diseases. BMC Ophthalmol 18, 324 (2018).
19. Terasaki, H. et al. More effective screening for epiretinal membranes with multicolor scanning laser ophthalmoscope than with color fundus photographs. Retina (Philadelphia, Pa.) 40, 1412–1418 (2020).
20. Shin, Y. U., Lee, B. R., Kim, S. & Lee, W. J. A novel noninvasive detection method for retinal nonperfusion using confocal red-free imaging. Ophthalmology 119, 1447–1454 (2012).
21. Nicholson, L. et al. Diagnostic accuracy of disorganization of the retinal inner layers in detecting macular capillary non-perfusion in diabetic retinopathy. Clin Exp Ophthalmol 43, 735–741 (2015).
22. Moein, H.-R. et al. Optical coherence tomography angiography to detect macular capillary ischemia in patients with inner retinal changes after resolved diabetic macular edema. Retina (Philadelphia, Pa.) 38, 2277–2284 (2018).
23. Rajalakshmi, R., Subashini, R., Anjana, R. M. & Mohan, V. Automated diabetic retinopathy detection in smartphone-based fundus photography using artificial intelligence. Eye (Lond) 32, 1138–1144 (2018).
24. Rajalakshmi, R. et al. Validation of Smartphone Based Retinal Photography for DiabeticRetinopathy Screening. PLoS One 10, e0138285 (2015).
25. Wilkinson, C. P. et al. Proposed international clinical diabetic retinopathy and diabetic macular edema disease severity scales. Ophthalmology, 110, 1677–1682 (2003).

Tables