Purpose
To characterize microaneurysms in diabetic retinopathy (DR) depicted by spectral-domain optical coherence tomography (SD-OCT).
Design
Retrospective, observational case series.
Methods
We surveyed a consecutive series of 76 eyes from 60 patients with DR (22 mild nonproliferative diabetic retinopathy [NPDR]; 43 moderate NPDR; 9 severe NPDR; 2 proliferative diabetic retinopathy [PDR]) who underwent Spectralis OCT, fluorescein angiography (FA), and color fundus photography on the same day. The microaneurysms on OCT were oval and well demarcated at the points where those on color fundus photographs and FA were delineated. The characteristics of microaneurysms were evaluated.
Results
Based on the status of the capsular structure shown in the sectional images of OCT (called ring sign), we classified 147 microaneurysms depicted by all of SD-OCT, FA, and color fundus photographs in 76 eyes: 28 with complete ring sign, 54 with incomplete one, and 65 with no structure. Microaneurysms with no ring sign had hyperreflective spots in the lumen and were accompanied by nearby cystoid spaces more frequently than other types ( P = .033 and P = .007). Thirteen of 75 microaneurysms with nearby cystoid spaces protruded into the cystoid spaces, and 11 of those 13 microaneurysms presented with no ring sign. Microaneurysms resided mainly in the inner nuclear layer (INL) (80.3%), and 65 of such microaneurysms (55.1%) were accompanied by nearby cystoid spaces.
Conclusions
SD-OCT delineated the capsular structure, hyperreflective spots, and location of microaneurysms, and microaneurysms with the ring sign were positively correlated with nearby cystoid spaces and protrusion into the cystoid spaces.
Diabetic retinopathy (DR) is a very serious and frequently occurring complication that causes severe visual loss in people of working age. Adequate prevention and therapy have not been established. Microaneurysms are hallmarks of the clinical diagnosis of DR, and the total number of microaneurysms indicates the likely progression to more severe retinopathy in the future, which has led to the development of automated algorithms for their detection and calculation.
Histopathologic studies, based on light microscopy or electron microscopy of sectional images and 2-dimensional images of trypsin digestion preparation, have documented various changes in microaneurysms compared to the physiologic retinal vasculature: thick or thin basement membranes, loss of pericytes, and endothelial hypercellularity or acellularity. Pathophysiologic changes, such as rheologic and fibrinolytic properties of the blood in patients with diabetes, also might affect microaneurysm formation and disappearance. However, it is unclear how hyperglycemia induces these changes and the concomitant microaneurysm formation. Although microaneurysms are clinically known to be dynamic in nature, it is unknown if the diversity in their appearance depends on their stages or origins.
Microaneurysms often present as hyperfluorescent dots on fluorescein angiography (FA) images, and some microaneurysms have been accompanied by focal leakage of fluorescence dye. Vascular hyperpermeability in DR may induce diabetic macular edema (DME) and reduced visual function, although the pathogenesis of the breakdown of inner blood-retinal barrier (BRB) and concomitant retinal edema remain to be elucidated. Clinically, focal photocoagulation of microaneurysms and grid photocoagulation applied to the diffuse leakage reduce the risk of poor visual prognosis, suggesting that vascular leakage from microaneurysms contributes to the development or exacerbation of DME. However, not all microaneurysms are hyperpermeable, and we sometimes observe that microaneurysms with focal leakage are not accompanied by retinal edema. In addition, histopathologic studies have not documented the detailed correlation between the characteristics of microaneurysms and retinal edema.
Optical coherence tomography (OCT) is a noninvasive technique for obtaining cross-sectional retinal images for the diagnosis and management of retinal diseases. Several years after the introduction of time-domain OCT, spectral-domain OCT (SD-OCT), which provides images with an axial resolution of less than 5 μm, became available, albeit not widely. SD-OCT, with a substantially faster rate of image acquisition and multiple B-scan averaging, may be useful for obtaining improved images of the retinal pathologic features, which might correspond to histologic sections observed with light microscopy. SD-OCT identifies the individual retinal layers and provides much-needed clinicopathologic information.
In the current study, we characterized for the first time the in vivo images of microaneurysms using SD-OCT, investigated the relationship with nearby retinal cystoid spaces, and found a novel association between the vascular walls of the microaneurysms and the cystoid spaces.
Methods
Patients
Seventy-six consecutive eyes of 60 patients (mean age ± SD, 67.7 ± 7.9 years; range, 50–83) who visited the Department of Ophthalmology of Kyoto University Hospital from September 2008 to March 2009 were evaluated retrospectively. Eyes with microaneurysms for which good-quality fundus photographs and FA and OCT images were available were included. Twenty-two eyes presented with mild nonproliferative diabetic retinopathy (NPDR), 43 with moderate NPDR, 9 with severe NPDR, and 2 with PDR.
Image Acquisition
After a routine examination including fundus biomicroscopy and best-corrected visual acuity (BCVA) measurement, 45-degree (3216 × 2136 pixels) color fundus photographs were obtained using a fundus camera (TRC-50LX; Topcon, Tokyo, Japan), and the retinal sections were depicted using SD-OCT (Spectralis OCT; Heidelberg Engineering, Heidelberg, Germany) with infrared fundus photograph. The foveal centered images of retinal sections were acquired with the 30-degree crosshair mode or raster scan mode (20 degrees horizontal scan × 19 lines in vertical 20 degrees), and more than 20 scans were averaged using the manufacturer’s software (Spectralis Acquisition and Viewing modules, version 4.0; Heidelberg Engineering). Thirty-degree FA images (1536 × 1536 pixels) were obtained using Heidelberg Retinal Angiography 2 ([HRA2] Heidelberg Engineering).
The microaneurysms were seen as white, red, or multicolored dots in the color fundus photographs, and 1 spot sometimes contained multiple colors, although the microaneurysms that had red spots can be confused with dot-like intraretinal hemorrhages. The microaneurysms were detected as hyperfluorescent dots in the early or late phase compared with the fluorescence that is blocked by retinal hemorrhages. However, it can be confusing in that some microaneurysms detected in the color fundus photographs do not have hyperfluorescent dots and that, conversely, some hyperfluorescent dots are not visible in color photographs, and it is difficult to differentiate these microaneurysms from dot-like hemorrhages. We therefore investigated microaneurysms detected in both color fundus photographs and FA in this study, and found that all of them were well-demarcated, round or oval lesions on the OCT images, whereas all the blot-like intraretinal hemorrhages had blurred margins, as reported in histopathologic studies. We also often observed cystoid spaces near the microaneurysms on the OCT images; cystoid spaces within 100 μm of the edge of the microaneurysms were defined as being nearby ones. We further analyzed focal retinal edema: the localized retinal thickening with the area less than 2 disc area that contained microaneurysm(s), confirmed by both biomicroscopy and OCT sectional images. We sometimes observed microaneurysms in diffuse edema; they were excluded from this current study, because it was difficult to determine whether or not the microaneurysms contributed to these edematous changes.
Statistical Analysis
The results are expressed as the mean ± SD. Significant differences in sampling distribution were determined using the χ 2 test. A P value of .05 was considered statistically significant.
Results
Microaneurysm Characterization
We first evaluated microaneurysms, which were seen as hyperfluorescent dots on FA and which were inadvertently imaged on OCT, and found that all the intraretinal lesions were well demarcated and round or oval ( Figures 1 and 2 ) , which agrees with clinicopathologic reports that documented that microaneurysms appear saccular or fusiform with a circumscribed basement membrane. The average values of horizontal and vertical diameter of microaneurysms on Spectralis OCT were 118.3 ± 43.3 μm and 111.6 ± 38.4 μm (range, 49.0–233.7 μm and 54.0–216.1 μm, respectively) in this current study, which is, to some extent, compatible with the previous publications reporting their diameter (range, 14–200 μm).
Although ophthalmologists are often confused by the similarity between microaneurysms with red spots and dot-like intraretinal hemorrhages on color fundus photographs, histologic reports have documented the differences between well-demarcated, round or oval microaneurysms and amorphous intraretinal hemorrhage with blurred margins. Spectralis OCT also delineated such features as shown histopathologically, which seems useful for differentiating these lesions, in addition to FA ( Figures 1 and 2 ).
Capsular Structure of Microaneurysms
Although the physiologic vascular walls are composed of a basement membrane, a monolayer of endothelial cells, and pericytes, histopathology has shown the heterogeneity in these components, ie, thin or thick basement membranes and multilayers or no endothelial cells. These reports prompted us to evaluate the status of the vascular wall of microaneurysms on Spectralis OCT sectional images. The capsular structure with a high signal intensity completely circumscribed the round or oval spaces in 28 microaneurysms (referred to as the complete ring sign on the sectional images of Spectralis OCT) ( Figure 3 ). Compared to these microaneurysms, the ring sign was absent in 65 microaneurysms, and 54 microaneurysms were demarcated partially with the capsule (referred to as the incomplete ring sign) ( Figure 3 ). Intriguingly, Spectralis OCT sometimes delineated the hyperreflective spots in the lumen of microaneurysms, which might be compatible with the previous reports demonstrating that their lumen was often filled with erythrocytes or leukocytes ( Figure 3 ). Furthermore, 41 of 65 microaneurysms (63.1%) with no ring sign had hyperreflective spots, whereas these spots were delineated only in 12 of 28 microaneurysms (42.9%) with complete ring sign and 22 of 54 microaneurysms (40.7%) with incomplete ring sign, which showed the significant differences in the frequency ( P = .033; Table 1 ).
| Ring Sign | Complete (n = 28) | Incomplete (n = 54) | Absent (n = 65) | P Value |
|---|---|---|---|---|
| Hyperreflective spot | .033 | |||
| Absent | 16 | 32 | 24 | |
| Present | 12 | 22 | 41 | |
| Focal retinal edema | .661 | |||
| Absent | 17 | 28 | 33 | |
| Present | 11 | 26 | 32 | |
| Nearby cystoid spaces | .007 | |||
| Absent | 21 | 25 | 26 | |
| Present | 7 | 29 | 39 |
| Ring Sign | Complete (n = 7) | Incomplete (n = 29) | Absent (n = 39) | P Value |
|---|---|---|---|---|
| Signal intensity in the cystoid space | .32 | |||
| Homogeneous | 7 | 15 | 28 | |
| Heterogeneous | 0 | 14 | 11 |
Relationship Between Microaneurysms and Retinal Edema
We then investigated the relationship between the status of the capsular structure of the microaneurysms and focal retinal edema, but could not find the significant association between them ( Table 1 ). We further evaluated the association between their ring sign and the nearby cystoid spaces. Thirty-nine of 65 microaneurysms (60.0%) with no ring sign were accompanied by 1 or more cystoid spaces, whereas nearby cystoid spaces were observed in only 7 of 28 microaneurysms (25.0%) with a complete ring sign ( Table 1 ), which showed the significant differences in the frequency. Interestingly, the signal intensity of these cystoid spaces was often heterogeneous ( Figure 4 ), and microaneurysms with either an incomplete or no ring sign were accompanied by the cystoid spaces more frequently than those with a complete ring sign, although the difference was not significant ( Table 1 ).
Microaneurysms Adjacent to or Protruding Into Cystoid Spaces
When we investigated the relationship between microaneurysms and cystoid spaces, we found that 13 of 75 microaneurysms (17.3%) accompanied by cystoid spaces protruded into the cystoid spaces, whereas another 62 microaneurysms (82.7%) were simply adjacent to them ( Figure 4 ). Most microaneurysms that protruded into the cystoid spaces had no ring sign, and those that were adjacent to the cystoid spaces had a heterogeneity in their ring sign, suggesting an interaction between the capsular structure of microaneurysms and the cystoid spaces. However, we could not find a significant difference in the heterogeneity of the signal intensity in the nearby cystoid spaces between the 2 types ( Table 2 ).
| Protrusion Type (n = 13) | Adjacent Type (n = 62) | P Value | |
|---|---|---|---|
| Ring sign | .032 | ||
| Complete | 0 | 7 | |
| Incomplete | 2 | 27 | |
| Absent | 11 | 28 | |
| Signal intensity in the cystoid spaces | .750 | ||
| Homogeneous | 8 | 42 | |
| Heterogeneous | 5 | 20 |
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