Optical Coherence Tomography

The morphologic features of DME, including the ELM, IS/OS, and hyperreflective foci, were assessed with SD-OCT (Spectralis; Heidelberg Engineering, Heidelberg, Germany). Twenty-degree radial scans centered on the fovea were obtained in a clockwise manner in all eyes, and 49 raster scans were used to evaluate the mean retinal thickness (from the innermost internal limiting membrane [ILM] to the retinal pigment epithelium [RPE]) at the fovea (radius, 500 μm). The central fovea was defined as the location without the inner retinal layers in the macular region. Subsequently, the morphologic features within a scanned 1-mm area centered on the fovea were evaluated for each eye. The status of the ELM and IS/OS was classified according to previously described methods with some modifications. Briefly, eyes with an ELM line that appeared to be complete at the fovea in all scans were classified as ELM (+); eyes with an interrupted ELM line in 1 scan or more were classified as ELM (±); and eyes with an undetectable ELM line in the fovea were classified as ELM (−). Each eye also was classified based on the status of the IS/OS line beneath the fovea using the same criteria described for the ELM line, that is, IS/OS (+), IS/OS (±), and IS/OS (−).

Since a number of studies have reported the photoreceptor status as a novel parameter in macular edema associated with retinal vascular diseases, we evaluated the presence of the hyperreflective foci in the outer retinal layers. It was previously reported that ELM acts as a barrier against macromolecules, which led us to hypothesize that an intact ELM might block diffusion of proteins or lipids from the damaged retinal vasculature, whereas they might otherwise migrate freely within the inner retinal layers. In other words, migration of hyperreflective foci into the outer retinal layers of the ELM might indicate that the barrier properties of the ELM are disrupted or that the inner or outer segments necessary for light perception have been damaged. Thus, we evaluated and defined the hyperreflective foci in the outer retinal layers from the ELM to the RPE within each 1-mm scanned area centered on the fovea ( Figure 1 ) . As discussed previously, the ELM was often interrupted or absent at the fovea. When 2 or more fragments of the ELM line were detected in the scanned area, we drew imaginary lines between the ends of the ELM lines ( Figure 2 ) . When the ELM line reached the outer side without interruption and ended at the RPE-choriocapillaris complex, we considered the area where the ELM line was absent as being above the ELM line and did not draw an additional line ( Figure 2 , Bottom row). The sparse hyperreflective foci were round or oval as reported previously, and the hyperreflective foci aggregates were often seen on the OCT images and corresponded to hard exudates in the fundus photographs. We excluded eyes with aggregates within the 1-mm central scanned area ( Figure 1 ), because the aim of this study was to evaluate the association between the photoreceptor status and sparse hyperreflective foci, which are considered as subclinical hard exudates.

Localization of hyperreflective foci at the fovea. Confluent hyperreflective foci (black arrow) on optical coherence tomography (OCT) images in diabetic retinopathy (Top right), which correspond to subfoveal hard exudates in a color fundus photograph (Top left). OCT shows sparse hyperreflective foci (black arrows) in the inner retinal layers inside the external limiting membrane (Middle right) or the outer retinal layers (Bottom right) at the fovea, whereas hard exudates are not seen in the corresponding area in the color fundus photographs (Middle left and Bottom left).

A disrupted external limiting membrane (ELM) and the junction between the inner and outer segments in eyes with hyperreflective foci in the outer retinal layers in diabetic retinopathy. Eyes with hyperreflective foci in the outer retinal layers have an intact (Top row), discontinuous (Second row), or absent (Third row) ELM on the optical coherence tomography images. (Top row) The ELM line is intact and the hyperreflective foci are present beneath the line (black arrow), whereas discontinuity of the photoreceptor inner segment/outer segment (IS/OS) line (black arrowhead) is seen. (Second row and Third row) The ELM line is not continuous in the area between the black arrows. Imaginary lines (red dotted lines) connect the terminals of the ELM and hyperreflective foci are observed beneath the lines (black arrowheads). (Second row) The fragments of both the ELM line (black arrows) and the IS/OS line (asterisk) are depicted within a 1-mm central scanned area. (Third row) The ELM and IS/OS lines are absent. (Bottom row) The ELM lines sometimes sank and merged with the retinal pigment epithelium (RPE) (black arrows). An irregular RPE line (red dotted line) and hyperreflective foci (black arrowheads) are seen in the areas where the ELM and IS/OS are absent.

Two experienced masked examiners (Y.M., N.A.) classified the status of the ELM and the IS/OS and the presence of the hyperreflective foci, and a third higher-level grader (T.H.) classified any images about which there was disagreement. The kappa coefficient was computed as a measure of reliability between the observers.

Statistical Analysis

All values are expressed as the mean ± standard deviation. All BCVA measurements were converted to the logarithm of the minimal angle of resolution (logMAR) equivalents before statistical analysis. Student t tests and χ ² tests were used to compare the 2 hyperreflective foci groups (foci absent in the outer retinal layers group vs foci present in the outer retinal layers group) regarding sex, age, duration of diabetes, HbA1C, total cholesterol, the presence of hypertension, logMAR VA, type of DR, the hyperreflective foci in the inner retinal layers of ELM line ( Figure 1 ), and the integrity of the IS/OS and the ELM lines. The χ ² test also was used to analyze the relationship between the integrity of the ELM line and the IS/OS line. Comparisons of the logMAR VA levels of the 3 groups that were classified based on the status of the IS/OS or ELM lines and comparison of the foveal thickness of the 3 ELM groups were carried out using 1-way analysis of variance, with post hoc comparisons tested by Scheffe procedure. The relationship between the logMAR VA and the foveal thickness was analyzed using the Pearson correlation coefficient. A P value < .05 was considered statistically significant. All analyses, except for the kappa coefficient, were performed using StatView version 5.0 (SAS Institute, Cary, North Carolina, USA). Calculation of the kappa coefficient was performed using SPSS version 17 (GraphPad Software, La Jolla, California, USA).

Assessment of Inter-observer Agreement

The kappa coefficient was 0.897 ( P < .001) for the ELM, 0.833 ( P < .001) for the IS/OS, and 0.926 ( P < .001) for location of the hyperreflective foci. These results indicated good inter-observer agreement.

Hyperreflective Foci in the Outer Retinal Layers of the External Limiting Membrane

Recent publications have documented the presence of hyperreflective foci in Spectralis OCT images of DR, but it is unclear whether the finding is related to visual function, which encouraged us to investigate the clinical relevance of hyperreflective foci in DME. We observed hyperreflective foci in the central 1-mm area of the fovea in the inner retinal layers in 107 of the 108 eyes (99.1%) with DME ( Figure 1 ). However, only 58 of the 108 eyes (53.7%) had hyperreflective foci in the outer retinal layers.

The logMAR VA was significantly ( P < .0001) worse in the group with hyperreflective foci in the outer retinal layers compared with the group without hyperreflective foci in the outer retinal layers ( Table 1 ), although no other systemic or ocular parameters differed between the groups. We further investigated how hyperreflective foci in the outer retinal layers contributed to the pathogenesis of DME and found that 45 of 50 eyes (90%) without hyperreflective foci in the outer retinal layers had an intact ELM, whereas 45 of 58 eyes (77.6%) with hyperreflective foci in the outer retinal layers had a disrupted ELM ( P < .0001) ( Table 2 ). The logMAR VA in the ELM (+) group also was significantly better than that in either the ELM (±) or ELM (-) group ( P < .0001 for both comparisons). These results suggested that the pathologic association between the hyperreflective foci in the outer retinal layers and disrupted ELM may contribute to visual dysfunction in DME.

TABLE 2

Association Between Hyperreflective Foci in the Outer Retinal Layers and the Status of the External Limiting Membrane Seen on Spectral-Domain Optical Coherence Tomography

	ELM (+)	ELM (±)	ELM (−)	P Value
Hyperreflective foci in outer retinal layers
Absent (no. eyes)	45	5	0	—
Present (no. eyes)	13	39	6	<.0001
Visual acuity (logMAR)	0.153 ± 0.207	0.416 ± 0.370	1.008 ± 0.229	<.0001

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