When diabetic macular edema (DME) is classified by findings on optical coherence tomography (OCT), edema in the retina and the macula is most often classified as subretinal or intraretinal; however, upon closer observation, it is apparent that another element is present in this case. In a study that was recently published in Ophthalmology,1 my colleagues and I sought to analyze the hyperreflective foci that seem to be evenly spread throughout the retinal layers in eyes with DME and consistent in eyes with this disease. In this article, I describe these hyperreflective foci, which to our knowledge, is the first description of these black spots associated with DME.

CASE PRESENTATION
We imaged a small sample of patients (n=12) who had treatment-naïve, clinically significant DME with the Stratus OCT (Carl Zeiss Meditec, Jena, Germany), the Cirrus HD-OCT (Carl Zeiss Meditec), and the SPECTRALIS SD-OCT (Heidelberg Engineering, Heidelberg, Germany). The arrows in the OCT slices identify the hyperreflective foci, or black dots, that are seen throughout the retina layers (Figure 1). The foci in the SPECTRALIS image (Figure 1, bottom right) are much more clearly defined.

If you compare the location on the OCT scans with that of the retina, you will see that most of the foci are hard exudates. Based on this observation, we decided that there must be a correlation between exudates and foci.

If one is trying to precisely scan where clinically relevant exudates are present, attention should be paid to areas of confluent aggregates of foci. These aggregates are located in deeper layers (Figure 2) as compared with individual foci that are more isolated and located superficially, suggesting some movement. A shadowing that appears to be a small vessel is present close to the spots, suggesting a close correlation between the two. These vessels can be found, of course, in the superficial layers of the retina. Upon scrutiny, foci or hard exudates can be found in the vessel walls.

We looked to the literature regarding the histology on hyperreflective foci and found some cases with similar findings. Cusick et al2 postulated that there is a high concentration of apolipoprotein B around retinal vessels in the contest of hard exudates in DME eyes.

Our hypothesis is that these are lipid apolipoprotein B aggregates exiting the small vessels and then traveling in the extravascular tissue. Progressive aggregation of these spots causes the development of large plaques that are visible with clinical ophthalmoscopy. The origin of lipid exudation is difficult to determine with their small size and location in the vessel wall, but as soon as the aggregates form, they gravitate to the deeper layers of the retina via the pumping mechanism of the retinal pigment epithelium. Visual function begins to deteriorate once the hard exudates travel to the deeper photoreceptor layers.

FOLLOW-UP AFTER THERAPY
The patient was treated with antivascular endothelial growth factor (anti-VEGF) therapy. At 4 months followup the retina appears flatter and the central retinal thickness decreased. The hard exudates, however, remain on pseudohistology; they have traveled downward to fill up the deeper layers of the retina (Figure 3). It is of no surprise that visual function does not improve with anti- VEGF therapy as quickly as it does in age-related macular degeneration (AMD). In AMD, there are no lipids in the retina, just fluid. Anti-VEGF, with its antipermeability effect, may be only half the solution in DME.

CONCLUSION
It is our conclusion that the SPECTRALIS is a useful way to screen for advanced vascular damage in DME that is not clinically available. This will also allow us to see in the future which patients respond better to therapy for DME.

Ursula Schmidt-Erfurth, MD, is Professor and Chair of the Department of Ophthalmology at the University Eye Hospital in Vienna, Austria. She states that she is a consultant to and/or received financial support from Novartis, Genentech, and Bayer Schering. Dr. Schmidt-Erfurth can be reached at +43 1 40400 7941; or fax: +43 1 40400 7912.

  1. Bolz M, Schmidt-Erfurth U, Deak G, Mylonas G, Kriechbaum K, Scholda C; Diabetic Retinopathy Research Group Vienna. Optical coherence tomographic hyperreflective foci: a morphologic sign of lipid extravasation in diabetic macular edema. Ophthalmology. 2009;116(5):914–920.
  2. Cusick M, Chew EY, Chan CC, et al. Histopathology and regression of retinal hard exudates in diabetic retinopathy after reduction of elevated serum lipid levels. Ophthalmology. 2003;110:2126–2133.