New concepts about macular edema emerge from modern imaging studies

Volume-rendered optical coherence tomography (OCT) imaging allows new insight into retinal vascular flow and morphological changes in eyes with macular edema (ME), and the information obtained is the basis for new ideas about the pathogenesis of ME and therapeutic intervention, according to Richard F. Spaide, MD, Vitreous Retina Macula Consultants of New York. 

Dr. Spaide presented images from eyes with ME related to different retinal vascular diseases. The examples included serial images taken pre- and post-treatment with anti-VEGF injections and cases with recurrent ME. The imaging was done using split-spectrum amplitude decorrelation, and volume rendering was achieved by integrating structural OCT data into angiographic data.

The studies revealed abnormalities in the inner layer of retinal vessels, decreased or absent flow in the deep vascular plexus, and co-localization of cystoid spaces with flow voids in the deep vascular layer.

Although cystoid spaces resolved with anti-VEGF treatment, there was persistence of flow void in the deep vessels, and in fluid accumulation in eyes with recurrent ME occurred in the same areas where altered inner and absent deep vascular plexus flow signal was noted previously.
Based on these observations, Dr. Spaide proposed that the deep vascular plexus plays an important role in the development of ME.

“ME is a common cause of vision loss in many blinding diseases, and better understanding of its mechanism of development can lead to identification of novel targets for intervention,” Dr. Spaide said.

“Previous theories on ME development did not consider the deep vascular plexus because only the inner vascular layer could be visualized using available techniques,” he said. “Although further study is needed, the early findings from volume rendered OCT suggest that effective control of fluid fluxes in the retina may require management of both main vascular layers.”

Dr. Spaide observed that study of the mechanism of ME development has also been limited by the absence of good animal models. In order to gain a better understanding, he applied recent discoveries from research involving the brain showing there is convective flow of fluid that is mediated by aquaporin-4 channels in astrocytes.

Mueller cells

He noted there is analogous anatomy in the eye where aquaporin-4 channels in Mueller cells control fluid flow in and out of the blood vessels.
“Current approaches to treating ME focus on modulating leakage from blood vessels. Perhaps targeting the Mueller cells and their aquaporin channels may be a better strategy for fluid removal,” Dr. Spaide said.

He proposed a pathway for the development of ME and damage to the deep vascular layer taking into account the watertightness of the external limiting membrane relative to the inner limiting membrane, the characteristics of vessels in the different layers, and the effects of ischemia-induced chemical mediators on hydrostatic pressure and vascular occlusion.

Based on Starling’s law, one would predict fluid would flow from the inner portion of the retina to the deeper layer, Dr. Spaide said.
When vascular occlusion and regional ischemia develop, cytokines, growth factors, and chemokines are released that increase hydrostatic pressure and leakage from the inner retina.

The chemical milieu also includes cytokines that increase expression of intercellular adhesion molecule-1 on small blood vessels and VEGF, which induces intravascular endothelial cell proliferation, resulting in vascular occlusion.

The impact of this cascade would be greater in the deeper vascular plexus where the entire network of vessels are capillary-sized versus in the inner plexus where capillaries represent only one small segment of the vasculature.

“We would expect greater damage to the deep plexus vessels that would account for the flow void,” Dr. Spaide said. “In the absence of deep plexus flow, there is no way to pump out the fluid, and it would accumulate as edema.”

Richard F. Spaide, MD

E: rick.spaide@gmail.com

This article was adapted from Dr. Spaide’s presentation at the 2016 meeting of the Association for Research in Vision and Ophthalmology. Dr. Spaide has financial interests with the Macula Foundation.