The Blood-Retinal Barrier in the Management of Retinal Disease: EURETINA Award Lecture

Abstract

Retinal diseases are the main causes of blindness in the Western world. Diabetic retinopathy and age-related macular degeneration continue to increase in prevalence and as main causes of vision loss. Intravitreal anti-VEGF and steroid injections have raised new expectations for their successful treatment. These agents act by stabilizing the blood-retinal barrier (BRB). Our group defined the BRB by identifying for the first time the tight junctions that unite retinal endothelial cells and are the basis for the inner BRB, an observation later confirmed in retinal pigment epithelial cells and in brain vessels. A major role of active transport processes was also identified. Today, the BRB is understood to play a fundamental role in retinal function in both health and disease. Retinal edema, an ubiquitous manifestation of retinal disease, is directly associated with breakdown of the BRB and with vision loss. In its most common form (i.e., vasogenic edema), due to breakdown of the BRB, Starling's law of capillary filtration may be used to interpret the mechanisms of fluid accumulation in the retina. The main factors involved in the development of retinal edema are BRB permeability, capillary hydrostatic pressure, tissue hydrostatic pressure, tissue osmotic pressure, and plasma osmotic pressure. In the clinical environment, breakdown of the BRB has been identified by fluorescein angiography and vitreous fluorometry, requiring the intravenous administration of fluorescein. An OCT-based method, OCT-Leakage, recently introduced by our group is capable of noninvasively identifying and quantifying sites of alteration of the BRB by mapping areas of lower-than-normal optical reflectivity, thus reflecting changes in the retinal extracellular fluid. We found good correspondence between the location of increased areas of low optical reflectivity identified by OCT-Leakage and the main sites of leakage on fluorescein angiography. Furthermore, with OCT-Leakage the areas of abnormal fluid accumulation can be identified in specific retinal layers, clearly offering more information than previously obtained with fluorescein angiography. OCT angiography has become available, replacing much of the information yielded by fluorescein angiography in a noninvasive manner. However, OCT angiography cannot visualize the leakage, i.e., the alteration of the BRB. OCT-Leakage is able to identify the locations of increases in extracellular fluid in the different layers of the retina. The complementarity of these 2 methods is of potential great interest for the diagnosis and management of several retinal diseases in which the presence and amount of fluid, as a marker of severity and activity, is paramount to treatment and management decisions in clinical practice.

Distinctive Mechanisms and Patterns of Exudative Versus Tractional Intraretinal Cystoid Spaces as Seen With Multimodal Imaging

“…Starling's law. 9 Accordingly, all cases of exudative macular edema in this study illustrated a compromise of the blood-retinal barriers, confirmed by dye leakage or pooling with FA and by the presence of cystoid spaces in both the INL and HFL, contiguous with the deep retinal capillary plexus. Exudative cystoid spaces displayed a characteristic petaloid pattern noted with en-face OCT.…”

“…1,4 It can be defined as an abnormal accumulation of intraretinal fluid, in which the normal fluid balance within the retina is disrupted such that fluid production exceeds fluid reabsorption. 2,9 Fluid leakage may accumulate in the retina mainly in extracellular cystoid spaces, presumably located in the interstitial space. 2 Although the pathophysiology, morphology and content of intraretinal fluid have been thoroughly investigated with histology, FA and OCT over the years, the precise mechanisms leading to macular edema are not yet fully understood.…”

“…Fluid normally flows in a vitreous to choroid direction due to osmotic gradient. 8,9,[15][16][17] In physiological conditions the retinal interstitial space is relatively dry, as the volume of interstitial fluid is strictly controlled by the retinal capillary plexus and the retinal glial cells, mainly the Müller cells, which can regulate fluid absorption via aquaporin channels. 2 This delicate equilibrium can be altered by RPE and vascular dysfunction, the action of mechanical forces, or any combination thereof.…”

Delivery of therapeutics for deep-seated ocular conditions – status quo

“…[27] -Limited permeability due to the narrow intercellular tight junctions in the endothelial layer. [28] retinal pigment epithelium (RPE). Together, these two layers of the BRB acts as a significant barrier impeding drug movement from the retina into the blood.…”

Appearance of cysts and capillary non perfusion areas in diabetic macular edema using two different OCTA devices

“…Diabetic macular edema (DME) is one of the most important causes of visual impairment in the working-age population in industrialized countries 1 . DME is directly associated with a breakdown of the blood retinal barrier (BRB) 2 , that determines fluid accumulation and an increase in retinal thickness 3 . The clinical and anatomical features of DME are the presence of hard exudates, microaneurysms, hyperreflective intraretinal deposits and cysts that are mostly confined to the outer nuclear and Henle layers 3 .…”