MACULAR OEDEMA

While the exact pathogenesis of cystoid macular oedema (CME) remains uncertain, significant advances have been made in recent years in understanding the complex cellular and molecular processes involved in the disruption to the blood-retinal barrier (BRB) implicated in the development of CME, according to Prof Reinier Schlingemann. “There is still a lot that we do not understand about the pathogenesis of macular oedema but we have made a lot of progress in recent years in learning more about BRB breakdown and the role played by endothelial cells and transcellular transport of large molecules in this complex process,” he told delegates attending the XXXI Congress of the ESCRS in Amsterdam.

Prof Schlingemann, Medical Retina Unit and Ocular Angiogenesis Group at the University of Amsterdam, the Netherlands, noted that CME represents a common pathologic sequel of the retina and occurs in a variety of pathological conditions such as intraocular inflammation, central or branch retinal vein occlusion, diabetic retinopathy and after cataract extraction.

He explained that the rules that determine whether oedema forms in tissue were first elucidated by the English physiologist Ernest Starling in 1896. His eponymous equation illustrated the role of hydrostatic and oncotic forces in the movement of fluid across capillary membranes and has direct relevance for BRB disruption. Of the known pathogenetic factors that determine whether macular oedema will develop in tissue, Prof Schlingemann cited capillary hydrostatic pressure and the properties of the inner blood-retinal barrier, among others, as potentially important catalysts.

“Other factors to bear in mind are what actually happens in the tissue itself such as retinal ischemia, inflammation or para-inflammation as a response to any tissue damage or tissue stress. This releases growth factors and cytokines from the tissue and can create the conditions for oedema. The role of retinal glial cells and the vitreous should also be borne in mind, and there might also be a role played by the outer blood-retina barrier although very little is known about that for the moment,” he said.

There is also a case to be made for chronic macular oedema perhaps being treated as a separate disease entity, said Prof Schlingemann. "We really do not understand the processes underling chronic CME and it may be that factors such as ischemia and inflammation and so forth are less important here and that the inherent properties of the blood vessels are primarily responsible for this chronicity," he said.

Trying to unravel the complex pathophysiological factors at work in each incidence of macular oedema is fraught with difficulty, said Prof Schlingemann. "In a patient with branch retinal vein occlusion, for instance, a small vein is occluded by a thickening of the retinal artery wall leading to increased hydrostatic pressure and retinal ischemia. Together they will cause macular oedema, so the balance of the Starling equation is disturbed by increased permeability causing increased colloid osmodic pressure in the tissue on the one hand and increased hydrostatic pressure on the other hand. By contrast, in diabetic macular oedema this increased hydrostatic pressure might be less important and the most important causes might be factors such as cytokines such as VEGF produced by ischemic retinal tissues," he said.

Prof Schlingemann said that research has primarily focused on two proposed pathways for blood-retinal barrier loss, one concerning the loss of endothelial cell tight junction integrity and the other, which has received less attention, related to the endothelial transcellular pathway mediated by endocytotic vesicles. Based on Starling's equation, active transcellular transport of plasma proteins by the BRB endothelial cells causing increased interstitial osmotic pressure is probably the main factor in the formation of macular oedema, he said.

"We know that colloid osmodic pressure is mainly determined by the dynamics of protein transport which happens through transcellular rather than paracellular transport. That suggests that that mechanism is basically the most important in causing macular oedema and might be a very interesting target for therapeutic intervention," he said. Prof Schlingemann noted that vascular endothelial growth factor (VEGF) has also been shown to be associated with breakdown of the blood retinal barrier and increased vascular permeability, thereby contributing to the development of macular oedema.

"We know that VEGF is important in CME in diabetics because when we treat it with intravitreal anti-VEGF injections we can see the profound effect on their oedema. But inflammation has also been identified as an important mechanism and these are some cytokines that are found in the vitreous of eyes of patients with diabetic macular oedema suggesting that the inflammatory mechanism and inflammatory media are also important," he said. In terms of pseudophakic CME, Prof Schlingemann said that known risk factors include posterior capsular rupture, vitreous loss, diabetic macular oedema, uveitis and use of prostaglandin analogues.

"When there is another condition that could cause macular oedema like DME or uveitis there is an enhanced risk of pseudophakic CME. It is easy to envisage that based on Starling's equation you have a patient that is just keeping the balance of not having macular oedema caused by diabetic retinopathy in the retina but if you add the effect of a cataract operation you will tip the balance of the equation and get oedema," he concluded.

Reinier Schlingemann: r.o.schlingemann@amc.uva.nl