Diabetic macular edema: passive and active transport of fluorescein through the blood-retina barrier. Invest Ophthalmol Vis Sci 42: 433–438

PURPOSE. To investigate the passive bidirectional and active outward transport of fluorescein through the blood-retina barrier (BRB) in diabetic patients with clinically significant macular edema and in healthy controls. METHODS. The passive and active transport of fluorescein through the BRB was quantitated by vitreous fluorometry. A previously developed method was used to model passive transport. A new simulation model was developed and evaluated for estimation of active transport. The study included 10 eyes of 5 healthy controls and 31 eyes of 20 diabetic patients with clinically significant diabetic macular edema (CSME) in at least one eye, totalling 25 eyes with CSME. RESULTS. Passive permeability of fluorescein was increased by a factor of 12 in eyes with edema compared to healthy controls (edema, 23.7 nm/sec; healthy subjects, 1.9 nm/sec, P Ͻ 0.01), whereas the active transport was doubled (edema, 84.1 nm/ sec; healthy subjects, 43.5 nm/sec, P Ͻ 0.01). Unlike active transport, passive permeability was related to the degree of retinopathy, in that eyes with severe non-proliferative diabetic retinopathy had a passive permeability that was significantly increased compared to moderate retinopathy (32.1 nm/sec and 14.6 nm/sec, respectively, P Ͻ 0.05). The passive movement quantitated with vitreous fluorometry was larger for diffuse and mixed leakage compared to focal (P ϭ 0.07). CONCLUSIONS. Insofar as the movement of fluorescein can be taken as a probe for the movement of electrolytes and water, the pathogenesis of diabetic macular edema seems to involve a disruption of the BRB, presumably its inner component. The active resorptive functions of the blood-retina barrier appear to be compensatorily increased to counteract edema formation, although the increase is too small to prevent edema in the face of severe leakage through the blood-retina barrier. (Invest Ophthalmol Vis Sci. 2001;42:433-438) T he blood-retina barrier separates the neuroretina from the blood. The barrier function is located at the retinal pigment epithelium and the endothelium of the retinal vessels. The movement of water through the blood-retina barrier appears to have two dominant components: A passive (bidirectional) transport and an active transport directed from the retina to the blood. Theoretically, macular edema develops when the inflow of fluid into the retina exceeds the outflow. Since the movement of water across the blood-retina barrier cannot be traced noninvasively, clinical research has been confined to the use of fluorescein as a surrogate marker of fluid and electrolyte movement. Passive transport (permeability) of fluorescein has been shown to increase in relation to the development of retinopathy in the presence of macular edema. 1,2 In vitro studies of isolated retinal pigment-epithelium-choroid preparations have shown that the outward active transport of fluorescein is substantially larger than the passive transport and that this transport is inhibited by metabolic (oubain) and competitive inhibitors (probenecid). 6 A study of patients with retinitis pigmentosa complicated with macular edema 7 has shown an increase in active transport, whereas the role of active transport in diabetic macular edema is unknown. In the clinical study presented here, we have examined the passive and the active transport of fluorescein through the blood-retina barrier to evaluate the relative importance of these components in the pathogenesis of diabetic macular edema. In addition, a simulation method has been developed for the calculation of active transport. SUBJECTS AND METHODS Subjects Twenty-four diabetic patients with clinically significant diabetic macular edema (CSME) in at least one eye were examined consecutively. Both patients with IDDM and NIDDM were included. Patients with proliferative retinopathy, cataract, pseudophakia, or aphakia were excluded. Clinically significant macular edema was defined according to the ETDRS criteria as retinal thickening within 500 m of the umbo, as hard exudates within the same 500 m if associated with retinal thickening, and as a Ͼ1 optic disc area of retinal thickening if any part of the edematous area is within 1-disc diameter from the umbo. 8 In eyes with posterior vitreous detachment or vitreous liquefaction near the optical axis, vitreous fluorometry is unreliable as a tool to assess the blood-retina barrier, because convection replaces the otherwise steep preretinal diffusion gradient by a flat curve in front of the retina. 7 Consequently, we used fluorometry scans obtained 30 minutes after fluorescein injection to assess the qualitative properties of the vitreous. If the vitreous curve was flat immediately in front of the retina or throughout the posterior vitreous, the eye was excluded. Fifteen eyes were excluded because of such signs of vitreous liquefaction. Two additional eyes were excluded because of a lid defect and vitreous hemorrhage. Of the remaining 31 eyes, 25 had CSME, whereas no CSME was found in 6 eyes ( Five healthy subjects (mean age, 24 years; range, 22-27) without eye diseases, vitreous liquefaction, or known systemic disease were also included. The study was approved by the local medical ethics committee. All participants gave their written informed consent after full information according to the Helsinki declaration