Retinal Blood Supply and Barriers

• The retina receives blood supply from two arteries: choriocapillaries and the central retinal artery.
• Choriocapillaries supply blood to the outer layers of the retina and originate from short posterior ciliary arteries.
• The central retinal artery supplies blood to the inner retinal layers.
• The superficial plexus, located in the nerve fiber layer (NFL), and the deep plexus, located in the inner nuclear layer (INL), are both supplied by the central retinal artery.

Retinal Barriers

• The outer retinal barrier, formed by tight junctions between Bruch’s membrane and the retinal pigment epithelium (RPE), prevents blood or fluid from the choriocapillaries from entering.
• The inner retinal barrier consists of tight junctions between endothelial cells of the vessel walls, preventing blood or fluid leakage.

Retinal Pigment Epithelium (RPE) Structure

• RPE comprises a single layer of cells.
• The outer, non-pigmented basal element contains the nucleus.
• The inner, pigmented apical section contains melanosomes, found in greater quantity in the foveal area to absorb more photons.
• The cell base is in contact with Bruch’s membrane.
• RPE cells are taller, thinner, and more regular with more melanosomes at the posterior pole and fovea compared to the periphery.

RPE function

• RPE and zonula occludens (tight junctions) form the outer blood-retinal barrier.
• Zonula occludens prevents leakage from Bruch’s membrane and choriocapillaries.
• Phagocytosis and lysosomal degradation of photoreceptor outer segments occur in the RPE.
• The RPE is responsible for phagocytosis of waste products from phototransduction; disruption leads to lipofuscin accumulation.
• RPE maintains the outer blood-retinal barrier and transports metabolites and metabolic waste products.
• Vitamin A is stored, metabolized, and transported by the RPE for the visual cycle.
• RPE acquires Vitamin A from choriocapillaries to facilitate phototransduction (11-cis-retinal).
• Dense RPE absorbs light.

Bruch’s Membrane Structure

• Bruch’s membrane separates the RPE from the choriocapillaries.
• It prevents leakage from the choroid to the RPE and contributes to the outer-retina blood barrier.
• RPE depends on Bruch's membrane as a route for transporting waste metabolic products out of the retina.
• Changes in its structure are important in the pathogenesis of macular disorders.
• Bruch's membrane comprises five elastic collagen layers.
• Breaks in Bruch’s membrane will lead to visualization of vessels through the retinal layers.
• The integrity of Bruch’s membrane suppresses choroidal neovascularization (CNV).

Anatomical Landmarks

• Macula: 5-6 mm diameter, central 10-15 degrees visual field, contains yellow xanthophyll, and has a higher concentration of carotenoid pigments (lutein and zeaxanthin) than the periphery.
• Fovea: 1.5 mm diameter depression at the center of the macula.
• Foveola: 0.35 mm diameter center of the fovea, the thinnest part of the retina, contains cones and Muller cells.
• Bipolar cells are absent in the foveola.
• Foveal avascular zone (FAZ): no retinal blood vessels, but is surrounded by a network of capillaries.
• Umbo: depression in the center of the foveola and the location of the foveal reflex. Loss of the foveal reflex may be an early sign of a problem.

Diagnostic Tests

• Visual acuities and contrast sensitivity testing.
• Amsler grid.
• Fundus biomicroscopy (posterior and peripheral evaluation).
• Fluorescein angiography (FA).
• Indocyanine green angiography (IG) to evaluate choroidal circulation.
• Optical Coherence Tomography (OCT).
• Fundus Autofluorescence (FAF) to assess RPE function (loss of autofluorescence).

Macular Edema

• Macular edema typically results from pathologic hyperpermeability of retinal blood vessels.
• Increased vascular permeability leads to extravasation of fluid, proteins, and macromolecules into the retinal interstitium.
• Damage to the endothelium due to leukocyte adherence to vessel walls (leukostasis) contributes to vascular leakage.
• Inflammatory molecules like macrophages mediate the process.
• Molecules that induce retinal vascular hyperpermeability and extravasation include prostaglandins (PGD), leukotrienes, protein kinase C, nitric oxide, and cytokines.
• Protein kinase C is significantly involved in the macular ischemic cascade process.
• Nitric oxide is associated with oxidative stress.
• Cytokines: Vascular endothelial growth factor (VEGF), tumor necrosis factor-alpha, insulin-like growth factor-1, and interleukins.
• Pigment epithelium-derived growth factor (PEGF) maintains equilibrium and prevents the increase in VEGF. VEGF encourages the production of new vessels.

Macular Disease Symptoms

• Blurred vision, especially for close work.
• Scotoma: obstruction of central vision.
• Metamorphopsia: distortion of images.
• Micropsia: decrease in image size due to spreading apart foveal cones.
• Macropsia: increase in image size due to crowding together foveal cones.
• Difficulty with dark adaptation and poor vision in dim light.

Retinal Blood Barriers

• Outer retinal blood barrier: formed by RPE zonula occludens junctions, regulating movement of solutes and nutrients from the choroid to the subretinal space, blocking fluorescein that enters through the fenestrated capillaries in Bruch’s membrane.
• Inner retinal blood barrier: formed by tight junctions between retinal capillary endothelial cells, preventing fluorescein from passing through the wall of endothelial cells.

Fluorescein Angiogram (FA)

• FA is photographic surveillance of fluorescein passage through retinal and choroidal circulations after IV injection.
• Fluorescein enters through the ophthalmic artery (OA), passes through the short posterior ciliary arteries (SPCA) to reach the choroidal circulation.
• Choroidal circulation fills about 1 second before retinal circulation (9-15 seconds after injection).
• Normal FA findings: fovea shows no vessels within the FAZ and blockage of choroidal fluorescence by xanthophyll pigment and melanin in the RPE.

Hyperfluorescence on FA

• Window defect: atrophy or absence of RPE, such as in ARMD, macular hole, or RPE tears, which unmasks normal choroidal fluorescence, causing very early hyperfluorescence.
• Pooling: occurs in anatomical spaces due to breakdown of the outer blood retinal barrier (OBRB, RPE tight junctions), such as in central serous retinopathy (CSR) in the subretinal space, and slowly increases in area and intensity in sub-RPE pigment epithelial detachment.
• Leakage: early hyperfluorescence that increases in area and intensity due to breakdown of the inner blood-brain barrier (BBB) from dysfunction or loss of endothelial tight junctions, seen in proliferative diabetic retinopathy, central retinal vein occlusion (CRVO), cystoid macular edema (CME), and papilledema.

Hypofluorescence on FA

• Masking of retinal fluorescence by preretinal lesions like blood (subhyaloid or pre-retinal hemorrhage).
• Masking of background choroidal fluorescence by intraretinal hemorrhages, dense exudates, sub-RPE blood or lesions, and increased density of RPE (hypertrophy).
• Filling defects due to vascular occlusion.

Indocyanine Green Angiography

• Indocyanine Green Angiography (ICG) evaluates choroidal vascularization by delineating the choroidal vasculature, which may be masked by the RPE.
• ICG dye penetrates ocular pigments, including xanthophyll and melanin.
• Indications include polypoidal choroidal vasculopathy, exudative ARMD, retinal angiomas, chronic central serous chorioretinopathy (CSC), posterior uveitis, choroidal tumors, and breaks in Bruch’s membrane.

OCT Angiography

• OCT Angiography visualizes blood flow in the retina and choroid.

Fundus Autofluorescence (FAF)

• FAF uses an enhanced fundus camera to visualize accumulated lipofuscin in the RPE.
• It demonstrates and assesses the extent of macular diseases, useful in ARMD and detecting atrophic changes.