layer at A–V crossing sites. Muller cell and astrocyte processes surround the vessels, insulating them from surrounding retinal neural tissue.

1.1.8 Veins

The wall of the central retinal vein consists of a layer of endothelial cells, subendothelial connective tissue, a medium consisting mostly of elastic fibers, a few smooth muscle cells, and a thin connective tissue adventitia. It is separated from the surrounding neural tissue by Muller cell and astrocyte processes. The lumen decreases in size from 150 mm at the disc to 20 mm at the equator and smooth muscle cells are lost and replaced by pericytes. This allows the venous diameter to change according to the transluminal pressure differential. In patients with diabetes or carotid artery disease, the veins become sausage shaped in response to sluggish flow. Though the central vein is the only outlet for the retinal circulation, potential anastomoses exist between the retinal and choroidal circulations at the disc. They may become manifest in cases of central retinal vein occlusion or compressive lesions of the optic nerve.

1.1.9 Capillaries

Capillaries are distributed throughout the retina except in the foveal avascular zone, the retina adjacent to major arteries and veins, and the far peripheral retina. The capillary network originates from the arterioles in the ganglion cell layer and spreads through the inner nuclear cell layer, but there are no vessels in the outer plexiform and outer nuclear layers. Capillary vessels are distributed in a bilayer schema: a superficial network in the ganglion and nerve fiber cell layers, and a deeper layer in the inner nuclear layer. Vessels range from 5 to 10 mm in diameter. The volume of the outer vascular network is relatively constant, whereas the volume of the inner network varies with the thickness of the nerve fiber layer. Though the perifoveal region has only one capillary layer, up to four different capillary layers are found in the peripapillary region. Peripapillary

capillaries drain directly into venules lying on the optic nerve.24 Within 2 disc diameters of the nerve, these capillaries have long, straight, or slightly curved paths with minimal anastomoses. This unique anatomy makes the capillaries susceptible to elevated IOP and changes in retinal perfusion pressure. This has been used to explain arcuate scotomas in glaucoma, peripapillary flame-shaped hemorrhages in papilledema and hypertension, and cotton wool spots in disorders causing retinal ischemia.

The capillary wall consists of endothelial cells, pericytes, and a basement membrane. The narrow vascular lumen – 3.5–6 mm – coupled with the thin endothelial cell bodies causes nuclei to bulge inward. This requires passing erythrocytes to distort and mold. The endothelial cells are connected by tight junctions that form the blood–retinal barrier.22 Pinocytic vesicles provide the mechanism for transfer of metabolites from the circulation to the retina. Diseases such as diabetes that disrupt the endothelium also disrupt the blood–retina barrier, causing leakage of protein and lipid into the retina. The leakage is potentially reversible through endothelial cell mitosis and the formation of new tight junctions.25 The capillary pericytes lie within the endothelial basement membrane. In vivo contraction of mammalian pericytes has not been demonstrated, but pericytes contain contractile proteins and contract in vitro when exposed to endothelin,26 thromboxane A2,27 and angiotensin II.28 Loss of pericytes, as seen in ischemic retinopathies such as diabetes mellitus, results in weakening of the capillary walls and the formation of microaneurysms.29

1.2Hemodynamics, Macular Edema, and Starling’s Law

Movement both into and out of the body’s capillaries, including those of the retina, is dependent upon hydrostatic and oncotic pressures. The formation and resorption of macular edema can thus accurately be described by Starling’s law (see Fig. 1.5).

The four primary Starling’s forces are as follows:

1.Hydrostatic pressure within the capillary lumen (Pc)

2.Hydrostatic pressure within the retinal interstitium (Pi)

Fig. 1.5 Under physiological circumstances, the drop in transluminal hydrostatic pressure over the length of the capillary causes fluid filtration out of the first half of the capillaries and resorption into the second half. Perturbations in

the Starling’s equilibrium, by changes in either hydrostatic or oncotic pressures, will result in a horizontal shift of the graph’s equilibrium point (Pi)

3.Capillary oncotic pressure (Qc)

4.Interstitial oncotic pressure (Qi)

Capillary hydrostatic pressure is determined by systemic blood pressure, whereas tissue hydrostatic pressure is approximately the same as intraocular pressure. Most of the capillary oncotic pressure is created by albumin, whereas, with healthy vascular endothelium, tissue oncotic pressure is determined by interstitial proteins. The net force pushing fluid out of capillaries is the difference between hydrostatic pressures and oncotic pressures and can be represented by the following equation:

F ¼ ðPc PiÞ ðQc QiÞ;

where F is the resultant force determining fluid movement. If F is positive, fluid moves out of the capillary into the interstitium thereby forming tissue edema. However, if F is negative then the net movement of fluid is out of the tissue and into the capillary. At equilibrium,

F ¼ 0 ¼ DP DQ;

where there is no net movement of fluid across the capillary walls.

Edemacanbedefinedastheabnormalswellingofsoft tissues – in this case the retinal interstitium. Edema can becytotoxic,wherethefluidaccumulateswithincells,or vasogenic, where fluid accumulates within the interstitial spaces. Cytotoxic edema occurs with severe ischemia, such as following central retinal artery occlusions. Starling’s law applies to vasogenic edema, the most common form of edema in retinal vasculopathies such as diabetic macular edema and retinal vein occlusions.

Retinal edema occurs when the net hydrostatic force (forcing fluid into the interstitium) exceeds the net oncotic force (drawing fluid into the capillary lumen) across capillary walls. This is usually due to an increase in transluminal hydrostatic pressure, as occurs with systemic hypertension or ocular hypotony, or due to a decrease in transluminal oncotic pressure, as occurs with increased interstitial proteins due to breakdown of the blood–retinal barrier or with a decrease in plasma proteins as seen with liver disease or protein-wasting nephropathies.

Hydrostatic pressure in the capillaries and venules is dependent upon the arterial blood pressure and the pressure fall through the arterioles. Systemic arterial hypertension increases capillary hydrostatic pressure and aggravates the severity of diabetic macular edema. Patients with diabetic macular edema should