2. Background a. The eye

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2. Background
2.1.a. The eye
The eye, bulbus oculi, is a unique ball-shaped organ, consisting of refractive media surrounded by a tough fibrous tissue, the sclera, lined inside by the choroid and the retina (Fig. 1). Light passes through the refractive media(cornea, anterior chamber, lens, and vitreous), to reach the photoreceptors in the retina where it is transformed into neural impulses. These neural impulses are transported from the retina to the brain through the optic nerve, optic radiation and finally to the primary visual cortex in the occipital pole of cerebrum, where they are perceived as images.

Figure 1.Cross sectional schematic drawing of the human eye.

From: http://www.nei.nih.gov/photo/.

2.1. b. The retina
The human retina is the light sensitive tissue of the eye that enables us to see.It is supported by its retinal pigment epithelium and outlined by the choroid and thesclera. The retina can be divided into the following layers (Fig.2.1 a,b)

. Internal limiting membrane

. Nerve fiber layer (the axons of the ganglion cells, that transmit the visual signal to

the lateral geniculate nucleus and thence the visual cortex)

. Ganglion cell layer (the cell bodies of the ganglion cells)

. Inner plexiform layer (the axons of the bipolar cells)

. Inner nuclear layer (the cell bodies of the bipolar and horizontal cells)

. Outer plexiform layer (the dendrites of the horizontal cells and the inner segments

of the rod and cone photoreceptor cells)

. Outer nuclear layer (cell bodies—outer segments—of the photoreceptor cells)

. External limiting membrane

. Pigment epithelium

. Bruch’s membrane

. Capillary choroid (capillaries of the choroid);

. Choroid plexus.

Most of the retinal layers can be seen on optical coherence tomography (OCT) images;However, imaging of the capillary choroid and choroid plexus, though availablein a research setting, cannot yet be done with commercially available devices.

Figure 2.1 Illustration of eye anatomy(a) and retinal layers(b)
2.2. Anatomy and physiology of the retinal vascular system

The human retina is a light sensitive tissue lining the back of the eye. It is nourished by two discrete circulatory systems—the retinal blood vessels (Fig.2.2) and the uveal or choroidal blood vessels, both of which are derived from the ophthalmic artery, which is the first branch of internal carotid artery. Both the retinal and choroidal circulatory systems are in communication with the cavernous sinus. The mechanism of formation of retinal blood vessel patterns is an unresolved question but it is assumed that the existence of variable oxygen gradients across developing photoreceptors stimulates the release of angiogenic factors which diffuse in the retinal plane and result in differential growth of retinal blood vessels; thereby implying that the limiting factor in vascular development is the diffusion process. These vessels carry important oxygen and nutrients and are vital to the healthy functioning of retina. The choroid provides greater blood flow (65-85%) and is crucial to the maintenance of outer retina; particularly photoreceptors. The remaining 20-30% blood flow to the retina is through the central retinal artery which nourishes the inner retinal layers. The central retinal artery is an end artery with no significant anastomoses. Just before its exit from the optic nerve, the central retinal artery divides into superior and inferior papillary arteries, which in turn divide into four branched retinal arteries for the four quadrants: superior temporal, superior nasal, inferior temporal, inferior nasal. The corresponding venules enter the vortex veins at the equator of the eyeball, penetrate the sclera and merge into the ophthalmic vein. Usually, one or two vortex veins drain each quadrant of the eyeball. The arterial system is generally more variable than the venous system. The anatomical division of the retinal vessels into superior and inferior halves is usually maintained but collaterals across midline

develop in obstructive disease.The retinal capillary endothelial cells are the major component of the blood-retinal barrier.(Fig.3) Tight junctions restrict intercellular movement of water-soluble molecules and are associated with selective active transport into retina.Apparently, no central regulation of blood flow occurs in the retina itself, however, they do respond to smooth muscle tones in vessel wall governed by oxygen tension, ph changes, metabolites orhypoxia.

Figure 2.2Normal human retina showing blood vessels (Source: Wikipedia)

The blood-retinal barrier has tight junctions and is highly selective in regulating the passage of pathogens and intravascular leukocytes; thus protecting the eye from ‘surveillance’ by immune cells and infections (Forrester et al.,2002; Kaufman &A lm,2003).The formation and maintenance of blood-retinal barrier is required for proper vision and loss or violation of this barrier contributes to the pathology of a wide number of retinal diseases.The blood-retinal barrier is formed by both the retinal vasculature and the Retinal pigment Epithelium(RPE) (Cunha,1979). The barrier function depends on tight junctions, which restrict intercellular movement of all water-soluble molecules and thus prevent these molecules from entering the retina. Electron microscopy exhibits extensive zonular occludentes surrounding the retinal capillary endothelial cells and the apicolateral aspects of the RPE cells. Glial cells that surround the retinal capillaries may play a role as metabolic intermediaries between the retinal capillaries and retinal neurons. Hence, macromolecules and ions do not passively diffuse into the retina from circulation but are associated with selective active transport into the retina. Choriocapillaris with their numerous fenestrations, pinocytic vesicles, and lack of tight junctions are quite permeable to macromolecules and do not have much significance in the blood-retinal barrier. Bruch’s membrane acts as a diffusion barrier only to large molecules. However, the functional significance of having the outer blood-retinal barrier at the level of the RPE, rather than the choriocapillaris, is a subject of unresolved speculation (Bill,1975).This pattern allows the RPE to have ample access to necessary nutrients such as vitamin A and to better remove waste products. Also, the high protein permeability of the choriocapillaris results in greater oncotic pressure in choroid than in retina. The resultant differences in osmotic pressure facilitate absorption of fluid from retinal extracellular spaces into choroid; which may be a mechanism to keep the retina attached to RPE. Interestingly, no intraocular lymphatic channels exist. Although the retina is protected by blood-retinal barriers, some leakage does occur,mostly protein. This protein leakage is removed through Schlemm’s canal. Choroidal proteins exit the eye through emissary canals (openings in the sclera for vessels and nerves) or through the sclera, facilitated by the relatively high tissue pressure of the eye (the intraocular pressure).

Figure. 3A cross-section of the human retina, showing ten layers of the retina and the blood supply,with retinal arteries and veins to the left and the choroid to the right. (Source: Ciba-Geigy magazine).

The central retinal artery and vein
The central retinal artery and vein are respective branches from ophthalmic artery and vein. Approximately a cm.behind the eye, they pierce the optic nerve, and travel mesially within the centre of the optic nerve, to enter the eye through a gap in the lamina cribrosa. They divide into two smaller branches:The superior and the inferior branch or papillary trunks,as called by some anatomists. These further subdivide into superior and inferior nasal and temporal branches for the four quadrants of the retina. The four major arterial branches are functional end-arteries, with nooverlaps. These large arterial and venous branches travel right through the nerve fibre layer, just beneath the inner limiting membrane of the retina. They branch into two different capillary networks, one forms the plexus within the ganglion cell layer and another forms the plexus within the inner nuclear layer (Fig.3). The fovea is a 500 micrometer capillary-free zone, allowing for light to pass through undisturbed. The fovea is nourished from the choriocapillaris through diffusion. Retinal blood flow is autoregulated, and it is believed to be a combination of myogenic mechanisms and metabolic processes. Autoregulation of intraocular blood flow ensures a constant level of blood flow, despite mild to moderate variations in perfusion pressure.As a result of autoregulation, the oxygen tension in the inner retina can be constantly maintained at a normal level despite changes in blood pressure or intra ocular pressure(IOP). But,there is also an upper limit for the autoregulation mechanism to act, beyond which it fails and therefore an overwhelming increase in arterial blood pressure can result in increased retinal blood flow(Kaufman &Alm,2003).

The Choroid

The choroid is a pigmented, vascular, loose connective tissue layer that supplies perfusion to the outer third of retina .It also has a thermoregulatory role. It is supplied by the posterior ciliary arteries and issituated between the sclera outside and the retina inside. The choroid consists of five layers: Bruch’s membrane, Choriocapillary layer with fenestrated capillaries, Two vessel layers and the Suprachoroid (Forrester et al.,2002).Choroidal blood vessels do not respond to any elevation in IOP and significant reductions in choroidal blood flow cause no measurable effect on choroidal vasculature, therefore they are believed to be devoid of autoregulation(Kaufman &A lm,2003).

Cilioretinal arteries

Occasionally the central retinal artery is assisted by one or more cilioretinal arteries, that emerge from the optic disc rim (Fig.4). These arteries are derived directly from the circle of Zinn, which is formed by small branches from short posterior ciliary arteries, which also supplies the choroid. When a temporal cilioretinal artery supplying the fovea spares the fovea in cases of central retinal artery occlusion, it miraculously spares vision; an aspect of extreme clinical relevance(Brown &Shields,1979).

Figure .4 Fundus with two temporal cilioretinal arteries (CRA) supplying the fovea.(Source:clinical ophthalmology Kanski 7th edition)

2.3. Retinal blood vessel abnormalities
2.3-(A) Hypertensive retinopathy
Hypertensive retinopathy represents ocular end-organ damage secondary to arterial

hypertension. Pathological changes primarily affect the retina and are indicative of present or past elevations in blood pressure; but changes in choroid and optic nerve may also be involved. Essential arterial hypertension is a very common disease and is defined as having mean systolic blood pressure of >= 140mmHg and mean diastolic blood pressure of >= 90mmHg.Hypertension is usually associated with increased risk of carebrovascular events like stroke and cardiovascular disease. Hypertensiveretinopathy is generally asymptomatic and it rarely results in loss of vision. The primary pathologic change in hypertensive retinopathy is a protective vasoconstriction consequent of autoregulatory mechanisms of retinal vasculature, which is seen clinically as focal arterial narrowing, generalized arterial narrowing and arterial straightening or loss of wavyness. Physiologically, retinal arteries constrict in response to elevated blood pressure in order to maintain homeostasis in circulation dynamics.This works best in young people, because sclerosis in older patients´ arteries prevents the same degree of narrowing(Yanoff & Duker,2004). Still further increase in blood pressure level can break down theautoregulation system and eventually result in arterial dilation and tortuosity, which is common in sustained high blood pressure levels(Margerie J& Boyd 1961).Long-standing hypertension causes arteriosclerosis with thickening of arterial wallsresulting in luminal narrowing. Thickening of arteriosclerotic vessel walls occurs because of intimal hyalinization, medial hypertrophy, and endothelial hyperplasia. Arteriosclerotic changes manifest in fundus as copper wiring and silver wiring of the retinal arteries. (Fig.5)The age of the patient may confound interpretation of fundus changes, because arterial sclerosis occurs both in hypertensive patients and as a normal geriatric process of an ageing population. The arteriovenous crossings in the retina share a common adventitial sheath and are characteristically called 'nicking'.When arteriosclerotic arteries cross over veins, the venous part distal to the constrictioncan appear dilated, darker and more tortuousthan the rest . Arteriovenous nicking (AV-nicking) is diagnosed when the underlying vein becomes less apparent or disappears on either side of the artery. AV-nicking is an unambiguous finding characteristic of chronic hypertensive retinopathy. Sustained hypertension leads to disruption of the blood-retinal barrier compromising vision and vascular leakage results in haemorrhages, oedema, and hard exudates. Occlusion in smaller end arterioles leads to retinal ischemia seen as cotton wool spots. In very severe hypertension the optic nerve becomes swollen, and the patient’s vision is threatened(Kanski,2003).A classification system for hypertensive retinopathy was introduced by Keith, Barker, and Wagener in 1939, based on the physical status of retinal arteries and systemic arteries from pectoral muscle biopsies (Table 1)(Keith et al.,1974). The Keith-Barker-Wagenerclassification is still popular in modern clinics. Another popular classification that dealt with the vascular changes of hypertensive retinopathy and arterial sclerosis separately was introduced in 1952 by Scheie (Table 2)(Yanoff & Duker2004). In the West, hypertensive retinopathy of group 1 and 2 are common while patients treated with anti-hypertensive medication seldom develop retinopathy of group 3 and 4 (Table 1). Patients with hypertensive retinopathy of group 3 and 4 are seen in clinics on rare occasions and patients in group 4 are in a very critical state prognostically (Kanski ,2003).

Figure.5Severe hypertensive retinopathy. (A) Cotton wool spots, a few flame-shaped haemorrhages and arteriolosclerosis; (B) cotton wool spots, macular star and mild disc swelling(Source: Kanski clinical ophthalmology,7th edition)

2.3-(B) Diabeticretinopathy
Diabetes mellitus (DM) is a major medical problem throughout the world that causes an array of long-term systemic complications having considerable impact on the patient, as the disease typically affects individuals in their most productive years. An increasing prevalence of diabetes is occurring throughout the world, this increase appears to be greater in developing countries. The etiology involves changes in diet, with higher fat intake, lifestyle changes, and decreased physical activity. Diabetic retinopathy is the leading cause of new and sudden blindness in persons aged 25-74 years. Recent estimates of the prevalence of diabetic retinopathy showed a high prevalence of 28.5% among those with diabetes aged 40 years and older. Patients with diabetes often develop ophthalmic complications, such as corneal abnormalities, glaucoma, iris neovascularization, cataracts, and neuropathies. The most common and potentially most blinding of these complications, however, is diabetic retinopathy. In the initial stages, patients are asymptomatic, but in more advanced stages of the disease, patients generally experience symptoms like floaters, visual distortion, and /or and blurred vision. Presence of microaneurysms is a sure and earliest clinical sign of diabetic retinopathy. In early stages of diabetic retinopathy, blood vessels leak fluid and exudation causes distortion of sight. As the disease progresses, symptoms include blurred vision,fluctuating vision, floating spots, blind spots,changes in color perception,sudden loss of vision,double vision,eye pain in advanced cases.In more advanced stage of diabetic retinopathy, fragile new blood vessels grow around the retina and in the vitreous .If left untreated, these blood vessels may bleed, clouding vision, causing scars and detaching the retina.
This section presents details of the two types of diabetic retinopathy (DR):

Background or nonproliferative diabetic retinopathy (NPDR):

Inthis condition, damaged blood vessels in the retina begin to leak extra fluid and small amounts of blood into the eye. NPDR changes in the eye, includeMicroaneurysms, Retinal hemorrhages, Hard exudates,Macular edema,Macular ischemia (Kanski,2003).(Fig.6) Many people with diabetes have mild NPDR, which usually does not affect vision. Breakdown of the blood-retinal barrier can lead to fluid leakage, diabetic macular edema (DME) and damage to photoreceptors. The primary cause of visual loss in people with diabetes is DME, and it is more common in type 2 diabetes. The breakdown of the blood-retinal barrier causes leakage of dilated hyperpermeable capillaries and microaneurysms into intracellular and extracellular retinal tissue with subsequent fluid accumulation . Clinically significant macular edema (CSME) occurs when there is thickening of the retina involving central retina (macula) or the area within 500 um of the center. Visual loss occurs when macular edema involves the visual center, lesser degrees of Diabetic Macular Edema(DME) may cause visual deterioration. DME affects macular structure in both the short and long term. Leaking exudates in DME initially enter the cytoplasm of Muller’s cells (radial glial cells of the retina), mainly in the outer retina. Cysts (retinal extracellular fluid) occur predominantly in the outer retina. Over time, cysts fuse and extend from the outer into the inner retina. In these cases, atrophy or apoptosis of the remaining retinal tissue occurs. Serous detachment may occur in ~20% of DME cases even though this does not correlate with visual acuity. Hard exudates, if they occur, tend to be located at the level of the outer plexiform layer. Patients with longstanding DME withimpaired visual acuity have decreased directional sensitivity of photoreceptors and decreased visual pigment density.

Proliferative diabetic retinopathy (PDR):

Hyperglycemia damages the retinal vessel walls and can lead to ischemia, resulting in growth of new blood vessels, which may subsequently bleed and/or cause retinal detachment, a condition called proliferative diabetic retinopathy .This mainly occurs when many blood vessels in the retina close, preventing blood flow. In an attempt to supply blood to the area, the retina responds by growing new blood vessels called neovascularization. These new blood vessels are abnormal and bleed often accompanied by scar tissue that may cause the retina to wrinkle or detach.PDR may cause more severe vision loss than NPDR as it can affect both central and peripheral vision. Anyone with diabetes, both type 1 or type 2 diabetes is at a risk of developing fulminant diabetic retinopathy. However, the type of diabetes a person has, how frequently their blood glucose fluctuates, how well controlled the sugars in his/her body are, and how long a person has had diabetes; all these factors affect his or her risk of retinopathy.

DR is a complication of diabetes mellitus and the second most common cause of blindness and visual loss in the working age population of the developed and developing world. There is enough evidence that blindness and visual loss in these patients can be prevented through annual screening and early diagnosis. The better one controls blood sugar levels, the lower one's risk. One of the most important aspects in management of diabetic retinopathy is patient education. Information promotes the patients to play an integral role in their own eye care. The management of DR primarily involves lowering of blood sugar through diet, lifestyle changes and anti-diabetic drugs. Laser photocoagulation, administration of anti-vascular growth factors and steroids have been shown in large randomized clinical trials to preventblindness and further visual loss.

Figure.6 Retina showing signs of diabetic retinopathy like hemorrhages, exudates and neovascularization. (Source:http://www.geteyesmart.org/eyesmart/diseases/diabetic-retinopathy.cfm)

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