Atlas and Text of Corneal Pathology and Surgery Samuel Boyd, Angela Maria Gutierrez, James P McCulley
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1Basic Anatomy and Physiology2

Anatomy and Physiology of the CorneaChapter 1

Mauricio Latorre Cucalon, MD
Maria Victoria Baez Gonzalez, OD
Alejandra Giraldo Prieto, OD
The cornea is of utmost importance in the health of the visual system. Owing to its refractive and protecting role the eye is preserved from the aggressions of the environment. The cornea harbors specialized structures with specific functions for its stability and function.
The cornea is a highly sensitive structure. From an anatomical point of view it is formed by five layers that maintain its optical qualities of transparency and regeneration.
Owing to the transparency of the cornea we are able to receive and refract the light beams reaching our visual system, since it is the main refractive ocular structure focusing the light onto the retina. Additionally, it works as a physical barrier between the environment and the inner structures of the eye.
Corneal transparency is achieved thanks to a unique layer of endothelial cells in the innermost layer of the cornea; these cells form a filter between the aqueous and the corneal stroma allowing the entrance of nutrients into the avascular stroma.
 
Introduction
The cornea is an avascular, transparent tissue that permits light transmission into the eye. The cornea plays an important role in the refraction of the eye; it works as a concave-convex lens in contact with the aqueous and the tear film.[1]
The outer aspect of the cornea has an oval configuration with an average horizontal diameter of 12.6 mm and an average vertical diameter of 11.7mm. The outer surface of the cornea is the main refractive element of the eye contributing with approximately +48 diopters to the convergence of the light in the retina.[2]
Corneal sensitive innervations derive from the first branch of the trigeminal nerve (ophthalmic branch), above all via the long and short ciliary nerves. The nerves entering the retina may contain up to 30 axonal fibres and progressively ramify in the central stroma losing their myelin coat. These nerves are scarce in the deep stroma and inexistent in the endothelial layer; on the contrary there are plenty of these branches under the Bowman layer forming the subepithelial plexus. These branches go through the Bowman layer entering the epithelial layer forming complex free terminations. Thus the cornea is the most densely innervated structure in the human body with up to 10,000 terminations per square mm and its sensitivity is several hundreds of times higher than that of the skin.[3]4
Corneal metabolism depends on the atmospheric oxygen though smaller amounts of oxygen are provided by the aqueous and the limbal vasculature. Aqueous oxygen partial pressure is low (approximately 40mm Hg) compared with that in the tear film (150 mm Hg). During sleep and when the eyes are closed the corneal oxygen is provided by the highly vascularized upper lid conjunctiva; the oxygen partial pressure in this situation is much lower: 21% with the eyes wide open and 8% with the eyes closed.[4]
The mechanical resistance of the cornea is attributed to its structure formed by collagen fibrils forming approximately 200 parallel sheets from limbus to limbus. These fibrils are oriented forming angles with those of the neighboring sheets. This collagen network is responsible for the mechanical resistance of the cornea; the fibrils are more densely packed in the axial cornea than in the periphery. Corneal dehydration causes a redistribution of the tensile forces towards the posterior layers or more uniformly throughout the structure. In a healthy or edematous cornea the anterior layers sustain the tensional forces. The anterior and posterior stroma differ in the glycosaminoglycan composition as well as the more densely packed sheet in the anterior stroma; for this reason corneal edema is less intense in the anterior cornea.
 
Corneal Layers
The cornea is formed by five layers: Epithelium, Bowman, Stroma, Descemet membrane and Endothelium.
  1. Epithelium: The epithelium is the outermost layer of the cornea. This is a flat, stratified non keratinized tissue, about 50 microns thick in its central area and formed by 5 to 7 layers of cells belonging to three different groups. Directly over the basal membrane a single layer of basal cells with mitotic capacity can be found. As cellular division takes place, the new cells move towards the corneal surface and start differentiation forming three layers of squamous basal cells with terminal differentiation; three further layers of winged cells follow and last the surface cells. Eventually these cells degenerate and detach from the corneal surface. Corneal epithelial turnover takes place in seven days. The cornea is very regularly organized compared with other epithelial cells; this regularity is key for its optical properties.[6]
  2. Bowman Layer: The thickness of this layer is 12 microns. Primates are the only mammals with a Bowman layer. Bowman layer does not contain cells and can be considered a modification of the stromal superficial layer. It is formed by collagen fibres and helps the cornea to maintain its shape, lacking regenerative properties.
  3. Stroma: Is the thickest layer of the cornea measuring 450 microns, (approximately 90% of the total corneal thickness). It is formed by 200–250 bundles of collagen fibers, and composed by dense connective tissue formed mainly by perfectly arranged Type I collagen, proteoglycans and keratocytes. These cells are in charge of the maintenance of the stroma and elaborate and maintain collagen fibres. Following corneal damage, keratocytes change into fibroblasts, migrate to the margins of the wound and secrete collagen and glycoproteins. They may also migrate to the anterior cornea in response to epithelial damage.
  4. Descemet Membrane: Corneal endothelium is arranged on the Descemet membrane. This membrane is 10–15 microns thick and is formed by the endothelial cells and becomes progressively thicker during the lifespan. Descement membrane may remain healthy in cases of severe corneal ulceration and form a descemetocele following epithelial and stromal destruction. This fact proves the resistance of this membrane to proteolytic enzymes.
  5. Endothelium: This is a monolayer of polygonal cells (most of them hexagonal) arranged in an irregular pattern. The diameter of endothelial cells averages 20 microns and their thickness is about 4 to 6 microns. This tissue regulates corneal hydration and nutrition. The 5endothelium is constantly pumping ions and sending them (followed by water) back to the anterior chamber. These cells lack an effective mitotic activity. Their density decreases with aging and corneal aggressions. The adult eye harbors approximately 3.000 endothelial cells and their number decreases about 0.7% a year. In case of endothelial insufficiency their number may decrease under 400 causing endothelial incompetence and causing chronic corneal edema (Figures 1 and 2).[7]
 
Corneal Irrigation
Being the cornea avascular in nature, its blood supply derives mainly from conjunctival, scleral and episcleral vessels surrounding the sclerocorneal limbus.
 
Corneal Innervation
The cornea is highly innervated and most of the nerve fibers are originated in the trigeminal ophthalmic branch.
zoom view
Figure 1: A narrow slit lamp beam shows moderate hydration changes and a small irregular whitish paracentral inferior lesion at 6 o'clock, 6 mm wide and showing a mild epithelial loss.
zoom view
Figure 2: A narrow slit lamp beam and transilumination show a translucent irregular lesion 5 mm wide. High magnification reveals a healthy epithelium and good hydration.
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This innervation enters the eye through the long ciliary nerves which ramify in the external choroid near the ora entering the cornea through the sclera reaching the central third of the cornea as 70 to 80 nerves which lose their myelin coat 2 or 3 mm past the limbus. Corneal nerves form the corneal plexus:
  • Deep stromal plexus: deepest, demyelinized nerves (invisible) which do not interfere with light transmission through the cornea. Demyelinization reduces the speed of nerve signals.
  • Epithelial plexus: Is placed under the epithelium and its nerve density is 3 to 4 times superior to that of other body parts. The highest density is in the centre of the cornea.
 
Corneal Physiology
 
Corneal Biochemistry
  • Epithelium: The epithelium is responsible of 10% of the total weight of the cornea. It is formed by epithelial cells, is water rich (70%) and contains nucleic acids, lipids, proteins and phospholipids. Its metabolic function is very high. Energy is provided by glucosa from the tear film and the aqueous and necessary for its transparency.
    Energetic metabolic pathways are:
    • Glycolysis: producing energy and lactic acid
    • Krebs cycle: producing energy, H2O and CO2
  • Stroma: The stroma is unable to produce energy or new substrates, and its metabolic activity is very poor, as well as its metabolic activity. It is formed mainly by water (75-80%), and solutes such as type I collagen. There are solids such as glycosaminoglycans (GAG) (supporting structures formed by collagen and mucopolysaccharides). It also contains periodically arranged fibrils supported by GAG in the interfibrillary space such as: keratan sulphate, chondroitin, chondroitin sulphate A and dermatan sulphate.
 
Corneal Metabolism
Most of the corneal nutrients diffuse from the aqueous and the tear film. The flow of these substances is given by their concentration in the cornea, tear film and aqueous, and they flow from the higher to the lower concentration. Oxygen comes from the atmosphere through the tear film, and in lower quantities from the aqueous. During sleep oxygen is provided by the tarsal conjunctival vascular network. Decreased oxygen inflow causes corneal thickening.
The cornea generates its own metabolic energy as adenosine triphosphate (ATP). The most important metabolic pathway is that of aerobic glycolysis (Krebs cycle) with glucose as the most important substrate. Anaerobic glycolysis (incomplete degradation of carbohydrates) takes place during hypoxia producing only 25% of the total amount of energy. The metabolic efficiency of anaerobic glycolysis (2 ATP mol per glucose mol) is much lower than that of aerobic glycolysis (36 ATP mol per glucose mol).
About 90% of the metabolic reactions requiring oxygen take place in the epithelium. The rate of aerobic glycolysis in the stroma is very low. Absolute endothelial oxygen intake is much lower than that of the epithelium, but in terms of cell volume its metabolic rate is similar to that of the epithelium. Aqueous is the main supplier of oxygen for the endothelium.
Corneal metabolic function can be summarized as follows:
  • GLYCOLYSIS: Metabolises 85% of glucose. 1 mol of glucose produces 2 mol of ATP.
  • KREBS CYCLE: Metabolises 14% of glucose. Piruvic acid is metabolised with the aid of oxygen from the tear film. 1 mol of glucose produces 36 mol of ATP.
  • PENTOSE SHUNT: Metabolises 1% of glucose. It is a collateral pathway not intended for the production of energy; the products are used in the synthesis of nucleic acids (DNA, RNA).
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Corneal Dehydration
Corneal hydric balance is necessary for its transparency. Hyperhydration of the cornea reduces its transparency and the cornea becomes translucent. In normal conditions 80% of the cornea is water.
Corneal hydration is maintained by
  • Anatomic integrity of the endothelium and the epithelium: These two layers act as barriers: epithelial and endothelial cells prevent water from entering the corneal stroma.
  • Electrolytic and osmotic balance: The cornea floats between two liquids (aqueous and tear film) so a balance must exist to equally lose and gain water. Higher sodium (Na+) levels out from the cornea tend to dehydrate it whereas higher Na+ within the cornea tends to hydrate it. The endothelium pumps water and Na+ out from the stroma. This balance is maintained by the metabolic pumps.
  • Metabolism: energy is used for pumps such as the sodium potassium pump (Na+K+//ATPase) for the interchange of sodium and potassium using energy in the form of ATP.
  • Evaporation: contributes to maintain corneal hydration.
  • Intraocular pressure (IOP): is a force performed by the intraocular fluids and maintains intraocular pressure. Increased IOP causes an increased water content in the cornea and decreases transparency.
 
Corneal Transparency
As an optical mechanism the cornea achieves transparency through three different mechanisms:
  • Physical factors: The corneal lamellae are arranged in a grid like pattern eliminating the dispersion of light by mutual interference caused by the individual fibers (Maurice theory).
  • Factors affecting the barrier:
    • Surgical or mechanical harm to the cornea (as takes place when the structure is scratched or intervened, damaged or burned with acid): the epithelial layer becomes damaged.
    • Corneal pH: pH changes caused by topical treatments (drops).
    • Preservatives modify the drops to be more comfortable to the eye but they are calculated for a physiological pH.
    • Calcium free solutions may weaken the epithelium.
    • Glutathione affects the barrier.
  • Factors affecting the pump:
    • Ouabine: When topically applied it disturbs the functioning of the pumps and the cornea becomes less transparent.
    • Hypothermia: disturbs the corneal physiology and causes corneal edema and thus reduces its transparency.
    • Low levels of bicarbonate: the pumps need bicarbonate for a correct functioning; its absence makes it work at a slower pace.
    • Dystrophies: an accumulation of byproducts takes place in the endothelium, stroma and Bowman membrane disturbing the normal functioning of the cornea
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