TO PARAPHRASE AN OLD SAYING, THE CORNEA IS THE WINDOW to the soul. But, just like the soul, the window that looks onto it is a multifaceted, complex structure. In fact, there are significant differences between even the center and the periphery of the cornea that might surprise you. In this article, we'll take a look at these differences, which range from physiology to how the cornea fights disease.

Fundamental Differences
The cornea's major function is to refract and transmit light to the lens and retina while simultaneously providing protection for inner ocular structures. The cornea is composed of five layers: the epithelium; Bowman's membrane; stroma; Descemet's membrane; and endothelium; these act together to perform specified functions.

Though they seem identical on the surface, the central and peripheral parts of the cornea are actually two distinct sections, with the following anatomical, physiological and pathological differences:
• Anatomy. The central cornea is half as thick (0.5 mm) as the peripheral cornea (1 mm). However, the cells within the central cornea are more densely packed (five cells deep) than the cells within the periphery (six to seven cells deep).1 The central cornea also has five to six times as many nerve fibers as the peripheral cornea. Consequently, corneal sensitivity is higher in the central cornea compared to the periphery, where innervation is less dense.2 In the central cornea, both nerve fibers and collagen fibers are more precisely arranged and organelles are well-aligned, as opposed to the looser, more disordered arrangement within the peripheral cornea.2,3

In general, the epithelium of the central cornea is less adherent to its basal membrane than the peripheral cornea, which has a tighter adhesion complex to the basal membrane and underlying stroma.1 The peripheral stroma forms a transition zone from the organized corneal lamellae to the irregular scleral fibers. Due to its proximity to the conjunctiva, the peripheral stroma also contains blood and lymphatic vessels that are not present within the central cornea.4 In vitro studies indicate that human endothelial cells isolated from the central cornea are densely packed and non-mitogenic, whereas those isolated from the periphery have characteristic mitogenic activity and looser cell-to-cell attachments.4Such differences may explain variations in wound healing between the central and peripheral cornea.

Table 1. Anatomical Differences
Central Cornea Peripheral Cornea
• 0.5-mm thick
• 5 cells deep1
• 1-mm thick
• Peripheral cornea is twice as thick
as the central cornea
• 6-7 cells deep1
• Number of nerve fibers 5-6 times greater in central cornea; heavily innervated

• Corneal sensitivity higher in central cornea2

• Nerve fibers less dense in peripheral cornea

• Corneal sensitivity lower in peripheral cornea2

• Collagen fiber precisely arranged; organelles well aligned3 • Collagen fibers loosely arranged3
• Epithelium is less adherent to basal membrane in central cornea4 • Epithelium is more adherent to basal membrane in peripheral cornea4
• Central cornea has minimal blood and lymphatic vessel supply4 • Peripheral stroma has blood and lymphatic vessels forming a transition zone from the ordered arrangement of the corneal
lamellae to the irregularity of the scleral fibers4
• Serum albumin / protein level low

• Serum albumin / protein incentral cornea diffuses in from peripheral cornea9
• Serum albumin / protein level high (3 times higher than central cornea)

• Serum albumin / protein originates from capillaries around peripheral cornea9
• Central corneal thickness less than peripheral corneal thickness in dry-eye patientsi,16 • Peripheral corneal thickness greater than central corneal thickness in dry-eye patientsi,16
i. Liu Z, Pflugfelder SC. Corneal thickness is reduced in dry eye. Cornea 1999;18:4:403-7.

• Physiology. On a physiological basis, the concentration of epithelial stem cells is higher in the peripheral cornea where cell proliferation is higher, as demonstrated in vivo in rabbit and mouse cornea models.5,6 Damage to corneal tissues may be healed more readily within the periphery, where stem cell proliferation is abundant, vs. healing processes within the central cornea, in which most cells have lost their proliferative capacity. Central corneal endothelial cells have been demonstrated to occupy free space by cell enlargement vs. cell division, whereas the opposite is true in the peripheral cornea.4 Differences in basal cell types found within the central cornea have lead to the hypothesis that some epithelial stem cells within the peripheral cornea migrate centripetally toward the central cornea for wound repair.1

Table 2. Physiological Differences
Central Cornea Peripheral Cornea
• Concentration of epithelial stem cells lower in central cornea
• Endothelial cells in central cornea densely packed and enlarged
• Proliferation rate of epithelial cells lower in central cornea
• Endothelial cells non-mitogenic in central cornea
• Centripetal push of daughter cells from epithelium of peripheral cornea towards central cornea4-6,i
• Concentration of epithelial stem cells greater in peripheral cornea
• Proliferation rate of epithelial cells higher in peripheral cornea
• Mitotic rate higher in peripheral cornea4-6,i
• Healing results from disinsertion from hemidesmisomes and anchoring attachments; spreads by pseudopod movement ii • Healing results from stem cells
producing daughter cells ii
• Epithelial shedding rate is higher in central cornea7 • Epithelial shedding rate is lower in peripheral cornea7
• Central cornea depends on tear film and aqueous for nutrients (e.g. oxygenation)8 • Peripheral cornea depends on blood supply from capillaries at edge of cornea for nutrients (e.g. oxygenation)8
• MUC 1 and 16 dispersed
throughout central cornea
• Low levels of MUC 4 found in
central cornea10
• MUC 1 and 16 dispersed throughout peripheral cornea
• High levels of MUC 4 found in peripheral cornea; MUC 4 seems to be associated with serum albumin found in capillaries around peripheral cornea10
• Visual impairment possible—
central 5 mm needs to be clear,
otherwise glare is experienced11
• Visual impairment less critical11
i. Joyce N. Proliferative capacity of the corneal endothelium. Prog Retin Eye Res 2003; 22:3:359-89.
ii. Gipson IK, Spurr-Michaud S, Tisdale A, Elwell J, Stepp MA. Redistribution of the hemidesmosome components alpha 6 beta 4 integrin and bullous pemphigoid antigens during epithelial wound healing. Exp Cell Res 1993;207:1:86-98.

The rate of epithelial shedding is higher within the central cornea vs. the peripheral cornea, induced by molecules such as PKC and MAPK,7 leading to a higher cell-turnover rate centrally. For nutrients and oxygen, the central cornea relies mostly on the tear film and aqueous while the peripheral cornea depends on the blood supply from surrounding capillaries.8 Glucose, amino acids, vitamins, and minerals diffuse mainly from the aqueous to the central corneal epithelium and oxygen diffuses from the tears. The capillaries surrounding the cornea also provide soluble proteins such as serum albumin for the peripheral cornea, which then diffuse into the central cornea. Serum albumin levels within the peripheral cornea were found to be three times higher than in the central cornea.9

Researchers have also begun investigating the roles of various mucins within the central and peripheral cornea. The membrane-associated mucins MUC 1 and 16 have been demonstrated to be dispersed throughout the two corneal regions. However, MUC 4, another membrane-associated mucin, is present in higher levels in the periphery, which may be associated with serum albumin found in capillaries around the peripheral cornea. The central cornea, on the other hand, displays low levels of MUC 4.10 The variations in expression of these important mucins affect the manifestation of dry-eye conditions within the two regions of the cornea.

Also important when considering disease and ocular function is visual clarity of the central vs. peripheral cornea. Generally, the central 5 mm must be clear or an individual will experience glare. Visual impairment within the peripheral cornea, in contrast, is less critical.11 

 • Approach to pathology. The anatomical and physiological differences between the two corneas can account for variations in how certain diseases and conditions are manifested. For instance, central corneal thickening can be attributed to scleroderma12 and systemic sclerosis,13 which are not associated with thickening in the peripheral cornea. Another example is the herpes simplex virus, which presents as classic dendrites with a shorter time course in the central cornea and produces more indolent, short, serpiginous defects peripherally.14

Table 3. Differences in Pathology
Central Cornea Peripheral Cornea
• Oxygen deficiency and buildup of lactic acid in the stroma results in osmotic imbalance and corneal swelling—increased thickness of central cornea; can be attributed to scleroderma and systemic sclerosis13 • HSV appears as classic dendrites with a shorter time course in central cornea and produces more indolent, short, serpiginous defects peripherally14
• Central cornea prone to hypoxia and first part of cornea to exhibit stromal swelling15 • Peripheral cornea subject to melts, Mooren's ulcer and otherautoimmune disease20
• Central cornea perforates in severe dry eye state19,20,i,ii • Peripheral cornea has higher
incidence of immune infiltrates21
• Vitamin A deficiency in central corneaiii • Peripheral cornea prone to pellucid marginal degenerationiv
i. Lamberts D. Dry Eyes. In: Smolin G, Thoft A, eds. The Cornea. Boston: Little, Brown and Co., 1983:293-308.
ii. Tarasova LN, Kudriashovs IU. Clinical picture of pure corneal ulcers of different localizations. Vestn Ophthalmol 1999;115:1:29-31.
iii. Thoft R. Dietary deficiency. In: Smolin G, Thoft A, eds. The Cornea. Boston: Little, Brown and Co., 1983:401-411.
iv. Krachmer, JH. Pellucid marginal corneal degeneration. Arch Ophthalmol 1978;96:7:1217-21.

The central cornea is more prone to hypoxia and is the first part of the cornea to exhibit stromal swelling. Oxygen deficiency, chiefly associated with contact lens wear, causes a buildup of lactic acid in the stroma, resulting in osmotic imbalance, and thus corneal swelling manifests as an increase in thickness directed inward toward the anterior chamber.15 Central corneal thickness has actually been shown to be significantly reduced in patients with aqueous tear deficiency dry eye, suggesting that this condition can affect the central cornea more severely.16 This phenomenon may also predispose patients to corneal ulceration seen in some dry-eye patients.

Xerophthalmia is typically associated with central corneal ulcers, primarily caused by vitamin A deficiency. Studies have indicated that the chief effect of vitamin A deficiency in rabbits with xerophthalmia was a superficial epithelial change causing central corneal surface cells to appear "opaque and slightly greasy."17

One study demonstrated the association between rheumatoid arthritis and central ulcerative keratitis in patients with severe dry eye. Although the mechanism of central corneal ulceration is not completely understood, the presence of immune mediators as well as Sjögren's antibodies in the cornea suggests a T-cell mediated autoimmune process.18

Stromal melting has also been associated with dry eye, most often in patients with rheumatoid arthritis.19 The central cornea, being more prone to ulceration and xerophthalmia, therefore has a higher propensity to perforate in comparison to the peripheral cornea.

Being surrounded by blood vessels, the peripheral cornea has a higher concentration of immune cells to provide protection from disease and infection. Corneal infiltrates found in the periphery are normally sterile and self-limiting, whereas central infiltrates tend to be infectious and may lead to ulceration if left untreated.

Staphylococcus is the most common cause of central bacterial corneal ulcers in patients with a previous history of herpetic keratitis, bullous keratopathy, atopic disease and dry-eye conditions.20

The peripheral cornea is subject to melts, Mooren's ulcer, collagen vascular diseases and infiltration associated with other autoimmune diseases, all of which leave the central cornea unaffected. Peripheral corneal diseases caused by a hypersensitivity reaction to marginal antigens or from excessive contact lens wear include catarrhal infiltrates, ulcers and phlyctenules. These lesions are normally not found in the central cornea.21

Table 4. Differences in Therapy
Central Cornea Peripheral Cornea
• Antiviral agents work better for the central cornea. • Steroids work best for the peripheral cornea.
(See "Marginal infiltrates: a mysterious malady," Therapeutic Topics, January 2005.)

It's important to consider the differences between the "two corneas" when evaluating disease pathologies, since certain diseases affect the central cornea and not the peripheral, or vice versa. Carefully evaluating both corneal regions can provide evidence of old immune infiltrates or melts, autoimmune diseases, and aging conditions such as pellucid marginal degeneration. As a whole, the anatomical, physiological and pathological differences between the two corneas have important implications in areas such as corneal wound healing, contact lens wear and the effectiveness of therapies for various corneal diseases.
Future treatments that target ocular surface diseases will do well to consider the differences between our two corneas. 

Dr. Abelson, an associate clinical professor of ophthalmology at Harvard Medical School and senior clinical scientist at Schepens Eye Research Institute, consults in ophthalmic pharmaceuticals.

Mr. Ousler is director of the dry-eye department and Ms. Plumer is manager of medical communications at Ophthalmic Research Associates in North Andover.

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