Corneal Problems in Systemic Disease
Stephen P. Ginsberg
EMBRYOLOGY AND ANATOMY OF THE CORNEA
The cornea begins to assume its final structural orientation during the fifth week of gestation. Nearby mesodermal cells extend anteriorly into a position just beneath the surface ectoderm. These cells later differentiate to form the corneal endothelium. The surface ectoderm continues to differentiate until it finally becomes a five-cell-thick layer. Later, a second wave of mesoderm invades the fibrillary matrix already laid down, and these new mesodermal cells subsequently differentiate to form the substantia propria, or corneal stroma. During the fourth month of gestation, Bowman’s layer and Descemet’s membrane appear.
In the final months of gestation, the cornea increases slightly in thickness, and by birth its diameter has increased to approximately 10.0 mm. The final full dimensions of the cornea are reached at approximately 1 year of age.
When viewed from the anterior surface, the adult cornea measures approximately 11.7 mm in the horizontal plane and 10.6 mm in the vertical plane. The central corneal thickness is approximately 0.52 mm, and there is a gradual increase in corneal thickness until approximately 0.67 mm is reached near the limbus.
The sensory nerve supply to the cornea is one of the richest in the eye. Most of the nerves to the cornea are derived from the ophthalmic division of the fifth cranial nerve. Some superficial nerves enter from the subconjunctival and episcleral regions, but most of the nerves enter from the sclera. Finally, approximately 70 to 80 large nerves enter the cornea in its middle third. The nerves are myelinated in the peripheral 2 to 3 mm of the cornea but are nonmyelinated from that point centrally. There is characteristic dichotomous and trichotomous branching in the stroma.
The peripheral cornea is supplied by conjunctival, episcleral, and scleral blood vessels. These vessels are the terminal branches of the circumcorneal vascular supply. They are found in all levels of the limbus and in the anterior sclera in the region of Schlemm’s canal. Normally there are no blood vessels found in the cornea beyond the limbal structures, but in disease states these vessels frequently invade the cornea at a level corresponding to the disease process.
Most (90%) of the corneal stroma is composed of collagen lamellae. There are fibroblasts (keratocytes) and ground substance (mucopolysaccharides) within this lamellar network. Occasionally, lymphocytes, macrophages, and polymorphonuclear leukocytes can be found. The corneal lamellae are oriented parallel to each other and to the surface of the cornea. They are separated by exact spacing and are in most precise arrangement in the deeper layers of the cornea. Any disturbance in the spacing of the fibrils that results from swelling of the cornea or distortion results in decreased corneal clarity, presumably by the induction of interference with light passage.
The epithelial surface of the cornea provides a smooth convexity to incoming light. The corneal epithelium serves also as a barrier to the entrance of tears into the cornea proper. Similarly, the endothelium provides a mechanical barrier to aqueous entrance into the cornea, and most authorities agree that the endothelium also acts to continually pump water from the cornea; this water enters from the limbal circulation or by migration across the anterior and posterior corneal surfaces. The lamellar orientation and the water pump serve to maintain the cornea as a thin and extremely transparent structure. Disturbances in any of these physiologic functions, changes in the lamellar orientation, or invasion of the cornea by blood vessels, scarring, or deposits of extraneous materials can result in corneal opacification and loss of vision.
Systemic diseases manifest themselves in the cornea either directly or indirectly. There are basic anatomical and physiological principles used by the cornea in maintaining its clarity. The basic lamellar arrangement, the absence of corneal vascularization, the smooth convex surface, and the relative dehydration state of the cornea are all factors in its continued transparency. A process that alters any of these structural or physiologic parameters will almost assuredly result in loss of clarity and decreased vision. Those systemic diseases that alter the cornea do so in essentially the same manner as they bring about changes elsewhere in the body. If the major pathologic effect of a disease process is a vasculitis (e.g., the collagen-vascular diseases), then the cornea is also affected primarily with the results of a vasculitis. Similarly, if a disease entity causes the abnormal accumulation or deposition of some substance in the body, then that same substance often accumulates in the cornea and precipitates decreased vision through corneal clouding.
Metabolic disease processes usually result from an enzymatic defect that causes the failure of one substance to convert to another. This blockage results in increased levels of the precursor (or alternate breakdown products) either locally or in the bloodstream whereby it can be transported to distant sites such as the cornea. In ocular ochronosis, for example, a single gene defect results in a deficiency in the enzyme homogentisic acid oxidase. This results in the accumulation of homogentisic acid in the extracellular fluid. The homogentisic acid subsequently oxidizes and polymerizes to an ochronotic pigment in nonmineralized connective tissue. The pigment characteristically layers out along the collagen fibrils in the eye in areas that manifest evidence of previous collagen degeneration or injury.1 Similarly, there is a deposition of accumulated substances in the cornea in systemic conditions such as glycogen storage disease,2,3 mucopolysaccharidoses,4,5,6,7,8,9,10,11,12,13,14,15,16 hyperlipidemia,17,18 gout,19,20,21,22 cystinosis,23,24,25,26,27,28,29 Wilson’s disease,30,31 and argyrosis.3 If systemic therapy is used to correct the abnormal accumulation of a product, then the corneal clouding frequently reverses as well.
Band-shaped keratopathy reflects an abnormal accumulation of a substance (calcium) in the cornea. In typical band keratopathy the calcium crystals are deposited extracellularly along the subepithelial zone and Bowman’s membrane in the form of spherules and conglomerates. On the other hand, in the calcium deposition seen in parathyroidism, the hydroxyapatite crystals are deposited in the nucleus and cytoplasm of the corneal epithelium, keratocytes, and endothelium.32
The connective tissue diseases, however, usually exert their corneal effects indirectly. While the exact mechanism of the so-called autoimmune diseases is not well-known, they seem to act through the production of antibodies to various normal tissues. These antibodies can be either to a tissue found in many areas of the body or to one found only in a single organ. The antigen in the collagen diseases and rheumatic diseases seems to be somewhere in the walls of blood vessels, and the resulting immune reactions lead to vasculitis, ischemia, and tissue necrosis. Arthritis and glomerulonephritis can result. The cornea frequently reveals ischemia of the perilimbal tissues with marginal corneal thinning and ulceration. Progression to keratomalacia and perforation may also occur. The keratitis of severe rheumatoid arthritis, Wegener’s granulomatosis, and polyarteritis nodosa all reflect the basic condition of corneal ischemia.33,34,35
The corneal epithelium is ectodermal in its embryonic origin. Generalized skin and mucous membrane conditions that cause changes in the epidermal layers of the body likewise cause epithelial changes in the cornea. An example of this is seen in the ocular complications of pemphigus.36,37,38,39 The bullae seen over wide areas of the body are also occasionally seen in the cornea as epithelial bullae. These bullae, like their dermal counterparts, break down and scar. Systemic diseases that affect primarily the mucous membranes of the body cause similar changes in the mouth, vagina, and conjunctiva. Erythema multiforme causes widespread destruction of mucous membranes.40 The corneal findings are usually secondary to severe conjunctival shrinkage with subsequent loss of adequate tears coupled with corneal exposure problems.
Ichthyosis is primarily a dermatologic condition that results in epidermal thickening of the cornified corneal epithelium. Of the four different types of ichthyosis, only the so-called lamellar form results in severe scarring of the lower eyelid and subsequent cicatricial ectropion and exposure keratopathy. The early performance of an autoplastic skin graft to the lower lid is vital for the protection of the eye and preservation of vision.41
Some systemic conditions are congenital and reveal abnormalities in the formation of a structural building block. An example of this is seen in the Ehlers-Danlos syndrome. In this condition the body’s collagen bundles are formed abnormally, and these patients manifest increased skin fragility and extensibility of the joints. The cornea also suffers from this abnormal collagen production; structural alterations such as microcornea and keratoconus occur. Similarly, Marfan’s syndrome is occasionally associated with megalocornea.
Four types of collagen have been identified in man. All of these occur in triple helices, but they differ from each other based on the number of hydrolysines per chain, the presence or absence of other amino acids, and their carbohydrate content. Collagen type I is present in tendons, skin, and bone. Each chain is formed by two alpha 1 (type I) and one alpha 2 chains. Type II collagen is common in cartilage, and the whole chain is formed of three identical polypeptides of alpha 1 (type II). Type III collagen exists in fetal skin and blood vessels and is composed of three identical chains of alpha 2 (type III). Type IV collagen is probably specific to basement membranes, where it exists as alpha 1 (type IV) in a triple-helix form. In the human corneal stroma, only type I collagen is found, but a variant containing fructose with greater glycosylation may exist. The defect in Marfan’s syndrome has not been identified as yet but probably represents an abnormality in both type I and type III, with skin, tendons, and bones, as well as blood vessels, being involved.15
There are a host of systemic diseases that cause localized inflammatory reactions. These reactions can be related to localized ischemia or tissue immune reactions, or they may be due to local invasion of organs with infectious organisms. The cornea is especially likely to develop deep inflammatory reactions secondary to either local invasion with infectious agents or immune reactions brought about by the presence of these agents. Bacterial, vital, and parasitic organisms can all cause a deep corneal stromal inflammation called interstitial keratitis. Organisms as different as herpes simplex virus and Cysticercus can cause almost identical reactions in the cornea. The similarity of reaction is not because of the similarity of the inciting agents but is related to the fact that the cornea has only a few ways to react to any insult. The response is seen as a deep stromal opacification with vascular invasion at the level of the inflammation. The classic interstitial keratitis response is seen in syphilis, and although the keratitis may improve with time and treatment, some corneal scarring and associated “ghost” vessels always remain. A few other causes of interstitial keratitis are rubeola, vaccinia, onchocerciasis, and schistosomiasis.
Conditions that affect nerves in the body also affect the corneal nerves. There can be either decreased corneal sensation with normal-appearing nerves or normal corneal sensation with abnormal-appearing nerves. The cornea can become anesthetic either by some metabolic change in the corneal nerve or by some destructive process in the peripheral corneal nerve or trigeminal ganglion. Metabolic conditions that cause peripheral neuropathies, such as diabetes mellitus, vitamin B complex deficiencies, or scleroderma, also result in decreased corneal sensation. Invasion of the corneal nerves with either vital particles or viral products has been postulated as the cause of the decreased corneal sensation seen in herpes simplex and herpes zoster infections; this is a point of great diagnostic importance.
Neurofibromatosis is an hereditary disease that primarily affects peripheral nerves. The corneal nerves are thickened with or without bulbous swelling (neurofibromas?). There may be an associated arcus senilis, and occasionally nummular opacities in the midstroma of the cornea are seen.42 In general, corneal sensation is intact.
Leprosy is another condition that affects the nervous system, but through an infectious process involving an organism, Mycobacterium leprae. Degeneration of the axons and nerve sheath results in a beaded appearance. The organisms cause both hyperplasia and perivascular infiltration in the perineural and endoneural tissues. The bacilli are surrounded by epithelioid cells, plasma cells, and fibroblasts, and each of these accumulations represents a leprous nodule. The bacilli probably reach the nerve by way of the bloodstream.43 In contrast to neurofibromatosis, the nerves are beaded and the corneal sensation is considerably diminished.
Systemic diseases and their corneal manifestations are summarized in Table 1; corneal conditions and their systemic causes are summarized in Table 2.
TABLE 1. Systemic Diseases and Their Corneal Manifestations
TABLE 2. Corneal Conditions and Their Systemic Causes