Chapter 43
Corneal Problems in Systemic Disease
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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.

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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,4–16 hyperlipidemia,17,18 gout,19–22 cystinosis,23–29 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.33–35

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.36–39 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

  1. Metabolic and Endocrine Disorders
    1. Disorders of carbohydrate metabolism
      1. Diabetes mellitus. Deep stromal vascularization (rare); fold in Descemet's membrane; decreased corneal sensation; neurotrophic ulcerations44–46
      2. Glycogen storage disease of von Gierke. Marginal clouding of the cornea2,3
      3. Mucopolysaccharidosis (MPS IH, IS, IIB, IV, VIA, VIB, VII—variable). Bilateral clouding of the stroma; megalocornea (rare)4–16
      4. Lipid proteinosis (Urbach-Wiethe disease). Corneal ulceration due to lid margin infiltration (rare)3,47
      5. Dermochondral corneal dystrophy (of François). Superficial (subepithelial) central opacities3,48

    2. Disorders of lipid metabolism
      1. Hyperlipidemia. Discrete or generalized deposition of lipid throughout the cornea with secondary vascularization17,18
      2. Glycolipid lipidosis (Fabry's disease). Bilateral golden epithelial whorls, "vortex dystrophy,49–53
      3. Tay-Sachs disease and variants. Fine granular stromal opacities15
      4. Refsum's disease. Epithelial and stromal edema with vascularization and guttata54
      5. Familial plasma cholesterol ester (LCAT) deficiency. Fine gray stromal dots, gray areas55
      6. High-density alpha-lipoprotein deficiency (Tangier disease). Posterior stromal whorllike clouding17,56,57
      7. Histiocytosis X ( Hand-Schüller-Christian disease and Letterer-Siwe disease). Yellow white stromal haze (rare)58
      8. Mucolipidosis. Vascularization, annular opacification, peripheral thinning, flecklike epithelial or stromal opacities59–63
      9. Gangliosidosis type 2 (Sandhoff's disease). Stromal opalescence64

    3. Disorders of protein metabolism
      1. Gout. Band-shaped keratopathy—urate crystals (rare); marginal keratitis with ulceration (rare); punctate keratitis (rare)19–22
      2. Familial primary systemic amyloidosis. Bilateral latticelike stromal corneal deposits65

    4. Disorders of amino acid metabolism
      1. Cystinosis. Glistening crystal deposition in stroma23–29
      2. Alkaptonuria and ochronosis. Fine, brown superficial deposits in periphery (rare)1,66,67
      3. Porphyria. Exposure keratitis (rare); keratomalacia (rare) 68,69
      4. Tyrosinosis. Stellate corneal ulcers (bilateral); scarring, vascularization70,71
      5. Tyrosinemia (Richner-Hanhart syndrome). “Dendritic” ulcers72
      6. Phenylketonuria. Nonspecific opacities73

    5. Disorders of mineral metabolism
      1. Wilson's disease (hepatolenticular degeneration). Multicolored deposits in peripheral Descemet's membrane (Kayser-Fleischer ring)30,31
      2. Argyrosis. Grayish discoloration in peripheral deep stroma and Descemet's membrane3
      3. Chrysiasis. Purple or red stippling of peripheral stroma3
      4. Hypophosphatasia (Rathbun's syndrome) Band-shaped keratopathy74
      5. Idiopathic infantile hypercalcemia. Band-shaped keratopathy77,78
      6. Milk-alkali syndrome. Band-shaped keratopathy77
      7. Mercury exposure. Band shaped keratopathy79

    6. Thyroid disorders
      1. Hyperthyroidism. Exposure keratitis and ulceration (rare); superior limbic keratitis; superficial vertical corneal striations secondary to eyelid pressure80,81
      2. Hypothyroidism. Transient grayish central opacities (rare)82

    7. Pituitary disorders

        Laurence-Moon-Biedl syndrome. Keratoconus (rare)83,84

    8. Parathyroid disorders
      1. Hyperparathyroidism Band-shaped keratopathy32,85–87
      2. Hypoparathyroidism. Superficial keratitis (rare)87

    9. Endocrine neoplasia (multiple)

        Sipple-Gorlin syndrome (IIB). Corneal nerve medullation88,89

  2. Hematologic Disorders
    1. Anemia

        Chronic anemia (e.g., spherocytic anemia). Bilateral granular ringlike epithelial pigmentation (rare)3

    2. Dysproteinemias
      1. Macroglobulinemia. Central deep clouding of stroma90
      2. Cryoglobulinemia. Amorphous opacities of posterior cornea91
      3. Multiple myeloma. Crystals (cholesterol) in stroma (rare); central, deep, amorphous opacities of stroma; band-shaped keratopathy (rare)92–95

  3. Connective Tissue (Collagen) Disorders
    1. Rheumatoid arthritis, adult. Punctate keratopathy; marginal thinning with occasional perforation; bilateral central stromal opacities (rare); band-shaped keratopathy (rare)33
    2. Rheumatoid arthritis, juvenile. Band-shaped keratopathy96
    3. Systemic lupus erythematosus. Bilateral interstitial keratitis; superficial keratitis; corneal scarring; bilateral band-shaped keratitis97–100
    4. Discoid lupus erythematosus. Corneal irritation, vascularization and infiltration101
    5. Scleroderma. Ground-glass opacities (rare); circular epithelial snowflakes and transient ulceration (rare); decreased corneal sensation102
    6. Polyarteritis nodosa. Furrow ulceration of limbus with sclerosing keratitis; epithelial edema and punctate breakdown; interstitial keratitis (rare)32,103
    7. Wegener's granulomatosis. Perilimbal corneal infiltration with ring ulcer and sclerosing keratitis34,35,104–106
    8. Anklyosing spondylitis. Keratic precipitates107–109
    9. Sjögren's syndrome. Punctate keratitis; filamentary keratitis110
    10. Relapsing polychondritis. Punctate keratitis; filamentary keratitis115,116
    11. Reiter's syndrome. Keratitis; epithelial edema; peripheral erosions and infiltrates, corneal ulcerations and perforation (rare)116,117,252–254

  4. Skin and Mucous Membrane Disorders
    1. Bullous disorders
      1. Pemphigus. Epithelial bullae with secondary breakdown, vascularization, and scarring (especially inferiorly)36–39
      2. Bullous pemphigoid (dermatitis herpetiformis). Epithelial vesicles, ulceration, and scar-ring38, 118, 119
      3. Benign mucous membrane pemphigoid. Epithelial vesicles with erosion and indolent ulceration (rare); marginal ulceration with pannus formation (rare); exposure keratitis118,120–123
      4. Erythema multiforme. Corneal haze; punctate keratitis; ulceration with perforation; severe exposure keratitis with keratinization, vascularization, and scarring40,124
      5. Epidermolysis bullosa. Subepithelial vesicle formation with erosions, ulceration, and infiltrations; corneal perforation40,125–128

    2. Pigmentary disorders

        Xeroderma pigmentosum. Exposure keratitis with possible perforation129–132

    3. Hyperkeratotic disorders
      1. Ichthyosis41,134–136
        1. Primary. Minute punctate opacities anterior to Descemet's membrane; thickening of corneal nerves; nodular thickening of epithelium; refractile nodules of epithelium, anterior stroma, and endothelium; band-shaped keratopathy
        2. Secondary. Epithelial erosion; pannus infiltration

      2. Psoriasis. Epithelial thickening with erosions; sub-Bowman's infiltrate with vascularization; opacification of stroma; perilimbal congestion (rare); punctate filamentary keratitis with subepithelial infiltrates (rare)137,138
      3. Kyrle's disease. Minute, subepithelial yellow brown opacities139

    4. Disorders of skin elasticity

        Ehlers-Danlos syndrome. Microcornea, keratoconus15,140

    5. Disorders involving neoplasia
      1. Juvenile xanthogranuloma. Grayish white limbal mass141
      2. Fabry's disease. Bilateral golden epithelial whorls49–53

    6. Miscellaneous
      1. Acne rosacea. Bilateral marginal vascular infiltration; punctate keratitis; subepithelial vascularized infiltrates with ulceration, perforation (rare)142,143
      2. Hydroa vacciniforme. Exposure keratitis with vesicular eruption and ulceration; diffuse vascularized keratitis144
      3. Ectodermal dysplasia
        1. Anhidrotic ectodermal dysplasia. Granular corneal dystrophy145,146
        2. Werner's syndrome. Bullous keratopathy147–149

  5. Allergies and Hypersensitivity Diseases
    1. Serum sickness. Epithelial edema150,151
    2. Atopic dermatitis. Superficial vascularization and scarring; keratoconus (?)152,153
    3. Erythema multiforme. See skin and mucous membrane disorders`40,124
    4. Erythema nodosum. Phlyctenulelike lesions (rare)3
    5. Vernal catarrh. Epithelial keratitis (upper cornea), syncytial keratitis; micropannus, ulceration, keratoconus (rare)3

  6. Muscular Disorders

      Myotonic dystrophy. Epithelial dystrophy; decreased corneal sensation; exposure keratitis and pannus formation (rare)154

  7. Skeletal Disorders
    1. Facial deformity syndromes
      1. Facial hemiatrophy (Romberg's disease). Glassy opacities of posterior stroma (rare)155
      2. Mandibulo-oculofacial dyscephaly (Hallermann-Streiff syndrome). Sclerocornea, microcornea156

    2. Cranial deformity syndromes
      1. Oxycephaly (tower skull). Megalocornea (rare)157,158
      2. Platybasia. Decreased corneal sensation157,159

    3. Generalized skeletal disorders
      1. Acrocephalosyndactyly (Apert's disease). Keratoconus (rare)157,160–162
      2. Morquio-Ullrich disease. Clouding of superficial stroma (rare)163
      3. Blue sclera, brittle bones, deafness (osteogenesis imperfecta, Van der Hoeve's syndrome). Megalocornea, embryotoxin; keratoconus164
      4. Marfan's syndrome. Megalocornea (rare); pseudopannus; corneal-flattening high astigmatism,15,165–167
      5. Paget's disease. Oval gray opacities at Bowman's membrane; spheroidal bodies in Bowman's membrane; gray brown opacities at Descemet's membrane (rare)168–170
      6. Cerebrohepatorenal syndrome of Zellweger. Corneal edema, focal attenuation of Descemet's membrane171
      7. de Lange's syndrome. Microcornea, opacities172,173

  8. Gastrointestinal and Nutritional Disorders
    1. Ulcerative colitis. Bilateral marginal infiltrates and ulceration (rare)174–176
    2. Regional enteritis. Bilateral marginal infiltrates and ulceration (rare)
    3. Hepatic disease. Icterus; Kayser-Fleischer ring178
    4. Malabsorption syndrome. Corneal scratches (rare); unilateral keratitis (rare)179–182
    5. Pancreatic disease. See hyperparathyroidism and diabetes mellitus under Metabolic and Endocrine Disorders
    6. Vitamin deficiency states
      1. Vitamin A. Keratomalacia183–185
      2. Vitamin C. Exposure keratitis secondary to proptosis186
      3. Vitamin B complex. Keratinization; decreased corneal sensation; corneal ulceration and perforation (rare)187

    7. Hypervitaminosis states

        Vitamin D. Corneal calcification18

    8. Starvation. Keratomalacia; keratinization; decreased corneal sensation and perforation; exposure keratitis secondary to proptosis179–183,186,187
    9. Alcoholism. See vitamin deficiency states
    10. Toxic drug ingestions
      1. Chloroquine intake. Epithelial whorllike pattern189
      2. Indomethacin intake. Epithelial whorllike pattern190

    11. Intestinal parasites
      1. Amebiasis. Corneal ulceration; unilateral neurolytic keratitis191–193
      2. Sleeping sickness. Interstitial keratitis; Kayser-Fleischer-like ring194–196
      3. Malaria. Dendritic keratitis; interstitial keratitis; decreased corneal sensation197,198
      4. Cysticercosis. Interstitial keratitis199,200
      5. Onchocerciasis. Interstitial keratitis201–203
      6. Schistosomiasis. Interstitial keratitis; corneal nebulae204

  9. Renal Diseases
    1. Chronic. Band-shaped keratopathy; exposure keratitis205–207
    2. Alport's syndrome. Corneal thickening; corneal arcus and pigmentation208,209

  10. Infectious and Inflammatory Diseases
    1. Viral diseases
      1. Varicella. Vesicular lesions of limbus (rare); superficial punctate keratitis (rare); phlyctenular keratitis; corneal ulceration; interstitial keratitis210,211
      2. Herpes zoster. Discrete superficial and deep stromal infiltrates; Descemet's folds or ruptures (rare); vascularization';, transient decreased corneal sensation; epithelial and subepithelial punctate keratitis 212,213
      3. Rubella. Superficial (mild) keratitis214,215
      4. Rubeola. Superficial punctate keratitis; ulceration (rare); interstitial keratitis with occasional perforation (rare); superficial pannus3,216
      5. Vaccinia. Corneal ulceration and perforation (rare); central deep disciform keratitis with vascularization and decreased corneal sensation; grayish persistent subepithelial opacity; dendritic corneal ulceration (rare)97,217
      6. Herpes simplex. Punctate keratitis; dendritic keratitis; geographic (ameboid) keratitis; disciform stromal keratitis with or without ulceration and perforation; decreased corneal sensation; corneal scarring and late vascularization218–220
      7. Mumps. Interstitial keratitis (deep unilateral); superficial punctate keratitis (rare); corneal ulceration and scarring (rare)221–223
      8. Cytomegalic inclusion disease. Diffuse corneal opacities; keratomalacia; perforation with hypopyon224
      9. Molluscum contagiosum. Superficial punctate keratitis; epithelial and subepithelial infiltrates225
      10. Lymphogranuloma venereum. Superficial keratitis; thickened corneal nerves; keratoconus (?); punctate infiltrates with vascularization226–228
      11. Variola. Superficial pustules; ulceration and perforation (rare)97,229
      12. Influenza. Superficial punctate keratitis; dendritic keratitis (?); herpes simplex; interstitial keratitis3
      13. Pharyngoconjunctival fever. Punctate epithelial keratitis (rare); epithelial-subepithelial opacities (rare); subepithelial opacities (rare); linear or stellate opacities (rare)3
      14. Infectious mononucleosis. Nummular interstitial keratitis230

    2. Rickettsial diseases Typhus

        Epidemic. Keratitis and corneal ulceration (rare)231

    3. Bacterial diseases
      1. Tularemia. Ulceration and perforation (rare); limbal nodules with pannus232
      2. Brucellosis. Keratitis; ulceration233,234
      3. Diphtheria. Central ulceration235

    4. Mycobacterial diseases
      1. Tuberculosis. Band-shaped keratopathy; deep posterior abscess (rare); ,interstitial keratitis; phlyctenule3
      2. Leprosy. Exposure keratitis; decreased corneal sensation; superficial superior keratitis with late vascularization; beading of corneal nerves; reddish colored leproma with staphyloma; avascular keratitis of any layer43,236–239

    5. Spirochetal diseases
      1. Syphilis. Interstitial keratitis; suppurative keratitis with hypopyon (rare); deep punctate keratitis (rare); keratitis linear migrans (rare); corneal marginal ulceration (rare); posterior corneal abscess with ulcer; peripheral superficial opacification—late (rare)240
      2. Relapsing fever. Superficial interstitial keratitis; band-shaped keratopathy (rare); bullous keratopathy (rare)241,242

    6. Mycotic infections
      1. Candidiasis. Chronic, indolent, densely opaque ulceration243
      2. Mucormycosis. Exposure keratitis with secondary ulceration and perforation; decreased corneal sensation244,245

    7. Protozoan diseases
      1. Toxoplasmosis. Microcornea (rare)246
      2. Malaria. Dendritic keratitis; hypopyon corneal ulcers (rare)
      3. Leishmaniasis (American). Superficial stromal keratitis with vascularization and epithelial ulceration247

    8. Helminthic diseases
      1. Flatworms (cestodes)
        1. Cysticercosis (Taenia solium). Interstitial keratitis199,200
        2. Echinococcosis. Exposure keratitis secondary to proptosis; corneal ulceration (rare)248

      2. Roundworms (nematodes)

          Onchocerciasis. Microfilariae in stroma; superficial punctate keratitis with stromal opacities201–203

    9. Inflammatory diseases of unknown etiology
      1. Sarcoidosis. Band-shaped keratopathy (rare); decreased corneal sensation (rare); corneal ulceration (rare); interstitial keratitis (rare)249–251
      2. Reiter's syndrome. Keratitis; epithelial edema; peripheral erosion and infiltrates; corneal ulceration and perforation (rare)116,117,252–254
      3. Behçet's disease. Superficial punctate keratitis (rare); recurrent epithelial erosion (rare); circumscribed stromal vascularized opacity (rare); hypopyon ulcer (rare)3,255
      4. Cogan's interstitial keratitis syndrome. Marginal corneal melting; deep vascularized opacity; patchy marginal infiltrates256,257

  11. Neoplastic Diseases
    1. Lymphomas
      1. Hodgkin's disease. Superficial keratitis with vascularization (?); keratitis sicca (?); limbal nodule258, 259

    2. Metastatic disease. Exposure keratitis secondary to proptosis260,261
    3. Multiple myeloma. See dysproteinemias under Hematologic Disorders

  12. Chromosomal Disorders
    1. Trisomy 21 (mongolism). Keratoconus262,263
    2. Trisomy 13 (Patau's syndrome). Microphthalmic microcornea; cornea plana; scleralization264
    3. Trisomy 18 (Edwards' syndrome). Corneal opacities (rare); hyperplastic corneal endothelium265
    4. Turner's syndrome. Corneal nebulae, microcornea266,267
    5. Klinefelter's syndrome. Radial, linear stromal opacity; superior pseudopannus141

  13. Phakomatoses

      Neurofibromatosis (von Recklinghausen's disease). Giant corneal nerves with bullous nodules; unilateral keratoconus (?) 42,268

  14. Neurologic Diseases

      Adie's syndrome. Decreased corneal sensation269

  15. Congenital Disorders
    1. Anencephaly. Corneal dermoids; stromal thickening, mild hazing270
    2. Mieten's syndrome. Microsclerocornea271



TABLE 2. Corneal Conditions and Their Systemic Causes

  1. Corneal Vascularization
    1. Superficial
      1. Hyperlipidemia17,18
      2. Refsum's disease54
      3. Pemphigus36–39
      4. Psoriasis137, 138
      5. Acne rosacea142, 143
      6. Atopic dermatitis152, 153
      7. Herpes simplex218–220
      8. Molluscum contagiosum225
      9. Lymphogranuloma venereum226–230
      10. Hodgkin's disease258,259
      11. Leprosy43, 236–239
      12. Rubeola3, 216
      13. Marfan's syndrome15, 165,167
      14. Ichthyosis41,133–136
      15. Reiter's syndrome116, 117, 252, 254
      16. Benign mucous membrane pemphigoid114,120–123
      17. Rheumatoid arthritis, adult
      18. Vernal catarrh3
      19. Mucolipidosis59–63

    2. Deep (stromal)
      1. Diabetes mellitus (rare)44–46
      2. Hyperlipidemia17,18
      3. Refsum's disease54
      4. Rheumatoid arthritis, adult33
      5. Hydroa vacciniforme140
      6. Herpes zoster212, 213
      7. Herpes simplex218, 220
      8. Vaccinia97, 217
      9. Behçet's disease (rare)3, 255
      10. Tuberculosis3
      11. Syphilis240
      12. Sleeping sickness194–196
      13. Malaria198, 199
      14. Onchocerciasis201–203
      15. Schistosomiasis204
      16. Scleroderma102
      17. Polyarteritis nodosum32, 103
      18. Wegener's granulomatosis32, 35, 104–106
      19. Systemic lupus erythematosus97–100
      20. Discoid lupus erythematosus101
      21. Cogan's interstitial keratitis syndrome256, 257
      22. Leishmaniasis (American)

  2. Folds in Descemet's Membrane
    1. Diabetes mellitus44–46
    2. Mumps221–223
    3. Herpes zoster (rare)212, 213

  3. Decreased Corneal Sensation
    1. Diabetes mellitus44–46
    2. Scleroderma102
    3. Myotonic dystrophy150
    4. Platybasia153,155
    5. Vitamin B complex deficiency disease183
    6. Starvation179–183, 186, 187
    7. Amebiasis191–193
    8. Malaria197, 198
    9. Herpes zoster212, 213
    10. Vaccinia97,217
    11. Herpes simplex218–220
    12. Leprosy43,236–239
    13. Mucormycosis244, 245
    14. Sarcoidosis (rare)249–251
    15. Adie's syndrome269

  4. Corneal Clouding (Deposition of Material)
    1. Central
      1. Mucopolysaccharidosis (MPS IH, IS, IIB, IV, VIA, VIB, VII--variable)4–16
      2. Hyperlipidemia 17,18
      3. Cystinosis23–29
      4. Argyrosis3
      5. Multiple myeloma92–95

    2. Marginal
      1. Glycogen storage disease of yon Gierke2,3
      2. Hyperlipidemia17, 18
      3. Cystinosis23–29
      4. Alkaptonuria and ochronosis1, 66, 67
      5. Wilson's disease30,31
      6. Argyrosis3
      7. Chrysiasis3
      8. Chronic spherocytic anemia3
      9. Ichthyosis41, 133–136
      10. Amebiasis191-19
      11. Familial plasma cholesterol ester deficiency55
      12. Mucolipidosis59–63

  5. Corneal Opacities
    1. Superficial (discrete)
      1. Dermochondral corneal dystrophy of François3,48
      2. Ichthyosis41,133–136
      3. Anhidrotic ectodermal dysplasia145,146
      4. Paget's disease168–170
      5. Herpes zoster212,213
      6. Vaccinia97, 217
      7. Lymphogranuloma venereum226–228
      8. Kyrle's disease139

    2. Superficial (diffuse)
      1. Erythema multiforme40, 124
      2. Epidermolysis bullosa40, 125–128
      3. Pemphigus36–39
      4. Bullous pemphigoid38,118,119
      5. Myotonic dystrophy154
      6. Molluscum contagiosum225

    3. Deep (discrete)
      1. Ichthyosis41, 133–136
      2. Tay-Sachs disease and variants15
      3. Rheumatoid arthritis, adult33
      4. Trisomy 18265
      5. Turner's syndrome266,267
      6. Van der Hoeve's syndrome164
      7. Paget's disease168–170
      8. Schistosomiasis204
      9. Herpes zoster212, 213
      10. Syphilis (rare)240
      11. Behçet's disease3, 255
      12. Multiple myeloma92–95
      13. Familial plasma cholesterol ester (LCAT) deficiency55
      14. Cogan's interstitial keratitis syndrome256, 257
      15. Scleroderma102
      16. Cystinosis23–29
      17. Klinefelter's syndrome141
      18. de Lange syndrome172, 173

    4. Deep (diffuse)
      1. Hypothyroidism (rare)82
      2. Hyperparathyroidism32,85–87
      3. Cryoglobulinemia91
      4. Facial hemiatrophy155
      5. Hydroa vacciniforme144
      6. Multiple myeloma92–95
      7. Scleroderma102
      8. Psoriasis137
      9. Cytomegalic inclusion disease224
      10. Histiocytosis X (rare)58

  6. Epithelial Whorllike Configuration (Vortex Pattern)
    1. Glycolipid lipidosis (Fabry's disease)49–53
    2. Chloroquine administration189
    3. Indomethacin toxicity190

  7. Edema
    1. Epithelial
      1. Refsum's disease54
      2. Polyarteritis nodosa32,103
      3. Reiter's syndrome 112,117,252–254
      4. Werner's syndrome147–149
      5. Serum sickness150,151
      6. Relapsing fever (rare)241, 242

    2. Stromal
      1. Refsum's disease54
      2. Herpes simplex218–220
      3. Cerebrohepatorenal syndrome of Zellweger171

  8. Band-Shaped Keratopathy
    1. Gout19–22
    2. Hypophosphatasia74
    3. Hyperparathyroidism32,85–87
    4. Hypercalcemia75,76
    5. Rheumatoid arthritis adult (rare
    6. Rheumatoid arthritis, juvenile96
    7. Systemic lupus erythematosus97–100
    8. Ichthyosis41, 133–136
    9. Relapsing fever (rare]241, 242
    10. Hypervitaminosis D188
    11. Chronic renal disease205–207
    12. Tuberculosis3
    13. Sarcoidosis (rare)249–251

  9. Corneal Ulceration
    1. Central
      1. Scleroderma (rare)102
      2. Hydroa vacciniforme144
      3. Vitamin B complex deficiency (rare)187
      4. Starvation179–183, 186, 187
      5. Amebiasis191–193
      6. Varicella210,211
      7. Rubeola (rare)3
      8. Vaccinia97, 217
      9. Mumps221–223
      10. Molluscum contagiosum225
      11. Behçet's disease (rare) 3, 255
      12. Sarcoidosis249–251
      13. Variola97,229
      14. Epidemic typhus231
      15. Tularemia232
      16. Brucellosis233, 234
      17. Candidiasis243
      18. Malaria (rare)198, 199
      19. Echinococcosis248
      20. Tyrosinosis70,71
      21. Tyrosinemia72
      22. Diphtheria235
      23. Diabetes mellitus44–46
      24. Leishmaniasis (American)247

    2. Marginal
      1. Lipid proteinosis-Urbach-Wiethe disease (rare)3, 47
      2. Gout19–22
      3. Hyperthyroidism (rare)80, 81
      4. Polyarteritis nodosa32, 103
      5. Wegener's granulomatosis32, 35, 104–106
      6. Reiter's syndrome116, 117, 252–254
      7. Benign mucous membrane pemphigoid118, 120–123.
      8. Acne rosacea142, 143
      9. Erythema multiforme40,124
      10. Ulcerative colitis (rare)174–176
      11. Regional enteritis (rare)174–177
      12. Syphilis240

  10. Megalocornea
    1. Mucopolysaccharidosis (rare)4–16
    2. Oxycephaly (rare)157, 158
    3. Van der Hoeve's syndrome164
    4. Marfan's syndrome15, 165–167

  11. Microcornea
    1. Ehlers-Danlos syndrome15,140
    2. Toxoplasmosis246
    3. Trisomy 12 (microphthalmic)264
    4. Turner's syndrome266, 267
    5. Mieten's syndrome271
    6. Hallermann-Streiff syndrome156

  12. Keratomalacia
    1. Porphyria (rare)68,69
    2. Scleroderma102
    3. Wegener's granulomatosis32,35,104–106
    4. Vitamin A deficiency183–185
    5. Starvation179–183, 186, 187
    6. Cytomegalic inclusion disease224
    7. Polyarteritis nodosa32,10
    8. Rheumatoid arthritis, adult33

  13. Corneal Thinning
    1. Central (keratoconus)
      1. Laurence-Moon-Biedl syndrome (rare)83,84
      2. Ehlers-Danlos syndrome15,136
      3. Atopic dermatitis (7)152,153
      4. Acrocephalosyndactyly, Apert's disease (rare)157,160–162
      5. Van der Hoeve's syndrome164
      6. Lymphogranuloma venereum (?)226–228
      7. Mongolism262, 263
      8. Neurofibromatosis, unilateral G)42, 268
      9. Vernal catarrh (rare)3

    2. Marginal
      1. Rheumatoid arthritis, adult33
      2. Gout19–22
      3. Polyarteritis nodosa
      4. Wegener's granulomatosis32, 35, 104–106
      5. Relapsing polychondritis 115,116
      6. Scleroderma102
      7. Mucolipidosis59–63

  14. Superficial Keratitis
    1. Punctate
      1. Gout19–22
      2. Hypoparathyroidism87
      3. Rheumatoid arthritis, adult33
      4. Polyarteritis nodosa32,103
      5. Sjögren's syndrome110–114
      6. Relapsing polychondritis115,116
      7. Reiter's syndrome116,117,252–254
      8. Erythema multiforme40,124
      9. Psoriasis137,138
      10. Acne rosacea142, 143
      11. Varicella210,211
      12. Herpes zoster212, 213\
      13. Rubella214,215
      14. Rubeola3, 216
      15. Herpes simplex216–220
      16. Mumps (rare)221–223
      17. Molluscum contagiosum225
      18. Lymphogranuloma venereum226–228
      19. Influenza3
      20. Pharyngoconjunctival fever3
      21. Leprosy43,236–239
      22. Onchocerciasis201–203
      23. Behçet's disease (rare)3, 255

    2. Marginal
      1. Gout19–22
      2. Ulcerative colitis (rare)174–176
      3. Regional enteritis (rare)174–177

    3. Exposure
      1. Porphyria68,69
      2. Hyperthyroidism80,81
      3. Benign mucous membrane pemphigoid118,12–123
      4. Xeroderma pigmentosum129–132
      5. Hydroa vacciniforme144
      6. Myotonic dystrophy154
      7. Vitamin B complex deficiency187
      8. Echinococcosis248
      9. Mucormycosis244, 245
      10. Starvation179–181,186,187
      11. Chronic renal disease205–207
      12. Leprosy43,236–239
      13. Metastatic disease260,261
      14. Multiple myeloma92–95

    4. Filamentary
      1. Sjögren's syndrome110–114
      2. Relapsing polychondritis
      3. Psoriasis137,138
      4. Sarcoidosis249–253
      5. Benign mucous membrane pemphigoid118,120–123
      6. Erythema multiforme40,124

    5. Nodular
      1. Ichthyosis41, 133–136'
      2. Erythema nodosum3
      3. Varicella210,211
      4. Molluscum contagiosum225
      5. Tularemia232
      6. Tuberculosis3
      7. Leprosy43,236–239
      8. Hodgkin's disease258, 259

    6. Dendritic
      1. Malaria198, 199
      2. Vaccinia (rare)196,217
      3. Herpes simplex218–220
      4. Herpes zoster212, 213
      5. Influenza3
      6. Tyrosinemia (Richner-Hanhart syndrome)72

  15. Deep (Interstitial) Keratitis
    1. Systemic lupus erythematosus97–100
    2. Polyarteritis nodosa32, 103
    3. Sleeping sickness194–196
    4. Malaria197, 198
    5. Onchocerciasis201–203
    6. Schistosomiasis204
    7. Varicella210,211
    8. Rubeola3
    9. Vaccinia196, 217
    10. Herpes simplex218–220
    11. Mumps221–223
    12. Influenza3
    13. Syphilis240
    14. Tuberculosis3
    15. Relapsing fever241,242
    16. Cysticercosis199, 200
    17. Sarcoidosis (rare)249–253
    18. Leishmaniasis (American)247
    19. Infectious mononucleosis230

  16. Epithelial Bullae (Not Related to Edema)
    1. Pemphigus36–39
    2. Bullous pemphigoid dermatitis herpetiformis)38,118,119
    3. Benign mucous membrane pemphigoid 118,120–123
    4. Epidermolysis bullosa40, 125–128
    5. Varicella210,211
    6. Hydroa vacciniforme144

  17. Corneal Nerve Thickening (or Beading)
    1. Ichthyosis41, 133–136
    2. Lymphogranuloma venereum226–228
    3. Leprosy43,236–239
    4. Neurofibromatosis42,268
    5. Sippie-Gorlin syndrome (IIB)88, 89
    6. Refsum's disease54

  18. Pannus Formation
    1. Benign mucous membrane pemphigoid (rare)118, 120–123
    2. Ichthyosis41, 133–136
    3. Acne rosacea142, 143
    4. Myotonic dystrophy (rare)154
    5. Marfan's syndrome (pseudopannus)15, 165–167
    6. Rubeola3
    7. Tularemia232
    8. Hodgkin's disease (?)258, 259
    9. Klinefelter's syndrome141
    10. Vernal catarrh (pseudopannus)3

  19. Limbal Masses
    1. Juvenile xanthogranuloma141
    2. Leprosy43,236–239
    3. Tuberculosis (?)3
    4. Tularemia232
    5. Anencephaly270

  20. Keratinization
    1. Bullous pemphigoid38 118, 119
    2. Pemphigus36–39
    3. Benign mucous membrane pemphigoid118, 120–123
    4. Erythema multiforme40,120
    5. Epidermolysis bullosa40, 125–128
    6. Vitamin B complex deficiency 187
    7. Starvation179–183, 186, 187
    8. See causes of exposure keratitis under Superficial Keratitis

  21. Corneal Perforations (With or Without Hypopyon)
    1. Reiter's syndrome (rare116 117,252–256
    2. Erythema multiforme 40,124
    3. Epidermolysis bullosa40,125–128
    4. Xeroderma pigmentosum (rare)187
    5. Rheumatoid arthritis, adult (rare)33
    6. Acne rosacea (rare)142, 143
    7. Vitamin B complex deficiency (rare)187
    8. Rubeola (rare)3,216
    9. Vaccinia (rare)97,217
    10. Herpes simplex218–220
    11. Cytomegalic inclusion disease224
    12. Variola (rare)97, 229
    13. Tularemia (rare)232

  22. Epithelial Thickening (Not Related to Edema)
    1. Psoriasis137, 138
    2. Ichthyosis41, 133–136

  23. Stromal Thickening (Not Related to Edema)
    1. Alport's syndrome208, 209
    2. Anencephaly270

  24. Sclerocornea
    1. Mieten's syndrome271
    2. Hallermann-Streiff syndrome156


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