Corneal and Conjunctival Degenerations

Arcus Senilis

Corneal arcus, also known as arcus senilis after the fourth decade and arcus juvenilis or anterior embryotoxon prior to the fourth decade, is a degenerative change resulting in lipid deposition in the peripheral cornea ( Fig. 75.1 ). Lipid deposition starts clinically as a gray to yellow arc, first in the inferior cornea then the superior cornea. ^, As the deposition gradually progresses, the arcs meet, forming a complete ring.

The arcus has a sharp peripheral border ending at the edge of Bowman layer with a lucent zone (lucid interval of Vogt) to the limbus. The central edge is more diffuse. Fine dots with interweaving lines can be seen at the slit lamp. Lipid is first deposited at Descemet membrane and subsequently at Bowman layer. Histopathologically, the arcus has an hourglass appearance as the opacity extends into the corneal stroma from these two layers.

Histochemically, the opacity is made up of cholesterol, cholesterol esters, phospholipids, and neutral glycerides. ^, The lipid is predominantly extracellular cholesterol ester-rich lipid particles. These corneal lipid particles are similar to a type found in human atherosclerotic lesions, but, unlike atherosclerotic lesions, they accumulate in the absence of foam cells. Deposition is first seen in the anterior layers of Descemet membrane as a double lamina. Deposition then occurs in Bowman layer, ending abruptly with the termination of this structure. In advanced stages deposition is seen between the stromal lamellae, sparing the limbus. Similar deposition of lipid can be seen in the perilimbal sclera overlying the ciliary body.

Experiments have shown the lipids to be of vascular origin. Lipids in the form of low-density lipoprotein (LDL) cross the capillary wall. This is independent of arterial blood pressure, unlike the situation in the aorta. The limbal vasculature is part of a low-pressure perfusion system. The endothelium lining these blood vessels normally have tight intercellular junctions, but in the presence of elevated circulating LDL, may become dysfunctional. Although the lipid in the peripheral cornea likely originates from LDL, it is modified LDL and apo B sparse. Corneal arcus is usually bilaterally symmetric and progresses slowly over years. Hyperemia of the limbal vasculature has been associated with a more rapid rate of arcus formation. Corneal arcus may be deflected by the presence of corneal vascularization. A lucid interval is seen between the vascularization and the arcus, which may be due to the vessel’s ability to reabsorb the lipid in this area before it precipitates. Unilateral arcus may be seen with carotid artery occlusion on the side without the arcus.

The prevalence of corneal arcus has been shown to increase with age. The degeneration affects men more than women. The prevalence in women increases significantly in the postmenopausal period. Approximately two-thirds of all men are affected in the 40–60-year-old range. Virtually 100% of the population is affected after age 80. ^, Certain ethnic populations are affected less frequently. Black males have the highest incidence, followed by black females, then white males followed by white females. Blacks are affected at a younger age than whites. The opacity remains peripheral but may occasionally extend centrally. Some consider this to represent a lipid keratopathy rather than an arcus senilis.

Corneal arcus has no visual significance, and thus no treatment is necessary treatment. However, it can be clinically significant. Patients under the age of 40 with corneal arcus have an increased risk of coronary artery disease and should be evaluated for hyperlipoproteinemia. Hyperlipoproteinemia types IIa and IIb are associated with premature corneal arcus formation, the most commonly observed being type IIa hyperlipoproteinemia. These diseases may be primary or secondary and involve increased levels of β-lipoproteins rich in cholesterol. Primary disease is an autosomal dominant disorder with incomplete penetrance. In addition to corneal arcus, these patients have xanthelasma elsewhere including tendons and the vasculature. Diseases causing a rise in β-lipoproteins include nephrotic syndrome, hypothyroidism, increased cholesterol intake, obstructive jaundice, and diabetic ketoacidosis.

Rare genetic disorders of high-density lipoprotein (HDL) metabolism causing corneal deposits include lecithin-cholesterol acyltransferase (LCAT) deficiency, which has an autosomal recessive mode of inheritance with strong penetrance, fish eye disease, whose exact mode of inheritance is unknown, and Tangier disease, which occurs in homozygotically affected individuals with an autosomal recessive mutation. All of these diseases may produce a generalized corneal clouding that may affect visual acuity and manifest at an early age. An arcus may also be observed in LCAT deficiency. ^,

Limbal Girdle (of Vogt)

The limbal girdle of Vogt is a symmetric yellowish-white band located parallel to the interpalpebral limbus. It is found more frequently on the nasal limbus than on the temporal. Limbal girdle may be seen with direct illumination but is best seen with a combination of retroillumination and scleral scatter. The deposits are composed of fine granular opacities, often with linear-shaped extensions that are present on the central edge. They are located beneath the epithelial layer, adjacent to Bowman layer.

Vogt described two types, primarily differentiated by the presence (type I) or absence (type II) of a lucid interval separating it from the limbus. The first type is more consistent with early band keratopathy; the deposits being largely calcific in nature ( Fig. 75.2A ). Type II is more consistent with changes associated with chronic exposure to ultraviolet irradiation (see Fig. 75.2B ). Histopathologically, the changes occur just beyond the termination of Bowman layer and demonstrate focal areas of hyaline deposition, elastotic degeneration, and hypertrophy of the overlying epithelium, the same changes that are characteristic of pinguecula and pterygia.

The incidence of Vogt limbal girdle increases with age. It is clinically apparent in approximately 60% of people between the fourth and sixth decades of life and in most people over the age of 80. This degeneration is an incidental finding and is asymptomatic. No treatment is required.

Iron Deposits

Iron is present in the tear film in both free and bound forms. It is bound to both lactoferrin and transferrin and within the corneal epithelium. Although iron is essential for cellular metabolism, when present in excess, it can be toxic as a result of oxygen free radical production.

Iron deposition in the cornea is seen as a faint yellow to dark-brown discoloration in the corneal epithelium, and may assume various shapes (linear, stellate, globular). Clinically, iron lines are best detected with direct slit lamp illumination using a broad white beam. Cobalt blue light on the slit lamp may enhance detection of fainter lines.

Iron lines are found most often when there are alterations of the ocular surface that produce focal elevations or depressions. Disturbances in tear film distribution combined with secondary changes in the corneal epithelium can result in iron deposition, primarily in the form of ferritin, within the basal epithelial layer.

The most common iron line is the Hudson-Stahli line, which is located at the juncture of lower and middle thirds of the cornea where the eyelids meet on closure. The line usually runs horizontally, with a gradual downward arc. The line may be distinct or may be broad (1–2 mm) and faint, giving rise to a Hudson-Stahli zone. Hudson-Stahli lines may be altered by various factors including corneal scars and contact lens wear. ^, The lines increase in length and density with time. Typically, Hudson-Stahli lines are bilateral and symmetric. Although Hudson-Stahli lines have been identified in individuals as young as 2 years of age, they are most commonly identified in middle and older age groups. ^, After the age of 70, the incidence decreases for reasons that are unclear.

Iron lines have been observed after glaucoma surgery (Ferry line), usually located just anterior to the filtering bleb. Iron may also be seen at the advancing edge of a pterygium (Stocker line) and at the base of the cone ( Fig. 75.3 ) in keratoconus (Fleischer ring). Salzmann nodular degeneration and elevated scar tissue following trauma have also been associated with iron lines. ^,

Iron deposits have been described after a wide range of refractive corneal procedures, including laser in situ keratomileusis (LASIK), photorefractive keratectomy, radial keratotomy, and following placement of intracorneal ring segments. Iron deposition may take the form of small focal pericentral globules (myopic LASIK and photorefractive keratectomy [PRK]), a stellate pattern following radial keratotomy, or a semicircular or complete ring of pigmentation associated with penetrating keratoplasty. ^, Histologically, iron, in the form of ferritin, is found within the basal epithelial cells of the cornea as well as in the intercellular space, regardless of the type of iron line.

A less common form of iron deposition in the cornea was first described by Coats, who noted small (0.5–1 mm in diameter) white rings in the inferior cornea. The ring is often circular or oval in shape, is located within Bowman layer or the anterior stroma, and is composed of discrete white dots ( Fig. 75.4 ). The overlying epithelium is smooth and intact. The lesion(s) are associated with previous metallic corneal foreign bodies. Histochemical analysis has revealed iron within the lesion. Coats rings represent an incidental finding and are asymptomatic.

Calcific Degeneration

Band-shaped keratopathy occurs in calcific and noncalcific forms, such as in advanced spheroidal degeneration or urate keratopathy. It may be primary, unassociated with inflammatory or systemic disease. More commonly, band keratopathy is secondarily associated with chronic inflammation, systemic or hereditary disease states associated with abnormalities in calcium metabolism, or topical or intraocular medications that cause local disturbances in calcium metabolism within the tissues of the eye ( Box 75.1 ).

Calcific band keratopathy, first described by Dixon in 1848, usually occurs in the interpalpebral zone with a lucent interval adjacent to the limbus. It starts peripherally centered along the horizontal meridian and slowly progresses centripetally. Band keratopathy begins as a slight haze at the level of Bowman layer that slowly increases in density. Characteristic small, dark round holes are seen within the band and are thought to represent corneal nerves passing through Bowman layer. The band may or may not progress to involve the visual axis ( Fig. 75.5A ). Progression is usually slow (months to years); however, there are instances of rapid progression (weeks to months). ^{, ,} Band keratopathy is caused by many entities, most commonly with chronic uveitis such as in juvenile rheumatoid arthritis or in hypercalcemic states such as chronic renal failure ( Box 75.2 ).

Histopathologically, fine basophilic granules are first seen within the cytoplasm of the basal epithelium and are located in the extracellular space within Bowman layer and occasionally in the anterior stroma. The calcific particles gradually coalesce into larger plaques. ^, As the condition progresses, Bowman layer becomes more calcified and focal fragmentation may occur. Hyaline-like material is deposited in subepithelial tissue around the calcific depositions, giving the appearance of reduplication of Bowman layer. A fibrous pannus sometimes occurs between the basal epithelium and Bowman layer. The overlying epithelium may be atrophic. Conjunctival deposits of calcium may also be found when associated with hypercalcemia. Calcium is deposited in the form of hydroxyapatite, a phosphate salt.

The precipitation of hydroxyapatite is dependent upon the solubility of calcium phosphate within the local microenvironment. Under normal conditions, calcium and phosphate are present at levels that approach the solubility product. Minor changes in the local microenvironment of the ocular surface that alter the pH (lower pH) or that increase the concentration of calcium or phosphate ions (hypercalcemia; hyperphosphatemia; tear film evaporation) may result in precipitation. ^{, ,} This has been demonstrated clinically in cases of hyperparathyroidism, proximal renal tubular acidosis, intracameral phosphate buffered Viscoat, and with phosphate based topical ophthalmic drops. Experimental models of band keratopathy have also confirmed these findings. ^,

These lesions progress slowly over months to years. In patients with dry eye, however, calcium deposition may progress much more rapidly. In most cases, the associated disease causing the band keratopathy is known. In those patients who present with band keratopathy of unknown etiology, possible systemic causes should be investigated. After obtaining a history and ocular examination, a medical work-up should include serum calcium, phosphorus, vitamin D, uric acid, blood urea nitrogen (BUN), and creatinine. If hyperparathyroidism or sarcoidosis is suspected, parathyroid hormone (intact PTH) and angiotensin-converting enzyme (ACE) levels should be obtained. Patients should be questioned about their supplemental vitamin and calcium intake. In patients who have band keratopathy secondary to hypercalcemia, partial regression has been observed when the calcium levels are normalized.

Early stages of band keratopathy are asymptomatic. Later stages can be symptomatic with decreasing vision, foreign body sensation, tearing, or photophobia. If the patient becomes symptomatic, the preferred initial treatment is the application of disodiumethylenediamine tetraacetic acid (EDTA). ^, After instillation of topical anesthetic, the overlying epithelium is debrided with a blade and 1.7% (0.05 molar) EDTA is applied to the calcific areas for 2–3 minutes, either in a well (optical zone marker) or on saturated cellulose sponges. Usually Bowman layer is intact and smooth. A bandage contact lens is placed, and a topical antibiotic/steroid combination is applied 3–4 times per day until complete reepithelialization has occurred. If EDTA is unavailable, then a diamond burr or a No. 15 blade may used. ^, An excimer laser may used alone or in combination with chelation to produce a smoother, more regular ocular surface. ^, Phototherapeutic keratectomy is especially useful if Bowman layer has been damaged or destroyed. A rough, irregular surface generally requires manual removal of thicker calcific plaques combined with application of a masking fluid (1% carboxymethylcellulose or 1.4% polyvinyl alcohol applied with a surgical sponge) prior to ablation. This usually requires multiple reapplications of masking fluid combined with shorter bursts of laser energy. This technique produces a smoother ocular surface without removing a significant amount of stroma, thereby minimizing a secondary hyperopic shift. Occasionally, amniotic membrane might be required after primary surgical removal of band keratopathy in patients who are more prone to delayed epithelial healing.

Superficial reticular degeneration of Koby is a rare variant of band keratopathy in which a fine white reticular opacity is present at the level of Bowman layer. The corneal epithelium may have a faint brownish discoloration. Histopathology demonstrates calcium deposition in Bowman layer and focal iron staining in the basal epithelial layer. It responds to chelation therapy. This degeneration is most commonly reported in patients with chronic inflammation.

Calcareous degeneration of the cornea is a second type of calcific degeneration. Like band keratopathy, this degeneration occurs in diseased eyes with chronic inflammation, persistent epithelial defects, or that have undergone multiple intraocular surgeries. It differs from band keratopathy in that the calcium deposits extend deeper, beyond the anterior stroma (see Fig. 75.5B ). Calcium deposition in the cornea may be partial or full-thickness. The onset is usually gradual or may have a more rapid onset.

Crocodile Shagreen

Vogt described crocodile shagreen as a bilateral, symmetric corneal opacity that has a mosaic pattern resembling crocodile skin. Both anterior and posterior forms have been described and appear clinically as polygonal gray opacities separated by thin lucent zones ( Fig. 75.6 ). Crocodile shagreen is most prominent in the central cornea but may also be observed in the peripheral cornea.

Anterior shagreen is most often associated with trauma, hypotony, band keratopathy, X-linked megalocornea, and rigid contact lens wear in patients with keratoconus. A similar pattern may be observed with instillation of fluorescein after pressure is applied to the cornea through the eyelids.

Posterior shagreen is widely considered an age-related degenerative condition. It is clinically indistinguishable from central cloudy dystrophy of François. Autosomal dominant inheritance and earlier onset are the primary features that differentiate central cloudy dystrophy from posterior crocodile shagreen. No gene has yet to be identified. It is currently classified as a category 4 dystrophy in the International Classification of Corneal Dystrophies (IC3D). Posterior shagreen has been observed in association with fleck dystrophy, pseudoxanthoma elasticum, keratoglobus, polymorphic amyloid degeneration (PAD), and pre-Descemet dystrophy.

Histopathologic findings, most notable on transmission electron microscopy, demonstrate extracellular stromal vacuoles concentrated in the posterior stroma and just anterior to Descemet membrane. The vacuoles often contain fibrillar-granular material. Focal stromal undulations in a sawtooth-like configuration are often present beneath Bowman layer in the anterior form or in the posterior stroma anterior to Descemet membrane in the posterior form.

In vivo confocal microscopy has demonstrated polygonal-shaped areas of hyperreflectivity starting just below Bowman layer that are separated by hyporeflective diagonal striations in anterior shagreen. Findings in patients with the posterior shagreen have demonstrated multiple discrete punctate refractile granules in the anterior and posterior stroma. Acellular opacification of irregular intensity combined with intermittent linear clear zones were noted in the posterior stroma.

Collagen lamellae immediately adjacent to both the posterior-most layer of Bowman layer and the anterior-most layer of Descemet membrane insert obliquely. ^, Bron and Tripathi demonstrated that when tension on Bowman layer is reduced, such as occurs when the eye is hypotonus, the obliquely inserted lamellae form ridges that support Bowman layer. These ridges correspond to the clear spaces of the mosaic. This theory is supported by recent confocal microscopy findings.

The opacity seen with anterior and posterior crocodile shagreen is visually insignificant and requires no treatment.