Anterior Segment

• Cornea Layers & Cells
• Corneal Keratitis
• Bacterial keratitis
• Fungal keratitis
• Acanthamoeba keratitis
• Endothelium
• Fuch’s Dystrophy
• Contact Lens Complications

Cornea Layers and Cells

The cornea is the transparent dome-shaped part of the outer surface of the eye covering the iris. It protects the eye and acts as the “glass” through which light passes. The main purpose of the cornea is to focus light into the eye. Together with the lens, the cornea refracts light and helps the eye to focus. It is nourished and provided with oxygen anteriorly by tears and is bathed posteriorly by aqueous humor. Because there are no blood vessels in the cornea, it is normally clear and has a shiny surface. The cornea is extremely sensitive; there are more nerve endings in the cornea than anywhere else in the body.

One of the most common irritants to the cornea is dry eye, which affects between 10% and 15% of adult Americans. Other conditions that can cause pain and significant damage to the cornea include ulcers, abrasions, allergic reactions, and infections, which may be bacterial, fungal, viral, or parasitic. Ophthalmologists’ ability to identify and assessment these ailments have improved with the use of new diagnostic imaging modalities. Depending on the type of assault, treatment can range from simple rewetting tears to antibiotics or antifungal medication to corneal transplants, known as keratoplasty.

Layers of the Cornea

The visually important area of the cornea is approximately the same diameter as the pupil size. Normal cornea is a prolate surface that is steeper in the center and flatter in the periphery. The average central corneal thickness is approximately 550 µm. In one study, the average thickness in temporal, nasal, inferior, and superior quadrants of the cornea was 590, 610, 630, and 640 µm, respectively. The thinnest site on the entire cornea is located approximately 0.9 mm from the visual axis, most commonly in the inferotemporal quadrant. The cornea is avascular with oxygen supply coming mainly from the tear film and metabolic requirements from the aqueous humor. It is comprised of five distinct layers:

• Epithelium: The layer of cells that cover the outer surface of the cornea and comprises about 10 percent of the cornea’s total thickness. It is very thin, only 50 to 60 µm or 4 to 5 cell layers in thickness. These layers consist of a superficial layer of flattened keratin-rich cells, an intermediate layer of polyhedral cells called wing cells, a basal germinal layer, and a collagen-enriched basement membrane attached to Bowman’s layer. An injury to this level can result in corneal erosion syndrome. This layer regenerates about every 7 days. The epithelium functions primarily to:
  • Block passage of foreign material, such as dust, water, and bacteria, into the eye and other layers of the cornea
  • Provide a smooth surface that absorbs oxygen and cell nutrients from tears, then distribute these nutrients to the rest of the cornea.

The epithelium is filled with thousands of tiny nerve endings that make the cornea extremely sensitive to pain when rubbed or scratched. The part of the epithelium that serves as the foundation on which the epithelial cells anchor and organize themselves is called the basement membrane.

• Bowman’s Layer: A thin, homogeneous, transparent, condensed acellular stroma about 15 µm thick. Composed of compact collagen lamellae, it’s really part of the corneal substance and is composed of fine fibers which are tightly connected with the stroma. This layer is very tough and difficult to penetrate and helps to protect the cornea from injury. When disrupted it will not regenerate and can form a scar. If these scars are large and centrally located, some vision loss may occur.

• Stroma: Just beneath Bowman’s layer, the stroma is the thickest layer of the cornea representing 90% of total corneal thickness. It consists primarily of water (78%) and collagen (16%), and does not contain any blood vessels. About 250 to 300 regularly spaced collagen lamellae and fibrils run parallel and extend across the entire cornea. Collagen gives the cornea its strength, elasticity, and form. The collagen’s unique shape, arrangement, and spacing are essential in producing the cornea’s light-conducting transparency. The stroma is not renewable if injured.

• Descemet’s Membrane: A thin but strong sheet of tissue that serves as a protective barrier against infection and injuries. About 10 to 12 µm in thickness, Descemet’s membrane is composed of collagen fibers (different from those of the stroma) and is made by the endothelial cells that lie below it. The layer is firm and highly elastic.

• Endothelium: The extremely thin, innermost layer of the cornea responsible for keeping the cornea clear. It’s made of a single layer of densely packed flattened cells facing the anterior chamber. Working with metabolic enzymes this layer of cells pumps water from the cornea, keeping it clear. If damaged or diseased, these cells will not regenerate. Normally, fluid leaks slowly from inside the eye into the stroma. Without this pumping action, the stroma would swell with water, become hazy, and ultimately opaque. These cells do not multiply. Cell density is about 3,500 cells/mm² at birth and decrease gradually throughout life at about 0.6% per year and with about 10% loss per intraocular surgery. With normal ageing there is about an 80% reserve of endothelial cells. A minimum of 700 cells/mm² is required for endothelial integrity function and metabolism. Once endothelium cells are destroyed by disease or trauma, they are lost forever. If too many endothelial cells are destroyed, corneal edema and blindness ensue, with corneal transplantation the only available therapy.

Corneal Keratitis

Keratitis is an inflammation of the cornea. Corneal inflammation may be ulcerative or non-ulcerative and may arise because of infectious or non-infectious causes. The non-ulcerative corneal inflammation may be confined to the epithelial layer or to the stroma of the cornea, or it may affect both. Non-ulcerative superficial keratitis usually includes hypersensitivity responses to microbial toxins and unknown agents. Non-ulcerative stromal keratitis can be either infectious or noninfectious. Non-infectious ulcerative keratitis can be related to a variety of systemic or local causes, predominantly of autoimmune origin.

Infectious keratitis can be a sight-threatening condition and is a significant cause of ocular morbidity around the world. Severe infections, such as scleritis, endophthalmitis, or panophthalmitis, corneal ulceration and stromal abscess formation, surrounding corneal edema and anterior segment inflammation are characteristic of this disease.

These infections can be very difficult to treat and may result in severe visual loss or even loss of the eye. Some infections can be treated successfully with topical antibiotics. About 10%, however, result in the loss of two or more lines of visual acuity. Approximately 12% of all corneal transplantations are performed for active infectious keratitis.

Micro-organisms such as bacteria, fungi, parasites (acanthamoeba), or viruses play an important role in the pathogenesis of ulcerative infectious keratitis. Regardless of the source of infection, keratitis is a diagnostic and therapeutic challenge to the ophthalmologist. Difficulties are related to establishing a clinical diagnosis, isolating the etiologic organism in the laboratory, and treating the disease effectively.

Epidemiology - Keratitis

Microbial keratitis is an uncommon but potentially devastating complication of contact lens wear. The annual incidence of microbial keratitis associated with contact lens use is estimated to be two to four per 10,000 wearers of daily wear soft contact lenses and 10 to 20 per 10,000 for users of extended wear contact lenses in the U.S.

Bacterial Keratitis

The incidence of bacterial keratitis varies greatly, with less industrialized countries having a significantly lower number of contact lens users and, therefore, significantly fewer contact lens-related infections. In the U.S., approximately 25,000 people develop bacterial keratitis annually. One in 2,500 daily contact lens wearers and 1 in 500 overnight wearers develop bacterial keratitis each year. Incidence of bacterial keratitis secondary to use of extended-wear contact lenses is about 8,000 cases per year.

Case reports of contact lens-associated corneal infections first appeared in the ophthalmic literature two decades ago. Contact lenses were implicated as a causative factor, but it was not until the hallmark studies of Schein and colleagues that the incidence and relative risk of contact lens-associated corneal infections was elucidated. They found the incidence of ulcerative keratitis in New England to be 4.1 in 10,000 daily contact lens wearers per year. Incidence in extended contact lens wearers was even greater at 20.9 per 10,000. When the actual wearing patterns of users were studied, they found that patients who slept in their lenses had a 10 to 15-fold higher risk of developing an infection. Incidence in the United Kingdom and the Netherlands is similar.

Epidemiologic studies have shown that much of the risk associated with contact lens-related bacterial microbial keratitis is modifiable. Overnight wear has repeatedly been shown to be associated with excess risk and overwhelms all other known risk factors in its relative contribution to the risk of bacterial keratitis among contact lens wearers. Other consistently identified risk factors include smoking, male gender, younger age, low socioeconomic class and inadequate contact lens hygiene.

Fungal Keratitis

The epidemiology of fungal and acanthamoebic keratitis differs somewhat from the more common bacterial cases. The CDC study and others show that water sources, lens care products and hygiene are particularly relevant to the pathogenesis of these infections. The importance of overnight wear as a risk factor seems to be less for these pathogens.

The risk of fungal keratitis has long been recognized to be higher in hot, humid environments such as Florida, India, South America, and Asia. The incidence of fungal keratitis varies by geography and ranges from 2% of total fungal keratitis cases in New York to 35% in Florida. Historically, the most common risk factor has been ocular trauma, where the soil or water-borne fungus is introduced directly into the cornea at the moment of injury. Fusarium species are the most common cause of fungal corneal infection in the southern United States (45-76% of fungal keratitis), while Candida and Aspergillus species are more common in northern states. In temperate climates, fungal keratitis was a rare cause of microbial keratitis.

Fungal keratitis is more common in males than in females. Up to 20% of cases of fungal keratitis (particularly candidiasis) are complicated by bacterial co-infection.

The incidence of fungal keratitis has increased over the past thirty years. It has been theorized that this may be a result of the frequent use of topical corticosteroids and antibacterial agents in treating patients with keratitis, the rise in the number of patients who are immuno-compromised and better laboratory diagnostic techniques that aid in its diagnosis.

Reports of Fusarium ocular infections that have an apparent association with specific lens cleaning solutions have significantly increased in the last two years. One hundred and thirty cases were confirmed by the U.S. Center for Disease Control (CDC) from June 2005 to June 30, 2006 in 26 states and one territory. The CDC study indicated an excess risk of Fusarium keratitis associated with the use of Bausch & Lomb’s ReNu with MoistureLoc lens care solution. As a result, the product was voluntarily removed from the market place worldwide in May 2006.

Several behavioral risk factors were also implicated, including not replacing contact lenses as indicated on labeling and reusing or “topping off” contact lens solution.

Although the implicated lens care product met the standard quality assurance test required by the U.S. FDA, it is apparent that Fusarium found a particular niche with the combination of this product and certain patterns of contact lens hygiene. It has been hypothesized that chemical agents used as surfactants to improve the comfort of the product may have favored fungal growth. This possibility is consistent with some laboratory data and is indirectly supported by the finding that “topping off solution” increased the risk of acquiring fungal keratitis in the CDC study. The CDC data also showed that approximately one third of the reported cases occurred with other brands of contact lens solutions.

Acanthamoeba keratitis

The estimated rate of Acanthamoeba keratitis is 1 per 250,000 people in the United States, although rates vary among studies: from 1.65-2.01 per million in the general population, up to 1 per 10,000 people who wear contact lenses.

At least 85% of cases of Acanthamoeba keratitis in the U.S. have been associated with contact lens use. Keratitis has been associated with wearing non-disposable contact lenses, the use of homemade sodium chloride solution to clean the lenses, and wearing lenses while swimming.

The isolation of Acanthamoeba from swimming pool water is not unusual. Acanthamoeba cysts are very resistant to chlorine. Studies show that a higher percentage of isolates from swimming pools are pathogenic than those isolated from natural fresh water.

Other mechanism of acanthamoebic infection is ocular trauma, with direct inoculation of the cornea with water or soil contaminated with the organism.

Acanthamoeba keratitis has been, historically, an uncommon corneal infection. There have been several “outbreaks” recently. In 1993-1994, for example, risk was higher in Midwest counties affected by regional flooding. In a recent study, Joslin et al reported on the increasing frequency of acanthamoeba infection in the Chicago area between 2003 and 2005. They postulated that changes in water quality standards from the Environmental Protection Agency (EPA) may have played a role in this outbreak.

Acanthamoeba keratitis appears to be more common in the United Kingdom and Hong Kong. In contrast to the United States, domestic water is often stored in reservoir tanks in individual homes in the United Kingdom. These residential water tanks have been shown to harbor Acanthamoeba at high rates, and this mechanism has been proposed as a possible explanation for the higher rate of disease in the United Kingdom.

Endothelium

Structure & Function

The corneal endothelium is a single layer of hexagonal-shaped cells 4 to 6 mm thick. It plays a vital role in maintaining corneal transparency by pumping fluid out of the stroma and forming a barrier to fluid movement into the stroma from the aqueous humor. This movement of water counters a natural tendency for the stroma to swell and is necessary to maintain a transparent cornea. Without this pumping action, the stroma would expand with water, become hazy, and ultimately opaque. A perfect balance is maintained between the fluid moving into the cornea and fluid being pumped out of the cornea in healthy, normal eyes. If too many endothelial cells are damaged or destroyed due to disease or trauma, corneal edema and blindness are possible, with corneal transplantation the only available therapy.

Signs of Disease

The central endothelium changes, normally, as a function of age. At birth, endothelial cell count density is about 3,500 to 4,000 cells/mm². Published research shows that cell count density declines rapidly from birth to adolescence, seems to stabilize between ages 20 to 50 years, and again decreases significantly after age 60. Although there is a great deal of individual variability, adults typically have 1,500 to 2,000 cells/ mm² of endothelium. In addition to changes in cell density, variability of cell size (polymegathism), cell shape (pleomorphism) have been found to correlate with age.

Loss of transparency in many corneal diseases is associated with changes in endothelial cell density and morphology. In Fuchs Dystrophy, for example, the endothelial cells are larger than normal (decreased endothelial cell density) and often have increased variability in size (polymegethism) and shape (pleomorphism). Accompanying these changes is a decreased ability to pump fluid out of the cornea and, as a consequence, stromal edema.

Changes in the morphologic features of the endothelium are important for assessing physiologic health of the cornea, and differentiating possible disease. Typical measurements, conducted by specular microscopy, fluorophotometry and pachymetry, include:

• Endothelial cell density (cells/ mm2)
• Cell area (variation in cell size, coefficient of variation, polymegethism)
• Cell morphology (pleomorphism, index of hexagonality, shape factors, figure coefficients, elongation index).
• Percentage of hexagonal cells (cells that show polymegathism and pleomorphism and variation in shape from 6-sided endothelial cells)

Endothelium Cells & Ocular Disease

In addition to the normal ageing process, endothelium can be adversely affected by disease and trauma. Certain diseases that damage the corneal endothelium, such as Fuchs’ corneal dystrophy, lead to endothelial changes such as guttae and eventually lead to corneal edema. Additional insults include trauma during a prolonged cataract case, especially when extracting a large, mature cataract. This may lead to endothelial damage and additional cell loss. These individuals often require a corneal transplantation.

Furthermore, patients with relatively few endothelial cell counts undergoing cataract surgery may require extended recovery periods to resolve their corneal edema, chiefly because only a few endothelial cells are pumping fluid out of the stroma and into the anterior chamber.

Fuchs’ Dystrophy

Fuchs’ endothelial dystrophy is an asymmetrical, bilateral, slowly progressive edema of the cornea usually seen in elderly patients. Fuchs’ dystrophy is a slowly progressing disease that usually affects both eyes and is slightly more common in women than in men. When inherited, the transmission is autosomal dominant.
The root cause of the condition is a slowly progressive formation of guttate lesions between the corneal endothelium and the Descemet membrane. Cornea guttate found in Fuchs’ dystrophy are focal accumulations of collagen on the posterior surface of Descemet’s membrane that apparently are formed by stressed or abnormal endothelial cells. As the lesions enlarge, the covering endothelial cells initially become stretched, and they eventually fall off. They appear as warts or excrescences of Descemet’s membrane and can easily be seen with specular microscopy. Corneas guttate also occur as a result of aging and corneal inflammation.

Growth of cornea guttata progresses from the center of the cornea to the periphery. As the endothelial cells fall, the remaining cells enlarge to cover the gap. With the reduced number of endothelial cells, the pump-function suffers. Endothelial cell attrition rises with increasing number and size of the guttate. Cornea guttata may be discovered accidentally or when specular endothelial microscopy is performed to find out the cause of the visual disturbance. Fuchs endothelial dystrophy passes through three clinical stages. These stages evolve over a period of two or three decades. The changes are bilateral, but usually asymmetric.

Once corneal decompensation starts, the course is relentless. In a matter of months or years, the vision is progressively disturbed. Finally, the patient is crippled visually. In addition, problems caused by repeated bullae formation, ulceration, scarring and vascularization occur. If left untreated, the condition ends in near blindness, which may be painful.

The incidence of Fuchs’ endothelial dystrophy is not well known. Some symptoms such as cornea guttata are seen quite often and are associated with increasing age. After age 40, for example, publish reports show that 70% of patients have cornea guttata. Only 0.1% of these patients have epithelial edema and bullae formation. Females are affected more than males by a 3:1 ratio.

The corneal endothelium typically shows the presence of cornea guttata in the central area occurs, as seen on slit lamp examination under high magnification or on specular reflection. Cells may show a metallic appearance. A similar appearance may be visible at the edge of the central corneal on retroillumination.

Contact Lens Complications

Contact lens wear also may compromise the corneal endothelium. Published research shows that both acute and chronic endothelial changes can be seen following contact lens wear. Within minutes of application of a contact lens, small dark endothelial blebs occur that disappear quickly if the lens is removed. These endothelial blebs reach a maximum size in 20 to 30 minutes from the time the contact lens is placed on the cornea and then gradually decrease in size. Similar blebs occur during prolonged lid closure, such as during sleep, and possibly represent the effects of hypoxia or lactate accumulation.

Long term wear of either hard or soft contact lenses results in an increased polymegathism that is not reversed upon cessation of lens wear although some recovery towards normal might exist. The degree of polymegathism increases as the period of time the lenses are worn increases. The degree of increase in polymegathism depends upon the type of lenses worn.

An interesting finding has been the observation of small clusters of small cells possibly due to mitosis occurring as a result of contact lens wear. Contact lens wearers have a greater variation in endothelial cell size (polymegethism) and an increased frequency of nonhexagonal cells (polymorphism) than do non-wearers. Along with the striking alteration in endothelial cell morphology, a small decrease in endothelial cell density also has been found in long-term contact lens wearers in soft and PMMA lenses, and in RGP lenses.

Deswelling rates are reduced in contact lens wearers and may indicate a compromised pump reserve or increased endothelial cell permeability in these corneas. However, using fluorophotometric methodology, Bourne et al were unable to demonstrate any significant differences in permeability or pump function in contact lens wearers. Therefore, it appears clear that morphological changes occur in the endothelium with contact lens wear. However, it is not clear that this difference in morphology is translated to a difference in function.

Clinical Anterior Segment Bibliography