▃Anatomy and Physiology of Cornea

Cornea is avascular and transparent. Its horizontal and vertical diameters are 12 mm and 11.5 mm, respectively (Fig. 6.1). Its thickness at the center and periphery is 0.5 mm and 0.7 mm, respectively. Radius of curvature of anterior surface of cornea (in central region) is 7.8 mm, while that of posterior surface is 6.5 mm. Its refractive index is 1.376 (≈1.38). Cornea provides 3/4th of the total refractive power of the eye. Refractive power of anterior convex surface of cornea is +48.8 D; refractive power of posterior concave surface is −5.8 D, so the total refractive power of cornea is 43.0 D. The junction of cornea with sclera is called limbus. The corneal curvature is greater than the rest of the globe. Cornea is devoid of lymphatic channels.

■Histology

Histologically, cornea consists of five layers (Fig. 6.2):

1.Epithelium (anterior most).

2.Bowman’s membrane.

3.Stroma or substantia propria.

4.Descemet’s membrane.

5.Endothelium (posterior most).

Epithelium

It may be regarded as continuation of conjunctiva over cornea. Embryologically, it is derived from surface ectoderm at 5 to 6 weeks of gestation. Characteristic features of epithelium are as follows:

•It is stratified and 4 to 6 cell layers thick.

•The epithelial cells contain microvilli with glycocalyx layer which facilitate adsorption of mucinous portion of tear film and hydrophilic spreading of tear film with each eyelid blink. Loss of glycocalyx from injury or disease results in loss of stability of tear film.

•Superficial cells undergo desquamation and are replaced by deeper cells of corneal epithelium. Basal cells are the only corneal epithelial cells capable of mitosis. Because of excellent ability to regenerate, epithelium does not scar as a result of inflammation.

•Tight junctions between its cells provide barrier function and restrict entry of tears into intercellular spaces. Thus, healthy epithelial surface repels dyes such as fluorescein or Rose Bengal.

•Epithelial regeneration: Epithelial stem cells (undifferentiated pluripotent cells) are principally localized to limbal basal epithelium and serve as an important source of new corneal epithelium. Junctional barrier prevents conjunctival tissue from growing on the cornea. So, dysfunction or deficiency of limbal stem cells results in the following chronic epithelial defects:

♢Overgrowth of conjunctival epithelium onto the corneal surface.

♢Vascularization.

These problems can be treated by limbal cell transplantation.

Bowman’s Membrane

It is an acellular structure which, once destroyed, does not regenerate.

Stroma (Substantia Propria)

Stroma forms 90% of total corneal thickness. It may be regarded as forward continuation of sclera. It is composed of collagen fibrils, forming lamellae which are loosely adherent to each other and regularly arranged in many layers. The layers crisscross at approximately right angles to each other. Corneal lamellae become continuous with scleral lamellae at limbus. The layered structure of stroma results in corneal splitting, as in superficial keratectomy. Ground substance occupies the space in between lamellae and is composed of glycosaminoglycans (mucopolysaccharides). Corneal cells and keratocytes are found between lamellae which are collagen-producing fibroblasts. Corneal stroma is markedly hydrophilic due to osmotic force of stromal glycosaminoglycans (GAG).

Descemet’s Membrane

It is a thin elastic membrane secreted by endothelium throughout life. It is composed of collagen fibrils and separates corneal stroma from endothelium. Unlike Bowman’s membrane, it can regenerate (regenerated by endothelial cells). It is quite resistant to inflammatory process of cornea. Therefore, descematocele can maintain integrity of eye for long after all other layers of cornea are destroyed. It fuses with trabecular meshwork. The fusion site is known as Schwalbe’s line which defines the end of Descemet’s membrane and start of the trabecular meshwork.

Endothelium

It is derived from neural crest cells. It consists of single layer of flat hexagonal cells and appears as honey comb mosaic (Fig. 6.3). It contains a high-density of Na⁺–K⁺ ATPase pump. It secretes Descemet’s membrane throughout life. It cannot regenerate but adjacent cells slide to fill in a damaged area. Endothelial cell density decreases with advancing age and declines from 3,000–4,000 cells/mm² to 2,500 cells/mm² in adults. At a cell density of approximately 500 cells/mm², corneal edema develops. It is examined by a specular microscope.

The primary physiological role of endothelium is fluid regulation in corneal stroma. This function is most important as it keeps the cornea clear.

■Blood Supply of Cornea

Normal cornea is an avascular tissue which gets its nourishment from:

•Capillaries at limbus which are derived from episcleral branches of the anterior ciliary arteries.

•Aqueous by diffusion.

•Oxygen dissolved in tear film.

■Nerve Supply of Cornea

Cornea is supplied by the ophthalmic division of the trigeminal nerve (v₁) through long ciliary nerves (Fig. 6.4).

Course

Long ciliary nerves pierce sclera posterior to limbus and form annular plexus (pericorneal plexus). Branches from annular plexus travel radially to enter the corneal stroma and lose their myelin sheaths. They divide into anterior group, which forms subepithelial plexus, and posterior group, which forms stromal plexus. Branches from subepithelial plexus pierce Bowman’s membrane to form intraepithelial plexus. Due to rich nerve supply, cornea is extremely sensitive structure. In eyes with corneal abrasions or bullous keratopathy, direct stimulation of these nerve axons causes pain, reflex lacrimation, and photophobia.

■Metabolism of Cornea

Energy is needed for normal functions of a tissue. In cornea, energy is needed for maintenance of its transparency and dehydration. Energy in the form of adenosine triphosphate (ATP) is generated by breakdown of glucose and utilization of oxygen (Flowchart 6.1).

Source of glucose for cornea is aqueous (90%), tears and limbal capillaries (10%).

Source of oxygen for cornea—Most of the O₂ in cornea is consumed by epithelium and endothelium. Epithelium gets much of its O₂ from limbal capillaries or precorneal tear film. Endothelium gets most of its O₂ from aqueous humor, and the cornea is mainly aerobic.

▃Pathological Changes in Cornea

The pathological changes in cornea can be categorized in (Table 6.1) as follows:

•Loss of transparency (corneal edema and corneal opacity).

•Vascularization of cornea.

•Pigmentation of cornea.

•Corneal filaments.

•Prominent corneal nerves.

•Infiltrates.

■Transparency of Cornea (OP4.3, 4.5)

Normal cornea is a transparent structure. Corneal transparency occurs due to regular arrangement of collagen fibrils (corneal lamellae) in stroma, avascularity of cornea and relative state of dehydration. Water content of normal cornea is approximately 78%. It is maintained at a steady level by a balance between various factors. Disturbance of any of these factors leads to corneal edema.

Corneal Edema (OP4.3, 4.5)

It is the accumulation of fluid in the cornea. Corneal edema may be epithelial or stromal and can affect the entire cornea.

Factors Leading to Corneal Edema

Following factors are responsible for the development of corneal edema:

•Stromal GAG: Osmotic force of stromal GAG plays a role in hydration. Accumulation of GAG in the cornea (as in Mucopolysaccharidoses) leads to corneal edema.

•Intraocular pressure (IOP): Raised IOP (≥50 mm Hg) often results in corneal
edema due to easy passage of aqueous through corneal stroma but its escape is retarded by epithelium and accumulation of fluid in basal cells of epithelium results in epithelial edema.

•Integrity of endothelium and epithelium: Damage to epithelium or endothelium due to any cause results in corneal swelling and loss of transparency. However, damage to endothelium is far more serious which can occur during intraocular surgery/postuveitis.

•Corneal endothelial Na⁺–K⁺ ATPase pump and intracellular carbonic anhydrase pathway in endothelium: Activity in both these pathways produces a net flux from stroma to aqueous. Inhibition of endothelial Na⁺–K⁺ ATPase pump, as in Fuch’s endothelial dystrophy, leads to corneal edema.

If edema lasts for a long period, epithelium is raised into large vesicles or bullae (vesicular or bullous keratopathy). Bullae periodically burst and symptoms like ocular pain and irritation occur.

Clinical Features

Corneal edema presents with symptoms like impairment of vision, photophobia, watering, ocular discomfort, pain due to periodic rupture of bullae, and halos around light.

On slit lamp examination, corneal thickness is increased with haze. Epithelial edema is visible on retroillumination with slit lamp.

Management

It includes:

•Treatment of primary causes such as lowering of IOP, and control of ocular inflammation.

•Protection of endothelium during intraocular surgery by use of viscoelastics.

•Hypertonic agents:

♢5% sodium chloride eye drops × QID.

♢6% sodium chloride eye ointment at bed time.

♢Anhydrous glycerine.

•Bandage (therapeutic) contact lens to minimize discomfort of bullous keratopathy.

•Penetrating keratoplasty (corneal transplant) is done in long-standing corneal edema which is nonresponsive to medical treatment.

Prognosis

It depends on the status of corneal endothelium. If endothelium is healthy, edema usually resolves completely. Corneas with reduced endothelial cell counts may not be able to recover.

Corneal Opacity (OP4.5)

Corneal opacity occurs in the epithelial breech that involves Bowman’s membrane (Fig. 6.5). It may be congenital due to developmental anomalies or birth trauma. The common causes include infection, injury or corneal abrasion. Corneal opacification (loss of transparency) may follow the noninflammatory diseases or inflammation. The term “scar” is reserved for the opacity following inflammation. Scar tissue is white and opaque, and varies in density.

Based on the density of scarring, corneal opacity may be nebular, macular or leucomatous (Table 6.2).

Nebular corneal opacity may be so faint that it could be missed on routine examination. A corneal opacity in pupillary area causes blurring of vision.

•If iris becomes adherent to the back of leucoma in perforated corneal ulcer, it is called adherent leucoma.

•In a sloughing corneal ulcer, where the whole cornea sloughs, prolapse of iris occurs. Exudates which cover the prolapsed iris become organized and form a layer of fibrous tissue over which corneal epithelium rapidly grows, resulting in the formation of pseudocornea. More commonly, iris and cicatricial tissue are too weak to support the IOP. Cicatrix (scar) becomes ectatic. Ectasia of pseudocornea with incarceration of iris tissue is known as anterior staphyloma.

Treatment

The ideal procedure either involves

•Excimer laser PTK (phototherapeutic keratectomy), or

•Corneal transplantation (keratoplasty).

■Vascularization of Cornea (OP4.5)

Normal cornea is avascular. Vascularization of cornea is always pathological. Vascularization, which is considered as a defence mechanism (immunological defence) against disease, interferes with corneal transparency. It may be superficial or deep.

Superficial Vascularization

It arises from conjunctival superficial vascular plexus. The vessels are wavy and lie in the epithelial layer. Continuity of vessels can be traced with conjunctival vessels at the limbus. It is seen in the following:

•Trachoma.

•Phlyctenular keratoconjunctivitis.

•Superficial corneal ulcers.

•Rosacea keratitis.

•Contact lens wearers.

Pannus

When superficial vascularization is associated with cellular infiltration, it is termed as pannus. It may either be progressive when infiltration is ahead of vessels, or regressive, when infiltration is behind the vessels, that is, infiltration recedes. Pannus may be located superiorly, inferiorly, or generalized. Superior pannus occurs in trachoma and contact lens wearers. Inferior pannus is associated with exposure keratopathy and rosacea. Generalized pannus may be seen in chemical burns, Stevens–Johnson syndrome, and Mooren’s ulcer.

Deep Vascularization

It arises from anterior ciliary vessels. The vessels run a fairly straight course and lie in the corneal stroma. The continuity of vessels cannot be traced beyond the limbus. It is seen in the following:

•Chemical burns.

•Deep corneal ulcers.

•Disciform keratitis.

•Sclerosing keratitis.

•Interstitial keratitis (IK).

Once the cornea has been vascularized, the vessels remain throughout life, but these blood vessels may become empty (“ghost vessels”) when stimulus is eliminated.

Treatment

Vascularization can be prevented by timely and adequate treatment of predisposing conditions. Treatment is usually unsatisfactory. The following treatment regimens may be effective:

•Topical corticosteroid causes vasoconstriction and decrease in permeability of vessels.

•Beta irradiation.

•Peritomy is the surgical treatment of superficial vascularization in intractable cases.

■Pigmentation of Cornea (OP4.5)

Pigments deposited may be iron, silver, gold, copper, melanin, etc.

Deposition of Iron

In hyphema (blood in anterior chamber), hemosiderin becomes embedded in the corneal stroma. Rise of IOP promotes blood staining of cornea. Blood staining of cornea simulates dislocation of lens in the anterior chamber.

In keratoconus, deposition of iron hemosiderin surrounds the base of the cone in the corneal epithelium (Fleischer’s ring).

In pterygium, iron is deposited as a golden brown line in front of its head (Stocker’s line) in the corneal epithelium.

In filtering bleb, iron is deposited anterior to the filtering bleb (Ferry’s line) in the corneal epithelium.

In old age, deposition of iron is seen as a brown horizontal line (Hudson–Stahli line) in the corneal epithelium. It is located at the junction of the upper 2/3rd and 1/3rd along the line of lid closure.

Deposition of Silver

Prolonged topical use of silver nitrate causes impregnation of salt in the stroma and Descemet’s membrane, resulting in brownish discoloration of Descemet’s membrane (Argyrosis).

Deposition of Copper

When a copper foreign body is retained in the eye, deposition of copper occurs around the periphery of the cornea in the region of Descemet’s membrane and deeper stroma. A gray–green or golden–brown pigmentation of the peripheral corneal stroma is produced (Chalcosis).

In Wilson’s disease (hepatolenticular degeneration), deposition of copper in the periphery of Descemet’s membrane is seen as a golden-brown or green ring just inside the limbus when examined on slit lamp (Kayser–Fleischer ring, Fig. 6.6).

If viewed in cobalt blue light, the ring appears almost black. The condition is reversible with time, if the disease is treated with penicillamine.

Deposition of Melanin

In pigment dispersion syndrome, uveal pigment (melanin) is deposited on the corneal endothelium in the form of a vertical spindle (Krukenberg’s spindle). The spindle may be associated with pigment dispersion glaucoma.

Deposition of Gold

Gold is deposited in the epithelium in patients with chrysiasis.

■Corneal Filaments

These are the epithelial threads attached to cornea at one end, and the other unattached end is often club-shaped. These hang over the cornea and move freely with each blink, thereby producing irritation and foreign body sensation.

■Prominent Corneal Nerves

These may be associated with—Local ocular disorders, for example,

•Keratoconus.

•Acanthamoebic keratitis.

•Fuch’s endothelial dystrophy.

•Congenital glaucoma.

Systemic diseases, for example,

•Neurofibromatosis.

•Refsum syndrome.

■Infiltrates

These originate from the limbal vascular arcades and are indicative of active inflammation. These are located usually within the anterior stroma and appear as focal, granular, gray–white opacities. These are composed of leucocytes and cellular debris.

▃Symptoms of Corneal Diseases

Symptoms of corneal diseases include pain or slight irritation, visual impairment, lacrimation (excessive tear production), photophobia, halos, redness, and foreign body sensation. Specific symptoms pertaining to different pathologies of cornea are listed in Table 6.3.

▃Evaluation of Corneal Diseases

Corneal examination can be done with the following:

•Slit lamp.

•Placido’s disc.

•Pachymeter.

•Corneal staining.

•Specular microscopy.

•Confocal microscopy.

•Corneal aesthesiometer.

Cornea is examined for the following:

1. Size

•Normal size: Horizontal diameter 12 mm
and vertical diameter 11.5 mm.

•Megalocornea (increased size): It may be congenital and due to buphthalmos.

•Microcornea (decreased size): It may occur isolated or as a part of microphthalmos (small eye).

2. Shape:

•Normal cornea: It is like a part of a sphere.

•Flat cornea (cornea plana): It may occur congenitally or in phthisis bulbi.

•Conical cornea: In keratoconus.

•Globular cornea: In Keratoglobus.

3. Surface: Corneal surface and curvature can be evaluated by slit lamp, Placido’s disc, Placido keratoscope, corneal topography, and keratometer.

Placido’s keratoscopic disc: Kerato means cornea and scopic means visualization. The corneal surface is visualized by a disc painted with alternating black and white circles and contains a hole in the center. Light is kept behind the patient and the examiner looks at corneal image of circles through the hole.

Uniform and sharp image of circles is seen in normal cornea, while irregularities in rings are seen if corneal surface is uneven as in keratoconus, keratoglobus, and corneal astigmatism.

Corneal topography: It is computerized video keratography. It provides an objective record of the condition of anterior corneal surface (optical and anatomical condition) in the form of color-coded maps.

Green color represents normal curvature.

Blue color represents flat curvature.

Red color represents steep curvature.

It is important in preoperative evaluation for refractive surgery, for example, in patient with keratoconus, refractive surgery is deferred.

Orbscan is an improved technology which uses scanning slit technology with Placido disc. It provides information regarding curvature of anterior and posterior surfaces of cornea, and depth of anterior chamber. Curvature of anterior surface of cornea can also be measured by a keratometer.

4. Transparency: Cornea is optically transparent, and it becomes hazy in corneal edema, ulcers, opacity, vascularization, dystrophies and degenerations, and corneal deposits. The examination for corneal edema and corneal opacity is carried out with the help of a slit lamp. The corneal opacity is examined for its density (nebular, macular, or leucomatous), sensations, location, and its size.

If keratitis (ulcerative or nonulcerative) is suspected, corneal staining is performed.

5. Corneal Staining: Staining of cornea with vital dyes (Fluorescein or Rose Bengal, Table 6.4) is important in evaluating corneal epithelial lesions. It should be performed before corneal sensation is tested and also prior to measurement of IOP.

Alcian blue dye stains mucus selectively, so it stains excess mucus, as in keratoconjunctivitis sicca (KCS).

6. Corneal Vascularization: The normal cornea is avascular. If corneal vascularization is present, note the following points:

•Whether the vessels are superficial or deep.

•Whether the distribution is localized, circumferential, or peripheral.

7. Corneal Thickness (Pachymetry): Corneal thickness indirectly reflects endothelial function. It is measured by with the help of the pachymeter.

Average corneal thickness at center, that is, central corneal thickness (CCT) is about 0.5 mm (490–560 µm). CCT of ≥0.6 mm is suggestive of endothelial disease. At periphery corneal thickness is ≈ 0.7 mm.

CCT can alter measurement of IOP: Patients with increased CCT record high IOP, while patients with decreased CCT record low IOP.

8. Corneal Sensitivity: Cornea is richly supplied by nerves. Corneal sensitivity can be tested by:

•Touching cornea with wisp of cotton wool—Normally, there is brisk blink reflex as a response.

•Corneal aesthesiometer provides a more qualitative measurement of corneal sensations. In aesthesiometer, a single horse hair of varying length is used. The longest length which induces blinking is a measure of the threshold of corneal sensitivity. Normally, the cornea is most sensitive in the center.

Corneal sensations are diminished in the following:

•Herpetic keratitis.

•Neuroparalytic keratitis.

•Absolute glaucoma.

•Cerebellopontine angle tumor.

•Leprosy.

•Trigeminal block for neuralgia.

9. Endothelial Function: Corneal endothelium can be examined by specular microscopy or confocal microscopy on a slit lamp.

Specular microscopy: Specular microscope photographs the endothelial cells and enables the study of their morphology (their number [count], size and shape).

Average cell count is 2,500 cells/mm². In adults, it declines with age from 3,500 cells/mm² in children to 2,000 cells/mm² in old age. There is a certain amount of endothelial cell loss after intraocular surgery. Intraocular surgery is deferred in endothelial cell count cases of <1,000 cells/mm².

Abbreviation: KCS, keratoconjunctivitis sicca.

Normally, endothelial cells are hexagonal. Variability in the shape of cells is called pleomorphism. In the presence of 50% nonhexagonal cells, intraocular surgery is contraindicated. Variation in cell size is called polymegathism.

Confocal microscopy: It is performed by a confocal microscope. In cases with corneal edema, endothelium is not adequately visualized by specular microscopy due to edema. Confocal microscopy may be of value in cases with corneal edema.

Confocal microscope allows direct visualization of corneal cells. It acquires multiple images of cornea from epithelium to endothelium. Magnified images provide detailed information regarding cell count, shape, and size.

Confocal microscopes are of two types: Confocal slit-scanning microscope and confocal laser-scanning microscope.

▃Inflammation of Cornea

Inflammation of cornea is known as Keratitis.

■Source of Inflammation

Inflammation of cornea may arise from:

•Exogenous source: Cornea is involved by way of exogenous organisms.

•Endogenous source: Inflammation due to endogenous source is typically immunological in nature. As cornea is avascular, the immunological changes are common near limbal blood vessels close to the corneal margin and called marginal keratitis.

•Contiguous spread (owing to direct anatomical continuity).

•Diseases of conjunctiva spread to corneal epithelium, for example, trachoma and vernal keratoconjunctivitis.

•Diseases of sclera spread to corneal stroma, for example, sclerosing keratitis.

•Diseases of uveal tract spread to corneal endothelium, for example, herpetic uveitis with endotheliitis.

■Classification

Keratitis can be classified as follows:

•Based on depth:

♢Superficial keratitis: It is the inflammation involving epithelium and Bowman’s membrane.

♢Deep keratitis: It is the inflammation deep to Bowman’s membrane.

•Based on location:

♢Central.

♢Peripheral.

•Based on epithelial defect:

♢Ulcerative.

♢Nonulcerative.

•Based on etiology:

♢Infectious.

♢Noninfectious.

Infectious Keratitis (OP4.1, 4.2)

It is the corneal inflammation caused by bacterial, viral, fungal, or parasitic (protozoal or helminthic) organisms. It can be classified as:

•Depending on depth:

♢Superficial.

♢Deep.

•Depending on pus formation:

♢Purulent (suppurative).

♢Nonpurulent (Nonsuppurative).

•Depending on epithelial defect:

♢Ulcerative wherein corneal epithelium shows discontinuity. Loss of epithelium with inflammation in surrounding cornea is called corneal ulcer.

♢Nonulcerative wherein epithelium is intact (corneal abscess).

Inflammation in cornea is visible as a grayish haze. If it is accompanied by accumulation of leucocytes and cellular debris, this hazy area is called an infiltration and appears as gray–white or off–white opacities. Infiltrates are indicative of active inflammation.

Noninfectious Keratitis

It is the corneal inflammation with no known infectious cause. It may be:

•Allergic/immune-mediated:

1.Localized immune–mediated keratitis:

♢Phlyctenular.

♢Vernal.

♢Mooren’s ulcer.

♢Marginal.

♢Atopic.

2.Keratitis in systemic immunological disorders:

♢Associated with collagen disorders.

♢Dermatological disorders: Rosacea.

–Erythema multiforme.

–Mucous membrane pemphigoid.

•Nonimmune-mediated:

♢Neurotrophic in Vth cranial nerve (CN) palsy and diabetes.

♢Neuroparalytic in VIIth CN palsy.

♢Traumatic:

–Chemical injury.

–Thermal injury.

–Radiation.

♢Mechanical:

–Entropion with trichiasis.

–Lagophthalmos.

–Exophthalmos.

♢Nutritional in keratomalacia.

♢In KCS.

♢Others:

–Thygeson’s superficial punctate keratitis (SPK).

–Superior limbic keratoconjunctivitis.

■Infectious Keratitis

Bacterial Keratitis

The conjunctival sac is never free from organisms. Most of the organisms, normally, present on the ocular surface are:

•Staphylococcus albus or epidermidis.

•Propionibacterium acnes.

•Neisseria catarrhalis.

•Diphtheroids.

•Corynebacterium xerosis, etc.

All these organisms are nonpathogenic commensals. Streptococci, E. coli, B proteus, Neisseria gonorrhoeae, Hemophilus aegyptius, Moraxella, etc., are pathogenic and rarely found in normal eyes.

Defence Mechanisms

The following mechanisms help in defending against the microbial invasion of the corneal surface:

1.Blinking regularly sweeps away debris trapped in the mucin layer of tears.

2.Tight junctions between corneal and conjunctival epithelial cells.

3.Tears which contain:

•Lactoferin (secreted by lacrimal gland): It inhibits complement activation.

•Lysozyme, which promotes microbial aggregation and causes lysis of bacterial cell membrane.

•IgA: It causes bacterial agglutination and inhibits bacterial adherence to corneal and conjunctival surface.

•b-lysin: It causes bacteriolysis.

4.Mast cells of conjunctiva: Stimulation of mast cells cause degranulation of mast cells. It results in vascular dilation and increased vascular permeability. Thus, transudate is produced which is antimicrobial.

5.Resident normal microbes produces bacteriocins (high-molecular weight proteins), which inhibit growth of pathogens.

Predisposing Factors

Compromising one or more of the defense mechanisms represent a risk factor in the development of bacterial keratitis. These mechanisms are:

Trauma: Accidental, agricultural or surgical (refractive surgery).

Topical steroids (cause impairment of local immune defense).

Trigeminal nerve paralysis causes corneal anesthesia and exfoliation of epithelial cells.

A—Vitamin A deficiency.

B—Bullous keratopathy (corneal epithelial problem).

C—Chronic blepharitis.

Contact lens wear, particularly extended wear soft lenses, causing hypoxia and trauma to corneal epithelium.

D—Diabetes mellitus.

Dry eyes (Poor tear production results in reduction of antimicrobial tear component and epithelial desiccation and damage).

E—Entropion with trichiasis (results in breakdown of protective corneal epithelium).

F—Facial nerve palsy (results in exposure keratopathy).

It does not appear that AIDS serves as an independent risk for development of infectious keratitis, but infectious keratitis in AIDS patients might follow a more aggressive course.

Causative Organisms

Bacteria that can penetrate normal (intact) corneal epithelium are Neisseria gonorrhoeae, Neisseria meningitidis, and Corynebacterium diphtheriae.

However, most other bacteria are capable of producing keratitis with damaged epithelium. Purulent keratitis is usually exogenous due to pyogenic bacteria. The most common pathogens are listed in Flowchart 6.2.

Pseudomonas aeruginosa is a frequent cause of contact lens-associated keratitis and found in moist environments.

Pathogenesis of Corneal Ulcer

For a bacterial keratitis to become established, bacterial adherence to cornea requires a defect in the continuity of the corneal epithelium (Fig. 6.7). Pathological changes occurring during development of corneal ulcer can be described in four stages, namely, infiltration, ulceration, regression and cicatrization (Fig. 6.8).

Stage of Infiltration

The bacterial adherence to the cornea on damaged epithelium is facilitated by binding of microbial adhesins and toxins to host cell receptors and glycocalyx coat. The corneal infection and inflammation stimulates immigration of polymorphonuclear leucocytes (polymorphs) via tear film and proliferating limbal blood vessels. The epithelium becomes edematous and is raised at the site of infiltration.

Stage of Ulceration

The stage of infiltration is followed by the necrosis and desquamation of corneal stroma, leading to ulceration. Polymorphs phagocytose bacteria and necrotic stroma. If bacteria overwhelms host defense, necrosis progresses unchecked and corneal perforation takes place.

Stage of Regression

If infection is brought under control, infiltration decreases in size. Superficial vascularization develops from the limbus which supplies antibodies. Immune response increases and epithelium heals over ulcer.

Stage of Cicatrization

Cicatrization, which occurs in vascularized ulcer, involves regeneration of collagen and formation of fibrous tissue. Newly formed fibers are not arranged regularly as in normal corneal lamellae. These refract light irregularly. Scar is, therefore, opaque.

If ulcer is superficial and involves epithelium only, ulcer heals without leaving any opacity behind. If ulcer involves Bowman’s membrane, some degree of permanent opacification remains, as Bowman’s membrane never regenerates.

Clinical Features

Clinical features depend on virulence of organism, duration of infection, and use of steroids.

Symptoms

•Pain and photophobia (due to exposure of nerve endings of 1st division of trigeminal [V] nerve).

•Redness.

•Blepharospasm.

•Lacrimation.

•Discharge.

•Blurred vision.

Signs

•Circum corneal (ciliary) congestion of conjunctiva.

•Epithelial defect is associated with gray–white infiltrate around the margin of ulcer. Corneal lamellae imbibe fluid, and margin of ulcer becomes edematous and overhangs above the surface with sloping edges (saucer-shaped appearance of ulcer).

•Corneal ulcer takes a green stain with Fluorescein dye.

•Lid erythema and edema.

•Anterior chamber inflammation is often present with cells and flare and may produce a hypopyon.

Hypopyon Corneal Ulcer

Development of hypopyon: Some of the toxins produced by bacteria diffuse into the anterior chamber and irritate the vessels of iris and ciliary body (keratouveitis). Polymorphs from vessels are poured into the anterior chamber and thereafter gravitate to the bottom of the anterior chamber to form hypopyon. Hypopyon is sterile since accumulation of polymorphs is due to toxins, and not to actual invasion by bacteria. Indeed, bacteria and leucocytes are incapable of passing through the intact Descemet’s membrane. Such hypopyons are fluid and always move to the lowest part of the anterior chamber with change in the position of the patient’s head. Once the ulcerative process is controlled, hypopyon is easily and rapidly absorbed.

Thus, in absence of a full-thickness corneal perforation, hypopyon often represents a sterile accumulation. Development of hypopyon depends on:

•Virulence of infecting organism: Pyogenic organisms producing hypopyon are Staphylococci, Streptococci, Gonococci (N-gonorrhoeae), Moraxella, and Pseudomonas.

Pseudomonas and Pneumococcus (Streptococcus pneumoniae) are most dangerous and are likely to be present if there is dacryocystitis (inflammation of lacrimal sac).

•Resistance of tissues: Hypopyon corneal ulcers are much more common in elderly individuals, debilitated persons, and alcoholics.

Hypopyon corneal ulcer caused by pneumococci is characteristic and is called ulcus serpens because of its tendency to creep over cornea in a serpiginous fashion. It starts as a gray–white or yellowish disc-like lesion near the central part of the cornea with shaggy undermined infiltrating edges. One edge of the ulcer, along which the ulcer spreads, shows more infiltration which often looks like a yellow crescent. The tissues breakdown and ulcer spreads (Fig. 6.9).

There is violent iritis, leading to hypopyon, which increases in size very rapidly. Massive hypopyon often causes rise in IOP (secondary glaucoma).

In severe cases, ulcer spreads rapidly. The entire cornea is affected by the ulcerative process and perforation of ulcer results if there is sudden coughing or sneezing.

Management of Corneal Ulcer

It includes identification of organism and treatment. For identifying the causative organisms, corneal scrapings are taken from the margins and base of ulcer for Gram’s and Giemsa staining (Table 6.5) and culture and sensitivity (Table 6.6).

Treatment

Fundamental principles for treating corneal ulcer are protection, cleanliness, and specific treatment of infection. Treatment should be initiated before the results of culture and antibiotic sensitivity are available. Treatment includes the use of antibiotics and cycloplegics.

Antibiotics

Commonly used antibiotics are:

•Aminoglycosides, for example, Gentamicin, Tobramycin, and Amikacin.

•Fluoroquinolones, for example, Ciprofloxacin, Gatifloxacin, Ofloxacin, Moxifloxacin, and Levofloxacin.

•Cephalosporins, for example, Cefazolin.

•Penicillins, for example, Penicillin G, Methicillin, and Piperacillin.

•Vancomycin.

Routes of administration could be topical, subconjunctival, or systemic. Topical administration is the route of choice because it provides rapid, high-levels of drugs in the cornea and anterior chamber. The infection is controlled by the broad-spectrum antibiotic, while in severe infection, the fortified antibiotic drops are preferred. Fortified drops are not commercially available and are freshly prepared from their injectable preparations.

Treatment Regimen for Topical Antibiotics

Initial therapy should be initiated with a broad-spectrum regimen. Broad-spectrum coverage can be achieved with

•Fluoroquinolone antibiotic alone or

•Combination of aminoglycoside + cephalosporin.

Since increasing resistance to fluoroquinolones has been reported, therapy with fluoroquinolones is not a standard practice. Initial therapy should be a combination of two fortified antibiotics:

An aminoglycoside (gentamicin or tobramycin) for Gram –ve organisms

+

A cephalosporin (cefazolin is most commonly used for Gram +ve organisms)

Amikacin is useful against Gram –ve organisms resistant to gentamicin and tobramycin. The instillation frequency of topical antibiotics is as follows:

•Every 1 hour day and night for 48 hours.

•Every 2 hours during daytime for a further 48 hours.

•4–6 hourly for another week.

Treatment is continued until epithelium has healed. When combination of two antibiotics is prescribed, drops are given in an alternating fashion every half an hour.

Initial therapy with aminoglycoside and cephalosporin can be changed for effective treatment, if needed, after microbiological investigation (culture and sensitivity) reports. For example, fluoroquinolone treatment is significantly more effective in the treatment of Neisseria infection than an aminoglycoside combined with a cephalosporin.

Treatment Regimen for Oral Antibiotics

These are not usually necessary. Systemic antibiotics provide relatively low-level of antibiotic in the cornea because of avascularity. Therefore, these are advised only when keratitis is complicated by scleritis (as in peripheral ulcers with scleral extension) or there is risk of perforation or endophthalmitis.

N. gonorrhoeae should be treated systemically with IM ceftriaxone or IV penicillin G along with topical fluoroquinolone.

N. meningitidis should be treated with i.v. penicillin G along with topical fluoroquinolone.

Treatment Regimen for Subconjunctival Antibiotics

Subconjunctival injections are indicated if there is poor compliance with topical treatment (Table 6.7).

Cycloplegics

Atropine 1% as drops or ointment is preferred. Other cycloplegics are homatropine 2% eye drops and cyclopentolate 1% eye drops. These are instilled two to three times a day. Cycloplegics relieves ciliary spasm and reduces pain. These also prevent posterior synechiae formation as anterior uveitis generally accompanies corneal ulceration.

Treatment of Perforated Corneal Ulcer

If perforation has occurred, the treatment depends upon its size and location. Small perforation in pupillary area is managed with rest, antibiotics, atropine, and pressure bandage. Small perforation over iris results in adhesion of iris to cornea, forming adherent leucoma. In case of perforation, anterior chamber must be restored as quickly as possible. It can be done by use of tissue adhesive (cyanoacrylate glue). It is applied to the area of perforation after careful debridement. Drying of the adhesive may take 5 to 10 minutes. A surgical procedure such as therapeutic penetrating keratoplasty or conjunctival flap can be undertaken thereafter. Persistent anterior stromal scar can be removed by excimer laser phototherapeutic keratectomy.

Topical Corticosteroids in Corneal Ulcer

Steroids are best avoided, since they may retard epithelialization and inhibit repair by fibrosis. If inflammation is severe and persists, it is safest to use steroids when there is evidence of successful antibiotic treatment and cultures become sterile.

Additional therapeutic measures taken for healing of ulcer are as follows:

•Treatment of cause

♢Dacryocystitis should be treated with dacryocystorhinostomy (DCR).

♢If IOP is raised, it is reduced by antiglaucoma therapy.

♢Peritomy (excision of 2 mm strip of limbal conjunctiva) is performed for corneal vascularization.

•Removal of necrotic tissue by repeated scraping of the floor of ulcer.

•Cauterization of ulcer with pure (100%) carbolic acid or 10% trichloroacetic acid.

•Conjunctival flaps might be especially useful in peripheral infectious ulceration.

If infection is brought under control, cicatrization occurs in corneal ulcer. The residual scar may cause irregular astigmatism or may be visually debilitating (Table 6.8).

Treatment of Nonhealing Corneal Ulcer

If ulcer does not respond to therapeutic measures and continues to progress, a thorough search must be made for the cause, which could be either local or systemic. Local causes include lagophthalmos, trichiasis, raised IOP, dacryocystitis and vascularization of ulcer, while systemic causes include diabetes mellitus and systemic steroid administration (Fig. 6.11).

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