The Cornea CHAPTER 6

Anatomy and Physiology of Cornea...... 1 Pathological Changes in Cornea...... 3 Symptoms of Corneal Diseases...... 6 Evaluation of Corneal Diseases...... 6 Inflammation of Cornea...... 9 Corneal Degenerations...... 30 Corneal Dystrophies...... 31 Ectatic Conditions of Cornea...... 34

▄▄Anatomy and Physiology Epithelium of Cornea It may be regarded as continuation of conjunctiva Cornea is avascular and transparent. Its over cornea. Embryologically, it is derived from horizontal and vertical diameters are 12 mm and surface ectoderm at 5 to 6 weeks of gestation. 11.5 mm, respectively (Fig. 6.1). Its thickness at Characteristic features of epithelium are as the center and periphery is 0.5 mm and 0.7 mm, follows: respectively. Radius of curvature of anterior •• It is stratified and 4 to 6 cell layers thick. surface of cornea (in central region) is 7.8 mm, •• The epithelial cells contain microvilli with while that of posterior surface is 6.5 mm. Its glycocalyx layer which facilitate adsorption refractive index is 1.376 (≈ 1.38). Cornea provides of mucinous portion of tear film and 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. 12 mm ██ Histology Histologically, cornea consists of five layers (Fig. 6.2): 1. Epithelium (anterior most). 11.5 mm 2. Bowman’s membrane. 3. Stroma or substantia propria. 4. Descemet’s membrane. 5. Endothelium (posterior most). Fig. 6.1 Diameters of cornea.

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Glycocalyx layer

Surface cells Microvilli Wing cells Corneal epithelium Basal cells Basement membrane

Bowman’s membrane

Epithelium Bowman’s membrane

Stroma

Descemet’s membrane Endothelium

Anatomy of cornea

Fig. 6.2 Anatomy of cornea.

hydrophilic spreading of tear film with each of new corneal epithelium. Junctional eyelid blink. Loss of glycocalyx from injury or barrier prevents conjunctival tissue from disease results in loss of stability of tear film. growing on the cornea. So, dysfunction or •• Superficial cells undergo desquamation deficiency of limbal stem cells results in the and are replaced by deeper cells of corneal following chronic epithelial defects: epithelium. Basal cells are the only corneal šš Overgrowth of conjunctival epithelium epithelial cells capable of mitosis. Because onto the corneal surface. of excellent ability to regenerate, epithelium šš Vascularization. does not scar as a result of inflammation. These problems can be treated by limbal cell •• Tight junctions between its cells provide transplantation. barrier function and restrict entry of tears into intercellular spaces. Thus, healthy Bowman’s Membrane epithelial surface repels dyes such as It is an acellular structure which, once destroyed, fluorescein or Rose Bengal. does not regenerate. •• Epithelial regeneration: Epithelial stem cells (undifferentiated pluripotent cells) Stroma (Substantia Propria) are principally localized to limbal basal Stroma forms 90% of total corneal thickness. epithelium and serve as an important source It may be regarded as forward continuation of

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sclera. It is composed of collagen fibrils, forming ██ Blood Supply of Cornea lamellae which are loosely adherent to each other Normal cornea is an avascular tissue which gets and regularly arranged in many layers. The layers its nourishment from: crisscross at approximately right angles to each •• Capillaries at limbus which are derived other. Corneal lamellae become continuous with from episcleral branches of the anterior scleral lamellae at limbus. The layered structure of ciliary arteries. stroma results in corneal splitting, as in superficial •• Aqueous by diffusion. keratectomy. Ground substance occupies the space •• Oxygen dissolved in tear film. in between lamellae and is composed of glyco­ saminoglycans (mucopolysaccharides). Corneal ██ Nerve Supply of Cornea cells and keratocytes are found between lamellae Cornea is supplied by the ophthalmic division which are collagen-producing fibroblasts. Corneal of the trigeminal nerve (v ) through long ciliary stroma is markedly hydrophilic due to osmotic force 1 nerves (Fig. 6.4). of stromal glycosaminoglycans (GAG). Course Descemet’s Membrane Long ciliary nerves pierce sclera posterior to It is a thin elastic membrane secreted by limbus and form annular plexus (pericorneal endothelium throughout life. It is composed of plexus). Branches from annular plexus travel collagen fibrils and separates corneal stroma from radially to enter the corneal stroma and lose their endothelium. Unlike Bowman’s membrane, it can myelin sheaths. They divide into anterior group, regenerate (regenerated by endothelial cells). It is which forms subepithelial plexus, and posterior quite resistant to inflammatory process of cornea. group, which forms stromal plexus. Branches Therefore, descematocele can maintain integrity from subepithelial plexus pierce Bowman’s of eye for long after all other layers of cornea are membrane to form intraepithelial plexus. Due destroyed. It fuses with trabecular meshwork. to rich nerve supply, cornea is extremely sensitive The fusion site is known as Schwalbe’s line which structure. In eyes with corneal abrasions or defines the end of Descemet’s membrane and bullous keratopathy, direct stimulation of these start of the trabecular meshwork. nerve axons causes pain, reflex lacrimation, and Endothelium photophobia. It is derived from neural crest cells. It consists of ██ Metabolism of Cornea single layer of flat hexagonal cells and appears Energy is needed for normal functions of a tissue. as honey comb mosaic (Fig. 6.3). It contains a high-density of Na+–K+ ATPase pump. It secretes In cornea, energy is needed for maintenance of its 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 3000–4000 cells/mm2 to 2500 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 Fig. 6.3 Honey comb mosaic appearance of is most important as it keeps the cornea clear. endothelium of cornea.

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Pericorneal plexus (annular plexus) Long ciliary nerve

Subepithelial plexus 1st division of Intraepithelial trigeminal nerve plexus Stromal plexus

Corneal epithelium Bowman’s membrane Fig. 6.4 Nerve supply of corneal stroma Corneal endothelium cornea.

Glucose

Glycolysis ~ 2 ATP generated

Aerobic conditions Pyruvic acid (Via Kreb cycle) O2 H2O under anaerobic conditions

~36 ATP generated per mol of Lactic acid is produced by glucose (Corneal metabolism) corneal epithelium

Stromal changes result due to excess lactic acid

Flowchart 6.1 Metabolism of cornea.

transparency and dehydration. Energy in the form If access of O2 to epithelium is abolished by tight contact

of adenosine triphosphate (ATP) is generated by lenses or replacement of air in goggles with N2, cornea breakdown of glucose and utilization of oxygen swells and become cloudy due to production of lactic acid by corneal epithelium under anaerobic conditions. (Flowchart 6.1). Source of glucose for cornea is aqueous (90%), ▄▄Pathological Changes in tears and limbal capillaries (10%). Cornea Source of oxygen for cornea– Most of the The pathological changes in cornea can be O2 in cornea is consumed by epithelium and

endothelium. Epithelium gets much of its O2 categorized in (Table 6.1) as follows: from limbal capillaries or precorneal tear film. •• Loss of transparency (corneal edema and

Endothelium gets most of its O2 from aqueous corneal opacity). humor, and the cornea is mainly aerobic. •• Vascularization of cornea.

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•• Integrity of endothelium and epithelium: Table 6.1 Difference between normal and pathological cornea Damage to epithelium or endothelium due to any cause results in corneal swelling Normal cornea Pathological cornea and loss of transparency. However, damage Transparent Loss of transparency due to endothelium is far more serious which to corneal edema and corneal opacity can occur during intraocular surgery/ postuveitis. Avascular Vascularization of cornea •• Corneal endothelial Na+ – K+ ATPase Absence of pigments Corneal pigmentation pump and intracellular carbonic anhydrase pathway in endothelium: Activity in both these pathways produces a net flux from •• Pigmentation of cornea. stroma to aqueous. Inhibition of endothelial •• Corneal filaments. Na+–K+ ATPase pump, as in Fuch’s endothelial •• Prominent corneal nerves. dystrophy, leads to corneal edema. •• Infiltrates. If edema lasts for a long period, epithelium is raised into large vesicles or bullae (vesicular or ██ Transparency of Cornea (OP4.3, 4.5) bullous keratopathy). Bullae periodically burst and Normal cornea is a transparent structure. Corneal symptoms like ocular pain and irritation occur. transparency occurs due to regular arrangement Clinical Features of collagen fibrils (corneal lamellae) in stroma, avascularity of cornea, and relative state of Corneal edema presents with symptoms like dehydration. Water content of normal cornea is impairment of vision, photophobia, watering, approximately 78%. It is maintained at a steady ocular discomfort, pain due to periodic rupture of level by a balance between various factors. bullae, and halos around light. Disturbance of any of these factors leads to On slit lamp examination, corneal thickness is corneal edema. increased with haze. Epithelial edema is visible on retroillumination with slit lamp. Corneal Edema (OP4.3, 4.5) Management It is the accumulation of fluid in the cornea. It includes: Corneal edema may be epithelial or stromal and •• Treatment of primary causes such as can affect the entire cornea. lower­ing of IOP, and control of ocular Factors Leading to Corneal Edema inflammation. Following factors are responsible for the •• Protection of endothelium during intra­ development of corneal edema: ocular surgery by use of viscoelastics. •• Stromal GAG: Osmotic force of stromal GAG •• Hypertonic agents– plays a role in hydration. Accumulation of GAG šš 5% sodium chloride eye drops × QID in the cornea (as in Mucopolysaccharidoses) šš 6% sodium chloride eye ointment at bed leads to corneal edema. time •• Intraocular pressure (IOP): Raised IOP šš Anhydrous glycerine. (≥ 50 mm Hg) often results in corneal •• Bandage (therapeutic) contact lens to min­ edema due to easy passage of aqueous imize discomfort of bullous keratopathy. through corneal stroma but its escape is •• Penetrating keratoplasty (corneal trans­ retarded by epithelium and accumulation plant) is done in long-standing corneal of fluid in basal cells of epithelium results edema which is nonresponsive to medical in epithelial edema. treatment.

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Prognosis Nebular corneal opacity may be so faint that it could be missed on routine examination. A corneal It depends on the status of corneal endothelium. opacity in pupillary area causes blurring of vision. If endothelium is healthy, edema usually resolves •• If iris becomes adherent to the back of completely. Corneas with reduced endothelial cell leucoma in perforated corneal ulcer, it is counts may not be able to recover. called adherent leucoma. Corneal Opacity (OP4.5) •• In a sloughing corneal ulcer, where the whole cornea sloughs, prolapse of Corneal opacity occurs in the epithelial breech that iris occurs. Exudates which cover the involves Bowman’s membrane (Fig. 6.5). It may prolapsed iris become organized and be congenital due to developmental anomalies form a layer of fibrous tissue over which or birth trauma. The common causes include corneal epithelium rapidly grows, resulting infection, injury or corneal abrasion. Corneal in the formation of pseudocornea. More opacification (loss of transparency) may follow commonly, iris and cicatricial tissue are the noninflammatory diseases or inflammation. too weak to support the IOP. Cicatrix (scar) The term “scar” is reserved for the opacity becomes ectatic. Ectasia of pseudocornea following inflammation. Scar tissue is white and with incarceration of iris tissue is known as opaque, and varies in density. anterior staphyloma.

Based on the density of scarring, corneal Bowman’s membrane does not regenerate. So, some opacity may be nebular, macular or leucomatous opacity always remains when Bowman’s membrane has been destroyed. (Table 6.2).

a b Fig. 6.5 Corneal opacity. (a) Macula grade; (b) Leucoma grade.

Table 6.2 Types of corneal opacities

Nebular corneal opacity Macular corneal opacity Leucomatous corneal opacity (nebula) (macula) (leucoma)

Density Less dense + Moderately dense ++ Very dense +++ Involves Bowman’s membrane and Less than half the thickness More than half the superficial stroma of corneal stroma thickness of corneal stroma Structure seen through Details of iris can be seen Details of iris cannot be Obscures view of iris and opacity through opacity seen through opacity pupil

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Treatment •• Deep corneal ulcers. • The ideal procedure either involves • Disciform keratitis. • •• Excimer laser PTK (phototherapeutic • Sclerosing keratitis. • keratectomy) or • Interstitial keratitis (IK). •• Corneal transplantation (keratoplasty) Once the cornea has been vascularized, the vessels remain throughout life, but these blood ██ Vascularization of Cornea (OP4.5) vessels may become empty (“ghost vessels”) Normal cornea is avascular. Vascularization of when stimulus is eliminated. cornea is always pathological. Vascularization, Treatment which is considered as a defence mechanism (immunological defence) against disease, Vascularization can be prevented by timely and interferes with corneal transparency. It may be adequate treatment of predisposing conditions. superficial or deep. Treatment is usually unsatisfactory. The following treatment regimens may be effective: Superficial Vascularization •• Topical corticosteroid causes vasoconstric­ It arises from conjunctival superficial vascular tion and decrease in permeability of vessels. plexus. The vessels are wavy and lie in the •• Beta irradiation. epithelial layer. Continuity of vessels can be •• Peritomy is the surgical treatment of super­ traced with conjunctival vessels at the limbus. It ficial vascularization in intractable cases. is seen in the following: ██ •• Trachoma. Pigmentation of Cornea (OP4.5) •• Phlyctenular keratoconjunctivitis. Pigments deposited may be iron, silver, gold, •• Superficial corneal ulcers. copper, melanin, etc. •• Rosacea keratitis. •• Contact lens wearers. Deposition of Iron

Pannus In hyphema (blood in anterior chamber), When superficial vascularization is associated hemosiderin becomes embedded in the corneal with cellular infiltration, it is termed as pannus. stroma. Rise of IOP promotes blood staining It may either be progressive when infiltration is of cornea. Blood staining of cornea simulates ahead of vessels, or regressive, when infiltration dislocation of lens in the anterior chamber. is behind the vessels, that is, infiltration recedes. In keratoconus, deposition of iron hemosiderin Pannus may be located superiorly, inferiorly, or surrounds the base of the cone in the corneal generalized. Superior pannus occurs in trachoma epithelium (Fleischer’s ring). and contact lens wearers. Inferior pannus is In pterygium, iron is deposited as a golden brown associated with exposure keratopathy and line in front of its head (Stocker’s line) in the rosacea. Generalized pannus may be seen in corneal epithelium. chemical burns, Stevens–Johnson syndrome, and Mooren’s ulcer. In filtering bleb, iron is deposited anterior to the filtering bleb (Ferry’s line) in the corneal Deep Vascularization epithelium. It arises from anterior ciliary vessels. The vessels In old age, deposition of iron is seen as a brown run a fairly straight course and lie in the corneal horizontal line (Hudson–Stahli line) in the stroma. The continuity of vessels cannot be traced corneal epithelium. It is located at the junction beyond the limbus. It is seen in the following: of the upper 2/3rd and 1/3rd along the line of lid •• Chemical burns. closure.

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Deposition of Silver ██ Corneal Filaments Prolonged topical use of silver nitrate causes These are the epithelial threads attached to cornea impregnation of salt in the stroma and Descemet’s at one end, and the other unattached end is often membrane, resulting in brownish discoloration of club-shaped. These hang over the cornea and Descemet’s membrane (Argyrosis). move freely with each blink, thereby producing irritation and foreign body sensation. Deposition of Copper When a copper foreign body is retained in the eye, ██ Prominent Corneal Nerves deposition of copper occurs around the periphery These may be associated with: of the cornea in the region of Descemet’s Local ocular disorders, •• Keratoconus. membrane and deeper stroma. A gray–green or for example, golden–brown pigmentation of the peripheral •• Acanthamoebic corneal stroma is produced (Chalcosis). keratitis. •• Fuch’s endothelial In Wilson’s disease (hepatolenticular degen­ dystrophy. eration), deposition of copper in the periphery •• Congenital glaucoma. of Descemet’s membrane is seen as a golden- Systemic diseases, •• Neurofibromatosis. brown or green ring just inside the limbus when for example, •• Refsum syndrome. examined on slit lamp (Kayser–Fleischer ring, Fig. 6.6). ██ Infiltrates If viewed in cobalt blue light, the ring appears These originate from the limbal vascular arcades almost black. The condition is reversible with and are indicative of active inflammation. These time, if the disease is treated with penicillamine. are located usually within the anterior stroma and appear as focal, granular, gray–white opacities. Deposition of Melanin These are composed of leucocytes and cellular In pigment dispersion syndrome, uveal pigment debris. (melanin) is deposited on the corneal endothelium in the form of a vertical spindle (Krukenberg’s ▄▄Symptoms of Corneal Diseases spindle). The spindle may be associated with Symptoms of corneal diseases include pain or pigment dispersion glaucoma. slight irritation, visual impairment, lacrimation Deposition of Gold (excessive tear production), photophobia, halos, redness, and foreign body sensation. Specific Gold is deposited in the epithelium in patients symptoms pertaining to different pathologies of with chrysiasis. 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. Fig. 6.6 Kayser Fleischer ring (deposition of •• Corneal staining. copper). Source: Wilson disease (hepatolenticular •• Specular microscopy. degeneration). In: Biousse V, Newman N, ed. Neuro- •• Confocal microscopy. ophthalmology illustrated. 3rd Edition. Thieme; 2019. •• Corneal aesthesiometer.

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Table 6.3 Corneal pathology and symptoms

Corneal pathology Symptoms

▪▪Corneal abrasions or bullous keratopathy, ▪▪Lacrimation resulting in direct stimulation of bare nerve ▪▪Pain endings ▪▪Photophobia associated with reflex blepharospasm because of corneal irritation. The reflex blepharospasm is not completely abolished in dark but is greatly diminished by anaesthetization. ▪▪Loss of central corneal transparency due to Visual impairment šš Stromal edema šš Corneal opacity ▪▪Epithelial edema resulting in diffraction of light Halos around light with blue end of spectrum nearest to light source ▪▪Corneal foreign body or corneal filaments Foreign body sensation

Cornea is examined for the following: Corneal topography- It is computerized video keratography. It provides an objective record of 1. Size the condition of anterior corneal surface (optical Normal size– horizontal diameter 12 mm and anatomical condition) in the form of color- and vertical diameter 11.5 mm. coded maps. Megalo­cornea (increased size)– It may be Green color represents normal curvature. congenital and due to buphthalmos. Microcornea (decreased size)– It may occur iso­ Blue color represents flat curvature. lated or as a part of microph­thalmos (small eye). Red color represents steep curvature. 2. Shape It is important in preoperative evaluation for Normal cornea– It is like a part of a sphere. refractive surgery, for example, in patient with Flat cornea (cornea plana)– It may occur keratoconus, refractive surgery is deferred. congenitally or in phthisis bulbi. Orbscan is an improved technology which uses Conical cornea– in keratoconus scanning slit technology with Placido disc. It Globular cornea – In Keratoglobus provides information regarding curvature of 3. Surface anterior and posterior surfaces of cornea, and Corneal surface and curvature can be evaluated depth of anterior chamber. Curvature of anterior by slit lamp, Placido’s disc, Placido keratoscope, surface of cornea can also be measured by a corneal topography, and keratometer. keratometer.

Placido’s keratoscopic disc: Kerato means cornea 4. Transparency and scopic means visualization. The corneal Cornea is optically transparent, and it becomes surface is visualized by a disc painted with hazy in corneal edema, ulcers, opacity, alternating black and white circles and contains a vascularization, dystrophies and degenerations, hole in the center. Light is kept behind the patient and corneal deposits. The examination for corneal and the examiner looks at corneal image of circles edema and corneal opacity is carried out with the through the hole. help of a slit lamp. The corneal opacity is examined Uniform and sharp image of circles is seen in for its density (nebular, macular, or leucomatous), normal cornea, while irregularities in rings are sensations, location, and its size. seen if corneal surface is uneven as in keratoconus, If keratitis (ulcerative or nonulcerative) is keratoglobus, and corneal astigmatism. suspected, corneal staining is performed.

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5. Corneal Staining 8. Corneal Sensitivity Cornea is richly supplied by nerves. Corneal Staining of cornea with vital dyes (Fluorescein or sensitivity can be tested by: Rose Bengal, Table 6.4) is important in evaluating •• Touching cornea with wisp of cotton wool– corneal epithelial lesions. It should be performed Normally, there is brisk blink reflex as a before corneal sensation is tested and also prior to response. measurement of IOP. •• Corneal aesthesiometer provides a more Alcian blue dye stains mucus selectively, so it qualitative measurement of corneal stains excess mucus, as in keratoconjunctivitis sensations. In aesthesiometer, a single sicca (KCS). horse hair of varying length is used. The longest length which induces blinking In a geographical herpetic ulcer, peripheral devitalized is a measure of the threshold of corneal cells are stained with Rose Bengal dye, while the base of the ulcer (epithelial defect) is stained with sensitivity. Normally, the cornea is most Fluorescein dye. sensitive in the center.

6. Corneal Vascularization Corneal sensations are diminished in the The normal cornea is avascular. If corneal vascular­ following: •• Herpetic keratitis. ization is present, note the following points: •• Neuroparalytic keratitis. •• Whether the vessels are superficial or deep. •• Absolute glaucoma. •• Whether the distribution is localized, •• Cerebellopontine angle tumor. circumferential, or peripheral. •• Leprosy. 7. Corneal Thickness (Pachymetry) •• Trigeminal block for neuralgia.

Corneal thickness indirectly reflects endothelial 9. Endothelial Function function. It is measured by with the help of the Corneal endothelium can be examined by specular pachymeter. microscopy or confocal microscopy on a slit lamp.

Average corneal thickness at center, that is, Specular microscopy: Specular microscope central corneal thickness (CCT) is about 0.5 mm photographs the endothelial cells and enables the (490–560 µm). CCT of ≥ 0.6 mm is suggestive study of their morphology (their number [count], of endothelial disease. At periphery corneal size and shape). thickness is ≈ 0.7 mm. Average cell count is 2500 cells/mm2. In adults, it CCT can alter measurement of IOP: Patients with declines with age from 3500 cells/mm2 in children increased CCT record high IOP, while patients to 2000 cells/mm2 in old age. There is a certain with decreased CCT record low IOP. amount of endothelial cell loss after intraocular

Table 6.4 Difference between Fluorescein and rose Bengal dyes

Fluorescein dye 2% Rose Bengal dye 1%

▪▪It remains extracellular and does not stain mucus. ▪▪ It stains mucus as well as devitalized (dead and It stains tear film and shows up epithelial damaged) cells red as in superficial punctate keratitis corneal defects. and filamentary keratitis. ▪▪It delineates areas denuded of epithelium (abrasions, ▪▪ It is useful in diagnosis of KCS. ulcer) which stains brilliant green when examined under ▪▪ Rose Bengal dye is very irritating, so instill 2% xylocaine a cobalt blue filter. (local anesthetic) eye drop before using Rose Bengal.

Abbreviation: KCS: keratoconjunctivitis sicca.

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surgery. Intraocular surgery is deferred in •• Diseases of uveal tract spread to corneal endothelial cell count cases of < 1000 cells/mm2. endothelium, for example, herpetic uveitis

Normally, endothelial cells are hexagonal. with endotheliitis. Variability in the shape of cells is called ██ Classification pleomorphism. In the presence of 50% nonhexagonal cells, intraocular surgery is Keratitis can be classified as follows: contraindicated. Variation in cell size is called •• Based on depth polymegathism. Superficial keratitis– It is the inflammation Confocal microscopy: It is performed by a confocal involving epithelium and Bowman’s membrane. microscope. In cases with corneal edema, Deep keratitis– It is the inflammation deep to endothelium is not adequately visualized by Bowman’s membrane. specular microscopy due to edema. Confocal •• Based on location microscopy may be of value in cases with corneal šš Central edema. šš Peripheral Confocal microscope allows direct visualization of •• Based on epithelial defect corneal cells. It acquires multiple images of cornea šš Ulcerative from epithelium to endothelium. Magnified šš Nonulcerative images provide detailed information regarding •• Based on etiology cell count, shape, and size. šš Infectious Confocal microscopes are of two types: confocal šš Noninfectious slit-scanning microscope and confocal laser- Infectious Keratitis (OP4.1, 4.2) scanning microscope. It is the corneal inflammation caused by bacterial, ▄▄Inflammation of Cornea viral, fungal, or parasitic (protozoal or helminthic) organisms. It can be classified as: Inflammation of cornea is known as Keratitis. •• Depending on depth š ██ Source of inflammation š Superficial šš Deep Inflammation of cornea may arise from: •• Depending on pus formation •• Exogenous source– Cornea is involved by šš Purulent (suppurative) way of exogenous organisms. šš Nonpurulent (Nonsuppurative) •• Endogenous source– Inflammation •• Depending on epithelial defect due to endogenous source is typically šš Ulcerative wherein corneal epithelium immunological in nature. As cornea is shows discontinuity. Loss of epithelium avascular, the immunological changes are with inflammation in surrounding common near limbal blood vessels close cornea is called corneal ulcer. to the corneal margin and called marginal šš Nonulcerative wherein epithelium is keratitis. intact (corneal abscess). •• Contiguous spread (owing to direct anatomical continuity). Inflammation in cornea is visible as a grayish •• Diseases of conjunctiva spread to corneal haze. If it is accompanied by accumulation of epithelium, for example, trachoma and leucocytes and cellular debris, this hazy area is vernal keratoconjunctivitis. called an infiltration and appears as gray–white •• Diseases of sclera spread to corneal stroma, or off–white opacities. Infiltrates are indicative of for example, sclerosing keratitis. active inflammation.

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Noninfectious Keratitis •• Propionibacterium acnes. •• Neisseria catarrhalis. It is the corneal inflammation with no known •• Diphtheroids. infectious cause. It may be: •• Corynebacterium xerosis, etc. •• Allergic/immune-mediated All these organisms are nonpathogenic com­ 1. Localized immune-mediated keratitis: mensals. Streptococci, E. coli, B proteus, Neisseria šš Phlyctenular. gonorrhoeae, Hemophilus aegyptius, Moraxella, šš Vernal. etc. are pathogenic and rarely found in normal šš Mooren’s ulcer. eyes. šš Marginal. šš Atopic. Defence Mechanisms 2. Keratitis in systemic immunological The following mechanisms help in defending disorders against the microbial invasion of the corneal šš Associated with collagen disorders. surface: šš Dermatological disorders: Rosacea. 1. Blinking regularly sweeps away debris – Erythema multiforme. trapped in the mucin layer of tears. 2. Tight junctions between corneal and – Mucous membrane pemphigoid. conjunctival epithelial cells. •• Nonimmune-mediated 3. Tears which contain: šš Neurotrophic in Vth cranial nerve (CN) •• Lactoferin (secreted by lacrimal gland)– palsy and diabetes It inhibits complement activation. šš Neuroparalytic in VIIth CN palsy. •• Lysozyme, which promotes microbial šš Traumatic: aggregation and causes lysis of – Chemical injury. bacterial cell membrane. – Thermal injury. •• IgA– It causes bacterial agglutination and inhibits bacterial adherence to – Radiation. corneal and conjunctival surface. šš Mechanical: •• b-lysin– It causes bacteriolysis. – Entropion with trichiasis 4. Mast cells of conjunctiva: Stimulation – Lagophthalmos. of mast cells cause degranulation of mast cells. It results in vascular dilation – Exophthalmos. and increased vascular permeability. šš Nutritional in keratomalacia. Thus, transudate is produced which is šš In KCS. antimicrobial. šš Others: 5. Resident normal microbes produces – Thygeson’s superficial punctate bacteriocins (high-molecular weight pro­ keratitis (SPK). teins), which inhibit growth of pathogens. – Superior limbic keratoconjunctivitis. Predisposing Factors Compromising one or more of the defense mecha­ ██ Infectious Keratitis nisms represent a risk factor in the development Bacterial Keratitis of bacterial keratitis. These mechanisms are: The conjunctival sac is never free from organisms. Trauma– accidental, agricultural or surgical Most of the organisms, normally, present on the (refractive surgery). ocular surface are– Topical steroids (cause impairment of local •• Staphylococcus albus or epidermidis. immune defense).

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Trigeminal nerve paralysis causes corneal However, most other bacteria are capable of anesthesia and exfoliation of epithelial cells. producing keratitis with damaged epithelium. Purulent keratitis is usually exogenous due to A– Vitamin A deficiency. pyogenic bacteria. The most common pathogens B– Bullous keratopathy (corneal epithelial are listed in Flowchart 6.2. problem). Pseudomonas aeruginosa is a frequent cause C– Chronic blepharitis. of contact lens-associated keratitis and found in Contact lens wear, particularly extended wear soft moist environments. lenses, causing hypoxia and trauma to corneal Pathogenesis of Corneal Ulcer epithelium. For a bacterial keratitis to become established, D– Diabetes mellitus. bacterial adherence to cornea requires a defect Dry eyes (Poor tear production results in reduction in the continuity of the corneal epithelium of antimicrobial tear component and epithelial (Fig. 6.7). Pathological changes occurring during desiccation and damage). development of corneal ulcer can be described

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. Fig. 6.7 Bacterial corneal ulcer.

Pathogens

Gram +ve organisms Gram - ve organisms

Gram +ve cocci Gram +ve bacilli Gram –ve cocci Gram –ve bacilli • Staphylococcus aureus Aerobic- • Neisseria • Pseudomonas • Streptococcus • Bacillus cereus gonorrhoeae aeruginosa pneumoniae • Corynebacterium • Neisseria • Escherichia coli (Pneumococcus) diphtheriae meningitidis • Klebsiella Anaerobic- • Proteus • Clostridium • Moraxella

Flowchart 6.2 Types of pathogens causing keratitis.

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in four stages, namely, infiltration, ulceration, If ulcer is superficial and involves epithelium regression and cicatrization (Fig. 6.8). only, ulcer heals without leaving any opacity Stage of Infiltration behind. If ulcer involves Bowman’s membrane, some degree of permanent opacification remains, The bacterial adherence to the cornea on damaged as Bowman’s membrane never regenerates. epithelium is facilitated by binding of microbial adhesins and toxins to host cell receptors Clinical Features and glycocalyx coat. The corneal infection Clinical features depend on virulence of organism, and inflammation stimulates immigration of duration of infection, and use of steroids. polymorphonuclear leucocytes (polymorphs) via Symptoms tear film and proliferating limbal blood vessels. The epithelium becomes edematous and is raised •• Pain and photophobia (due to exposure of at the site of infiltration. nerve endings of 1st division of trigeminal [V] nerve). Stage of Ulceration •• Redness. The stage of infiltration is followed by the necrosis •• Blepharospasm. and desquamation of corneal stroma, leading •• Lacrimation. to ulceration. Polymorphs phagocytose bacteria •• Discharge. and necrotic stroma. If bacteria overwhelms •• Blurred vision. host defense, necrosis progresses unchecked and corneal perforation takes place. Signs •• Circum corneal (ciliary) congestion of Stage of Regression conjunctiva. If infection is brought under control, infiltration •• Epithelial defect is associated with gray– decreases in size. Superficial vascularization white infiltrate around the margin of ulcer. develops from the limbus which supplies Corneal lamellae imbibe fluid, and margin antibodies. Immune response increases and of ulcer becomes edematous and overhangs epithelium heals over ulcer. above the surface with sloping edges Stage of Cicatrization (saucer-shaped appearance of ulcer). Cicatrization, which occurs in vascularized ulcer, •• Corneal ulcer takes a green stain with involves regeneration of collagen and formation Fluorescein dye. of fibrous tissue. Newly formed fibers are not •• Lid erythema and edema. arranged regularly as in normal corneal lamellae. •• Anterior chamber inflammation is often These refract light irregularly. Scar is, therefore, present with cells and flare and may opaque. produce a hypopyon.

Stage of infiltration Stage of ulceration Stage of regression Stage of cicatrization a b c d Fig. 6.8 (a) Stage of infiltration. (b) Stage of ulceration. (c) Stage of regression. (d) Stage of cicatrization.

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Hypopyon Corneal Ulcer individuals, debilitated persons, and Development of hypopyon: Some of the toxins alcoholics. produced by bacteria diffuse into the anterior Hypopyon corneal ulcer caused by chamber and irritate the vessels of iris and pneumococci is characteristic and is called ulcus ciliary body (keratouveitis). Polymorphs from serpens because of its tendency to creep over vessels are poured into the anterior chamber cornea in a serpiginous fashion. It starts as a and thereafter gravitate to the bottom of the gray–white or yellowish disc-like lesion near the anterior chamber to form hypopyon. Hypopyon central part of the cornea with shaggy undermined is sterile since accumulation of polymorphs is due infiltrating edges. One edge of the ulcer, along to toxins, and not to actual invasion by bacteria. which the ulcer spreads, shows more infiltration Indeed, bacteria and leucocytes are incapable of which often looks like a yellow crescent. The passing through the intact Descemet’s membrane. tissues breakdown and ulcer spreads (Fig. 6.9). Such hypopyons are fluid and always move to There is violent iritis, leading to hypopyon, the lowest part of the anterior chamber with which increases in size very rapidly. Massive change in the position of the patient’s head. Once hypopyon often causes rise in IOP (secondary the ulcerative process is controlled, hypopyon is glaucoma). easily and rapidly absorbed. In severe cases, ulcer spreads rapidly. The Thus, in absence of a full-thickness corneal entire cornea is affected by the ulcerative process perforation, hypopyon often represents a sterile and perforation of ulcer results if there is sudden accumulation. Development of hypopyon coughing or sneezing. depends on: •• Virulence of infecting organism: Pyogenic Pseudomonas corneal ulcer organisms producing hypopyon are Pseudomonas produces destructive enzymes (such as protease, lipase, elastase, and exotoxin) which melt Staphylococci, Streptococci, Gonococci corneal stroma and results in a necrotic soupy ulceration (N-gonorrhoeae), Moraxella, and with greenish-yellow mucopurulent discharge adherent to the ulcer. The corneal epithelium away Pseudomonas. from the primary ulcer typically develops a diffuse, semi-opaque The ulcer Pseudomonas and Pneumococcus (Strepto­ “ground glass” appearance. is associated with marked anterior chamber reaction coccus pneumoniae) are most dangerous and and hypopyon formation. Rapidly spreading ulcer are likely to be present if there is dacryocystitis often extends peripherally, deeply involving the entire cornea and resulting in sloughing corneal ulcer and (inflammation of lacrimal sac). perforation. If cornea sloughs, iris is prolapsed and •• Resistance of tissues: Hypopyon corneal covered by exudates which become organized, resulting ulcers are much more common in elderly in formation of pseudocornea (Fig. 6.10).

Fig. 6.9 Hypopyon corneal ulcer. Fig. 6.10 Pseudomonas corneal ulcer.

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Management of Corneal Ulcer Routes of administration could be topical, sub­ It includes identification of organism and treat­ conjunctival, or systemic. Topical administration is the route of choice because it provides rapid, high- ment. For identifying the causative organisms, levels of drugs in the cornea and anterior chamber. corneal scrapings are taken from the margins The infection is controlled by the broad-spectrum and base of ulcer for Gram’s and Giemsa staining antibiotic, while in severe infection, the fortified (Table 6.5) and culture and sensitivity (Table 6.6). antibiotic drops are preferred. Fortified drops Treatment are not commercially available and are freshly Fundamental principles for treating corneal ulcer prepared from their injectable preparations. are protection, cleanliness, and specific treatment Treatment Regimen for Topical Antibiotics of infection. Treatment should be initiated before Initial therapy should be initiated with a broad- the results of culture and antibiotic sensitivity spectrum regimen. Broad-spectrum coverage can are available. Treatment includes the use of be achieved with antibiotics and cycloplegics. •• Fluoroquinolone antibiotic alone or Antibiotics •• Combination of aminoglycoside + cephalosporin Commonly used antibiotics are: •• Aminoglycosides, for example, Gentamicin, Since increasing resistance to fluoroquinolones Tobramycin, and Amikacin has been reported, therapy with fluoroquinolones •• Fluoroquinolones, for example, Ciprofloxacin, is not a standard practice. Initial therapy should be Gatifloxacin, Ofloxacin, Moxifloxacin, and a combination of two fortified antibiotics: Levofloxacin An aminoglycoside (gentamicin or tobramycin) •• Cephalosporins, for example, Cefazolin for Gram –ve organisms •• Penicillins, for example, Penicillin G, + Methicillin, and Piperacillin A cephalosporin (cefazolin is most commonly •• Vancomycin used for Gram +ve organisms)

Table 6.5 Staining of corneal scrapings

Stain Organism identified

▪▪Gram’s and Giemsa: Gram’s staining differentiate into Gram +ve and Gram –ve species. Bacteria, fungi ▪▪Potassium hydroxide (KOH) fixation. Fungi ▪▪Calcofluor white (it is a fluorescent dye with an affinity for amoebic cysts Fungi and acanthamoeba and fungi)

Table 6.6 Corneal scrapings for culture and sensitivity

Culture media Organism isolated

▪▪Blood agar It promotes growth of: ▪▪Aerobic bacteria except Neisseria, Haemophilus and Moraxella ▪▪Saprophytic fungi ▪▪Chocolate agar It is used to isolate neisseria, hemophilus, and moraxella ▪▪Sabouraud’s dextrose agar Promotes growth of fungi ▪▪E. coli plated non-nutrient agar For acanthamoeba

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Amikacin is useful against Gram –ve organisms prevent posterior synechiae formation as anterior resistant to gentamicin and tobramycin. The instil­ uveitis generally accompanies corneal ulceration. lation frequency of topical antibiotics is as follows: Treatment of Perforated Corneal Ulcer •• Every 1 hour day and night for 48 hours. If perforation has occurred, the treatment depends •• Every 2 hours during daytime for a further upon its size and location. Small perforation in 48 hours pupillary area is managed with rest, anti­biotics, •• 4–6 hourly for another week atropine, and pressure bandage. Small perfora­ Treatment is continued until epithelium has tion over iris results in adhesion of iris to cornea, healed. When combination of two antibiotics forming adherent leucoma. In case of perforation, is prescribed, drops are given in an alternating anterior chamber must be restored as quickly as fashion every half an hour. possible. It can be done by use of tissue adhesive Initial therapy with aminoglycoside and (cyanoacrylate glue). It is applied to the area of cephalosporin can be changed for effective perforation after careful debridement. Drying of treatment, if needed, after microbiological the adhesive may take 5 to 10 minutes. A surgical investigation (culture and sensitivity) reports. procedure such as therapeutic penetra­ting For example, fluoroquinolone treatment is keratoplasty or conjunctival flap can be under­ significantly more effective in the treatment taken thereafter. Persistent anterior stromal scar of Neisseria infection than an aminoglycoside can be removed by excimer laser phototherapeutic combined with a cephalosporin. keratectomy. Treatment Regimen for Oral Antibiotics Topical Corticosteroids in Corneal Ulcer These are not usually necessary. Systemic Steroids are best avoided, since they may retard antibiotics provide relatively low-level of epithelialization and inhibit repair by fibrosis. If antibiotic in the cornea because of avascularity. inflammation is severe and persists, it is safest to Therefore, these are advised only when keratitis use steroids when there is evidence of successful is complicated by scleritis (as in peripheral antibiotic treatment and cultures become sterile. ulcers with scleral extension) or there is risk of Additional therapeutic measures taken for perforation or endophthalmitis. healing of ulcer are as follows: N. gonorrhoeae should be treated systemically •• Treatment of cause š with IM ceftriaxone or i.v. penicillin G along with š Dacryocystitis should be treated with topical fluoroquinolone. dacryocystorhinostomy (DCR) šš If IOP is raised, it is reduced by N. meningitidis should be treated with i.v. antiglaucoma therapy. penicillin G along with topical fluoroquinolone. šš Peritomy (excision of 2 mm strip of Treatment Regimen for Subconjunctival limbal conjunctiva) is performed for Antibiotics corneal vascularization. Subconjunctival injections are indicated if there

is poor compliance with topical treatment Table 6.7 Dosage of subconjunctival injections for the (Table 6.7). treatment of corneal ulcers Cycloplegics Drug Subconjunctival dose Atropine 1% as drops or ointment is preferred. Gentamicin/tobramycin 40 mg Other cycloplegics are homatropine 2% eye Amikacin 50 mg drops and cyclopentolate 1% eye drops. These are Cefazolin 125 mg

instilled two to three times a day. Cycloplegics Note: Subconjunctival injections are given at 24 hourly relieves ciliary spasm and reduces pain. These also intervals for 5 days.

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•• Removal of necrotic tissue by repeated vascularization of ulcer, while systemic causes scraping of the floor of ulcer. include diabetes mellitus and systemic steroid •• Cauterization of ulcer with pure (100%) administration (Fig. 6.11). carbolic acid or 10% trichloroacetic acid. Complications •• Conjunctival flaps might be especially Following are the complications of corneal ulcers: useful in peripheral infectious ulceration. 1. Ectatic cicatrix (secondary keratectasia): If infection is brought under control, Deep ulcer may lead to marked thinning cicatrization occurs in corneal ulcer. The residual of cornea which may bulge under normal scar may cause irregular astigmatism or may be IOP. The corneal scar (cicatrix) becomes visually debilitating (Table 6.8). consolidated with permanent bulging as Treatment of Nonhealing Corneal Ulcer secondary keratectasia. If ulcer does not respond to therapeutic measures 2. Secondary glaucoma: Corneal ulcer and continues to progress, a thorough search causes absorption of toxins in the anterior must be made for the cause, which could be either chamber, leading to the formation of toxic local or systemic. Local causes include lagoph­ iridocyclitis. This further causes blockage thalmos, trichiasis, raised IOP, dacryocystitis and of an angle of the anterior chamber with fibrinous exudates leading to secondary

Table 6.8 Outcome of treatment in bacterial keratitis glaucoma. 3. Descemetocele: Some ulcers become Outcome of bacterial Treatment keratitis adequately deep (due to virulent organisms) to involve the whole thickness ▪▪If irregular ▪▪It is treated with rigid astigmatism occurs contact lens. of cornea except Descemet’s membrane. ▪▪If scar is anterior ▪▪It is removed by excimer Descemet’s membrane being elastic offers stromal laser phototherapeutic resistance to inflammation and is unable to keratectomy. support IOP and herniates. The herniation ▪▪If scar is deep ▪▪It requires lamellar or of Descemet’s membrane through the penetrating keratoplasty. ulcer is known as descemetocele. 4. Perforation of corneal ulcer (perforated Misdirected eye lashes corneal ulcer, Fig. 6.12) (trichiasis) Lagophthalmos Dacryocystitis Descemetocele is a sign of impending perforation which may convert into perforation

Raised IOPVascularisation of ulcer

Fig. 6.11 Local causes of nonhealing corneal ulcers. Fig. 6.12 Perforated corneal ulcer.

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on coughing, sneezing, straining at stool, or spasm •• Iris prolapse– If perforation is large and of orbicularis muscle. Pain is alleviated after opposite the iris, iris prolapse occurs. perforation. Perforation of ulcer is accompanied by There is deposition of exudates on the iris sudden escape of aqueous and fall in IOP. The iris surface which becomes organized. Iris and lens diaphragm moves forward and cicatrization cicatricial tissue are too weak to support of corneal ulcer results (Fig. 6.13). IOP, hence anterior ectasia of cicatrix Factors responsible for preventing perforation with incarceration of iris, which is called are as follows: anterior staphyloma, develops. • •• Forced expiration (blowing the nose, • Anterior capsular cataract– If perforation coughing, etc.) must be avoided. is opposite the pupil (central perforation), •• IOP is reduced by oral acetazolamide and/ the lens comes in contact with the ulcer- or i.v. mannnitol and topical IOP-lowering causing anterior capsular cataract. If eye drops. perforation is not plugged by iris but exudates fill the gap, the repeated ruptures Sequelae and complications of perforation– The of exudates fill the gap, causing the opening effect of perforation largely depends on its size to become permanent and leading to the and position. These include the following: formation of corneal fistula. •• Endophthalmitis or panophthalmitis– Due to perforation of ulcer, organisms gain Fungal Keratitis (Mycotic Keratitis) access to the interior of the eye, leading For clinical purpose, fungi are of the following two to the development of endophthalmitis or types: panophthalmitis. •• Filamentous fungi. •• Intraocular/expulsive hemorrhage– •• Nonfilamentous fungi (yeasts). Sudden perforation of large ulcer causes sudden lowering of IOP, hence there is Risk Factors dilatation of intraocular blood vessels. This The following risk factors are involved in the leads to the development of intraocular/ development of fungal keratitis: expulsive hemorrhage (profuse bleeding •• Trauma with vegetable matter or animal along with extrusion of contents of globe). tail. •• Anterior synechiae– If perforation is small •• Systemic immunosuppression by use of and opposite the iris, anterior synechiae corticosteroids or immunosuppressives. develop, leading to leucoma adherens. •• Diabetes.

PerforationDescemetocele a b Fig. 6.13 (a) Perforation; (b) Descemetocele.

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•• Hydrophilic contact lens wear. Investigations helpful for coming to a diagnosis •• Corneal surgery (fungal infection at lamellar include: interface has been described following •• Scrapings from the floor of ulcer are stained LASIK). with 10% KOH. Etiology •• Scrapings are also plated on Sabouraud dextrose agar for culture and sensitivity. Fungal keratitis is rare in temperate countries but Cycloheximide should not be included in common in tropical countries, warm and humid the medium since it inhibits fungal growth. climates, rural areas, and immuno-compromised individuals. It is most prevalent in agricultural Treatment areas and typically preceded by ocular trauma As most antifungals are only fungistatic, topical with vegetable matter. It is commonly due to treatment should be continued for several weeks. infections with Aspergillus, Fusarium and Candida Removal of epithelium over the lesion enhances albicans. penetration of antifungal agents. Clinical Features Topical treatment includes the following The onset is gradual and slowly progressive. considerations: Symptoms are relatively minimal, much milder •• Infection due to filamentous fungi is treated than clinical signs, and include foreign body with natamycin 5%, amphotericin B 0.15%, sensation, photophobia, blurred vision, and or miconazole 1% drops. Voriconazole eye discharge. drops are more effective against Aspergillus. The drops are instilled initially every 1 hour Clinical signs of filamentous fungi are: and tapered gradually. •• Organism adherence results in gray–white, •• Candida infection (yeast) is usually treated elevated infiltrate. Epithelium over infiltrate with amphotericin B. Nystatin eye ointment may be elevated above the remainder of the applied five times a day is only effective corneal surface. against candida. •• Invasion into corneal lamellae and extension along corneal lamellae results in If infection fails to respond to single agent feathery borders and satellite lesions. therapy, amphotericin B and natamycin can be •• Penetration of intact Descemet’s membrane used alternatively on an hourly basis. by filamentous fungi results in thick and Systemic antifungal drugs (itraconazole or immobile hypopyon with upper convex voriconazole) may be required in endophthalmitis. border (Fig. 6.14). Infection in anterior chamber is difficult to eradicate. •• Sometimes, a white immune ring (Wessely ring) may be seen around the ulcer due to deposition of immune complexes. In case of nonfilamentous fungi (candida), keratitis is characterized by a yellow–white stromal infiltrate, associated with dense suppuration, which appears as a collar-button abscess without feathery edge. Diagnosis History of trauma with vegetable matter, wood, Fig. 6.14 Fungal keratitis with satellite lesions and animal tail, or chronic use of steroid is present. hypopyon.

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If medical treatment fails, surgical intervention HSV-2 passes through the birth canal, so may be required. Penetrating keratoplasty neonatal HSV infection occurs by way of Type-2 should be performed sooner to minimize the virus (Fetus). It may affect the central nervous risk of endophthalmitis or infectious scleritis. system (CNS) or can remain localized to the Clear margins should be included in excised eye. Neonatal ocular HSV infection can present cornea. Corticosteroid use is not recommended in as conjunctivitis, keratitis, iridocyclitis, iris management of fungal keratitis. atrophy, cataract, chorioretinitis, or optic neuritis (Fig. 6.15). Viral Keratitis Primary Infection (i.e., no previous virus Viruses are obligate, intracellular parasites. exposure) Viruses that cause corneal disease include: Neonates are usually protected by maternal •• Herpes simplex virus (HSV). antibodies against HSV infection during the first •• Varicella zoster virus (VZV). 6 months of life. So, primary infection by HSV-1 •• Epstein–Barr virus (EBV). is uncommon during the first 6 months of life. •• Adenovirus. Transmission occurs by droplet transmission via •• Cytomegalovirus (CMV)– It is a more contaminated adult saliva. So, children under 3 common entity in association with AIDS. years of age are more prone to get HSV infection, Herpes Simplex Keratitis owing to close contact, that is, it typically occurs HSV is a DNA virus and is of two types: HSV-1 between 6 months to 5 years of age.

and HSV-2. HSV-1 causes infection above waist Primary infection remains often subclinical and and affects face, lips and eyes, while HSV-2 is may cause mild fever, malaise, upper respiratory associated with genital infection (genital herpes). tract symptoms, and local lymphadenopathy HSV infection can be categorized into neonatal, (Fig. 6.16). Oral mucosa is more commonly primary, and recurrent infections. involved than eye in primary infection.

Neonatal Infection Children may develop follicular kerato It is the infection of newborns by maternal genital conjunctivitis. Epithelial punctate keratitis herpes may be found in nearly 50% of the cases. Primary

1. conjunctivitis

2. Keratitis

3. Iridocyclitis and iris atrophy

6.Optic neuritis Fig. 6.15 Presentation of neo­ natal ocular HSV. Abbreviation: 4. Cataract 5. Chorioretinitis HSV, Herpes simplex virus.

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II. Involvement of conjunctiva manifests as severe follicular conjunctivitis.

III. Involvement of corneal epithelium by way of HSV results in epithelial keratitis. Symptoms include mild discomfort, foreign body sensation, redness, watering, blurred vision, and photophobia., Following are the clinical signs of involvement of corneal epithelium due to recurrent HSV infection: Fig. 6.16 Herpes simplex infection. •• Characteristic epithelial lesion of recurrent HSV infection is dendritic ulcer (Fig. 6.17a). Virus replication results in opaque herpetic infection is usually benign and self-limited. epithelial cells on the cornea, arranged An attack does not produce lasting immunity and in a row or group. Central desquamation recurrences are frequent, particularly associated of these results in linear branching ulcer with upper respiratory tract infection (URTI). A (dendritic ulcer). The ends of the ulcer person once infected frequently becomes a carrier. have characteristic terminal knobs which Recurrent Infection (i.e., reactivation in are pathognomonic. The central ulcerated presence of cellular and humoral immunity) area stains with Fluorescein dye, while the After primary infection with HSV-1, the virus peripheral cells at the margin containing reaches the sensory ganglion, where it may lie live virus stain with Rose Bengal dye. dormant for many years. Risk factors for recurrence Indiscriminate use of topical steroids results are fever, stress, trauma, malnourishment, in progressive enlargement of dendritic measles, and use of corticosteroids and other ulcer to an amoeboid or geographical immunosuppressive. configuration known as geographical ulcer The above stimuli (risk factors) may cause a (Fig. 6.17b). • clinical reactivation and replication of the virus. • Corneal sensation is reduced. The ulcer may The virus travels down the sensory ganglion (e.g., resolve spontaneously or with treatment trigeminal ganglion) and result in recurrent ocular over 1 to 2 weeks. A nonhealing epithelial HSV disease. Fortunately, ocular HSV disease defect after live virus disappears with tends to be a form of unilateral disease. prolonged topical treatment is referred to as “metaherpetic” ulcer. It is caused by Clinical Features basement member damage, resulting in Clinical features depend upon the part affected. failure of reepithelialization. It is not caused Recurrent ocular HSV infection can affect lids, by reactivation of virus (viral replication). conjunctiva and cornea (epithelium, stroma and Margins of these ulcers do not stain with Rose endothelium). Bengal. Note: Epithelial lesions are caused by IV. Involvement of corneal stroma: Stromal lesion replicating live virus. Stromal and endothelial might be an immunological reaction, be infectious, lesions involve both live virus activity and or may involve combined mechanism. Stromal immune reaction to viral antigen. lesions in herpetic disease include disciform I. Involvement of lids causes lid vesicles and keratitis and stromal necrotizing keratitis. blepharitis. Disciform keratitis: It is a hypersensitivity reaction

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a b Fig. 6.17 (a) Dendritic ulcer. Source: Uveitis. In: Glass L, ed. Ophthalmology Q&A board review. 1st Edition. Thieme; 2019. (b) Geographical ulcer.

Immunological reaction low grade endotheliitis between viral antigens and host antibodies

Deposited in stroma as Mild anterior uveitis Aqueous into stroma wessely ring

KP’s Disc shaped stromal oedema

Corneal thickening and folds in Descemet’s membrane.

Flowchart 6.3 Signs of disciform keratitis.

to HSV antigen in the cornea. Symptoms include viral antigen and host antibody complexes blurred vision and halos around lights. Following (Fig. 6.18). are the clinical signs of disciform keratitis due to •• Corneal sensations are reduced. There is no recurrent HSV infection (Flowchart 6.3): stromal neovascularization or necrosis. •• Disc-shaped stromal edema, often with Stromal necrotizing keratitis: It is caused overlying epithelial edema, is a dominant by active viral invasion. The infiltration of cornea feature. by polymorphs, lymphocytes, macrophages, •• Folds in Descemet’s membrane. and plasma cells mediate tissue destruction and •• Mild anterior uveitis with keratic stromal necrosis. precipitates (KPs). Typical lesion has a cheesy, yellow–white •• A ring of stromal haze may be present necrotic appearance. There may be associated surrounding the stromal edema called the anterior uveitis with KPs. Scarring, vascularization, Wessely ring. It signifies deposition of and lipid deposition are common.

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Treatment Treatment of HSV ocular disease depends on the nature of ocular involvement. Ocular HSV disease is treated by antiviral agents. These are purine or pyrimidine analogues that are incorporated to form abnormal viral DNA.

To define the role of oral antiviral agents and topical corticosteroids in the treatment and prevention of recurrent HSV ocular disease, a study termed Herpetic Eye Disease Study (HEDS) was conducted. According to HEDS: 1. Oral acyclovir– Provides no extra benefit over Fig. 6.18 Wessely ring in disciform keratitis. topical steroids and topical antiviral agents in treatment of stromal keratitis. It provides benefit in •• In advanced disease, corneal stromal HSV iridocyclitis. So, concurrent administration of oral acyclovir is recommended in HSV iridocyclitis. It melting results in descematocele formation does not seem to prevent recurrent stromal keratitis and perforation. or iridocyclitis. 2. Topical steroids– In absence of accompanying HSV • • If peripheral cornea is involved, inflam­ epithelial keratitis, topical steroids along with topical mation and necrosis spread to sclera, antiviral agents reduce progression of stromal resulting in sclerokeratitis. inflammation and shorten the duration of stromal keratitis (i.e., stromal keratitis improves more V. Involvement of corneal endothelium rapidly). (endotheliitis) results in corneal edema, anterior •• Treatment of epithelial keratitis without uveitis, which in turn leads to hypopyon and stromal involvement includes the following synechiae formation, and trabeculitis resulting in considerations: elevated IOP. 1. Debridement of the edges of dendritic Complications ulcer with cotton-tipped applicator to Complications of herpetic eye disease include: reduce infected (virus-laden) epithelial •• Secondary infection. cells. •• Secondary glaucoma. 2. Antiviral agents - •• Cataract (secondary to inflammation or – TFT (Trifluorothymidine) 1% drops prolonged use of steroids). every 2 hours •• Iris atrophy (secondary to keratouveitis). or Diagnosis – Vidarabine (Ara - A) 3% ointment five Diagnosis of ocular HSV disease is based on a times daily. constellation of: •• Assessment of corneal sensations. TFT and acyclovir both are active against HSV-1 •• Staining characteristics with Fluorescein and HSV-2. and Rose Bengal dye. Early IDU (Idoxuridine) 0.1% drops and 0.5% •• Enzyme-linked immunosorbent assay ointment were used, but due to the relative toxic (ELISA) test identifying viral antigens effect on epithelium (punctate keratopathy), it is •• Polymerase chain reaction (PCR) which seldom used now. The most frequently used drug detects HSV viral DNA in tissues, aqueous, is Acyclovir 3% ointment. Recently, Ganciclovir and tears. 0.15% gel five times daily is effectively used.

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Antiviral agents are used until the epithelial ulcer •• Treatment of patients with HSV has healed. iridocyclitis: HSV endotheliitis, trabeculitis, 3. Lubricants are also given. and iridocyclitis are treated with topical 4. Cycloplegics, if required. steroids (Prednisolone 1% drops tapered 5. Topical antibiotics to prevent secondary gradually) plus topical antiviral agent bacterial infections. (Acyclovir 3% ointment five times daily) 6. Topical steroids are contraindicated in and oral Acyclovir (400 mg five times daily epithelial HSV keratitis because of the for 7–10 days). presence of active viral replication in •• To reduce rate of recurrent herpetic eye HSV epithelial keratitis. disease: Low-dose oral Acyclovir 400 mg BD for 6 to 12 months reduces the rate of Advantages of acyclovir over IDU, TFT, and Vidarabine 1. It has less epithelial toxicity. recurrent HSV ocular disease but this effect 2. It penetrates intact corneal epithelium and stroma, reduces or even disappears when the drug achieving therapeutic levels in aqueous humour. is discontinued. So, long-term prophylactic 3. It acts preferentially on virus-laden epithelial cells and has low-toxicity for host cells. treatment should be considered in patients with frequent recurrences and at the risk •• Treatment of metaherpetic ulcers of visual loss, particularly involving an (postinfectious ulcer): If ulcer is truly only eye. metaherpetic, that is, persistent epithelial •• Patients with stromal scarring and defect after live virus disappears with opacity can be treated by penetrating topical treatment; antiviral agent serves keratoplasty (PKP). Recurrence of active no purpose and most likely will only herpetic infection in corneal grafts is often inhibit epithelial regeneration. Treatment a problem. Since long-term oral antiviral is directed toward encouraging epithelial treatment can reduce recurrence rate, oral healing and includes: Acyclovir 400 mg BD should be given to šš Lubrication of eye with preservative free patients undergoing PKP for herpetic eye drops. disease to improve the survival of corneal šš Therapeutic (bandage) soft contact lens. grafts. šš Temporary tarsorrhaphy (if above measures fail). Varicella-Zoster Virus Keratitis (VZV Keratitis) šš Conjunctival flap. Varicella-zoster virus causes varicella •• Treatment of stromal keratitis: It is treated (chickenpox) on initial infection and zoster or with topical steroids and topical antiviral shingles on recurrence (herpes zoster). Thus, agents. Important points of consideration herpes zoster is caused by same virus that causes are: chicken pox. After initial varicella (chicken šš Topical Prednisolone (1% drops) is used pox) infection in childhood or youth, the virus 4 to 5 times daily and gradually tapered. remains latent in a sensory ganglion (like herpes It reduces inflammation. simplex virus). It can reactivate to cause shingles šš Acyclovir 3% ointment is recommended (herpes zoster) after depressed cellular immunity. five times daily. It penetrates intact Depressed cellular immunity can occur with age, corneal epithelium and stroma and AIDS, immunosuppressives, blood dyscrasias, can therefore be used to treat stromal neoplasms, and radiotherapy. Thus, herpes zoster herpetic keratitis. represents a form of recurrent disease.

Oral acyclovir provides no extra benefit over The virus travels via sensory nerve to skin topical steroids and topical antiviral agents in dermatome or eye where peripheral inflammation treatment of stromal keratitis. develops. Trigeminal nerve infection is second

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in frequency as a site of recurrence after the of the trigeminal nerve and does not cross the thoracic region. midline. The pain sometimes diminishes after the Herpes zoster ophthalmicus (HZO) is a appearance of vesicles but may persist for months consequence of Gasserian ganglion (trigeminal or years. nerve) involvement. Involvement of ophthalmic The skin of lid and affected area becomes red (1st) division occurs far more commonly than and edematous. The vesicles suppurate before they involvement of 2nd or 3rd divisions of trigeminal crust and leave behind pitted scars. Anesthesia of nerve. Of the 1st division, frontal nerve is the most skin follows as the eruptions subside. commonly involved branch. The virus travels via Postherpetic neuralgia is the pain that branches of ophthalmic division of trigeminal persists for months to years after the skin lesions nerve to the skin, eye, and adenexae (Fig. 6.19). (rashes) have healed. Pathology Contact with nonimmune or immunosuppressed There is prominent vasculitis with granulomatous individuals should be avoided until the crusting is or lymphocytic infiltration. Tissue damage caused complete. by zoster infection is due to both inflammation Ocular involvement: Ocular complications and vasculitis-induced ischemia. arise as the eruptions subside. The eye is Clinical Features frequently affected if the vesicles appear on the Prodromal stage of HZO precedes the appearance tip and the side of the nose due to involvement of rashes (eruptive stage) and lasts 3 to 5 days. The of the nasociliary branch of the trigeminal nerve disease starts with fever, malaise, and headache (Hutchinson sign). The eye involvement may followed by neuralgic pain along the distribution rarely occur when disease affects maxillary nerve of the 1st division of the trigeminal nerve. (2nd division of trigeminal nerve) (Table 6.9). Eruptive stage follows the prodromal stage Treatment and lasts for approximately 3 weeks. The vesicles A. Treatment of acute systemic herpes zoster appear on one side of the forehead of the scalp 1. Systemic antiviral agents: Oral Acyclovir – along the distribution of the ophthalmic division 800 mg five times daily × 7 to 10 days and initiated within 72 hours of the onset of symptoms. It accelerates healing of skin lesions. It reduces period of viral shedding, severity of acute pain, incidence of episcleritis, keratitis, and iritis. Other antivirals are oral Famciclovir 500 mg TDS × 7 to10 days and oral Valaciclovir 1000 mg TDS × 7 to 10 days. 2. Systemic steroids are used in combination with antiviral agents. These are not only recommended to reduce acute pain but also used in the treatment of inflammatory Fig. 6.19 Herpes zoster ophthalmicus. Source: The complications of HZO such as severe diagnosis of binocular diplopia. In: Biousse V, Newman scleritis, uveitis or orbital inflammation. N, ed. Neuro-ophthalmology illustrated. 3rd Edition. Dose– 60 mg/day and then reduced Thieme; 2019. gradually.

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Table 6.9 Ocular manifestations in HZO

Structure involved Ocular manifestation

▪▪Involvement of lid ▪▪Lid scarring may result in cicatricial entropion or ptosis. ▪▪Involvement of conjunctiva ▪▪Conjunctivitis is common. It can be follicular or necrotizing. ▪▪Involvement of sclera ▪▪Scleritis may become chronic and frequently recurrent, leading to staphyloma. ▪▪Involvement of cornea ▪▪Corneal involvement in acute phase can manifest as: šš Punctate epithelial keratitis šš Dendritic lesions (in contrast to HSV dendrites, these have tapered ends without terminal bulbs) šš Nummular keratitis šš Disciform keratitis šš Sclerokeratitis šš Kerato uveitis ▪▪Chronic corneal lesions that follow HZO are: šš Mucous plaque keratitis šš Neurotrophic keratitis šš Exposure keratitis ▪▪Involvement of uvea ▪▪Anterior uveitis is frequently associated with sector iris atrophy. ▪▪Involvement of trabecular ▪▪Trabeculitis may cause secondary glaucoma. meshwork ▪▪Occlusive vasculitis ▪▪It may cause ARN and anterior segment ischemia ▪▪Involvement of optic nerves ▪▪Optic neuritis is rare and a late complication. ▪▪Involvement of motor nerves ▪▪HZO affecting 3rd, 4th and 6th CN results in extraocular muscle palsy, while facial N (7th CN) involvement results in facial palsy (Bell’s palsy) Abbreviations: ARN, acute retinal necrosis; CN, cranial nerve; HZO, herpes zoster ophthalmicus.

B. Treatment of postherpetic neuralgia •• Topical steroids and antiviral eye ointment Nonsteroidal anti-inflammatory drugs (NSAIDS) are given if there is scleritis, sclerokeratitis, are ineffective in postherpetic neuralgia. Initially, or iridocyclitis to reduce inflammation. it is treated with: Steroids are tapered gradually. •• Major complication of HZO, neurotrophic Topical Lidocaine 5% gel (local anesthetic) or ulceration, is treated with bandage contact topical Capsaicin cream (depletes substance P). If lens, tarsorrhaphy, and cyanoacrylate glue/ it is ineffective, then the following drugs are given penetrating keratoplasty (in case of corneal •• Amitriptyline (a tricyclic antidepressant)– perforation). 12.5 to 25 mg at night and increased gradually to 75 mg/day, or Parasitic Keratitis •• Carbamazepine 400 mg daily to reduce pain Acanthamoeba Keratitis C. Local ocular treatment of HZO It is caused by Acanthamoeba (a protozoan) found For cutaneous lesions, antibiotic–corticosteroid in soil and water environments such as ponds, skin ointment is applied on skin and lids. swimming pools, contact lens solutions, and tap Calamine lotion is better avoided as it promotes water. crust formation. In the eye itself, •• Topical antivirals are not effective. Source of infection •• Topical antibiotics are instilled to prevent •• Contact lens solutions are the usual secondary bacterial infection in acute stage source of infection. Once contact lens of disease. is contaminated, risk of infection is

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established, since the organism can adhere •• Corneal melting may occur at the periphery to and penetrate an intact epithelium. of the area of infiltrates. Satellite lesions can •• Swimming or bathing in contaminated appear. Anterior chamber inflammation water may be the source in noncontact lens can cause anterior uveitis and hypopyon. wearers. Differential Diagnosis Acanthamoeba exists in dormant cystic This condition should be differentiated from form and active trophozoite form. Trophozoite herpetic keratitis and fungal keratitis. Patients with produces a variety of enzymes and binds to acanthamoeba keratitis are younger than patients corneal epithelium, resulting in thinning and with bacterial keratitis or fungal keratitis, and necrosis of corneal epithelium. Early infection can have a longer duration of symptoms before being be confined to the epithelium, but in advanced treated. In terms of clinical signs, acanthamoeba cases, the organism can enter the stroma and keratitis is more likely to have disease confined to anterior chamber. the epithelium and ring infiltrate. Clinical Features Diagnosis Symptoms of acanthamoeba keratitis include •• Staining of corneal scrapings with calcofluor severe ocular pain, blurred vision, photophobia, white stain. It is a fluorescent dye with and lacrimation. an affinity for amoebic cysts which Clinical signs of acanthamoeba keratitis demonstrates the walls of the cysts but include the following: requires a fluorescent microscope. • • Early infection is confined to the epithelium •• Polymerase chain reaction (PCR) to detect which shows irregular surface as well as acanthamoebic DNA. infiltrates and pseudodendrites mimicking Nonsuppurative keratitis in a contact lens H simplex keratitis. The epithelium is intact wearer is a high-index of suspicion, and treatment initially and later breaks down. •• Deep linear stromal infiltrates might should be as for acanthamoeba infection. be seen around corneal nerves (radial Treatment keratoneuritis) and are pathognomonic. It includes the following considerations: •• The infiltrates coalesce to form a ring Debridement to remove infected epithelium for abscess in stroma and resemble stromal early disease. Topical antiamoebics which include: herpetic disease (Fig. 6.20). Scleritis may •• Cationic antiseptics (inhibit membrane develop. In spite of severe inflammation, function) include Chlorhexidine and PHMB corneal vascularization is typically absent. (polyhexamethylene biguanide). •• Azoles (destabilize cell walls) include Clotrimazole, Fluconazole, Ketoconazole, and Miconazole. •• Aminoglycosides (disrupt plasmalemma of organism) include Neomycin and Paromomycin. •• Aromatic diamidines (inhibit DNA synthesis) include Propamidine isethionate, Hexamidine, and Pentamidine.

Topical ameobicides are given as dual therapy (diamidines + cationic antiseptics) with: Fig. 6.20 Ring abscess. •• Propamidine isethionate + PHMB drops

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or immune-mediated reaction. Treponema pallidum is not seen in cornea even during the acute phase. Hexamidine + Chlorhexidine Topical neomycin and miconazole are quite Course of the Disease effective. The diseases may require a prolonged It is divided into three stages: Progressive, florid, treatment for several months. Since cysts are and regressive stages. difficult to eradicate, stromal relapses are Progressive Stage common, as treatment is tapered. The cellular infiltration in deeper layers of cornea •• Topical steroids should be avoided, if (just anterior to Descemet’s membrane) occurs possible. after anterior uveitis with ciliary congestion. •• Persistent corneal inflammation occurs The stromal cloudiness involves the whole due to necrotic protozoa (acanthamoeba cornea, giving it a ground glass appearance in 2 antigen) rather than viable organism and to 4 weeks. Anterior uveitis may be obscured by may result in scarring and impaired vision. corneal clouding. PKP is needed for residual scarring. Florid Stage ██ Noninfectious Keratitis In this stage, deep vascularization of stroma occurs. The vascular growth begins at the limbus Interstitial Keratitis (IK) and grows in a brush-like manner. Since these It is an inflammation of the corneal stroma vessels are covered by hazy cornea, vessels look without primary involvement of epithelium or dull reddish pink, resulting in a characteristic endothelium. salmon patch. There is superficial vascularization Etiology but it never extends far over the cornea. Conjunctiva may heap up at the limbus. It is most often associated with congenital syphilis but may also be seen in acquired Regressive Stage syphilis, tuberculosis, leprosy, and viral infections In this stage, stromal vessel become nonperfused (Table 6.10). Cogan’s syndrome (IK and deafness) and remain as fine opaque lines (empty or ghost is a rare cause affecting both eye and ear. vessels), which indicates the previous occurrence IK due to congenital syphilis occurs via of the disease. The cornea clears slowly from transplacental route, usually bilateral, and affects periphery toward center. If cornea does not clear children between the ages of 5 and 25 years. within 18 months, visual prognosis is poor.

In IK, the uveal tract is almost always affected. Clinical Features The disease is fundamentally uveitis and Symptoms include pain, blurring of vision, keratitis is secondary. Keratitis is the result of photophobia, and watering of eyes.

Table 6.10 Differentiating features of syphilitic and tubercular IK

Syphilitic IK Tubercular IK

Laterality Usually Bilateral Usually unilateral Involvement Involves whole cornea Frequently sectorial involving lower sector of cornea Treatment (Systemic) Antisyphilitic Antitubercular (Topical treatment is same in both)

Abbreviation: IK, interstitial keratitis.

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Following are the clinical signs of IK: •• Keratitis secondary to conjunctival diseases, •• Signs in progressive stage: Keratic preci­ for example, phlyctenular keratitis and pitates, ciliary congestion, and ground glass vernal keratitis. appearance of cornea with stromal edema. •• Marginal ulcer (catarrhal ulcer). •• Sign in florid stage: Deep vascularization •• Mooren’s ulcer. with salmon patch. •• Keratitis associated with collagen vascular •• Sign in regressive stage: Ghost vessels. Since disorders such as rheumatoid arthritis, infiltration of cornea is almost limited to systemic lupus erythematosus (SLE), deeper layers, ulceration of corneal surface polyart­eritis nodosa, and Wegener’s is rare. granulomatosis Diagnosis Phlyctenular Keratitis It depends on: Cornea is often involved in phlyctenular •• Other evidences of congenital syphilis keratoconjunctivitis, which is essentially a include: conjunctival disease. š š Frontal eminence Phlyctens are commonly found at the limbus š š Flat nasal bridge but may occur within the corneal margin (corneal š š Hutchinson’s teeth (notching of two phlycten) upper central incisors in permanent dentition) Etiology šš Vestibular deafness It is thought to be delayed hypersensitivity (Type šš Rhagades at the angles of the mouth IV and cell-mediated) to an endogenous microbial •• Hutchinson’s triad includes IK, antigen, mostly staphylococcal or tubercular. Hutchinson’s teeth, and vestibular deafness. Clinical Features Coagan’s syndrome include non syphillitic Symptoms include photophobia, lacrimation, IK and deafness. blepharospasm, and pain. Corneal phlyctens cause •• Serological tests– All patients with IK much pain and photophobia. should have treponemal serology including rapid reagin test, FTA–ABS (fluorescent Clinical signs of phlyctenular keratitis include: treponemal antibody absorption) test, •• Phlycten appears as a gray nodule at the and venereal disease research laboratory limbus, which is associated with superficial (VDRL) test. vascularization (Fig. 6.21). •• A limbal phlycten may extend onto the Treatment cornea and appear as slightly raised Active IK is dealt with the help of: •• Systemic treatment with penicillin and systemic steroids tapered gradually. •• Topical treatment with topical steroids (as IK is a hypersensitivity reaction), and cycloplegics for uveitis. •• Lubricating eye drops. •• PKP in cases with dense corneal opacity.

Immunologically Mediated Keratitis Immunologically mediated keratitis includes the following: Fig. 6.21 Limbal phlycten.

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above the corneal surface. The overlying Marginal Ulcer (Catarrhal Ulcer) epithelium breaks down and a triangular Marginal ulcer is a superficial ulcer situated near yellowish ulcer is formed with prominent the limbus and frequently seen in old people. vascularization known as fascicular ulcer. Etiology As the disease is essentially conjunctival, so the epithelium and superficial layer of cornea It is thought to be caused by immune reaction are involved. The ulcer remains superficial and to exotoxins produced by Staphylococcus aureus. seldom perforates. A healed corneal phlycten These ulcers may also be caused by Moraxella leaves a triangular scar associated with superficial and Haemophilus. They are often associated with vascularization and thinning. Staphylococcal blepharitis in which an immune reaction occurs in the toxins produced by Treatment staphylococcus. This antigen–antibody complex is Treatment includes use of topical steroids, topical deposited in the peripheral cornea with secondary antibiotics, and cycloplegics, in case of corneal lymphocytic infiltration. involvement. Clinical Features It is also essential to treat associated Symptoms include mild irritation, lacrimation, staphylococcal blepharitis. photophobia, and pain. The subepithelial marginal Vernal Keratitis infiltrates, separated from limbus by a clear zone Cornea can be involved in up to 50% of cases with of cornea, are typically located at the point of vernal keratoconjunctivitis. It is more frequent in contact of eyelids with cornea (i.e., at 4, 7, 10, and palpebral type of disease. Several types of corneal 2 o’clock positions). The infiltrates coalesce with lesions may be produced such as: the circumferential spread which is accompanied •• Punctate epithelial keratitis which begins by the breakdown of overlying epithelium. The as discrete micro erosions in the superior ulcer formed is shallow and frequently become cornea (punctate epithelial erosions). vascularized. Resolution occurs but recurrences are •• Epithelial macro erosion due to continued common and ulcer runs a chronic indolent course epithelial loss (Fig. 6.22, Table 6.11). Differentiating features •• Shield ulcer (vernal ulcer): A vernal ulcer between marginal keratitis and bacterial keratitis is noninfectious, horizontally oval, shallow, can be remembered by the mnemonic, PEDAL. nonvascularized, and indolent ulcer of Lesions are culture negative, but S. aureus can the superior cornea. It is associated with frequently be isolated from lid margins. subepithelial scarring and mild corneal opacity. Chronic inflammation in the Treatment absence of ulcer may develop peripheral Treatment includes topical antibiotic + steroid superficial vascularization, especially drops. Treatment of coexisting blepharitis is done superior. to prevent recurrences. Treatment Mooren’s Ulcer •• Punctate epithelial keratitis responds It is a rare peripheral ulcerative keratitis also to usual treatment of vernal known as chronic serpiginous ulcer or rodent keratoconjunctivitis. ulcer. •• For persistent epithelial defects with ulceration, amniotic membrane graft with Etiology lamellar keratoplasty is carried out to Its exact etiology is unknown but autoimmune enhance reepithelialization. mechanism appears to be involved. It can be

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Table 6.11 Comparison between marginal and bacterial keratitis (i.e., distinction between noninfectious and suppurative infiltrates)

Marginal keratitis Bacterial keratitis

Pain Less More Epithelial defect Small or absent (< 1 mm) Present (> 1 mm) Discharge Watery Purulent Anterior chamber reaction (uveitis) − + Location Peripheral Central

and opaque. It rarely perforates. Spontaneous perforation is rare; however, minor trauma may lead to perforation. Differential Diagnosis It includes the conditions that are characterized by peripheral corneal ulceration and/or melting. Patients with bilateral Mooren’s ulcer must be investigated for collagen vascular disorders. Treatment Fig. 6.22 Marginal ulcer. Treatment for Mooren’s ulcer is difficult and disappointing as ischemia is the underlying cause.

triggered in genetically susceptible individuals by Stepladder approach to manage this aggressive trauma. disease includes local, systemic, and surgical therapy. It may be unilateral or bilateral and affects •• Local treatment includes– Topical treat­ males more commonly than females. Unilateral ment with corticosteroids, cyclosporine, involvement affects older patients, is slowly and Acetylcysteine 10% (collagenase progressive and responds better to treatment; inhibitor). Conjunctival resection is done if bilateral involvement affects younger patients inflammation is not controlled. It eliminates and is more aggressive. conjunctival sources of collagenase, Clinical Features proteo­glycanase, and other inflammatory Symptoms include severe pain, lacrimation, mediators. photophobia, and blurred vision due to irregular •• Systemic treatment– Systemic immuno­ astigmatism. suppression with cyclophosphamide, cyclo­ sporine, steroids, or methotrexate may be It begins as gray infiltrates near the margin of initiated if the treatment with conjunctival the cornea which breakdown, forming peripheral resection fails. ulcer. The ulcer spreads circumferentially and •• Surgical treatment– It includes lamellar toward the center of the cornea. Typically, keratoplasty and cyanoacrylate glue to advancing edge of ulcer undermines the corneal treat small perforations. epithelium and superficial stroma. The base of the ulcer soon becomes vascularized. Healing Lamellar keratoplasty with systemic immunosuppression takes place behind the active margin of the ulcer, may reduce the risk of recurrence; without systemic immunosuppression, recurrence rate is high. but the healed area remains thin, vascularized

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Conditions causing peripheral corneal ulceration and •• Toxic- it may be due to staphylococcal thinning toxins in blepharoconjunctivitis. ▪▪Marginal ulcer •• Dry eye syndrome: In KCS. ▪▪Mooren’s ulcer ▪▪Systemic collagen vascular disorders– •• Idiopathic: Thygeson’s SPK. šš Rheumatoid arthritis šš Polyarteritis nodosa Location š š SLE Location of lesions may serve as a clue to the šš Wegener’s granulomatosis ▪▪Oculo-dermatologic conditions - etiology of SPK. šš Rosacea keratitis ▪▪Corneal degenerations– Superior location of SPK– The probable šš Terrien’s marginal degeneration etiology may be vernal keratoconjunctivitis (VKC), šš Pellucid marginal degeneration superior limbic keratoconjunctivitis (SLK), and trachoma. ██ Miscellaneous Keratitis Inferior location– The probable etiology is Superficial Keratitis Staphylococcal blepharitis, trichiasis, entropion, and lagophthalmos. It involves corneal epithelium, Bowman’s Interpalpebral location– The probable etiology membrane, and superficial corneal stroma. It is is seborrheic blepharitis and KCS. divided into: •• Superficial punctate keratitis (SPK). Clinical Features • • Superior limbic keratoconjunctivitis. Symptoms include mild ocular discomfort, • • Filamentary keratitis. photophobia, and lacrimation. It is characterized • • Recurrent corneal erosions. by punctate epithelial lesions which stain with • • Photophthalmia. Fluorescein dye. Subepithelial lesion may be Superficial Punctate Keratitis (SPK) present which do not stain with Fluorescein dye. It is characterized by multiple, punctate lesions in It is usually associated with conjunctivitis. the superficial layers of the cornea (Fig. 6.23). It is One of the most characteristic features of caused by: Thygeson’s SPK is lack of associated conjunctival •• Viral infections– Most common causes are: inflammation (conjunctivitis). All other disease adenovirus, H-simplex and H-zoster. entities have associated conjunctivitis. •• Chlamydial infections: trachoma and Treatment inclusion conjunctivitis. It is treated with topical steroids with gradual tapering, lubricants, and treatment of cause. Superior Limbic Keratoconjunctivitis (SLK) As the name suggests, it is superior, limbic, corneal and conjunctival inflammation. It typically affects those belonging to the middle age group, with a greater affinity for females than males. It is usually bilateral. It is associated with abnormal thyroid dysfunction, usually hyperthyroidism. Its exact etiology is unknown. It appears to be the result of blink-related mechanical trauma which is supported by increased lid apposition of exophthalmic thyroid patients, who are known Fig. 6.23 Superficial punctate keratitis. to have an increased incidence of SLK. SLK runs a

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chronic course with remissions and exacerbations. keratitis, prolonged eye patching, neurotropic Thyroid function tests should be performed due to keratitis, and SLK. strong association with thyroid disease. Clinical Features Clinical Features Symptoms include irritation and foreign body Symptoms include foreign body sensation, sensation. Filaments consist of the core of mucous burning, irritation, redness, watering and strands lined with epithelium. One end of the photophobia. filament is attached to the corneal epithelium, Characteristic signs are seen in cornea and while the other is unattached (free), moves with conjunctiva: each blink, and causes foreign body sensation. •• Conjunctiva– Hyperemia of superior bulbar They stain well with Rose Bengal (Fig. 6.24). conjunctiva and opposing superior tarsal Treatment (palpebral) conjunctiva with papillary Treatment includes the following: reaction is marked. •• Mechanical removal of filaments. • • Cornea shows filamentary keratitis of the •• Hypertonic 5% saline drops to encourage superior cornea and limbus. adhesion of loose epithelium. š š SPK in the superior part of cornea which •• A topical mucolytic agent such as Acetyl stains with Fluorescein and Rose Bengal. Cysteine (10%). š š Superior corneal pannus. •• Bandage contact lens. • • KCS in 25 to 50% of cases. •• Treatment of underlying cause Treatment •• Short-term topical steroids. Treatment is symptomatic as the condition is Recurrent Corneal Erosions usually self-limiting and include the following: It is characterized by recurrent breakdown of •• Topical lubricants to reduce friction epithelium. The basic cause is abnormalities in the between lid and bulbar conjunctiva. underlying basement membrane microstructure. Lubricant must be preservative-free. The condition may be associated with trauma, •• Topical steroids to reduce inflammation. epithelial basement membrane or anterior •• Topical Acetyl Cysteine drops (10%) for stromal dystrophy, and diabetes. filamentary keratitis. Pathogenesis •• Topical retinoic acid to prevent keratinization. Trauma or epithelial basement membrane •• Punctal occlusion as 25 to 50% patients with dystrophy results in microscopic derangement SLK also have KCS (dry eyes). •• Soft contact lenses which intervene between lid and superior bulbar conjunctiva and may be useful. •• Resection of superior limbal conjunctiva and Tenon’s capsule. Filamentary Keratitis It is a superficial keratitis associated with formation of corneal filaments. Etiology KCS is the most common cause. Other causes include recurrent corneal erosions, H. simplex Fig. 6.24 Filamentary keratitis.

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in the epithelial basement membrane (such is both wavelength- and intensity-dependent. as thickening and discontinuity). It leads to For short wavelength, a very small amount of abnormally weak attachment between basal cells UV energy may produce a corneal lesion. Nucleic of epithelium and basement membrane. Thus, acids of corneal epithelium maximally absorb epithelial layers are prone to separation and these wavelengths. Sources of UV rays are welding frequent erosions. flashes, germicidal lamps, and snow surface. Minor injuries such as opening the eyes after Most damaging range of wavelength is 260 to 290 nm sleep can cause shearing forces, resulting in but absorbed by ozone layer. So, radiation of these tearing of epithelium. wavelengths rarely penetrates the Earth’s surface. Clinical Features Pathology Symptoms often occur on wakening and include After 4 to 6 hours of exposure to UV rays damaged severe pain, blurring, photophobia, foreign body epithelial cells desquamate and multiple erosions sensation, blepharospasm, and watering. result, which produces characteristics punctate Characteristic Signs of recurrent corneal Fluorescein staining (superficial punctate erosions include the following: keratitis). •• Frank epithelial defects, particularly in the Symptoms lower part of cornea. •• Signs of epithelial basement membrane Symptoms include burning pain, lacrimation, dystrophy (intraepithelial microcysts and photophobia, and blepharospasm. finger print lines) may be present in both Prophylaxis consists of wearing dark glasses eyes. made of crooks glass which cuts off nearly all Typically, onset of corneal erosion occurs upon infrared and UV rays. awakening in the morning, although it may occur Treatment at any time. Sleep causes relative anoxia, leading Treatment includes cold compression, lubricant to edema of corneal epithelium. Vulnerable epithelium is easily rubbed off on sudden opening drops, and bandaging both eyes for a day. of eyelids upon awakening. ██ Trophic Keratitis Treatment Neurotrophic Keratitis Treatment includes the following: •• Lubricants: Eye drops during waking hours Sensory innervation is vital for the health of and gel or ointment at night. corneal epithelium and stroma. Neurotrophic •• Therapeutic soft contact lenses (bandage keratitis occurs in an anesthetic cornea, that is, it contact lens). results from damage to the trigeminal nerve which •• Topical antibiotics and cycloplegics. supplies the cornea. Following are the causes of •• If erosions are severe or frequent, excimer neurotrophic keratitis: laser phototherapeutic keratectomy can be 1. Damage to trigeminal nerve– It may occur performed. due to surgery for trigeminal neuralgia, •• Anterior stromal micropunctures over and injection of alcohol in gasserian ganglion surrounding the erosions not involving the for trigeminal neuralgia, and tumors: visual axis. acoustic neuroma and neurofibroma. Photophthalmia 2. Ocular disease such as the following: It is caused by exposure to ultraviolet (UV) rays in •• Herpes simplex keratitis. the range of 290 to 311 nm. UV damage to cornea •• Herpes zoster keratitis.

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3. Systemic diseases such as diabetes Following are the clinical signs of neurotrophic (peripheral neuropathy may result in keratitis: decreased corneal sensation) and leprosy. •• Presence of ciliary congestion. Pathogenesis of neurotrophic keratitis is •• Decreased corneal sensation. explained in Flowchart 6.4. •• Persistent epithelial defects. The ulcer Clinical Features is typically found in the interpalpebral Symptoms include red eye, absence of pain, area, and the cornea appears dull. It is decreased aqueous tear production, mild foreign followed by stromal edema and melting body sensation, and blurred vision. (Flowchart 6.5).

Damage to ophthalmic division (1st division) of Trigeminal nerve

Loss of neural reflex

Reflex tear secretion is reduced Altered metabolic activity of epithelial cells

Oedema and exfoliation of epithelial cells

Epithelial breakdown and persistent ulceration

Flowchart 6.4 Pathogenesis of neurotrophic keratitis.

Trigeminal nerve damage (1st decrease corneal sensation No pain division) in neurotrophic keratitis

damage to lacrimal nerve (a branch Intracellular oedema due to of ophthalmic division of Vth CN) loss of neural influences & cornea appears which supplies lacrimal gland exfoliation dull

Decreased aqueous tear production persistent epithelial defect

Foreign body sensation stromal oedema and melting

Flowchart 6.5 Clinical features in neurotrophic keratitis.

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Treatment the lower part of cornea, leading to inferior •• Decreased aqueous tear production in punctate epithelial keratitis followed by epithelial neurotrophic keratitis is treated with: breakdown, stromal melting, infection, and even •• Topical lubricant eye drops perforation (Fig. 6.25). (preservative-free) Treatment •• Punctal occlusion abolishes drainage of •• Tear substitutes (preservative-free lubri­ tears. cants) during day time. •• Tarsorrhaphy to prevent drying and reduce •• At night, application of eye ointment and exposure. It is a good alternative and kept closure of lids by tape or bandage. for at least 1 year. •• Treatment of the cause of exposure, but •• Amniotic membrane transplantation. in the meantime, tarsorrhaphy may be Exposure Keratitis required by suturing lids together. Lids resurface the cornea with the help of precor­ Combined neurotrophic (Vth CN damage) and neuro­ paralytic (VIIth CN palsy) keratitis is difficult to manage. neal tear film at each blink and keep the cornea moist. Exposure keratitis is caused by improper wetting of corneal surface by precorneal tear film Nutritional Deficiency (Vitamin A despite the presence of normal tear secretions. Deficiency) Etiology Ocular manifestations caused by vitamin A deficiency are referred to as xerophthalmia. It is caused by the conditions that lead to exposure Cornea in vitamin A deficiency shows the of cornea, that is, due to incomplete closure of lids. following changes: Causes of exposure keratitis (lagophthalmos) are: 1. Corneal xerosis– Earliest changes in 1. Facial nerve palsy (neuroparalytic cornea involve loss of corneal luster due keratitis): VIIth nerve palsy may be to xerosis and bilateral punctate corneal idiopathic or can follow surgery for epithelial erosions. acoustic neuroma/parotid tumor. It results 2. Keratomalacia– It reflects very severe in the paralysis of orbicularis muscle and vitamin A deficiency, often as early as incomplete closure of lid. the first year of life. Night blindness and 2. Severe proptosis due to thyroid conjunctival signs of vitamin A deficiency ophthalmopathy and orbital tumor. precede keratomalacia. The condition 3. Eyelid scarring associated with cicatricial pemphigoid, burns, and trauma. 4. Reduced muscle tone as in coma. Occasionally corneal exposure during sleep may occur in normal healthy individuals if there is poor Bell’s phenomenon. Pathogenesis Incomplete closure of lids results in desiccation of cornea. The epithelium is cast off, and invasion of cornea by infective organisms may occur. Clinical Features Because of lagophthalmos, cornea is exposed in lower part. So, initial desiccation occurs in Fig. 6.25 Exposure keratitis.

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is usually bilateral. Bilateral melting of •• Yellowish-white infiltrates are seen in the cornea is associated with conjunctival cornea near the limbus which may ulcerate xerosis, and vitamin A deficiency is and then corneal vascularization takes referred to as keratomalacia. place. In keratomalacia, cornea becomes dull, •• Punctate epithelial keratopathy involving insensitive, and hazy. The ulcer is formed with lower cornea. yellow infiltrates. Typically, it is devoid of usual Treatment inflammatory reaction and is a characteristic Local treatment: Topical corticosteroids as drops or feature. The lesion rapidly involves full-thickness ointment. of cornea. Finally, whole tissues undergo necrosis and melt away (corneal melting by liquefactive Systemic treatment: The essential treatment necrosis). involves treating the skin condition with systemic tetracycline 250 mg 4 times daily for 3 weeks and Treatment then once daily for 6 months or doxycycline 100 Systemic treatment involves oral or IM mg twice daily for 3 weeks. administration of vitamin A. Locally, intense lubrication and topical antibiotics are advised. ▄▄Corneal Degenerations

Atheromatous Corneal Ulcer There is marked distinction between degeneration It occurs in old leucoma undergoing degenerative and dystrophy. Degenerations are nonhereditary changes or it may start after a minor trauma. It and usually unilateral, while dystrophies are is readily vulnerable to infection, as cornea is hereditary and usually bilateral. devitalized and insensitive. It is treated with the ██ usual treatment, conjunctival flap, or keratoplasty. Etiology The amniotic membrane transplantation may be Degenerations could arise due to age-related effective for the treatment of deep ulceration. changes like arcus senilis, Vogt limbal girdles and Hassell–Henle bodies or pathological changes like ██ Keratitis Associated with Skin lipid degenerations, amyloid degeneration, band Diseases keratopathy, Salzmann’s nodular degeneration, Rosacea Keratitis Terrien’s marginal degeneration, and spheroidal degeneration. Acne rosacea is a skin disease characterized by erythema of cheeks and nose in butterfly ██ Classification configuration, progressing to telangiectasia, Corneal degenerations can be divided into: hypertrophy of sebaceous glands, papules and •• Primary degenerations. pustules. Rosacea keratitis is usually associated •• Secondary degenerations due to some with seborrheic blepharitis. It is generally seen compromising factors, for example, among elderly women. trauma, chemicals, systemic diseases, or Clinical Features inflammation. Symptoms include irritation, mild redness, and •• Infiltration associated with lipid and lacrimation. mucopolysaccharide metabolisms. Clinical signs of rosacea keratitis are: ██ Arcus Senilis (Gerontoxon) •• Seborrheic blepharitis and recurrent chalazia. It is a lipid infiltration of peripheral corneal •• Conjunctival vessels in the interpalpebral stroma. It begins in the superior and inferior region are dilated. perilimbal cornea as a crescent and gradually

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progresses circumferentially to form a circle. It (Bowman’s layer, epithelial basement membrane, is approximately 1 mm wide and does not affect and anterior stroma) of the cornea. Calcium is vision. It is seen among the elderly population. deposited as hydroxyapatite salt. It has a diffuse central border and a sharper peripheral border. It is separated from limbus by Etiology a clear zone which is known as the lucid interval 1. Ocular causes– It occurs in eyes with of Vogt. chronic diseases, particularly chronic Arcus juvenilis (anterior embryotoxon): If uveitis, glaucoma, chronic keratitis, the arcus appears in young persons (below 40 Pthisis bulbi, and silicone oil in anterior years of age), it is known as arcus juvenilis. It may chamber, that is, in aphakic eyes which be associated with familial lipidemia. have undergone vitrectomy with silicone oil. ██ Vogt Limbal Girdle 2. Increased serum calcium or phosphate. It is an age-related change characterized by 3. Systemic associations like sarcoidosis, bilateral, chalky white crescentric lines in the hyperparathyroidism, vitamin D toxicity, interpalpebral area along both nasal and temporal and metastatic neoplasms to bone. All limbus. these conditions are associated with elevated serum calcium. ██ Hassell–Henle Bodies 4. Juvenile rheumatoid arthritis (Still’s These are the excrescences of hyaline material disease)– Chronic uveitis in Still’s disease present in peripheral Descemet’s membrane and causes band-shaped keratopathy. are part of normal aging process. 5. Chronic renal failure (CRF). Clinical Features ██ Terrien’s Marginal Degeneration Calcium is deposited as a horizontal band in the It is an idiopathic, noninflammatory thinning of interpalpebral area of the cornea. Calcification peripheral cornea. It is usually bilateral, but may starts near the corneal periphery which is be unilateral. It is more frequently seen in males. It separated from the limbus by a clear zone of is most frequent in middle-aged to elder persons. cornea as in so many degenerative conditions, Signs– It starts with fine yellow–white probably owing to better nutrition close to blood punctate stromal opacities and superficial vessels. Calcium deposition gradually progresses vascularization, usually superiorly. The lesion toward the center to form a band-like chalky spread circumferentially and separated plaque (Fig. 6.26). The calcium plaque contains from the limbus by a clear zone. Progressive clear holes where Bowman’s membrane is circumferential thinning results in peripheral traversed by nerve endings and the surface of this gutter. Astigmatism develops from associated opaque band appears stippled. Epithelium usually corneal flattening which may be irregular and remains intact as deposition is beneath it. results in visual deterioration. Usually, there is no pain or inflammation. Perforation may rarely Treatment occur following blunt trauma. It is indicated if the vision decreases or persistent discomfort occurs. Central deposits may be ██ Band Shaped Keratopathy (Calcific removed by: Degeneration) •• Chelation– It involves removal of epithe­ Band keratopathy is characterized by deposition lium over deposits followed by application of calcium salts in the subepithelial layers of 0.01 molar solution of EDTA (ethylene

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Fig. 6.26 Band-shaped keratopathy. Source: Band-shaped keratopathy. In: Gulani A, ed. The art of pterygium surgery: mastering techniques and optimizing results. 1st Edition. Thieme; 2019.

diamine tetra acetic acid), which is a chelator of calcium. It removes most of the deposited calcium. Pad and bandage for reepithelialization is taken care of. •• Treat any underlying systemic conditions or persistent uveitis to prevent recurrences. •• PTK with excimer laser to remove band keratopathy. •• Lamellar keratoplasty may be performed.

██ Spheroidal Degeneration (Climatic Droplet Keratopathy) Fig. 6.27 Early Salzmann nodular degeneration. It is also called oil droplet keratopathy or actinic droplet keratopathy. Treatment Etiology Majority of cases are asymptomatic. In cases with It is thought to be a result of UV light exposure and central lesions affecting vision, PTK with excimer occurs most often in men who work outdoor in laser or lamellar keratoplasty can be carried out. the sun and in areas that have sunlight reflection ██ off snow or sand. Salzmann Nodular Degeneration

Clinical Features Etiology It is always bilateral and characterized by the It occurs in persons with previous chronic presence of subepithelial, golden or yellow, fine keratitis, particularly associated with trachoma, droplets in the interpalpebral area of peripheral phlyctenular keratitis, vernal keratitis and IK. cornea and advance toward the center. Droplets It is characterized by bluish-white, avascular appear oily although they are not of lipid origin. nodules in superficial stroma and Bowman’s These globules are made up of a protein material membrane that elevate the epithelium and may with elastotic features. As the condition advances, be associated with recurrent corneal erosions. The droplets become larger and form large corneal base of the nodule may be outlined by epithelial nodules with elevated corneal epithelium. iron deposits (Fig. 6.27).

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Treatment •• Endothelial dystrophies šš Fuch’s endothelial dystrophy. Most of the cases are asymptomatic and require šš Posterior polymorphous dystrophy. no treatment. If nodules encroach the central šš Congenital hereditary endothelial cornea, affecting vision, PTK with excimer laser or dystrophy. lamellar keratoplasty can be done. Epithelial Dystrophies ▄▄Corneal Dystrophies (OP4.5) Epithelial dystrophies include: Corneal dystrophies are a group of opacifying •• Epithelial basement membrane dystrophy disorders of cornea which are progressive, bilateral, (Cogan’s microcystic dystrophy or map-dot- symmetrical, hereditary, non inflammatory fingerprint dystrophy) and nonvascularized. All corneal dystrophies are •• Meesmann’s dystrophy (juvenile epithelial autosomal dominant except macular dystrophy dystrophy). which has autosomal recessive inheritance. Epithelial Basement Membrane Dystrophy ██ Classification Onset– In the second decade, the condition is asymptomatic. In a few patients, recurrent corneal On the basis of corneal layer primarily involved, erosions develop in the third decade. corneal dystrophies are classified into (Fig. 6.28): •• Epithelial dystrophies Clinical Features– It is characterized by šš Epithelial basement membrane bilateral, intraepithelial lesions which are best dystrophy. visualized by retroillumination. The pattern of šš Meesmann dystrophy. lesions may be: dot-like opacities, epithelial •• Bowman layer dystrophies microcysts, fingerprint-like lines or map-like gray šš Reis-Buckler dystrophy. patches. Simultaneous bilateral recurrent corneal šš Thiel-Behnke dystrophy. erosions suggest epithelial basement membrane •• Stromal dystrophies dystrophy. šš Lattice dystrophy. Histology– It shows thickening of basement šš Granular dystrophy. membrane and deposition of fibrillar material šš Macular dystrophy. between basement membrane and Bowman’s šš Gelatinous drop-like dystrophy. membrane.

Fig. 6.28 Classification of corneal dystrophies.

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Meesmann’s Dystrophy (Juvenile Epithelial Stromal Corneal Dystrophies Dystrophy) •• These include: Granular corneal dystrophy. Onset– It is in the first 2 years of life, and has •• Macular corneal dystrophy. autosomal dominant inheritance. •• Lattice corneal dystrophy. Clinical Features– It is characterized by multiple, •• Schnyder crystalline dystrophy. tiny intraepithelial vesicles which are maximum Granular Dystrophy centrally. The patient remains asymptomatic until middle age, then vesicles break through the Inheritance– autosomal dominant. anterior epithelial surface and cause intermittent Onset– In first decade of life. irritation and decrease in visual acuity. Corneal Clinical features– Opacities are dense, white and sensations are reduced. granular in the anterior stroma of central cornea, Bowman Layer Dystrophies sparing the peripheral cornea. The intervening cornea between the opacities also remains clear These include: (Fig. 6.29). •• Reis–Buckler dystrophy (corneal dystrophy of Bowman’s layer type I or Histopathology– The opacities are formed due to granular corneal dystrophy) the hyaline degeneration of collagenous protein •• Thiel–Behnke dystrophy (Honey comb and stain with Masson trichrome. dystrophy or corneal dystrophy of Effect on vision– Glare is present but the vision is Bowman’s membrane Type II) good. The opacities coalesce into various irregular Characteristics of both types of Bowman layer shapes and vision is impaired. dystrophies: Treatment– PKP is usually required by the fifth Inheritance– Autosomal dominant. decade. Clinical Features– These are characterized by Macular Dystrophy gray–white, round opacities in the central cornea. Inheritance– autosomal recessive. Over time, these result in a reticular pattern in the – In the first decade of life (6–9 years). Reis- Buckler dystrophy and assume a honeycomb Onset pattern in the Thiel–Behnke dystrophy. Patients have recurrent corneal erosions which are painful initially. Later, the pain diminishes, as corneal sensitivity decreases. Vision is impaired due to fibrosis at Bowman’s layer.

Histology– It shows destruction of Bowman’s membrane and fibrous tissue, replacing Bowman’s layer in both dystrophies.

Treatment– Symptomatic for recurrent erosions. Excimer laser keratectomy for visual disturbance. Lamellar keratoplasty is associated with relatively Fig. 6.29 Granular dystrophy. Source: Corneal rapid recurrence of dystrophy on the graft and disorders. In: Narang P, Trattler W, ed. Optimizing penetrating keratoplasty (PKP), may become suboptimal results following cataract surgery. 1st necessary in both dystrophies. Edition. Thieme; 2018.

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Clinical features– Opacities assume a discrete •• Posterior polymorphous dystrophy. granular form in the central cornea which spreads Fuch’s Endothelial Dystrophy to the periphery. There is no clear space between It is bilateral and associated with increased the opacities. incidence of primary open-angle glaucoma. Histopathology– The opacities are composed of – It is autosomal dominant. glycosaminoglycans (GAG) and stain with alcian Inheritance blue. Age– It occurs after 50 years.

Effect on vision– Vision is affected at an early age. Sex– It is more common in females.

Treatment– Penetrating keratoplasty is indicated Staging– It is characterized by progressive loss but recurrence in graft may occur. of corneal endothelial cells, resulting in reduced Lattice Dystrophy vision, and the severity of disease varies as follows (Flowchart 6.6): Inheritance– autosomal dominant. Stage 1: Earliest finding in Fuch’s dystrophy is Onset– During the second decade. the presence of excrescences (irregular warts) of Clinical features– It is characterized by presence Descemet’s membrane called guttae in the central of branched, crisscross lines along with punctate corneal endothelium (corneal guttata) which opacities in between. involve the corneal periphery as well with time.

Histopathology– Histopathology reveals that it is The confluence of guttae produces a roughened a form of amyloidosis, that is, amyloid is deposited surface with beaten metal appearance. Stroma in the corneal stroma and stain with Congo red. and epithelium are uninvolved and patient’s vision is normal at this stage. Effect on vision– The crisscross lines form an irregular lattice work and cause impairment of Stage 2: Disruption of normal endothelial mosaic visual acuity. takes place with endothelial dysfunction. It results in stromal edema which is significant Treatment– PKP is the treatment of choice when upon awakening and clears later in the day due to acuity decreases significantly. evaporation. Stromal edema results in Descemet Schnyder Crystalline Dystrophy membrane’s folds with increase in corneal It is a disorder of corneal lipid metabolism thickness. associated with systemic hypercholesterolemia Patient complains of blurred vision in morning (raised serum cholesterol). that improves during the day, Glare and colored Inheritance– autosomal dominant. halos around lights in the morning.

Features– It is caused by central subepithelial Stage 3: Due to progressive endothelial corneal crystals, often in a ring pattern, initially decompensation, epithelial edema with bullae in the first decade of life. With advancing age, formation takes place (bullous keratopathy). The central corneal haze becomes evident. periodic rupture of bullae causes: Histology– Shows accumulation of cholesterol •• Pain and discomfort due to exposure of and phospholipids throughout stroma. naked nerve endings, and eye is prone to secondary infection. Treatment– Excimer laser keratectomy is advised. •• Profound reduction in vision.

Endothelial corneal dystrophies Diagnosis– It is diagnosed by: •• These include: Fuch’s endothelial •• Specular microscopy– It is done for dystrophy. endothelial cell count (Fig. 6.30).

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Corneal guttata (excrescences of Descemet’s membrane)

Stage 1 Beaten metal appearance due to confluence of guttae - v ision is normal at this stage

Disruption of normal endothelial mosaic • Blurred vision Stage 2 in morning • Glare Endothelial dysfunction with stromal oedema • Coloured halos

Progressive endothelial decompensation

• Pain and Stage 3 Epithelial oedema with bullae formation discomfort • Profound Rupture of bullae reduction in vision

Flowchart 6.6 Staging of Fuch’s endothelial dystrophy.

a b c

Fig. 6.30 Fuchs’ dystrophy. (a) On slit lamp. (b) Moderate type. (c) Advanced type with endotheliopathy (on specular biomicroscopy). Source: (a) History. In: Singh K, Smiddy W, Lee A, ed. Ophthalmology review: a case- study approach. 2nd Edition. Thieme; 2018. (b, c) Specular microscopy and pachymetry. In: Narang P, Trattler W, ed. Optimizing suboptimal results following cataract surgery. 1st Edition. Thieme; 2018.

•• Corneal pachymetry– It is done to document edema (corneal opacification precludes increased corneal thickness. specular microscopy). •• Confocal microscopy– It is done to image Differential diagnosis– It includes: endothelium in the presence of corneal •• Posterior polymorphous dystrophy.

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•• Congenital hereditary endothelial is transformed into a multilayered epithelium- dystrophy. like tissue. The posterior surface of cornea shows •• Aphakic/pseudophakic bullous keratopathy vesicular pattern, band-like lesions of diffuse (Fig. 6.31). opacities. •• Hassell–Henle bodies. Treatment Treatment It is usually asymptomatic and treatment is •• Topical Sodium Chloride as drops (5%) and not required. Those with corneal opacification ointment (6%). require PKP. •• Lubricating eye drops. •• Bandage contact lenses to relieve pain ▄▄Ectatic Conditions of Cornea caused by rupture of bullae. •• PKP. Disorders of corneal shape include: •• If IOP is > 20 mm Hg, reduce it. Lowering •• Keratoconus. of IOP may reduce the force that drives the •• Keratoglobus. fluid into stroma. •• Pellucid marginal degeneration.

Cataract surgery and Fuch’s endothelial dystrophy ██ Keratoconus (Conical Cornea) Cataract surgery may accelerate endothelial cell loss. (OP4.5) Extra precautions during intraocular surgery (such as intraoperative soft shell viscoelastics technique) should It is a progressive steepening of cornea secondary be taken to protect the endothelium from surgical to stromal thinning whereby it assumes a conical trauma. ▪▪In eye with corneal epithelial edema or corneal shape. The apex of cone always being slightly thickness > 640 µm by pachymetery, consider below the center of cornea. It occurs around pub­ triple procedure, that is, cataract surgery + IOL implantation + keratoplasty erty with slow progression. It is usually bilateral ▪▪If corneal thickness is < 640 µm, good visual but the patients have asymmetrical involvement. outcome is expected. Etiology Posterior Polymorphous Dystrophy It is unknown but seems to be multifactorial. It Inheritance– usually autosomal dominant. may be: Clinical Features: It occurs early in life and is •• Due to congenital weakness of the cornea. characterized by the presence of multilayered •• Secondary to trauma. endothelium. The single cell layer of endothelium •• Associated with Down syndrome. •• Due to repeated rubbing of the eyes.

Clinical Features Symptoms include progressive bulging of cornea which induces myopic astigmatism and subsequently becomes irregular. It causes marked visual impairment and the patient may complain of frequent changes in spectacle power and decreased tolerance to contact lens wear.

Ocular manifestations of keratoconus are limited to cornea and include: •• Conical protrusion of cornea with apex of cone slightly below the center of cornea Fig. 6.31 Pseudophakic bullous keratopathy. (Fig. 6.32a).

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a b

Fig. 6.32 (a) Conical protru­ sion of cornea. (b) Munson’s sign. (c) Oil droplet red reflex. (d) Vogt’s striae. Source: (c) Monocular visual loss. In: Biousse V, Newman N, ed. Neuro-ophthalmology illustrated. 3rd Edition. c d Thieme; 2019.

•• Bulging of lower eyelid by cone of cornea Table 6.12 Grading of keratoconus on down gaze (Munson’s sign) (Fig. 6.32b). •• With direct ophthalmoscope at 1 m Grade of keratoconus Keratometry reading distance, a ring of shadow concentric with Mild < 48 D the margin of cone is seen in red reflex “oil Moderate 48–54 D droplet” reflex which alters its position on Severe > 54 D moving the ophthalmoscope (Fig. 6.32c). •• Retinoscopy shows irregular “scissor” Sometimes, rupture in Descemet’s membrane reflex. develops, which causes influx of aqueous into •• A ring of iron deposition occurs in the cornea (acute hydrops) and sudden stromal epithelium at the base of cone (Fleischer edema with opacification. It results in sudden ring). It is best seen with a cobalt-blue filter. impairment of visual acuity. Break usually heals •• Presence of vertical striae in deep stroma within 6 to 10 weeks, corneal edema clears, and (Vogt striae) may be noticed. These deep stromal scarring may develop. stromal stress lines disappear with external pressure on the globe (Fig. 6.32d). Keratoconus can be graded by keratometry, as •• Distortion of corneal reflex is best seen with depicted in Table 6.12. Placido disc or corneal topography. Associations •• When light beam is focused from the temporal side across the cornea, a conical Systemic associations- keratoconus may be reflection is seen on the nasal cornea associated with (Rizutti’s sign). •• Down’s syndrome.

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•• Marfan’s syndrome. formation of intrafibrillary and interfibrillar •• Ehlers Danlos syndrome. covalent bonds and stabilizes the corneal •• Apert’s syndrome. stroma. Bandage soft contact lenses are •• Atopy. prescribed to permit the epithelium to heal. •• Corneal transplantation (Keratoplasty)– Ocular associations– These include: It is done if disease progresses despite all •• Vernal keratoconjunctivitis. measures and in case of acute hydrops. •• Leber’s congenital amaurosis. •• Retinopathy of prematurity. PKP or deep lamellar keratoplasty is currently •• Fuch’s dystrophy. becoming procedure of choice. It removes entire •• Blue sclera. corneal stroma, sparing the host’s Descemet •• Aniridia. membrane and endothelium. It reduces the •• Ectopia lentis. risk of rejection and the donor cornea with low endothelial cell count can be used. Posterior Keratoconus In posterior keratoconus, the posterior corneal surface ██ Keratoglobus protrudes into the stroma. Frequently, scarring occurs in stroma, anterior to Descemet’s bulge. It is congenital, It is congenital, nonprogressive, and bilateral. It nonprogressive, and usually unilateral. is inherited as an autosomal recessive trait. It is characterized by hemispherical (globular) corneal Treatment protrusion due to thinning of entire cornea (i.e., •• Spectacles in early stages to correct limbus-to-limbus corneal thinning). In contrast, refractive errors. keratoconus shows central stromal thinning. •• Rigid gas permeable contact lenses to It may be associated with blue sclera and systemic eliminate irregular corneal curvature. So, connective tissue abnormalities. Vogt striae and these are required to correct higher degree Fleischer’s ring are absent. It must be differentiated of astigmatism. from buphthalmos (Table 6.13). •• Intracorneal rings in low to moderate Corneal topography shows generalized keratoconus. steepening, and cornea is more prone to rupture •• Corneal collagen cross linking (CCC)– It on relatively mild trauma in keratoglobus. It is is a new technique to arrest progression treated with scleral contact lenses because results of keratoconus. In this procedure, corneal of surgery are very poor. epithelial is removed and riboflavin 0.1% eye ██ drops are instilled over cornea till cornea is Pellucid Marginal Degeneration adequately saturated, which is exposed to It is a progressive, bilateral peripheral corneal UV radiation. Riboflavin triggers increased thinning typically affecting the inferior cornea cross-linking of corneal collagen fibrils by (usually 4 to 8 o’clock positions.

Table 6.13 Differentiating features between keratoglobus and buphthalmos

Keratoglobus Buphthalmos

Corneal transparency Clear cornea Hazy IOP Normal Increased Angle of anterior chamber Normal Angle anomaly present Optic disc No cupping Cupping present

Abbreviation: IOP, intraocular pressure.

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The following clinical signs helps in diagnosing •• Acute hydrops is rare. pellucid marginal degeneration: •• Corneal topography shows a classical •• Area of thinning is 1 to 2 mm inside the “butterfly” pattern. inferior limbus and measures approximately 2 mm in width and 6 to 8mm in horizontal Treatment extent (4–8 o’clock). •• Contact lenses are prescribed for correction •• Cornea above the crescent-shaped band of astigmatism. Spectacles usually fail due of thinning protrudes with flattening in to increasing irregular astigmatism. vertical meridian. Therefore, there is a •• Surgery includes: marked against-the-rule astigmatism and 1. Large eccentric penetrating keratoplasty. reduced visual acuity. 2. Crescentric lamellar keratoplasty. •• Epithelium is intact. 3. Thermocauterization. •• Vogt striae (deep stromal stress lines) and Fleischer’s ring do not occur.

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