Manual of Ocular Diagnosis and Therapy
6th Edition

5
Cornea and External Disease
Deborah Pavan-Langston
Kathryn Colby
I. Normal anatomy and physiology
  • Conjunctiva: Anatomy
    • Gross anatomy. The conjunctiva is a thin, transparent mucous membrane lining the inner surface of the eyelid (palpebral conjunctiva) and covering the anterior sclera (bulbar conjunctiva). The palpebral portion is designated as marginal, tarsal, and orbital and merges with the conjunctiva of the superior and inferior fornices in loose folds. The bulbar conjunctiva is adherent to the underlying Tenon capsule and therefore to sclera, with the tightest adhesion occurring in a narrow band at the corneoscleral limbus. A delicate vertical crescent, the semilunar fold (plica semilunaris), separates the bulbar conjunctiva from the lacrimal caruncle at the medial canthus. The conjunctiva tends to be a mobile tissue and is capable of great distention with edema fluid, as is often seen with trauma or inflammation.
    • Microscopically, the conjunctiva is composed of (a) an anterior stratified columnar epithelium that is continuous with the corneal epithelium, and (b) a lamina propria composed of adenoid and fibrous layers. The epithelium is from two to seven layers thick and contains numerous unicellular mucous glands (goblet cells) that secrete the inner mucoid layer of the tear film. Although the healthy epithelium is never keratinized, it may become keratinized in certain disease states. The lamina propria is composed of connective tissue housing blood vessels, nerves, and glands. The accessory lacrimal glands of Krause are located deep in the substantia propria in the superior and inferior fornices. The accessory lacrimal glands of Wolfring are situated near the upper margin of the superior tarsal plate. The adenoid layer of the lamina propria, which develops particularly after 3 months of age, contains lymphocytes enmeshed in a fine reticular network without the presence of true lymphoid follicles. The fibrous layer of the lamina propria surrounds the smooth palpebral muscle of Müller.
    • The blood supply of the palpebral conjunctiva originates from peripheral (bulbar and fornix) and marginal arterial arcades of the eyelid. Within 4 mm of the limbus, the vascular supply is derived from the anterior conjunctival branches of the anterior ciliary arteries (superficial plexus), which anastomose with the posterior conjunctival vessels from the peripheral arcade. Conjunctival vessels move with the conjunctiva and constrict with instillation of 1:1,000 epinephrine—a point of differentiation from the deeper episcleral and ciliary vessels.
    • Innervation of the bulbar conjunctiva is via the sensory and sympathetic nerves from the ciliary nerves. The remaining palpebral and fornix conjunctiva is innervated by the ophthalmic and maxillary divisions of the trigeminal nerve (cranial nerve V).
    • Lymphatic drainage of the conjunctiva parallels that of the lid, with lateral drainage to the preauricular nodes and medial drainage to the submandibular nodes.
  • Cornea
    • Gross anatomy. The cornea represents the anterior 1.3 cm2 of the globe and is the main refracting surface of the eye. Although the cornea is continuous with the sclera at the limbus, the anterior corneal curvature (radius equal to 7.8 mm) is greater than that of the sclera, with the central 4-mm optical zone almost
      P.74

      spherical and the periphery gradually flattening toward the scleral curve. The horizontal diameter of the anterior surface of the cornea (11.6 mm) is longer than the vertical diameter (10.6 mm), so that the anterior aspect of the cornea forms a horizontal ovoid. Viewed from the posterior surface, the cornea is circular (with a diameter of 11.6 mm). A corneal diameter greater than 12.5 mm is termed megalocornea; a corneal diameter less than 11 mm is termed microcornea. The height of the cornea from the basal plane of the visible limbus to the apex is 2.7 mm. The central thickness of the cornea is 0.52 mm, which increases to 0.7 mm in the far periphery.
    • Microscopically, the cornea consists of five strata: the epithelium and its basement membrane, Bowman layer, stroma, Descemet membrane, and endothelium.
      • The corneal epithelium is a uniform five- to six-layer structure 50 μm to 100 μm thick and composed of (a) a basal cell layer of replicating cylindric cells, 18 μm high and 10 μm wide, (b) a wing cell layer with superior convex–inferior scalloped cells interdigitating between the apices of the basal cells, and (c) surface cells composed of flat cells in two or three layers culminating in a smooth corneal surface that is studded with ultrastructural microplicae and microvilli. Corneal nerves passing from the corneal stroma through Bowman layer terminate freely between the epithelial cells, thus accounting for the great sensitivity of the cornea. The epithelium is firmly attached to the underlying Bowman layer by a continuous basement membrane that is a very important source of firm epithelial adhesion.
      • The Bowman layer is a homogeneous condensation of the anterior stromal lamellae continuous with the corneal stroma. Its termination at the corneal periphery marks the anterior margin of the corneoscleral limbus.
      • The stroma represents 90% of the corneal thickness, with bundles of collagen fibrils of uniform thickness enmeshed in mucopolysaccharide ground substance. These bundles form 200 lamellae arranged parallel to the corneal surface but with alternate layers crisscrossing at right angles. This regular lattice structure, coupled with the deturgescent state of the stroma, has been credited with providing the extreme transparency of the cornea necessary for optical clarity.
      • The Descemet membrane is the basement membrane of the endothelial cells and can be easily stripped from the stroma. When torn or traumatized, the ends will tend to retract, indicating an inherent elasticity. Gradual thickening of this layer with age is noted, with the thickness approximately 3 μm to 4 μm at birth but increasing to 10 μm to 12 μm in adulthood. Peripheral dome-shaped excrescences of the Descemet membrane (Hassall-Henle warts) occur in persons older than 20 years. Histologically, the membrane is a homogeneous glasslike structure, but ultrastructurally, it is composed of stratified layers of very fine collagenous filaments in the anterior layer (anterior banded layer) with an amorphous posterior layer that increases with age.
      • The endothelium is a single layer of approximately 500,000 polygonal cells, 5 μm to 18 μm in size, which spread uniformly across the posterior surface of the cornea. The corneal endothelium maintains corneal deturgescence and contributes to the formation of the Descemet membrane. Corneal endothelial cells generally do not divide after birth and are arrested in the G1 phase of the cell cycle. These cells can be stimulated to divide in vitro using a combination of growth factors. Since the endothelium is post-miotic in the adult, cell loss (due to trauma or underlying corneal dystrophy) is compensated for by migration and enlargement of the remaining endothelial cells.
    • The blood supply of the cornea arises predominantly from the conjunctival, episcleral, and scleral vessels that arborize about the corneoscleral limbus. The cornea itself is avascular.
    • The innervation of the cornea is that of a rich sensory supply mostly via the ophthalmic division of the trigeminal nerve. This innervation is via the long ciliary nerves that branch in the outer choroid near the ora serrata region. These
      P.75

      nerves pass via the sclera into the middle third of the cornea as 70 to 80 large nerve trunks that lose their myelin sheaths approximately 2 to 3 mm from the limbus but can be visualized as fine filaments beyond. There is significant dichotomous and trichotomous branching, and the subsequent passage of nerve fibers through the Bowman layer ends freely between the epithelial cells.
  • Physiology: Precorneal tear film
    • The physiology of the cornea and conjunctiva is best introduced in a discussion of the precorneal tear film. This film, which is 6 to 10 μm thick, is composed of three layers: (a) superficial lipid layer, (b) middle aqueous layer, and (c) inner mucous layer. The normal tear volume in the conjunctival sac is about 3 to 7 μL and can increase to the conjunctival sac capacity of 25 μL before overflow occurs. Tear flow rate is approximately 1 μL per minute and comes from the secretion of the main and accessory lacrimal glands. After their release in the superotemporal region, the tears are distributed by the blinking action of the lids, with the tear meniscus forming superior and inferior marginal tear strips before draining into the lacrimal puncta located near the medial canthus. With a pH of 7.6 and an osmolarity comparable to sodium chloride 0.9%, there is a low glucose concentration and an electrolyte distribution similar to plasma, with the exception of a slightly greater potassium content. Oxygen dissolves readily in the tear film, and the dissolved protein content of the tear film includes immunoglobulins and lysozyme. These characteristics allow the tear film to provide a smooth surface for refraction, to mechanically wash and protect the cornea and conjunctiva, to provide oxygen exchange for the epithelium, to lubricate the surface during a blink, and to provide bacteriostasis. Tear film homeostasis requires an intact “lacrimal function unit,” which is a feedback loop involving cranial nerves V (sensory) and VII (motor), the lacrimal apparatus, and integrative structures within the central nervous system. Perturbation of any of these components can interfere with the proper composition and function of the tear film.
    • Corneal function. The primary physiologic function of the cornea is to maintain an optically smooth surface and a transparent medium while protecting the intraocular contents of the eye. This duty is fulfilled by the effective interaction of the epithelium, stroma, and endothelium. The epithelium, endothelium, and Descemet membrane are transparent because of the uniformity of their refractive indices. The transparency of the stroma is conferred by the special physical arrangement of the component fibrils. Although the refractive index of collagen fibrils differs from that of the interfibrillar substance, the small diameter of the fibril (300 Å) and the small distance between them (300 Å) provide a separation and regularity that causes little scattering of light despite the optical inhomogeneity. The relative state of deturgescence is provided by the barrier functions of the epithelium and endothelium, as well as by the dehydrating function of the endothelium. Disturbance of this equilibrium, such as occurs in corneal edema, will increase light scattering and the opacity of the stroma.
      • The anterior epithelial surface, with its microplicae and microvilli, provides the scaffold for a smooth and continuous precorneal tear film. In addition, the epithelium serves as a relatively impermeable barrier to water-soluble materials. The epithelium also provides an effective barrier to many infectious agents. The epithelium is the most mitotically active layer of the cornea and, because of its high cellular density, consumes considerable glucose and oxygen. The major source of oxygen for the epithelium is atmospheric oxygen dissolved in the tear film, which explains the sensitivity to hypoxia that occurs with improperly fitted or overworn contact lenses. Glucose for the epithelium is obtained from the aqueous humor by diffusion through the corneal stroma. The substance is either used or stored as glycogen. Epithelial metabolism occurs through the hexose monophosphate shunt or tricarboxylic acid cycle in the presence of oxygen, or via the anaerobic glycolysis pathway in the absence of oxygen. With these metabolic capabilities, the turnover of the epithelium is rapid, occurring approximately
        P.76

        once every 7 days, and explains the ability of the epithelium to heal itself rapidly.
      • Stroma. There is little turnover of the stromal matrix, and the keratocytes may survive as long as 2 years under normal conditions. Glucose is obtained from the aqueous humor and oxidized via the Embden-Meyerhof tricarboxylic acid cycle. Interaction of the interfibrillar substances, particularly the acid mucopolysaccharides, generates a swelling pressure for the stroma both in vivo and in vitro. This tendency to imbibe fluid results in light scattering if it is not kept in check by the dehydrating function of the endothelium.
      • Endothelium. The major function of the endothelium is the maintenance of proper corneal hydration. The endothelium requires oxygen and glucose to maintain the metabolically active process, but the exact nature of the endothelial pump is not completely clear. Impairment of the pump function can occur in dystrophic conditions (Fuchs dystrophy), injury (postsurgical or traumatic), and in some inflammatory conditions (anterior segment necrosis).
II. Acute traumatic conditions
  • Abrasions and lacerations (see Chapter 2)
  • Perforations
    • Etiologically, corneal perforation can result from any corneal ulceration, either infectious (bacterial, fungal, or viral), inflammatory (rheumatoid arthritis or collagen disease), posttraumatic (burn), or trophic defects of degenerations, neurotrophic ulcer, or postherpetic ulcer. Use of topical nonsteroidal anti-inflammatory drugs (NSAIDs) such as diclofenac in at-risk patients may trigger or worsen thinning and perforation.
    • Treatment. Occasionally, these perforations will seal with a small knuckle of iris and rarely can be self-sealing, but they usually result in partial or complete loss of the anterior chamber. Thus, in most cases, they represent an urgent situation to be treated. Small, noninfectious perforations can often be splinted by use of a therapeutic soft contact bandage lens (Permalens, Kontur). Such treatment will sometimes allow healing of the perforation but often is a stabilizing or interim treatment that requires further definitive therapy. Medical adhesive is of great use in helping to seal small perforations. Cyanoacrylate tissue adhesive (Dermabond Ethicon; not U.S. Food and Drug Administration [FDA] approved for ocular use) can successfully seal a perforation without excess ocular toxicity. It is essential that epithelium and necrotic stroma be débrided to allow firm adhesion of the cyanoacrylate glue to surrounding healthy basement membrane. A thin application of this glue will often remain intact for several months and is tolerated by the patient if covered with a continuously worn soft contact lens (Plano T). Healing of the corneal defect will often occur beneath the glue. Even if spontaneous healing of the leak is not expected, the glue will provide adequate time to obtain corneal donor material if keratoplasty becomes necessary. It is essential to observe the patient closely to ensure that the anterior chamber has reformed and that there is no associated superinfection. Topical antibiotic coverage is advisable after gluing and with the use of a soft contact lens. When contact lens or adhesive therapy is inadequate, surgical patch grafting will usually be successful. For moderate-size perforations, a small lamellar button may be sutured into the débrided defect. In the event of large central perforations, it may be preferable to perform penetrating keratoplasty.
  • Burns. Anterior segment burns may be chemical, thermal, radiation, or electric (see Chapter 2).
  • Subconjunctival hemorrhage may be induced with major, minor, or no detectable trauma to the front of the eye. Occasionally, a patient will wake up with a “spontaneous” hemorrhage. Clinically, it presents as a striking flat, deep-red hemorrhage under the conjunctiva and may become sufficiently severe to cause a dramatic chemotic “bag of blood” to protrude over the lid margin. Occasionally, pneumococcal or adenoviral conjunctivitis may be associated, in which case there will be
    P.77

    discomfort and discharge. In the absence of infection or significant trauma to the eye, treatment is unnecessary. The patient should be reassured that the blood will clear over a 2- or 3-week period.
III. Lid and conjunctival infection and inflammation
  • Blepharitis and conjunctivitis can be acute or chronic, infectious or inflammatory.
    • Acute blepharitis often overlaps with meibomian gland dysfunction. Staphylococcus aureus is the most common cause of infection, but other species may be at fault. It is characterized by tender lid edema; erythema; lash loss; hard, anterior lid location of fibrinous crusts and scales; and occasional lid ulceration, tear instability, corneal punctate keratitis, infiltrates, vascularization, and phylctenulosis.
    • Chronic bacterial blepharoconjunctivitis, rosacea, and meibomian gland dysfunction (MGD)
      • S. aureus is the most common cause of chronic bacterial conjunctivitis or blepharoconjunctivitis, with S. epidermidis, Propionibacterium acnes, Corynebacterium sp, and the yeast Pityrosporium being other etiologic agents. Often this conjunctivitis is associated with ocular rosacea or rosacea of the skin, and MGD. Rosacea, a cutaneous vascular, acneiform disorder with four forms (erythematotelangiectasia, papulopustular, phymatous, and Ocular), presents with facial flushing, telangiectatic vessels, papules and pustules, and occasional sebaceous gland hyperplasia of the nose (rhinophyma). More than 50% of patients will have ocular changes that include dryness and irritation, burning, stinging, low tear production, MGD with telangiectasia, hordeola + chalazia (see Chapter 3), chronic conjunctivitis, marginal corneal infiltrates or scarring, and episcleritis. MGD, another infrequently recognized cause of ocular irritation, may be “obstructive,” found with anterior blepharitis, or “nonobstructive,” posterior blepharitis. Anterior blepharitis (seborrheic) has oily crusts on the lashes and lids; red, thickened lids anterior to the grey line; expressible turbid oil in the glands; aqueous tear deficiency (30%); punctate keratitis (15%); and often oily crusting of the brows and scalp. Posterior blepharitis is hypersecretory meibomian seborrhea with inspissated oil glands, fluorescein staining along the palpebral conjunctival margin, notable telangiectatic blood vessels, foam, hordeola, stys, and often rapid tear breakup time. There is often colonization of the meibomian orifices and lash follicles with Staphylococcus. If there is associated Staphylococcus, it can produce a variety of exotoxins. An ulcerative blepharitis can occur, as well as an eczematoid scaling and sometimes weeping inflammation.
      • Eczema blepharitis, scaly crusts on a red base, is usually distinguishable from the less severe, oily seborrheic blepharitis. There is often colonization of the meibomian orifices and lash follicles with Staphylococcus. An angular blepharoconjunctivitis with maceration of the tissue at the lateral canthus, at one time most commonly associated with Moraxella sp, is now most commonly produced by Staphylococcus. The cornea also can be involved, with an inferior superficial punctate keratitis or by limbal infiltrates. Marginal corneal ulcers can be produced by chronic staphylococcal blepharoconjunctivitis (see Section IV.B.2).
      • Other causes of chronic blepharitis are the mite Demodex and lice. The former obligate parasites inhabit hair follicles and sebaceous glands and appear as waxy sleeves around lashes or cylinders protruding from sebaceous glands. Treatment is lid hygiene. Lice infestations (phthiriasis palpebrum) are caused by the pubic louse and may be treated by smothering them with any eye ointment bid for at least 10 days. The pubic area is treated with a pediculocide.
    • Acute and chronic bacterial conjunctivitis. Conjunctivitis is an inflammation of the conjunctiva characterized by vascular dilation, cellular infiltration,
      P.78

      and exudation. The differential features of bacterial conjunctivitis versus those caused by virus, allergy, or toxic factors are listed in Table 5.1.
      TABLE 5.1 Clinical Features of Conjunctivitis
      Sign Bacterial Viral Allergic Toxic TRIC
      Injection Marked Moderate Mild/Moderate Mild/Moderate Moderate
      Hemorrhage + + - - -
      Chemosis ++ +/- ++ +/- +/-
      Exudate Purulent Scant/watery Stringy/white - Scant
        Mucopurulent        
      Pseudomembrane +/- Streptococcus +/- - - -
        Corynebacterium        
      Papillae +/- - + - -
      Follicles - + - +
      (Medication)
      +
      Preauricular node + ++ - - +/-
      Pannus - - -
      (Except vernal)
      - +
      TRIC, trachoma-inclusion conjunctivitis; ++, strongly positive; +, positive; +/-, sometimes positive; -, negative.
      The acute stage of conjunctivitis is classically recognized by vascular engorgement and mucopurulent discharge, with the associated symptoms of irritation, foreign body sensation, and sticking together of the lids. Occasionally, a severe reaction with purulent conjunctivitis and corneal involvement can occur. The chronic conjunctival infection is more innocuous in its onset, runs a protracted course, and is often associated with involvement of the lids or lacrimal system by low-grade inflammatory reaction. A wide variety of bacterial organisms can infect the conjunctiva. Although the bacterial etiology is often clinically apparent, the identity of the causative organism may not be obvious. Certain clinical features determined by the pathogenicity of the infectious agent, however, may provide an accurate clinical diagnosis.
      • Staphylococcus aureus is probably the single most common cause of bacterial conjunctivitis and blepharoconjunctivitis in the Western world. The aerobic Gram-positive coccus is often harbored elsewhere on the skin or in the nares. It may affect any age group. Although usually not aggressively invasive, the organism is very toxigenic and can provide corneal infiltrates, eczematous blepharitis, phlyctenular keratitis, and angular blepharitis.
      • Staphylococcus epidermidis is usually considered an innocuous inhabitant of the lids and conjunctiva, but in some instances it can cause blepharoconjunctivitis. The organism is capable of producing necrotic exotoxin and has been shown to colonize eye cosmetics, with subsequent production of blepharoconjunctivitis.
      • Streptococcus pneumoniae (pneumococcus) is an aerobic encapsulated Gram-positive diplococcus that is often present in the respiratory tracts of asymptomatic carriers. This organism more commonly affects the conjunctiva of children and can run a self-limiting course of 9 to 10 days.
      • Streptococcus pyogenes is an aerobic Gram-positive coccus. Although an infrequent cause of conjunctivitis, the organism is invasive and toxigenic, and thus is capable of producing a pseudomembranous conjunctivitis. The pseudomembrane consists of a fibrinous layer entrapping inflammatory cells and is attached to the conjunctival surface. Removal of this pseudomembrane is possible with minimal bleeding of the underlying tissue.
      • P.79

      • Haemophilus influenzae (H. aegyptius, Koch-Weeks bacillus) is a fastidious aerobic Gram-negative pleomorphic organism often seen as a slender rod or a coccobacillary form. It is frequently isolated from upper respiratory tracts of healthy carriers and most commonly causes conjunctivitis in children rather than in adults. It is a toxigenic organism and can be accompanied by patchy conjunctival hemorrhages during an acute infection. An untreated case can last for 9 to 12 days, occurring as a self-limited infection, but occasionally can be part of a more ominous periorbital cellulitis associated with respiratory infection that can lead to bacteremia in young children. Accompanying the acute infection and probably a manifestation of the toxigenic potential is the presence of inferior corneal limbal infiltrates.
      • Moraxella lacunata is an aerobic Gram-negative diplobacillus once considered the most common cause of angular blepharoconjunctivitis. Although angular blepharoconjunctivitis is now more commonly the result of staphylococcal infection, Moraxella sp can produce an acute conjunctivitis that occasionally results in a chronic conjunctivitis with follicular reaction.
    • Hyperacute conjunctivitis (acute purulent conjunctivitis)
      • Neisseria sp (gonococcus, meningococcus) are Gram-negative diplococci. Like Haemophilus sp, Streptococcus sp, and Corynebacterium diphtheriae, they are aggressively invasive bacteria that can produce a severe, often bilateral conjunctivitis. Occurring in the child as an infection from the maternal genital tract, in adolescents via fomite transmission, or in via inoculation from infected genitalia, the conjunctivitis can start as a routine mucopurulent conjunctivitis that rapidly evolves into a severe inflammation with copious exudate and marked chemosis and lid edema. This clinical appearance demands laboratory confirmation, immediate therapy, and occasionally hospitalization.
      • Neonatal conjunctivitis (ophthalmia neonatorum). Conjunctivitis of the newborn deserves special mention because of the severity and threatening potential of this condition. Conjunctivitis caused by Neisseria sp usually becomes symptomatic in the newborn 2 to 4 days following inoculation of the conjunctival mucosa at the time of birth. Clinically, a yellow purulent discharge with prominent lid edema and conjunctival chemosis appears. This condition needs to be distinguished from the neonatal conjunctivitis caused by inclusion conjunctivitis agents, chemical keratoconjunctivitis, nasolacrimal obstruction with other bacterial superinfection, or trauma. The differential points in diagnosis are listed in Table 5.2 (see Sections III.C.2 and Chapter 11).
      • Chronic conjunctivitis can also be produced by Gram-negative rods including Proteus mirabilis, Klebsiella pneumoniae, Serratia marcescens, and Escherichia coli. Gram-negative diplobacilli (M. lacunata) can produce a
        P.80

        chronic blepharoconjunctivitis (angular conjunctivitis), as previously mentioned, and may be present with a chronic follicular reaction. The giant fornix syndrome is a little recognized cause of chronic, relapsing, grossly purulent conjunctivitis in the elderly. There is an unusually large upper conjunctival fornix, which houses copious amounts of purulent debris and usually S. aureus. Treatment is cipro- or ofloxacin 6 to 8 times per day, with prednisolone 1% or rimexolone bid to tid. Recurrences may be prevented by a single steroid-antibiotic drop daily. A noninfectious cause of chronic conjunctivitis and irritation is floppy eyelid syndrome, a condition seen most often in obese patients with sleep apnea. The loose, lax upper tarsus everts easily to expose tarsal conjunctiva and eye during sleep to cause papillary conjunctivitis and red eye. Treatment is bedtime lid taping shut, an eye shield, or horizontal lid shortening.
        TABLE 5.2 Neonatal Conjunctivitis
        Agent Onset Cytology Culture
        Neisseria 2 d to 4 d Gram-negative intracellular diplococci Blood + chocolate agar (37°C, 10% CO2)
        Other bacteria 1 d to 30 d Gram-positive or Gram-negative organisms Blood agar
        Inclusion blenorrhea (TRIC) 2 d to 14 d Giemsa-positive intracytoplasmic inclusions Negative
        Chemical 1 d to 2 d Negative Negative or normal flora
        TRIC, trachoma-inclusion conjunctivitis.
      • Parinaud ocular glandular syndrome (catscratch disease, bartonellosis) is a febrile illness caused by the bacillus Bartonella henselae and is usually contracted through cat or flea exposure. Eye findings include unilateral conjunctival redness, often with epithelial ulceration, foreign body sensation, epiphora, mild lid swelling, serous to purulent discharge, and the disease hallmark, regional lymphadenopathy. Neuroretinitis and focal chorioretinitis are not uncommon (2%) (see Section III.D.4). Diagnosis is most cost-effective using serology, fluorescein antibody, or enzyme immunoassay.
  • Laboratory diagnosis in bacterial conjunctivitis is not routine. However, when clinical findings are insufficient to confidently diagnose the etiology of an infection, or in those situations in which the reaction is severe or has not responded to routine therapy, conjunctival scrapings for microscopic examination and cultures are indicated. These should also be performed in cases of neonatal conjunctivitis, hyperacute conjunctivitis, and chronic recalcitrant conjunctivitis.
    • Conjunctival cultures should be taken prior to the use of topical anesthetics, because these agents and their preservatives will reduce the recovery of certain bacteria. Cultures are taken by moistening a sterile alginate or dacron (not cotton) swab with sterile saline and wiping the lid margin or conjunctival cul-de-sac. The culture medium is then inoculated directly with the swab tip. Inoculation of solid media can be made in the shape of the letter R for the right lid and L for the left lid margin. On the same plate, a conjunctival culture may be inoculated at a different site using a zigzag pattern. In this way, the site of culture may be distinguished by the pattern of growth on the plate. After inoculating solid media, the tip of the applicator may be broken off and dropped into a tube of liquid culture medium (e.g., thioglycollate broth).
    • For bacterial isolation and identification, the most widely used and generally available media are blood agar and chocolate agar. Meat broth has a significantly higher growth rate for most common organisms but must be secondarily plated for identification. Chocolate agar is well suited for growth of any organism that can be isolated on blood agar and has the added advantage of isolating Haemophilus, the fastidious Neisseria organisms, and fungi. Thayer-Martin medium is a chocolate agar medium containing vancomycin, colistimethate, and nystatin and is of use in culture and isolation of gonococcus. Thioglycolate medium is a commonly used medium in cultivating aerobic and anaerobic organisms from ocular infection. Liquid Sabouraud medium may be useful in isolating fungal organisms when solid agar medium has failed. Table 5.3 summarizes the culture media of use in specific ocular infectious states. Cultures for B. henselae (catscratch disease) are difficult. Diagnosis is usually based on polymerase chain reaction (PCR) testing on local tissue biopsy and serology.
    • Scrapings for microscopic examination are made after cultures have been taken. Local anesthetic is instilled. A platinum spatula is flamed and allowed to cool to room temperature. The spatula can then be used to gently scrape the involved conjunctival surface, and the material obtained can be spread in a thin layer on a precleaned glass slide. If possible, two or three such slides are made and stained for microscopic examination (Table 5.4). Because scrapings
      P.81

      P.82

      are only about 70% reliable and may be traumatic to the patient, cultures take priority, and in appropriate situations, scrapings are omitted.
      TABLE 5.3 Culture Media
      General media Bacterial Fungal Parasitic Viral
      Blood agar plate Good recovery (37°C) Good recovery (room temperature)    
      Chocolate agar plate Especially Haemophilus, Neisseria, fungus      
      Sabouraud   Good recovery (broth or agar)    
      Chopped-meat broth Good recovery (37°C) Good recovery    
      Thioglycolate broth Microaerophilic species      
      Special media        
      (Lowenstein-Jensen, Thayer-Martin) Mycobacteria, Neisseria      
      Page medium to Escherichia coli plates     Good for Acanthamoeba  
      Viral carrier medium (minimal essential medium, Hank balanced salt solution) to human cell tissue culture       Good for herpes simplex, herpes zoster, adenovirus, pox
      TABLE 5.4 Cytologic Features of Conjunctivitis
      Cell Bacterial Viral Allergic TRIC
      Polymorphonuclear
      Neutrophil + + (Early) - +
      Basoeosinophil (occasional) - - +  
      Mononuclear        
        Lymphocyte - + - +
        Plasma cell - - - +
      Multinuclear - + - -
      Inclusion        
        Cytoplasm - + (Pox) - +
        Nucleus - + (Herpes) - -
      Organism + - - -
      TRIC, trachoma-inclusion conjunctivitis (group); +, present; -, absent.
    • Stains most useful for identifying organisms and inflammatory cell type are the Gram or acridine orange. The Hansel stain is also a useful technique for rapid identification of any eosinophilic response. The Giemsa and Wright stains are most useful in revealing the condition and character of epithelial cells and inflammatory cells. The Giemsa stain is most effective in showing the presence or absence of viral cytoplasmic or intranuclear inclusion bodies and outlining the morphology of bacteria. The Gram stain is useful in revealing whether an organism is Gram positive or negative. It also provides some information about the morphology of the organism. For mycobacteria acid fast, lectin, and Gram stain, for fungi and acanthamoeba calcofluor white, and acridine orange are most useful. These organisms very rarely colonize the lids or conjunctiva.
    • The cytologic features of each type of conjunctivitis are helpful in diagnosis. As a rule, a polymorphonuclear leukocyte response occurs with bacterial conjunctivitis (with the exception of diplobacillus). Acute Stevens-Johnson syndrome may produce a polymorphonuclear response, as will the early stages of a viral infection. A mixed outpouring of polymorphonuclear leukocytes and lymphocytes is commonly noted with adult and neonatal inclusion conjunctivitis. Such a mixed response, with the added presence of plasma cells and macrophages (Leber cells), is almost diagnostic of trachoma. Chemical conjunctivitis can also produce a polymorphonuclear response. A predominantly lymphocytic response is most commonly seen in viral infections but can also be seen in drug-induced toxic follicular conjunctivitis. Numerous eosinophils are indicative of vernal conjunctivitis or allergic conjunctivitis. The appearance of eosinophils and polymorphonuclear leukocytes in conjunction with a hyperacute conjunctivitis may be indicative of early erythema multiforme, particularly if associated with systemic symptoms. Basophils, rarely seen in conjunctival scrapings, are equivalent in interpretation to eosinophilic reaction. Epithelial cells may demonstrate cytoplasmic inclusions that, if basophilic, suggest inclusion conjunctivitis and, if eosinophilic, suggest pox virus. Pink intranuclear inclusions on Giemsa stain are diagnostic of herpesvirus infection (either simplex or zoster). Multinucleate giant cells are suggestive of a viral disorder.
    • When organisms are identified, Gram-positive cocci in pairs or chains may indicate S. pyogenes. The Gram-negative diplococci, appearing within polymorphonuclear leukocytes and having the “coffee bean” shape, indicate Neisseria
      P.83

      sp. Large Gram-negative diplobacilli characterize Moraxella sp. H. influenzae is a pleomorphic organism variably appearing as Gram-negative coccobacillus or slender rods. Gram-negative rods may also be noted but are difficult to differentiate as to species. Candida may appear hyphate on scrapings but are round organisms on culture.
  • Treatment of bacterial conjunctivitis and blepharitis (see also Chapter 3, Section I.1).
    • Acute mucopurulent conjunctivitis
      • Topical antibiotic therapy. Acute mucopurulent conjunctivitis will typically respond to topical antimicrobial therapy in solution or ointment form. If treatment is based on clinical diagnosis alone, topical antibiotics should be broad spectrum (i.e., anti- Staphylococcus sp, Streptococcus sp, and anti-Gram-negative organisms such as Moraxella, Serratia, Haemophilus, and Pseudomonas). Erythromycin or bacitracin ointment or sodium sulfacetamide 10% to 15% solution or ointment effectively covers only the more common Gram-positive infections. About 50% of staphylococci are resistant to the sulfonamides and erythromycin. There has been a significant increase in resistance to ciprofloxacin and cefazolin. Neomycin–polymyxin–bacitracin (Neosporin, Ocutricin, AK-Spore) is a very effective broad-spectrum antimicrobial (Gram-positive and -negative organisms are covered), but there is a 6% to 8% allergic sensitivity to neomycin. Polymyxin B–bacitracin (Polysporin, AK Poly-Bac) ointment and polymyxin B–trimethoprim drop (Polytrim) have excellent broad-spectrum coverage. Gentamicin (generics) and tobramycin (Tobrex), drops or ointment, are very good broad-spectrum agents but are usually reserved for suspected Gram-negative organisms. They are poorly effective against Streptococcus sp, and there is increasing incidence of resistance to Staphylococcus sp. The quinolones, ciprofloxacin (Ciloxan), ofloxacin (Ocuflox), levofloxacin (Quixin), gatifloxacin (Zymar), moxifloxacin (Vigamox), and norfloxacin (Chibroxin), have very broad and potent Gram-positive and -negative antibacterial activity with low, but unfortunately increasing, Gram-positive and -negative rates of bacterial resistance, especially for ciprofloxacin. Because of this and their potency, the quinolones should probably be reserved for more serious infections. Gram-negative coccobacilli are probably Haemophilus and should be treated with Polytrim as well as systemically (see below). Dosing schedules for all medicines are qid for 7 to 10 days, unless otherwise indicated.
      • Systemic therapy. For particularly acute staphylococcal blepharitis, oral dicloxacillin, or if penicillin allergy exists, erythromycin or azithromycin, are very effective adjuncts (see Appendix B). Methicillin-resistant staphylococci (MRSA) organisms are effectively treated with appropriate topical therapy, such as q2h to qid moxifloxacin or vancomycin along with p.o. doxy- or minocycline 100 mg p.o. bid for 10–14 days. Blepharokeratoconjunctivitis in children is not uncommon. Oral erythromycin for 1 to 12 months as needed and topical antibiotic therapy is an effective treatment. Recurrences are common and may be managed with low-dose steroid therapy such as fluoromethalone FML.
      • Local measures are of great value in treatment for both acute and chronic blepharitis. Warm wet compresses improve circulation, mobilize meibomian secretions, and help cleanse crusting deposits of the lashes. Thick or inspissated lid secretions may require the physician to express the lids between cotton-tipped applicators after topical anesthesia, followed by daily lid margin scrubs with commercial cleansing pads (Eye Scrub, Lid Wipes SPF) or daily baby shampoo scrubs (using fingertips) performed by the patient in the shower or at the sink. Seborrheic blepharitis is often improved by use of dandruff shampoo to the scalp and eyebrows. Daily application of steroid ointment such as fluoromethalone 0.1% ointment to lid margins for 2 to 3 weeks often controls the pronounced lid inflammation.
    • Hyperacute bacterial conjunctivitis (acute purulent conjunctivitis) is a more serious situation and demands more vigorous therapy. After the patient is
      P.84

      examined and the necessary cultures and scrapings are obtained, it is important to institute treatment prior to obtaining the culture results.
      • Systemic therapy is indicated for Neisseria gonorrhoeae, N. meningitidis, and H. influenzae and is far more critical than topical therapy. Because more than 20% of N. gonorrhoeae cases are resistant, penicillin and tetracycline are no longer adequate as first-line treatment. If there is no corneal ulceration, recommended therapy that covers antimicrobial-resistant strains is ceftriaxone 1 g i.m. × 1, or for penicillin-allergic patients, spectinomycin 2 g i.m. × 1 or a fluoroquinolone such as moxifloxacin 400 mg p.o. qd × 5 d. If there is corneal ulceration, the patient should be admitted and treated with ceftriaxone 1 gm i.v. q12h × 3 days. For penicillin-allergic patients, treat with spectinomycin 2 g/d × 3 days or a quinolone such as moxifloxacin or gatifloxacin 400 mg p.o. qd × 7 to 10 days. All of the above regimens should be accompanied by frequent, copious sterile saline irrigation to remove debris and topical bacitracin or gentamicin ointment qid. Systemic therapy is followed by a 1-week course of either doxy- or minocycline 100 mg p.o. bid or erythromycin 250 to 500 mg p.o. qid. An alternative combination is ceftriaxone 1 g or 50 mg per kg i.v. once on an outpatient basis, followed by a week of doxycycline or erythromycin p.o. Doses are adjusted per Appendix B, in consultation with a pediatric or infectious disease consultant. For patients who may only be treated with oral medication, moxifloxacin, levofloxacin, or other quinolone, and cefaclor with probenecid are recommended (see Appendix B).
      • Prophylactic therapy for intimate contacts of N. gonorrhoeae patients is 1 g of ceftriaxone i.v. once or, for N. meningitidis, rifampin 600 mg p.o. q12h for 4 days. Isolation of H. influenzae in children warrants therapy with ampicillin 100 mg to 200 mg/kg i.m. or i.v. for 7 to 10 days or 50 mg to 100 mg/kg q6h to q8h p.o. for 10 to 14 days; neonates receive 50 mg to 200 mg/kg q12h i.m. or i.v. for 10 days (see Appendix B). Adult dosage is 2 g to 4 g p.o., i.m., or i.v. q6h to q8h for 10 to 14 days. If the Haemophilus strain is ampicillin resistant or the patient is penicillin allergic, a quinolone (e.g., levofloxacin, gatifloxacin, moxifloxacin), in the dosages described in Appendix B, is given for 10 to 14 days. The quinolones should not be used in neonates or children without consultation with a pediatrician or infectious disease consult.
      • Topical bacitracin or erythromycin ointment is instilled every 2 hours for the first 2 to 3 days for N. meningitidis, Streptococcus sp, C. diphtheriae, and N. gonorrhoeae in the neonate, child, or adult, and then five times daily for 7 days. Haemophilus or Moraxella infections are treated with topical quinolones, such as moxifloxacin, ofloxacin, or gentamicin, or tobramycin in the same dosage schedule as that for Neisseria. Frequent irrigation with sterile saline is very therapeutic in washing away infected debris.
    • Chronic conjunctivitis and blepharitis (see Sections III.B, earlier, and VII.I, as well as Chapter 3 for anterior and posterior blepharitis review) are especially common in patients with acne rosacea. It is rarely cultured, and then only if there is no response to standard treatment, and is then retreated in accordance with the sensitivities obtained after the pathogen is cultured.
      • Recalcitrant blepharitis, meibomitis, or infectious eczema dermatitis in association with chronic staphylococcal blepharoconjunctivitis requires not only topical antibiotic, bacitracin, or erythromycin bid, but also intensive hygiene of the lid margins. This hygiene may be initiated in the office by expression of the lid meibomian glands (using topical anesthesia) with cotton-tipped applicators. Daily lid hygiene with 5-minute warm compresses and lid margin massage with Eye Scrub or baby shampoo by the patient using the lathered fingertips are important in completely eradicating the inflammation. Daily hand and face scrubs with pHisoHex soap for 2 to 3 weeks and then three to four times weekly will lower the facial germ count and reduce acneiform eruptions and styes.
      • P.85

      • Certain systemic antibiotics also inhibit lid inflammation by decreasing production and activation of cytokines, nitric oxide, and matrix metalloproteinases. Doxycycline or minocycline 100 mg p.o. qd with a meal not containing calcium (which inactivates these drugs), oxytetracycline 250 to 500 mg p.o. bid (less convenient) on an empty stomach, or erythromycin 250 mg p.o. bid for 12 to 24 weeks are all generally very effective at relieving symptoms of dryness, blurring, itching, and photosensitivity and reducing inflammation and rosacea.
      • Metronidazole 1% gel (Metro Gel) bid to the facial skin and lid margins for 9 to 12 weeks is effective adjunctive rosacea therapy. Repeat all above as necessary.
      • Steroids. The inflammatory and vascular aspects of the lids and keratitis are extremely sensitive to low doses of topical steroid. Steroids must be used with caution, however, because there is a tendency for ulceration that may perforate. It is probably best to limit any steroid treatment to lotoprednol 0.2% or fluoromethalone 0.1% qd to bid.
      • Picrolimus (Elidel) cream or tacrolimus (Protopic) 0.03% ointment to the lids and periorbital tissues bid is effective in atopic dermatitis/blepharitis such as in excema.
    • Corneal marginal infiltrates and ulcerations that occur with chronic staphylococcal blepharoconjunctivitis respond to mild topical steroids with antibiotic cover, usually within 4 or 5 days. See IV.B.2.
    • Hordeolum, a tender, sometimes fluctuant lid margin nodule, is commonly seen with chronic blepharitis and may be multiple. Internal hordeola are inflammatory or infectious nodules in the meibomian glands, and external hordeola are the same but in the glands of Zeiss or lash follicles. Many will resolve within 2 weeks with warm compresses, lid hygiene, manual expression, and topical bacitracin tid or trimethoprim-polymyxin drops (Polytrim) qid. A nonresolving internal hordeolum becomes a chalazion, a chronic granulomatous nodule. Treatment is intralesional injection of 0.1 mL of triamcinolone 25 mg/mL to 40 mg/mL, or incision and drainage (vertical cut along the tarsal conjunctiva). As depigmentation may occur with dark-skinned patients, incision is probably the better choice for them. The steroid injection may be repeated if necessary. Meibomian gland carcinoma should be considered in the event of recurrence or nonresponse to therapy.
  • Catscratch fever (Parinaud ocular glandular syndrome, bartonellosis) responds well to doxycycline 100 mg p.o bid. Erythromycin 250 to 500 mg p.o. qid, or azithromycin (per ID consult) are effective and may be combined with adjuvent rifampin 300 mg p.o. bid for more severe infections. Duration of treatment is 2 to 4 weeks in immunocompetent patients and 4 months in immunocompromised patients
IV. Corneal infections and inflammation (keratitis and keratoconjunctivitis)
  • Superficial keratitis includes inflammatory lesions of the corneal epithelium and adjacent superficial stroma. Although some of the changes described in this section can be produced by noninflammatory conditions and therefore would more appropriately be considered keratopathy, they are considered here because of their diagnostic importance. The etiologies of this clinical condition include numerous infective, toxic, degenerative, and allergic conditions that can often be characterized by the morphology and distribution of the lesions produced. These conditions may occur with bacterial, viral, and fungal infections. Degenerative states resulting from dry eye, neurotrophic defects, or in association with systemic disease can also produce ulceration of the cornea. When accompanied by infiltration or significant ocular anterior chamber reaction, infection must be excluded or diagnosed and treated.
    • Morphology. The lesions include punctate epithelial erosions that are focal defects in the corneal epithelium, best visualized by rose bengal and fluorescein
      P.86

      staining and slitlamp biomicroscopy. Punctate epithelial keratitis is characterized by focal inflammatory infiltration of the epithelium, resulting in minute opaque epithelial lesions observed in focal illumination or with the slitlamp. Although they may occur without staining, they often do stain with rose bengal or fluorescein because of associated punctate epithelial erosion. Punctate subepithelial infiltrates are nonstaining focal areas that occur as semiopaque spots in the superficial stroma.
    • Identification of the morphology and distribution of the lesions is greatly enhanced by the use of clinical vital stains, most notably rose bengal, lisamine green and fluorescein. Rose bengal and lissamine green stain dead or degenerating cells or cells without their normal mucin surface and are available as sterile paper strips (wet with saline, not proparacaine). Prior instillation of proparacaine 0.5% will relieve the smarting sensation produced by rose bengal, but tetracaine and cocaine should be avoided because they will often produce an artifactual rose bengal staining pattern. Rose bengal and lissamine green are also excellent stains for mucus and filaments. Fluorescein in combination with an anaesthetic solution (Fluress) or from a Fluri-strip wet with saline will stain epithelial defects or bared basement membrane and is also used when highlighting corneal filaments.
    • The distribution of the epithelial and subepithelial lesion is of diagnostic value. Figure 5.1 summarizes the six clinical patterns and their respective etiologies. Diffuse and nonspecific punctate epithelial erosions may occur with early bacterial or viral infections of many types. Breakdown of microcystic areas of epithelial edema can also produce this pattern, and such areas of edema will also demonstrate areas of negative staining in the fluorescein film corresponding to intact epithelial microcysts. Any toxic reaction to topical medications, chemicals, or aerosol sprays can produce this pattern. Mechanical trauma from a foreign body or eye rubbing must also be considered. The epithelial erosions secondary to molluscum contagiosum of the lids will occur in areas contiguous to the lesion. Inferior punctate epithelial erosions frequently result from staphylococcal blepharitis or blepharoconjunctivitis and are often accompanied by epithelial keratitis and subepithelial infiltrates. Trichiasis or incomplete lid closure (exposure keratopathy) can produce this distribution of erosion, and the pattern is also occasionally seen in dry eye patients. The interpalpebral distribution is typical of keratitis sicca, ultraviolet radiation exposure, chronic exposure, or incomplete blinking. Conjunctival staining usually will accompany the corneal lesion. Episodic recurrent erosions frequently will occur in the inferior area or interpalpebral area. The superior distribution of epithelial erosion is typical of superolimbic keratoconjunctivitis but can also be seen in vernal conjunctivitis and with trachoma. Corneal epithelial filaments (filamentary keratitis) consisting of coiled epithelial remnants and adherent mucous strands may be associated with any of these patterns, but most typically appear with superolimbic keratoconjunctivitis or keratoconjunctivitis sicca. Central lesions, with or without some peripheral punctate, suggest contact lens malfit or overwear, and linear lesions suggest a foreign body on the lid rubbing the cornea.
    • The etiology of punctate epithelial erosion is often local desiccation. Instability of the tear film results in focal dry spots and epithelial breakdown. Epithelial membrane damage from detergent chemicals, liquid solvents, quaternary amines, and a variety of drugs also results in erosions. Superficial viral and chlamydial infections can produce focal erosions, as can the epithelial hypoxia of contact lens overwear. Punctate epithelial keratitis with minute focal opacities is typical of viral keratitis, especially that associated with epidemic keratoconjunctivitis of adenovirus, but may also be seen with staphylococcal and chlamydial infections. The infiltrates also occur with vaccinia, Reiter syndrome, and acne rosacea. The coarse, granular infiltrates of punctate epithelial keratitis are quite characteristic of Thygeson superficial punctate keratitis.
    • Nonstaining punctate subepithelial infiltrates in the superficial stroma are sometimes seen after such entities as adenoviral, herpes simplex, herpes zoster,
      P.87

      Epstein-Barr viral, vaccinial, chlamydial, Reiter, Lyme disease, and rosacea keratitis. Staphylococcal infection must be considered when this pattern appears in a marginal infiltrate distribution. Inferior peripheral limbal infiltrates can accompany acute H. influenzae conjunctivitis.
      Figure 5.1. Staining patterns of the cornea and conjunctiva in various disease states. TRIC, trachoma-inclusion conjunctivitis.
  • Bacterial corneal ulcers. Risk factors include contact lens wear, abnormal corneal surface, poor immune defense, trauma, topical steroids, and herpes.
    • Central ulcer. Predominant causes of central bacterial keratitis are Staphylococcus (e.g., S. aureus and S. epidermidis), Streptococcus (e.g., S. pneumococcus and groups A–G Streptococcus), other Gram-positive organisms (e.g., Bacillus and Propionibacterium sp), the Gram-negative organisms Haemophilus, Pseudomonas, and Moraxella, and other Enterobacteriaceae (e.g., Proteus, Serratia,
      P.88

      E. coli, and Klebsiella
      ). Mycobacterium chelonae keratitis may follow laser-assisted in situ keratomileusis (LASIK) surgery. Gram-negative diplococci are an uncommon cause of corneal ulceration except in inadequately treated cases of hyperacute gonococcal conjunctivitis. Infection of the cornea usually tends to occur after injury to the epithelium or in compromised hosts, except for Neisseria and Corynebacterium, which may invade intact epithelium. Stromal infiltration in an area of an epithelial defect with surrounding edema and folds associated with endothelial fibrin plaques or anterior chamber reaction is usually indicative of microbial infection. Staphylococcal ulcers are often more localized, whereas pneumococcus may produce a shaggy undermined edge of an ulcer that is associated with a hypopyon. A destructive keratitis with rapid necrosis and adherent mucopurulent discharge is highly suggestive of Pseudomonas, Streptococcus, or anaerobic infection. Other uncommon causes are Nocardia and non–spore-forming anaerobes. Infectious crystalline keratopathy is an indolent, noninflammatory branching crystalline growth commonly associated with Streptococcus viridans, but also reported with Peptostreptococcus sp, S. epidermidis, H. influenzae, and two fungal species. There is also often a history of local ocular trauma, contact lens use, steroid use, and/or chronic antibiotic administration. Response to antibiotic therapy is very slow and may fail. Surgical intervention with neodymium:yttrium, aluminum, garnet (Nd:YAG) laser disruption (e.g., 3.2 mJ × 30) creates diffuse haze of the protective glycocalyx matrix within the intrastromal crystals, making the bacteria drug-susceptible. This should be considered before more extensive surgical steps are taken.
    • Marginal ulcers. The corneal limbus contains many antigen-presenting cells that mobilize T-lymphocytes to produce immune peripheral corneal infiltrates with or without ulceration. These usually sterile superficial white infiltrates are a hypersensitivity reaction seen most commonly with staphylococcal blepharoconjunctivitis but may also be seen with contact lens wear, trauma, and endopthalmitis. They are located 1 mm inside the limbus leaving a clear zone to the limbus. The ulceration must be distinguished from the Mooren ulcer and the peripheral ulceration seen with collagen vascular diseases such as rheumatoid arthritis. Moraxella sp has also been described as producing ulcers that extend to the limbus, especially inferiorly. Treatment is topical antibiotic with or without mild steroid for 7 to 10 days.
    • Laboratory tests similar to those for hyperacute conjunctivitis (see Section III.C) apply also to bacterial corneal disease.
      • Cultures are performed after instillation of topical proparacaine 0.5% (tetracaine, benoxinate, and cocaine are more likely to interfere with recovery of the organisms) and should obtain as much material as feasible, particularly from the deeper areas and the margin of the ulcer, using a sterile broth or saline-moistened calcium alginate or dacron–rayon swab. Organism recovery is much higher when alginate or Dacron swabs are used rather than cotton swabs or spatulas. Cultures are done on meat broth, blood agar plates (at room temperature and 38°C), chocolate agar, thioglycolate broth, and Sabouraud agar-broth (fungus), and Page’s medium (Acanthamoeba), if suspected. Scrapings taken from a nonnecrotic area may be examined microscopically with Gram and Giemsa stains. Because 30% to 40% will be negative even if infection is present, these scrapings may be judiciously omitted.
      • Corneal biopsy is often diagnostic in cases that progress despite seemingly adequate treatment; even if an organism has been identified, another may have been missed. In the minor operating room or at the slitlamp, after local anesthesia (drops or xylocaine block), a 2 to 3 mm sterile disposable dermatologic trephine is advanced to partial depth into the anterior corneal stroma, taking both clinically infected and adjacent clear cornea. The base is then undermined with a surgical blade to complete the lamellar keratectomy.
    • Treatment of central bacterial ulcers is based on clinical impression and results, if any, of the scraping. Coverage should be broad, intensive, and
      P.89

      amenable to change when final culture and sensitivity reports are available. Contact lens wearers with central corneal ulcers should particularly be covered for Pseudomonas (q1h fortified tobramycin, netilmicin, and/or a quinolone [moxifloxacin, levofloxacin] for broader-spectrum cover). Antibiotic treatment of infectious corneal ulcers must be aggressive using fortified solutions (made up by compounding pharmacists), and patients should be kept under close observation to prevent serious scarring or frank perforation. Initial antibiotic therapy may be guided by the results of the Gram stain of the corneal scraping, but broad-spectrum therapy should be used (see Tables 5.5, 5.6, and 5.7 and Appendix B for detailed lists of drug indications, dosage, and routes of administration).
      TABLE 5.5 Initial Topical Antibiotic Therapy of Bacterial Keratitis Based on Gram-stain Findingsa
      Bacterial type Drugs of choice (fortified) Alternative drugs (fortified and nonfortified)
      Gram-positive cocci Cefazolin, 100 mg/mL,
      Moxifloxacin,b,c
      Gatifloxacin,b,c
      Vancomycin, 25 mg/mL (MRSA)a
      Bacitracin, 10,000 U/mL
      Ciprofloxacin,b,c ofloxacin,b,c or levofloxacinb,c
      Gram-positive bacilli (filaments) Penicillin G, 100,000 U/mL Vancomycin, 25–50 mg/mL
      Bacitracin, 10,000 U/mL
      Gram-positive rods Tobramycin, 14 mg/mL Gentamicin, 14 mg/mL
      Gram-negative cocci Ceftriaxone or ceftazidime, 50 mg/mLd
      Moxifloxacinb,c,d5 mg/ mL
      Levofloxacin,b,c,dGatifloxacin,b,c Ofloxacin,b,c,dor Ciprofloxacinb,c,d3 or 5 mg/mL
      Gram-negative bacilli Moxifloxacinb,c,dplus
      Tobramycin, 14 mg/mL or
      Ceftazidime, 50 mg/mLdor
      Ticarcillin, 6 mg/mL
      Gentamicin, 14 mg/mL or Amikacin, 10 mg/mL (replace tobramycin)
      Ciprofloxacin,b,c ofloxacin,b,c gatifloxacin, or levofloxacinb,c in place of moxifloxacin
      No organisms seen, but bacteria suspectede Cefazolin, 100 mg/mL, plus tobramycin 14 mg/mL or moxifloxacinb,c,d Gentamicin, 14 mg/mL, or amikacin, 10 mg/mL, plus vancomycin, 25 mg/mL, or bacitracin, 10,000 U/mL (MRSA suspected)a or other quinolone
      aSee also Table 5.7 for dosage and preparation of fortified drops and subconjunctival doses, and Appendix B for expanded drug dosage list and organism-susceptibility guide. MRSA = methicillin-resistant Staph. aureus Subconjunctival and systemic therapy use is based on extent of disease (see Table 5.7).
      bDrops available as commercial ophthalmic preparations.
      cNot available in fortified form. Commercial strength only. Systemic therapy should be used in addition to local treatment for Neisseria or Hemophilus infection (see Section III.D.2).
      dNot U.S. Food and Drug Administration approved for topical therapy of Neisseria.
      eSmall to medium peripheral infiltrates may be treated with a quinolone (moxifloxacin, ofloxacin, levofloxacin, ciprofloxacin).
      • Gram-positive cocci. In mild to moderate infections, frequent topical therapy alone may be used, but it may be advisable to give subconjunctival therapy as well in severe infections, or apply a collagen contact lens soaked 10 minutes in fortified antibiotic solution (see Section IV.B.6).
        P.90

        TABLE 5.6 Subsequent Therapy for Most Common Culture-Identified Bacterial Ulcersa
        Organisms Topical Subconjunctivala
        Pseudomonas Tobramycin, 14 mg/mL, or amikacin, 10 mg/mL, and moxifloxacin Tobramycin, 40 mg (1 mL), amikacin, 25 mg, or ticarcillin, 100 mg
        Staphylococcus Cefazolin, 100 mg/mL, vancomycin,c 25–50 mg/mL, or bacitracin, 10,000 U/mL and/or a quinolone Cefazolin, 100 mg, oxacillin, 100 mg, or vancomycin, 25 mg (MRSA)
        Proteus, Enterobacter, Escherichia coli, Klebsiella, Acinetobacter Tobramycin, 14 mg/mL, gentamicin, 14 mg/mL, amikacin, 10 mg/mL, or ceftriaxone, 50 mg/mL, and/or a quinolone Tobramycin amikacin, 25 mg, or carbenicillin, 100 mg
        aSee Appendix B for parenteral use of these and other drugs and organism-susceptibility guide. See Table 5.7 for method of preparation of fortified drops and subconjunctival doses.
        bUncooperative patient or pending of actual scleral involvement. Add systemic antibiotics.
        cMRSA = Methicillin-resistant organisms.
        • Coupled fortified cephalosporin–aminoglycoside therapy is common. Topical cefazolin solution, 100 mg/mL, should be used q1min for five doses to achieve high stromal levels quickly and then q1h 24 hours per day or 16 times per day with a polymyxin–bacitracin ointment HS depending on severity of disease. Tobramycin is often effective against Staphylococcus, but poorly effective against pneumococcus or other Streptococcus. Fortified drops of one of these aminoglycosides are used in the same regimen as cefazolin to cover any Gram-negative organisms that may be revealed only by culture. Vancomycin (14 to 25 mg/mL) or bacitracin (10,000 U/mL) is effective in Gram-positive coccal and bacillus infections, and especially methicillin-resistant Staphylococcus, where cephalosporins would fail. As Streptococciare variably sensitive to second generation quinolones such as cipro and oxyfloxacin, cell wall-active agents such as bacitracin, cefazolin, or vancomycin are preferable. Drops are tapered over a 1- to 2-week period to qid for 3 weeks more as indicated. Other Gram-positive coverage is with cefuroxime, cefazolin or neomycin while Gram-negative cover is achieved with gentamicin, amikacin, ceftazidime, levofloxacin or ofloxacin. For methicillin-resistant organisms, vancomycin (25 mg/mL) is the drug of choice, with linezolid (25 mg/mL) as an excellent alternative in cases of vancomycin-resistance. Intraocular penetration of linezolid 600 mg p.o. is in excess of the MC90 of Gram-positive bacteria, including vancomycin-resistant enterococcus, MRSA, and streptococcal species, after 2 doses 12 hours apart. Trimethoprim-sulfamethosazole (Bactrim DS) 1 p.o. bid × 10 to 21 days with drops (Polytrim) q1h by day to qid is also effective in MRSA infections.
        • Single-agent broad-spectrum drops of the quinolones may be used alone (moxifloxacin, gatifloxacin, levofloxacin, ciprofloxacin–although the latter two have an increasing incidence of resistance). More severe ulcers should probably be treated at least initially with fortified double agents such as cephazolin and tobramycin (Section IV.B), but a quinolone may be substituted when the situation is under control and organism(s) known, as they are highly effective an commercially available. Organisms covered are similar to those for cefazolin or vancomycin and an aminoglycoside and include the microbes listed in Section III.B.1.
          P.91

          TABLE 5.7 Preparation of Antibiotics for Fortified Topical and Subconjunctival use
          Antibiotic (i.m. or i.v. Formulation) Commercial Solution Fortified Topical Drops Subconjunctival
          Diluenta (mL) Added to 1.0 mL Commercial Solution Final Concentration Shelf Life (4°C)b (d) Diluent (mL) Volume of Added to 1.0 mL Commercial Solution Final Concentration Final Dose
          Amikacin 100 mg/1 mL 9.0 10 mg/mL 30 1.0 50 mg/mL 25 mg–50 mg
          Bacitracin 50,000 U/5 mL 10,000 U/mL 7 10,000 U/mL 5000 U
          Carbenicillin 1.0 g/10 mL 24.0 4 mg/mL 3 100 mg/mL 100 mg
          Cefamandole 1.0 g/7.5 mL 133 mg/mL 4 0.3 100 mg/mL 100 mg
          Cefazolin 1.0 g/10 mL 2.0 33 mg/mL 10
          Cefazolin 1.0 g/7.5 mL 133 mg/mL 10 0.3 100 mg/mL 100 mg
          Ceftriaxone 1.0 g/7.5 mL 133 mg/mL 10 0.3 100 mg/mL 100 mg
          Chloramphenicol 1.0 g/10 mL 19.0 5 mg/mL 7 100 mg/mL 100 mg
          Gentamicin 80 mg/2 mL 1.8 14 mg/mL 30 40 mg/mL 20 mg–40 mg
          Penicillin G potassium 1 million U/mL 9.0 100,000 U/mL 7 1 million U/mL 1 million U
          Polymyxin B 500,000 U/20–50 mL 10–25,000 U/mL 3 10,000 U/mL 10,000 U/mL
          Ticarcillin 1.0 g/10 mL 16.0 6 mg/mL 14
          Tobramycin 80 mg/2 mL 1.8 14 mg/mL 30 40 mg/mL 20 mg–40 mg
          Vancomycin 500 mg/10 mL 1.0 25 mg/mL 14 50 mg/mL 25 mg
          i.m., intramuscular; i.v., intravenous.
          aWith the exception of carbenicillin and vancomycin (sterile water for injection only) and bacitracin (normal saline for injection only), diluent may be sterile water or saline for injection (USP), or sterile artificial tears using the original tears bottle to administer the reconstituted drug solution.
          b Freezing extends expiration time to 12 weeks for aminoglycosides, cephalosporins, and vancomycin; 4 weeks for ticarcillin.
        • P.92

        • Subconjunctival therapy is usually used only in severe cases or for uncooperative or unreliable patients. Because a 10% cross-sensitivity between cephalosporins and penicillin has been reported in penicillin-allergic patients, it is usually safer to proceed with vancomycin therapy. Subconjunctival injections are painful and best preceded by topical anesthetic (or general anesthetic when treating children) and adequate postinjection analgesics.
      • Gram-negative cocci (N. meningitidis, N. gonorrhoeae) and Haemophilus require systemic and topical therapy and are discussed under hyperacute conjunctivitis (see Section III.C). Topical therapy should be q1h for 2 to 4 days with taper over 2 to 4 weeks.
      • Gram-positive rods. These uncommon agents of ocular infection usually respond to systemic penicillin (see Appendix B). Bacillus sp are susceptible to moderate doses of penicillin; clostridial organisms require higher doses. Bacillus cereus infections may be extremely hard to treat, even using tobramycin, moxifloxacin, ofloxacin, norfloxacin, ciprofloxacin, or clindamycin. Topical drops and subconjunctival injections are used q1h. Tetracycline topically (compounding pharmacist) and orally is a useful adjunctive.
      • Gram-negative rods
        • Topical therapy initially should be fortified tobramycin ophthalmic solution q1min for five doses, then q1h for 3 to 6 days before starting slow taper. Important adjunctive therapy is topical ticarcillin 6 mg/mL, or carbenicillin 4 mg/mL, q1h. Treat Pseudomonas at least 1 month, or rebound infection may occur. Aminoglycoside-resistant strains are increasing. If Pseudomonas is gentamicin-resistant, a quinolone drop should be coupled with ticarcillin or carbenicillin, as above. If the strain is quinolone-resistant, amikacin is often effective.
        • Subconjunctival therapy, if used, should include tobramycin or amikacin 40 mg and carbenicillin 100 mg, each injected in a different area of the conjunctiva.
      • Anaerobic Gram-positive filaments (Actinomyces, Nocardia [formerly Streptothrix]) are sensitive to penicillins and tetracyclines.
      • Mycobacterium chelonae are acid-fast organisms culturable on Lownestein-Jensen medium. Ulcers are treated with a combination of oral and topical clarithromycin (10 mg/mL) or moxifloxacin or gatifloxacin. The drops are hourly around the clock to start with, then tapered over weeks. Oral doxycycline 100 mg bid is additive therapeutically for 4 to 6 weeks.
      • When no organisms are identified but bacterial etiology is strongly suspected on clinical grounds:
        • Topical therapy should be with fortified cefazolin q1min for five doses, then coupled with tobramycin 14 mg/mL q1h, at least 16 doses/day for 3 to 6 days before taper over 4 to 6 weeks. Use vancomycin in place of cepahzolin in severe cases and suspected methicillin-resistant or penicillin-allergic patients. See Gram-positive cocci above.
        • Subconjunctival therapy, if used, should be cefazolin 100 mg, plus tobramycin 40 mg, until culture results are available. A fortified antibiotic-soaked collagen lens (see Section IV.B.6) may also be effective adjunctively.
      • Systemic antibiotics are used if there is scleral extension of the infection or a threatened perforation. Levofloxacin 500 mg p.o. q24h or ofloxacin 200 mg to 400 mg p.o. q12h for 7 days both have excellent aqueous and vitreous penetration after oral dosing. A cephalosporin or vancomycin and an aminoglycoside may also be used p.o. or i.v., with doses given as in Appendix B. In cases of vancomycin resistance, which is an emerging problem, linezolid 600 mg i.v. or p.o. q12h is indicated. Optic neuropathy may be a complication of this route. Tables 5.5, 5.6, 5.7, and Appendix B summarize the recommended therapy. Therapy may be refined when culture and sensitivities return.
      • The antibiotic regimen is altered, if necessary, when final culture and sensitivity information is available. Fortified vancomycin and bacitracin are
        P.93

        used if MRSA are recovered. Most strains are also sensitive to linezolid, trimethoprim SMX, doxy- or minocycline but should be tested for sensitivity. Many MRSA strains are resistant to levofloxacin (and other quinolones) and erythromycin, as well as penicillins and cephalosporins. In the event that a suspected Gram-negative coccus infection was initially treated with penicillin and the subsequent culture results disclose Acinetobacter sp, penicillin should be discontinued because these organisms are often not sensitive to penicillin.
    • Other treatment modalities
      • Dilation. Long-acting cycloplegics such as atropine 1% or scopolamine 0.25% should be used if significant anterior chamber reaction is present. Initial instillation is usually required at least three times a day. If significant synechiae are forming at the pupillary margin, one or two doses of topical 2.5% phenylephrine are often indicated to ensure mobility of the pupil.
      • Corticosteroid use in treatment of infectious corneal ulcers is less controversial than in past years. It is probably unwise to use steroids until at least 24 to 48 hours of antibacterial treatment has been completed, or until the etiologic agent has been identified and shown to be sensitive to the antibiotics being used. Corticosteroid use is contraindicated if Pseudomonas or fungus are at all suspected. Both of these organism types tend to persist in low numbers for weeks after apparent clinical resolution. Low-dose topical corticosteroids (e.g., prednisolone 0.12% rimexolone or lotoprednol qid) have a place in limiting the inflammatory reaction once the clinician is satisfied that the antibiotic treatment is effective.
    • Collagen shields (Surgilens, Bausch & Lomb) are contact lenses initially developed to enhance corneal epithelial healing after surgery, trauma, or dystrophic erosions and filaments, but are also used as effective high-dose drug delivery systems (the lenses are not FDA approved as drug delivery systems). The lenses come in two sizes and dissolve spontaneously over 24 to 72 hours. Soaking the lenses in antibiotics, such as tobramycin 40 mg solution for 10 minutes, results in a 30-fold increase in antibiotic penetration into the aqueous compared to subconjunctival injection or a regular therapeutic soft contact lens (TSCL) and q1h drops. The high level of drug may be maintained with q4h drops using the collagen shields.
    • Special pediatric considerations. Subconjunctival therapy is usually not feasible unless the child is under general anesthesia at the time of a corneal culture and scraping. Should systemic medication be considered necessary, it is best done with the consultation of a pediatrician or internist. See Appendix B for dosages and organism indications.
    • Signs of clinical improvement include decreased density of the infiltrate, increase in discreteness of infiltrate edge, less stromal edema and endothelial plaque, and, if present, corneal thinning stops.
  • Chlamydia (trachoma-inclusion conjunctivitis) organisms are obligate intracellular bacteria having enzyme systems similar to bacteria. They can produce acute inflammatory diseases of the conjunctiva and cornea that will often progress to a more chronic follicular conjunctivitis. Infection with inclusion conjunctivitis usually takes different forms in children and adults (see also Chapter 11).
    • Neonatal inclusion conjunctivitis (inclusion blennorrhea) has an acute onset 5 to 12 days after birth, presenting as an acute conjunctivitis with purulent discharge.
      • Organisms that may cause neonatal bacterial conjunctivitis include Chlamydia trachomatis, Streptococcus viridans, Staphylococcus aureus, Hemophilus influenzae, Moraxella, Escherichia coli, other Gram-negative rods, and Neisseria gonorrhoeae.
      • Clinical presentation includes mucopurulent discharge, conjunctival membranes, and no follicular response.
      • Diagnosis of neonatal Chlamydia trachomatis infection is facilitated by the presence of intracytoplasmic inclusion bodies apparent in epithelial cells
        P.94

        obtained by conjunctival scraping. Giemsa stain is the most effective method for demonstrating the individual elementary bodies or larger initial bodies as basophilic inclusions with, at times, small eosinophilic opacities. It is obviously important to distinguish this infection from N. gonorrhoeae. Although the infection can resolve without sequelae, a membranous conjunctivitis may develop and result in conjunctival scarring, and a definite keratitis may supervene with superficial corneal vascularization.
      • Treatment is topical 10% sulfacetamide or erythromycin qid and systemic. Erythromycin 12 mg/kg p.o. or i.v. daily in four divided doses for 2 weeks is the preferred therapy in newborns. Oral sulfisoxazole is the alternative drug (see Appendix B). Children under 8 years of age should not receive systemic tetracyclines. Because the condition is acquired by the presence of Chlamydia in the birth canal, it should be assumed that the parents are infected and probably require treatment with systemic tetracycline to eliminate the source of the infection. If the mother is breast-feeding, erythromycin 250 mg p.o. qid or sulfonamides 500 mg p.o. qid should be used for 21 days (see Section IV.C.2.b).
    • Adult inclusion conjunctivitis usually presents as an acute follicular conjunctivitis mot prominent in the lower fornix with a little mucopurulent discharge and preauricular adenopathy occurring after an incubation period of 4 to 12 days. The disease usually occurs in sexually active young adults but may occur in senior citizens as well, often after having acquired a new sexual partner in the preceding 2 months. The acute conjunctivitis often evolves into a chronic follicular conjunctivitis. An epithelial keratitis may develop, as well as marginal and more central corneal infiltrates accompanied by superficial vascularization as an inferior limbal pannus. Iritis has been reported later in the condition, as well as Reiter syndrome. Untreated disease often resolves in 6 to 18 months.
      • Diagnosis by Giemsa-stained scraping of the epithelium is less likely to show inclusion bodies, but these may be seen in a number of patients with the acute disease. Microtrak assay of scrapings is far more reliable diagnostically, but any culture or immune laboratory test may still have false positives or negatives.
      • Treatment. Systemic azithromycin is more effective and efficient than either erythromycin or tetracycline and is given as 1 g p.o. for single dose. Alternative first-line therapies are doxycycline 100 mg p.o. bid with a meal, or tetracycline 250 to 500 mg p.o. qid 30 minutes before meals or 2 hours after meals, sulfisoxazole 500 mg p.o. qid, or erythromycin 500 mg p.o. qid for 7 days. Sulfonamides are also effective. Topical antibiotics are relatively ineffective in treating the eye disease, but may modify a conjunctivitis. Because the condition may be associated with an asymptomatic venereal infection, partners should also be treated systemically and the possibility of other venereal disease must be excluded. Tetracyclines should not be used in women who are pregnant or breast-feeding. Azithromycin 1 g p.o. qd for 2 days, erythromycin 250 mg p.o. qid, or sulfisoxazole 500 mg p.o. qid for 7 days are effective alternatives. High-dose amoxicillin may be used in pregnancy (Appendix B).
    • Trachoma, the most common preventable cause of blindness, is a disease of communities with poor hygiene affecting 150 million of the world’s population. Transmission is by flies and household fomites. The initial manifestation of trachoma is a chronic follicular conjunctivitis that is classically more marked on the upper tarsal plate, with progressive disease scarring of the conjunctiva occurring on the superior tarsal conjunctiva as fine linear scars and often as a transverse band of scar (Arlt line). When marked, this scarring can lead to entropion and trichiasis, with secondary ocular surface breakdown, including corneal ulceration. Primary corneal involvement occurring with the conjunctivitis can include an epithelial keratitis, marginal and central corneal infiltrates, and superficial vascularization. This is usually more pronounced on the upper half of the cornea and can appear as a fibrovascular pannus. Follicle formation
      P.95

      at the limbus regresses to sharply defined depressions (Herbert pits) at the base of the pannus.
      • The disease, as classically described by MacCallan. considers the conjunctival changes according to the following classification:
        • Trachoma I. Immature follicles on the upper tarsal plate including the central area, but without scarring.
        • Trachoma II. Mature (necrotic or soft) follicles on the upper tarsus obscuring tarsal vessels, but without scarring.
        • Trachoma III. Follicles present on the tarsus and definite scarring of the conjunctiva.
        • Trachoma IV. No follicles on the tarsal plate but marked scarring of the conjunctiva. This infection is not commonly seen in developed countries, but only the United Kingdom and some parts of Europe are totally free of endemic disease.
      • Treatment. Azithromycin 1 g p.o. qd single dose is efficient, effective, but expensive therapy. Individual patients with trachoma will also respond to a 3-week course of either tetracycline or erythromycin p.o. in full dosages (250 mg qid) along with topical 1% tetracycline or erythromycin ointment. Clinical response may be slow, and prolonged treatment may be required. When large groups are treated, topical tetracycline or erythromycin ointments may be given twice daily for 2 months. When systemic treatment is used, tetracycline should be used in preference to oral sulfonamides due to the lower incidence of side effects with tetracycline (see Sections IV.C.1 and C.2 for further therapy information).
  • Herpes simplex virus (HSV) keratoconjunctivitis and iritis. Ocular infections with herpesvirus are the most common infectious cause of corneal blindness in the developed world. Primary ocular herpes is rare and usually occurs as an acute follicular keratoconjunctivitis with regional lymphadenitis, with or without vesicular ulcerative blepharitis or cutaneous involvement. The keratitis can occur as a coarse punctate or diffuse branching epithelial keratitis that does not usually involve the stroma. The condition is self-limited, but the virus establishes a latent infection in the trigeminal ganglion. It may reactivate under various forms of physical stress (recent fever, flu, or surgical or dental procedures), possibly with the prostaglandin analogs used in glaucoma therapy, as well as with any form of ocular laser treatment, and cause recurrence of the disease in a host who has both competent cellular and humoral immunity. Recurrent disease of the anterior segment may occur as one or a combination of the following: epithelial infectious ulcers, epithelial trophic ulcers, stromal interstitial keratitis (IK), stromal immune diskiform keratitis, and iridocyclitis. Management of this disease, with its chronic recurring and often progressive nature, can be difficult and must be tailored to minimize permanent ocular damage.
    • Epithelial infection. Dendritic or geographic ulceration of the cornea is caused by live virus present in intracellular and extracellular locations, particularly in the basal epithelium. Patients with poorly controlled diabetes or atopy, especially eczema, generally require longer therapy with higher antiviral dosage and sometimes require both oral and topical antiviral therapy. The use of steroids in purely infectious epithelial disease serves only to make the ulceration spread and to prolong the infectious phase of the disease. Fluorescein or rose bengal staining make the ulcers easier to see.
      • Topical antiviral therapy is effective but less convenient than oral antivirals with possible patient compliance problems. Trifluridine 1% solution nine times a day for 5 days, then 5id for 9 to 21 days, or vidarabine 3% ointment (compounding pharmacist) qid to 5id arrests viral replication until infected cells slough from the eye. Limbal ulcers are more resistant to healing, but eventually close without much scarring. HSV infections in human immunodeficiency virus-positive (HIV positive) patients show a predilection for peripheral versus central involvement, moderately prolonged course with mean healing time of 3 weeks with topical antivirals, rare stromal
        P.96

        involvement, and tendency to frequent recurrence (more than two times per year). With prolonged treatment, the topical antivirals can produce a toxic punctate keratopathy, retardation of epithelial healing, superficial stromal opacification, follicular conjunctivitis, or lacrimal punctal occlusion.
      • Systemic antiviral acyclovir is becoming the treatment of choice for many physicians as an off-label use of this drug. It is FDA-approved for other forms of H. simplex and zoster. A dosage of 400 mg p.o. tid to 5id (atopy, immunocompromised) for 10 to 21 days delivers high-titer therapeutic doses in tear film and aqueous for treatment of acute infectious epithelial HSV in those patients for whom topical therapy is difficult (those with severe arthritis or in children) or those who prefer pills to drops. Pediatric dosing ranges from 20 mg/kg/day to 40 mg/kg/day in suspension form (200 mg/teaspoon). Post-HSV keratoplasty dosage of 400 mg bid for 18 months is indicated therapy and may successfully prevent recurrent infection and graft rejection. Both epithelial and stromal recurrences are inhibited by 400 mg bid. This long-term prophylaxis is recommended for use in patients with stromal keratitis and therefore at risk of recurrent scarring stromal disease. Infectious epithelial dendro-geographic ulcers are generally treated by individual recurrences unless scarring occurs, in which case long-term prophylaxis is given. Prophylactic treatment is usually given for 1 year, but may go significantly longer (genito-urinary HSV prophylaxis goes for 8 years or longer). Acyclovir is equivocally effective in iritis and not generally used.
      • Systemic antiviral famciclovir and valacyclovir are highly effective off-label alternatives to acyclovir. Dosage is famciclovir 125 mg to 250 mg p.o. tid for 10 to 21 days or valacyclovir 500 to 1 g p.o. bid for 10 to 21 days. For long-term prophylactic viral suppression, dosages are 125 mg p.o. qd to bid and 500 mg p.o. qd to bid, respectively. Valaciclovir should not be used long term in immunosuppressed patients because of potential myelosuppression.
      • Acyclovir 3% ophthalmic ointment, applied five times a day, is available outside of the United States.
    • Episcleritis or scleritis may be recurrent but are usually responsive to tapered topical NSAIDs, such as nepafenac (Nevanac), ketorolac (Acular, and others (see Appendix A) qid or topical steroids with slow taper.
    • Neurotrophic keratopathy (NTK) and trophic ulceration (persistent epithelial defect, PED). One result of herpetic infection (simplex and zoster) is the damage to the subbasal neural plexus just beneath the epithelium with subsequent loss of epithelial and neural growth factors critical to cellular growth and healing after an infectious or immune recurrence. A key sign of NTK is partial or complete corneal anaesthesia often associated with unhealthy epithelium and reduced tear volume and stability. If lubricant and other protective therapy is not begun at this point, and sometimes despite it, an indolent sterile epithelial defect with thickened borders can occur at the site of a previous herpetic ulcer and be confused with infectious geographic ulcer. These PEDs are often associated with damage to the basement membrane as well as the neural damage sustained during the acute infectious epithelial stage. The membrane heals extremely slowly over many weeks to months, and there may be very little healing of the neural plexus, resulting in an abnormal corneal surface prone to insult and stubborn ulceration.
      • Treatment. Because of the mechanical/physiologic nature of the problem, treatment is designed to protect and reinstate as much as possible the ocular surface. Preservativefree (PF) or oxidative preservative artificial tears, gels, and tear ointments or cominations thereof four to eight times daily are essential. Any lid exposure problems must be corrected and inflammatory lid disease such as MGD treated with lid hygiene and systemic doxy- or minocycline (see Section III.C.3). These two drugs also inhibit matrix metalloproteinases, thus inhibiting corneal melting and thinning If there is need for antibiotic therapy, ointments are PF, as are moxifloxacin drops. Other PF drops can be made by a compounding pharmacist. Mild steroid
        P.97

        such as FML, lotoprednol, or rimexolone qd to tid may also be used to calm inflammation that interferes with healing. Omega 3 fish oil, three capsules per day (1 dose) helps to stabelize the tear film in these eyes, which are often dry due to loss of the nasolacrimal reflex.
        If, despite preventive steps, the surface threatens to break or actually ulcerates, a high-water-content plano TSCL (Permalens, Kontur, Acuvue, Focus Day and Night) with antibiotic drops bid and worn for 3 to 6 months or longer is indicated. (see Section XI). Patching or lid taping are less successful, but lateral tarsorrhaphy is often an effective adjunct. Systemic doxy- or minocycline should be continued. PF artificial tears or gel are indicated for several months or indefinitely after the lens has been removed.
      • If active corneal thinning (melting) progresses, sealing off the ulcer with cyanoacrylate tissue adhesive (Dermabond, Epidermglu, Histoacryl; not FDA-approved for ocular use) should be considered. With the patient under topical anesthesia, the physician débrides and dries the ulcer and periulcer area of debris and loose cells with Weckcell sponges and applies the liquid adhesive in short strokes or concentric spots. It polymerizes almost instantly to the tissue. Sterile saline is dripped on the eye to complete polymerization, a Plano T TSCL is applied, and antibiotic drops are given bid. If needed for inflammation, steroids may now be used with greater safety. The cornea should heal and dislodge the glue in 1 to 3 months, usually leaving the eye quiet but scarred, and it is hoped that it will be amenable to transplant if vision is significantly compromised.
      • Autologous serum drops 20% solution in sterile saline four to eight times daily have also proved effective in healing indolent, nonhealing trophic ulcers. These may be made in a hospital pharmacy in collaboration with the blood lab. Serum contains such proteins as nerve and epithelial growth factors, missing in NTK corneas.
      • Amniotic membrane transplants (AMT), either in the form of an AMT contact lens (Pro-Kera, Biotissue, Miami) easily placed in minor surgery or a single or double AMT sutured in place, are proving to be excellent theraputic approaches if despite all attempts the ulcer does not heal or progresses.
    • Stromal interstitial keratitis (IK), immune rings, and limbal vasculitis result from antigen–antibody complement-mediated immune reaction in the stroma. Viral IK presents as necrotic, blotchy, white, indolent infiltrates of 10 with neovascularizaton, which may lie under ulcers or appear independently. Immune rings are gray anterior stromal Wessley rings, and limbal vasculitis is a local Arthus reaction. These lesions must be distinguished from secondary bacterial or fungal infections, which are usually much less indolent. After several weeks of smoldering inflammation, dense leashes of stromal vascularization may begin to advance into the cornea.
      • Therapy is suppression of immune damage. If the inflammatory infiltrates do not involve the visual axis or there is no active necrosis or neovascularization, steroid therapy may be avoided because the process often burns itself out spontaneously in weeks to months and, with the exception of limbal vasculitis, scars form despite steroid therapy. The vascularization regresses to leave ghost vessels. Treatment may be limited to lubricants.
        Generally, if corticosteroids have never been used in an eye, the clinician should try to do without them, because subsequent recurrences will then require reinitiation of steroids and treatment is prolonged over a taper period. However, if the inflammatory reaction is moderate to severe, if steroids have been used previously, if the visual axis is threatened, or if there is active necrosis or neovascularization, the use of steroids will speed resolution of the inflammation and decrease formation of scar tissue and deep vessel invasion that could later compromise success of surgery. The corticosteroid dosage is whatever controls the disease and may range from dexamethasone 0.1% q3h to prednisolone 0.12%, rimexolone, or lotoprednol every other day. Once hyperemia and edema begin to decrease, steroids should be
        P.98

        tapered downward over several weeks to several months. Prophylactic antiviral agents such as acyclovir 400 mg p.o. bid or famciclovir 125 bid should be used for one year or longer and daily antibiotics continued until steroid dose is reduced to the equivalent of prednisolone 1% bid unless the patient is prone to bacterial infections.
    • Diskiform keratitis results from a delayed hypersensitivity reaction characterized by sensitized T lymphocytes and macrophages reacting to viral antigen in the cornea. Clinically, there is a focal or diffuse, nonnecrotic disk-shaped area of stromal edema, often with focal keratic precipitates (endotheliitis) with no cells in the anterior chamber (no iritis). With progressive severity, more diffuse edema with folds in the Descemet membrane, neovascularization, and iritis may appear.
      Therapeutically, the same rules apply to treatment of diskiform keratitis as to viral IK (see Section IV.D.4). Oral antivirals will have no effect on active immune keratitis, but acyclovir 400 mg p.o. bid for 1 year or more inhibits recurrence of stromal inflammation. Famciclovir 125 mg p.o. bid or valacyclovir (in the nonimmunosuppressed patient) 500 mg p.o. per day to bid for 1 year are alternatives.
    • If diskiform stromal disease is present with an HSV- infected epithelial ulcer, gentle débridement of the epithelium and full antiviral therapy should be started a day or two before steroids or at least concomitantly. If the ulcer progresses despite antiviral therapy, steroid dosage should be reduced and antiviral therapy increased to oral and topical until the ulcer is under control and healing. If diskiform keratitis is combined with trophic ulceration, control of underlying stromal edema with low-dose topical steroids and the application of a TSCL will aid healing. A persistent epithelial defect carries the added risk of collagenase release, and steroids may enhance melting, with ultimate corneal perforation. (see Section IV.D.3).
    • Iridocyclitis, retinitis, and occasionally panuveitismay occur with herpes simplex infection. Intraocular inflammation may occur without concomitant keratitis but almost invariably accompanies active keratitis. Uveitis in an eye with previous herpetic keratitis should be considered herpetic until proved otherwise. (Therapy is discussed in Chapter 9, Section VIII.A.2). Prophylactic antivirals and antibiotic agents should be used with topical steroids and dilatation. If ulcerative keratitis supervenes, particularly if the cornea is melting, systemic steroids such as oral prednisone 60 mg to 80 mg per day for 2 to 3 weeks, may be substituted for part or all of the topical steroid regimen until the ulceration is under control.
    • Glaucoma is not uncommon and is usually due to inflammatory trabeculitis clogging the trabecular meshwork with monocytes. Pressures may go to the 50s fairly quickly but will respond quickly to topical steroid, such as prednisolone 1% qid followed by taper. If the patient is already on steroids, one must decide whether it is a steroid glaucoma or trabecultitis, as the treatments are the opposite. It is usually best to increase the steroid dose and see the patient in 2 to 3 days to check what the pressure is doing. If it is down, it is trabeculitis. If it is up, steroids need to be cut way back. Glaucoma drops may be started at any point if the physician feels the pressure must be taken down as quickly as possible. The pressure drop will be more dramatic if it is trabeculitis treated with steroids. Another cause of glaucoma not to be forgotten is synechial angle closure, especially if there has been iritis.
    • Steroid tapering. Special comment should be made regarding the gradual reduction and termination of steroid treatment. Because too rapid a steroid taper or abrupt cessation of treatment can often be accompanied by recrudescence of the inflammation, it is essential to carefully control the steroid dose. The rule of thumb is never taper steroids by more than 50% at any given time. Each level should be maintained for several days or, at lower doses, for several weeks depending on the severity of inflammation at the initiation of treatment and the therapeutic response. One method uses progressively decreasing strengths
      P.99

      of glucocorticoid such that, from the dexamethasone 0.1% or prednisolone 1% daily, tapered from four times down to once, prednisolone 0.12%, rimexolone, or lotoprednol solution can be used qid with gradual reduction to tid, bid, once a day, every 2 days, and so forth, until cessation of treatment. Occasionally, patients will require chronic low-dose (once or twice weekly) prednisolone to maintain a quiet eye. Coverage with antiviral medication should be continued for 1 year or longer to inhibit recurrent stromal disease.
    • Penetrating keratoplasty (corneal transplant) of the herpes simplex–scarred eye has about an 85% five-year success rate on first procedure in the quiet eye. Emergency surgery on inflamed eyes has a success rate of between 40% and 60%. Interrupted 10-O sutures, intensive topical steroids for several weeks, and acyclovir 400 mg p.o. bid for 18 months are factors favoring success. Famciclovir 125 mg or valaciclovir 500 mg bid are good alternative antivirals but more expensive. Full-dose oral antivirals are also critical if steroids are being used to treat an allograft rejection. See also Section IX.B.4 for management of graft rejection. The Boston keratoprosthesis has proved very effective in restoring vision and quieting inflammation in severely damaged corneas.
  • Herpes zoster ophthalmicus. Herpes zoster afflicts 20% of the world’s population with 11% being ophthalmic. It is an acute infection of a dorsal root ganglion by the varicella-zoster virus (VZV, chickenpox) usually characterized by vesicular skin lesions distributed over the sensory dermatome innervated by the affected ganglion. Regional lymphadenopathy with dermatomal pain is common. The ophthalmic (trigeminal ganglion, cranial nerve V) form of the disease usually presents with any of the following: VI headache, VI dermatomal vesicular dermatitis, lid or orbital cellulitis, conjunctivitis, episcleritis, scleritis, keratitis, iridocyclitis, and glaucoma. Chorioretinitis, extraocular muscle palsies and optic neuritis may also be seen (see Chapter 9). Herpes zoster is increasing in frequency due to the HIV epidemic, aging population, chemotherapy, increasing clinical depression, and adverse life circumstances in the population. This may soon decrease and certainly be greatly ameliorated with the release of the adult zoster vaccine, Zostavax (Merck), which lowers incidence and severity of shingles and post–herpetic neurlagia by 50% to 60%.
    • Conjunctivitis, episcleritis, and scleritis occur in about half of cases. Conjunctival involvement is common and may occur as watery hyperemia with petechial hemorrhages, follicular conjunctivitis with regional adenopathy, or severe necrotizing membranous inflammation. Scleritis or episcleritis may be diffuse or focal nodular. On resolution, scleritis can leave scleral thinning and staphyloma.
    • Keratitis occurs acutely in about 55% of all patients and may precede the neuralgia or skin lesions. It may occur as a fine or coarse punctate epithelial keratitis with or without stromal edema, or as actual vesicle formation with ulceration in a dendritiform pattern that can be mistaken for herpes simplex keratitis. VZV DNA is present from 2 to 34 days after acute onset, especially in patients over 66 years old (HIV negative). Delayed mucoid plaques resembling dendrites may occur months later and also contain VZV DNA. Corneal sensation is usually greatly reduced in herpes zoster keratitis due to Vth N. ganglionic damage and CNS spino-mesancephalic pain center damage in the pons and brain stem due to posterograde spread of virus and inflammation from the ganglionic branch to that area. Neurotrophic keratopathy with decreased or absent corneal sensation leading to trophic neuroparalytic ulcers may occur with melting and corneal perforation if the epithelial defect persists. Stromal keratitis, similar to herpes simplex, either immune diskiform or white necrotic IK, may occur with or independent of epithelial disease. See Section IV.D, earlier, under herpes simplex for greater detail on these forms of keratitis and their treatment.
    • Iridocyclitis is a frequent occurrence (45%) and may appear independent of corneal activity. After resolution of the acute perineuritis and vasculitis, there may be focal or sector atrophy of the iris. Hypopyon, hemorrhage into the anterior chamber (anterior segment necrosis), and phthisis bulbi may result from zoster vasculitis and ischemia.
    • P.100

    • Glaucoma may occur acutely or months later due to inflammatory trabeculitis. In later stages, synechial closure of the angle may also occur (see Section IV.D.7 and Chapter 10).
    • Postherpetic neuralgia and/or itch (PHN/PHI), defined as having either for longer than 1 month after the acute attack, are two common, distressing, and occasionally incapacitating consequences of zoster. Patients over 55 years presenting with severe pain and rash at onset are at greatest risk for permanent or prolonged neuralgia. Younger patients rarely have sustained pain. The neuralgias appear to result primarily from peripheral and CNS damage (spinothalmic pain path in brain stem and pons) resulting in an imbalance between the nociceptor pain fibers and their large fiber inhibitors, and ectopic firing of damaged nerves, as well as establishment of abnormal pain pathways to the cerebrum. Patients complain of lancinating, burning, and aching pain, as well as allodynia (pain without a painful stimulus) and sometimes intractable severe itch. Ninety percent of neuralgias resolve spontaneously over the first year, but treatment must be maintained during that time.
    • Therapy. Systemic antivirals (famciclovir, valacyclovir, and acyclovir) significantly decrease acute pain, stop viral progression and vesicle formation, and reduce the incidence and severity of acute and recurrent episcleritis, dendritic keratitis, and iritis if started within 72 hours of rash onset or continuing rash activity (new vesicles). Significant inhibition of PHN and PHI is established for famciclovir and valacyclovir. The following regimen is presently recommended for ocular management: Therapy is most effective if started using both oral antiviral and tricyclic antidepressant (TCA) therapy. If used in acute disease, the latter greatly inhibits development of PHN. Much of the therapy for zoster is similar to that of anterior segment herpes simplex. That section, IV.D, earlier, should also be referred to for greater detail of findings and therapy.
      • Antiviral drugs of choice, famciclovir (Famvir) 500 mg p.o. tid for 7 days or valacyclovir (Valtrex) 1 g p.o. tid for 7 days, are equal to acyclovir in acute disease and better in reducing late neuralgia or itch. A second-line drug is acyclovir (Zovirax) 800 mg tablet p.o. 5id (4,000 mg/day total) for 7 days in the immunocompetent patient. In very ill immunosuppressed patient, 5 to 10 mg per kg or 500 mg/m2 i.v. q8h for 5 to 7 days followed by 2 to 3 weeks of oral dosing is recommended. Brivudine 125 mg/day for 7 days is as effective as the above famciclovir and valaciclovir regimen, but currently is available only in Europe.
      • TCAs are highly effective in inhibiting acute and long-term pain, but success depends on how early in the illness they are started: 85% success if started immediately or within a few weeks, decreasing to 45% by year 1 start and 33% by year 2 start. Nortriptylene is best tolerated, desipramine next, and amitriptylene least tolerated. The drug should be started during acute illness if possible at 25 to 50 mg p.o. HS with increase over 2 to 3 weeks to 75 to 100 mg if needed and tolerated. These same dosages are used for long-term therapy of PHN if it does develop.
      • Systemic steroids are indicated in nonimmunosuppressed, nondiabetic patients with marked pain and/or orbital edema that could cause superior orbital fissure syndrome. Dosage is prednisone 20 mg p.o. tid to qid × 5 days, then 20 mg p.o. bid to tid × 5 days, then 20 mg p.o. q AM × 5 days, ending with 10 mg q AM for a total time of 2 to 3 weeks.
      • Topical steroids are prescribed only if needed for corneal diskiform immune edema or iritis (e.g., 1% to ⅛% [0.012%] prednisolone qid with gradual taper). Use cycloplegia and steroids for iritis. See Section IV.D, earlier, for more detail.
      • Topical antiviral Vidarabine 3% antiviral ointment (compounding pharmacist) is prescribed 5id for 7 to 14 days for recurring dendritic ulcers if they persist without therapy. Alternatives are trifluridine drops or p.o. antivirals. Response is variable, and the dendrites often self-resolve.
      • P.101

      • Topical antibiotic and nonpreserved artificial tears or gel are prescribed if the the tear film is unstable, the epithelium is unhealthy or ulcerated, or topical steroids are in use.
      • Lateral tarsorrhaphy, by suture, Botox ptosis, or a gold weight in the upper lid can be performed if the cornea is anesthetic, with frequent nonpreserved artificial tear lubrication to inhibit neurotrophic ulceration.
      • TSCLs are used for neurotrophic keratopathy (i.e., reduced corneal sensation with unhealthy epithelium or trophic ulceration. See Section IV.D.2 (herpes simplex), earlier, for details of treatment. Neovascular pannus may heal ulcerated corneas and should not be blocked with steroid therapy.
      • Cyanoacrylate tissue adhesive (glue, Dermabond, Epidermglu, Histoacryl; not FDA-approved for the eye—off-label use) may be used if there is corneal ulcer melting (thinning). Cover with a soft contact lens, and administer prophylactic antibiotics and lubricants (see Section IV.D.3 [herpes simplex], above for details).
      • For secondary glaucoma beta-adrenergic blockers, adrenergic agonists, antiprostaglandins, carbonic anhydrase inhibitors, and other nonmiotic agents are used to control pressure. If trabelulitis is suspected, prednisolone 1% qid should be started. Pressure drop should occur within 2 to 4 days if the diagnosis is correct. Mydriatic cycloplegics prevent synechiae (see Section IV.D.7 [herpes simplex] above for greater detail and Chapter 10, Section XVIII and Chapter 9).
      • PHN/PHI are often relieved in great part by TCAs (such as in Section IV.E.6, earlier). Therapy may last for years.
        • The anticonvulsants, Gabapentin (Neurontin) 600 mg p.o. bid to 6id, or pregabalin (Lyrica) 50 to 300 mg p.o. bid are two of the most effective anti-PHN therapies available and may be coupled with all other anti-PHN treatments.
        • Nonnarcotic or narcotic analgesics for neuralgia may be used to control pain for many months. Patients over 55 years presenting with severe pain and rash at onset are at greatest risk for permanent or prolonged neuralgia. Oxycontin-CR 10 to 40 mg p.o. q12h is commonly used and relieves allodynia and improves quality of life and sleep. Other agents are dihydrocodeine or tramadol in more frail patients.
        • Topical anaesthetics Lidocaine 5% ointment or EMLA cream (2.5% lidocaine-2.5% prilocaine) cream applied q4h to q12h as needed are excellent adjuncts for reducing or eliminating constant and paroxysmal pain, burning, itch, and allodynia. The lidocaine patch is awkward around the eye but is also very effective if it can be applied (12h on, 12h off).
        • Anaesthetic injections with bupivicaine to the supraorbital, infraorbital, and infratrochlear nerves with or without stellate ganglion block often results in weeks to many months of relief from otherwise intractable pain.
      • Penetrating keratoplasty (corneal transplant), keratoprosthesis. Corneas sufficiently scarred by herpes zoster to warrant keratoplasty for restoration of sight are usually sufficiently anesthetic and susceptible to repeated inflammatory reaction and nonhealing that they are a poor risk for surgical rehabilitation. Corneas with partial sensation are reasonable but still at-risk candidates for keratoplasty. If done, a lateral tarsorrhaphy and punctal occlusion should also be done and copious postoperative lubrication used. An apparently safer and more effective alternative is the Boston keratoprosthesis (K-Pro) that rapidly quiets an inflamed eye and gives good vision (provided the fundus is in good condition). Although not visually effective, the amniotic membrane transplant or conjunctival flap are effective for static or progressive melting defects if tissue adhesive has not aided healing. A K-Pro can be done later. (See Section IV.D.3.)
      • P.102

      • Bell’s palsy or Ramsay Hunt syndrome. Acute VII and VIII cranial nerve paralysis appear to involve to herpetic infection and should be treated with full p.o. antiviral therapy, acyclovir 800 mg po tid, and prednisone 40 to 60 mg/day for 14 days (1 mg/kg) (see Section V.D and E).
  • Varicella or chickenpox virus is the same organism that causes VZV, and is morphologically indistinguishable from HSV. It is decreasing greatly in incidence due to early vaccination of infants (Varivax), although breakthrough infections are now increasing in frequency.
    • The most common clinical manifestation of the virus, chickenpox, is a contagious disease, predominantly of children, transmitted by droplet infection and characterized by fever and papulovesicular rash that is usually self-limiting and uncomplicated. The infectious period is from 2 days prerash until crusting. Vesicular lesions may appear along the lid margin and eyelids during an episode of chickenpox and rarely may appear on the conjunctiva. Usually unilateral, small, papular lesions that can be contiguous with the lid margin, commonly occurring at the limbus, may resolve or form a punched-out dark-red ulcer with swollen margins, causing pain and inflammation in the eye. More rarely, the cornea may become involved, with superficial punctate keratitis or a more serious stromal diskiform keratitis accompanied by plastic iridocyclitis. A late immune keratitis or recurrent VZV dendritic ulcerations may appear. Iritis, retinitis, optic neuritis, ophthalmoplegia, and cataract are infrequent.
    • Therapy includes the following:
      • Acyclovir 200 mg pills or suspension 20 mg/kg/day (not more than 800 mg) p.o. in children under 40 kg or 800 mg p.o. qid if >40 kg for 5 days. 30 mg/kg/day i.v. divided q8h for 7 days in immunocompromised patients.
      • Good hygiene, cool compresses, low illumination.
      • Cycloplegics for iritis or keratitis.
      • Antibiotic prophylaxis bid for surface vesicles or ulcers.
      • Cautious use of mild topical steroid for nonulcerative interstitial or diskiform stromal keratitis. Dissemination of varicella in children from exogenous systemic steroids is a well-recognized hazard.
  • Adenoviral infections are frequent and classic causes of acute follicular conjunctivitis. Clinically, they are usually encountered as epidemic keratoconjunctivitis (EKC), usually associated with adenovirus types 8 and 19, and pharyngoconjunctival fever (PCF), usually associated with adenovirus type 3. After an incubation period of 5 to 12 days following droplet or fomite inoculation onto the conjunctival surface, symptoms of irritation and watery discharge are accompanied by hyperemia of the conjunctiva and follicle formation, often in association with preauricular adenopathy. Patients are highly contagious for 10 to 12 days, starting 1 day before onset, and should avoid close contact or sharing towels with others during this time (patients should take sick leave from work). Medical personnel examining or treating patients with this condition should be very vigilant about handwashing and cleansing of instruments.
    • EKC usually is not accompanied by systemic symptoms, and one eye is often involved prior to the other. There may be conjunctival hemorrhages or membrane formation, and marked lid swelling. The conjunctivitis runs a course of 7 to 14 days, at which time a keratitis may develop, often unilateral. There are six stages: (0) Poorly staining fine, intraepithelial opacities; (I) staining fine punctate EK (PEK); (II) fine and coarse PEK; (III) coarse granular infiltrates in deep epithelium, (IV) subepithelial infiltrates without PEK, (V) Punctate epithelial granularity around sub-EK.
    • PCF is characterized by pharyngitis, fever, and follicular conjunctivitis. The highly contagious (10 to 12 days) condition is usually unilateral and self-limited over 5 to 14 days. In the early stages, the condition can be confused with herpes conjunctivitis, acute inclusion conjunctivitis, and acute hemorrhagic conjunctivitis. The keratitis is similar to EKC but is usually bilateral and much milder.
    • Treatment is primarily supportive management, using astringent drops and cool compresses. Currently available antivirals, with the exception of cidofovir drops, have been ineffective in limiting the severity or course. Topical antibiotics
      P.103

      prevent secondary bacterial infection. Some patients may be so immobilized by the symptoms that they will require mild topical steroids tid to qid (e.g., 1/8% prednisolone), but this will prolong the period of active viral shedding by several days. Topical steroids will inhibit the appearance of subepithelial corneal infiltrates in EKC and PCF, but on discontinuation of the steroids, infiltrates will recur. A few patients require a long and gradual tapering of the steroid dose because of symptom recurrence. With time, all infiltrates generally clear spontaneously.
  • Human immunodeficiency virus, the single stranded RNA virus, is the cause of acquired immune-deficiency syndrome (AIDS), a progressive, profound CD4 T-lymphocyte cellular immunodeficiency characterized by multiple opportunistic infections and malignancies. Kaposi sarcoma is due to human herpesvirus 8. Prior to current therapy, more than 60% of patients had ocular lesions, most chorioretinal. The virus has been isolated from the tear film and almost all ocular structures including cornea, vitreous, and chorioretinal tissues. Anterior ocular lesions include follicular conjunctivitis, Kaposi sarcoma of the conjunctiva (a deep purple-red soft tumor), a punctate or geographic ulcerative keratitis that may mimic herpes infection, and nongranulomatous iritis. These are HIV-1 induced and occur independently of any opportunistic infection. Opportunistic infections include herpes simplex, herpes zoster, molluscum contagiosum, microsporidial keratoconjunctivitis, fungal amoebic, and bacterial ulcers of the anterior segment, as well as dry eye. In the posterior segment occur retinal microvasculopathy, cryptococcal optic neuritis, choroidiitis, and retinitis due to cytomegalovirus, pneumocystis, mycopbacteria, syphilis, toxoplasma, and herpes simplex or zoster. Therapy of AIDS is effective now as HAART (highly active antiretroviral therapy), which usually combines protease inhibitors with nucleoside or nonnucleoside/tide reverse-transcriptase inhibitors (see Chapter 9). Opportunistic infections are discussed in their respective sections by diagnosis.
  • Molluscum contagiosum virus is a large member of the pox group that causes epithelial tumorlike eruptions involving the skin and chronic conjunctivitis.
    • Ophthalmic interest centers around the lesions that affect the brow area, eyelids (particularly the eyelid margins), and, rarely, the conjunctiva. The skin lesion often starts as a discrete papule that eventually becomes multiple pale nodules up to 2 mm in size (larger in AIDS patients) with umbilicated centers from which a cheesy mass can be expressed. When one of the pearly umbilicated lesions affects the lid margin, a chronic follicular conjunctivitis and an epithelial keratitis can result that is thought to be the result of toxicity to products released by the lesion into the cul-de-sac. The keratitis is fine diffuse or focal epithelial that can, if chronic and untreated, lead to subepithelial infiltration and vascularization from the periphery that resembles a trachomatous pannus. The lid lesion(s) must be differentiated from other eyelid tumors, including sebaceous cyst, verruca, chalazia, keratoacanthoma, and small fibroma.
    • Treatment consists of complete eradication of the lesion. Following removal of the skin lesion, the conjunctivitis and keratitis rapidly clear. Cauterization and cryotherapy have been successful, but simple superficial excision or curettage is easily accomplished. HIV-positive patients are very prone to recurrence of multiple lesions.
  • Ocular vaccinia occurs following an inoculation to the eye. The vaccine is no longer in use, but the virus is stored in the United States and Russia. There are pustular skin lesions that can extend to the adjacent conjunctiva or cornea to produce an acute ulcer or late diskiform opacity. In a previously vaccinated individual with a good level of immunity, little more than an acute focal purulent blepharoconjunctivitis can be seen; in the unvaccinated or weakly immune individual, a severe reaction may occur. Treatment, if the cornea is involved, is with hyperimmune vaccinia immune globulin (CDC, Atlanta) 0.25 to 0.5 mL/kg body weight i.m., repeated in 48 hours if there is no improvement. Oral antivirals are ineffective. Trifluridine 1% drops 9id or Vidarabine antiviral ointment 5id for 2 weeks and antibiotic qid are used for acute blepharoconunctivitis infection. Topical steroids bid to qid are used for diskiform keratitis if the epithelium is healed and the infection is resolved.
  • P.104

  • Other infectious or autoimmune causes of interstitial keratitis (IK) are syphilis, M. leprae and tuberculosis, Epstein Barr virus, Lyme disease, sarcoidosis, Cogan syndrome, mumps and rubeola keratitis, Chlamydia, Lymphogranuloma venereum, Acanthamoeba, Leishmania, and Oncocerciases. Specific treatment is usually effective, and control of the IK with topical steroids is often of benefit.
  • Spirochetal infections
    • Syphilis (Treponema pallidum; lues). Ocular findings in lues include IK, conjunctivitis, episcleritis, scleritis, dacryoadenitis, Argyll Robertson pupil, uveitis, chorioretinitis, and optic neuritis. More than 90% of the cases of diffuse IK are congenital, starting with widespread, deep, infiltrative inflammation of the corneal stroma, and iritis; 80% are OU. Acquired adult syphilis produces IK much less frequently. It is usually uniocular, whereas the congenital variant is most often bilateral. Even in congenital disease, the keratitis is usually not apparent until ages 10 to 20 years. Disease begins with endothelial and deep stromal disease associated with pain, circumcorneal injection lacrimation, photophobia, and blepharospasm that progresses to a diffuse corneal haze which often obscures iritis. Nonulcerative stromal keratitis presents as marginal, central, or multifocal inflammation and neovascularizaton. The disease responds to topical steroids (e.g., 1% prednisolone qid to 8id for 1 m to 2 m then tapered. Scleritis may also occur and be treated similarly. All may recur and need retreatment. The acute inflammatory edema resolves with the progressive vascular invasion from the periphery, leaving deep opacities and ghost vessels with hyaline excrescences on the Descemet membrane as secondary guttae. Hearing impairment and chorioretinal scarring (bone corpuscle or salt-and-pepper fundus) are often associated with the congenital variety of lues and IK. Neurosyphilis and cardiovascular syphilis are late forms of the systemic disease. Any patient with syphilis should be evaluated for AIDS and other sexually transmitted diseases (see Chapter 9). Diagnosis is confirmed with blood tests: fluorescent treponemal antibody-absorption test (FTA-ABS) or microhemagglutination- Treponema pallidum (MHA-TP) tests that never revert to negative (or may never become positive in concurrent HIV and syphilis). Response to therapy is followed with venereal disease research laboratory or rapid plasmin reagin blood tests because these will revert to negative (1:4) within 1 year of cure. HIV testing is indicated and lumbar puncture may be recommended by an infectious disease consultant.
      • Systemic treatment of the newborn for congenital syphilis is indicated if the mother’s serology (FTA-ABS) is positive or becomes positive during pregnancy, even if the infant remains seronegative. Benzathine penicillin 50,000 U/kg i.m. (up to 2.4 million U) once or procaine penicillin 10,000 U/kg i.m. daily for 10 days is the therapy for such infants. Even this therapy may be insufficient for congenital ocular or neurosyphilis, and treatment of 50,000 U/kg benzathine penicillin weekly for 3 weeks may be required. Children or adults with acute syphilitic IK are usually treated with ampicillin, 1.5 g p.o., in combination with probenecid 500 mg p.o. q6h on an empty stomach, for 1 month. Penicillin-allergic patients may be treated effectively with doxycycline or, in children younger than 8 years, erythromycin 50 mg/kg/day p.o. in four divided doses for 2 weeks. Some strains are very resistant to erythromycin. A pediatric or infectious disease consult is recommended. Topical steroids such as 0.1% dexamethasone q2h to q4h and cycloplegics (homatropine tid) are initiated and gradually tapered off as the disease responds. For severe IK, subconjunctival decadron 4 to 12 mg qd or 0.1 dexamethasone drops qid to 6id may be necessary as initial steroid therapy along with atropine cycloplegia.
      • Treatment of adult early primary, secondary, or latent acquired syphilis (< 1 year duration) is 2.4 million U of i.m. benzathine G penicillin once, or once weekly for 3 weeks if disease is late (>1 year duration). For neurosyphilis, treatment is 3 million to 4 million U aqueous penicillin i.v. q4h for 10 to 14 days. For penicillin-allergic patients, treatment is doxycycline 100 mg p.o. bid for 14 days (early) or 4 weeks (late—more than 1 year’s
        P.105

        duration) with nondairy-product meal, or tetracycline 500 mg on an empty stomach, p.o. qid for 4 weeks. Use neither for neurosyphilis. An internist or infectious disease consult should be obtained. Topical treatment with steroids and mydriatic cycloplegics is similar to that for congenital syphilis.
    • Lyme disease (erythema chronicum migrans), an infectious and immune-mediated inflammatory disease caused by the spirochete Borrelia burgdorferi, has numerous ocular, neuroophthalmic, and systemic manifestations. There are three defined stages of disease.
      • Stage 1. Within 1 month of an infected deer tick bite, a characteristic macular rash of varying severity and often with a clear center usually appears at the area of the bite. There may be associated fever, chills, fatigue, and headache. A malar rash and conjunctivitis (11% incidence) may also occur.
      • Stage 2. After several weeks to months, neurologic (meningitis, radiculoneuropathies, severe headache) and cardiac (atrioventricular block, myopericarditis) signs may begin. Neuro-ophthalmic findings include optic neuritis and perineuritis, papilledema, ischemic optic neuropathy, optic nerve atrophy, pseudotumor cerebri, diplopia secondary to third and sixth nerve palsies, Bell palsy, and multiple sclerosislike disease. Other ocular manifestations include retinal hemorrhages, exudative retinal detachments, iritis followed by panophthalmitis, and bilateral keratitis. The keratitis is characterized by multiple focal, nebular subepithelial opacities at all levels of the stroma, limbus to limbus, and may progress to corneal edema and neovascularization.
      • Stage 3. Up to 2 years after the bite, a migratory oligoarthritis may develop initially without joint swelling, but later with effusions and degeneration. Extreme fatigue, lymphadenopathy, splenomegaly, sore throat, dry cough, testicular swelling, mild hepatitis, and nephritis are not uncommon. The ocular manifestations of Lyme disease may appear at any stage but are more common in the later two stages and may occur despite “adequate” treatment. Most resolve spontaneously, waxing and waning.
      • Diagnosis. Either the indirect fluorescent antibody method or the enzyme-linked immunosorbent assay is reliable; confirm with Western blot for B. burgdorferi. Lyme titers of 1:256 are diagnostic. In chronic Lyme disease, absence of antibodies against the spirochete does not exclude the disease; a specific T-cell blastogenic response to B. burgdorferi may make the diagnosis in seronegative patients. There is cerebrospinal fluid pleocytosis.
      • Systemic treatment is still controversial, and any manifestation of the disease may recur and require treatment.
        • Early rash, nonspecific symptoms with positive Lyme titers:
          • Adults. Doxycycline 100 mg p.o. bid or tetracycline 500 mg p.o. qid; penicillin V or amoxicillin 500 mg qid; or azithromycin 500 mg p.o. qd for 4 weeks.
          • Children. Penicillin V potassium p.o. 50 mg/kg/day in four divided doses, amoxicillin 125 mg to 250 mg p.o. tid, or erythromycin 40 mg/kg/day in four divided doses, each regimen 4 weeks.
        • Definite neuroophthalmic, ocular, neurologic, or cardiac disease:
          • Adults. Penicillin G i.v. 24 million U/day in four divided doses for 14 days, or ceftriaxone i.v., 2 g/day for 14 days.
          • Children. Penicillin G 250,000 U/kg/day in four divided doses for 14 days, or ceftriaxone 100 mg/kg/day in two divided doses i.m. or i.v. for 14 days.
      • Topical treatment is adjunctive to systemic therapy. Keratitis is responsive to 1% prednisolone qid with taper over several months and reinstitution as needed. Iritis may self-resolve and require only mydriatic-cycloplegic therapy (0.25% scopolamine bid) or be more severe, requiring addition of topical steroids four to six times per day with taper.
  • Mycobacteria
    • Leprosy (Hansen disease). The IK of leprosy (Mycobacterium leprae [M. leprae]) is a deep infiltration, usually bilateral and extending from the periphery to the center of the cornea. The IK may be associated with a punctate epithelial
      P.106

      keratitis, and, although corneal nerves are notably thickened and beaded, the interstitial vascularization is not prominent. The keratitis rarely occurs alone, but can occur with involvement of the ciliary body or a limbal leukoma. Nodular lepromas are frequently seen in the subconjunctival tissues, and iritis is severe. The cornea can be greatly thickened, and the opacity usually does not clear. Treatment. Systemic sulfones (Dapsone) 100 mg p.o. qd with rifampin 600 mg qd or clofizamine 100 mg qd to start then taper over months. Monitor CBC and LFTs. Topical steroid and atropine are needed to control inflammatory eye disease. Tuberculoid (neurasthetic) leprosy is treated with dapsone 100 mg p.o. qd and 600 mg of rifampin monthly for 6 months. For lepromatous (granulomatous) leprosy, 50 mg of clofazimine is added to this regimen daily and 300 mg is given monthly. Such treatment should be carried out by a physician familiar with lepromatous disease.
    • M. fortuitum and M. chelonae account for about 50% of all post-LASIK bacterial keratitis. These two most common causes of nontuberculous keratitis result in indolent whitish infiltrates diagnosed by cultures and scrapings. Therapy is effective using q1h topical gatifloxacin or, alternatively, oral and topical clarithromycin 20 mg/mL. Amikacin 10 mg/mL with vancomycin 25 mg with gradual tapering over weeks has been largely replace by the former therapies, particularly gatifloxacin.
    • M. tuberculosis (see Chapter 9).
  • Fungal keratitis. Fungal infections of the eye are less common than bacterial or viral (5% to 10% of corneal infections), but they pose a threat both because of the damage caused by the fungus and because of the limited number of approved antifungal agents available for treatment.
    • Yeast fungi. Candida ulcers commonly occur in eyes with predisposing alterations in host defenses, including chronic use of corticosteroids, exposure keratitis, keratitis sicca, corneal debilitation from such causes herpes simplex keratitis, contact lens wear, and prior keratoplasty. Candida is a common offender in the northern and coastal regions of the United States, constituting 32% to 43% of keratomycoses. It is unwise and often not possible to determine the species of infecting organism by the clinical features, but the clinical appearance may suggest the infecting agent. Candida ulcers occasionally have distinct oval outlines with a plaquelike surface or can produce a relatively indolent stromal infiltration with smaller satellite lesions.
    • Filamentous fungi. Fusarium, Cephalosporium, and Aspergillus are the most common filamentous fungi in the United States, with Fusarium more common in the South and Aspergillus in the North, causing 45% to 60% of filamentous keratitis cases. These ubiquitous organisms usually infect normal eyes following mild abrasive corneal trauma, especially after injury from vegetable matter. They can be isolated readily from soil, air, and organic waste. The clinical appearance can be characteristic, with a gray or dirty-white dry, rough, textured surface that often has an elevated margin. There may be feathery extensions beneath epithelium into the adjacent stroma, or the infiltrate may be entirely intrastromal. Satellite lesions separated from the central infectious area may occur and correspond to microabscesses in the surrounding tissue. Occasionally, ring abscesses have been described. If the infection is deep, there can be endothelial plaque formation. Anterior chamber reaction and hypopyon can occur with large or deep infections. In contact lens wearers, filamentous fungi are more associated with cosmetic lens wear, and yeasts are more associated with therapeutic lenses.
    • Diagnosis. Scraping and inoculation of media should be performed (see Section III.C, IV.B earlier, and Tables 5.3 and 5.4). It is important to scrape multiple sites in the ulcer crater, particularly at the margins, to enhance recovery of organisms. Because the organisms tend to be deep within the stroma, superficial keratectomy (corneal biopsy; see Section IV.B.3.b, earlier) may be necessary to obtain diagnostic material. Because the organism is often not seen on the scraping, it is important to inoculate each culture medium with multiple
      P.107

      scrapings. Although Gram stain may identify some fungal forms, particularly the yeast forms of Candida, Giemsa stain is more likely to define the structure of filamentous fungi. The Grocott modification of Gomori methenamine-silver stain often provides greater definition of fungal cytology. Sabouraud broth and agar and a blood agar plate kept at room temperature, as well as brain–heart infusion broth, are essential. More specialized media (e.g., Nickerson media for identification of Candida organisms) may be used but are not essential.
    • Treatment is initially medical and potentially surgical, as fungal infection can be rapidly destructive to the integrity of the eye. Hospital admission may be advisable. Lack of disease progression is the first sign of therapeutic response. Topical and systemic treatment usually lasts for several weeks (2 to 5 months).
      • Medical therapy is limited by the number of approved antifungal drugs and by the poor penetration of the available agents. Table 5.8 summarizes the most commonly used drugs, dosages, and indicated organisms. Prior to identification of the infectious agent, therapy should begin with as broad a spectrum as possible in highly suspect cases (e.g., no response to fortified
        P.108

        antibiotics, clinical appearance, vegetable matter, injury, positive scrapings). The cornea should be cleaned of debris when needed to enhance drug penetration. Natamycin (Natacyn, pimaricin, Alcon corp.) 5% suspension, or amphotericin B 0.15% are active against yeast and filamentous fungi, with Fusarium being most susceptible to natamycin. Drops are started at q1h (at least 16 doses per day) with taper to q2h after several days. Oral voriconazole 200 mg p.o. bid should also be started and usually continued for 3 months depending on response. Cultures may take from 3 to 30 days to become positive. Substitution of a specific antifungal agent according to the clinical response or in vitro sensitivities may be indicated. When fungal elements are confirmed on direct smears, culture, or from histologic biopsy examination, therapy should be oriented toward the type of organism and extent of disease. Filamentous cases are usually responsive to the topical polyenes, natamycin, or amphotericin B, but refractory cases may usually be successfully treated with the addition of topical voriconazole and continuation of that drug orally. Itraconazole 200 mg p.o. qd or ketaconazole 200 to 600 mg/day are very good for aspergillus curvularia, and candida but have variable response against fusarium; voriconazole is the drug of choice. Yeasts such as Candida usually respond to the synergistic combination of topical amphotericin B and oral fluconazole 200 to 400 mg/day or oral voriconazole, or ketoconazole. Daily epithelial débridement by the physician (if the surface heals over) is useful in aiding drug penetration for at least the first several days of therapy.
        TABLE 5.8 Antifungal Therapeutic Regimen Used in Fungal Keratitisa
        Regimen Drug efficacious against
        Amphotericin B (Fungizone)
        Topical: 0.15% drop q1h
        Subconjunctival: 0.8–1.0 mg q48h for one to two doses (toxic)
        Candida, Aspergillus, Cryptococcus, Coccidioides, Sporothrix, Blastomyces, Histoplasma, Paracoccidioides mucormycosis
        Systemic: Test dose 1 mg slow i.v. If tolerated, at 2 to 4 h start 0.25 mg/kg i.v. over 4 to 6 h/d. Work up to 0.5 to 1.5 mg/kg/d depending on fungus and tolerance. Hydrate well.
        Fluconazole (Diflucan)
        200 mg i.v./p.o. initial dose; 100 mg/d i.v./p.o. qd
        Candida, Cryptococcus, Coccidioides
        Flucytosine (5-FC, Ancobon)
        Topical: 10 mg/mL drop q1h; taper as above
        Oral: 50 mg to 150 mg/kg/d in four divided doses
        Candida, Aspergillus, Cryptococcus, Cladosporium
        Itraconazole (Sporanox)
        Oral: 200 mg qd to bid p.o.
        Topical: 1% drop q1h; taper as above
        Aspergillus, Cryptococcus, Histoplasmosis, Candida, blastomycosis, paracoccidioidomycosis, sporotrichosis
        Ketoconazolec (Nizoral)
        Oral: 200 mg to 400 mg/d p.o.
        Candida, Fusarium, Penicillium, Aspergillus, Alternaria, Rhodotorula, Histoplasma, Cladosporium, Coccidioides Paracoccidioides, Phialophora, Actinomyces
        Natamycin (pimaricin) See ketoconazole
        Topical: 5% drop q1h; taper as above
        Voriconazole 200 mg po bid
        See ketoconazole. Main use is filamentous organisms. Candida and other yeasts may be treated with one of the above oral imidazoles plus topical therapy.
        i.v., intravenous; p.o., oral.
        aSee also Table 9.7.
        bOnly Pimaricin is approved by the U.S. Food and Drug Administration for ocular use.
        cOral absorption enhanced by taking with acidic beverage (e.g., orange juice, cola).
        Cycloplegics such as atropine or scopolamine should be used liberally to prevent posterior synechiae and help reduce uveal inflammation. Secondary glaucoma may require topical beta-blockers, prostaglandin analogs, or other nonmiotic agents. During therapy of a fungal ulcer, corticosteroids are contraindicated because of the documented enhancement of fungal growth and persistence of low titers of fungi even after the eye is clinically quiet.
      • Surgical therapy may be required not only for complications of the acute infectious processes, but also should medical management fail. Débridement and superficial keratectomy, although mostly of diagnostic benefit, may enhance the effectiveness of medical treatment. Conjunctival flaps have been advocated for nonhealing ulcers and are often effective, although fungal organisms have been found to persist under a conjunctival flap. Lamellar keratoplasty is generally ineffective in treating fungal keratitis because of the inability to completely remove the infectious agent with recurrence in the graft. If the area of infection can be completely encompassed by a penetrating graft and if there has been inadequate response to medical treatment, the corneal graft may provide an effective cure, but prognosis is often poor. Lens extraction should be avoided if the posterior segment is not involved and as a barrier to its involvement.
  • Nontrue fungi of the family Actinomycetaceae and Nocardiaceae. Two organisms that superficially resemble fungi but are related to the true bacteria cause disease in humans.
    • Actinomyces can infect the lacrimal system, particularly the canaliculi, producing a chronic conjunctivitis and canaliculitis. Rarely, a nodular keratitis similar to atypical mycobacteria may be produced. The Gram-positive, non-acid-fast, nonmotile filamentous organism microscopically shows branching filaments when granules expressed or curetted from the canaliculi are smeared. The organism grows on blood agar or in chopped meat infusion, usually anaerobically. Treatment of the canaliculitis usually requires surgical removal or expression of the granules, but the organism is sensitive to penicillin and sulfa drugs (see Appendix B). Irrigation of the expressed canaliculus with a penicillin solution is often effective.
    • Nocardia asteroides is a Gram-positive filamentous organism and may stain acid-fast. The organism grows aerobically very slowly on many simple media. It
      P.109

      can produce a chronic corneal ulcer with a gray sloughing base and undermined overhanging edges. Nocardia can rarely produce endophthalmitis. Topical and systemic sulfonamides are the drugs of choice (see Appendices A and B).
  • Amoeba (Acanthamoeba). Corneal ulceration and keratitis due to Acanthamoeba species of parasite are being seen more frequently in the United States, possibly because of relaxed water-purification standards. They must be considered in a nonhealing, culture-negative corneal infection. Typically, it has been noted in patients who wear contact lenses (even disposables) or who had exposure to hot tubs, communal baths, or just plain lake or tap water.
    • Diagnosis. About 65% are initially diagnosed as herpetic keratitis, and 30% of patients are not definitely diagnosed for many weeks after onset and failure of antivirals or antibiotics to alter the progressive course. Inordinate pain is one of the cardinal signs. The lesions are often multicentric, but a ring-shaped lesion with stromal infiltrate is characteristic. The peripheral corneal nerves may be quite visible due to radial keratoneuritis. Amoeba can often be cultured from scrapings or biopsy on confluent layers of coliform bacteria or in Enterobacter suspensions. Calcofluor white stain of scrapings is positive in 70% of cases. Confocal microscopy gives a presumptive diagnosis in revealing high-contrast, ovoid, double-walled structures and round bodies that must be differentiated from keratocytes and inflammatory cells. However, a positive corneal biopsy for microscopy and PCR testing for amoebic DNA are diagnostic.
    • Therapy is still controversial, unsatisfactory, and often started empirically; many medical cures have now been reported, but none are FDA approved. Penetrating keratoplasty in combination with medical treatment may still be required. Epithelial débridement combined with topical treatment is highly therapeutic in early cases. The organism exists in the cornea in both trophozoite and encysted states, thus requiring extremely prolonged therapy. A currently used and often successful regimen is 0.1% propamidine isethionate (Brolene), one drop followed 5 minutes later by one drop of neomycin–polymyxin B–gramicidin (Neosporin, AK-Spore), followed 5 minutes later by 0.02% polyhexamthylene biguanide (PHMB, Bacquicil) or chlorhexidine 0.02% every hour, 18 hours per day. Frequency is then tapered over several weeks to months qid to bid. Ketoconazole 200 to 400 mg p.o. qd or itraconazole 150 mg p.o. qd and 1% clotrimazole may be added to the above regimen. The average duration of therapy is 70 to 90 days but may last much longer if response is slow. Topical steroids will reduce inflammation and pain and inhibit trophozoite conversion to cysts, thus keeping them susceptible to amebicides, but may also allow deeper penetration of organisms. Their role is still unestablished and equivocal.
  • Microsporidia are spore-forming, intracellular protozoa that are ubiquitous opportunistic pathogens and may cause multifocal epithelial and anterior stromal keratitis, particularly in HIV-positive patients and contact lens wearers. In immunocompetent patients, a stromal keratitis may be seen, whereas in HIV-positive patients, a conjunctivitis with an epithelial keratopathy occurs. Patients present with ocular irritation, blurred vision, and photophobia, but with little inflammation. In HIV patients, the keratitis is nonstaining superficial “mucoid” opacities with dense areas of fine punctate staining. Diagnosis is by Brown and Hopps or trichrome stain of corneal scrapings, and treatment is albendazole 400 mg p.o. bid with topical 0.1% brolene and/or 0.02% PHMB (see Section V.P, Acanthamoeba, earlier) and moxifloxacin q2h for several weeks.
V. Noninfectious keratitis, keratoconjunctivitis, and keratopathies
  • Exposure keratopathy. Any loss of the normal protective mechanisms of corneal sensation or lid blinking function can lead to exposure keratopathy.
    • Causes are Bell palsy, Ramsay Hunt syndrome (herpes zoster), neurotrophic keratopathy, traumatic facial palsy, or exophthalmos and other causes of incomplete lid closure.
    • P.110

    • Clinically, there is corneal desiccation, most notable in the inferior interpalpebral area of the conjunctiva and cornea, which can lead to a frank epithelial defect and noninfiltrated ulceration. Superinfection is a constant threat.
    • Treatment. In addition to the treatments described below, lateral tarsorrhaphy (closure of the lateral 25% to 33% palpebral fissure) is generally indicated in persistent epithelial defects or other ocular surface problems with neurotrophic ulcer, penetrating keratoplasty, postinfection, exposure keratopathy, dry eye syndromes, radiation keratopathy, entropion, some ocular cicatricial pemphigoid, and Stevens-Johnson syndrome.
      • Mild exposure. Frequent instillation of artificial tears during the day and lubricant ointment at night with taping of the lid closed is usually sufficient. Frequent observation is needed.
      • Moderate exposure. Application of a soft contact lens with frequent instillation of lubricant may suffice. Usually lid surgery (intermarginal lid adhesions, starting laterally) is required.
      • Severe exposure. Marked exophthalmos of thyroid endocrine etiology requires urgent treatment with high-dose systemic steroids (e.g., prednisone), 80 to 100 mg/day for a few days, to control the acute infiltrative ophthalmopathy most commonly into the maxillary and ethmoid sinuses or orbital decompression (Ogura technique). Antibiotic prophylaxis and lubrication should be instituted.
  • Thygeson superficial punctate keratitis. The clinical entity of a coarse punctate (“snowflake”) epithelial keratitis in an uninflamed eye is often misdiagnosed as adenovirus (which has a red eye). It runs a chronic course with exacerbations and remissions, is associated with foreign body sensation, photophobia, and tearing, and is usually bilateral, but can be asymmetric. These circular-to-oval epithelial lesions usually occur centrally and are slightly elevated, with central fluorescein staining and a cluster of heterogeneous, granular gray dots. It usually self-resolves in 6 years or less.
    • Treatment. The lesions and associated symptoms usually respond quickly to topical corticosteroids, which may be tapered rapidly, but recurrence of the keratitis is common. One drop of prednisolone 0.12% weekly or even less frequently may keep a patient asymptomatic. It is not necessary to treat until all lesions are gone, but only to the point of comfort. Application of a TSCL will often relieve symptoms if the use of steroids is not possible or advisable. Antiviral drugs are not advised, because they may induce scarring beneath the lesions.
  • Filamentary keratopathy. A variety of conditions can produce filamentary keratopathy, which is probably best considered as a form of aberrant epithelial healing. Consequently, any condition that leads to focal epithelial erosions may produce filamentary keratopathy.
    • The following conditions are probably most commonly associated with this entity.
      • Keratitis sicca. Filaments frequently occur in corneas that are subject to the epitheliopathy of keratitis sicca. These filaments can be distributed diffusely and are often associated with areas that stain with fluorescein on the corneal surface. Excess mucous production in this syndrome probably aggravates filament formation.
      • Superior limbic keratoconjunctivitis. This condition, initially described as mild inflammation and vascular injection of the superior conjunctiva associated with rose bengal staining of the superior bulbar conjunctiva, is often associated with filaments distributed over the superior portion of the cornea.
      • Other causes include: prolonged patching following cataract or other ocular surgery, epitheliopathy due to aerosol or radiation keratitis, herpetic epithelial defects, and systemic disorders, including diabetes, psoriasis, and ectodermal dysplasias.
    • Treatment. The specific etiology of the filamentary keratopathy should be identified and treated.
      • Débridement. If only a few filaments exist, they may be removed at their base with a pair of jeweler’s forceps following topical corneal anesthesia.
      • P.111

      • Medication. In the dry eye or in the eye with unstable tear film, lubricants in the form of drops q2h or ointments q4h may be tried. Lid hygiene should be encouraged.
      • Therapeutic contact lens. If symptoms are severe or if medication has failed, application of a high-water-content (70%) TSCL (Permalens, Kontur) will provide relief and usually allow adequate epithelial healing without filament formation. Antibiotic drops bid (e.g., trimethoprim–polymyxin B [Polytrim]), should be used for the first few weeks of wear.
      • Lateral tarsorrhaphy (see Section V.A.3, above).
  • Superior limbic keratoconjunctivitis presents as bilateral ocular irritation with dilated conjunctival vessels over the superior bulbar conjunctiva. It is often associated with superior corneal filaments. Rose bengal reveals prominent staining in the superior bulbar conjunctiva. The superior conjunctival cells are often keratinized. No organisms have ever been associated conclusively with superior limbic keratoconjunctivitis, and the role of the tarsal conjunctiva in provoking the reaction is speculative. Superior limbic keratoconjunctivitis has been reported to occur with greater frequency in patients with hyperthyroidism.
    • Treatment. Topical lubricants and low-dose topical steroids may alleviate the symptoms, but usually do not completely reverse the conjunctival changes. Some success has been achieved with topical application of silver nitrate solution 1% to the involved area, but application may need to be repeated. Silver nitrate cautery sticks should not be used for this purpose because severe conjunctival burn and necrosis can occur. Various surgical procedures have been advised. Acceptable results can be achieved after application of faint diathermy in a checkerboard pattern across the superior bulbar conjunctiva. Recession or resection of a perilimbal strip of conjunctiva from the superior limbus is usually effective if other measures fail. Long-term wear of TSCLs may be required.
  • Neuroparalytic keratitis
    • Bell palsy. Acute “idiopathic” palsy of the facial nerve (VIIth) may be herpetic in etiology and may result in paralysis of the orbicularis muscle and lagophthalmos, with incomplete closure of the lids and incomplete lubrication of the ocular surface, with resultant desiccation and epithelial breakdown. If Bell phenomenon is weak or absent, frank ulceration of the corneal surface may occur. Emergency treatment is needed to prevent permanent paralysis. Prednisone, 40 mg p.o. bid for 10 to 14 days, coupled with acyclovir, 400 mg qid p.o. for 14 to 21 days, should be initiated on presentation.
    • Herpes zoster ophthalmicus. Involvement of the eye by herpes zoster ophthalmicus can result in severe corneal epithelial defect during the acute episode, but also in diminished to absent corneal sensitivity because of ganglionic (Vth) damage in the recovery stage. Loss of the protective corneal innervation results in a surface that breaks down readily and is very prone to desiccation with minimum exposure. The predisposition of the eye to inflammation makes treatment with contact lenses or surgery more complex (see Section IV.E.). Ramsay Hunt syndrome is Bell palsy combined with VIIIth nerve zoster, with the latter causing tinnitus, vertigo, and permanent hearing loss.
    • Status post-trigeminal section for tic douloureux. Neurosurgical procedures to interrupt the sensory root of the trigeminal nerve (V) often result in corneal anesthesia. There may be desiccation and exposure, with subsequent epithelial breakdown.
    • Postradiation keratopathy. After radiotherapy to lesions of the head and neck, trophic changes can occur in the eye, with corneal epithelial breakdown.
    • Syphilitic (luetic) neuropathy. Hypesthesia of the corneal nerves from luetic involvement predisposes to epithelial breakdown.
    • Neuroparalytic keratitis treatment
      • Lubricants. Specific treatment for zoster is indicated for acute Bell palsy. The mainstay of treatment of exposure keratopathy, particularly in the mild stages, is topical lubricants consisting of artificial tears (the more viscous bases being more effective) instilled q1 to 2h during the day, with lubricant
        P.112

        ointment or antibiotic ointment applied at night. In many cases this treatment will be sufficient.
      • Mechanical. Significant lid dysfunction or lagophthalmos needs to be treated. Bedtime ointment or taping the lid shut at night is often efficacious, and, although inconvenient, can be used intermittently during the day. Lateral tarsorrhaphy usually produces good results (see sec. V.A.3, above). Side shields for glasses worn during the day are also effective.
      • Soft contact lens. Application of a therapeutic, high-water-content soft contact lens (Permalens, Kontur) in conjunction with copious artificial tears can provide a reservoir to prevent desiccation. It must be remembered, however, that eyes with impaired sensation are at greater risk than those with normal sensation, and the patient requires close follow-up to detect any signs of neovascularization, infiltration, or anterior chamber reaction. Antibiotics such as trimethoprim-polymyxin B (Polytrim) should be instilled to minimize the chance of infection.
      • Thinning ulcers are treated as in Section IV.D.2, above.
  • A pterygium is a fleshy triangular band of fibrovascular tissue with a broad base on the nasal or temporal epibulbar area, a blunt apex or head on the cornea, and a gray zone, or cap, which just precedes the apex. It is most common in the 20- to 30-year age group, in males, in tropical climates, and in people exposed to the elements and ultraviolet light. The episcleral portion usually develops rapidly over 2 to 3 months, but corneal growth takes many years. Signs and symptoms include congestion, photophobia, tearing, foreign body sensation, progressive astigmatism, diplopia, and restriction of extraocular movement. Often pterygia will spontaneously become inactive before any vision-threatening lesions occur. There is absence of periodic congestion, loss of punctate staining over the body, and shrinkage of the cap. Involution usually occurs, leaving a flat inconspicuous scar. Because of a strong tendency of aggressive recurrence after surgical excision, and the good chance for involution, great care must be taken to document progressive, vision-threatening, or disturbing corneal or episcleral growth with recorded sequential size measurements and, if possible, photography before any surgical therapy is performed. The key to inhibition of pterygium if surgery is performed is excision of the pterygium down to bare sclera leaving wide conjunctival (2 to 3 mm) margins and excising the corneal head. Conjunctival autografts cover the bared sclera and mitomycin-C 0.01% to 0.02% either as a single application at surgery or bid for 5 days will significantly inhibit recurrence. Because of increased complications with delayed epithelial healing and avascularity of sclera and cornea, mitomycin should be used to treat severe pterygia only and avoided in patients with Sjögren syndrome, or other dry eyes.
  • Climatic keratopathy (actinic keratopathy) is a slowly progressive degeneration caused by years of outdoor exposure in any climate. There are coalescent, elevated yellowish nodules and plaques in the lower half of the cornea. Treatment is avoidance of outdoor exposure and as in Section V.E.6, above.
  • Marginal degenerations, peripheral ulcerative keratopathies (PUK)
    • Terrien marginal degeneration is an uncommon, painless, nonulcerative thinning of the marginal cornea. Often bilateral, the condition predominantly affects males in the late teens or older. The process usually begins superiorly with opacification and progresses over many years with thinning and superficial vascularization and, in younger patients, may be inflammatory. Lipid deposits may be seen at the leading edge. Symptoms of mild irritation may occur and respond to lubricants or, in the inflammatory cases, to intermittent mild steroid qd to bid (0.1% fluoro-methalone, FML). Pellucid marginal degeneration is painless, bilateral thinning of the inferior corneal periphery and may have similar complications. The most bothersome problem can be progressive astigmatism with some diminution of vision. Spontaneous perforation is rare, but trauma can rupture the thin cornea. Treatment is nonspecific. Gas-permeable rigid contact lenses or piggyback hard and soft lenses are effective in correcting astigmatism in mild to moderate cases. Surgical reinforcement with peripheral crescentic lamellar keratoplasty, sometimes coupled with penetrating keratoplasty, often provides stable visual recovery.
    • P.113

    • Furrow degeneration is a thinning of the peripheral cornea occurring in older patients in the area of an arcus senilis. There is no ulceration or epithelial defect, no vascularization, and no tendency to perforate. Treatment is usually not necessary.
    • Furrow degeneration or inflammatory ulceration associated with rheumatoid arthritis may occur in marginal and central cornea and is seen with greater infiltration than furrow degeneration. Progressive melting to perforation is common if systemic disease is not controlled. NSAIDs and systemic steroids are only palliative. Immunosuppressive agents such methotrexate, coupled with the drugs such as sulfasalazine, cyclophosphamide, etanercept, infliximab, or leflunomide, appear to control the ocular inflammation and may prolong survival by controlling other vasculitis. Such therapy for rheumatoid or collagen-vascular disease should be undertaken in consultation with a rheumatologist (see Chapter 9). Local ocular therapy is lubrication, antibiotic ointment, soft contact lenses, and, if perforation threatens, tissue adhesive (Dermabond). Topical mild steroids are useful in sclerosing or acute stromal keratitis, but should be avoided in furrowing or keratolysis.
    • Mooren ulcer is a severe inflammatory ulcerating disease of the marginal cornea running a painful and progressive course. The characteristic clinical picture is that of an overhanging advancing edge of an epithelial defect with vascularization of the ulcer base. The condition has been described in two forms, the first a more benign unilateral affliction of older males, and the second a bilateral ulceration of relentless progression in younger patients. Advancement of the inflammatory ulceration is both centrally and peripherally around the limbus and may extend into the sclera in severe cases. Scleral involvement, however, usually means there is another diagnosis (i.e., vasculitis), not Mooren. Spontaneous perforation is uncommon but certainly can occur. Vascularization can advance to cover the cornea (autoconjunctival flap).
      Treatment is often disappointing. Systemic interferon has been useful in hepatitis C-associated Mooren. Topical and systemic steroids are of some help, and immunosuppression with cyclosporin A or cytotoxic agents may be quite useful (see sec. V.H.3, above, and Chapter 9 for use and dosage of these drugs), as is early tissue adhesive for filling the bed of the ulcer (see sec. IV.D.2.b). Conjunctival excision and recession with or without cryotherapy of the recessed edge has been reported to be successful in some cases, but the condition can recur. Soft contact lens therapy may benefit milder cases. Lamellar or full-thickness corneal grafts often melt or vascularize. Topical and systemic corticosteroids and systemic immunosuppression may be quite effective.
    • Infectious agents associated with PUK include ocular infection with the viruses herpes simplex, varicella-zoster, or HIV, and a variety of bacterial (especially Staphylococcus), fungal, and parasitic agents. Systemic infections include gonococcus, HIV, bacillary dysentery, tuberculosis, and syphilis.
    • Noninfectious systemic vasculitic diseases associated with PUK include Wegener granulomatosis, relapsing polychondritis, systemic lupus erythematosus, Sjögren syndrome, polyarteritis nodosa, malignancy, and giant-cell arteritis. Other immune disorders include progressive systemic sclerosis, graft versus host reactions, Behçet syndrome, sarcoid, and inflammatory bowel disease. Hematologic diseases include porphyria and leukemia, and dermatologic diseases are acne rosacea, psoriasis, cicatricial pemphigoid, and Stevens-Johnson syndrome. Many of these are discussed in this chapter, in Chapter 9, and in Tables 15.1, 15.2, and 15.9.
VI. Dry eyes (keratoconjunctivitis sicca)
  • Mechanisms. One of the most common causes of chronic irritation of the eyes, particularly in the elderly population, is dry eye. Six percent of the population over age 40 and 15% over age 65 suffer from this condition, which is more common in women due to androgen deficiency and worsens after menopause. Tear film instability and dessication result from malfunction of the ocular surface afferent sensory nerves, efferent autonomic and motor nerves that induce tear secretion and
    P.114

    blinking, and function of the tear secretory glands: the main and accessory lacrimal glands, meibomian glands, and conjunctival goblet cells. Desiccation causes hyperosmolarity, cytokine and chemokine release stimulating matrix metalloproteinases, T-cell infiltration, and cell apoptosis with subsequent inflammatory response and further tear layer and ocular surface disturbance. Loss of mucins (tear spreading agents) also results from a variety of inflammatory illnesses.
    • Symptoms range from mild to severe irritation (burning, dry, gritty, itch, pain, photophobia, sticky tears, watery) and do not necessarily correlate with severity of ocular surface findings except in severe disease.
    • Clinical diagnosis is aided by the height of the tear meniscus or marginal strip (less than 0.3 mm), the presence of lissamine green or rose bengal staining, particularly of the inner palpebral conjunctiva and inferior cornea, a consistently diminished 5 or 1 minute Schirmer strip test, a low tear film meniscus along the lower lid, and rapid tear film breakup time (<5 seconds).
  • Etiologies. Although reflex tearing can decrease with advancing age, a variety of diseases and surgical procedures (e.g., LASIK) can also diminish basal tear secretion.
    • Idiopathic. Many patients with chronic low-grade keratoconjunctivitis sicca, usually of a mild degree, will demonstrate no systemic or other ocular disease to account for the lacrimal insufficiency or symptoms. Local eye findings are the key to diagnosis. It is important to exclude drug-induced tear hyposecretion, which can occur with a variety of drugs, including phenothiazines, antihistamines, oral contraceptives (although estrogen alone is helpful), antihypertensives, antidepressants, antiulcer agents, anti–muscle spasmodics, nasal decongestants, and anticholinergics (Parkinson).
    • Lupus erythematosus. Both systemic and discoid lupus erythematosus can result in the complex of keratoconjunctivitis sicca and xerostomia due to infiltration of the lacrimal and salivary glands. Superficial punctate epitheliopathy and corneal erosions accompany the dry eye. Diagnostic features of importance are the butterfly rash of the cheek, nose, and lower lids. Treatment is systemic with NSAIDs, steroids, and cytotoxic agents (see Chapter 9). Local ocular therapy is lubrication.
    • Ocular pemphigoid (essential shrinkage of the conjunctiva, benign mucous membrane pemphigoid). Although chronic low-grade inflammation is a common feature of this disease, the more severe dry eye is encountered late in the disease, after significant scarring of the accessory lacrimal glands and ducts has occurred. Keratinization of the surface is further aggravated by distortion of the lid anatomy and trichiasis. Dry eye and keratinization with scarring may be prevented with early systemic therapy. Immunosuppressives such as cyclophosphamide control ocular pemphigoid in 90% of cases, but often induce dangerous side effects. Dapsone 100 mg p.o. qd is the first line of treatment and often arrests the disease, but the drug may cause hemolytic anemia. An effective alternative is sulfasalazine 1 g to 4 g/day p.o. This precursor of sulfapyridine is used to treat other autoimmune diseases and is a good alternative to Dapsone if there are unacceptable side effects. All treatment should be done in consultation with an oncologist (see Chapter 9, Section VI.D).
    • Sjögren syndrome (Gougerot-Sjögren syndrome) with keratoconjunctivitis sicca, xerostomia, and arthritis has been described as the prototype of this disease state. The dryness is due to autoantibodies that bind to muscarinic acetylcholine receptors in the exocrine glands. Seventy-five percent of the patients have associated rheumatoid arthritis. Approximately 15% of patients with rheumatoid arthritis will develop the sicca syndrome.
    • Erythema multiforme (Stevens-Johnson syndrome). The postinflammatory mucosal scarring that occurs as a result of an acute episode of erythema multiforme involving the eyes can result in chronic dry eye. Resolution of the acute mucosal necrosis leaves symblepharon and scarring of the accessory lacrimal glands and the ducts of the main lacrimal gland. Keratinization can occur. Immunosuppressive agents (see Chapter 9, Section VI.D) may be useful
      P.115

      in therapy of chronic complications and cycloplegia, and mild topical steroids may be needed for chronic iritis. Lubrication is discussed in Section VI.D, and acute disease is discussed in Section VII.I.
    • Scleroderma (progressive systemic sclerosis) may have associated keratoconjunctivitis sicca.
    • Periarteritis nodosa. Keratoconjunctivitis sicca occurs as a late development in some patients with inflammatory ocular involvement from periarteritis.
    • Sarcoidosis. In this chronic granulomatous disease, infiltration of the lacrimal gland can result in keratoconjunctivitis sicca and occurs with relative frequency in older patients afflicted with the disorder.
    • Excision of the lacrimal gland. In most patients, excision of the lacrimal gland or obliteration of its ducts by removal of the palpebral portion will not cause keratoconjunctivitis sicca because the basal and mucosal secretors are preserved. In a small number of patients, however, a frank keratoconjunctivitis sicca will develop.
    • Mikulicz syndrome results from a variety of infiltrative diseases such as tuberculosis, leukemia, Hodgkin lymphoma, amyloid, or sarcoidosis. Characterized by symmetric enlargement of the lacrimal glands and salivary (parotid) glands, the condition can result in keratoconjunctivitis sicca.
    • Other diseases associated with dry eyes are diabetes mellitus (especially dia-betic retinopathy), graft versus host, polymyositis, post-head and -neck radiation, HIV, hepatitis B and C, syphilis, tuberculosis, trachoma, and seventh nerve palsy.
  • Dry eye severity levels are: Level 1—mild to moderate symptoms, conjunctival signs, no corneal signs; level 2—moderate to severe symptoms, visual and tear film signs, and conjunctival and corneal staining; level 3—severe symptoms, marked corneal punctate and central staining, filamentrary keratitis; level 4—extremely severe symptoms, altered lifestyle, conjunctival scarring, severe corneal staining, erosions (Delphi Dry Eye Panel of 2005, Wilmer Institute).
  • Treatment. If the patient is only level 1, there may be few if any objective findings, and treatment must be based on response to treatment. Lissamine green is the preferred stain in these mild patients. Because of the notable inflammatory component in dry eyes, topical steroids and other anti-inflammatory agents such as doxy- or minocycline have come to play an important therapeutic role The following sequence of therapy is suggested (see Appendix A):
    • Lid hygiene to stabilize the tear film is indicated at all levels. This removes oil and scruff: (a) in the shower or at a sink lather baby shampoo on finger tips and wash lashes and lid margins of gently closed eyes, then rinse clean qd; (b) warm, wet facecloth compresses 5 minutes, one to two times a day to the lids. Wipe gently closed lids with facecloth after soak to remove softened oil or scales. Treat any blepharitis or rosacea as under Sections III.A and C earlier.
    • Artificial tear (AT) replacement is indicated at all levels. Numerous ATs are available and are very helpful in milder cases or when alternated with gels in more advanced dry eye conditions. More viscous vehicles such as gels provide a longer contact time but may slightly blur vision and may do better when alternated with artificial tears. The many different brands confirm the variable effectiveness of these agents, and patients have varying preferences for different formulations and frequency that may vary from tid to several times daily, depending on disease severity. PF or oxidative preservative tears should be used if greater than qid or the cornea is hypesthetic (see Appendix A for available agents). Sodium hylauronate drops made up from the surgical viscoelastic or commercially available as contact lens rewetting agents (“blink” contacts [AMO], AQuify [CIBAVision]) may be of greater benefit when commercial ATs are not fully effective. In level 2 or higher, bedtime ATs or antibiotic ointments are advisable.
    • Eliminate use of tear drying conditions (all levels), such as use of antihistamines (control allergies with nonantihistamine agents), artificially dry work atmosphere, and prolonged computer time without a break. Discontinue any unnecessary topical medications that may be causing toxic medicamentosa.
    • P.116

    • Topical steroids should be started in level 2 patients. Steroids inhibit inflammatory cytokines, chemokines, matrix metalloproteinases and prostaglandins and stimulate lymphocyte apoptosis. Recommended agents are lotoprednol 0.5% to 0.2%, (Lotemax-Alrex), rimexolone 1% (Vexol), or FML 1% bid to qid because of their low propensity to raise intraocular pressure (IOP) and excellent therapeutic efficacy. Stronger steroids (1% prednisolone) may be used to start, if necessary, and then changed to the former types or to cyclocsporin A. After 2 to 4 weeks of treatment, there should be decrease in corneal staining and conjunctival hyperemia as well as improved symptomatology. NSAIDs appear to have no beneficial effect on dry eye.
    • Cyclosporin A 0.05% drops (Restasis™, Cy A), a fungal-derived peptide, may be used instead of steroids. This drug inhibits epithelial apoptosis and T-cell activation. Given bid clinical response is similar to topical steroids and has an excellent safety profile, possibly better than steroids.
    • Omega-3 fish oils combat dry eye by decreasing inflammation in skin thus reducing blepharitis and rosacea as well as the viscosity of meibomian gland secretions. Flaxseed oils have Omega 3 and 6, both of which are beneficial, but unopposed Omega 6 increases arachidonic acid and thus inflammatory prostaglandins. Pregnant women should not use flax seed oils, but fish oils are fine. Both purified fish and flaxseed oils are available as capsules or liquid with dosing being three daily or 1 teaspoon.
    • Tear stimulating drugs are particularly effective in Sjögren syndrome because of the muscarinic acetylcholine receptors block in the exocrine glands. Oral cevimeline (Evoxac) 20 mg tid or pilocarpine (Salagen) 5 to 10 mg bid to tid, muscarinic Ach receptor agonists stimulate salivary and tear secretion and relieve dry mouth and often dry eyes in these patients. These agents are variably effective in other forms of dry eye but worth trying as a number of non-Sjögren patients respond to them.
    • Punctal occlusion is indicated in patients at levels 2–4 but should not be done before anti-inflammatory therapy is in effect, as it may worsen ocular surface disease in patients with overt clinical inflammation. Temporary punctal occlusion (2 to 3 weeks) can be achieved by insertion of 0.2- to 0.6-mm collagen plugs (Eagle Vision, Lacrimedics). Reversible “permanent” occlusion of the puncta is achieved by insertion of 0.4- to 0.8-mm silicone plugs (Eagle, Oasis) at the slitlamp. These may easily be removed later. Six months after placement, about 85% of patients are asymptomatic, about 75% use little to no lubricants, and surface staining is notably decreased. Plugs are particularly efficacious when topical steroid or CyA is in use. About 40% will lose a plug within the first 6 months, especially upper lid plugs. Electrocautery after local anesthesia produces permanent closure. Temporary occlusion may be used to predict those patients who would suffer from epiphora if permanent occlusion were performed.
    • Doxy- or minocycline (tetracyclines) are useful in levels 2–4. They relieve dry eye via their anti-inflammatory properties of decreasing production and activation of cytokines, nitric oxide, and matrix metalloproteinases. Dosing of 100 mg p.o. qd for many months is the most effective. Food or vitamins with calcium should be avoided within 2 hours of these drugs because they can be inactivated. In about 4 weeks, patients usually note less irritation. Exam reveals increased tear film stability, and decreased severity of ocular surface disease, especially in rosacea patients. These drugs are also effective in recurrent erosion syndrome and phylyctenular keratitis.
    • TSCL therapy is used in levels 3–4. Hydrophilic bandage lenses such as Kontur or Permalens often provide a tear reservoir if used in conjunction with copious PF artificial tears. These patients are prone to contact lens intolerance and superinfection and should be followed carefully. Forniceal scarring may dislodge the lenses. Newer lenses, the gas-permeable scleral contact lenses, have been very effective in otherwise contact lens–intolerant eyes with extensive ocular surface disease. Their large size provides a sclera-bearing surface retaining a precorneal fluid pool that provides hydration and optical
      P.117

      neutralization of irregular corneal surface. Indications include the more severe dry eyes: Stevens-Johnson disease, cicatricial pemphigoid, exposure keratitis, toxic epidermal necrolysis, herpetic trophic ulceration, congenital meibomian gland deficiency, superior limbal keratitis, Sjögren syndrome, and inflammatory corneal degeneration (see Sections VI and IX).
    • Lateral tarsorrhaphy is indicated in levels 3–4 using suture or Botox injection into the levator (2 to 4 months effect) to decrease tear evaporation.
    • Autologous serum, 20% drops in sterile saline six to eight times daily inhibit inflammatory cytokines and matrix metalloproteinases, thus improving symptomatology and decreasing ocular surface staining.
    • Other methods. Moist chambers achieved by an occlusive plastic shield across the eye have helped in some cases. Close-fitting glasses with side shields often achieve the same effect. Amniotic membrane and stem-cell transplantation has been used successfully with increasing numbers of patients with severe ocular surface disorders, including severe dry eye, chemical burns, and neurotrophic ulcers.
VII. Allergy and hypersensitivity
present in the eye as type IV delayed hypersensitivity (T-cell mediated), usually a contact dermatitis, or as type I reaction, an immediate hypersensitivity from allergen–immunoglobulin E (IgE) reaction on the mast cell surface triggering mast cell degranulation and release of inflammatory mediators, including histamine. The ocular histamine receptors are H1 (itching) and H2 (erythema). Other mast cell inflammatory mediators include prostaglandins and leukotrienes, which increase local blood flow, activate pain receptors, release serotonin, are pyogenic, enhance vascular permeability and dilation, and are white cell chemotactic, all contributing to the clinical disease.
  • Seasonal and perennial allergic conjunctivitis (SAC, PAC, respectively) are type I reactions, cause the vast majority of allergic conjunctivitis, and may be associated with hay fever, rhinitis, or asthma. Allergens are usually airborne, and allergy onset is rapid. SAC symptoms are very itchy, watery eyes, often with rhinitis or allergic pharyngitis. Eye signs are lid edema, mucoid discharge, fine papillary hypertrophy, bulbar conjunctival hyperemia, and, in some cases, chemosis but in both SAC and PAC there is little to no corneal or conjunctival staining. Corneal involvement is rare. Common inciting antigens are grass and tree pollens in the spring and ragweed pollen in the fall. PAC is less common and less severe, but tends to occur year-round because of the nonseasonal nature of the antigens (e.g., dust, animal dander, house mite feces, mold, and some foods). Chronic symptoms of itching, burning, and tearing in sometimes normal-appearing eyes often indicate PAC as opposed to SAC, which is seasonal and has more florid clinical findings. In severe atopic conjunctivitis, there may also be subepithelial fibrosis, symblepharon, corneal ulcers, and neovascularization. Conjunctival scrapings reveal eosinophils, and serum IgE is markedly elevated. Differentiation from acute viral infections can be made by lack of adenopathy, but differentiation from contact or toxic exposure often relies on the history and IgE levels. Atopy does not resolve spontaneously over time.
  • Atopic keratoconjunctivitis (AKC) is seen in 30% of atopic dermatitis, particularly excema, patients as a year-round affliction with some seasonal exacerbations. A thickened, scaly dermatitis affecting the lids (tylosis), face, neck, popliteal, and antecubital areas can be associated with keratoconjunctivitis that is characterized by thickening and hyperemia of a small- to medium-size papillary tarsal conjunctivitis with milky edema and occasional subepithelial fibrosis. The tarsal infiltrates include CD4+, lymphocytes (cytokine release), macrophages, mast cells, and eosinophils (cationic protein, peroxicdase, neurotoxin, collagenases), all of which contribute to the inflammatory disease. Mast cells, in particular, release histamine, chymases, and interleukins 3–6, which cause collagen IV degradation and breakdown of the corneal eptithelial surface and basement membrane. This, along with limbal stem-cell dysfunction, cause superficial opacification and vascularization of the cornea. Multiple other allergies, including hay fever, rhinitis,
    P.118

    asthma, and urticaria, are often concurrently present. A higher occurrence of keratoconus (KC) than in the normal population has been reported with this condition, possibly because of chronic eye rubbing. Because AKC is basically a type IV reaction, mast cell therapy may be less than effective. As there is also some depressed cell-mediated immunity in atopy, these patients are more susceptible to ocular herpes simplex and staphylococcal infections. Therapy of the dermatitis is picrolimus (Elidel) cream or tacrolimus (Protopic) 0.03% ointment to the lids and periorbital tissues bid is effective in atopic dermatitis/blepharitis such as in excema.
  • Vernal keratoconjunctivitis (VKC) is a combined type I and IV reaction seen mainly in teenage males with other atopy, of African or Asian descent, and in hot climates. This seasonally recurrent bilateral inflammation of the conjunctiva, producing itching, tearing, photophobia, foreign body sensation, and copious mucoid discharge, occurs in two forms: palpebral and limbal. The inflammatory infiltrate is made up of eosinophils, lymphocytes, plasma cells and monocytes. See AKC for agents released.
    • The palpebral form is distinguished by cobblestone papillae on the tarsal conjunctiva (mainly upper), hyperemia, and occasional chemosis.
    • The limbal form occurs with papillary hypertrophy on the limbal conjunctiva associated with white, chalky concretions known as Trantas dots near the limbus. Limbal and tarsal conjunctival VKC may occur together.
    • Corneal changes may include punctate superficial erosions in the upper and central cornea, superior pannus, 360-degree vascularization, and occasional shield ulcers of the superior cornea. These may require antibiotic prophylaxis and, occasionally, soft contact lens therapy in the form of a hydrophilic bandage lens, or papillary excision to debulk the source of toxic inflammatory chemicals.
    • Diagnosis. One of the main diagnostic features is the conjunctival scraping showing prominent eosinophils, many of which will be fractured, releasing their granules. (See AKC cell types.) A seasonal predilection is for the spring and early summer, as well as for the fall. The condition usually runs a course of from 4 to 10 years before remission.
  • Treatment of ocular allergy. (See Appendix A for categories and dosage.) Where it can be established, remove the offending antigen and improve atmosperic conditions (e.g., electrostatic air purifier). Rule out allergy from other eye drops such as glaucoma drugs. For contact dermatitis, apply topical steroid tid for 4 to 7 days.
    • Commercial OTC decongestant-antihistamines qid offer rapid-onset (15 minutes) palliative treatment, with decongestants vasoconstricting blood vessels to reduce redness and chemosis and the antihistamine blocking H1 receptors to reduce lid and conjunctival edema, hyperemia, itching, and tearing (Visine A, Naphcon-A, Opcon A, others, generic). Use these no more than 4 to 6 days, as they contain benzalkonium or other preservative, which may produce corneal toxicity. As relief is only for about 2 hours, overdosing tends to occur with rebound conjunctival dilation occurring on withdrawal.
    • Dual-action antihistamine/mast cell stabilizer drugs are usually the first-line medication, with nonresponsive patients having steroid added or replacing the dual agents. The antihistamine gives rapid symptom relief, and the mast cell stabilizer treats the cause of the allergic process. Dosing is bid and available drugs are olopatidine (Patenol), ketotifen (Zaditor), epinastine (Elestat), and azelastine (Optivar)
    • Pure Mast cell stabilizers qid prevent mast cell degranulation and mediator release (lodoxamide [Alomide], cromolyn [Crolom], nedocromil [Alocril], pemirolast [Alamast]). Because these agents do not block histamine that has already been released, there is a 2- to 4-day delay in onset of effect (which may be addressed by also using an antihistamine drop for a few days). They are excellent for long-term prophylaxis and may be started a few weeks ahead of an anticipated reaction such as SAC. H1 blockers bid are good when only antihistamine is needed, as in mild cases or when combination with pure mast cell stabilizers (rather than a precombined drug) is desired (emedastine [Emadine], levacobastine [Livostin]).
    • P.119

    • Topical steroids. Patients with a moderate to severe disease or history of atopy, hay fever, eczema, or other systemic allergy often respond well to newer “soft” topical steroids bid to qid because of excellent surface-acting anti-inflammatory properties and low tendency for elevating IOP (rimexolone 1% [Vexol], loteprednol as 0.2% [Alrex] or 0.5% Lotemax suspension). Stronger topical steroids, such as 0.1% dexamethasone phosphate (qid taper to bid in 1 week), may be needed for acute exacerbations of more severe allergic disorders such as VKC or AKC, especially if there are corneal complications. Although pred acetate 1% suspension (Pred Forte) is stronger than the soluble pred phosphate 1% (Inflamase Forte, AK Pred) and dexamethasone phosphate 0.1% (Maxidex), the latter two are preferred because particles of drug do not lodge in between the papillae. Pulse therapy is very effective in these exacerbations: q2h for about 14 doses/day × 5 to 7 days and then rapidly tapered over 10 days. Every attempt should be made to discontinue or minimize steroid use between exacerbations (e.g., switching to a soft steroid as just noted above).
    • Cyclosporin A 0.05% (Restasis) or 2% bid to qid is a steroid-sparing, effective anti-inflammatory drug that may be used during exacerbations and then continued at bid after steroids have been stopped. Shield ulcers, refractory to topical steroids, antihistamines, and mast cell stabilizers have been resolved with addition of 1% or 2% CyA qid for 10 days. This is a useful approach in refractory AKC or VKC exacerbations.
    • Steroid nasal inhaler (Beconase, Vancenase, Rhinocort) bid is often additive therapeutically if there is any rhinitis. Desensitization by a dermatologist should be reserved for more severe cases in which a specific allergen can be unequivocally identified.
    • Oral antihistamines should probably be avoided, as their ocular drying effects may worsens ocular disease.
  • Giant papillary conjunctivitis (see Section XI.D and Chapter 14).
  • Phlyctenular keratoconjunctivitis. This nodular inflammatory response of the conjunctiva or cornea appears to be a type IV (delayed hypersensitivity) allergic reaction to a bacterial antigen, especially Staphylococcus in developed countries and M. tuberculosis in emerging nations with endemic tuberculosis (TBC). The clinical evolution of the phlyctenule is usually that of a small vesicle that forms a nodule that breaks down, with subsequent spontaneous healing of a wedge-shaped fibrovascular scar at the limbus. A local leash of vessels is common and may be most prominent if the phlyctenule moves onto the corneal surface. Symptoms of irritation, tearing, and redness tend to be more severe when corneal involvement occurs. The condition is recurrent if not treated and must be distinguished from an inflamed pinguecula, small pterygium, or from limbal corneal involvement by acne rosacea or limbal herpes simplex keratitis.
    • Treatment includes daily lid hygiene as described under blepharitis (Section III.C.3) and topical antibiotic such as bacitracin ointment bid or trimethoprim sulfate-polymyxin (Polytrim) qid for several weeks. Systemic therapy is doxycycline 100 mg or erythromycin 250 mg p.o. tid for 2 to 3 months or antituberculous therapy, if this is the causative agent. Metronidazole 0.75% skin gel bid for 6 months for associated rosacea is therapeutically useful (see Section III.D.3). Topical steroids should be avoided except early in therapy if there are marginal corneal infiltrates (e.g., rimexolone or lotoprednol bid to qid for 2 to 3 weeks).
  • Ligneous conjunctivitis is a rare, chronic disorder of the conjunctiva and other mucous membranes due to systemic plasminogen deficiency and characterized by inflamed (lymphocytes, plasma cells, and eosinophils) thick membranes formed on the palpebral conjunctiva and other mucosal sites. It may occur at any age. Treatment with excision followed by steroids, cyclosporine A, plasmin, cromolyn, fibrinolysin, or silver nitrate usually fails with rapid recurrence. Several successes using excision followed by topical purified plasminogen concentrate q2h to q6h over several weeks have been reported (not FDA approved). Prophylactic topical antibiotics should be used. The disease self-resolves after several months to years.
  • P.120

  • Cicatrizing conjunctivitis may be caused by (a) post-severe infections with trachoma, adenovirus, or streptococcus; (b) autoimmune or autoreactive conditions such as scleroderma, atopic KC, sarcoid, lichin planus, Stevens-Johnson syndrome, ocular pemphigoid, epidermolysis bullosum, dermatitis herpetiformis, and graft versus host disease; (c) old conjunctival trauma; (d) severe chronic blepharoconjunctivitis (rosacea, atopic).
  • Erythema multiforme (Stevens-Johnson syndrome). Usually occurring before the age of 30 years, this potentially fatal disease presents with fever, arthralgia, malaise, respiratory symptoms, and a mucous membrane and cutaneous eruption of sharply defined erythematous vesicular and bulbous patches scattered about the hands, forearms, face, and neck. New lesions appear over 2 to 4 weeks. This condition also affects the mucous membranes, resulting in severe stomatitis and conjunctivitis. It results from a hypersensitivity reaction to infections (herpes, mumps, Coxsackie virus, echovirus, mycoplasma, psittacosis, scarlet fever) or to drugs (sulfonamides, sulfones, penicillin, barbiturates). Ocular complications are common. Immune complex deposition in the dermis and conjunctival stroma is implicated. The conjunctivitis usually occurs in one of three forms: (a) catarrhal—circumscribed raised patches of edema that may lead to frank bullae formation that resolves with disappearance of the eruption, (b) purulent—usually severe and associated with extreme chemosis and corneal involvement (epithelial keratitis, ulceration) or exudative iridocyclitis, or (c) pseudomembranous—most common and associated with extensive discharge and pseudomembrane formation with subsequent symblepharon and scarring. Optic neuritis may develop in either eye. There is a mucopurulent conjunctivitis and episcleritis. Corneal involvement is most likely to occur with the pseudomembranous eye form and can result in frank ulceration and perforation. Iritis or panophthalmitis may occur. Late ocular complications include severe keratoconjunctivitis sicca, forniceal shrinkage with symblepharon, and trichiasis, neovascularization, and keratinizaton of the cornea. Treatment of acute systemic disease with high-dose systemic steroids is controversial and has no bearing on ocular prognosis. Systemic antibiotics are given if pneumonia is found. Ocular therapy in acute disease is topical antibiotic particularly for staphylococcal infection, which is common. Bacitracin, erythromycin, or a quinolone (moxifloxacin, gatifloxacin, ofloxacin) drops or ointment is given q4h to qid. Topical corticosteroids will help to control inflammation—less potent drugs such as lotoprednol or rimexolone are effective and safer. Long-term efficacy of steroids is still under debate. The fornices should be gently swept qd to bid with a glass rod after topical anesthetic to break fresh adhesions, along with daily lid hygiene. Late management is that of keratoconjunctivitis sicca, which may be severe, and iritis (see Section V and Chapter 9, Section VI.A). Immunosuppressives may be effective. Surgical keratoprosthesis (Boston kertoprosthesis) may restore good vision in end-stage disease, although the incidence of postoperative complications is higher in this group and in cicatricial pemphigoid than in in noncicatrizing ocular disease.
  • Cicatricial pemphigoid (ocular pemphigoid, benign mucous membrane pemphigoid), usually seen in patients over 60, is a relatively rare chronic inflammatory systemic disease of the mucous membranes (especially oral and eye) probably due to a cytotoxic (type II) hypersensitivity in which autoantibodies are directed against a cell surface antigen in the basement membrane zone. In the eye, there is mucoid discharge, redness, and conjunctival subepithelial fibrosis with foreshortening of the fornices, symblepharon formation, entropion, trichiasis, and, ultimately, severe dry eye with corneal ulceration, neovascularization, and keratinization.
    Treatment is primarily systemic, immunosuppressive, and done with a physician familiar with the drugs used. The earlier the treatment is started, the better the outcome. Initial treatment for mild, nonprogressive early ocular disease is suppression with steroids(e.g., prednisone 40 to 60 mg p.o. qd, tapering to alternate-day therapy ranging from 2.5 to 60 mg/day). Steroids do not stop progressive pemphigoid, but the sulfone, dapsone, is effective for mild to moderately progressive oral and ocular lesions. The starting dosage is 50 mg p.o. qd for 1 to 2 weeks, then, if tolerated, increased to 50 mg p.o. bid, but monitored for the
    P.121

    expected side effect of hemolytic anemia. Dosage should be adjusted up and down as needed. Successful maintenance doses range from 50 mg to 150 mg p.o. qd for years. Glucose-6-dehydrogenase-deficient patients should not receive this drug, or hemolysis will be severe. Rapidly progressive pemphigoid is usually responsive to combined cyclophosphamide 1.5 mg to 2 mg per kg p.o. qd in divided doses, and prednisone 1 mg per kg p.o. qd for 1 month. The target WBC is 2,000 to 3,000 cells/uL. If disease activity is still significant, cyclophosphamide is increased in 25-mg amounts monthly and prednisone tapered to 40 mg p.o. qd. Once disease is controlled, therapy is usually continued for 12 to 18 months total. Lid hygiene, topical lubricants, and blepharitis therapy should be maintained indefinitely. Oculoplastic surgery may be required for more advanced cases, and keratoprosthesis (Boston keratoprosthesis) with a valve shunt has been successful in restoring vision. Unfortunately, these advanced disease states do not respond well to systemic or topical treatment. Drug-induced pemphigoid (pseudopemphigoid) has been seen with echothiophate, pilocarpine, idoxuridine, and epinephrine. Administration of the offending drug should be stopped.
  • Graft versus host disease (GVHD) is a not uncommon complication of allogenic bone-marrow transplantation. The grafted cells see the patient’s tissues as “foreign” and attack the skin, gut, lungs, liver, and gastrointestinal system. GVHD may be acute or chronic. Ocular disease occurs in the chronic form characterized either by conjunctival inflammation with or without subepithelial fibrosis, or severe keratoconjunctivitis sicca due to T-lymphocyte infiltration of the lacrimal glands. There may be limbal stem cell deficiency and corneal scarring, erosions, and exposure due to cictricial lagophthalmos. Treatment is aggressive lubrication and punctal occlusion (which my be pushed out by fibrosis) or hyfrecation. Systemic tacrolimus and cyclosporin A along with topical CyA are often of benefit, especially if there is active skin disease. There is a high incidence of posterior subcapsular cataract, which will reduce vision and should be checked for on exam.
VIII. Dystrophies
Corneal dystrophy describes primary, inherited, bilateral changes of the cornea that occur unaccompanied by systemic disease. Characteristic corneal changes are also encountered in certain inherited metabolic and skin disorders.
  • Meesman epithelial dystrophy. This dominantly inherited dystrophy presents in the fully developed form a corneal epithelium diffusely studded with minute flecklike opacities of variable density and distribution that, on retroillumination with the slitlamp, appear to be minute collections of debris in an otherwise clear, spherical microvesicle. These spherical microcysts may elevate the corneal surface sufficiently to disturb the tear film. Superficial corneal scarring is rare. The epithelial changes have been demonstrated as early as 7 months of age and tend to increase with age. Although usually asymptomatic, some pedigrees have shown mild ocular discomfort and slight decrease in visual acuity to the 20/40 range. This condition must be differentiated from bilateral microcystic epithelial changes that may also be seen with corneal edema, with vernal conjunctivitis, or in association with disturbed tear function. Pathologically, the small round intraepithelial cysts appear to represent degenerated epithelial cells and contain periodic acid–Schiff (PAS)-positive cellular debris. Pathologic changes are usually confined to the epithelium. Hereditary epithelial dystrophy (Stocker-Holt, Schneider) occurs as a dominantly inherited dystrophy presenting with minute epithelial droplets that are transparent and have predilection for the center of the cornea. There can be fluorescein staining, but pathologic changes are confined to the epithelium. This condition may be a variant of the Meesman corneal dystrophy. Treatment is usually not necessary, but first line would be lubrication with artificial tears and ointments. If the discomfort is severe, TSCLs with continued tear lubrication may be helpful. If visual impairment is unusually severe, laser keratectomy or lamellar keratoplasty may be indicated.
  • Anterior membrane dystrophy. There is an increasing tendency to label the epithelial basement membrane disorders as anterior membrane dystrophies.
    • Cogan microcystic epithelial dystrophy. This epithelial disorder, with no obvious hereditary tendency, appears in females as bilateral, gray-white, round or
      P.122

      comma-shaped deposits in the corneal epithelium (“putty marks”). Mild foreign body sensation is often a complaint, but visual acuity and corneal sensation are unaffected. Histologically, the deposits represent intraepithelial cysts containing cellular debris. PAS-positive nodular substance on the anterior surface of an irregular basement membrane is also seen.
    • Fingerprint dystrophy. Bilateral curvilinear lucent opacities (seen best on retroillumination at the slitlamp) at the level of the Bowman layer and variously described as “fingerprint” or “mare’s tail” lines are the characteristic of this condition in which no consistent hereditary pattern is described.
    • Map-dot-fingerprint dystrophy. Polymorphic epithelial and anterior Bowman layer microcystic opacities described as a map-dot pattern or a fingerprintlike wrinkling of the basement membrane (seen best by slitlamp retroillumination) have been observed in bilateral distribution idiopathically or after fingernail or other corneal abrasions, and are often associated with recurrent epithelial erosions.
    • Recurrent corneal erosion syndrome (RES). Anterior membrane dystrophies may be accompanied by recurrent epithelial erosions. Often a fourth category of dystrophic recurrent erosion is described with similar epithelial changes but occurring in a dominantly inherited fashion. All are probably associated with an abnormality of basement membrane adhesion that accounts for the recurrent erosive episodes, causing eye discomfort and foreign body sensation (see Chapter 2). Trauma such as a fingernail or paper cut may also cause RES.
    • Treatment of anterior membrane–epithelial disorders is essentially treatment of recurrent erosion and includes patching with an antibiotic during the acute phase and an attempt at aborting recurrences by use of artificial tears several times daily and tear ointment nightly. For frequent or more severe erosions, a TSCL (Permalens) should be fitted and left in place for 3 to 6 months. Antibiotic drops bid and lubrication should be used if the epithelium is disrupted. Abnormalities of the lids, including chronic low-grade blepharomeibomitis, can aggravate the epithelial changes and predispose to recurrent erosion. Meticulous lid hygiene and control of any blepharitis are often necessary to prevent repeated attacks of erosion. Recent work has shown that oral doxycycline and mild topical steroids, both of which inhibit matrix metalloproteinases, are effective in treating recurrent erosion. Addition of these medications has increased the success of conservative measures such as lubrication and bandage contact lenses and has reduced the need to resort to surgical management of recurrent erosion. Superficial keractectomy or anterior stromal puncture is advocated in persistent cases. If an individual area of erosion can be identified, stromal puncture may be attempted. The puncture technique is done under topical anesthesia at the slitlamp. A 20- to 30-gauge bent needle tip is used to place 20 to 40 micro-punctures directly over and surrounding the erosion. Depth is through epithelium to its underlying basement membrane with the purpose of creating microfibrotic adhesions that will hold the epithelium in place. The visual axis may be included because scarring is negligible. After treatment, antibiotic ointment is instilled and a 24-hour pressure patch applied. Lubricants are used regularly starting 1 day postoperatively. Occasionally, the erosion will recur in the same area or adjacent to it, requiring retreatment with anterior stromal puncture or, if due to local edema, treatment with ointment only. If no discrete area can be identified, then superficial keratectomy can be performed. Using topical anesthesia, the surgeon removes all of the loose epithelium with surgical sponges. Often the entire epithelium is found to be loosely adherent. The underlying Bowman layer is then polished with a no. 57 blade to encourage adherence. A bandage contact lens and a punctal plug are typically placed. Topical antibiotics should be used until the epithelium has healed. The bandage contact lens remains in place for 3 to 6 months, until the hemidesmosomes are formed. Oral doxycycline is also prescribed due to its inhibitory effects on corneal matrix metalloproteinases. Excimer laser has been successful in resolving recalcitrant cases of recurrent erosion, although ablation of the cornea may induce hyperopia.
  • P.123

  • Reis-Bücklers dystrophy is an autosomal-dominant condition of the cornea characterized by a network of ringlike opacities occurring at the level of the Bowman layer and protruding irregularly into the epithelium, with subsequent distortion of the anterior corneal surface. The disorder may present at about 5 years of age and shows a progressive course, with increasing frequency of attacks of recurrent erosions that usually result in a diffuse anterior scarring corresponding to a reduction in visual acuity and a decrease in corneal sensation. Histopathologic studies show widespread destruction of the Bowman layer, with replacement by irregular scar tissue interspersed with aggregates of microfilamentous material. Absence of hemidesmosomal attachments accounts for the faulty adherence of epithelium. Early therapy with lubrication and TSCL (Permalens) is effective, but in severe cases laser keratectomy or lamellar keratoplasty may be indicated.
  • The anterior dystrophy described by Grayson and Wilbrandt is similar to Reis-Bücklers dystrophy, with variable effects on vision and of corneal sensation.
  • Vortex dystrophy was the diagnosis once applied to the pigment lines occurring in a whorllike fashion over the surface of the cornea and located in the area of the Bowman layer and adjacent stroma. This appears to be the same corneal lesion seen in Fabry diseaseand is thought to be a manifestation of the asymptomatic carrier state of females with X-linked Fabry disease. In general, it must be distinguished from the corneal deposits seen in phenothiazine keratopathy, amiodarone, chloroquine, indomethacin, or tamoxifen toxicity, and occasionally the pattern of fingerprint lines. Drug-induced vortex keratopathy is not an indication to stop the drug if it is needed. The condition is often reversible if the medication is stopped, however.
  • Granular dystrophy (Groenouw type I) is an autosomal-dominant dystrophy characterized by stromal opacities of dense, milky, granular-appearing deposits occurring in the axial portion of the cornea, most prominently in the anterior stroma. Intervening stroma is clear. The lesions may be manifest in the first decade of life, but visual acuity is usually not affected until late in the disease. The histochemical characteristics are listed in Table 5.9. The deposits are principally hyaline degeneration of collagenous protein. When visual acuity is notably impaired, penetrating keratoplasty is indicated. The βIG-H3 gene, which is found on chromosome 5 and codes for the protein keratoepithelin, has been implicated in several corneal dystrophies, including granular, lattice, Avellino, and Reis-Bücklers dystrophy, supporting the idea that these dystrophies are related.
  • Macular dystrophy (Groenouw type II), an autosomal-recessive dystrophy, appears as a diffuse clouding in the central cornea between the ages of 5 and 9 years. Gradual increase in the density of the opacity with development of gray-white nodular deposits of varying size within the corneal stroma is accompanied by progressive diminution of vision and episodic irritation and photophobia. The severe decrease in visual acuity often necessitates penetrating keratoplasty. Histologically and histochemically, the deposits in and around the keratocytes appear as accumulation of mucopolysaccharide as a result of a local enzyme deficiency. Monoclonal gammopathy may cause deposits similar to macular dystrophy and should be
    P.124

    considered (serum protein electrophoresis), because it may be a forerunner of multiple myeloma (Table 5.9).
    TABLE 5.9 Histologic Staining Characteristics of Stromal Dystrophies
    Dystrophy Masson trichrome PASa Congo red Birefringence
    Granular Bright red Negative Negative Negative
    Macular Negative Pink Negative Negative
    Lattice Red Pink-red Red Positive
    aPAS, periodic acid–Schiff (reaction).
  • Lattice dystrophy (Biber-Haab-Dimmer) is an autosomal-dominant dystrophy characterized by the appearance in the corneal stroma of relucent branching filaments interlacing and overlapping at different levels and forming an irregular latticework with dichotomous branching. Fine dots, flakes, and stellate opacities may appear between the filaments. Although appearing as early as 2 years of age, the occurrence of recurrent erosive episodes and progressive clouding of the central cornea is apparent by the age of 20 and is associated with decreased visual acuity such that penetrating keratoplasty is often indicated when the patient is in the fourth decade of life. Histopathologically and histochemically, the stromal deposits appear as hyaline fusiform deposits of amyloid. Avellino dystrophy is dominantly inherited and shares features of lattice and granular dystrophy (Table 5.9).
  • Fleck dystrophy (central speckled dystrophy) is an autosomal-dominant condition involving all layers of the cornea with oval to round gray-white opacities. The lesions are well circumscribed and separated from each other by clear cornea. Corneal sensation and visual acuity are usually not affected. Treatment is usually not necessary.
  • Central cloudy and parenchymatous dystrophy is an apparently autosomal-dominant condition that involves particularly the deep stroma, but sometimes extends to the Bowman layer. The condition is quite variable and usually does not result in visual impairment. Treatment is usually not indicated.
  • Schnyder crystalline dystrophy, an autosomal-dominant condition, is characterized by a round, ring-shaped, central corneal opacity consisting of white-to-yellow or polychromatic crystals in the stroma. Peripheral deposits separated from the limbus by a clear line also appear. The lesions may be apparent as early as 18 months and may progress, but usually are not destructive to visual acuity. Corneal sensation is usually normal. Pathologically, the needlelike crystals contain cholesterol. Occasionally, the visual acuity is decreased, and laser keratectomy or penetrating keratoplasty is indicated. Some patients with this dystrophy exhibit elevated blood lipids, xanthelasma, and corneal arcus.
  • Congenital hereditary endothelial dystrophy (CHED) is characterized by diffuse milky or ground-glass opacification of the stroma associated with a thickening of the cornea up to four times normal. It has been described as both a dominantly and a recessively inherited disorder. Both forms of CHED have been linked to chromosome 20, although in different regions, supporting the idea that these conditions are distinct. Despite the gross stromal edema, the epithelium has only a mild roughening associated with fine microbullae. Visual acuity varies according to the degree of corneal clouding. Corneal sensation is normal and vascularization is rare. Histopathologically, there are rare to absent endothelial cells and an overall increase in thickness of the Descemet membrane, in contrast to Fuchs’ dystrophy. Nystagmus is common and congenital glaucoma must be ruled out. The prognosis for penetrating keratoplasty in these patients is fair. Keratoprosthesis may offer a more favorable prognosis and provides for rapid visual rehabilitation, which simplifies amblyopia management. Examination of asymptomatic relatives of patients with congenital hereditary endothelial dystrophy may reveal clear vacuolar lesions with surrounding white haze and an irregular endothelial mosaic despite normal corneal thickness and visual acuity. The high risk of producing offspring with CHED makes examination of relatives important.
  • Fuchs endothelial dystrophy is seen most often in females in the fifth to sixth decades of life. Approximately 30% of patients have a family history of the disease. Prior studies have suggested an autosomal dominant inheritance pattern. However, the late onset of the disease and the fact that it is aymptomatic in its early stages makes accurate determination of the inheritance pattern difficult. The etiology of Fuchs dystrophy is unclear, although perturbations in the energy metabolism of the endothelium have been suggested, as has increased apoptosis and changes in the collagen compostion of the Descemet membrane. The endothelium has scattered guttae (Descemet “warts”) progressing to a “beaten silver” appearance. There may
    P.125

    be increasing stromal edema from endothelial dysfunction that culminates in epithelial edema, painful bullous keratopathy, and peripheral vascularization. Frequently, the condition is associated with cataractous changes in the lens nucleus, and a higher incidence than normal of chronic open-angle glaucoma and angle-closure glaucoma has been reported. Histopathologically, there is a paucity of endothelial cells which may be quantitated on specular or in vivo confocal microscopy, which provides a measure of disease status. Initial palliative therapy includes the use of hypertonic sodium chloride ointments at night and drops during the day. If painful bullous keratopathy ensues, a soft contact lens will often provide relief, although it rarely improves visual acuity. Penetrating keratoplasty is the mainstay of therapy for both visual rehabilitation and relief of pain. Recently, various techniques for selective transplantation of the endothelium have become popularized for surgical management of Fuchs’ dystrophy. The long-term success of these endothelial transplants has not yet been determined.
  • Posterior polymorphous dystrophy, a dominantly inherited dystrophy of the endothelium and Descemet membrane, presents clinically with a variable number of round, elliptical, or irregular lesions, often with vesicular appearance, bulging into the stroma or projecting into the anterior chamber. Although generally benign and nonprogressive, it can be associated with corneal edema, requiring penetrating keratoplasty for restoration of vision. Abnormal iris processes and peripheral anterior synechiae have been described. Histopathologically, a thickening of the posterior lamellae of the Descemet membrane and the presence of atypical cells on the posterior corneal surface suggestive of metaplasia to a fibroblastic cell suggest that it may represent a form of the anterior cleavage syndrome.
  • Keratoconus (KC, ectatic corneal dystrophy) is a disorder characterized by conical ectasia (bulging) of the paracentral cornea, with thinning and scarring resulting in a painless, progressive loss of vision due to an increasingly severe irregular myopic astigmatism. Corneal topography is useful in detecting early cases and following progression. Subclinical KC may be detected by doing keratography in upgaze and looking for inferior steepening. These patients should not have refractive surgery. Familial occurrence has been noted, although the majority of cases show no definitive inheritance pattern. There is often a history of eye rubbing. In the early stages, distortion of the retinoscopic reflex, keratoscopic figures, and keratometric mires are apparent. As the condition advances, vertical striae (Vogt striae) may be seen in the posterior stroma along with axial thinning and an increase in the axial corneal curvature. Reticular scarring of Bowman membrane can occur, the appearance of a Fleischer ring (epithelial iron deposits at the base of the cone), and bulging of the lower eyelid (Munson sign) on downgaze are often noted. Stromal corneal nerves tend to be more visible, and fine fibrillary lines may be seen along the internal edge of the Fleischer ring. Occasionally, a break in the endothelium and Descemet membrane results in gross stromal edema with bullous epitheliopathy (corneal hydrops) accompanied by pain and a rapid decrease in vision. Treatment is correction of the refractive error by spectacles or gas-permeable hard contact lenses or, in advanced cases, penetrating keratoplasty, with good prognosis for this condition. Recent work has suggested that intracorneal rings (Intacs) may improve best-corrected vision and contact lens tolerability. The femtosecond laser has increased the safety of placing intracorneal rings in thinned, ectatic corneas. Corneal hydrops is self-resolving and managed conservatively with antibiotic ointments and moderate pressure patching. Patients with KC should not have routine pupillary dilation because permanent mydriasis may ensue (Urrets-Zavalia syndrome). This idiopathic condition is uncommon. If there is an indication for dilation (e.g., with new floaters or following trauma), then it is worth the risk of dilation. KC has been described in association with various ocular anomalies, such as blue sclera, ectopia lentis, cataract, aniridia, retinitis pigmentosa, and optic atrophy. It is also associated with systemic conditions, Down syndrome, Ehlers-Danlos syndrome, Marfan syndrome, Addison disease, neurofibromatosis, Apert anomaly, and allergic disease, including vernal conjunctivitis and atopic eczema. Association with chronic rubbing of the eyes and eyelids has been suggested.
P.126

IX. Corneal edema
Corneal deturgescence is achieved when pump function of the corneal endothelium balances the fluid-accumulating effect of intraocular hydrostatic pressure and corneal swelling pressure. Disturbance of this balance or disruption of the limiting membranes of the cornea (epithelium and endothelium) results in corneal edema. Stromal edema may minimally decrease visual acuity; epithelial edema, however, results in significant visual impairment and painful surface breakdown.
  • Causes of corneal edema
    • Elevated IOP
      • Acute angle-closure glaucoma results in marked and often rapidly increased IOP. Corneal stroma thickness may not be increased despite prominent epithelial edema, but in some cases the pressure will aggravate prior endothelial dysfunction or produce temporary dysfunction resulting in stromal edema. Epithelial edema is a classic sign of acute glaucoma with resultant decreased vision. Although both epithelial and stromal edema usually resolve with control of the IOP, there occasionally can be residual stromal haze, which does not greatly affect vision.
      • Congenital glaucoma can produce corneal haze that is usually most marked centrally, but that can involve the entire cornea. Edema involves stroma and epithelium. Normalization of the pressure may permit clearing of the cornea, although residual endothelial damage as manifested by horizontal (Haab) striae of the Descemet membrane may predispose to future corneal decompensation and edema late in life.
    • Trauma
      • Birth trauma (forceps injury) results in relucent double-contoured striae of the Descemet membrane that signal endothelial damage. The cornea is often clear during youth but can become edematous after an interval of several decades, with both stromal and epithelial edema.
      • Nonsurgical contusion injury (e.g., following blunt trauma from airbag deployment) can cause focal endothelial dysfunction, with typical annular or diskiform areas of endothelial and stromal edema. Often transient and resolving over a few days, these focal areas of edema usually cause little long-term visual disability.
      • Penetration of a foreign body into the anterior chamber can result in a retained foreign body in the inferior anterior chamber angle, with resultant focal (wedge-shaped) inferior corneal edema. Removal of the foreign body can be curative.
      • Surgical trauma from cataract extraction, intraocular lens implantation, and prolonged or profuse anterior chamber irrigation can damage endothelial cells to produce corneal edema. Of the 31,532 corneal transplants done in the United States in 2000, the greatest numbers were for pseudophakic edema (20%). The edema can occur following vitrectomy or retinal detachment surgery and is more prone to occur in diabetics. Extensive extraocular muscle detachment procedures can also result in corneal decompensation if anterior segment necrosis occurs. Vitreous adherent to the cornea following cataract extraction may produce focal edema and stimulate metaplasia of the endothelium with resultant persistent edema.
    • Dystrophy. Endothelial dystrophies such as Fuchs, CHED, and posterior polymorphous (see Sections VIII.L–O) may all cause edema. Although usually not considered as a cause of corneal edema, the anterior membrane dystrophies are characterized by corneal changes that can be accompanied by epithelial edema in very discrete distribution, especially if recurrent breakdowns have occurred. An acute and painful cause of corneal edema occurs in some cases of keratoconus KC (acute hydrops).
    • Endothelial dysfunction secondary to inflammation. Uveitis or intraocular inflammation can temporarily depress endothelial function to produce edema. Control of inflammation often restores endothelial integrity and reversal of edema. Herpetic uveitis is a common offender and should be suspected in
      P.127

      patients with unilateral corneal edema and uveitis. Focal keratitis (bacterial, fungal, or viral) can provoke edema both by local inflammatory response and by compromising endothelial function. The infectious nature of the disease process is often suggested by the clinical features of focal infiltration of inflammatory cells that accompany the edema. Corneal graft rejection in patients who have undergone penetrating keratoplasty is a classic example of endothelial damage. The clinician should be alert to any inflammation or the earliest sign of edema in a corneal graft no matter how distant the surgery.
    • Epithelial damage resulting from mechanical, chemical, or radiation injury disrupts the barrier effect of the epithelium, allowing passage of fluid into the anterior corneal stroma. Metabolic disturbance of the cornea, such as hypoxia of contact lens overwear or toxic effects of medications and anesthetics, can also provoke intra- and intercellular epithelial edema.
  • Treatment is first to address the primary problem to restore the normal physiologic balance of corneal hydration. Should that be impossible, attempts should then be made to compensate for the fluid accumulation. Although visual acuity may be improved, the treatment often must strive for comfort and protection of the cornea.
    • Lower IOP. If IOP is pathologically elevated, attempts should be made medically or surgically to lower that pressure. In patients with borderline endothelial function and early corneal edema, reduction of the pressure from high-normal to low-normal levels will often relieve the edema.
    • Control of inflammation may improve corneal edema if dysfunction is the result of that inflammation. Topical steroids often are sufficient to achieve this.
    • Hypertonic agents, such as sodium chloride 5% (drops or ointment), colloidal osmotic solutions, or anhydrous, may provide sufficient dehydrating effect. Discomfort from such applied solutions can be significant, especially with glycerine, and limits their acceptance. Other mechanical measures for encouraging evaporation of tears, such as dehumidification of the environment, glycerine, or gentle dehydration with a handheld hairdryer may be used with some success.
    • Graft rejection (penetrating keratoplasty) usually presents with slight red eye, blurred vision, endothelial keratic precipitates (lymphocytes), and sectoral or total graft edema. It requires emergency therapy with topical steroids (e.g., 0.1% dexamethasone q1h by day and q2h by night for several days, followed by taper down to qid by about 3 to 4 weeks and to qd for 2 to 3 months). Rejections with edema delimited by an endothelial lymphocyte (KP) line respond far better than total diffuse edema of the entire graft. If there is no response to therapy within 3 to 4 weeks, the graft has probably failed due to permanent endothelial damage and may need to be replaced. Herpetic graft rejections should be treated with steroids (see Section IV.D), plus antiviral acyclovir p.o. 400 mg bid for 12 to 18 months because of the high incidence of dendritic keratitis in the face of rejection. Topical cyclosporine, a selective T-cell immunosuppressant currently marketed for dry eye therapy (Restasis), has been used successfully as prophylaxis against rejection in high-risk patients (several graft failures, heavy neovascularization, severe alkali burn, severe dry eye).
    • For those cases of painful corneal edema unresponsive to more conservative measures, penetrating keratoplasty offers the most effective method of restoring vision. Obviously, the prognosis for successful keratoplasty depends on the etiology of the corneal edema, with inflammatory conditions being less sure than dystrophic causes.
    • If visual rehabilitation is not essential, several procedures may be used to ensure comfort and protection of the edematous cornea. Therapeutic soft contact lens therapy (Permalens, Kontur) will often ensure comfort (see Section X.A). Conjunctival flap surgery after epithelial débridement gives relief and does not preclude subsequent keratoplasty. Amniotic membrane may also be used, although the membrane does dissolve within several months, limiting this to a temporary solution. The Boston keratoprosthesis also has been
      P.128

      successful and restores vision, but should be reserved for those patients with severe disease or prior keratoplasty failures.
X. Congenital anomalies of the cornea
Congenital lesions of the cornea may be inherited as developmental defects or errors of metabolism, or may result from intrauterine infection or injury.
  • Anomalies of size, shape, and contour
    • Megalocornea is an enlargement of the cornea beyond 13 mm in diameter. The cornea is usually clear with normal vision, but there may be astigmatic refractive errors. The condition is usually not progressive and requires no treatment. The developmental condition must be distinguished, however, from corneal enlargement due to congenital glaucoma. The buphthalmic cornea often has central or peripheral clouding and Haab striae or Descemet tears. IOP is elevated in buphthalmos but normal in megalocornea.
    • Microcornea is a cornea with a diameter less than 11 mm. Occurring as a developmental defect, the cornea is often steeper than normal, producing myopia. Microcornea can occur as part of other congenital abnormalities, including rubella syndrome. If there is no corneal opacification, treatment is often not necessary except for correction of the refractive error.
    • Cornea plana is a rare flattening of the anterior contour of the cornea. The cornea may be small in addition to its markedly flattened shape and marked astigmatism.
    • Keratoglobus is a rare bilateral enlargement of the cornea in which it assumes a globular shape. Myopic and astigmatic refractive errors often occur.
  • Congenital corneal opacities
    • Edema can occur as a result of congenital hereditary endothelial dystrophy or congenital glaucoma. Edema can also occur with Descemet ruptures resulting from forceps injury or birth trauma.
    • Congenital malformations. A rather confusing array of congenital corneal opacities associated with abnormalities of the anterior chamber angle has been described as part of the anterior chamber cleavage syndrome. A recent classification helps to categorize the appearance of central or peripheral opacification with or without corneal–iris or corneal–lenticular touch (Fig. 5.2).
    • Epibulbar and limbal dermoid tumors also can occur as congenital lesions. Treatment for these congenital malformations can be difficult and usually requires penetrating keratoplasty or anterior segment reconstruction with or without lensectomy. Because the surgical technique can be difficult and graft rejection is not uncommon, it is probably best to perform surgery on the worse eye only. Developmental abnormalities of the posterior segment may be present and further interfere with visual function.
    • Inborn errors of metabolism (see Chapter 11). Mucopolysaccharidoses occurring as autosomal-recessive traits can present with corneal hazy opacification, particularly in the Hurler, Scheie, Morquio, and Maroteaux-Lamy syndromes. Corneal opacification can also be noted in cystinosis, mucolipidosis, gangliosidosis, Lowe syndrome, Riley-Day syndrome, and von Gierke disease.
    • Chromosomal defects can be associated with corneal opacification, especially with trisomy 21, trisomy 13 to 15, and trisomy 18 (see Chapter 11).
    • Postinflammatory opacities of the cornea can be present with the rubella syndrome, luetic IK, or congenital herpes simplex infection.
XI. Therapeutic soft contact lens (TSCL)
(see Chapter 14, Section VIII and Table 14.4).
  • TSCL (bandage contact lens). The hydrophilic soft contact lenses (Permalens, Coopervision; Kontur, Kontur Kontact Lens) offer a valuable method of treatment for a variety of corneal abnormalities. The Permalens has base curves from 7.7 to 9 and diameters 13.5 to 15 mm. The 14.5 mm Plano T lens (Bausch & Lomb) is most useful over tissue adhesive because of its greater thickness and low tendency to tear on the rough glue surface. The most frequent use for TSCLs is as a protective
    P.129

    P.130

    bandage for a diseased epithelial surface (epithelial defect, corneal edema), but the hydrophilic lens can also provide a reservoir for tears or medications and can be used for cosmetic or therapeutic occlusion. Antibiotic drops (e.g., Polytrim bid) are used where the epithelium is disturbed. Ointments are not indicated because they dislodge the lenses. Specific indications and precautions are as follows:
    Figure 5.2. Composite illustration of the anatomic findings in the anterior chamber cleavage syndrome. The stepladder table demonstrates the spectrum of anatomic combinations and terms by which they are commonly known. (Adapted from
    Waring GO III, Rodrigues M, Laibson PR. Anterior chamber cleavage syndrome: a stepladder classification. Surv Ophthalmol 1975;20:3.
    )
    • Alkali burns. After immediate removal of the offending chemical and appropriate irrigation, the ocular surface is often left deepithelialized or populated by a markedly abnormal epithelium. A TSCL applied to the alkali-burned eye when conjunctival edema has subsided will aid in the re-epithelialization and provide protection to the fragile and easily dislodged epithelial layer. Encouragement of re-epithelialization of the ocular surface is necessary to avoid the progressive ulceration that can occur in response to local collagenase production in the second to third week following the injury. Topical antibiotics are used to prevent infection.
    • Bullous keratopathy. Epithelial edema of aphakic bullous keratopathy or Fuchs dystrophy that does not respond to topical hyperosmotic agents can result in bullous epithelial lesions that are painful on breakdown. TSCLs can protect against recurrent epithelial breakdown and will provide comfort in many patients. Visual acuity is rarely improved but comfort is attained. Prolonged epithelial edema, particularly with the use of a large contact lens, can lead to vascularization that can interfere with future corneal surgery.
    • Corneal perforations. Pinpoint perforations or flap lacerations that are otherwise in good apposition can often be splinted with a soft contact lens until wound healing occurs. Frank perforations that can be sealed with cyanoacrylate tissue adhesive are best managed by application of a TSCL to improve patient comfort and prevent the mechanical dislodgment of the adhesive by the action of the lids.
    • Corneal transplants. In cornea with diseased epithelium (chemical burns, herpes simplex keratitis), delay in epithelialization of the corneal donor or secondary breakdown of that epithelial layer frequently responds to soft contact lens treatment. Pinpoint leaks at the wound margin or slight anterior shifting of the wound edge that is not sufficient to require positioning of new sutures can often be splinted and sealed with the use of a TSCL. TSCL therapy also provides comfort in those patients with epithelial defects.
    • Dry eye syndrome. Patients with lacrimal insufficiency that does not respond to replacement lubricants and lacrimal punctal occlusion may benefit from PF artificial tear lubrication q1h to q2h plus a TSCL that provides a tear reservoir. These eyes may also be less tolerant of a TSCL, however. Topical antibiotic drops bid should be used as prophylaxis against infection. The gas-permeable scleral contact lens has been very effective in otherwise contact lens–intolerant eyes with extensive ocular surface disease (see Section VI.B.3).
    • Epithelial erosions. Epithelial defects occurring in a cornea prone to epithelial breakdown (diabetes mellitus, anterior membrane dystrophy, lattice corneal dystrophy) are effectively managed with a TSCL plus tear drop lubricants. Treatment is required for several months for complete reformation of the basement membrane adhesions (hemidesmosomes).
    • Filamentary keratitis. This abnormality of the epithelial surface, probably the result of aberrant healing of multiple small erosions, usually responds well to TSCLs. Relief of the irritative symptoms and loss of the filaments is usually rapid. In a dry eye, the tear reservoir effect of the lens is also of some benefit.
    • Irregular astigmatism. Whereas a soft contact lens usually is not effective in relieving high degrees of astigmatism, a mildly irregular anterior corneal surface can be smoothed to better optical clarity with a TSCL, and any tendency to dellen formation can be minimized.
    • KC. TSCLs alone are inadequate to treat most cases of KC. It is possible, however, in patients who are intolerant of hard contact lenses, to provide a better surface for a hard contact lens by application of a soft contact lens. The “piggyback” technique can provide tolerance of an optically efficient lens system.
    • P.131

    • Neurotrophic keratopathy. Patients with neurotrophic breakdown of the corneal epithelial surface (herpes zoster ophthalmicus, status posttrigeminal rhizotomy) often will have epitheliopathy and recurrent epithelial breakdown. These patients can be treated with a TSCL, but great care is required because the protective mechanisms of sensation are diminished and a greater incidence of intolerance with corneal infiltration and vascularization as well as superinfection is possible. If intolerance develops, partial tarsorrhaphy should be considered instead, adjunctively or prophylactically.
    • Trichiasis. Scarring of the lids or inturning of the lashes from any etiology will result in chronic irritation of the epithelium, which can be minimized by wearing TSCLs as a protective barrier. Posttraumatic or cicatricial entropion is especially well treated this way, particularly if lid surgery is difficult or inadvisable. Patients with benign mucous membrane pemphigoid are more difficult to fit because of the frequent shortening of the cul-de-sac. Extended-wear gas-permeable scleral lenses are more effective.
    • Postherpetic or postinfectious (trophic) defects. Following an infectious epithelial defect, when the primary infection has been adequately controlled, TSCLs are of great value in promoting reepithelialization. Control or several days of adequate drug therapy of the underlying infectious element is advisable before such lens insertion.
    • Descemetocele. In an eye that has sustained a thinning of the stroma to the point of descemetocele formation, a TSCL may be applied as reinforcement until such time as definitive therapy of tissue adhesive, lid adhesion, or keratoplasty may be done.
    • Medications. Although a TSCL can serve as a barrier to penetration of some medications, it is also possible by saturation of the lens to provide a higher and more uniform concentration of delivery to the anterior corneal surface. Instillation of drops into the eye with a soft contact lens will also provide a mild reservoir effect. Epinephrine-containing compounds can become entrapped in the soft contact lens and oxidize to the adrenochrome pigments, producing a black tint to the lens. Fluorescein is a well-known stain that can be absorbed by the hydrophilic material but wash out within a few hours. Collagen shields (Surgilens) are discussed in Section IV.B.6.
  • Care of the soft contact lens. The flexibility of the soft contact lens sometimes poses problems on insertion and removal. The tendency of the lens to desiccate and deform its contour is also a problem at times. The lens should be kept hydrated at all times in a saline solution without preservatives. It should be cleaned and sterilized prior to insertion. Care should be taken not to apply any sharp object to the lens, because this may tear it. In many cases in which there are organic abnormalities of the cornea, it is advisable to use prophylactic antibiotic drops. Antiviral ointment will dislodge the lens.
  • Complications of soft contact lens therapy (see Chapter 14 for cosmetic hard, gas-permeable, and daily- and extended-wear lenses).
    • Tight lens syndrome with a red, sore, tearing eye may occur weeks after placement. It has fairly sudden onset and is due to spontaneous tightening of the lens causing limbal compression and vascular engorgement. It resolves several hours after lens removal. A new, possibly larger, flatter lens may be inserted at the time of removal or days later.
    • Loss or damage to lens. The flexibility of the lens and irregular contour of the diseased cornea can result in repeated loss of the lens. Tears or fractures in the lens can cause discomfort and irritation.
    • Sterile infiltrates are white and tend to appear peripherally, but can be paracentral or central, and are usually multiple and subepithelial. They disappear with removal of the lens. Pain, discharge, epithelial staining, and anterior chamber reaction are associated with an infectious etiology; their absence is associated with sterile infiltrates. Size of infiltrate is not a factor. Prophylactic quinolone drops qid for a few days until probable sterile infiltrate clears is advisable. Evaluation and therapy for infectious keratitis should be undertaken if there is any question about diagnosis.
    • P.132

    • Infection. The soft contact lens has been associated with the complication of infection. Although this is usually bacterial, fungal infection can also occur. It is therefore essential that the lens be periodically sterilized and that a prophylactic topical antibiotic be used if the epithelium is unhealthy. Frequent follow-up is essential (see Section IV.B, E, and F).
    • Anterior chamber reaction. The inflammatory reaction that can be provoked by a contact lens can include flare and cell or frank hypopyon. This reaction is usually sterile and resolves after removal of the lens.
    • Vascularization. Peripheral vascularization can occur, particularly in a patient with chronic epithelial edema or postinfectious ulcer. The lens should be removed unless this will further compromise the cornea.
  • Giant papillary conjunctivitis (GPC) is a local allergy to antigen coating on soft or hard contact lenses, ocular prostheses, and sutures. Tear levels of IgE, IgG, and IgM are elevated and, as in vernal conjunctivitis, which is clinically similar, the mast cell system is activated.
    • Clinical findings are decreased contact lens tolerance, itching, photophobia, mucous discharge, redness, punctate staining at the upper limbus, and giant papillae (<0.3 mm in diameter) on the upper tarsal conjunctiva.
    • Treatment includes:
      • Eliminate contact lens wear (or prosthesis or sutures) for several weeks until all inflammation and punctate staining are gone.
      • Start a mast cell stabilizer (e.g., lodoxamide, olopatadine, or cromolyn) qid and use for several weeks until GPC is resolved.
      • Once the eyes are quiet, fit new contact lenses, possibly of a material different from the original offending set. Daily disposable contact lenses are recommended for patients with GPC once the disease is under control, as this eliminates the problem of protein build-up on the lens.
  • Hard contact lenses are most effective in optically correcting high degrees of ametropia or corneal astigmatism as in KC or post-thinning distortion (see Chapter 14).
  • Microbiologic study of contact lens–related keratitis indicates that cosmetic contact lenses were worn in about 45% of cases, with extended-wear soft contact lens incidence 2.5 times that of daily-wear soft contact lenses and daily-wear hard lenses in only 3% of cases. Aphakic contact lenses were worn in about 32% of cases, with aphakic extended-wear soft contact lenses accounting for about 90% of this group. TSCLs were worn in about 25% of cases. Of organisms cultured, 52% were Gram-positive, 36% Gram-negative, 4% fungi, and 4% Acanthamoeba. Pseudomonas was highly associated with cosmetic soft lens use. Other studies on contact lens–related fungal keratitis indicate 4% incidence in cosmetic or aphakic hard or soft contact lenses and 27% incidence in therapeutic soft lenses. Fusarium and Cephalosporium predominated in cosmetic lenses and Candida predominated in therapeutic lenses. Disposable extended-wear soft contact lenses have also been associated with bacterial keratitis, even with proper lens care (70% Pseudomonas, 10% Acanthamoeba, 30% other bacteria). In 2006, an epidemic of Fusarium keratitis in healthy soft contact lens wearers was linked to a particular contact lens cleaning solution (ReNu with MositureLoc), which was removed from the market.
  • Contact lens disinfection studies indicate that although available hard lens regimens and soft lens cold hydrogen peroxide or heat disinfection effectively eliminate bacteria from the lenses, bacterial contamination was found in the contact lens cases or solutions: 75% in chemical disinfection, 50% in peroxide disinfection, and 28% in heat procedure. Acanthamoeba was effectively eliminated from lenses by not less than 2-hour exposure to 3% hydrogen peroxide followed by enzyme catalyst. Also effective in eliminating the trophozoite and cysts from solutions and lens cases was 4-hour exposure to thimerosal 0.001% to 0.004% or benzalkonium chloride 0.005%, both with edetate or 1-hour exposure to chlorhexidine 0.005% with edetate. Other commercial preparations were not effective or effective only with prolonged exposure (12 to 24 hours). The safest and best-proven method of Acanthamoeba disinfection is still heat sterilization. HIV virus and the herpesviruses are also all effectively killed by heat and the above-described disinfecting systems. Cold cleaning–disinfection effective against these viruses includes Boston
    P.133

    cleaner and Boston conditioner for hard contact lenses and Pliagel, Miraflow, or Softmate for soft contact lenses.
XII. Radial keratotomy
(see Chapter 6).
XIII. Sclera and episclera
  • Anatomy and physiology
    • The sclera constitutes five-sixths of the anterior tunic of the globe as an almost spherical segment 22 mm in diameter. It is continuous with the cornea at the limbus anteriorly and with the optic nerve posteriorly at the scleral fibers of the lamina cribrosa.
      • The thickness of the sclera varies from a maximum of 1 mm near the optic nerve to 0.5 mm at the equator and 0.8 mm anteriorly. The thinnest portion (0.3 mm) is found just behind the insertions of the recti muscles.
      • The stroma is composed of collagen bundles varying in size from 10 to 15 μm in thickness and 100 to 150 μm in length, interlacing in an irregular crisscross pattern roughly parallel to the surface of the globe. When compared to cornea, the scleral fibers have greater birefringence, absence of fixed spacing, and greater variation in fiber diameter. All of these anatomic features contribute to the opaque character of the sclera.
      • The avascular sclera transmits blood vessels but retains scant supply for its own use, obtaining nutrition from the underlying choroid and the overlying episclera. The long posterior ciliary vessels course anteriorly in the horizontal meridian of the sclera, whereas six to seven oblique channels posteriorly transmit the vortex veins.
      • Innervation of the sclera is from the long and short posterior ciliary nerves and is especially prominent in the anterior portion where stimulation of the nerve endings by inflammation or distention can produce marked pain.
      • The function of the sclera is to provide a protective shell for the intraocular contents that will prevent distortion of the globe to maintain optical integrity, yet allow for variation in IOP. The viscoelastic ocular coat provides mobility without deformation by the attached muscles. Primarily supportive, the metabolic activity of the sclera is low and easily satisfied by the adjacent vascularity of episclera and choroid. The high hydration of the sclera contributes to the opaque nature of the tissue, which can become translucent if the water content is reduced to about 40%, as is seen clinically in scleral dellen. The collagenous nature of the sclera and its encasement by an episclera that acts much like a synovium have suggested the comparison of the eye to an exposed and modified ball-and-socket joint. This comparison has some merit because diseases that affect articular structures often can involve the scleral–episcleral coat.
    • The episclera provides much of the nutritional support of the sclera, which itself is permeable to water, glucose, and proteins. The episclera also serves as a synovial lining for the collagen and elastic sclera and reacts vigorously to scleral inflammation. The fibroelastic episclera has a visceral layer closely opposed to the sclera and a parietal layer that fuses with the muscle sheath and the conjunctiva near the limbus. These two layers are connected and bridged by delicate connective tissue lamellae. The posterior episcleral plexus of vessels comes from the short posterior ciliary vessels. The anterior episcleral circulation is more complex, with communications among a conjunctival plexus, superficial episcleral plexus, and deep episcleral plexus that anastomose at the limbus with the superficial and deep intrascleral venous plexus. This interconnection of intrascleral and episcleral venous systems drains the anterior portion of the ciliary body. The conjunctival and episcleral vessels can be blanched with 1:1,000 adrenalin or 2.5% phenylephrine, whereas the deep vessels are little changed, thus providing a useful method of differentiating superficial from deep inflammatory congestion.
  • Diseases of the sclera and episclera: inflammation. The most important clinical afflictions of the sclera and episclera are inflammatory. Either condition may
    P.134

    be associated with systemic disease (33% of episcleritis cases, >50% of scleritis cases). Although congenital, metabolic, degenerative, and neoplastic disease can also affect the sclera and episclera, the most common, diagnostically perplexing, and therapeutically difficult conditions are inflammatory.
    • Classification
      • Episcleritis—simple and nodular.
      • Anterior scleritis—diffuse, nodular, or necrotizing with or without inflammation (scleromalacia perforans).
      • Posterior scleritis
    • Clinical differentiation of these types of inflammations is of diagnostic and therapeutic importance. Episcleritis is often a benign condition requiring modest treatment; scleritis, however, can signal destructive disease involving collagen tissues in general and can require potent therapy.
  • Episcleritis is a usually benign, uni- or bilateral inflammatory reaction localized to the superficial layers of Tenon capsule. In children, there is almost always spontaneous regression in 7 to 10 days and rarely recurrence. In adults, 30% of cases are associated with an underlying connective tissue, inflammatory bowel disease, herpetic infection, gout, or various vasculitides. Systemic disease is rare in children.
    • Simple episcleritis (about 80% of cases). There is discomfort localized to the eye, accompanied by variable degrees of lacrimation and photophobia. Segmental or diffuse vascular engorgement and edema of the episclera are usually present, and, diagnostically, congestion of the superficial episcleral vessels disappears after administration of one drop of 2.5% phenylephrine. Women are more often affected than men, and the peak age incidence is the fourth decade.
    • Nodular episcleritis (about 20% of cases) is similar in its incidence and pattern but may run a more protracted course. The incidence of episcleritis is difficult to determine because many patients undoubtedly do not seek treatment. About three fourths of the cases are simple and the remainder are nodular in character. About 30% of cases of nodular episcleritis can be associated with general medical problems: 5% occurring with collagen vascular disease (rheumatoid arthritis), 7% with prior herpes zoster ophthalmicus or herpes simplex, and 3% with gout or atopy. Extensive laboratory workup is not rewarding with most episcleritis cases, but clinical examination for evidence of rheumatoid arthritis, herpes zoster ophthalmicus, or gout can be supplemented by serologic tests for rheumatoid arthritis and serum uric acid. Most cases of episcleritis resolve within 3 to 6 weeks without complication.
    • Ocular complications of episcleritis occur in approximately 15% of cases but are usually not severe or permanent. Elevation of the limbal area due to episcleral edema or nodule can result in corneal dellen. This local desiccation phenomenon may respond to patching, lubrication, or resolution of the limbal swelling. With significant inflammation, there can be superficial and midstromal infiltration and edema of the cornea that rarely provoke vascularization. IK, iritis (7%), and secondary glaucoma are uncommon.
    • Treatment is often not required, and symptoms can sometimes be relieved by topical decongestants. Symptomatic cases usually respond to modest topical steroid treatment (prednisolone 1% bid to tid) coupled with systemic NSAIDs (e.g., ibuprofen 400 mg p.o. tid, or naproxen 250 mg q12h with a meal over several weeks). Topical NSAIDs, such as those listed in Appendix A, are also effective and tapered over time.
  • Scleritis. Inflammation of the sclera can result in severe destructive disease that causes pain and threatens vision. Occurring more commonly in females than in males, with a peak incidence in the fourth to sixth decades, the condition is bilateral in approximately 50% of cases. Pain can be severe and is often described as a deep boring ache. There is often associated photophobia and lacrimation as well as chronic systemic inflammatory disease.
    • Anterior scleritis. Ninety-five percent of cases of scleritis are in the anterior portion of the sclera. Superficial and deep episcleral vessels are congested, and the deep ones remain so after one drop of 2.5% phenylephrine.
      P.135

      • Diffuse anterior scleritis occurs approximately 60% of the time, and nodular anterior scleritis approximately 25% of the time. Necrotizing scleritis, occurring 15% of the time, is usually more severe and is twice as frequent with inflammation as without. Posterior scleritis occurs in about 10% of cases. The specific pattern of scleritis is usually not distinctive enough to prove an etiology, although the clinical course and prognosis are often predictable on the basis of the pattern of inflammation. The necrotizing form is the most severe and unremitting. Only 8% of cases progress from one form of scleritis to another. Ocular complications occur in 50% of anterior scleritis cases and in about 90% of necrotizing or posterior scleritis cases.
      • Diseases associated with the various types of scleritis vary; 45% of scleritis patients have a systemic disorder. These include rheumatoid arthritis, ankylosing spondylitis, Wegener granulomatosis, systemic lupus erythematosus, relapsing polychondritis, polyarteritis nodosa, herpes simplex or zoster, syphilis, psoriatic arthritis, Behçet disease, temporal arteritis, Reiter syndrome, early HIV infection, sarcoidosis, thyroid disease, lymphoma, pancreatic carcinoma, multiple myeloma, primary biliary cirrhosis, and atopy. These diseases may be associated with any form of scleritis. Postoperative scleritis may occur without systemic disease.
        • The diffuse anterior pattern can be associated with rheumatoid arthritis (24% of cases), prior herpes zoster ophthalmicus, and gout.
        • The nodular anterior variety has been associated most frequently with prior episodes of herpes zoster ophthalmicus.
        • The necrotizing variety is rare (3% of cases) but the most ominous and can be associated with ocular or systemic complications in 60% of patients. Forty percent may show decreased visual acuity. Twenty-nine percent of patients with necrotizing scleritis may be dead within 5 years. The necrotizing variety must be distinguished on the basis of focal areas of avascular scleral dropout. In those cases of necrotizing scleritis without inflammation (scleromalacia perforans), most patients have longstanding rheumatoid arthritis involving multiple joints. More than half of the time the condition is bilateral in patients with rheumatoid arthritis. Clinically, large areas of avascular sclera may appear as a sequestrum with adjacent exposure of the uveal pigment through a markedly thin sclera. Anterior chamber reaction can occur with this type of scleritis and is an ominous sign. Perforation is not common but can occur.
    • Posterior scleritis is difficult to diagnose and often overlooked. One histopathologic series of enucleated eyes documented posterior involvement in 43% of eyes diagnosed with anterior scleritis. Certainly, posterior scleritis can occur alone, but it is then more difficult to diagnose. Symptoms of deep, unremitting aching pain unresponsive to topical or nonimmunosuppressive systemic therapy and, in some cases, decreased visual acuity suggest posterior scleritis. Physical signs suggesting posterior scleritis include occasional episcleral forniceal hyperemia, fundus changes (particularly exudative retinal detachment), annular choroidal folds or detachments, subretinal mass, patchy chorioretinal changes, vitritis optic nerve edema, or macular edema. Severe posterior inflammation can result in shallowing of the anterior chamber, proptosis, limited extraocular movement, and lower lid retraction. Posterior scleritis can be associated with rheumatoid arthritis or systemic vasculitis. Ultrasound or computed tomography scan will reveal diagnostic scleral thickening.
    • Complications of scleritis
      • Corneal changes occur in approximately 37% of cases of anterior diffuse and nodular scleritis. There are four characteristic patterns of corneal involvement.
        • Diffuse stromal—midstromal opacities occurring with immune ring patterns and keratic precipitates.
        • P.136

        • Sclerosing stromal keratitis—edema and infiltration of the stroma with vascularization and scarring resulting in subsequent crystalline formation.
        • Deep keratitis—white, opaque sheets of infiltration at the Descemet membrane.
        • Limbal guttering—a limbal gutter progressing to ectasia and characterized by lipid deposits with or without vascularization.
      • The necrotizing forms of scleritis can produce more significant corneal changes, occurring primarily in three forms.
        • Acute stromal keratitis—edema and dense white infiltration associated with ring infiltrates and keratic precipitates.
        • Peripheral ulcerative keratitis (PUK)—marginal thinning with prominent inflammation indicative of a vasculitis that must be differentiated from the Mooren ulcer.
        • Keratolysis—diffuse areas of corneal infiltration that will suddenly thin by stromal melting to result in descemetocele surrounded by irregularly scarred and vascularized tissue. Without inflammation, this is scleromalacia perforans.
      • Other ocular complications of scleritis include uveitis in approximately 35% of cases and scleral thinning in 27% of cases. There can also be both open- and narrow-angle glaucoma (13.5%), as well as cataract, retinal detachment, and optic neuritis.
    • Because of the high incidence of associated systemic or collagen disease, it is often wise to obtain ancillary laboratory investigations as a diagnostic routine.
      • Hematology studies
        • Complete blood count and erythrocyte sedimentation rate.
        • Plasma protein and immunoglobulin level.
        • Antineutrophil cytoplasmic antibodies (ANCA). A negative ANCA posttreatment does not mean vasculitis is quiet. Nephritis may be ongoing. Obtain sedimentation rate and urinalysis.
        • Other immune profile tests as listed in Chapter 9.
        • Antinuclear and rheumatoid factors.
        • Serum uric acid.
        • Serologic tests for syphilis and HIV.
      • X-rays of chest, hands and feet, lumbosacral spine.
      • Fluorescein angiography, anterior or posterior segment, for evidence of vasculitis.
      • B-scan ultrasound for posterior scleritis.
      • Results of the tests need interpretation in light of the history, associated physical findings, and the pattern of positive results (see Chapters 1 and 9).
    • Treatment of noninfectious scleritis
      • Medical therapy is the first line of defense. About 30% of scleritis patients require oral NSAIDs, >30% require oral corticosteroids, and >25% require immunosuppressive drugs.
        • Although topical steroids frequently increase comfort and occasionally maintain a remission, the topical preparations may not be sufficient to induce a remission and will exacerbate keratolysis.
        • In addition to topical steroids, oral NSAIDs are also effective. Such treatment (e.g., indomethacin 25 mg qid to 50 mg tid for 7 to 12 weeks) may suppress the inflammation in diffuse and nodular varieties but is often not effective for the necrotizing form. Naproxen 375 mg to 500 mg q12h, or diflunisal 500 mg q12h have also proved effective in nonnecrotizing scleritis. Cyclooxygenase-2 inhibitors (celecoxib [Celebrex] 100 mg bid, rofecoxib [Vioxx] 12.5 to 25 mg qd) are also effective.
        • For unresponsive cases or scleromalacia perforans, initial treatment is systemic steroids in a dosage of 80 mg to 120 mg prednisolone per day for the first week with tapering. Median duration of therapy is about
          P.137

          30 weeks in patients responding to prednisone alone. Topical steroids may be used to sustain a remission. Subconjunctival steroids are to be discouraged because the scleral thinning per se and sustained local suppression of wound healing by subconjunctival route can be hazardous.
        • Severe unremitting, unresponsive, or necrotizing cases require treatment with immunosuppressive drugs. Methotrexate 2.5 to 15 mg p.o. every week, cyclosporine 3 to 5 mg/kg/day, azathioprine 1 to 2 mg per kg p.o. qd, or cyclophosphamide, starting at 100 mg p.o. qd and increasing the dosage to 150 to 200 mg p.o. qd over 2 weeks are often effective regimens. Patients should be warned of the potential serious side effects (see Chapter 9, Section VI.D). Immunosuppressive agents are effectively coupled with other antirheumatoid drugs, such as sulfasalzine, cyclophosphamide, chlorambucil, etanercept, infliximab, or leflunomide to control the ocular inflammation, and may prolong survival by controlling other vasculitis. An internist or other physician familiar with the use of these drugs should be consulted before and during the course of treatment.
        • If fluorescein angiography reveals a vasculitis or blood tests indicate immune complex disease, both life-threatening processes, and/or the presence of a progressive destructive ocular lesion, inflamed or not inflamed, cyclophosphamide 100 mg p.o. qd or less, with prednisolone 15 mg p.o. qd, may control the process. If there is little response, pulsed i.v. methylprednisolone over 1 to 2 hours should be given with 500 mg of cyclophosphamide i.v. over several hours and washed through with i.v. 5% dextrose with water or saline over 24 hours to decrease the incidence of hemorrhagic cystitis. This pulsed therapy is not without hazard and may be repeated if necessary under desperate circumstances to save not only vision but life itself. Once the disease process is under control using systemic therapy, mild topical steroids should be used qd to tid to maintain suppression and systemic treatment should be stopped. Subconjunctival steroids should never be given, because scleral or keratolysis may result.
        • Adverse effects. It is important to recognize the potential serious adverse reactions to systemically administered anti-inflammatory agents. The serious adverse effects of steroid therapy with adrenal suppression can be avoided with short-term therapy, but gastrointestinal disturbance, aggravation of hyperglycemia, fluid retention, and acute psychoses may occur. Long-term systemic or local steroid therapy obviously can produce cataracts and elevate IOP. Immunosuppressives may cause severe bone marrow suppression, gastrointestinal toxicity, and serious infection (see Chapter 9, Section VI.D).
      • Surgical treatment
        • Extreme scleral thinning or perforation requires reinforcement. Whatever material is used must be covered with conjunctiva to maintain its integrity. Donor sclera or cornea may be used but usually swells with edema and softens. Fascia lata or periosteum is somewhat more resistant to the melting process. All grafts should be completely covered by sliding conjunctiva or donor conjunctiva from the same or opposite eye should be used.
        • Extreme corneal marginal ulceration or keratolysis may require corneal grafting, usually as a lamellar patch graft in addition to systemic therapy.
        • Treatment of infectious scleritis involves aggressive, specific systemic and topical antibiotics and, if needed, conjunctival recession and local cryotherapy. M. tuberculosis is treated with amikacin 10 mg per mL drops q1h, and oral rifampin and isoniazid. Taper drops over 2 to 4 weeks and oral medication in 1 year (see Section IV.B for other treatment).
P.138

XIV. Tumors of the ocular surface
  • Pigmented tumors
    • Conjunctival pigmentation can be benign, premalignant, or frankly malignant.
    • Benign lesions include racial melanosis and nevi. Racial melanosis is a flat lesion occurring in deeply pigmented patients. It is bilateral and more prominent at the limbus. The pigment fades as one approaches the fornices. Treatment is not necessary. Conjunctival nevi are typically pigmented, although there are amelanotic variants. Nevi may be somewhat elevated. Cysts are often seen within a conjunctival nevus. Nevi may grow, especially during puberty. Periodic examination is needed to rule out malignant transformation. Approximately 25% of conjunctival melanomas arise from preexisting nevi.
    • Primary acquired melanosis (PAM) is a premalignant lesion. PAM is typically seen in older Caucasian patients as a patch of flat golden brown pigmentation, typically on the bulbar conjunctiva. The main determinant of malignant potential is the presence of cellular atypia, which can only be determined by histopathological evaluation following biopsy. Small, isolated patches of PAM can be followed regularly. Large areas and any areas that display thickness or increased vascularity should be completely excised. Incisional biopsies should be avoided if possible, since this can spread tumor cells if malignancy is present. Approximately 75% of conjunctival melanomas arise from PAM.
    • Conjunctival melanoma is an uncommon tumor, although there appears to be an increase in its frequency recently. At 10 years following diagnosis, 51% of patients have experienced at least one recurrence, 26% have metastases, and 13% have died from the disease. Conjunctival melanomas are typically pigmented, although amelanotic lesions can occur. Recurrent melanomas are often amelanotic, even if the primary tumor was pigmented. Treatment involves complete excision using a no-touch technique. Adjuvant cryotherapy is applied to the edges of the conjunctiva following excision. Topical chemotherapy such as mitomycin C can be used postoperatively once the ocular surface has healed. Patients must be followed for life at 4- to 6-month intervals to allow early detection of tumor recurrence.
  • Squamous cell tumors
    • Squamous cell tumors arise from the transitional cells at the limbus. There is a spectrum of malignancy, ranging from mild dysplasia to carcinoma in situ to invasive squamous cell carcinoma, based upon the extent of epithelial atypia and whether the disease has breached the basement membrane. These lesions typically appear gelatinous and occur in sun-exposed areas of the conjunctiva. Management includes complete excision with adjuvant cryotherapy. Mitomycin C or alpha-interferon can be used as adjuvant treatment following surgical management. These agents are also useful for treating recurrences.
  • Lymphoid tumors
    • Conjunctival lymphoproliferative lesions appear as salmon-colored, fleshy masses that can occur in any part of the conjunctiva. They can be isolated lesions, although up to 80% of patients with conjunctival lymphomas will develop systemic lymphoma within 10 years. Diagnosis is made by biopsy. The excised tissue should be sent in saline (not formalin) for flow cytometry to determine the cellular characteristics of the lesion. B-cell lymphomas are much more common that T-cell lymphomas. Once a conjunctival lymphoma is diagnosed, the patient is referred to an oncologist to determine the stage of the disease, which determines the treatment. For disease confined to the conjunctiva, observation, excision, cyrotherapy and low-dose radiation have been used. Orbital disease necessitates low dose radiation. Systemic disease is typically treated with chemotherapy.