18 Conjunctiva

176 ALLERGIC CONJUNCTIVITIS

372.05

(Allergic Rhinoconjunctivitis, Hay Fever

Conjunctivitis)

Russell Pokroy, MD

Rehovot, Israel

ETIOLOGY/INCIDENCE

This common conjunctivitis, caused by exposure of sensitive individuals to specific allergens, is recurrent: seasonal (spring and summer due to pollens) or perennial (house dust, animal dander). Airborne allergens presumably traverse the conjunctiva and cause cross-linking of mast cell-bound IgE antibody, resulting in mast cell degranulation, release of vasoactive mediators and allergic signs and symptoms.

COURSE/PROGNOSIS

Isolated conjunctivitis runs a milder course than cases with associated rhinitis or asthma. In children, seasonal allergic conjunctivitis often improves with age.

TREATMENT

Although avoidance of the offending allergen is the most effective treatment, this is often impractical. Concurrent blepharitis and dry eye should be treated. Rhinitis may require nasopharyngeal referral. Topical treatment is usually adequate, a graded approach according to the severity and response is recommended as follows:

●Artificial tears (preferably nonpreserved);

●Cool compresses;

●Vasoconstrictors (chronic use should be avoided because of rebound hyperemia);

●Antihistamines (H1 receptor antagonists);

●Mast cell stabilizers;

●Nonsteroidal antiinflammatories;

●Steroids (fluorometholone is safer than prednisolone);

●Systemic antihistamines.

COMMENTS

Although allergic conjunctivitis is common, it is usually benign without ocular sequelae. Topical treatment is effective and should be used prudently to avoid side effects.

Conjunctiva • 18 SECTION

REFERENCES

Abelson MB, Schaefer K: Conjunctivitis of allergic origin: immunologic mechanisms and current approaches to therapy. Surv Ophthalmol 38(suppl):115–126, 1993.

Friedlaender MH: Conjunctival provocation testing: overview of recent clinical trials in ocular allergy. Int Ophthalmol Clin 49:95–104, 2003.

Friedlaender MH, Ohashi Y, Kelley J: Diagnosis of allergic conjunctivitis. Arch Ophthalmol 102:1198, 1984.

Greiner JV, Mundorf T, Dubiner H, et al: Efficacy and safety of ketotifen fumarate 0.025% in the conjunctival antigen challenge model of ocular allergic conjunctivitis. Am J Ophthalmol 136:1097–1105, 2003.

177 BACTERIAL CONJUNCTIVITIS

372.05

(Infective Conjunctivitis, Mucopurulent

Conjunctivitis, Purulent Conjunctivitis)

Aziz Sheikh, BSc, MBBS, MSc, MRCP, MRCGP, DCh,

DRCOG, DFFP

Edinburgh, Scotland

Brian Hurwitz, MD, FRCP, FRCGP

London, England

ETIOLOGY/INCIDENCE

Community acquired bacterial infections of the conjunctiva are relatively common, generating an incident consultation rate in primary care of about 2% of all consultations per annum. These infections are more common in children and occasionally are seen in the elderly, but are relatively rare in younger and middleaged adults; they affect both genders and all ethnic groups.

Most cases of infective conjunctivitis are caused by bacteria. The infective process is usually acute, but occasionally, a lowgrade chronic infection may occur. This chapter concentrates on infection by bacteria other than Chlamydia trachomatis.

The most common mode of transmission is hand-to-eye spread of bacteria from the nasopharynx. For children, important risk factors include close contact with other children, superinfection after viral conjunctivitis, and bouts of otitis media, sinusitis and pharyngitis. In adults, chronic blepharitis, contact lens use, tear deficiency and lacrimal obstructions are important additional etiological and predisposing factors.

A number of different bacteria can infect the conjunctiva, the most important being Streptococcus pneumoniae, Staphylococcal aureus and Hemophilus influenza. Differentiating between these is not possible clinically. The only certain way to implicate a particular agent is to isolate it from swab material in the laboratory. There is considerable variation in causative organisms with the age of the patient, the locality and the season. Causative organisms include:

●Pathogenic gram-positive cocci, principally Staphylococcus aureus, Streptococcus pneumoniae and Streptococcus pyogenes.

●Aerobic gram-negative bacilli such as Pseudomonas aeruginosa, Moraxella catarrhalis and, particularly in children,

Hemophilus influenzae and Hemophilus parainfluenzae.

●Overgrowth of normal skin flora, most commonly coagu- lase-negative staphylococci, and corynebacteria.

●Many enteric gram-negative bacilli.

●Genital infections that are transmitted to the eyes by hand or passed on to infants during birth, classically Neisseria gonorrhoeae and Chlamydia trachomatis.

COURSE/PROGNOSIS

Bacterial conjunctivitis is usually a mild affliction. Infection, which in only a minority of cases results in a mucopurulent discharge, typically begins in one eye, with the second eye becoming involved 2 or 3 days later. Infection is usually mild and resolves spontaneously in around 65% of cases within 2–5 days. Topical antibiotics do however significantly improve rates of clinical and microbiological remission (Figure 177.1).

A few organisms, particularly N. gonorrhoeae, can induce a profuse, purulent discharge with severe chemosis of the lids. Preauricular adenopathy is often present. The initial symptoms are similar to those of mucopurulent conjunctivitis but then rapidly worsen. Although very uncommon, prolonged exposure of the cornea to exudate containing hydrolytic enzymes can result in abscess formation and corneal perforation. Prompt diagnosis and therapy are essential in these cases.

DIAGNOSIS

Clinical signs and symptoms

Only about a half of patients presenting with conjunctivitis in primary care can be expected to have a demonstrable bacterial etiology. Patients with bacterial conjunctivitis typically present with rather non-specific features: redness, tearing, itching, periorbital edema and discharge; vision is generally normal.

a

b

FIGURE 177.1. a) Random effects meta-analysis of efficacy of topical antibiotics vs. placebo in improving early (days 2–5) clinical remission (n = number of subjects in remission; N = number of subjects tested; CI = confidence intervals; RR = relative risk). b) Early microbiological remission. For abbreviations see above. (Reproduced with kind permission of British Journal of General Practice from: Sheikh A, Hurwitz B: Topical antibiotics for acute conjunctivitis: Cochrane systematic review and meta-analysis update. Br J Gen Pract 5(521):962–964, 2005.)

Differentiating between bacterial and non-bacterial etiologies is however helped by asking three simple clinical questions:

●The number of glued eyes in the morning (0, 1 or 2)?

●Itchy eyes?

●History of conjunctivitis (i.e. has the patient suffered prior ‘eye infections’ with comparable symptoms)?

A positive response to the first question and negative responses to the second and third questions significantly increase the likelihood of identifying the presence of bacterial involvement.

Laboratory fndings

Patients to investigate

The following groups of patients should be investigated with swabs:

●Those with severe fulminating conjunctivitis;

●Patients not responding to initial therapy;

●All neonates with conjunctivitis.

Any patient with purulent conjunctivitis failing to respond to initial antibiotics should have medication withdrawn for 24 hours after which material should be collected for culture. Specific chemotherapy can then be initiated based on swab results.

Specimen collection

Pus is collected on a moist swab and sent to the laboratory. If plating out in the clinic, a swab or Kimura spatula is used to transfer material to a blood agar plate, a chocolate agar plate and a slide for a Gram’s stain. One swab or scrape per medium is preferred. If local anesthesia is necessary in order to take a swab, preservative-free drops are recommended. Most laboratories will choose to incubate the blood agar plate under anaerobic conditions. Although obligate anaerobes are rarely cultured from the conjunctiva, the use of both an aerobic and an anaerobic plate can speed up the identification of isolates.

Culture interpretation

An obvious pathogen is isolated from around 30% of community conjunctival specimens. On other occasions, the cultures are negative or there is light growth of mixed skin flora only. In these cases, there is no specific indication for antibiotic treatment. In some instances, polymorphonuclear cells are seen in the Gram’s stain, and there is a heavy growth of an organism of relatively low pathogenicity, such as one of the coagulasenegative staphylococci or viridans streptococci. Here, the isolate should be identified to at least genus level and reported to the clinician. Antibiotic treatment is then considered on a case-by- case basis.

Antimicrobial susceptibility testing

The need to test the susceptibility of an isolate depends on the proposed treatment and the likelihood of resistance for that species. Rates of resistance can vary markedly from community to community. Often, the pattern of antibiotic susceptibility of an isolate will depend on whether the infection was acquired in a hospital. Some laboratories do not routinely test conjunctival pathogens, and a specific request will have to be made in problem cases. Because high concentrations of antibiotics in the conjunctivae are achieved with topical treatment and susceptibility assays are traditionally based on levels attainable with systemic treatment, some laboratories are moving to increase the concentration at which conjunctival isolates are classified

as resistant. This has particular relevance in automated, brothdilution systems but is not yet accepted widely as an improvement over the traditional method.

Differential diagnosis

The main differential factors that need to be considered are: ● Conjunctivitis caused by Chlamydia or viruses such

as herpes simplex, varicella zoster, adenovirus, or enterovirus;

●Allergic or toxic conjunctivitis, i.e. in response to local irritants such as chemicals or dust. Occupational history may be a helpful guide to the cause;

●Conjunctivitis associated with erythema multiforme or Reiter’s syndrome;

●Obstruction of the lacrimal drainage system with a mucocele of the lacrimal sac;

●Malignancies such as sebaceous gland carcinoma and lacrimal gland tumors;

●Parinaud’s oculoglandular syndrome, a unilateral chronic granulomatous conjunctivitis with regional adenopathy; most cases caused by Bartonella henselae.

TREATMENT

The management of bacterial conjunctivitis involves recognition of the disease at a clinical level, identification of the etiologic agent, appreciation of the importance of the case from a public health point of view, and considering the role of antimicrobial agents in the context of understanding that most cases will resolve spontaneously. A satisfactory antibiotic is one that is active against expected pathogens, has low local and systemic toxicity, and is nonallergenic.

Systemic

Systemic and local treatment is given for gonococcal conjunctivitis. Systemic treatment should be considered for children with H. influenzae type b (Hib) infection in whom the instillation of eyedrops is difficult. Hib is now less frequent due to the success of the immunization program.

●For gonococcal conjunctivitis, a single intramuscular injection of ceftriaxone is effective. The dose ranges from 125 mg in neonates to 250 mg in adults. The eye should be lavaged to remove pus.

●For Hib conjunctivitis, oral amoxicillin is recommended; the dosage for children less than 20 kg is 20 mg/kg/day every 8 hours. The dose for heavier children and adults is 250 mg every 8 hours. Continue the treatment for 2 to 3 days after symptoms have disappeared. If the strain is resistant to amoxicillin, a third-generation cephalosporin should be considered.

Local

Broad spectrum topical antibiotic therapy in specialist care patient settings results in significantly higher early (days 2 to 5) clinical remission rates, and in better early and late (days 6 to 10) microbiological remission rates. Most cases respond to a low dose of any broad-spectrum antibiotic applied locally. These agents are often used before laboratory results are known or, in most cases, without collection of material for microbiologic assessment. Ointments are useful with children or for overnight use in adults. Treatment should be given every 2 hours for 2 or 3 days until the process is controlled and then 4 times daily for another week.

177 CHAPTERConjunctivitis Bacterial •

Conjunctiva • 18 SECTION

Adverse effects from topically applied agents are uncommon; however, the prolonged use of bacitracin or polymyxin B may be toxic at the site of delivery, neomycin can induce hypersensitivity that typically presents as a periocular contact dermatitis. Chloramphenicol drops have been implicated in fatal aplastic anemia, although the risk is very low being estimated to be 1 in 220,000 prescriptions.

●Broad-spectrum single agents: chloramphenicol solution or ointment, fucidic acid, sulfacetamide solution or ointment, ciprofloxacin, norfloxacin, or ofloxacin solution.

●Broad-spectrum combinations: bacitracin-polymyxin B ointment, neomycin-polymyxin B-bacitracin ointment, neomycin-polymyxin B-gramicidin solution, or polymyxin B-trimethoprim solution. In cases of suspected infective conjunctivitis there is no place for antibiotic and steroid combination treatment.

●For most gram-positive infections: bacitracin ointment.

●For most gram-negative infections: gentamicin or tobramycin solution or ointment.

●For Neisseria or serious streptococcal infections, 100,000 units/ml penicillin G drops may be given; if the isolate is resistant or if the patient is allergic to penicillin, chloramphenicol 0.5% drops can be substituted.

PRECAUTIONS

A patient with purulent conjunctivitis may fail to respond to topical medication for a number of reasons. The disease may be due to an intracellular bacterial infection such as C. trachomatis or to one of the noninfective processes listed. If the condition is due to bacterial infection, the agent may be not be susceptible to the drug administered. Alternatively, the conjunctival sac may be full of organisms from the lacrimal sac or other nonocular sites under various circumstances. A persistent, uniocular, purulent discharge should alert the ophthalmologist to the possibility of a foreign body. Another reason for treatment failure is poor patient compliance with medication.

COMMENTS

The majority of cases are mild and will resolve spontaneously relatively quickly. Two broad approaches to management can be followed in primary care. A broad-spectrum antibiotic may be prescribed on the suspicion of bacterial infection for either immediate or ‘delayed’ use (i.e. in cases which do not spontaneously resolve within 3 days of onset) with laboratory investigations reserved for refractory cases (i.e. those with poor or no response to treatment), in which case treatment should ideally be discontinued for 24 hours before the swab is taken. Alternatively, more specific chemotherapy can be prescribed, based on the bacteria isolated if cultures are initiated as a first step. In favor of broad-spectrum therapy is the excellent response achieved in most patients with simple treatment. Against this approach are: the difficulty of distinguishing bacterial from non-bacterial etiologies at the clinical level, the fact that not all bacteria will respond to simple broad-spectrum therapy, and that when a patient has not responded to a trial of chemotherapy, the chance of achieving a microbiologic diagnosis may have been lost.

In most situations, broad-spectrum antibiotics are used based on a clinical diagnosis of bacterial conjunctivitis. Severe purulent conjunctivitis, however, requires initial laboratory investigation.

REFERENCES

Coster, DJ, Badenoch, PR: Bacterial conjunctivitis. In: Fraunfelder FT, Roy FH (eds): Current Ocular Therapy, 5th edn. Philadelphia, WB Saunders, 2000:323–325.

Donahue SP, Khoury JM, Kowalski RP: Common ocular infections: a prescriber’s guide. Drugs 52:526–540, 1996.

Hwang DG: Bacterial conjunctivitis. In: Pepose JS, Holland GN, Wilhelmus KR, eds: Ocular infection and immunity. St Louis, Mosby, 1996: 99–817.

Laga M, Naamara W, Brunham RC, et al: Single-dose therapy of gonococcal ophthalmia neonatorum with ceftriaxone. N Engl J Med 315:1382– 1385, 1986.

Lancaster T, Swart AM, Jick H: Risk of serious haematological toxicity with use of chloramphenicol eye drops in a British general practice database. BMJ 316:667, 1998.

Rietveld RP, van Weert HC, ter Riet G, Bindels PJ: Diagnostic impact of signs and symptoms in acute infectious conjunctivitis: systematic literature search. BMJ 327:789, 2003.

Rietveld RP, ter Riet G, Bindels PJ, Sloos JH, van Weert HC: Predicting bacterial cause in infectious conjunctivitis: cohort study on informativeness of combinations of signs and symptoms. BMJ 329:206–210, 2004.

Sheikh A, Hurwitz B: Topical antibiotics for acute bacterial conjunctivitis: Cochrane systematic review and meta-analysis update. Br J Gen Pract 55:962–964, 2005.

178 CONJUNCTIVAL MELANOTIC

LESIONS 224.3

(Conjunctival Nevus, Conjunctival

Junctional Nevus, Subepithelial Nevus,

Compound Nevus, Blue Nevus,

Melanosis Oculi, Conjunctival

Melanosis, Epithelial Melanosis, Racial

Melanosis, Subepithelial Melanocytosis,

Congenital Melanocytosis, Primary

Acquired Melanosis, Malignant

Melanoma, Conjunctival Melanoma,

Conjunctival Malignant Melanoma)

Manolette R. Roque, MD

Manila, Philippines

Barbara L. Roque, MD

Manila, Philippines

ETIOLOGY/INCIDENCE

Conjunctival melanotic lesions may be due to melanocytic or nonmelanocytic lesions. Conjunctival melanocytic lesions are secondary to disorders of melanocyte proliferation or of melanin production, may be primary or secondary, congenital or acquired, and benign or malignant, with unknown causes.

Lesions178 CHAPTERMelanotic Conjunctival •

Conjunctiva • 18 SECTION

Shields CL, Demirci H, Karatza E, Shields JA: Clinical survey of 1643 melanocytic and nonmelanocytic conjunctival tumors. Ophthalmology 111(9):1747–1754, 2004.

179 CORNEAL AND CONJUNCTIVAL

CALCIFICATIONS 371.43

F. Hampton Roy, MD, FACS

Little Rock, Arkansas

ETIOLOGY/INCIDENCE

Corneal and conjunctival calcifications may occur as isolated conditions or in association with a variety of disease entities. The corneal involvement is described as calcific band keratopathy because of the band-like distribution of the deposits across the interpalpebral zone. Clinically, calcific band keratopathy appears as a superficial corneal opacity resembling frosted or ground glass, with ‘white flecks’ and ‘clear spots’ interspersed within the band, giving it a ‘Swiss cheese’ appearance. The opacity is covered by clear epithelium and usually is localized to the area of exposed cornea in the interpalpebral fissure. The band is concentric with the limbus but is separated from it by a clear layer. Unlike calcific band keratopathy, calcareous degeneration usually spares the basement and Bowman’s membranes and is characterized by clumps of calcium salts in the superficial and deep stroma. Conjunctival calcification appears as small, hard, white, or yellow elevated concretions in the palpebral conjunctiva.

Although the exact cause of calcific band keratopathy is not known, a combination of factors is thought to be responsible. Band keratopathy is the probably the result of precipitation of calcium salts on the corneal surface (directly under the epithelium). Serum and normal body fluids (e.g. tears, aqueous humor) contain calcium and phosphate in concentrations that approach their solubility product. Evaporation of tears tends to concentrate solutes and to increase the tonicity of tears; it is especially true in the intrapalpebral area where the greatest exposure of the corneal surface to ambient air occurs. Elevated serum calcium and phosphorus concentrations may also result in tissue deposition of calcium phosphate salts. Histologically, calcium salts are deposited in the extracellular space when the condition is secondary to local ocular disease and in the intracellular space when the condition is secondary to systemic alterations of calcium metabolism. The epithelial basement membrane, Bowman’s layer and superficial stroma are involved.

Band keratopathy is associated with local ocular and systemic disease.

Chronic uveitis of any cause and ocular trauma, along with its accompanying chronic inflammation, are the most common ocular causes of band keratopathy. Systemic disease with altered calcium metabolism, such as hyperparathyroidism, vitamin D toxicity, and uremia, also are commonly associated with calcific band keratopathy. Calcific band keratopathy also has been described in persons treated with or exposed to organomercurials, such as phenylmercuric nitrate or thimerosal, and to intraocular silicone oil. Band keratopathy has been reported after the use of Viscoat (hyaluronate sodium and chondroitin sulfate sodium) during routine cataract extraction. Inborn errors of metabolism, such as hyperphosphatemia and hypophosphate-

mia, may also predispose patients to develop corneal and conjunctival calcification. Calcified deposits may occur within the palpebral conjunctiva; these generally represent chronic degenerative changes and often are observed in patients with chronic blepharitis or other external eye disease. Band keratopathy associated with hyperuricemia can occur and is differentiated based on historical data, the golden-brown color on examination and elevated uric acid levels.

The causes of calcific band keratopathy can be divided into five categories:

1.Chronic keratitis or uveitis (the most common causes);

2.Degenerative calcium deposition associated with chronic damage from mercurial preservatives in many ophthalmic preparations (e.g. phenylmercuric nitrate or thimerosal);

3.Hypercalcemia secondary to milk alkali syndrome, vitamin D toxicity, sarcoidosis, hyperparathyroidism, lytic lesions affecting the bones, and other systemic diseases;

4.Chronic renal failure, uremia, or other conditions that may cause a rise in serum phosphorus levels;

5.Heredity.

Calcareous degeneration occurs in severely diseased eyes with exposed stroma and vascular compromise or in eyes undergoing multiple operations. It also has been reported in a failed corneal graft. Conjunctival concretions are usually products of cellular degeneration, but they also may be associated with any chronic conjunctival inflammation.

COURSE/PROGNOSIS

As calcification progresses, fragmentation and even destruction of Bowman’s membrane may ensue. Early in its course, before the calcific band approaches the pupillary area, there is no immediate effect on visual acuity. With progression, however, plaques composed of coalesced calcium replace the subepithelial layers of the cornea, resulting in epithelial erosions, accompanied by marked irritation and pain. Eventual involvement of the central cornea and pupillary axis results in decreased visual acuity. A limbus pannus may also develop. Calcareous degeneration can occur rapidly, especially with anterior segment ischemia. Conjunctival concretions may be accompanied by hyperemia and symptoms of irritation.

DIAGNOSIS

Patients should be questioned concerning excessive vitamin D ingestion. Although corneal and conjunctival calcification may be reversible with discontinuation of the vitamin, nephrocalcinosis may still develop. A general medical workup is advisable. Laboratory tests may include renal function test; serum calcium, phosphorus, uric acid, parathyroid hormone, and angiotensinconverting enzyme levels; and a search for lytic lesions affecting the bones.

TREATMENT

Surgical

Treatment of band keratopathy is indicated in patients with symptomatic irritation or decreased vision. The success of therapy in restoring vision may be limited if the underlying disease process has produced decreased acuity. In addition,

Calcifications179ConjunctivalCHAPTERand Corneal •

Conjunctiva • 18 SECTION

unless the underlying disease process is controlled, calcium deposition may recur after therapy. In this situation, the treatment may need to be repeated. The surgical goal is to remove the opaque calcium deposits without producing stromal scarring. The initial approach is to attempt chelation of the calcium salt deposits with edetate disodium (EDTA).

A topical anesthetic agent instilled into the conjunctival cul-de-sac is sufficient to achieve intraoperative anesthesia; however, due to the frequent incidence of severe postoperative discomfort, many surgeons elect to use supplemental retrobulbar anesthesia with 0.5% bupivacaine HCl. Next, the epithelium is mechanically removed. The distal end of a Weck-cel sponge is saturated with 0.5% EDTA (prepared by mixing a 20% stock of NaEDTA with 0.9% sodium chloride) and held against the area of calcium deposition. A to-and-fro abrasive action is used to help remove the calcium deposits; this is best accomplished at the slit-lamp examination. If significant clearing has not occurred after 10 minutes of treatment, higher concentrations of EDTA (1.0% or 1.5%) should be used. Sometimes, the treatment must be continued for 20 to 30 minutes. In refractory cases, gentle curettage with a scalpel may be necessary. An antibiotic solution and weak cycloplegic then are instilled. A patch or bandage lens may be used for comfort and to facilitate epithelial healing.

If the opacification cannot be removed with chelation or curettage, lamellar keratoplasty should be considered. A technique using EDTA and a diamond bur on a Fisch drill has been shown to be effective in removing deposits without significant scarring. The excimer laser phototherapeutic keratectomy has also been shown to be effective for the removal of band keratopathy. Excimer keratectomy alters the corneal curvature with a shift toward hyperopia. In addition, the more peripheral deposits cannot be removed without inducing even greater changes in refraction.

Conjunctival concretions causing irritation and a foreign body sensation often can be shelled out with a sharp pointed knife or broad needle. On occasion, this procedure may be difficult; if so, it should be reserved for symptomatic lesions.

REFERENCES

Binder PS, Deg JK, Kohl FS: Calcific band keratopathy after intraocular chondroitin sulfate. Arch Ophthalmol 105:1243, 1987.

Bokosky JE, Meyer RK, Sugar A: Surgical treatment of calcific band keratopathy. Ophthalmic Surg 16:645–647, 1985.

Duffey RK, LoCascio JA: Calcium deposition in a corneal graft. Cornea 6:212–215, 1987.

O’Brart DPS, Gartry DS, Lohmann CP, et al: Treatment of band keratopathy by excimer laser phototherapeutic keratectomy: Surgical techniques and long term follow up. Br J Ophthalmol 77:702–708, 1993.

Pecorella I, McCartney AC, Lucas S, et al: Acquired immunodeficiency syndrome and ocular calcification. Cornea 15:305–311, 1996.

Sternberg P, Jr, Hatchell DL, Foulks GN, Landers MB, III: The effect of silicone oil on the cornea. Arch Ophthalmol 103:90, 1985.

Taravella MJ, Stulting RD, Mader TH, et al: Calcific band keratopathy associated with the use of topical steroidphosphate preparations. Arch Ophthalmol 112(5):608, 1994.

180 FILTERING BLEBS AND

ASSOCIATED PROBLEMS 997.9

Linda Her-Shyuan Lin, MD

Houston, Texas

Adam C. Reynolds, MD

Eagle, Idaho

FILTERING BLEB

A bleb is a blister-like elevation of conjunctiva and Tenon’s capsule overlying a subconjunctival reservoir of aqueous fluid. This intraocular fluid comes from a fistula connecting the anterior or posterior chamber to the subconjunctival space. It is absorbed through veins and conjunctival lymphatics, and with thin conjunctiva, it may pass directly into the tear film.

Blebs are clinically described by their elevation, vascularity, extent in clock hours, microcyst presence, and wall thickness. Varying morphologic bleb appearances include being diffuse or localized, cystic (thin, localized, walled off at the edges) (Figure 180.1), or overhanging (extending onto the cornea). Scarring affects the function and morphology of a filtering bleb and can be modulated with topical steroids and antifibrosis agents.

Antimetabolite/antifibrotic usage in trabeculectomy

The antimetabolites mitomycin C (MMC) and 5-Fluorouracil (5FU) reduce fibroblast proliferation in the subconjunctival space and Tenon’s capsule preventing episcleral fibrosis of the scleral flap. In trabeculectomy surgery, they are increasingly used to achieve lower intraocular pressures and to improve functional success of the surgeries in eyes at high risk for surgical failure.

The pyrimidine base analogue 5FU competitively inhibits the enzyme thymidylate synthase. Incorporated into the replicating nucleic acid strands, it is active only in the S (synthesis) phase of the cell cycle. This specificity makes 5FU more toxic to replicating cells. It is used intraoperatively over the scleral flap or as postoperative subconjunctival injections.

MMC is an alkylating agent secreted by the bacteria Streptomyces caespitosus. Independent of the cell cycle, it crosslinks DNA to inhibit cell synthesis. Its toxicity to the vascular

FIGURE 180.1. Thin polycystic filtration bleb (type 1) (From: Salmon JF, Kanski JJ: Glaucoma: a colour manual of diagnosis and treatment. 3rd edn. Butterworth Heinemann, 2004:144.)

Problems Associated180 CHAPTERand Blebs Filtering •

Conjunctiva • 18 SECTION

conjunctival shrinkage and retraction, wound dehiscence, bleb dysesthesia, ptosis, and hyperopia. Decreased bleb function requires resuming glaucoma medications and possibly more glaucoma surgery.

Conservative treatment options for bleb dysesthesia, overfiltering bleb, and bleb leaks

Pressure patching, large diameter (20or 22-mm) bandage contact lenses, collagen shields, symblepharon rings, and Simmons shells tamponade overfiltering blebs in the early postoperative period. Bandage contact lenses encourage epithelial migration to reepithelialize bleb defects.

Inflammation and scarring is a shared mechanism for chemical irritants, cryotherapy, laser thermotherapy, and autologous blood injection in the treatment of bleb dysesthesia, overfiltering blebs, and bleb leaks. For chemical cauterization, 0.25% to 1% silver nitrate or 50% trichloroacetic acid is applied to bleb surfaces and rinsed after drying. Cryotherapy is performed with the cryoprobe apposing the bleb surface to sclera at temperatures of −50ºC to −80ºC for 10–30 seconds. Argon laser treatment requires conjunctival painting with methylene blue or rose Bengal for laser energy absorption. Laser parameters are 200–500 micron spot size, 300–500 milliwatts power, and 0.2 seconds duration.

Autologous blood injection success rate has been reported to be 57–72%. Complications include hyphema, vitreous hemorrhage, severe visual loss, endophthalmitis, increased IOP requiring surgical intervention, bleb failure, corneal blood staining, corneal graft rejection, and reactivation of previously quiescent ocular toxoplasmosis.

Cyanoacrylate tissue adhesive is applied to dry conjunctiva to close bleb leaks. A bandage contact lens or collagen shield is placed to prevent dislodging of the adhesive, which spontaneously sloughs after epithelialization closes the defect. The most frequent complication is corneal abrasions at the application site.

Compression sutures remodel the bleb by walling off the leaking area from the main cavity when the leak is located away from the scleral flap. The suture is tied in an X compressing bleb to sclera. More than one suture can be placed. Epiphora, discomfort, and bleb erosion can occur.

Needling of thin, cystic blebs and late multifocal bleb leaks has been reported. Eliminating the physical barrier to posterior flow, the fibrotic ‘ring of steel,’ and decreasing hydrostatic pressure allows conjunctival epithelial cells to repopulate the bleb wall to heal the leak.

The effect of conservative treatment options in bleb leaks is usually not sustained. Consequently, these procedures often need to be repeated. They are less effective in thin avascular blebs and may even tear a hole or enlarge a previous break.

Bleb infections

Bleb-related ocular infection is a potentially devastating complication of glaucoma filtering surgery and can occur months to years after the initial surgery.

Blebitis is a limited anterior form of endophthalmitis. Presenting complaints include ocular pain, sudden redness and decreased vision, tearing, purulent discharge, photophobia, and foreign-body sensation. Examination reveals conjunctival and ciliary injection most intense around the bleb edge, mucopurulent discharge, periorbital chemosis, corneal edema, and anterior chamber reaction. A milky white bleb may contain a pseudohypopyon. A positive Seidel’s test is common with possible hypotony. Increased IOP occurs when purulence and

debris close the sclerostomy. Vitreous reaction is not evident early. After trabeculectomy with MMC, blebitis incidence is 5.7% per year.

Untreated blebitis rapidly spreads posteriorly causing blebassociated endophthalmitis characterized by hypopyn, vitreous cells, and a guarded visual prognosis. Bleb-associated endophthalmitis after glaucoma filtering surgeries is reported to be 0.2% to 9.6%. Risk for endophthalmitis is estimated at 9% for full-thickness filtration blebs compared to 0.3% to 1.5% per year for partial-thickness filtration blebs. Incidence of bleb-associ- ated endophthalmitis after MMC ranges from 0.8% to 2.6% per patient year and 1.7% per year with intraoperative 5FU. Most of the risk is concentrated in the first year, but the potential for infection lasts a lifetime. After trabeculectomy with MMC, blebitis incidence is 5.7% per year.

Numerous risk factors for bleb-associated infections exist. Surgical causes include antimetabolite use, full-thickness filtering surgery, releasable sutures, and silk conjunctival sutures. Chronic, episodic antibiotic use and early postoperative complications are associated with late-onset infections. Bleb leaks and postoperative bleb manipulations increase the likelihood of bleb-related infections with infections occurring 25 times more frequently in leaking blebs. Blepharitis, conjunctivitis, and nasolacrimal duct obstruction amplify the bacterial load. Patient characteristics for bleb-related infections include young age at surgery, male sex, a broken posterior capsule, and black race.

Streptococcus sp., Staphylococcus sp., and Haemophilus influenzae are the most common organisms associated with bleb-related infections. Conjunctival exudates are stained and cultured. The value of positive conjunctival cultures remains questionable since colonization and infection are not always differentiated. Anterior chamber tap and vitreous tap or vitrectomy with intraocular antibiotic injection is done depending on the areas involved.

Early intervention prevents progression to endophthalmitis. Blebitis without anterior chamber reaction is treated empirically with frequent topical broad-spectrum antibiotics, such as a fluoroquinolone, every half-hour to every hour until culture results are available.

Anterior chamber reaction with blebitis is treated with fortified topical antibiotics around the clock. Lack of clinical improvement or appearance of vitreous cells after 24–48 hours leads to intraocular antibiotic administration.

Bleb-related endophthalmitis is an emergency requiring aggressive management. More severe infection and poorer visual acuity prompt immediate pars plana vitrectomy. An oral fluoroquinolone and fortified topical antibiotics are used with intravitreal antibiotics. Intraocular and topical corticosteroid use is controversial.

Eyes successfully treated for bleb-related infection remain at risk for recurrent infection. Leaking or inferiorly located blebs are particularly vulnerable. Antibiotic prophylaxis may be used in high-risk blebs. Infected eyes retain good visual function if monitored closely and treated intensely. Good post-infection IOP control suggests that bleb function can survive blebitis episodes.

Encapsulated bleb

Also known as a Tenon’s capsule cyst, an encapsulated bleb is a localized, high, tense, firm, ‘tight-appearing’ bleb with conjunctival vascular engorgement, thick connective tissue walls, and few microcysts. It appears 2–4 weeks after surgery. After initial pressure control, IOP rises with Tenon’s cyst formation. IOP often decreases within several weeks to several months.

Long-term prognosis for IOP control is relatively good, although medical therapy is often required.

Encapsulated blebs occur commonly after trabeculectomy (10–14% of cases) with decreased incidence in trabeculectomy with MMC compared to 5FU. Associated factors include male sex, glove powder, topical steroids, prior sympathomimetic use, prior argon laser trabeculoplasty, and prior conjunctival surgery.

Initial management includes antiglaucoma medication, topical steroids, and digital ocular massage. Deciding between conservative medical management and a surgical approach depends on the severity of glaucomatous damage, the IOP level, and the response to conservative treatment.

Needling immediately lowers IOP. Cutting the fibrotic wall of the encapsulated bleb restores aqueous runoff to a larger subconjunctival area. Occasionally, there is no response to needling with multiloculated blebs. Even when successfully needled, Tenon’s cysts can reform requiring another needling or more extensive surgical revision.

To surgically remove a Tenon’s cyst, conjunctiva is bluntly dissected off the underlying fibrotic wall, and the fibrous capsule is excised. Subconjunctival 5FU injections after surgical revision increases success. If a Tenon’s cyst recurs after surgical excision, repeat trabeculectomy (usually with tenonectomy) is indicated.

Failing and failed blebs

Failing blebs have uncontrolled IOP and impending or established obstruction of aqueous outflow. These blebs appear low or flat with minimal to no microcysts. Warning signs are increased bleb vascularization, bleb inflammation, and/or bleb thickening. These blebs should be recognized promptly to relieve aqueous outflow obstruction. Otherwise, permanent adhesions develop between conjunctiva and episclera making the bleb intractable to revision.

Bleb failure is usually a late occurrence. ‘Early failing/failed blebs’ occur within the first postoperative month mostly because of inadequate flow at the scleral flap site. Bleb failure is usually a late occurrence. ‘Late failing/failed blebs’ have a history of at least 1 month of good bleb function and adequate IOP control postoperatively. Subconjunctival and episcleral fibrosis cause most filtration failures. Factors accelerating subconjunctival fibrosis are black race, childhood, postoperative subconjunctival hemorrhage, reactive sutures, and inflammation.

In early bleb failure, 5FU enhances filtration. Subconjunctival 5FU in 5-mg aliquots is administered during the first 2 weeks after surgery. The frequency of administration is adjusted according to the occurrence of complications, which include corneal and conjunctival epithelial toxicity, corneal ulcers, conjunctival wound leaks, subconjunctival hemorrhage, and inadvertent intraocular spread of 5FU.

During the early postoperative period, sutures are removed when there is a high IOP, a flat filtration bleb, a deep anterior chamber, and an open sclerostomy. In a conservative stepwise manner, one suture is laser suture lysed or extracted at a time to avoid overfiltration. Releasable sutures are used when inflamed or hemorrhagic conjunctiva and thickened Tenon’s tissue preclude suture lysis. Many different releasable suture techniques exist. Timing of suture release is critical. Without antimetabolites, this should be performed within 2–3 weeks. The time frame for successful suture release after trabeculectomy is 1–2 months with 5FU and several months with MMC.

Digital ocular compression/massage is directed through the eyelids to the inferior sclera or sclera posterior to the scleral flap

to elevate the bleb and reduce IOP. Especially useful after suture release, it is less responsive with internal obstruction of the sclerostomy. Patients are instructed to massage several times a day during the early postoperative period. Potential complications include corneal abrasions, hypotony, flat anterior chamber, and choroidal effusion or hemorrhage.

Recombinant tissue plasminogen activator (tPA) is a serine protease with clot-specific fibrinolytic activity. TPA converts plasminogen to plasmin, which mediates fibrin degradation into fibrin-split products and fibrinogen-degradation products to lyse new clots. The most common dose is 7–10 micrograms. TPA is injected subconjunctivally or into the anterior chamber when hemorrhage or fibrin clots occlude the sclerostomy. Hyphema is the most frequent complication after glaucoma surgery (up to 36% of cases).

Management of late failing blebs depends on the site of aqueous resistance. Internal revision with Nd:YAG or Argon laser is useful early and late in the postoperative period when there is sclerostomy obstruction. Nd:YAG treats nonpigmented tissues (vitreous, lens capsule) while argon laser is effective for pigmented tissue (iris, ciliary body). A more favorable outcome occurs if the filtration bleb was well established before the fistula was occluded and if there is no significant subconjunctival scarring. Hemorrhage is a complication.

Laser external revision is directed to episcleral or subconjunctival fibrosis with or without simultaneous internal revision. To treat blebs transconjunctivally, a Nd:YAG Abraham iridotomy lens is placed over the bleb with 2% methylcellulose. Energies from 2.9–10.0 mJ in single pulse mode are used. The laser is retrofocused through the bleb onto episclera. Bubble formation indicates adequate power. After the procedure, Seidel to detect conjunctival breaks.

External revision by needling cuts the edge of the scleral flap to restore aqueous runoff. A short 1/4 to 5/8 inch 25–30 gauge needle penetrates conjunctiva 5–10 mm from the scleral fistula. Balanced saline solution or 1% lidocaine is injected to balloon up the conjunctiva. The needle is advanced into the bleb cavity beneath the scleral flap. A sweeping motion or to-and-fro movements lyse fibrotic strands at the bleb edges tearing a hole in the cyst wall. Avoid multiple punctures to prevent conjunctival buttonholes and excessive bleeding. An ‘aggressive’ alternative advances the needle through the internal ostium until visualized in the anterior chamber (use extreme caution in phakic eyes). Seidel for wound leaks. Pressure patch, cauterize, or suture with 10-0 nylon on a vascular needle if there is a brisk leak. Topical antibiotics and steroids are used postoperatively with or without additional subconjunctival 5FU.

Transient bleb leak is the most frequent complication. Other complications include endophthalmitis, choroidal hemorrhage, subconjunctival hemorrhage, choroidal detachment, and hypotony. The success rate is directly related to lower preneedling IOP and fewer previous surgical procedures. Use of 5FU or MMC with needling is controversial. A mixture of 0.02 mL of bupivacaine 0.75% with epinephrine and 0.01 mL of MMC (0.4 mg/mL) may be injected 20 minutes before needling.

If there is adequate conjunctiva elsewhere, it may be preferable to perform a MMC-augmented trabeculectomy in healthy tissue at another site or a glaucoma drainage implant rather than a bleb needling.

Potential bleb complications

●Hypotony (intraocular pressure less than 6 mm Hg). ● From excessive filtration or a bleb leak.

Problems Associated180 CHAPTERand Blebs Filtering •

Conjunctiva • 18 SECTION

of the eyes upon awakening, and slight blurring of vision. These symptoms are so common that patients are not likely to report them. As GPC progresses, patients may report blurring of vision after wearing the contact lenses for several hours, excessive movement of the contact lenses, mucus discharge and contact lens awareness. The examination may reveal mucus strands and mild hyperemia of the upper tarsal conjunctiva. In early to moderate cases, the conjunctiva is usually translucent, but it may be somewhat thickened.

As inflammation increases, the conjunctiva may become opaque. In the late stages of GPC, patients develop contact lens intolerance and describe dryness, foreign body sensation or pain when wearing the lens. Sheets or ropes of mucus are usually present, contributing to sticking of the eyelids. Upon awakening, hyperemia is marked, and pseudoptosis may appear in some patients.

Concurrent with the opacification of the upper tarsal conjunctiva, enlarged collagen structures (papillae) begin to emerge from the tarsal plate. As they grow, they push aside the normal smaller papillae, and their apexes flatten gradually. The overlying conjunctiva may break down, resulting in fluorescein staining, which is critical sign of moderate-to-severe disease. In soft contact lens wearers, papillae appear on the upper tarsal conjunctiva and advance to the lid margin. In rigid gas-permeable contact lens wearers, papillae are fewer and smaller and appear first on the lid margin.

DIAGNOSIS

Clinical signs and symptoms

The syndrome includes a spectrum of clinical signs and symptoms. Abnormally large papillae (diameter of more than 0.3 mm) are diagnostic and best visualized with fluorescein and the cobalt-blue light. Giant papillae are classically described as 1 mm or larger in diameter and are concentrated in the superior tarsal conjunctiva (Figure 181.1). They are usually not seen except in advanced cases. Increased production of mucus results in strings or sheets that coat the contact lens may cloud vision.

Giant papillary conjunctivitis can resemble vernal conjunctivitis. In fact, similar immunologic process may be involved in both diseases. Both conditions present with ocular itching and mucoid discharge. However, the itching of GPC is usually milder than with vernal conjunctivitis. Also, unlike vernal conjunctivitis, GPC is not associated with atopy. GPC occurs in all age groups and both sexes, whereas vernal conjunctivitis is more common in young males. Vernal conjunctivitis usually displays seasonal variation, worsening in warm weather.

FIGURE 181.1. Giant papillary conjunctivitis.

Patients with GPC experience a rapid relief of symptoms upon discontinuation of contact lens wear, whereas vernal conjunctivitis patients do not have a dramatic response with any one treatment.

Early symptoms include lens awareness, excessive lens movement, dryness, inner canthal mucus on awakening, redness, burnings, itching and blurring.

Later key signs include the following:

●Conjunctival injection;

●Upper tarsal papillae (at least 0.3 mm): macropapillae (0.3 to 1.0 mm), giant papillae (more than 1.0 mm). fluorescein staining of papillae, papillary flattening;

●Tarsal thickening/opacity;

●Mucus strands;

●Superficial punctate keratopathy;

●Eyelid: pseudoptosis (edema);

●Other: mucus coating/protein deposits on contact lenses.

Ocular or periocular

●Conjunctiva: macropapillae (0.3 to 1.0 mm diameter), giant papillae (more than 1.0 mm diameter), fluorescein staining of papillae, tarsal and bulbar conjunctival injection, tarsal conjunctival thickening and opacity, mucus strands, Horner–Trantas dots, gelatinous limbal nodules.

●Cornea: superficial punctate keratopathy.

●Eyelid: pseudoptosis.

●Other: mucus coating of contact lenses, protein deposits on contact lenses.

Differential diagnosis

●Vernal keratoconjunctivitis.

PROPHYLAXIS

●Consider more frequent replacement of disposable contact lenses (including daily disposable contact lenses) or reduce daily wear time.

●Encourage strict lens hygiene.

●Recommend preservation-free solution.

●Encourage enzymatic cleaning with papain preparations.

●Remove offending foreign body.

TREATMENT

The primary treatment of GPC involves removal of the foreign body and treatment of inflamed conjunctiva with pharmacotherapy. The removal of a prosthesis or contact lens or trimming of an offending suture barb usually results in prompt resolution of the problem. Most patients who wear contact lenses, however, wish to continue wearing their lenses.

Supportive

In severe cases, patients must stop wearing their contact lenses until symptoms such as hyperemia and mucus discharge resolve and the eye is ‘quiet.’ Fluorescein staining of the apexes of papillae, copious mucus discharge, tarsal hyperemia, and decentering of the contact lens are all indications for lens removal. Lenses should be discontinued for at least 4 weeks and may be reintroduced several days after the signs and symptoms have resolved. Patients should be free of injection, mucus discharge, and punctate keratopathy before being fitted with a new contact lens. Enlarged papillae may take months or year to regress.

Conjunctivitis181 CHAPTERPapillary Giant •

Conjunctiva • 18 SECTION

Some patients will be able to continue contact lens wear without stopping, provided certain strategies are followed. First, lens replacement (with a new and preferably different type of contact lens) is recommended. A smaller-diameter, thinneredge lens should be fitted. In addition, meticulous attention to lens hygiene is essential. Contact lens cleaners should be free of preservatives, such as thimerosol. Nonpreserved saline in an aerosol can is recommended. These steps will help minimize antigenic exposure. Sterilization with hydrogen peroxide has been found to be the best-tolerated disinfection method. Weekly enzymatic cleaning to remove deposits is necessary.

The patient should understand that regular replacement of traditional soft contact lenses should occur every 6 to 12 months or at the first sign of any significant lens coating or mucus discharge. In some soft contact lens wearers, a switch to a daily disposable or rigid gas-permeable contact lens may be the only alternative to increase contact lens tolerance.

Frequent-replacement (disposable) contact lenses are an important addition to the supportive treatment regimen for GPC patients. Disposable contact lenses may obviate the need for enzymatic cleaning; deposits are minimized because the contact lenses are discarded and replaced every 1 to 2 weeks. Daily disposable contact lenses may be indicated in some wearers. For patients with a history of GPC, disposable contact lenses should be worn on a daily basis with daily cleaning. Patients should not sleep in their lenses.

Ocular

After the discontinuation of contact lens wear, topical lubrication may be the only therapy required. In cases of advanced GPC in which inflammation is marked, a short course of topical corticosteroids may be appropriate to quiet the eye before initiating further treatment. However, corticosteroids have not proven particularly effective in the long-term management of GPC.

A recent double-blind, placebo-controlled study of loteprednol etabonate in 223 patients with GPC revealed a significant improvement in itching and lens intolerance, with only 7% showing a 10 mm Hg or greater increase in intraocular pressure. Pressure returned to normal after discontinuing of the drops. Other studies showed a significant reduction in papillae and symptoms for patients receiving loteprednol compared to placebo.

Cromolyn sodium, a mast cell stabilizer, has had a beneficial effect in the management of GPC. In conjunction with lens replacement and rigorous lens hygiene, 4% cromolyn sodium ophthalmic solution q.i.d. (even while the lens is in place) may help resolve early GPC before it progresses. More advanced cases of GPC are not amenable to treatment with cromolyn sodium alone. Once the signs and symptoms of GPC are brought under control with supportive therapy, cromolyn sodium may be introduced as part of regular maintenance therapy. Other agents (olopatadine 0.1%, ketotifen 0.025%) combine antihistamine (H1 receptor) and mast cell stabilizer properties in the treatment of allergic conjunctivitis.

Both ketorolac tromethamine, a topical nonsterioidal antiinflammatory drug and prostaglandin inhibitor, and lodoxamide tromethamine, a topical mast cell stabilizer, have been shown to improve contact lens tolerability in patients with GPC.

Levocabastine, a potent topical histamine (H1 receptor) antagonist, has recently been extensively evaluated for allergic conjunctivitis. Results indicate that it has efficacy similar to or

better than that of topical cromolyn sodium. Its safety and efficacy in patient with GPC remain to be determined.

A newer agent (epinastine hydrochloride 0.05%) has recently been introduced in the treatment of allergic conjunctivitis. It acts as a mast cell stabilizer and antihistamine, but blocks both short-term (H1) and long-term (H2) histamine receptors. Its utility in GPC patients remains to be determined.

●General:

●Decreased contact lens coating (decreased antigen load/ trauma to ocular surface);

●Modulate immune response after the initiation of inflammation.

●Decrease contact lens coating:

●Decrease wear time; consider the use of disposable contact lenses;

●Improve the cleaning/enzyming regimen;

●Change the lens material or design.

●Modulate the immune response:

●Topical steroids can be used;

●Topical nonsteroidal anti-inflammatory drugs can be used;

●Topical mast cell stabilizers can be used.

There is no systemic or surgical treatment.

PRECAUTIONS

The successful treatment of GPC depends on the earliest possible recognition of the disease process and initiation of appropriate therapy. The symptoms of GPC usually precede the earliest subtle signs; therefore, the proper diagnosis requires careful examination and a high index of suspicion. Patient education regarding the nature of GPC is crucial to the successful continuation of resumption of contact lens wear. Patients should thoroughly understand the importance of meticulous lens care and frequent lens replacement as well as such alternatives as disposable contact lenses.

COMMENTS

To follow the progression of the clinical signs of PC with contact lens wear and therapy, it is necessary to accurately describe the appearance of the upper tarsal conjunctiva to each visit. A record should be made indicating the zone of involvement, the size and elevation of the papillae, the fluorescein-staining pattern of the tops of papillae, and the presence of mucus. The progression of these signs and symptoms in the initial disease state has some prognostic value. The earlier the GPC is treated, the more likely treatment will arrest progression of the disease while maintaining long-term tolerance of the contact lens.

REFERENCES

Allansmith ME, Ross RN: Giant papillary conjunctivitis. In: Duane TD, Jaeger EA, eds: Clinical ophthalmology. Philadelphia, Harper & Row, 1987:4:1–10.

Allansmith MR, Korb DR, Greiner JV: Giant papillary conjunctivitis in contact lens wearers. Am J Ophthalmol 83:697–708, 1977.

Allansmith MR, Ross RN: Ocular allergy and mast cell stabilizer. Surv Ophthalmol 20:229–244, 1986.

Donshik PC, Porazinski AD: Giant papillary conjunctivitis in frequent replacement. Trans Am Ophthalmol Soc 97:205–216, 1999.