1. List the factors to consider when prescribing corticosteroids for the treatment of infectious keratitis.

2. Explain the mechanisms by which corticosteroids resolve keratitis.

3. Select among preparations available for the treatment of severe dry eye.

4. Distinguish types of blepharitis and describe the treatment approach for each.

5. Describe the role of oral acyclovir in the treatment of herpetic eye disease.

Treatment of Infectious Keratitis: The Role of Corticosteroids
John A. Irvine, MD, Professor of Ophthalmology, Doheny Eye Institute, the Keck School of Medicine of the University of Southern California, Los Angeles

Possible effects of steroids on keratitis: may potentiate infection; predispose to infection; mask infection; alleviate infection

How steroids can be used (and issues with use): as prediagnosis treatment; inappropriately by noncompliant patients; may predispose some patients to superinfection; following diagnosis and initiation of treatment (“oftentimes, the best and most satisfying role”)

Key considerations: infectious agent—bacteria, viruses, fungi, and amoeba all respond differently; timing—when to initiate, when to stop

Timing: when used before correct diagnosis, usually not helpful and possibly harmful; after diagnosis and initiation of treatment, helpful against selected infections; do not initiate too early, or stop too soon

Key considerations: do not use in “cookbook” fashion; monitor closely

Use without antiviral agent: to enhance patient comfort, eg, when adenoviral infection present; monitor patient closely (may have herpes simplex virus [HSV] infection)

Use before diagnosis: sometimes used to treat chronic viral infections, often without understanding of harmful potential (eg, conjunctivitis, corneal abrasions, increased risk for infection, masking of underlying infection)

Contact lens–related infection: steroid use contraindicated without appropriate antibiotic coverage, due to possibility that Pseudomonas or other gram-negative organisms etiologic agents

Acanthamoeba infection: frequently misdiagnosed as HSV or fungal infection, although clinicians better trained today to consider acanthamoeba if infection appears unusual or does not respond to standard treatment for HSV; misdiagnosis prolongs time to correct diagnosis and treatment; exacerbated by steroids because patient feels better, but does not actually improve, and in meantime, organism becomes more entrenched; false sense of improvement delays further investigation and consultation, allowing organism to penetrate deeper into stroma; early diagnosis and treatment associated with better prognosis

Steroids as cause of keratitis: long-term use, eg, after corneal transplant (to minimize risk for graft rejection), can predispose to fungal or streptococcal infection; sutures or suture remnant may act as nidus for infection; speaker now asks patients whether they have history of recurrent eye inflammation to determine whether HSV might be present (if patient answers “yes,” course of low-dose acyclovir [“low consequence, high efficacy”] used during treatment for graft rejection)

Bacterial keratitis: inflammatory cells (neutrophils) infiltrate cornea and release proteolytic enzymes (collagenases, gelatinases) that dissolve corneal stroma, resulting in perforation or ulceration; bacteria release toxins that also damage cornea

Role of corticosteroids: decrease tissue destruction caused by inflammatory response; as with inflammation, steroids retard epithelialization, but to lesser extent; solution—treat inflammation and infection; clinical studies show combination therapy of antibiotics plus steroids has either no effect or resolves stromal inflammation faster than antibiotics alone

When to start steroid therapy: obtain cultures and preliminary results; assess antibiotics according to clinical response; then add or modify topical steroids

Initiating steroids: begin with 4 times/day regimen; monitor at 24 and 48 hr; if no adverse effect, increase frequency of drops briefly, depending on clinical response

Peripheral Staphylococcus infiltrates: speaker believes reasonable to treat initially with topical steroids; treat with broad-spectrum antibiotic for ≈24 hr if identity of organism unclear; add steroid if epithelium heals

Fungal keratitis: response often slow; drugs penetrate cornea poorly; may result in chronic scarring; if patient responds to antifungal treatment, carefully add mild steroid and monitor response

Viral keratitis: steroids can decrease discomfort in cases due to varicella zoster or adenovirus; use in conjunction with antiviral agents; speaker uses topical and systemic (ie, oral) forms to initiate epithelial healing, then discontinues topical agent; oral acyclovir alone recommended for peripheral or superficial lesions

Recurrent infection in corneal transplant: inflammation causes graft failure; steroids may prolong active infection; therefore, important to balance steroids and antimicrobials; monitor patient closely and adjust medication accordingly

Disciform keratitis: very responsive to topical steroids; antivirals usually not necessary because immune response drives inflammation, with no active infection; zoster dendrites “exquisitely sensitive” to topical steroids

Adenoviral infection: subepithelial infiltrates debilitating (cause extreme photosensitivity); topical steroids improve vision and comfort, as well as hasten recovery, but antigen remains; warn patients that long-term steroid therapy may be required; use controversial, however

Acanthamoeba keratitis: prognosis best when diagnosed quickly

Summary: positive effects of steroids—modify inflammatory response, thereby decreasing tissue destruction and improving visual acuity by minimizing scar formation; improve epithelial healing by decreasing inflammation, which retards epithelial migration; valuable when inflammatory component still prevalent after infection controlled; cautions—injudicious use may 1) predispose cornea to infection, 2) mask infection, and 3) possibly aggravate infection; proper timing, pathogen identification, and close follow-up essential

Severe Dry Eye
Herbert E. Kaufman, MD, Boyd Professor Emeritus of Ophthalmology, Pharmacology, and Microbiology, Louisiana State University School of Medicine, New Orleans

Background: condition hard to define; therefore, developing and obtaining approval for drugs to treat this condition extremely difficult; dry eye may be idiopathic or due to autoimmune disease; rule out lagophthalmos (ask patient to gently close eyes as if sleeping; shine penlight; any corneal reflex evidence of lagophthalmos; symptoms resemble those of recurrent erosion); often missed in children (uncommon but devastating; may be seen in otherwise healthy children)

Treatment: artificial tears—most patients have preference for one type over another (may bear no relationship to cause of dry eye); cyclosporine “worth a try”; combine with loteprednol to resolve inflammation; acetylcysteine in 50% combination with artificial tears helps control discharge; severe vision impairment indication for bandage lens (thick, low-water-content lens recommended; water evaporates from thinner lens, leaving “a potato chip”); occlusive edges around spectacles; avoid direct air flow, air conditioning, and dry heat; some evidence that omega-3 fatty acid supplements helpful, but “by and large, we don’t know how to treat dry eyes”

Hydroxypropyl cellulose ophthalmic insert: Food and Drug Administration (FDA)–approved for treatment of moderate to severe dry eye; preservative-free insert that slips under lower eyelid (inferior cul-de-sac); use daily; provides sustained-release artificial tears; many (but not all) patients find preferable to eye drops; stabilizes tear film, lubricates surface, and helps retain moisture throughout day; water-soluble, dissolves over course of day (no removal necessary); seems to be most effective in severe cases, but milder cases may also benefit, especially if patient wears contact lenses; greatest benefits associated with long-term use

Blepharitis and Meibomian Gland Dysfunction
Mark S. Milner, MD, Associate Clinical Professor of Ophthalmology, Yale University School of Medicine, New Haven, CT

Dysfunctional tear syndrome: more precise name than dry eye (encompasses tear quality as well as quantity)

Tear components: lipid layer—produced by meibomian glands; helps prevent evaporation; aqueous layer— produced by lacrimal and accessory lacrimal glands; mucin layer—produced by goblet cells; helps maintain surface tension; aqueous-mucin gel; soluble mucins give tears viscosity; disruption in any layer may cause dysfunctional tear syndrome

Categories: tear deficiency; evaporative tear disease (what most people mean by dry eye); blepharitis and meibomian gland disease; exposure keratopathy

Blepharitis

Cutaneous: eg, allergic blepharitis, contact dermatitis, eczematoid, seborrheic blepharitis

Anterior: almost always infectious, usually Staphylococcus aureus; other causes include HSV, fungus, and Demodex

Posterior: usually meibomian gland dysfunction

Sequelae: recurrent conjunctivitis (meibomian gland disease commonly underdiagnosed cause); phlyctenulosis (type IV hypersensitivity response); classic rose-bengal staining (wedge-shaped or triangle-shaped pattern), but also look for inferior rose bengal; meibomian gland disease differential diagnosis for chronic follicular conjunctivitis; Salzmann’s nodular corneal dystrophy; phlyctenulosis may occur on conjunctiva and cornea as well as limbus; corneal ulceration

Anterior blepharitis caused by S aureus: signs include morning crusting, loss of eyelashes and/or crusting around eyelashes (hordeola); folliculitis; Staphylococcus immune disease (eg, phlyctenulosis, inferior conjunctival or corneal staining, pannus, marginal infiltrates, angular blepharitis); treatment—eyelid hygiene with hot compresses, commercial eyelid scrubs, antibiotic ointment, and corticosteroids

Posterior blepharitis: characterized by inspissated glands producing “toothpaste-like” secretions; pathophysiology— normal meibomian gland secretions saturate unsaturated lipids, which then inspissate meibomian glands; also lead to irritation and inflammation; lipases break down fats into monoglycerides and diglycerides, which are inflammatory, helping to solidify secretions; eyelid bacteria secrete lipases that break down lipids into soaps and free fatty acids; symptoms—burning; foreign body sensation; filmy vision; purulent or toothpaste-like secretions; telangiectasia, erythema, or thickening of eyelid margin; rose-bengal staining; causes—evaporative tear disease (disrupts lipid layer); goblet cell inflammation; ocular surface inflammation; treatment—hot compresses, topical antibiotics, steroids; oral tetracycline or doxycycline; nutritional supplements; small potato placed in microwave for 1 to 2 min, and then wrapped in moist paper towel acts as heat sink (holds heat longer than hot compress with washcloth)

New trends in therapy: anti-inflammatory treatment (topical cyclosporine); topical azithromycin has anti-inflammatory as well as antibiotic effects; prevents pro-inflammatory mediators, cytokines, prostaglandins, and TNF-α, leading to inhibition of neutrophil migration, cytokine production, phagocytosis, and antioxidant activity; effective against broad spectrum of bacteria; achieves high concentration in tissue, tears, and conjunctiva; use for blepharitis off-label

Other innovative treatments: metronidazole ophthalmic ointment (can be compounded); topical doxycyline or clindamycin (also compounded); flaxseed oil (contains short-chain omega-3 fatty acids that thin meibomian gland oils); fish oil (contains long-chain omega-3 fatty acids that suppress inflammation; androgen therapy now being studied

What’s New with Herpes?
Dr. Kaufman

Herpes zoster vaccine: live-virus vaccine recommended for everyone >60 yr of age; reduces burden of illness associated with herpes zoster and post-herpes zoster pain

Ganciclovir: associated with fewer adverse effects than trifluridine; selectively inhibits viral DNA; formulated with gel vehicle, making it easier to use and tolerate than acyclovir ointment; may also work against adenovirus; in animal studies, ganciclovir works synergistically with trifluridine; expected to be available in United States within 1 yr; associated with marked reduction in subepithelial infiltrates

Herpetic Eye Disease (HED) study: one of goals to determine whether oral acyclovir prevents stromal disease or iritis (it does not); efficacy against herpes zoster—eye disease late manifestation of infection; does not respond to oral antiviral agents; “basically, there is no reason to give oral acyclovir as an adjunct to topical therapy in the treatment of herpes”

Risks and complications of steroids and antiviral drops: animal studies suggest steroid administration slows viral clearance; however, no evidence in humans; combination therapy leads to resolution of disease and symptoms

Shedding and dissemination of virus: acyclovir decreases risk for clinical recurrence by 40% to 50% (however, herpes recurrences do not stop completely)

New antiviral agents: helicase primase inhibitors—prevent unwinding of viral DNA; new chain cannot form, so virus cannot replicate

Surgery for herpes: virus probably latent in cornea; excision of entire visible scar recommended; phototherapeutic keratectomy can be performed, but first start patient on acyclovir and maintain for 2 wk

Asymptomatic carriage of infectious virus: speaker found virus present in tear swabs from healthy people; in follow-up study, 36% of subjects shed virus every time they were tested; findings included several people who were antibody-negative; conclusion—most people probably infected with HSV, even without previous clinical disease; suppression of immune system activates virus; patients who have undergone corneal transplants or cataract surgery may develop epithelial herpes even without previous history of HSV disease; if patient develops epithelial defect after surgery, which does not resolve, consider possibility of HSV infection and perhaps conduct trial of empiric therapy (scarring and perforation may occur if infection not treated); reported in patients with no history of eye disease or HSV who had undergone laser in situ keratomileusis (LASIK); acyclovir reduces incidence of clinical disease, but does not appreciably affect viral shedding; may decrease end-organ susceptibility to infection