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Management of Dry Eye

Michael A. Lemp, MD
Several small, randomized studies investigating autologous serum tears versus unpreserved saline drops,29 unpreserved artificial tears,30 and/or other conventional treatment28 suggest that autologous serum tears are effective in improving symptoms and signs of severe or refractory DED—although, in one of these studies, only nonsignificant trends were observed.29 A randomized study in post–laser-assisted in situ keratomileusis (LASIK) DED demonstrated significant improvement in rose bengal staining and TBUT, but not in the Schirmer test or symptom scores, with autologous serum tears compared with artificial tears.31 Differences in efficacy may result from differences in production, storage, and treatment protocols. An optimized production protocol has recently been published.2

Few complications have been reported with autologous serum tears; however, circulating antibodies in serum could theoretically cause an inflammatory response.27 Other potential adverse effects (AEs) from prolonged exposure of the ocular surface to serum components have not been ruled out.28

Tear retention
Lacrimal outflow occlusion slows tear clearance, and is indicated in patients with aqueous-deficient DED.2 However, it is relatively contraindicated in the presence of clinically apparent inflammation. When inflammation is present, occlusion prolongs pocular surface exposure to abnormal tears containing proinflammatory cytokines; therefore, treatment of inflammation before plug insertion is usually recommended.2,32,33

Punctal plugs are the most commonly used means of occlusion, and have been shown to improve DED symptoms and signs in a number of clinical studies. There are 2 main types of punctal plugs: absorbable and nonabsorbable. Absorbable plugs are made of collagen or various polymers, and may last for days to months.2 Some newer absorbable materials may last as long as 6 months.33 Nonabsorbable plugs, often made of silicone or hydrophilic acrylic, are intended to be permanent.

A common complication of punctal plugs is epiphora (tear overflow). Mild epiphora has been reported in up to 36% of patients. Epiphora is usually well tolerated, but as many as 5% of patients request plug removal.33 Other AEs include infection2 and conjunctival irritation.33 Short-term absorbable plugs may be used initially to predict which patients are likely to tolerate nonabsorbable plugs; however, this test is not completely reliable.33

Spontaneous extrusion of plugs occurs in up to 50% of patients within 3 months, requiring replacement. In contrast, internal migration is uncommon but troublesome, because removal of a migrated plug may require surgery. If not removed, a migrated plug can cause complete occlusion, which may lead to epiphora, infection, or fistulas. Newer plug designs minimize the risk of spontaneous extrusion or migration.33

Intracanalicular plugs are an alternative to punctal plugs with less risk of extrusion or conjunctival irritation. However, canalicular inflammation or infection may occur. Furthermore, removal is more difficult than with punctal plugs, requiring more invasive procedures.33

Surgical occlusion (eg, using electrocautery, laser, or glue) is an option for patients who tolerate plugs but repeatedly extrude them. However, the wide choice of reversible devices currently available has decreased the need for occlusive surgery.33

Moisture spectacles/goggles reduce tear evaporation by increasing humidity around the eye. The patient’s glasses can be modified using commercially available top and side shields or swimming goggles can be used.34 However, evidence of efficacy is limited2 and adherence may be poor for cosmetic reasons.1

Therapeutic contact lenses (also called bandage contact lenses) may be used in severe DED, or when other therapy has failed, to help retain the tear film and/or promote ocular surface healing.35 For example, therapeutic contact lenses may be useful in the management of filamentary keratitis.35-37 However, because contact lenses can also exacerbate DED, patients using them for DED must be monitored closely.35

Silicone hydrogel lenses have been recommended for use in DED because of their high oxygen permeability and relatively low water content. The low water content makes them less likely to dehydrate35 in the presence of a hyperosmolar tear film.

The Boston scleral lens is a therapeutic contact lens that is custom-manufactured using a computerassisted design program.38,39 It is a rigid gas-permeable lens that vaults the cornea and rests entirely on the sclera, creating a fluid-filled precorneal space.38,40 In this way, it provides a “liquid bandage” for the corneal surface, reducing or eliminating desiccation, hyperosmolarity, and friction with the eyelids.39 It is also fluid-ventilated—designed with channels that allow tears to flow into the precorneal space, avoiding the development of negative pressure.38,40

The Boston scleral lens is indicated for management of severe, refractory ocular surface disease, for example, to relieve disabling pain and photophobia or treat persistent epithelial defects.38-40 It is also used to improve visual acuity when conventional lenses are inadequate or are not tolerated.38 Successful use has been reported in DED, including DED with filamentary keratitis38,40 and severe DED secondary to graft-versus-host disease,38,39 Sjögren syndrome,38 or radiation.38 Additional information about the Boston scleral lens can be obtained from the Boston Foundation for Sight at http://www. bostonsight.org or (781) 726-7337.

Tarsorrhaphy (closure of the eyelids) is reserved for severe or refractory DED.1,34 Methods include:

• Short-term tarsorrhaphy using, for example, tape, adhesive glue (lasts a few days), or botulinum toxin (lasts an average of 16 days).41
• Temporary suture tarsorrhaphy (lasts as long as 4-6 weeks).41
• “Permanent” tarsorrhaphy. The lid margins are excised and sutured so that they heal together. The procedure can be reversed later.41

In most cases, only the lateral portions of the lids are closed to narrow the palpebral aperture, decreasing evaporation.34,41 A partially open eye allows partial vision, administration of drops, and corneal examination; it also allows more oxygen to reach the cornea.41 However, if partial closure fails, complete closure may be indicated.34

In a retrospective review of 77 tarsorrhaphy patients, complications included trichiasis (ingrown eyelashes) in 18.2%; adhesion of the upper and lower lids after tarsorrhaphy removal in 2.6%; pyogenic granuloma in 1.3%; and keloid formation in 1.3%. All of these complications occurred in patients with permanent tarsorrhaphies. Other reported complications have included lid margin deformities, suture granulomas, focal cellulitis, skin breakdown, and distichiasis.41

Tear stimulation: secretagogues
Cholinergic agents (ie, muscarinic acetylcholine receptor agonists) are sometimes given orally to treat aqueous-deficient DED. Two agents, pilocarpine and cevimeline, have FDA-approved indications for treatment of dry mouth associated with Sjögren syndrome; however, they are off-label for treatment of dry eye.42,43

Pilocarpine. Two multicenter, 12-week, randomized, placebo-controlled trials of oral pilocarpine have been conducted, involving a total of 629 patients with Sjögren syndrome. In these trials, pilocarpine significantly improved global assessment of DED symptoms44-46 at doses of 5.0 to 7.5 mg QID.46 Pilocarpine also significantly decreased the use of artificial tears and improved salivary flow (measured by 5-minute saliva sample collection).44

A single-center, randomized trial of pilocarpine (5 mg BID) versus punctal occlusion versus artificial tears alone involved 85 Sjögren syndrome patients. (All patients received artificial tears.) Pilocarpine significantly improved global symptom assessment compared with the other 2 groups; it also significantly improved rose bengal staining, but not Schirmer scores or goblet cell numbers.47

In the placebo-controlled trials, the most common drug-related AE was sweating.44-46 Other AEs probably related to pilocarpine included urinary frequency, flushing, and hypersalivation.46 Headache, nausea, rhinitis, and dizziness were also common, but occurred with similar frequency in the pilocarpine and placebo groups.46 AEs were typically mild to moderate, and were roughly dose-dependent. 46 No serious AEs were reported.44-46 Among patients receiving pilocarpine 5.0 to 7.5 mg QID, 3.9% to 8.6% withdrew because of AEs, compared with 4.0% to 4.7% of those receiving placebo.44

Cevimeline. Two multicenter, randomized trials of oral cevimeline have been conducted, involving a total of 257 patients with Sjögren syndrome. In the first trial, 197 patients were randomized to cevimeline (15 or 30 mg TID) or placebo for 12 weeks. The 30-mg dose significantly improved both Schirmer scores and global symptom self-assessment, compared with placebo. The 15-mg dose also relieved some symptoms and improved Schirmer scores, but less so than the higher dose. Common drug-related AEs included increased sweating and nausea. Headache and diarrhea were also common, but occurred with similar frequency in the cevimeline and placebo groups. AEs led to withdrawal in 16.1% of the cevimeline 30-mg group, 13.8% of the 15-mg group, and 4.3% of the placebo group.48

In the second trial, 60 patients were randomly assigned to cevimeline (20 or 30 mg TID) or placebo for 4 weeks. Compared with placebo, both cevimeline doses improved subjective symptoms, tear dynamics, ocular surface condition, and global assessment; however, statistical significance was not reached for all parameters at all time points, and not all parameters showed a dose response. The 20-mg dose demonstrated the most consistent improvements at 4 weeks. Inconsistencies in the results may be attributed, in part, to the fact that the study was underpowered (the intended enrollment of 80 patients was not reached), and to between-group differences at baseline. The most common AEs were gastrointestinal symptoms (including nausea and diarrhea) and increased sweating, all mild to moderate.49

Anti-inflammatory agents
Topical corticosteroids are approved by the FDA for corticosteroid-responsive inflammatory conditions of the conjunctiva, cornea, and anterior globe. This indication can be interpreted as including DED.2

Several randomized trials have demonstrated that short-term topical corticosteroid use (as long as 4 weeks) improves signs and symptoms of DED2:

 
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