LASIK Issues

From the 2010 Annual Clinical Conference, presented by the Kansas City Society of Ophthalmology and Otolaryngology

Marguerite McDonald, MD, Clinical Professor of Ophthalmology, New York University Langone Medical Center, New York, NY; Adjunct Clinical Professor of Ophthalmology, Tulane University Health Science Center, New Orleans, LA; and Ophthalmic Consultants of Long Island, Lynbrook, NY

Educational Objectives

The goals of this program are to improve the management of dry eye after LASIK, keratoconus, and post-LASIK ectasia, and to examine recent research on the use of LASIK for presbyopia. After hearing and assimilating this program, the clini­cian will be better able to:

1.   Choose among a variety of options for treatment of dry eye after LASIK.

2.   Compare and contrast alternative agents and those under development for treatment of dry eye.

3.   Summarize the evidence supporting the use of photo-polymerization for the treatment of keratoconus and post-LASIK ectasia.

4.   Describe the benefits and limitations of LASIK correction for presbyopia.

5.   Evaluate the results of the clinical studies using LASIK in patients with hyperopia and presbyopia.

Faculty Disclosure

In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of in­terest. Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary business or commercial interest. For this program, Dr. McDonald reported financial relationships with Abbott Medical Optics (formerly AMO), Allergan, Bausch & Lomb, Essilor, FOCUS Laboratories, Foresight Biotherapeutics, For­Sight Labs, Inspire, Optical Express, Pfizer, Santen, and VISTAKON. The planning committee reported nothing to disclose. In her lectures, Dr. McDonald presents information on the off-label or investigational use of therapies, products, and/or devices.

Acknowledgments

Dr. McDonald was recorded at Annual Clinical Conference, held January 8-9, 2010, in Overland Park, KS, and sponsored by the Kansas City Society of Ophthalmology and Otolaryngology. The Audio-Digest Foundation thanks Dr. McDonald and the Kansas City Society of Ophthalmology and Otolaryngology for their cooperation in the production of this program.

Dry Eye and Lasik: New Drugs, New Plugs

Background: incidence of dry eye 85% 1 wk after laser in situ keratomileusis (LASIK; incidence 16% before surgery) and 59% at 1 mo; symptoms can persist for 16 mo

Severity: treat patients with dry eye after LASIK as if severity 2 grades higher

Standard treatment regimen: cyclosporin emulsion twice per day, unpreserved tears every 2 hr while awake, bland ointment at night, oral supplementation with omega-3 fatty acids, and punctal plugs; all patients have faster recovery, greater chance of 20/20 best uncorrected visual acuity (BUVA), and lower enhancement rate if standard regimen with cyclosporin emulsion used

Punctal plugs: limitations  —  silicon plugs require dilation; sizing difficult; insertion time-consuming; many patients have foreign-body sensation with collar button plugs; may cause abrasion; high rates of extrusion, migration, infection, and al­lergic reaction; hydrogel plugs (eg, Form Fit)  —  has not shown complications (eg, dacryocystorhinitis) seen with other in­tracanalicular plugs; universal size; preloaded on disposable inserter; fits »99% of patients (»1% need pediatric dilator); plugs swell to >20 times original volume within 10 min; easily removed; collar button plugs  —  speaker uses Snug Plug (also single size); fits most puncta

Tear substitute: LACrisert insert approved for treatment of moderate to severe dry eye; water-soluble pellet placed lat­erally into inferior cul de sac; delivers constant level of artificial tears (cellulose, 2-hydroxypropyl ether); ameliorates symptoms, increases tear film breakup time, and decreases rose bengal staining; no serious adverse effects; well ac­cepted by patients; more beneficial if used long-term

Study results: 58 patients with dry eye (not secondary to LASIK); statistically significant decrease (from 0.92 to 0.24) in average grade of corneal symptoms after 52 wk; other symptoms decreased significantly from grade of 2.09 to 0.24; no additional saline solution required; the greater the severity of symptoms pretreatment, the greater the bene­fit; greatest benefit provided when used ³10 wk

Second study: 22 patients with severe rheumatoid arthritis and moderate to severe keratoconjunctivitis sicca (KCS) evaluated LAC­risert vs artificial tears; patients reported little or no difficulty with insertion; 86% found LACrisert acceptable and 64% preferred it to other regimens; no significant difference in levels of blurring, tearing, and photophobia; beneficial effects greater in patients with more severe symptoms 

Liposome spray: speaker uses Tears Again (available online or by phone); contains vitamins A, C, and E; spray on closed eye lids and rub into base of lashes; liposomes on base of lashes enter tears, melt, spread, and reduce evaporation

Posterior blepharitis: patients who express no secretion from meibomian gland may have posterior blepharitis; treat with azithromycin 1% applied to eyelids twice per day for 2 days, then once per day for remainder of month

Other options: medroxyprogesterone 1% or 0.5% used 4 to 6 times per day for 4 to 6 wk (available from compounding pharmacy); dehydroepiandrosterone (DHEA; topical androgen), vitamin A (retinoic acid) ointment for goblet cell defi­ciency, or autologous serum

Alternative and Pipeline Drugs

Pilocarpine (Salagen): oral agent; effective for Sjögren’s syndrome, dry mouth, and dry eye; may cause gastritis and lower gastrointestinal problems

Cevimeline (Evoxac): oral agent; improved dry mouth in 65% and dry eye in 39% of »200 tested patients; nausea, sweat­ing, diarrhea, and headache limit acceptance

Rebamipide: topical ophthalmic agent that stimulates production of mucin, scavenges free radicals, and alters production of prostaglandins; phase II studies show improved corneal staining and symptoms; not yet approved in United States (US)

Diquafosol tetrasodium: analogue of uridine triphosphate (UTP); potent selective purinergic agonist at P2Y2 receptor; causes secretion of ions, fluid, mucin, and surfactant on mucosal surface; increases chloride secretion, fluid transport, and production of lipids

Mechanism: purinergic receptor family has ligand ion channel receptors (P2X) and G-protein-coupled receptors (P2Y); of 8 characterized P2Y receptors, this responds most completely to UTP; stimulation causes massive production of fluid; diquafosol causes release of burst of calcium into cell, which triggers production of fluid

Animal studies: diquafosol stimulated transport of chloride and fluid in rabbit conjunctiva ex vivo; in vivo, caused cells to degranulate, and fewer stained during impression cytology; possible to stimulate cells again in 25 min; amounts of cho­lesterol and phospholipid showed dose response to diquafosol in cultured rabbit meibocytes; in rats with lacrimal glands removed, diquafosol increased production of tears and density of goblet cells

Human studies: produced statistically significant improvement in corneal and conjunctival staining, foreign-body sensation, and Schirmer test scores, with good patient tolerance and adverse event profile

Hormonal therapy: topical androgens help control or prevent inflammation in lacrimal glands and ocular surface; levels of androgens decline with age and may drop below threshold required by lacrimal gland to function (especially in women); top­ical androgen therapy expected in future; topical estrogen enhances health and function of epithelial surface and goblet cells

Other effective therapies: sutureless cryopreserved amniotic membrane (eg, ProKera, AmnioGraft or fresh amniotic membrane sewn over cornea; remains in place until healthy epithelium established; Boston Scleral Lens  —  large (22-mm) lenses filled with contact lens solution from Boston Foundation for Sight

US Corneal Collagen Cross-linking Clinical Trial For Keratoconus and Post-LASIK Ectasia

Photopolymerization: uses UV-A light; irradiation of riboflavin-soaked cornea at 365 nm for 30 min produces numerous cross-links; other cross-linking methods  —  glutaraldehyde highly toxic; aldehyde sugars effective and safe but slow (2 wk); additional molecular bonding increases mechanical strength of tissue, stops progress of keratoconus and post-LASIK ectasia, and reverses process slightly; cross-linking of collagen occurs with age and diabetes; photopolymeriza­tion with UV light nontoxic; if cornea soaked with soluble photomediator (riboflavin), it penetrates anterior chamber and protects deeper layers of eye during irradiation; procedure approved (considered standard of care) in Europe; still investi­gational in United States

Procedure: remove epithelium to 9 mm centrally; for patients with post-LASIK ectasia, stroke away from center of cornea to avoid lifting flap; apply drops of riboflavin for 30 min (1 drop every 2 min); examine anterior chamber with slit lamp; dis­tinct yellow flare confirms cornea adequately saturated; perform pachymetry to confirm ³400 m of thickness (if not, use hy­potonic riboflavin to swell cornea) to protect endothelium and deeper layers; UV irradiation then administered; treatment after procedure identical to that for photorefractive keratectomy (PRK; eg, bandage contact lens, topical steroids, antibiotics, nonsteroidal anti-inflammatory drugs [NSAIDs], artificial tears)

Study results: improved best corrected visual acuity (BCVA) in 85% of treated eyes with post-LASIK ectasia and keratoconus; increase of 1 to 2 Snellen lines 9 to 30 mo after treatment and 3 to 4 lines after 30 to 60 mo; refractive cylinder reduced in >80% of eyes, and steepest keratometric (K) value decreased by »1 diopter (D) in 86% of eyes; topography flatter and smoother; an­other study showed slow improvement after treatment (flattening of K values); 6-yr follow-up showed results fairly stable; third study showed improved BCVA in >50% of treated eyes

Safety: corneal thickness of ³400 m required after removal of epithelium to protect endothelium from UV irradiation; if cornea soaked adequately with riboflavin and instrument used correctly, almost no UV reaches endothelium; removal of epithelium controversial; study examined anterior corneal surface of porcine eyes after 35 min of riboflavin drops applied every 5 min; 12 eyes had no epithelial trauma (received tetracaine), 12 had superficial corneal abrasions (basal epithelium left intact), and 12 had deep abrasions (epithelium fully removed); analysis with spectrophotometer showed less transmission of light if epithelium re­moved; concluded complete removal essential for ocular safety; without adequate absorption (of riboflavin), UV induces dam­age to endothelium of lens (eg, cataracts) and macula

US clinical trial: study design  —  prospective block randomized treatment for progressive keratoconus and corneal ectasia after LASIK or PRK; one eye cross-linked; measured maximum K (Kmax) at 3 mo, BUVA, and manifest refraction spherical equiva­lent (MRSE); followed patients for 1 yr; topography monitored before and after procedure

Results: 321 eyes treated; in eyes with keratoconus, Kmax values at apex became steeper immediately after treatment, but flattened at 3 mo by »0.5 D, compared to control eyes (not statistically significant); in eyes with ectasia, Kmax values steepened immediately, but became significantly flatter at 3 mo by >1 D, compared to untreated eyes; change in Kmax for all eyes »0.75 D (significantly flatter in treated group); average K (Kave) values showed increase immediately, then be­came flatter (compared to untreated group) by 0.5 D for eyes with keratoconus and by 0.75 D for eyes with ectasia; >0.5 D difference for all eyes; reason for immediate increase in steepness unknown; cross-linked tissue becomes thinner (by »25 m at 1 mo and 27 m at 3 mo); MRSE flattened by 2.5 D in treated group at 3 mo (difference not significant); BCVA im­proved by average of 2.35 lines (difference not significant)

Complications: incidence of infiltrates 1.2% (1 culture-positive and 1 culture-negative); 1.2% had slow re-epithelializa­tion; 1 eye had mild uveitis; all patients recovered with no loss of BCVA

Future applications: orthokeratology; pretreatment of eyes at risk for ectasia; antimicrobial therapy; treatment of sterile corneal ulceration or edema; cross-linking of sclera for prevention of myopic progression

Interim conclusions of US trial: collagen cross-linking appears to halt progression of keratoconus and ectasia after LASIK; decreases corneal curvature and thickness; improvement seen in MRSE and BCVA; excellent safety profile; ex­pected to become standard of care for ectatic corneal disease

PresbyLASIK: Does it Work?

Approaches: inferior off-centered or transitional ablations; ablation with near add in periphery using presbyopia Avalos Rozakis method (PARM) procedure; center-near pattern; easier to correct hyperopia with near add; ablation customized to patient’s pupil size and wavefront; near vision provided by center and distance by periphery; volumetric point spread function for patient with 2 D of hyperopia shows only one plane in sharp focus; if both hyperopia and presbyopia cor­rected, point spread function becomes trumpet-shaped and allows better vision over long distance; iris registration critical for wavefront-guided ablation; must compensate for pupil centroid shift and cyclotorsion (match preoperative iris crypts with eye under microscope); some loss of contrast sensitivity occurs

Canadian study: 82 eyes from 49 patients with hyperopia and presbyopia; eyes had average of +1.66 D (range up to 3.5 D) with slightly less than 0.5 D (up to 1.5 D) of cylinder; used reading acuity (measurement of letters, speed, and critical print size patient can read) to assess outcomes; found gradual improvement in monocular uncorrected distance acuity (UDA) in multifocal eyes (level achieved after 12 mo similar to that of nonpresbyopic hyperopic treatments); binocular UDA showed cortical summation (also gradual improvement over 1 yr);  improved monocular uncorrected near acuity (UNA) in multifocal eyes (98% could read J5 print without glasses); 88% had J1 binocular UNA and 100% had J3; for monocular distance-corrected near acuity (DCNA), 59% had J1 and 96% had J3; mean logarithm of minimum angle of resolution (logMAR) acuity over time showed stable improvement at 12 mo; MRSE drifted slowly back toward hypero­pia because of lenticular changes; at 6 mo, 73% of eyes within ±0.5 D of emmetropia (80% at 12 mo); at 12 mo, 80% of eyes achieved 20/25 at distance and ³J3l at near monocularly; 100% achieved 20/25 and ³J3 binocularly, and 88% achieved 20/25 and J1; after surgery, »50% free of glasses for reading, >50% free of glasses for computer, and all free of glasses for driving and recreation

Complications: few patients lost BCVA; distance loss of >2 lines occurred in 3 eyes (2 patients) at 6 mo because of dry eyes and one eye of one patient at 12 mo (no eyes worse than 20/25 minus 2); loss of >2 lines at near occurred because of dry eye, with none worse than J1; contrast sensitivity decreased but remained within population norms; higher order aberrations  —  negative spherical aberration induced (intentionally)

Second study: 80 eyes with slightly more hyperopia (+2.28- to 6 D) and astigmatism (+0.75- to 1.75 D); good refractive ac­curacy (80% at ±0.5 D and 100% at ±1 D) at 2 yr; 80% had 20/20 binocular UDA; binocular UNA also good

Clinical data from study in United States: 20 patients underwent procedure in one eye; UDA in treated eye  —  58% had ³20/20 and 95% had ³20/25 at 12 mo; uncorrected intermediate acuity (UIA)  —  58% had ³20/20 and 74% had ³20/25 at 1 yr; UNA at ³J1  —  5% of patients preoperatively; 79% 1 yr postoperatively; DCNA at ³J1  —  60% before surgery; 84% 1 yr postsurgically; binocular UDA  —  95% of patients ³20/20 at 1 yr (vs 0% preoperatively); binocular UIA  —  improved from 10% to 68% of patients at ³20/20; binocular UNA at ³J1  —  improved from 5% to 74%; binocular DCNA at ³J1  —improved from 65% to 100%; BCVA  —  0% with >2-line (10-letter) loss at distance, intermediate, or near; some patient dissatisfaction noted at near vision

Suggested Reading

Alio JL et al: Corneal multifocality with excimer laser for presbyopia correction. J Refract Surg 25:516, 2009; Bakke EF et al: Pen­etration of riboflavin and postoperative pain in corneal collagen crosslinking: excimer laser superficial versus mechanical full-thick­ness epithelial removal. J Cataract Refract Surg 35:1363, 2009; Coskunseven E et al: Effect of treatment sequence in combined intrastromal corneal rings and corneal collagen crosslinking for keratoconus. J Cataract Refract Surg 35:2084, 2009; Craig JP et al: Effect of a liposomal spray on the pre-ocular tear film. Cont Lens Anterior Eye Jan 20, 2010 [Epub ahead of print]; Donnenfeld E, Pflugfelder SC: Topical ophthalmic cyclosporine: pharmacology and clinical uses. Surv Ophthalmol 54:321, 2009; Durrie D, Stahl J: A randomized clinical evaluation of the safety of Systane Lubricant Eye Drops for the relief of dry eye symptoms following LASIK refractive surgery. Clin Ophthalmol 2:973, 2008; El Daasoury AM et al: Multizone LASIK with peripheral near zone for correction of presbyopia in myopic and hyperopic eyes: 1-year results. J Refract Surg 25:296, 2009; Epstein RL, Gurgos MA: Pres­byopia treatment by monocular peripheral presbyLASIK. J Refract Surg 25:516, 2009; Hadassah J et al: Preparation and clinical evaluation of succinylated collagen punctual plugs in dry eye syndrome: a pilot study. Ophthalmic Res 43:185, 2010; Hafezi F et al: Collagen crosslinking with ultraviolet-A and hypoosmolar riboflavin solution in thin corneas. J Cataract Refract Surg 35:621, 2009; Holzer MP et al: Early outcomes of INTRACOR femtosecond laser treatment for presbyopia. J Refract Surg 25:855, 2009; Koller T et al: Complication and failure rates after corneal crosslinking. J Cataract Refract Surg 35:1358, 2009; Konomi K et al: Preoperative characteristics and a potential mechanism of chronic dry eye after LASIK. Invest Ophthalmol Vis Sci 49: 168, 2008; McDonald M et al: Hydroxypropyl cellulose ophthalmic inserts (lacrisert) reduce the signs and symptoms of dry eye syndrome and improve patient quality of life. Trans Am Ophthalmol Soc 107:214, 2009; Quinto GG et al: Postrefractive surgery dry eye. Curr Opin Ophthalmol 19:335, 2008; The pseudoaccomodative cornea multifocal ablation with a center-distance pattern: a review. J Refract Surg 25(Suppl 1):S156, 2009; Wollensak G, Iomdina E: Biomechanical and histological changes after corneal crosslinking with and without epi­thelial debridement. J Cataract Refract Surg 35:540, 2009. Yu et al: Effect of laser in situ keratomileusis on tear stability. Ophthalmol 107:2131, 2000.