REVIEW URRENT C OPINION
Ocular surface diseases and corneal refractive surgery Debora Garcia-Zalisnak, David Nash, and Elizabeth Yeu
Purpose of review The purpose of this article is to provide an overview and update on recent literature regarding ocular surface disease and corneal refractive surgery. Recent findings Studies involving ocular surface disease and/or keratorefractive (corneal) surgery published found on the Medline database were included in the report. Studies focused on mechanisms of refractive surgery induced dry eye disease, surgical options, including modification of technique, to prevent dry eye, and postoperative dry eye prevention and management by way of both established and novel therapies. Summary By understanding the mechanisms of postoperative dry eye as well as patient risk factors for dry eye, patient satisfaction and surgical outcomes can be maximized. Patients identified as having an increased risk for postoperative dry eye may benefit from surgical techniques such as small-incision lenticule extraction (SMILE) and femtosecond laser-assisted in-situ keratomileusis (LASIK). Employing well known therapies such as preserved and nonpreserved artificial tears, nutritional supplements, topical cyclosporins, punctal plugs and autologus serum as well as novel therapies such as insulin-like growth factor 1, neuropeptides and acupuncture could provide improve outcomes and, if started early, could allow more patients to be candidates for corneal refractive surgery. Keywords dry eye, ocular surface disease, refractive surgery
INTRODUCTION Dry eye disease is the popular broad name for a common risk factor and complication after corneal refractive laser surgery. More appropriate is the term ocular surface disease. This encompasses aqueous deficiency, meibomian gland dysfunction, blepharitis, rosacea, allergies, medication-induced scarring and chemical or thermal burns. Any preoperative ocular surface conditions can affect patient outcomes after corneal refractive surgery and therefore all patients considering refractive surgery should be thoroughly evaluated for ocular surface disease. A history of irritation, tearing, burning, stinging, foreign body sensation, mild itching, photophobia, contact lens intolerance, redness, mucous or watery discharge, increased frequency of blinking, eye fatigue and diurnal fluctuation of symptoms usually worse later in the day should be solicited. Patients with ocular surface disease usually endorse exacerbating factors such as wind, air, travel, decreased humidity and/or prolonged visual efforts leading to a decreased blink rate. Topical medications such as glaucoma drops, www.co-ophthalmology.com
vasoconstrictors, corticosteroids, antihistamines and some homeopathic preparations, as well as the preservative such as benzalkonium chloride, can exacerbate symptoms as well. It is also important to note any prior ocular disease that could predispose to surface conditions such as herpes simplex virus (HSV), herpes zoster virus, mucous membrane pemphigoid, Stevens– Johnson syndrome, Bell’s palsy with resultant orbicularis weakness or graft-versus-host disease as well as any ocular or eyelid surgery. Pertinent past medical history to obtain when evaluating a patient for ocular surface disease includes history of dermatological diseases such as Eastern Virginia Medical School, Virginia Eye Consultants, Norfolk, Virginia, USA Correspondence to Elizabeth Yeu, MD, Eastern Virginia Medical School, Virginia Eye Consultants, 241 Corporate Blvd, Norfolk, VA 23502, USA. Tel: +1 757 622 2200; fax: +1 757 622.4866; e-mail: eyeu@vec2020. com Curr Opin Ophthalmol 2014, 25:264–269 DOI:10.1097/ICU.0000000000000077 Volume 25 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Ocular surface diseases and refractive surgery Garcia-Zalisnak et al.
KEY POINTS Postoperative dry eye disease is one of the most common transient side effects of laser refractive surgery, although it can become a chronic disease in upwards of 20% of patients. Regarding the incidence of dry eye disease, femtosecond laser-created LASIK flaps likely create less dry eye disease than microkeratome flaps; a greater loss of corneal nerve sensitivity is seen with LASIK as compared with advanced surface ablation, and small incision lenticule extraction (SMILE) results in less postoperative dry eye issues than LASIK does. Aggressive postoperative treatment of dry eye disease includes preservative-free lubrication, punctual occlusion, topical cyclosporine emulsion, topical steroids, and may require greater therapies such as autologous serum, amniotic membrane transplantation, scleral lenses. A topical secretagogue, diquafosol tetrasodium solution, although not available in the USA, appears to be a promising therapy internationally.
rosacea, psoriasis, atopy, systemic rheumatologic or autoimmune diseases such as Sjogren’s syndrome, rheumatoid arthritis, systemic lupus erythematous, scleroderma and sarcoidosis. Inquiring about menopause is also pertinent, as postmenopausal women are at an increased risk of developing ocular surface disease. History of eye or facial trauma, chronic infections such as hepatitis C or HIV, radiation to the orbit, neurologic diseases, dry mouth, dental cavities and/or oral ulcers are all important information to include in the patient’s history. Physical examination should include a visual acuity, examination of the skin, eyelids and adnexa, evaluation for proptosis, cranial nerve function and a slit lamp examination focused on tear film integrity, eyelashes, anterior and posterior eyelid margins, puncta, fornix, bulbar and tarsal conjunctiva, and a detailed examination of the cornea to assess for localized areas of dryness, epithelial erosions, punctate staining, filaments, epithelial defects, basement membrane irregularities, mucous plaques, keratinization, pannus formation, thinning, infiltrates, ulceration, scarring, neovascularization or any evidence of prior refractive surgery [1].
PREVALENCE AND INCIDENCE Dry eye disease prevalence can be estimated at a range of about 7–15% in the USA and 5 to over 35% worldwide at various ages [2]. The incidence of dry eye disease has been reported on the basis of data from repositories and federal or public databases such as the Medicare/Medicaid databases or health
maintenance organizations. It was found that dry eye case incidence per 100 fee-for-service Medicare beneficiaries increased by 57.4% from 1.22 in 1991 to 1.92 in 1998 [2]. Transient ocular surface disease occurs in almost all patients shortly after refractive surgery, but that patients with preexisting dry eye symptoms are at a greater risk of postoperative ocular surface disease. Dry eye symptoms peak at 1 week to 3 months after LASIK and are irrespective of prior ocular surface disease, although the magnitude is higher in patients with prior disease [3]. Patients who have flaps created using a microkeratome are at a greater risk of having dry eye symptoms as well. Approximately 10–20% of post-LASIK patients may suffer from chronic dry eye disease with more severe discomfort after LASIK [4,5]. Regarding photorefractive keratectomy (PRK), long-term results demonstrate that 7% of post-PRK patients had foreign body sensation at 12 years out and 3% had dry eye [6].
CAUSE AND RISK FACTORS The exact pathophysiology of dry eye disease status postlaser refractive surgery is not certain, but it is likely a multifactorial phenomenon between neurotrophic epitheliopathy, altered tear film coverage of the changed corneal contour and an inflammatory desiccation of ocular surface [4]. This likely creates a cyclical process with further damage to the ocular surface from the pro-inflammatory tear film that is rich in MMP-9 and other inflammatory cytokines [7]. Studies have shown that patients with Schirmer scores below 10 mm preoperatively have statistically more postoperative tear dysfunction up to the 9-month follow up [8 ]. Contact lens wear also predisposes for increased risk of post-LASIK tear dysfunction, likely because these patients tend to have worse tear function and decreased corneal sensitivity preoperatively. Interestingly, although older age and female sex are known risk factors for ocular surface disease in general, some studies have not found them to be a risk factor for post-LASIK tear dysfunction [9]. Patients with ocular allergies have been associated with worse postoperative outcomes, with greater irritation and a higher incidence of diffuse lamellar keratitis. In fact, Bielory and O’ Brien [10] consider greater atopic disease and ocular allergies to be an absolute contraindication for LASIK. It has also been postulated that LASIK is associated with loss of goblet cells in the conjunctiva and can take up to 6 months for the goblet cell density to return to baseline again. The corneal contour changes induced by corneal refractive surgeries also lead to abnormal tear distribution and contribute to
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ocular surface disease. Other factors thought to contribute to postoperative dry eye symptoms include ablation depth and hyperopic corrections [6]. Characteristics of the flap hinge, including the width and the hinge location, may be associated with a higher incidence of postoperative dry eye disease. The width of the flap hinge may be related to increased dry eye disease, with narrow hinges resulting in statistically greater corneal anaesthesia through postoperative month 6 than wide hinges, as demonstrated by Donnenfeld et al. [11]. The hinge location may also serve as a risk factor for dry eye symptoms as the horizontally oriented long posterior ciliary nerves (LPCNs) travelling through a nasal or temporal hinge would be preserved, in contrast to being transected with a superior hinge location. Theoretically, a horizontally oriented flap hinge would improve postoperative corneal sensation. Studies on this, however, have produced conflicting results. Feng et al. [8 ], for example, found that horizontally oriented hinge flaps caused statistically significant less loss of corneal sensation than the vertical-hinge group at 3 months after surgery; however, no difference was seen at the 6-month visit. At present, more studies suggest that hinge location is not considered a risk factor for postoperative ocular surface disease [6,9,12]. Lastly, the flap hinge angle and flap thickness have not been associated with postoperative LASIK dryness [9]. &
with or without medication for over 6 months without any active symptoms or signs confirmed by the treating physician, there is no active ocular complications secondary to the disease and the patient exhibits a normal tear film. Laser refractive surgery should proceed with caution though, as mild well controlled Sjogren’s syndrome could progress to a severe, more refractory dry eye disease after LASIK, as demonstrated by Liang et al. [15]. Lastly, patients with AIDS, ocular complications related to HIV or AIDS and patients who are noncompliant with HIV/ AIDS medications should not undergo keratorefractive surgery [13].
PRE-OPERATIVE EVALUATION Every patient being considered for a keratorefractive surgery should undergo a baseline systemic evaluation to rule out any of the above contraindications and/or relative contraindications. A careful tear film and ocular surface evaluation, including tear film inspection, tear break up time (TBUT) and ocular surface staining, are very important components of the laser refractive surgery evaluation. Meiyan et al. [16 ] used TBUT measurements to compare postLASIK versus post-SMILE dry eye disease. TBUT was statistically decreased post-SMILE in the 1-week, 1-month and 3-month postoperative visit, although they were decreased at all visits up to 6 months after FS-LASIK [16 ]. Although there have not been any studies published on the relationship specifically between refractive surgery and anterior blepharitis or meibomian gland disease (MGD), assessing the lid margin and meibomian gland function is an important part of the preoperative evaluation. Clinically, greater blepharitis can translate to conjunctivitis and/or keratitis in general, and this may certainly lead to worse cause ocular surface disease and inflammatory problems after LASIK, both to the corneal epithelium and within the LASIK flap interface. As greater options become available to objectively quantify dry eye disease severity, such as lactoferrin, MMP-9 testing and tear osmolarity, it will be interesting to see how these may affect laser refractive surgery evaluations. Because of the established relationship between a low preoperative Schirmer’s score and increased incidence of postoperative dry eye disease, this should always be performed preoperatively. &
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CONTRAINDICATIONS TO CORNEAL REFRACTIVE SURGERY One of the most important aspects to ensure a successful keratorefractive procedure is proper patient selection. Contraindications for keratorefractive surgery include unstable refraction over a 12-month period, patients younger than 18 years of age (21 for PRK), insufficient corneal thickness, visually significant cataract, uncontrolled glaucoma or external disease, and of course, unrealistic patient expectations [13]. Relative contraindications include prior history of diseases that lead to neurotrophic keratopathy such as HZO, HSV keratitis and uncontrolled diabetes mellitus. Recently, however, Simpson et al. [14] showed that LASIK can be well tolerated in diabetic patients with tight glycemic control and no ocular or systemic complications. Another relative contraindication is uncontrolled systemic immune-mediated diseases such as Sjogren’s syndrome, rheumatoid arthritis, systemic lupus erythematous, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease (IBD) with arthritis and Behc¸et’s disease. Patients with these conditions may be candidates for LASIK if the disease is controlled 266
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SURGICAL OPTIONS The options for laser refractive surgery include LASIK, advanced surface ablation and small-incision lenticule extraction (SMILE). The various forms of surface ablation procedures include phototherapeutic Volume 25 Number 4 July 2014
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keratectomy (PRK); epi-LASIK, wherein a dull microkeratome is used to create an epithelial flap; and laser-assisted sub-epithelial keratomileusis (LASEK), wherein alcohol is used to loosen the epithelium flap, which is then preserved and replaced over the stromal bed at the end. It is postulated that PRK has less risk of causing tear dysfunction when compared with LASIK because the LPCN are preserved, leading to quicker recovery of corneal sensation and there is less decrease in Schirmer scores. PRK patients have less change from their preoperative tear breakup time and tear osmolarity. However, subjectively, patients do not report a statistically significant increase of dry eye symptoms after LASIK when compared with PRK [6]. Thin flap LASIK may decrease corneal sensation less and patients generally return to normal tear function faster than traditional LASIK [6]. When thin flap LASIK is compared with PRK, PRK eyes had less absolute decrease in corneal sensitivity, but there was no difference in Schirmer scores between the two treatment modalities. Another study comparing LASEK with traditional LASIK concluded that LASEK results in less decrease in corneal sensitivity than LASIK and in a faster recovery. LASIK patients complained of more severe dry eye symptoms up to 16 months postoperatively, while dry eye symptoms in LASEK patients returned to baseline at 3 months. However, when comparing thin flap LASIK versus LASEK, no statistically significant difference was found in postoperative corneal sensitivities up to 6 months postoperatively [6]. When comparing microkeratome versus femtosecond LASIK flaps, FS-LASIK appears to lead to a quicker normalization of the ocular surface, as a faster recovery time in central corneal sensitivity and less dry eye symptoms occurred in the femtosecond-assisted LASIK group [7]. SMILE procedure is a fairly new procedure that is rapidly gaining popularity. This procedure involves placing femtosecond incisions in the posterior surface of the lenticule, the lenticule border, the anterior surface of the lenticular and the side cut incision to access the lenticule. After that, a thin spatula is inserted via the side-cut incision to blunt dissect the intrastromal lenticule. This lenticule is the extracted from the cornea. It has been proposed that SMILE induces less inflammatory reaction and cell death when compared with FS-LASIK, as it does not entail creating and lifting a corneal flap. The process of corneal wound healing after flap creation involves a variety of cytokines and growth factors that directly induce keratocyte apoptosis and consequently attract inflammatory cells [17 ]. &&
Because SMILE is still a very new technique, there are conflicting views whether SMILE refractive surgery decreases central corneal sensitivity or not. When subjectively comparing dry eye symptoms using the Ocular Surface Disease Index (OSDI) between FS-LASIK versus SMILE, OSDI scores increased significantly in both groups in comparison to preoperative scores but returned to preoperative levels by 1 month postoperatively. Tear secretion levels also showed a transient decrease after undergoing FS-LASIK. There is conflicting evidence between the literature, but in general, it appears that in post-FS-LASIK, tear secretion reaches preoperative levels by at least 6 months postoperatively [16 ]. Patients undergoing a SMILE procedure had significantly less corneal fluorescein staining that patients undergoing FS-LASIK [16 ]. SMILE procedures seem to have less postoperative ocular surface issues because there is less transection of corneal nerves in the anterior third of the corneal stroma as compared with FS-LASIK, which is one of the main causes of postrefractive surgery ocular surface disease [16 ]. &
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PERI-OPERATIVE MANAGEMENT If a patient undergoing evaluation for keratorefractive surgery is determined to have ocular surface disease, this should be treated before proceeding with surgery. Treatment options include artificial tears, nutritional supplementation, topical cyclosporine, topical steroids and punctal plugs. Recent literature also suggests using metalloproteinase (MMP) inhibitors to treat perioperative ocular surface disease, as it is known that MMPs, especially MMP-9, play a major role in the inflammatory response component of ocular surface disease [18]. Although less conventional and arguably risky, preoperative moderate to severe dry eye disease may not be an absolute contraindication to performing LASIK. Toda et al. [19 ] demonstrated that Sjogren’s syndrome patients with preoperative severe ocular surface disease may be able to successfully and safely undergo LASIK when they are aggressively managed with artificial tears, topical autologous serum and punctual occlusion. Topical cyclosporine 0.05% emulsion after LASIK may effectively accelerate the recovery of corneal sensitivity, which suggests the benefit of improved corneal stromal nerve regeneration [20]. Although there are conflicting data, topical cyclosporine may also promote an expedited visual recovery and refractive stability after LASIK or PRK as well [21,22]. Amniotic membrane could be another potential treatment for postrefractive surgery ocular surface disease. Not much has been published about this
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modality. However, Dua et al. [23] demonstrated the effectiveness in the application of an amniotic membrane after PRK in one patient with marked haze and residual myopia after excimer laser surgery. The surgeons retreated with PRK and sutured a 9 mm amniotic membrane graft immediately after laser ablation. Postoperatively, the patient had minimal postlaser pain and a rapid (5-day) re-epithelialization. The haze was reduced by 50% but did not significantly improve his vision [23]. A new therapy, 3% diquafosol tetrasodium ophthalmic solution, has recently gained popularity for the treatment of post-LASIK dry eye disease. This drug is a purinergic P2Y2 receptor agonist that stimulates water and mucin secretion from conjunctival epithelial and goblet cells. Toda et al. [19 ] published a study comparing artificial tears, sodium hyaluronate and diquafosol tetrasodium for the treatment of post-LASIK dry eye. This study found that combination therapy with sodium hyaluronate and diquafosol tetrasodium significantly improved near uncorrected vision and 1 week and 1 month after LASIK and distance functional visual acuity at 1 month postoperatively. It also found that the patients in the combination group had a higher Schirmer’s value, and that subjective dry eye symptoms were significantly less at 1 week after surgery [19 ]. Postoperatively, more severe dry eye disease can be quite recalcitrant to conventional therapy. Although it may result in part from a neurotrophic process, patients can have significant positive symptoms postoperatively, rather than a lack of sensation, but have suffered from chronic foreign body sensation, burning and sometimes hyperesthesia. Such patients may require more specialized, advanced forms of dry eye therapies, such as autologous serum tears, thermal pulsation therapy or intense pulsed light therapy to the lids, or scleral lenses, although there is little published on the efficacy of these therapies specifically of dry eye disease induced by corneal refractive surgery. Segal et al. [24] mentioned of at least one patient suffering from dry eye after hyperopic LASIK whose symptoms improved using daily gas-permeable scleral contact lenses. Autologous serum has been successfully used to treat ocular surface disease. Autologous serum contains growth factors, vitamins, fibronectin and other components that are vital for corneal and conjunctival integrity. Autologous serum is usually prepared as an unpreserved blood solution in eye drop form [25]. Noda-Tsuruya et al. [26] demonstrated that the use of autologous serum drops after LASIK improved the TBUT and led to decreased ocular surface staining as compared with the use of artificial tears alone, &&
but no statistically significant difference was observed in subjective dryness scores between the two treatment modalities.
CONCLUSION Ocular surface disease is a general umbrella term than a single disease entity, as previously discussed, and it is the job of the physician to find an individualized treatment plan that best serves each patient. This common risk factor and complication of refractive surgery must be part of the evaluation and surgical discussion. When any ocular surface disease is present, it should be properly managed and maximally optimized before proceeding with surgery. Advanced surface ablation and thin flap LASIK appears to result in less overall dry eye disease and should be preferentially considered for those with greater risk factors or mild dry eye disease. Postoperative dry eye disease is generally transient, but can be chronic in up to 20% of patients and will likely require a customized combination of therapies to stabilize. The emerging surgical techniques and pre and postoperative dry eye management options on the horizon show a promising future for corneal refractive surgery and patients ocular surface disease.
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Acknowledgements None. Conflicts of interest Dr Yeu is a consultant to Allergan, Nicox and TearLab.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. AAO Cornea/External Disesase PPP Panel, Hoskins Center for Quality Eye Care. Dry Eye Syndrome Summary Benchmark – 2013. Cornea/External Disease. American Academy of Ophthalmology. October 2013. 2. The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007; 5:93– 107. 3. Chao C, Golebiowski B, Stapleton F. The role of corneal innervation in LASIKinduced neuropathic dry eye. Ocul Surf 2014; 12:32–45. 4. Ambro´sio R Jr, Tervo T, Wilson SE. LASIK-associated dry eye and neurotrophic epitheliopathy: pathophysiology and strategies for prevention and treatment. J Refract Surg 2008; 24:396–407. 5. Shoja MR, Besharati MR. Dry eye after LASIK for myopia: incidence and risk factors. Eur J Ophthalmol 2007; 17:1–6. 6. Nettune G, Pflugfelder S. Post-LASIK tear dysfunction and dysesthesia. Ocular Surface 2010; 8:135–145. 7. Salamao MQ, Ambrosio R, Wilson SE. Dry eye associated with laser insitu keratomileusis: mechanical microkeratome versus femtosecond laser. J Cataract Refract Surg 2009; 35:1756–1760. 8. Feng Yi-fan, Yu Ji-guo, Wand Dan-dan, et al. The effect of hinge location on & corneal sensation and dry eye after LASIK: a systematic review and metaanalysis. Graefe’s Arch Clin Exp Ophthalmol 2013; 5:357–366. Hinge flap may statistically affect corneal sensation postoperatively, at least in the acute postoperative period.
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Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Ocular surface diseases and refractive surgery Garcia-Zalisnak et al. 9. Mian SI1, Li AY, Dutta S, et al. Dry eyes and corneal sensation after laser in situ keratomileusis with femtosecond laser flap creation. Effect of hinge position, hinge angle, and flap thickness. J Cataract Refract Surg 2009; 35:625– 631. 10. Bielory BP, O’Brien TP. Allergic complications with laser-assisted in-situ keratomileusis. Curr Opin Allergy Clin Immunol 2011; 11:483–491. 11. Donnenfeld ED, Ehrenhaus M, Solomon R, et al. Effect of hinge width on corneal sensation and dry eye after laser in situ keratomileusis. J Cataract Refract Surg 2004; 30:790–797. 12. Huang JC, Sun CC, Chang CK, et al. Effect of hinge position on corneal sensation and dry eye parameters after femtosecond laser-assisted LASIK. J Refract Surg 2012; 28:625–631. 13. Quality of Care Secretariat, Hoskings Center for Quality Eye Care. Summary recommendations for keratorefractive laser surgery - 2013. Refractive Management/Intervention. American Academy of Ophthalmology. June 2013. 14. Simpson RG, Moshirfar M, Edmonds JN, Christiansen SM. Laser in-situ keratomileusis in patients with diabetes mellitus: a review of literature. J Clin Ophthalmol 2012; 6:1665–1674. 15. Liang L, Zhang M, Zou W, Liu Z. Aggravated dry eye after laser in situ keratomileusis in patients with Sjo¨gren syndrome. Cornea 2008; 27:120– 123. 16. Meiyan Li, Zhao Jing, Shen Yang, et al. Comparison of dry eye and corneal & sensitivity between small incision lenticule extraction and femtosecond LASIK for myopia. PLoS One 2013; 8:e77797. SMILE can potentially reduce significantly postrefractive surgery dry eye.
17. Dong Z, Zhou X, Wu J, et al. Small incision lenticule extraction (SMILE) and femtosecond laser LASIK: comparison of corneal wound healing and inflammation. Br J Ophthalmol 2014; 98:263–269. In-depth explanation in the SMILE procedure. 18. Sambursky R, O’Brien TP. MMP-9 and the perioperative management of LASIK surgery. Curr Opin Ophthalmol 2011; 22:294–303. 19. Toda I, Takeshi I, Teruki F, et al. Combination therapy with diquafosol && tetrasodium and sodium hyaluronate in patients with dry eye after laser in situ keratomileusis. Am J Ophthalmol 2014; 157:616–622. Latest new drugs in treating ocular surface disease. 20. Peyman GA, Sanders DR, Batlle JF, et al. Cyclosporine 0.05% ophthalmic preparation to aid recovery from loss of corneal sensitivity after LASIK. J Refract Surg 2008; 24:337–343. 21. Salib GM, McDonald MB, Smolek M. Safety and efficacy of cyclosporine 0.05% drops versus unpreserved artificial tears in dry-eye patients having laser in situ keratomileusis. J Cataract Refract Surg 2006; 32:772–778. 22. Ursea R, Purcell TL, Tan BU, et al. The effect of cyclosporine A (Restasis) on recovery of visual acuity following LASIK. J Refract Surg 2008; 24:473–476. 23. Dua H, Gomes J, King A, Maharajan V. The amniotic membrane in ophthalmology. Survey Ophthalmol 2004; 49:51–77. 24. Segal O, Barkana Y, Hourovitz D, et al. Scleral contact lenses may help where other modalities fail. Cornea 2003; 22:308–310. 25. Quinto G, Campos M, Behrens A. Autologous serum for ocular surface diseases. Arq Bras Oftalmol 2008; 71(Suppl 6):47–54. 26. Noda-Tsuruya T, Asano-Kato N, Toda I, Tsubota K. Autologous serum eye drops for dry eye after LASIK. J Refract Surg 2006; 22:61–66. &&
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Ocular surface diseases and corneal refractive surgery Debora Garcia-Zalisnak, David Nash, and Elizabeth Yeu
Purpose of review The purpose of this article is to provide an overview and update on recent literature regarding ocular surface disease and corneal refractive surgery. Recent findings Studies involving ocular surface disease and/or keratorefractive (corneal) surgery published found on the Medline database were included in the report. Studies focused on mechanisms of refractive surgery induced dry eye disease, surgical options, including modification of technique, to prevent dry eye, and postoperative dry eye prevention and management by way of both established and novel therapies. Summary By understanding the mechanisms of postoperative dry eye as well as patient risk factors for dry eye, patient satisfaction and surgical outcomes can be maximized. Patients identified as having an increased risk for postoperative dry eye may benefit from surgical techniques such as small-incision lenticule extraction (SMILE) and femtosecond laser-assisted in-situ keratomileusis (LASIK). Employing well known therapies such as preserved and nonpreserved artificial tears, nutritional supplements, topical cyclosporins, punctal plugs and autologus serum as well as novel therapies such as insulin-like growth factor 1, neuropeptides and acupuncture could provide improve outcomes and, if started early, could allow more patients to be candidates for corneal refractive surgery. Keywords dry eye, ocular surface disease, refractive surgery
INTRODUCTION Dry eye disease is the popular broad name for a common risk factor and complication after corneal refractive laser surgery. More appropriate is the term ocular surface disease. This encompasses aqueous deficiency, meibomian gland dysfunction, blepharitis, rosacea, allergies, medication-induced scarring and chemical or thermal burns. Any preoperative ocular surface conditions can affect patient outcomes after corneal refractive surgery and therefore all patients considering refractive surgery should be thoroughly evaluated for ocular surface disease. A history of irritation, tearing, burning, stinging, foreign body sensation, mild itching, photophobia, contact lens intolerance, redness, mucous or watery discharge, increased frequency of blinking, eye fatigue and diurnal fluctuation of symptoms usually worse later in the day should be solicited. Patients with ocular surface disease usually endorse exacerbating factors such as wind, air, travel, decreased humidity and/or prolonged visual efforts leading to a decreased blink rate. Topical medications such as glaucoma drops, www.co-ophthalmology.com
vasoconstrictors, corticosteroids, antihistamines and some homeopathic preparations, as well as the preservative such as benzalkonium chloride, can exacerbate symptoms as well. It is also important to note any prior ocular disease that could predispose to surface conditions such as herpes simplex virus (HSV), herpes zoster virus, mucous membrane pemphigoid, Stevens– Johnson syndrome, Bell’s palsy with resultant orbicularis weakness or graft-versus-host disease as well as any ocular or eyelid surgery. Pertinent past medical history to obtain when evaluating a patient for ocular surface disease includes history of dermatological diseases such as Eastern Virginia Medical School, Virginia Eye Consultants, Norfolk, Virginia, USA Correspondence to Elizabeth Yeu, MD, Eastern Virginia Medical School, Virginia Eye Consultants, 241 Corporate Blvd, Norfolk, VA 23502, USA. Tel: +1 757 622 2200; fax: +1 757 622.4866; e-mail: eyeu@vec2020. com Curr Opin Ophthalmol 2014, 25:264–269 DOI:10.1097/ICU.0000000000000077 Volume 25 Number 4 July 2014
Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
Ocular surface diseases and refractive surgery Garcia-Zalisnak et al.
KEY POINTS Postoperative dry eye disease is one of the most common transient side effects of laser refractive surgery, although it can become a chronic disease in upwards of 20% of patients. Regarding the incidence of dry eye disease, femtosecond laser-created LASIK flaps likely create less dry eye disease than microkeratome flaps; a greater loss of corneal nerve sensitivity is seen with LASIK as compared with advanced surface ablation, and small incision lenticule extraction (SMILE) results in less postoperative dry eye issues than LASIK does. Aggressive postoperative treatment of dry eye disease includes preservative-free lubrication, punctual occlusion, topical cyclosporine emulsion, topical steroids, and may require greater therapies such as autologous serum, amniotic membrane transplantation, scleral lenses. A topical secretagogue, diquafosol tetrasodium solution, although not available in the USA, appears to be a promising therapy internationally.
rosacea, psoriasis, atopy, systemic rheumatologic or autoimmune diseases such as Sjogren’s syndrome, rheumatoid arthritis, systemic lupus erythematous, scleroderma and sarcoidosis. Inquiring about menopause is also pertinent, as postmenopausal women are at an increased risk of developing ocular surface disease. History of eye or facial trauma, chronic infections such as hepatitis C or HIV, radiation to the orbit, neurologic diseases, dry mouth, dental cavities and/or oral ulcers are all important information to include in the patient’s history. Physical examination should include a visual acuity, examination of the skin, eyelids and adnexa, evaluation for proptosis, cranial nerve function and a slit lamp examination focused on tear film integrity, eyelashes, anterior and posterior eyelid margins, puncta, fornix, bulbar and tarsal conjunctiva, and a detailed examination of the cornea to assess for localized areas of dryness, epithelial erosions, punctate staining, filaments, epithelial defects, basement membrane irregularities, mucous plaques, keratinization, pannus formation, thinning, infiltrates, ulceration, scarring, neovascularization or any evidence of prior refractive surgery [1].
PREVALENCE AND INCIDENCE Dry eye disease prevalence can be estimated at a range of about 7–15% in the USA and 5 to over 35% worldwide at various ages [2]. The incidence of dry eye disease has been reported on the basis of data from repositories and federal or public databases such as the Medicare/Medicaid databases or health
maintenance organizations. It was found that dry eye case incidence per 100 fee-for-service Medicare beneficiaries increased by 57.4% from 1.22 in 1991 to 1.92 in 1998 [2]. Transient ocular surface disease occurs in almost all patients shortly after refractive surgery, but that patients with preexisting dry eye symptoms are at a greater risk of postoperative ocular surface disease. Dry eye symptoms peak at 1 week to 3 months after LASIK and are irrespective of prior ocular surface disease, although the magnitude is higher in patients with prior disease [3]. Patients who have flaps created using a microkeratome are at a greater risk of having dry eye symptoms as well. Approximately 10–20% of post-LASIK patients may suffer from chronic dry eye disease with more severe discomfort after LASIK [4,5]. Regarding photorefractive keratectomy (PRK), long-term results demonstrate that 7% of post-PRK patients had foreign body sensation at 12 years out and 3% had dry eye [6].
CAUSE AND RISK FACTORS The exact pathophysiology of dry eye disease status postlaser refractive surgery is not certain, but it is likely a multifactorial phenomenon between neurotrophic epitheliopathy, altered tear film coverage of the changed corneal contour and an inflammatory desiccation of ocular surface [4]. This likely creates a cyclical process with further damage to the ocular surface from the pro-inflammatory tear film that is rich in MMP-9 and other inflammatory cytokines [7]. Studies have shown that patients with Schirmer scores below 10 mm preoperatively have statistically more postoperative tear dysfunction up to the 9-month follow up [8 ]. Contact lens wear also predisposes for increased risk of post-LASIK tear dysfunction, likely because these patients tend to have worse tear function and decreased corneal sensitivity preoperatively. Interestingly, although older age and female sex are known risk factors for ocular surface disease in general, some studies have not found them to be a risk factor for post-LASIK tear dysfunction [9]. Patients with ocular allergies have been associated with worse postoperative outcomes, with greater irritation and a higher incidence of diffuse lamellar keratitis. In fact, Bielory and O’ Brien [10] consider greater atopic disease and ocular allergies to be an absolute contraindication for LASIK. It has also been postulated that LASIK is associated with loss of goblet cells in the conjunctiva and can take up to 6 months for the goblet cell density to return to baseline again. The corneal contour changes induced by corneal refractive surgeries also lead to abnormal tear distribution and contribute to
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ocular surface disease. Other factors thought to contribute to postoperative dry eye symptoms include ablation depth and hyperopic corrections [6]. Characteristics of the flap hinge, including the width and the hinge location, may be associated with a higher incidence of postoperative dry eye disease. The width of the flap hinge may be related to increased dry eye disease, with narrow hinges resulting in statistically greater corneal anaesthesia through postoperative month 6 than wide hinges, as demonstrated by Donnenfeld et al. [11]. The hinge location may also serve as a risk factor for dry eye symptoms as the horizontally oriented long posterior ciliary nerves (LPCNs) travelling through a nasal or temporal hinge would be preserved, in contrast to being transected with a superior hinge location. Theoretically, a horizontally oriented flap hinge would improve postoperative corneal sensation. Studies on this, however, have produced conflicting results. Feng et al. [8 ], for example, found that horizontally oriented hinge flaps caused statistically significant less loss of corneal sensation than the vertical-hinge group at 3 months after surgery; however, no difference was seen at the 6-month visit. At present, more studies suggest that hinge location is not considered a risk factor for postoperative ocular surface disease [6,9,12]. Lastly, the flap hinge angle and flap thickness have not been associated with postoperative LASIK dryness [9]. &
with or without medication for over 6 months without any active symptoms or signs confirmed by the treating physician, there is no active ocular complications secondary to the disease and the patient exhibits a normal tear film. Laser refractive surgery should proceed with caution though, as mild well controlled Sjogren’s syndrome could progress to a severe, more refractory dry eye disease after LASIK, as demonstrated by Liang et al. [15]. Lastly, patients with AIDS, ocular complications related to HIV or AIDS and patients who are noncompliant with HIV/ AIDS medications should not undergo keratorefractive surgery [13].
PRE-OPERATIVE EVALUATION Every patient being considered for a keratorefractive surgery should undergo a baseline systemic evaluation to rule out any of the above contraindications and/or relative contraindications. A careful tear film and ocular surface evaluation, including tear film inspection, tear break up time (TBUT) and ocular surface staining, are very important components of the laser refractive surgery evaluation. Meiyan et al. [16 ] used TBUT measurements to compare postLASIK versus post-SMILE dry eye disease. TBUT was statistically decreased post-SMILE in the 1-week, 1-month and 3-month postoperative visit, although they were decreased at all visits up to 6 months after FS-LASIK [16 ]. Although there have not been any studies published on the relationship specifically between refractive surgery and anterior blepharitis or meibomian gland disease (MGD), assessing the lid margin and meibomian gland function is an important part of the preoperative evaluation. Clinically, greater blepharitis can translate to conjunctivitis and/or keratitis in general, and this may certainly lead to worse cause ocular surface disease and inflammatory problems after LASIK, both to the corneal epithelium and within the LASIK flap interface. As greater options become available to objectively quantify dry eye disease severity, such as lactoferrin, MMP-9 testing and tear osmolarity, it will be interesting to see how these may affect laser refractive surgery evaluations. Because of the established relationship between a low preoperative Schirmer’s score and increased incidence of postoperative dry eye disease, this should always be performed preoperatively. &
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CONTRAINDICATIONS TO CORNEAL REFRACTIVE SURGERY One of the most important aspects to ensure a successful keratorefractive procedure is proper patient selection. Contraindications for keratorefractive surgery include unstable refraction over a 12-month period, patients younger than 18 years of age (21 for PRK), insufficient corneal thickness, visually significant cataract, uncontrolled glaucoma or external disease, and of course, unrealistic patient expectations [13]. Relative contraindications include prior history of diseases that lead to neurotrophic keratopathy such as HZO, HSV keratitis and uncontrolled diabetes mellitus. Recently, however, Simpson et al. [14] showed that LASIK can be well tolerated in diabetic patients with tight glycemic control and no ocular or systemic complications. Another relative contraindication is uncontrolled systemic immune-mediated diseases such as Sjogren’s syndrome, rheumatoid arthritis, systemic lupus erythematous, ankylosing spondylitis, psoriatic arthritis, inflammatory bowel disease (IBD) with arthritis and Behc¸et’s disease. Patients with these conditions may be candidates for LASIK if the disease is controlled 266
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SURGICAL OPTIONS The options for laser refractive surgery include LASIK, advanced surface ablation and small-incision lenticule extraction (SMILE). The various forms of surface ablation procedures include phototherapeutic Volume 25 Number 4 July 2014
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Ocular surface diseases and refractive surgery Garcia-Zalisnak et al.
keratectomy (PRK); epi-LASIK, wherein a dull microkeratome is used to create an epithelial flap; and laser-assisted sub-epithelial keratomileusis (LASEK), wherein alcohol is used to loosen the epithelium flap, which is then preserved and replaced over the stromal bed at the end. It is postulated that PRK has less risk of causing tear dysfunction when compared with LASIK because the LPCN are preserved, leading to quicker recovery of corneal sensation and there is less decrease in Schirmer scores. PRK patients have less change from their preoperative tear breakup time and tear osmolarity. However, subjectively, patients do not report a statistically significant increase of dry eye symptoms after LASIK when compared with PRK [6]. Thin flap LASIK may decrease corneal sensation less and patients generally return to normal tear function faster than traditional LASIK [6]. When thin flap LASIK is compared with PRK, PRK eyes had less absolute decrease in corneal sensitivity, but there was no difference in Schirmer scores between the two treatment modalities. Another study comparing LASEK with traditional LASIK concluded that LASEK results in less decrease in corneal sensitivity than LASIK and in a faster recovery. LASIK patients complained of more severe dry eye symptoms up to 16 months postoperatively, while dry eye symptoms in LASEK patients returned to baseline at 3 months. However, when comparing thin flap LASIK versus LASEK, no statistically significant difference was found in postoperative corneal sensitivities up to 6 months postoperatively [6]. When comparing microkeratome versus femtosecond LASIK flaps, FS-LASIK appears to lead to a quicker normalization of the ocular surface, as a faster recovery time in central corneal sensitivity and less dry eye symptoms occurred in the femtosecond-assisted LASIK group [7]. SMILE procedure is a fairly new procedure that is rapidly gaining popularity. This procedure involves placing femtosecond incisions in the posterior surface of the lenticule, the lenticule border, the anterior surface of the lenticular and the side cut incision to access the lenticule. After that, a thin spatula is inserted via the side-cut incision to blunt dissect the intrastromal lenticule. This lenticule is the extracted from the cornea. It has been proposed that SMILE induces less inflammatory reaction and cell death when compared with FS-LASIK, as it does not entail creating and lifting a corneal flap. The process of corneal wound healing after flap creation involves a variety of cytokines and growth factors that directly induce keratocyte apoptosis and consequently attract inflammatory cells [17 ]. &&
Because SMILE is still a very new technique, there are conflicting views whether SMILE refractive surgery decreases central corneal sensitivity or not. When subjectively comparing dry eye symptoms using the Ocular Surface Disease Index (OSDI) between FS-LASIK versus SMILE, OSDI scores increased significantly in both groups in comparison to preoperative scores but returned to preoperative levels by 1 month postoperatively. Tear secretion levels also showed a transient decrease after undergoing FS-LASIK. There is conflicting evidence between the literature, but in general, it appears that in post-FS-LASIK, tear secretion reaches preoperative levels by at least 6 months postoperatively [16 ]. Patients undergoing a SMILE procedure had significantly less corneal fluorescein staining that patients undergoing FS-LASIK [16 ]. SMILE procedures seem to have less postoperative ocular surface issues because there is less transection of corneal nerves in the anterior third of the corneal stroma as compared with FS-LASIK, which is one of the main causes of postrefractive surgery ocular surface disease [16 ]. &
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PERI-OPERATIVE MANAGEMENT If a patient undergoing evaluation for keratorefractive surgery is determined to have ocular surface disease, this should be treated before proceeding with surgery. Treatment options include artificial tears, nutritional supplementation, topical cyclosporine, topical steroids and punctal plugs. Recent literature also suggests using metalloproteinase (MMP) inhibitors to treat perioperative ocular surface disease, as it is known that MMPs, especially MMP-9, play a major role in the inflammatory response component of ocular surface disease [18]. Although less conventional and arguably risky, preoperative moderate to severe dry eye disease may not be an absolute contraindication to performing LASIK. Toda et al. [19 ] demonstrated that Sjogren’s syndrome patients with preoperative severe ocular surface disease may be able to successfully and safely undergo LASIK when they are aggressively managed with artificial tears, topical autologous serum and punctual occlusion. Topical cyclosporine 0.05% emulsion after LASIK may effectively accelerate the recovery of corneal sensitivity, which suggests the benefit of improved corneal stromal nerve regeneration [20]. Although there are conflicting data, topical cyclosporine may also promote an expedited visual recovery and refractive stability after LASIK or PRK as well [21,22]. Amniotic membrane could be another potential treatment for postrefractive surgery ocular surface disease. Not much has been published about this
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modality. However, Dua et al. [23] demonstrated the effectiveness in the application of an amniotic membrane after PRK in one patient with marked haze and residual myopia after excimer laser surgery. The surgeons retreated with PRK and sutured a 9 mm amniotic membrane graft immediately after laser ablation. Postoperatively, the patient had minimal postlaser pain and a rapid (5-day) re-epithelialization. The haze was reduced by 50% but did not significantly improve his vision [23]. A new therapy, 3% diquafosol tetrasodium ophthalmic solution, has recently gained popularity for the treatment of post-LASIK dry eye disease. This drug is a purinergic P2Y2 receptor agonist that stimulates water and mucin secretion from conjunctival epithelial and goblet cells. Toda et al. [19 ] published a study comparing artificial tears, sodium hyaluronate and diquafosol tetrasodium for the treatment of post-LASIK dry eye. This study found that combination therapy with sodium hyaluronate and diquafosol tetrasodium significantly improved near uncorrected vision and 1 week and 1 month after LASIK and distance functional visual acuity at 1 month postoperatively. It also found that the patients in the combination group had a higher Schirmer’s value, and that subjective dry eye symptoms were significantly less at 1 week after surgery [19 ]. Postoperatively, more severe dry eye disease can be quite recalcitrant to conventional therapy. Although it may result in part from a neurotrophic process, patients can have significant positive symptoms postoperatively, rather than a lack of sensation, but have suffered from chronic foreign body sensation, burning and sometimes hyperesthesia. Such patients may require more specialized, advanced forms of dry eye therapies, such as autologous serum tears, thermal pulsation therapy or intense pulsed light therapy to the lids, or scleral lenses, although there is little published on the efficacy of these therapies specifically of dry eye disease induced by corneal refractive surgery. Segal et al. [24] mentioned of at least one patient suffering from dry eye after hyperopic LASIK whose symptoms improved using daily gas-permeable scleral contact lenses. Autologous serum has been successfully used to treat ocular surface disease. Autologous serum contains growth factors, vitamins, fibronectin and other components that are vital for corneal and conjunctival integrity. Autologous serum is usually prepared as an unpreserved blood solution in eye drop form [25]. Noda-Tsuruya et al. [26] demonstrated that the use of autologous serum drops after LASIK improved the TBUT and led to decreased ocular surface staining as compared with the use of artificial tears alone, &&
but no statistically significant difference was observed in subjective dryness scores between the two treatment modalities.
CONCLUSION Ocular surface disease is a general umbrella term than a single disease entity, as previously discussed, and it is the job of the physician to find an individualized treatment plan that best serves each patient. This common risk factor and complication of refractive surgery must be part of the evaluation and surgical discussion. When any ocular surface disease is present, it should be properly managed and maximally optimized before proceeding with surgery. Advanced surface ablation and thin flap LASIK appears to result in less overall dry eye disease and should be preferentially considered for those with greater risk factors or mild dry eye disease. Postoperative dry eye disease is generally transient, but can be chronic in up to 20% of patients and will likely require a customized combination of therapies to stabilize. The emerging surgical techniques and pre and postoperative dry eye management options on the horizon show a promising future for corneal refractive surgery and patients ocular surface disease.
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Acknowledgements None. Conflicts of interest Dr Yeu is a consultant to Allergan, Nicox and TearLab.
REFERENCES AND RECOMMENDED READING Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest 1. AAO Cornea/External Disesase PPP Panel, Hoskins Center for Quality Eye Care. Dry Eye Syndrome Summary Benchmark – 2013. Cornea/External Disease. American Academy of Ophthalmology. October 2013. 2. The epidemiology of dry eye disease: report of the Epidemiology Subcommittee of the International Dry Eye WorkShop (2007). Ocul Surf 2007; 5:93– 107. 3. Chao C, Golebiowski B, Stapleton F. The role of corneal innervation in LASIKinduced neuropathic dry eye. Ocul Surf 2014; 12:32–45. 4. Ambro´sio R Jr, Tervo T, Wilson SE. LASIK-associated dry eye and neurotrophic epitheliopathy: pathophysiology and strategies for prevention and treatment. J Refract Surg 2008; 24:396–407. 5. Shoja MR, Besharati MR. Dry eye after LASIK for myopia: incidence and risk factors. Eur J Ophthalmol 2007; 17:1–6. 6. Nettune G, Pflugfelder S. Post-LASIK tear dysfunction and dysesthesia. Ocular Surface 2010; 8:135–145. 7. Salamao MQ, Ambrosio R, Wilson SE. Dry eye associated with laser insitu keratomileusis: mechanical microkeratome versus femtosecond laser. J Cataract Refract Surg 2009; 35:1756–1760. 8. Feng Yi-fan, Yu Ji-guo, Wand Dan-dan, et al. The effect of hinge location on & corneal sensation and dry eye after LASIK: a systematic review and metaanalysis. Graefe’s Arch Clin Exp Ophthalmol 2013; 5:357–366. Hinge flap may statistically affect corneal sensation postoperatively, at least in the acute postoperative period.
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Ocular surface diseases and refractive surgery Garcia-Zalisnak et al. 9. Mian SI1, Li AY, Dutta S, et al. Dry eyes and corneal sensation after laser in situ keratomileusis with femtosecond laser flap creation. Effect of hinge position, hinge angle, and flap thickness. J Cataract Refract Surg 2009; 35:625– 631. 10. Bielory BP, O’Brien TP. Allergic complications with laser-assisted in-situ keratomileusis. Curr Opin Allergy Clin Immunol 2011; 11:483–491. 11. Donnenfeld ED, Ehrenhaus M, Solomon R, et al. Effect of hinge width on corneal sensation and dry eye after laser in situ keratomileusis. J Cataract Refract Surg 2004; 30:790–797. 12. Huang JC, Sun CC, Chang CK, et al. Effect of hinge position on corneal sensation and dry eye parameters after femtosecond laser-assisted LASIK. J Refract Surg 2012; 28:625–631. 13. Quality of Care Secretariat, Hoskings Center for Quality Eye Care. Summary recommendations for keratorefractive laser surgery - 2013. Refractive Management/Intervention. American Academy of Ophthalmology. June 2013. 14. Simpson RG, Moshirfar M, Edmonds JN, Christiansen SM. Laser in-situ keratomileusis in patients with diabetes mellitus: a review of literature. J Clin Ophthalmol 2012; 6:1665–1674. 15. Liang L, Zhang M, Zou W, Liu Z. Aggravated dry eye after laser in situ keratomileusis in patients with Sjo¨gren syndrome. Cornea 2008; 27:120– 123. 16. Meiyan Li, Zhao Jing, Shen Yang, et al. Comparison of dry eye and corneal & sensitivity between small incision lenticule extraction and femtosecond LASIK for myopia. PLoS One 2013; 8:e77797. SMILE can potentially reduce significantly postrefractive surgery dry eye.
17. Dong Z, Zhou X, Wu J, et al. Small incision lenticule extraction (SMILE) and femtosecond laser LASIK: comparison of corneal wound healing and inflammation. Br J Ophthalmol 2014; 98:263–269. In-depth explanation in the SMILE procedure. 18. Sambursky R, O’Brien TP. MMP-9 and the perioperative management of LASIK surgery. Curr Opin Ophthalmol 2011; 22:294–303. 19. Toda I, Takeshi I, Teruki F, et al. Combination therapy with diquafosol && tetrasodium and sodium hyaluronate in patients with dry eye after laser in situ keratomileusis. Am J Ophthalmol 2014; 157:616–622. Latest new drugs in treating ocular surface disease. 20. Peyman GA, Sanders DR, Batlle JF, et al. Cyclosporine 0.05% ophthalmic preparation to aid recovery from loss of corneal sensitivity after LASIK. J Refract Surg 2008; 24:337–343. 21. Salib GM, McDonald MB, Smolek M. Safety and efficacy of cyclosporine 0.05% drops versus unpreserved artificial tears in dry-eye patients having laser in situ keratomileusis. J Cataract Refract Surg 2006; 32:772–778. 22. Ursea R, Purcell TL, Tan BU, et al. The effect of cyclosporine A (Restasis) on recovery of visual acuity following LASIK. J Refract Surg 2008; 24:473–476. 23. Dua H, Gomes J, King A, Maharajan V. The amniotic membrane in ophthalmology. Survey Ophthalmol 2004; 49:51–77. 24. Segal O, Barkana Y, Hourovitz D, et al. Scleral contact lenses may help where other modalities fail. Cornea 2003; 22:308–310. 25. Quinto G, Campos M, Behrens A. Autologous serum for ocular surface diseases. Arq Bras Oftalmol 2008; 71(Suppl 6):47–54. 26. Noda-Tsuruya T, Asano-Kato N, Toda I, Tsubota K. Autologous serum eye drops for dry eye after LASIK. J Refract Surg 2006; 22:61–66. &&
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