REVIEW ARTICLE

Corneal Debridement Update: Adjuvant Therapies and Wound Healing Lindsay A. McGrath, MBBS*Þ and Graham A. Lee, MD, FRANZCO*Þþ

Abstract: Corneal debridement techniques have seen evolution in instrumentation and indication. Although the techniques themselves are simple and usually effective, there is often the need for adjuvant topical therapies to augment healing and/or prevent recurrence of disease. To better understand the requirement for adjuvant therapies, the current theories of corneal wound healing are reviewed. Key Words: corneal debridement, mitomycin C, amniotic membrane, corneal collagen cross-linking, wound healing (Asia Pac J Ophthalmol 2013;2: 237Y243)

D

ebridement of the cornea is used for diagnosis or therapy of disease and can be augmented with a number of agents. The use of antibiotic prophylaxis is widely accepted; however, the use of chemotherapeutic substances, steroids, nonsteroidal anti-inflammatory drugs, autologous serum drops, amniotic membrane, and bandage contact lenses are options for consideration. These adjuvants modify the natural mechanisms of wound healing. An understanding of these physiologic processes allows appropriate case selection and follow-up to optimize patient outcomes. This review summarizes the current knowledge on the adjuvant therapies and physiology of corneal wound healing in the context of epithelial debridement.

ADJUNCTIVE THERAPIES Mitomycin C Mitomycin C (MMC) has gained popularity as a topical adjunctive therapy in anterior eye diseases over the past 2 decades. This medication is an antitumor antibiotic that was first isolated from Streptomyces caespitosus by Wakaki1 in 1958. Applied topically, MMC inhibits DNA synthesis and has been shown to inhibit cell migration and extracellular matrix production.2 This alkylating agent was first used by an ophthalmologist in 1963 for pterygia but has recently gained popularity for its promising effects in glaucoma filtering and surface ablation surgery and treatment of ocular surface neoplasia and cicatrization (Fig. 1). Laser surface ablation for refractive correction has been associated with loss of corneal transparency due to haze. Mitomycin C is effective in reducing the incidence of this complication, and its widespread use has seen a revival in surface ablation techniques.3 During laser ablation, keratocyte apoptosis has been documented, which leads to a proliferation and migration of

From the *City Eye Centre; †University of Queensland; and ‡Royal Brisbane and Women’s Hospital, Brisbane, Queensland, Australia. The authors have no funding or conflicts of interest to declare. Reprints: Graham A. Lee, MD, FRANZCO, City Eye Centre, 10/135 Wickham Terrace, Brisbane, Queensland, Australia. E-mail: [email protected]. Copyright * 2013 by Asia Pacific Academy of Ophthalmology ISSN: 2162-0989 DOI: 10.1097/APO.0b013e31829e69b0

Asia-Pacific Journal of Ophthalmology

&

surrounding keratocytes to replace the denuded stroma.4 In response, some keratocytes differentiate into myofibroblasts, which scatter light from their nuclei, cell bodies, and dendritic processes.3 These myofibroblasts are the cause of clinically observable corneal haze. When applied over de-epithelialized stroma, MMC has a dose-dependent cytotoxic effect causing further keratocyte apoptosis followed by a reduced keratocyte and myofibroblast repopulation. In this way, MMC has been shown to be effective in reducing postoperative haze associated with surface ablation procedures.3,5 Teus et al3 conducted a literature review of MMC use in refractive surgery and reported 0.02% MMC concentration was the most commonly used for this indication. They found that the easiest way to avoid leaching of the MMC to the peripheral cornea or limbus was to use a round cellulose sponge 7 to 9 mm in diameter, soaked in MMC and applied over the ablated stroma for up to 2 minutes. Although there is a propensity of literature highlighting the effectiveness of MMC in the management of ocular pathologies, there are potentially sight-threatening complications associated with this agent that have limited its widespread use by ophthalmologists. Known complications include punctate keratitis, chemosis, delayed conjunctival wound healing, scleral melting, corneal melting, iritis, and sudden onset of mature cataract.6 In particular, the use of MMC should be avoided in patients with combined dry eye and neurotropic disease, given the known impairment of wound healing inherent in this condition.6 The complications associated with MMC are largely seen in pterygium and glaucoma surgery, and there are few reports of adverse effects or toxicity after use in surface ablation.3,7 There are, however, a lack of clinical trials with extended follow-up of the use of MMC in ocular surface disease; therefore, judicious use of this medication is prudent at this point in time.

Influence of Anti-inflammatory Drugs Anti-inflammatory agents have a broad spectrum of application in ophthalmology. Corticosteroids, in particular, have long been the standard of care for treatment and prophylaxis of postoperative inflammation.8 Steroids are the most effective drugs for nonspecific suppression of inflammation and have been shown to inhibit corneal neovascularization.9 Despite their known antiinflammatory properties and widespread use, application of topical steroids to the ocular surface may delay the healing of corneal stromal wounds, induce glaucoma, form cataracts, and increase liability to infection.9 A study of the effect of topical corticosteroids on corneal epithelial wound healing found that topical application of prednisolone 1% and dexamethasone 0.1% 6 times daily caused a statistically significant (P G 0.001) decrease in epithelial healing rate.9 Srinivasan and Kulkarni, in another study, found that these drug concentrations cause retardation in healing rate proportional to the diameter of epithelial denudation. This study also hypothesized that conjunctival epithelial cell migration may be more corticosteroid sensitive than corneal epithelium.10 Studies investigating corneal tensile strength have found that application of corticosteroids decreases stromal tensile strength during the first

Volume 2, Number 4, July/August 2013

www.apjo.org

Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.

237

McGrath and Lee

Asia-Pacific Journal of Ophthalmology

&

Volume 2, Number 4, July/August 2013

FIGURE 1. A, Reis-Buckler dystrophy after epithelial debridement showing irregular anterior stromal surface. B, Diamond burr superficial keratectomy to stromal surface. C, Application of 0.02% MMC with a cellulose sponge for 20 seconds. D, Anterior stroma demonstrating smoother surface.

few weeks of corneal stromal healing.11 This inhibition of scar formation is presumed to be due to diminished fibroblast activity and the production of new collagen.8,12 The known effects of corticosteroids on wound healing have led to their administration after refractive surface ablation procedures, such as photorefractive keratectomy (PRK) or laserassisted in situ keratomileusis (LASIK). Corneal haze, the major adverse effect of PRK, results from stromal wound healing and proliferation of keratocytes in the cornea immediately subadjacent to the epithelium.13 Lu et al13 compared the antiproliferative effects of steroidal and nonsteroidal anti-inflammatory effects on human corneas and found that nonsteroidal agents were more potent in inhibiting proliferation of keratocytes and suggested their use in modulating wound healing after PRK. A later study by Kaji et al14 found that topical application of betamethasone decreased corneal haze formation by inhibiting the deposition of extracellular matrix components. In contrast, topical diclofenac did not significantly affect corneal haze formation or deposition of type IV collagen. These authors postulated that corneal haze is therefore independent of early-phase conjunctival inflammation.14 Studies comparing steroidal and nonsteroidal preparations after cataract surgery have indicated that topical nonsteroidal antiinflammatory drugs carry a reduced risk of complications relating to prolonged wound healing and should therefore be considered in the management of patients having uneventful cataract surgery.8 The local irritant effects of topical ophthalmic nonsteroidal agents, including conjunctival hyperemia, stinging, burning, and corneal anesthesia, however, have limited their widespread use for longterm suppression of inflammation.15 These drugs also have rare associations with indolent corneal ulceration and full-thickness corneal melts.15

intractable to conventional therapy. Tsubota et al17 reported that the presence of growth factors, vitamins, and fibronectin in these drops might have a true epitheliotropic potential for the ocular surface. Eye drops produced from serum (Fig. 2) have since been shown to provide both lubrication and nutrition for ocular surface epithelium in diseases such as superior limbic keratoconjunctivitis, Sjo¨gren syndrome, Stevens-Johnson syndrome, persistent epithelial defects, and keratopathies of various etiologies.18Y21 The first randomized controlled clinical trial of the use of autologous serum for ocular surface disease was published in 2004.22 The authors found that 12 of 16 patients reported improvement in comfort, and 12 of 25 eyes showed objective improvement by impression cytology. Subjective and objective improvements were seen to regress when the treatment was reverted to conventional therapy. A prospective study of the use of serum tears for recurrent corneal erosions found that 85% of 33 treated eyes remained symptom-free throughout a mean follow-up of 30 months.23 No patients had a relapse while under treatment, and the authors found that a 6-month treatment was sufficient to keep patients symptom-free for at least 2.5 years. There have been 2 studies analyzing the combined use of serum tears and a bandage contact lens for the treatment of epithelial defects.24,25 Schrader et al24 found that although hydrogel lenses attracted lysozyme, lactoferrin, mucin, and albumin deposits

Autologous Serum Eye Drops Eye drops made from autologous serum have seen renewed interest in the past decade, although their initial use was described in 1984.16 These drops offer therapy for ocular surface disorders such as persistent epithelial defects and severe dry eyes

238

www.apjo.org

FIGURE 2. Crimped tube containing autologous serum drops. * 2013 Asia Pacific Academy of Ophthalmology

Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.

Asia-Pacific Journal of Ophthalmology

&

Volume 2, Number 4, July/August 2013

Corneal Debridement Update

after 12.3 T 5.1 days, the combination of epithelial stimulation by autologous serum and the prevention of mechanical stress by the contact lens is likely to have a positive effect on corneal wound healing. Overall, the efficacy of serum eye drop therapy varies between 30% Y 100% for symptomatic relief and 39% Y 61% for objective reduction of corneal staining.18

Amniotic Membrane Human amniotic membrane has been used in the treatment of corneal surface disease over the past 3 decades. Studies in the mid-1990s found that preserved human amniotic membrane was effective in promoting healing of persistent corneal epithelial defects with ulceration,26 as a substrate alternative to conjunctival autograft in pterygium removal,27 and for surgically induced conjunctival defects.28 This tissue has been shown to facilitate epithelialization and to reduce inflammation, vascularization, and scarring. These actions are due to the unique matrix component on the stromal side of the amniotic membrane, which suppresses transforming growth factor A (TGF-A) signaling and the proliferation and differentiation of corneal and limbal fibroblasts.29,30 Furthermore, amniotic membrane offers antiadhesive effects, bacteriostatic properties, wound protection, analgesia, and a lack of immunogenicity.31 The surgical use of amniotic membrane involves covering the epithelial-stromal defect with a fragment of amniotic membrane, occasionally using more than 1 layer.32 The membrane fragment should be sutured edge to edge to the surrounding healthy epithelium without extending beyond the margins of the epithelial defect. In this way, the amniotic membrane acts as a basement membrane allowing overlying epithelialization stemming from the surrounding healthy epithelium. Alternatively, the entire corneal surface can be covered by the amniotic membrane, overlapping the edges of the epithelial defect, so that the epithelialization occurs beneath the graft. In this case, the amniotic membrane acts as a therapeutic lens and detaches or dissolves over time completely restoring corneal transparency.32 Amniotic membrane has shown promising results in the treatment of acute and chronic limbal stem cell deficiency.33 In particular, etiologies such as Stevens-Johnson syndrome, chemical (Fig. 3) or thermal burns, and ocular cicatricial pemphigoid have been shown to achieve successful re-epithelialization with amniotic membrane transplantation.33 Pires et al34 described its use in bullous keratopathy and found that 90% of 50 patients with intolerable pain were pain free 33 weeks after epithelial debridement and amniotic membrane transplantation. The longer-term efficacy, however, is less certain. Persistent corneal defects and perforations have also been successfully treated with amniotic membrane. Azuara-Blanco et al31 reported the success of amniotic membrane transplantation in promoting epithelialization if the stroma was not too severely thinned. Despite the widespread use of amniotic membranes in ophthalmology, there have been few reported adverse effects.30 In a major review, Dua et al30 suggest that failure to achieve the intended effect with the amniotic membrane is perhaps the most significant drawback. This may occur by loss of the membrane either by degradation or by cheese wiring of the sutures in the immediate postoperative period. In other cases, the residual subepithelial membrane may persist, leading to problems with corneal transparency. Maharajan et al35 analyzed 74 consecutive procedures using amniotic membrane for different indications and found that success was achieved in only 22% to 58%, partial success in 6% to 34%, and failure in 33% to 44%. Thus, the amniotic membrane is yet to find its niche in ophthalmology, with further research required to define its clinical role in the treatment of corneal and conjunctival disease. * 2013 Asia Pacific Academy of Ophthalmology

FIGURE 3. Amniotic membrane applied to the ocular surface, fornix, and lid with bolsters after acute alkali burn.

Therapeutic Contact Lenses There are a wide variety of indications for the therapeutic use of contact lenses in Ophthalmology. The first modern report of a contact lens as a bandage and drug delivery system was in 1886 by the French ophthalmologist Galezowski.36 He reported success using gelatin shields soaked in cocaine and sublimate as an anesthetic and antiseptic depot after contact lens surgery. Soft contact lenses were originally fabricated in Czechoslovakia in the early 1960s, but the first documented therapeutic use of these lenses was not until 1970 when Gasset and Kaufman popularized their use.37Y39 The rationale of using such a lens is to provide symptomatic relief of corneal discomfort of pathologic or surgical origin. Contact lenses protect the nerve endings in the corneal epithelium to shield them from the abrasive forces of lid blinks and rapid eye movement sleep and to splint, with a relatively tight-fitting lens, the healing epithelium against Bowman layer.40 In addition to pain relief, contact lenses can be used to enhance corneal healing, protect the corneal surface, improve vision, hydrate the cornea, or seal corneal perforations.37,41 There are also sporadic reports of success using soft contact lenses as drug delivery systems.37 The use of bandage soft contact lenses has increased in the last decade with the introduction of surgical techniques to correct refractive errors. Soft contact lenses can aid in corneal protection and analgesia by preserving the epithelial flap after LASIK or by promoting re-epithelialization after PRK or laser subepithelial keratomileusis.42 There is little consensus between ophthalmologists as to the utility of a bandage lens after PRK or LASIK because blinded trials are impossible.43 Sekundo et al43 published the first prospective randomized trial of bandage soft contact lens use after LASIK. In a study of 200 eyes (one eye with a bandage lens and the other eye without), they found that 54% of patients reported discomfort in the eye with the contact lens, and only 27% noticed an improvement in comfort. This is similar to a previous study that found 58% of patients disliked wearing a bandage soft contact lens.44 Contact lenses can also be useful for short-term wear after application of cyanoacrylate adhesives. The soft lens reduces the foreign body sensation produced by the dried adhesive and prevents dislodging of the glue by eyelid forces.41,45 Liu and Buckley40 advocate the fitting of soft contact lenses for patients with recurrent corneal erosions after conservative measures (lubricants and removal of epithelial slough) have been trialed. They warn, however, that some patients cannot tolerate the www.apjo.org

Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.

239

McGrath and Lee

Asia-Pacific Journal of Ophthalmology

contact lens especially during an acute erosive episode. They also discuss the difficulty in the timing of removal of the contact lens but advocate that the lens should be removed if the patient is symptom-free for 3 months. This recommendation was echoed by Fraunfelder and Cabezas,46 who carried out a retrospective study of 12 patients with recurrent corneal erosions. They prescribed a bandage contact lens for 3 months, replaced every 2 weeks, and found that this produced a long-term resolution in most recalcitrant cases of recurrent corneal erosions. Most patients reported immediate relief of pain and symptoms. Only 1 patient developed objective findings of recurrence of disease after 3 months of contact lens wear over a follow-up of 50.4 T 14.3 weeks. In a study of 37 patients receiving silicone hydrogel contact lenses for therapy of bullous keratopathy, recurrent corneal erosions, filamentous keratitis, or trauma, Ozkurt et al47 reported that pain relief was achieved in 91% of patients, visual acuity improved in 56%, and 84% of eyes healed completely over an undisclosed follow-up period. Complications of therapeutic contact lens use tend to be associated with predisposing corneal disease and poor compliance.48 Of these complications, the most frequently seen are corneal edema, microbial keratitis, and neovascularization.37,49 McDermott and Chandler described a higher relative incidence of infection with less virulent organisms in therapeutic contact lens wearers, secondary to a lower overall resistance to microbial infection.37 Several factors have been shown to limit contact lens contamination and hence minimize the risk of corneal infection.50 Examples of these include prophylactic antibiotics, patient selection, absence of contact lens manipulation, protective eye shield wear, and the use of silicone hydrogel material to maximize oxygen transmissibility. The need for continued ocular lubrication and regular bandage contact lens exchange should be emphasized to all patients.48

Corneal Collagen Cross-linking Corneal collagen cross-linking (CXL) is used for the control of progressive corneal ectasia in keratoconus (Fig. 4). The technique of CXL involves the photopolymerization of stromal fibers by the combined action of riboflavin and ultraviolet light from a solid-state UV-A source.48 This process has been shown to increase the rigidity of the corneal collagen and its resistance to keratectasia. More recently, studies have shown that this technique may be of value as an adjuvant to LASIK to prevent postoperative ectasia.49,50 The incidence of keratectasia after LASIK has been estimated at 0.04% to 0.60%, although the developmental mechanisms remain unclear. Celik et al hypothesized that CXL at the time of LASIK would potentially reduce the incidence of postoperative ectasia in a population where susceptible patients are difficult to discern. The process of CXL involves using UV-A at 365 to 370 nm and the photosensitizer riboflavin. The photosensitizer is excited and generates reactive oxygen species, which are released into the surrounding stroma, inducing chemical covalent bonds bridging amino groups of collagen fibrils.48 This photopolymerization increases the rigidity of corneal collagen and its resistance to ectasia.51 Traditionally, before treatment, the central 7 to 9 mm of corneal epithelium is debrided with a dry sponge or blade to aid in the penetration of riboflavin. The open flaps seen in LASIK procedures, however, provide a natural opportunity for CXL.49 All corneas for cross-linking should be measured at least 400 Km in thickness to protect the endothelium.52 In a pilot study of CXL and LASIK, immediately after LASIK, 1 drop of 0.1% riboflavin solution was instilled onto the cornea.50 After 2 minutes, it was rinsed off with balanced salt solution, and the flap was replaced. Another drop was instilled alternately with balanced salt solution

240

www.apjo.org

&

Volume 2, Number 4, July/August 2013

FIGURE 4. Collagen cross-linking with riboflavin applied to the debrided corneal surface.

every 5 minutes. The cornea was then exposed to UV-A light for a total of 30 minutes, at a power of 30 mW/cm2. Riboflavin was instilled onto the cornea every 3 to 5 minutes during the treatment. No endothelial damage has been reported with similar treatment parameters in keratoconus treatments.53 Very early studies of this technique have found that LASIK with concomitant CXL appears to be a promising modality for future applications to prevent corneal ectasia. There are no significant adverse effects reported to date, although there may be visually insignificant corneal edema or haze.49,50 There is only 1 study with long-term follow-up of 4 years; however, this case series included only 5 eyes.50 Therefore, further long-term studies with larger cohorts are awaited before widespread implementation of this adjuvant therapy.

PHYSIOLOGY OF EPITHELIAL WOUND HEALING When injuries or insults to the cornea occur, ideally, the cell layers would perfectly regenerate, and function would be restored.54 With the exception of minor superficial epithelial scrapes, few corneal injuries heal by true regeneration. Most corneal injuries heal by repairing damaged tissue with scar tissue that is opaque and of low tensile strength.55 The past few years have seen important advancements in the understanding of corneal wound healing, which will allow the possibility for improved clinical outcomes for corneal injuries.4,54 Injuries that cause damage to the corneal epithelium heal by a combination of 3 components: migration, mitosis, and differentiation.56 The type of corneal injury and extent of epithelial damage dictate the intensity of the wound healing response.57Y59 The migration phase begins within 4 to 6 hours of epithelial injury. The first step in this process is the removal of necrotic epithelial cells at the injury border by polymorphonuclear leukocytes derived from tear fluid. The basal cells then flatten and separate and begin to produce cellular processes at the edges of cells bordering the wound. Migrating epithelial cells move across the surface of the wound with the aid of filopodia and lamellipodia derived from actin filaments.54 These processes bind and cleave from the underlying matrix because of the action of fibronectin, which appears on the corneal surface within 1 hour after cellular injury. The epithelial cell mass movement was described by Thoft and Friend in 1983.60 According to the authors’ hypothesis, X is the proliferation of the basal epithelium, Y is the centripetal movement of the peripheral epithelial cells, and Z is the cell loss * 2013 Asia Pacific Academy of Ophthalmology

Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.

Asia-Pacific Journal of Ophthalmology

&

Volume 2, Number 4, July/August 2013

due to death and desquamation. Using these representations, the equation X + Y = Z was created to illustrate the balance between cell loss and proliferation (Fig. 5). Corneal epithelial wound healing is not complete until the newly regenerated epithelium is anchored firmly to the underlying stroma.61 Regenerating epithelium forms fairly weak cell to substrate adhesions and can be easily peeled off in the early phase. Synthesis of hemidesmosomes and anchoring filaments occurs approximately 12 to 24 hours after injury.62 The mitotic differentiation and proliferation of corneal epithelial cells are thought to arise from stem cells at the limbus. Evidence for this includes observations in the 1980s that larger epithelial wounds heal faster than do smaller central wounds.63 It has recently been shown that centrally located corneal epithelium is also capable of regeneration for an extended period using only the cells of its basal stratum.64 The 500-Km human cornea stroma heals slower than other connective tissues because of its inherent avascularity.56 Immediately after an incisional injury, the stromal matrix imbibes fluid and becomes edematous in the area adjacent to the wound. The cellular activation and metabolic activities of stromal keratocytes are strongly influenced by the epithelium.65 When the epithelial defect has healed, fibroblast growth factor and epidermal growth factors stimulate keratocytes to undergo fibroblastic transformation and repopulation via mitosis, peripheral to the epithelial defect. Proliferation of keratocytes occurs within 12 to 24 hours and gives rise to activated keratocytes, fibroblasts, and myofibroblasts responsible for repopulating the depleted stroma.4,62 The successive tissue repair is mediated by myofibroblasts, which play an important role in the deposition and arrangement of collagen fibrils, and hence resultant corneal transparency.4 Transforming growth factor may be the factor responsible for increased synthesis of collagen and therefore increased strength of stromal wounds.66 Initially, the newly synthesized extracellular matrix is quite disorganized, resulting in stromal opacification.56 The remodeling of stromal components eventually restores the lamellar collagen pattern to normal dimensions resulting in near-normal corneal transparency at the site of injury. The strength of corneal scars never reaches that of uninjured corneal tissue.56 It is well known that TGF-A is produced by the basal epithelial cells of both wounded and unwounded corneas.62 Because of their affinity for collagen type IV, TGF-A cytokines are unlikely to penetrate the corneal stroma to modify myofibroblast development in a healthy cornea. However, damage to the basement membrane during corneal epithelial debridement can increase TGF-A penetration into the underlying stroma.61 This acute increase in cytokine is likely to be maintained only until the basement membrane has regenerated. At this time, the barrier once

Corneal Debridement Update

again limits migration of TGF-A and thus decreases the development of myofibroblasts.61 It has been shown that mechanical epithelial scraping triggers events that lead to cell death in the anterior stroma.67 One event is triggered by direct mechanical trauma, and the other is mediated by extracellular cytokines from the injured epithelium.67 It has been hypothesized that this early apoptosis of keratocytes after epithelial injury may be a mechanism to limit viruses, such as herpes simplex, from extending further into the eye or brain.68 An important requirement of surface ablation procedures to improve visual acuity is that the tissue healing processes must not result in scar formation or significantly distort the induced correction.69 If distortion is inevitable, it should occur in a predictable fashion, and the procedure should show long-term maintenance of transparency and stability of anatomical features. Important differences in the speed, intensity, and spatial distribution of wound healing activity exist as a function of the surgical technique of laser vision correction.4 Wu et al70 studied ultramicroscopic changes in the cornea after excimer laser keratectomy and found that the precision of the laser was well demonstrated by the abrupt termination and relatively smooth edges of collagen bundles at the edge of the ablation. Re-epithelialization of the ablated zone was found to occur with variable thickening, perhaps because of the irregularities of the underlying stroma. In PRK, disruption of the epithelial basement membrane over the central cornea amplifies the wound healing response and has been shown to account for higher rates of regression and haze.4 Keratocyte apoptosis is localized to the anterior stroma, whereas keratocyte proliferation dominates the posterior and peripheral stroma. Keratocyte apoptosis appears to be mediated by cytokines released from the injured epithelium, including interleukin, Fas/Fas ligand, bone morphogenic protein, and tumor necrosis factor.4 Most commonly, progressive subepithelial fibrosis occurs between 2 and 6 months postoperatively, after which time the fibrotic haze begins to dissipate and the refraction begins to stabilize.71 Some patients, however, may experience severe fibrosis leading to almost complete regression of effect or minimal fibrosis, which may leave them slightly hyperopic.71 Overall, refractive regression continues to be a major challenge after PRK, and it can be seen to be a function of postoperative time, type of refractive surgery, and refractive aims.4 The distance of the ablation bed and resulting stromal cellular responses from the epithelium after LASIK favor a more moderate healing response.4 Keratocyte apoptosis and proliferation are observed immediately anterior and posterior to the lamellar interface. Diffuse lamellar keratitis can occur after LASIK because of ingrowth of epithelium into the lamellar interface, causing release of epithelial cytokines.59 This diffuse, inflammatory

FIGURE 5. The corneal epithelium is maintained by a balance of sloughing of cells from the surface (Z), cell division in the basal layer (X), and centripetal migration of cells from the limbus (Y). From Thoft and Friend,60 courtesy of Dr Richard Thoft. * 2013 Asia Pacific Academy of Ophthalmology

www.apjo.org

Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.

241

Asia-Pacific Journal of Ophthalmology

McGrath and Lee

infiltrate occurs at the level of the flap-residual stromal interface and can up-regulate growth factors in the tears, which stimulate wound healing.4 Often, the multifaceted wound healing response to keratorefractive surgery can act to reverse the achieved refractive outcome; however, it is a vital force in reestablishing corneal integrity, stability, and strength. The postoperative interventional strategies should be selected with care to suit the individual patients’ corneal properties and the type of surgical procedure that was performed.

CONCLUSIONS There are a number of modalities useful in enhancing the effect of corneal debridement. Mitomycin C has found a number of uses in ophthalmology, particularly in regard to its effect on modifying wound healing. By reducing scar formation after debridement, corneal clarity can be improved. It is associated with significant ocular surface adverse effects and must be used with careful application. Topical steroids and nonsteroidal antiinflammatory drugs can also modify the healing response by reducing fibrosis, however, at the expense of slowing epithelial regrowth. In contrast, autologous serum and amniotic membrane provide a biologically active substance that not only modifies but also improves the healing response. The use of a therapeutic contact lens has been useful to aid epithelial healing but needs careful follow-up to avoid potential for keratitis. With further research, the mechanisms of wound healing will be further elucidated and lead to development of novel effective therapies. REFERENCES 1. Wakaki S. Recent advance in research on antitumor mitomycins. Cancer Chemother Rep. 1961;13:79Y86. 2. Abraham LM, Selva D, Casson R, et al. Mitomycin: clinical applications in ophthalmic practice. Drugs. 2006;66:321Y340. 3. Teus MA, de Benito-Llopis L, Alio JL. Mitomycin C in corneal refractive surgery. Surv Ophthalmol. 2009;54:487Y502. 4. Dupps WJ Jr, Wilson SE. Biomechanics and wound healing in the cornea. Exp Eye Res. 2006;83:709Y720. 5. Jain S, McCally RL, Connolly PJ, et al. Mitomycin C reduces corneal light scattering after excimer keratectomy. Cornea. 2001;20:45Y49. 6. Mearza AA, Aslanides IM. Uses and complications of mitomycin C in ophthalmology. Expert Opin Drug Saf. 2007;6:27Y32. 7. Taneri S, Koch JM, Melki SA, et al. Mitomycin-C assisted photorefractive keratectomy in the treatment of buttonholed laser in situ keratomileusis flaps associated with epithelial ingrowth. J Cataract Refract Surg. 2005;31:2026Y2030. 8. Barba KR, Samy A, Lai C, et al. Effect of topical anti-inflammatory drugs on corneal and limbal wound healing. J Cataract Refract Surg. 2000;26:893Y897. 9. Petroutsos G, Guimaraes R, Giraud JP, et al. Corticosteroids and corneal epithelial wound healing. Br J Ophthalmol. 1982;66:705Y708. 10. Srinivasan BD, Kulkarni PS. The effect of steroidal and nonsteroidal anti-inflammatory agents on corneal re-epithelialization. Invest Ophthalmol Vis Sci. 1981;20:688Y691. 11. Waterbury L, Kunysz EA, Beuerman R. Effects of steroidal and non-steroidal anti-inflammatory agents on corneal wound healing. J Ocul Pharmacol. 1987;3:43Y54.

&

Volume 2, Number 4, July/August 2013

14. Kaji Y, Amano S, Oshika T, et al. Effect of anti-inflammatory agents on corneal wound-healing process after surface excimer laser keratectomy. J Cataract Refract Surg. 2000;26:426Y431. 15. Gaynes BI, Fiscella R. Topical nonsteroidal anti-inflammatory drugs for ophthalmic use: a safety review. Drug Saf. 2002;25:233Y250. 16. Fox RI, Chan R, Michelson JB, et al. Beneficial effect of artificial tears made with autologous serum in patients with keratoconjunctivitis sicca. Arthritis Rheum. 1984;27:459Y461. 17. Tsubota K, Goto E, Shimmura S, et al. Treatment of persistent corneal epithelial defect by autologous serum application. Ophthalmology. 1999;106:1984Y1989. 18. Geerling G, Maclennan S, Hartwig D. Autologous serum eye drops for ocular surface disorders. Br J Ophthalmol. 2004;88:1467Y1474. 19. Lee GA, Chen SX. Autologous serum in the management of recalcitrant dry eye syndrome. Clin Experiment Ophthalmol. 2008;36:119Y122. 20. Liu L, Hartwig D, Harloff S, et al. An optimised protocol for the production of autologous serum eyedrops. Graefes Arch Clin Exp Ophthalmol. 2005;243:706Y714. 21. del Castillo JM, de la Casa JM, Sardina RC, et al. Treatment of recurrent corneal erosions using autologous serum. Cornea. 2002;21:781Y783. 22. Noble BA, Loh RS, MacLennan S, et al. Comparison of autologous serum eye drops with conventional therapy in a randomised controlled crossover trial for ocular surface disease. Br J Ophthalmol. 2004;88: 647Y652. 23. Ziakas NG, Boboridis KG, Terzidou C, et al. Long-term follow up of autologous serum treatment for recurrent corneal erosions. Clin Experiment Ophthalmol. 2010;38:683Y687. 24. Schrader S, Wedel T, Moll R, et al. Combination of serum eye drops with hydrogel bandage contact lenses in the treatment of persistent epithelial defects. Graefes Arch Clin Exp Ophthalmol. 2006;244: 1345Y1349. 25. Choi JA, Chung SH. Combined application of autologous serum eye drops and silicone hydrogel lenses for the treatment of persistent epithelial defects. Eye Contact Lens. 2011;37:370Y373. 26. Lee SH, Tseng SC. Amniotic membrane transplantation for persistent epithelial defects with ulceration. Am J Ophthalmol. 1997;123: 303Y312. 27. Prabhasawat P, Barton K, Burkett G, et al. Comparison of conjunctival autografts, amniotic membrane grafts and primary closure for pterygium excision. Ophthalmology. 1997;104:974Y985. 28. Tseng SC, Prabhasawat P, Lee SH. Amniotic membrane transplantation for conjunctival surface reconstruction. Am J Ophthalmol. 1997;124: 765Y774. 29. Tseng SC, Li DQ, Ma X. Suppression of transforming growth factor-beta isoforms, TGF-beta receptor type II, and myofibroblast differentiation in cultured human corneal and limbal fibroblasts by amniotic membrane matrix. J Cell Physiol. 1999;179:325Y335. 30. Dua HS, Gomes JA, King AJ, et al. The amniotic membrane in ophthalmology. Surv Ophthalmol. 2004;49:51Y77. 31. Azuara-Blanco A, Pillai CT, Dua HS. Amniotic membrane transplantation for ocular surface reconstruction. Br J Ophthalmol. 1999;83:399Y402. 32. Gris O, del Campo Z, Wolley-Dod C, et al. Amniotic membrane implantation as a therapeutic contact lens for the treatment of epithelial disorders. Cornea. 2002;21:22Y27.

12. Hersh PS, Rice BA, Baer JC, et al. Topical nonsteroidal agents and corneal wound healing. Arch Ophthalmol. 1990;108:577Y583.

33. Tsubota K, Satake Y, Ohyama M, et al. Surgical reconstruction of the ocular surface in advanced ocular cicatricial pemphigoid and Stevens-Johnson syndrome. Am J Ophthalmol. 1996;122:38Y52.

13. Lu KL, Wee WR, Sakamoto T, et al. Comparison of in vitro antiproliferative effects of steroids and nonsteroidal antiinflammatory drugs on human keratocytes. Cornea. 1996;15:185Y190.

34. Pires RT, Tseng SC, Prabhasawat P, et al. Amniotic membrane transplantation for symptomatic bullous keratopathy. Arch Ophthalmol. 1999;117:1291Y1297.

242

www.apjo.org

* 2013 Asia Pacific Academy of Ophthalmology

Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.

Asia-Pacific Journal of Ophthalmology

&

Volume 2, Number 4, July/August 2013

35. Maharajan VS, Shanmuganathan V, Currie A, et al. Amniotic membrane transplantation for ocular surface reconstruction: indications and outcomes. Clin Experiment Ophthalmol. 2007;35:140Y147. 36. Mely R. Therapeutic and cosmetic indications of lotrafilcon a silicone hydrogel extended-wear lenses. Ophthalmologica. 2004;218 (Suppl 1):29Y38; discussion 26Y45. 37. McDermott ML, Chandler JW. Therapeutic uses of contact lenses. Surv Ophthalmol. 1989;33:381Y394. 38. Amos DM. The use of soft bandage lenses in corneal disease. Am J Optom Physiol Opt. 1975;52:524Y532. 39. Gasset AR, Kaufman HE. Therapeutic uses of hydrophilic contact lens. Am J Ophthalmol. 1970;69:252Y259. 40. Liu C, Buckley R. The role of the therapeutic contact lens in the management of recurrent corneal erosions: a review of treatment strategies. CLAO J. 1996;22:79Y82. 41. Lim LT, Tan DT, Chan WK. Therapeutic use of Bausch & Lomb PureVision contact lenses. CLAO J. 2001;27:179Y185. 42. Grentzelos MA, Plainis S, Astyrakakis NI, et al. Efficacy of 2 types of silicone hydrogel bandage contact lenses after photorefractive keratectomy. J Cataract Refract Surg. 2009;35:2103Y2108. 43. Sekundo W, Dick HB, Meyer CH. Benefits and side effects of bandage soft contact lens application after LASIK: a prospective randomized study. Ophthalmology. 2005;112:2180Y2183. 44. Ahmed IK, Breslin CW. Role of the bandage soft contact lens in the postoperative laser in situ keratomieusis patient. J Cataract Refract Surg. 2001;27:1932Y1936. 45. Boruchoff SA, Donshik PC. Medical and surgical management of corneal thinnings and perforations. Int Ophthalmol Clin. 1975;15: 111Y124. 46. Fraunfelder FW, Cabezas M. Treatment of recurrent corneal erosion by extended-wear bandage contact lens. Cornea. 2011;30:164Y166. 47. Ozkurt Y, Rodop O, Oral Y, et al. Therapeutic applications of lotrafilcon a silicone hydrogel soft contact lenses. Eye Contact Lens. 2005;31:268Y269. 48. Wollensak G. Crosslinking treatment of progressive keratoconus: new hope. Curr Opin Ophthalmol. 2006;17:356Y360. 49. Celik HU, Alagoz N, Yildirim Y, et al. Accelerated corneal crosslinking concurrent with laser in situ keratomileusis. J Cataract Refract Surg. 2012;38:1424Y1431.

Corneal Debridement Update

53. Dahl BJ, Spotts E, Truong JQ. Corneal collagen cross-linking: an introduction and literature review. Optometry. 2012;83:33Y42. 54. Tuli SS, Goldstein M, Schultz GS. Modulation of corneal wound healing. In: Krachmer JH, Mannis MJ, Holland EJ, eds. Cornea. 2nd ed. Philadelphia, PA: Elsevier; 2005:133Y150. 55. Ellis JS, Paull DJ, Dhingra S, et al. Growth factors and ocular scarring. Eur Ophthal Rev. 2009;3:58Y63. 56. Steele C. Corneal wound healing: a review. Part 1. Optom Today. 1999;24:28Y32. 57. Kamma-Lorger CS, Boote C, Hayes S, et al. Collagen ultrastructural changes during stromal wound healing in organ cultured bovine corneas. Exp Eye Res. 2009;88:953Y959. 58. Edelhauser HF. The resiliency of the corneal endothelium to refractive and intraocular surgery. Cornea. 2000;19:263Y273. 59. Wilson SE, Mohan RR, Hutcheon AE, et al. Effect of ectopic epithelial tissue within the stroma on keratocyte apoptosis, mitosis, and myofibroblast transformation. Exp Eye Res. 2003;76:193Y201. 60. Thoft RA, Friend J. The X, Y, Z hypothesis of corneal epithelial maintenance. Invest Ophthalmol Vis Sci. 1983;24:1442Y1443. 61. Dua HS, Gomes JA, Singh A. Corneal epithelial wound healing. Br J Ophthalmol. 1994;78:401Y408. 62. Fini ME. Keratocyte and fibroblast phenotypes in the repairing cornea. Prog Retin Eye Res. 1999;18:529Y551. 63. Matsuda M, Ubels JL, Edelhauser HF. A larger corneal epithelial wound closes at a faster rate. Invest Ophthalmol Vis Sci. 1985;26:897Y900. 64. de Faria-e-Sousa SJ, Barbosa FL, Haddad A. Autoradiographic study on the regenerative capability of the epithelium lining the center of the cornea after multiple debridements of its peripheral region. Graefes Arch Clin Exp Ophthalmol. 2010;248:1137Y1144. 65. Campos M, Raman S, Lee M, et al. Keratocyte loss after different methods of de-epithelialization. Ophthalmology. 1994;101:890Y894. 66. Klenkler B, Sheardown H. Growth factors in the anterior segment: role in tissue maintenance, wound healing and ocular pathology. Exp Eye Res. 2004;79:677Y688. 67. Zhao J, Nagasaki T. Mechanical damage to corneal stromal cells by epithelial scraping. Cornea. 2004;23:497Y502.

50. Aslanides IM, Mukherjee AN. Adjuvant corneal crosslinking to prevent hyperopic LASIK regression. Clin Ophthalmol. 2013;7:637Y641.

68. Ambrosio R Jr, Kara-Jose N, Wilson SE. Early keratocyte apoptosis after epithelial scrape injury in the human cornea. Exp Eye Res. 2009;89:597Y599.

51. Mazzotta C, Traversi C, Baiocchi S, et al. Conservative treatment of keratoconus by riboflavin-UVAYinduced cross-linking of corneal collagen: qualitative investigation. Eur J Ophthalmol. 2006;16: 530Y535.

69. Marshall J, Trokel SL, Rothery S, et al. Long-term healing of the central cornea after photorefractive keratectomy using an excimer laser. Ophthalmology. 1988;95:1411Y1421.

52. Mazzotta C, Balestrazzi A, Traversi C, et al. Treatment of progressive keratoconus by riboflavin-UVAYinduced cross-linking of corneal collagen: ultrastructural analysis by Heidelberg Retinal Tomograph II in vivo confocal microscopy in humans. Cornea. 2007;26:390Y397.

* 2013 Asia Pacific Academy of Ophthalmology

70. Wu WC, Stark WJ, Green WR. Corneal wound healing after 193-nm excimer laser keratectomy. Arch Ophthalmol. 1991;109:1426Y1432. 71. Assil KK, Quantock AJ. Wound healing in response to keratorefractive surgery. Surv Ophthalmol. 1993;38:289Y302.

www.apjo.org

Copyright © 2013 Asia Pacific Academy of Ophthalmology. Unauthorized reproduction of this article is prohibited.

243

Corneal Debridement Update: Adjuvant Therapies and Wound Healing.

Corneal debridement techniques have seen evolution in instrumentation and indication. Although the techniques themselves are simple and usually effect...
2MB Sizes 0 Downloads 11 Views