506
CONSULTATION SECTION
the patient should quit smoking.2 Also, oral administration of omega 3 fatty acids and the use of high-oxygen permeable silicone hydrogel contact lenses may help speed epithelial healing.3,4 Once the right eye has recovered to a satisfactory level, treatment in the fellow eye can be performed. I would advise transepithelial PRK, which is a 1-step treatment modality available on the laser machine that was used in the first eye. Transepithelial PRK makes the smallest epithelial abrasion on any optical zone and hence heals more quickly than alcoholassisted manual abrasion. Also, I would use MMC to prevent haze formation. Alternatively, LASIK is a good option. However, I do not advocate the use of different procedures in each eye of 1 patient. Photorefractive keratectomy in a young patient with low myopia is a safe and effective approach. Typically, young patients recover quickly. Delayed epithelial healing is a fairly rare condition that may occur after surface ablation. Michiel H.A. Luger, MD Naarden, The Netherlands
REFERENCES 1. Anitua E, Muruzabal F, Alcalde I, Merayo-Lloves J, Orive G. Plasma rich in growth factors (PRGF-Endoret) stimulates corneal wound healing and reduces haze formation after PRK surgery. Exp Eye Res 2013; 115:153–161 2. Roszkowska AM, De Grazia L, Visalli M, Mondello M, Teti D, Venza M, Venza I. Contact lens wearing and chronic cigarette smoking positively correlate with TGF-b1 and VEGF tear levels and impaired corneal wound healing after photorefractive keratectomy. Curr Eye Res 2013; 38:335–341 3. Ong NH, Purcell TL, Roch-Levecq A-C, Wang D, Isidro MA, Bottos KM, Heichel CW, Schanzlin DJ. Epithelial healing and visual outcomes of patients using omega-3 oral nutritional supplements before and after photorefractive keratectomy: a pilot study. Cornea 2013; 32:761–765 4. Plaka A, Grentzelos MA, Astyrakakis NI, Kymionis GD, Pallikaris IG, Plainis S. Efficacy of two silicone-hydrogel contact lenses for bandage use after photorefractive keratectomy. Cont Lens Anterior Eye 2013; 36:243–246
- This case of early mild stromal haze is typical of delayed epithelial healing after PRK for mild myopic correction. It illustrates the need for refractive surgeons to understand corneal wound healing at the cellular and molecular biology level.1 The patient has a history of contact lens and smoking; both are related to significant changes in tear cytokine network epithelialization, impairing corneal epithelial healing and causing early haze formation after PRK.2 Roszkowska et al.2 found contact lens use to
be positively correlated with transforming growth factor (TGF)-b1 amounts and early haze formation and chronic smoking to be positively correlated with vascular endothelial growth factor production and delayed reepithelialization. It is important to determine whether the patient was exposed to cigarette smoke during the healing process. A study of mice3 found cigarette smoking was associated with defective formation of the fibronectin layer in the wounded area and with accumulation of neutrophils in the stroma beneath the deepithelialized area. Fibronectin is an extracellular matrix (ECM) molecule that is critical for epithelial cell migration and the formation of the epithelial basement membrane; thus, this impairment is related to delayed corneal epithelial healing. Also, anther study4 elucidated the role of the generation of corneal myofibroblasts in the development of haze after surgery or other types of injury and the importance of the basement membrane, which functions as a barrier between the epithelium and stroma and modulates the cytokines that promote and maintain myofibroblasts (eg, TGF- b1, platelet-derived growth factor, interleukin-1). Thus, although functional defects in basement membrane formation lead to prolonged elevation of cytokine levels in the stroma necessary to promote differentiation of myofibroblasts, repair of the epithelial basement membrane determines elimination of myofibroblasts so that repopulating keratocytes subsequently reorganize ECM to reestablish transparency.5 There is no mention of whether MMC was used. Although MMC has been associated with slightly longer epithelial healing,6 it has been associated with a lower risk for corneal haze.7,8 Postoperatively, a bandage contact lens was applied and the patient received topical fluorometholone and ketorolac tromethamine 0.4%. Ketorolac, like most topical NSAIDs, has been associated with corneal wound-healing problems and melting.9 Once delayed epithelial healing is noticed, the proper management is to discontinue NSAIDs and reduce the steroid dosage. Although topical corticosteroids may delay epithelial healing, they are important to suppress stromal scarring and fibrosis and should usually be continued. Along with preservative-free artificial tears with hyaluronate, which have a positive impact on corneal epithelial healing,10 I would consider autologous serum in such cases.11,12 Considering the presentation of the case, I would like to have total wavefront data and a proper assessment of the ocular surface. Considering the natural history of corneal haze, I would not consider surgical treatment. Therapeutic ablation would be an option at least 1 year after the first procedure.13 I would recommend omega-3 essential fatty acid supplementation along
J CATARACT REFRACT SURG - VOL 40, MARCH 2014
CONSULTATION SECTION
with vitamin C, preservative-free artificial tears, and possibly topical cyclosporine A and inferior punctual plug occlusion.14 For the fellow eye, I would recommend femtosecond laser–assisted custom LASIK. Renato Ambr osio Jr, MD, PhD Rio de Janeiro, Brazil
REFERENCES 1. Salomao MQ, Wilson SE. Corneal molecular and cellular biology update for the refractive surgeon. J Refract Surg 2009; 25: 459–466 2. Roszkowska AM, De Grazia L, Visalli M, Mondello M, Teti D, Venza M, Venza I. Contact lens wearing and chronic cigarette smoking positively correlate with TGF-b1 and VEGF tear levels and impaired corneal wound healing after photorefractive keratectomy. Curr Eye Res 2013; 38:335–341 3. Ma C, Martins-Green M. Second-hand cigarette smoke inhibits wound healing of the cornea by stimulating inflammation that delays corneal reepithelialization. Wound Repair Regen 2009; 17:387–396 4. Mohan RR, Hutcheon AEK, Choi R, Hong JW, Lee JS, sio R Jr, Zieske JD, Wilson SE. Apoptosis, Mohan RR, Ambro necrosis, proliferation, and myofibroblast generation in the stroma following LASIK and PRK. Exp Eye Res 2003; 76:71–87 5. Wilson SE. Corneal myofibroblast biology and pathobiology: generation, persistence, and transparency. Exp Eye Res 2012; 99:78–88 6. Kremer I, Ehrenberg M, Levinger S. Delayed epithelial healing following photorefractive keratectomy with mitomycin C treatment. Acta Ophthalmol 2012; 90:271–276. Available at: http:// onlinelibrary.wiley.com/doi/10.1111/j.1755-3768.2010.01894. x/pdf. Accessed December 10, 2013 sio R Jr, Chalita MR, Krueger RR, Wilson SE. 7. Netto MV, Ambro Resposta cicatricial corneana em diferentes modalidades de cirurgia refrativa. [Corneal wound healing response following different modalities of refractive surgical procedures]. Arq Bras Ophthalmol 2005; 68:140–149. Available at: http://www.scielo. br/pdf/abo/v68n1/23276.pdf. Accessed December 10, 2013 8. Santhiago MR, Netto MV, Wilson SE. Mitomycin C: biological effects and use in refractive surgery. Cornea 2012; 31:311–321 9. Khalifa YM, Mifflin MD. Keratitis and corneal melt with ketorolac tromethamine after conductive keratoplasty. Cornea 2011; 30:477–478 10. Gomes JAP, Amankwah R, Powell-Richards A, Dua HS. Sodium hyaluronate (hyaluronic acid) promotes migration of human corneal epithelial cells in vitro. Br J Ophthalmol 2004; 88:821–825. Available at: http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC1772195/pdf/bjo08800821.pdf. Accessed December 10, 2013
507
11. Chen Y-M, Hu F-R, Huang J-Y, Shen EP, Tsai T-Y, Chen W-L. The effect of topical autologous serum on graft re-epithelialization after penetrating keratoplasty. Am J Ophthalmol 2010; 150:352–359 12. Das S, Langenbucher A, Seitz B. Delayed healing of corneal epithelium after phototherapeutic keratectomy for lattice dystrophy. Cornea 2005; 24:283–287 sio R Jr, Jardim D, Netto MV, Wilson SE. Management of 13. Ambro unsuccessful LASIK surgery. Compr Ophthalmol Update 2007; 8:125–141; discussion, 143–144 sio R Jr, Tervo T, Wilson SE. LASIK-associated dry eye 14. Ambro and neurotrophic epitheliopathy: pathophysiology and strategies for prevention and treatment. J Refract Surg 2008; 24:396–407
EDITOR’S COMMENTS In general, PRK is a safe procedure for treatment of mild to moderate myopia. However, sporadically problems, such as delayed epithelial healing, may occur that convert a highly successful procedure to a disappointing journey for patient and surgeon. Prevention of complications and case selection appear crucial when performing refractive surgery, and some respondents point to the role of smoking, which may interfere with delayed reepithelialization in surface ablation. Meanwhile, communication with the patient with a postoperative refractive surgery complication is essential, and one of the most difficult tasks for the surgeon is to reestablish the patient–doctor relationship. This is difficult because the perceived loss of quality of vision warrants immediate action from the perspective of the patient even when a more conservative approach may be preferable. As the majority of reviewers point out, it is worthwhile to give corneal wound-healing modulation a chance for at least a year before additional surgical interventions (eg, PTK) are proposed to the patient with delayed reepithelialization in surface ablation.
J CATARACT REFRACT SURG - VOL 40, MARCH 2014
Rudy Nuijts, MD, PhD Maastricht, Netherlands
CONSULTATION SECTION
the patient should quit smoking.2 Also, oral administration of omega 3 fatty acids and the use of high-oxygen permeable silicone hydrogel contact lenses may help speed epithelial healing.3,4 Once the right eye has recovered to a satisfactory level, treatment in the fellow eye can be performed. I would advise transepithelial PRK, which is a 1-step treatment modality available on the laser machine that was used in the first eye. Transepithelial PRK makes the smallest epithelial abrasion on any optical zone and hence heals more quickly than alcoholassisted manual abrasion. Also, I would use MMC to prevent haze formation. Alternatively, LASIK is a good option. However, I do not advocate the use of different procedures in each eye of 1 patient. Photorefractive keratectomy in a young patient with low myopia is a safe and effective approach. Typically, young patients recover quickly. Delayed epithelial healing is a fairly rare condition that may occur after surface ablation. Michiel H.A. Luger, MD Naarden, The Netherlands
REFERENCES 1. Anitua E, Muruzabal F, Alcalde I, Merayo-Lloves J, Orive G. Plasma rich in growth factors (PRGF-Endoret) stimulates corneal wound healing and reduces haze formation after PRK surgery. Exp Eye Res 2013; 115:153–161 2. Roszkowska AM, De Grazia L, Visalli M, Mondello M, Teti D, Venza M, Venza I. Contact lens wearing and chronic cigarette smoking positively correlate with TGF-b1 and VEGF tear levels and impaired corneal wound healing after photorefractive keratectomy. Curr Eye Res 2013; 38:335–341 3. Ong NH, Purcell TL, Roch-Levecq A-C, Wang D, Isidro MA, Bottos KM, Heichel CW, Schanzlin DJ. Epithelial healing and visual outcomes of patients using omega-3 oral nutritional supplements before and after photorefractive keratectomy: a pilot study. Cornea 2013; 32:761–765 4. Plaka A, Grentzelos MA, Astyrakakis NI, Kymionis GD, Pallikaris IG, Plainis S. Efficacy of two silicone-hydrogel contact lenses for bandage use after photorefractive keratectomy. Cont Lens Anterior Eye 2013; 36:243–246
- This case of early mild stromal haze is typical of delayed epithelial healing after PRK for mild myopic correction. It illustrates the need for refractive surgeons to understand corneal wound healing at the cellular and molecular biology level.1 The patient has a history of contact lens and smoking; both are related to significant changes in tear cytokine network epithelialization, impairing corneal epithelial healing and causing early haze formation after PRK.2 Roszkowska et al.2 found contact lens use to
be positively correlated with transforming growth factor (TGF)-b1 amounts and early haze formation and chronic smoking to be positively correlated with vascular endothelial growth factor production and delayed reepithelialization. It is important to determine whether the patient was exposed to cigarette smoke during the healing process. A study of mice3 found cigarette smoking was associated with defective formation of the fibronectin layer in the wounded area and with accumulation of neutrophils in the stroma beneath the deepithelialized area. Fibronectin is an extracellular matrix (ECM) molecule that is critical for epithelial cell migration and the formation of the epithelial basement membrane; thus, this impairment is related to delayed corneal epithelial healing. Also, anther study4 elucidated the role of the generation of corneal myofibroblasts in the development of haze after surgery or other types of injury and the importance of the basement membrane, which functions as a barrier between the epithelium and stroma and modulates the cytokines that promote and maintain myofibroblasts (eg, TGF- b1, platelet-derived growth factor, interleukin-1). Thus, although functional defects in basement membrane formation lead to prolonged elevation of cytokine levels in the stroma necessary to promote differentiation of myofibroblasts, repair of the epithelial basement membrane determines elimination of myofibroblasts so that repopulating keratocytes subsequently reorganize ECM to reestablish transparency.5 There is no mention of whether MMC was used. Although MMC has been associated with slightly longer epithelial healing,6 it has been associated with a lower risk for corneal haze.7,8 Postoperatively, a bandage contact lens was applied and the patient received topical fluorometholone and ketorolac tromethamine 0.4%. Ketorolac, like most topical NSAIDs, has been associated with corneal wound-healing problems and melting.9 Once delayed epithelial healing is noticed, the proper management is to discontinue NSAIDs and reduce the steroid dosage. Although topical corticosteroids may delay epithelial healing, they are important to suppress stromal scarring and fibrosis and should usually be continued. Along with preservative-free artificial tears with hyaluronate, which have a positive impact on corneal epithelial healing,10 I would consider autologous serum in such cases.11,12 Considering the presentation of the case, I would like to have total wavefront data and a proper assessment of the ocular surface. Considering the natural history of corneal haze, I would not consider surgical treatment. Therapeutic ablation would be an option at least 1 year after the first procedure.13 I would recommend omega-3 essential fatty acid supplementation along
J CATARACT REFRACT SURG - VOL 40, MARCH 2014
CONSULTATION SECTION
with vitamin C, preservative-free artificial tears, and possibly topical cyclosporine A and inferior punctual plug occlusion.14 For the fellow eye, I would recommend femtosecond laser–assisted custom LASIK. Renato Ambr osio Jr, MD, PhD Rio de Janeiro, Brazil
REFERENCES 1. Salomao MQ, Wilson SE. Corneal molecular and cellular biology update for the refractive surgeon. J Refract Surg 2009; 25: 459–466 2. Roszkowska AM, De Grazia L, Visalli M, Mondello M, Teti D, Venza M, Venza I. Contact lens wearing and chronic cigarette smoking positively correlate with TGF-b1 and VEGF tear levels and impaired corneal wound healing after photorefractive keratectomy. Curr Eye Res 2013; 38:335–341 3. Ma C, Martins-Green M. Second-hand cigarette smoke inhibits wound healing of the cornea by stimulating inflammation that delays corneal reepithelialization. Wound Repair Regen 2009; 17:387–396 4. Mohan RR, Hutcheon AEK, Choi R, Hong JW, Lee JS, sio R Jr, Zieske JD, Wilson SE. Apoptosis, Mohan RR, Ambro necrosis, proliferation, and myofibroblast generation in the stroma following LASIK and PRK. Exp Eye Res 2003; 76:71–87 5. Wilson SE. Corneal myofibroblast biology and pathobiology: generation, persistence, and transparency. Exp Eye Res 2012; 99:78–88 6. Kremer I, Ehrenberg M, Levinger S. Delayed epithelial healing following photorefractive keratectomy with mitomycin C treatment. Acta Ophthalmol 2012; 90:271–276. Available at: http:// onlinelibrary.wiley.com/doi/10.1111/j.1755-3768.2010.01894. x/pdf. Accessed December 10, 2013 sio R Jr, Chalita MR, Krueger RR, Wilson SE. 7. Netto MV, Ambro Resposta cicatricial corneana em diferentes modalidades de cirurgia refrativa. [Corneal wound healing response following different modalities of refractive surgical procedures]. Arq Bras Ophthalmol 2005; 68:140–149. Available at: http://www.scielo. br/pdf/abo/v68n1/23276.pdf. Accessed December 10, 2013 8. Santhiago MR, Netto MV, Wilson SE. Mitomycin C: biological effects and use in refractive surgery. Cornea 2012; 31:311–321 9. Khalifa YM, Mifflin MD. Keratitis and corneal melt with ketorolac tromethamine after conductive keratoplasty. Cornea 2011; 30:477–478 10. Gomes JAP, Amankwah R, Powell-Richards A, Dua HS. Sodium hyaluronate (hyaluronic acid) promotes migration of human corneal epithelial cells in vitro. Br J Ophthalmol 2004; 88:821–825. Available at: http://www.ncbi.nlm.nih.gov/pmc/ articles/PMC1772195/pdf/bjo08800821.pdf. Accessed December 10, 2013
507
11. Chen Y-M, Hu F-R, Huang J-Y, Shen EP, Tsai T-Y, Chen W-L. The effect of topical autologous serum on graft re-epithelialization after penetrating keratoplasty. Am J Ophthalmol 2010; 150:352–359 12. Das S, Langenbucher A, Seitz B. Delayed healing of corneal epithelium after phototherapeutic keratectomy for lattice dystrophy. Cornea 2005; 24:283–287 sio R Jr, Jardim D, Netto MV, Wilson SE. Management of 13. Ambro unsuccessful LASIK surgery. Compr Ophthalmol Update 2007; 8:125–141; discussion, 143–144 sio R Jr, Tervo T, Wilson SE. LASIK-associated dry eye 14. Ambro and neurotrophic epitheliopathy: pathophysiology and strategies for prevention and treatment. J Refract Surg 2008; 24:396–407
EDITOR’S COMMENTS In general, PRK is a safe procedure for treatment of mild to moderate myopia. However, sporadically problems, such as delayed epithelial healing, may occur that convert a highly successful procedure to a disappointing journey for patient and surgeon. Prevention of complications and case selection appear crucial when performing refractive surgery, and some respondents point to the role of smoking, which may interfere with delayed reepithelialization in surface ablation. Meanwhile, communication with the patient with a postoperative refractive surgery complication is essential, and one of the most difficult tasks for the surgeon is to reestablish the patient–doctor relationship. This is difficult because the perceived loss of quality of vision warrants immediate action from the perspective of the patient even when a more conservative approach may be preferable. As the majority of reviewers point out, it is worthwhile to give corneal wound-healing modulation a chance for at least a year before additional surgical interventions (eg, PTK) are proposed to the patient with delayed reepithelialization in surface ablation.
J CATARACT REFRACT SURG - VOL 40, MARCH 2014
Rudy Nuijts, MD, PhD Maastricht, Netherlands
