Ablação personalizada guiada por frente de onda após complicação na dissecção lamelar de FemtoLasik / Personalized wavefront-guided ablation after complication in FemtoLasik lamella dissection

RESUMO O FemtoLasik é uma das técnicas mais empregadas em cirurgia refrativa, por seus bons resultados refracionais, sua previsibilidade, sua reprodutibilidade e sua segurança. Tem alto grau de satisfação, com rápida recuperação visual. Apesar de as taxas de complicações do FemtoLasik serem pequenas, intercorrências podem existir. O objetivo deste trabalho foi relatar um caso de uma complicação na dissecção da lamela por Lasik com laser de femtossegundo com consequente rasgadura da lamela, sendo aplicado Excimer Laser com mitomicina C 0,02%. O retratamento foi realizado com ablação de superfície (ceratectomia fotorrefrativa) guiada por frente de onda, evoluindo com boa qualidade visual final.

ABSTRACT Femtolasik is one of the most used techniques in refractive surgery due to good refractive results, predictability, reproducibility, and safety, achieving excellent results and a high degree of satisfaction. Although the complication rates are small, it is worth noting that there may be intercurrences. The objective of this work is to report a case of complication in the dissection of the lamella of laser in situ keratomileusis (Lasik) with Femtosecond laser, and subsequent lamella tear. Excimer Laser was applied with mitomycin 0.02% and re-approached with wavefront guided surgery, evolving with good final visual quality.

Corneal epithelial basement membrane: Structure, function and regeneration.

Basement membranes are highly specialized extracellular matrices. More than providing scaffolds, basement membranes are recognized as dynamic and versatile structures that modulate cellular responses to regulate tissue development, function, and repair. Increasing evidence suggests that, in addition to providing structural support to adjacent cells, basement membranes serve as reservoirs and modulators of growth factors that direct and fine-tune cellular functions. Since the corneal stroma is avascular and has a relatively low keratocyte density, it's likely that the corneal BM is different in composition from the BMs in other tissues. BMs are composed of a diverse assemblage of extracellular molecules, some of which are likely specific to the tissue where they function; but in general they are composed of four primary components-collagens, laminins, heparan sulfate proteoglycans, and nidogens-in addition to other components such as thrombospondin-1, matrilin-2, and matrilin-4 and fibronectin. Severe injuries to the cornea, including infection, surgery, and trauma, may trigger the development of myofibroblasts and fibrosis in the normally transparent connective tissue stroma. Ultrastructural studies have demonstrated that defective epithelial basement membrane (EBM) regeneration after injury to the cornea underlies the development of myofibroblasts from both bone marrow- and keratocyte-derived precursor cells. Defective EBM permits epithelium-derived and tear-derived transforming growth factor beta (TGF-ß), platelet-derived growth factor (PDGF), and possibly other modulators, to penetrate the stroma at sustained levels necessary to drive the development and persistence of vimentin + alpha-smooth muscle actin + desmin+ (V + A + D+) mature myofibroblasts. A recent discovery that has contributed to our understanding of haze development is that keratocytes and corneal fibroblasts produce critical EBM components, such as nidogen-1, nidogen-2 and perlecan, that are essential for complete regeneration of a normal EBM once laminin secreted by epithelial cells self-polymerizes into a nascent EBM. Mature myofibroblasts that become established in the anterior stroma are a barrier to keratocyte/corneal fibroblast contributions to the nascent EBM. These myofibroblasts, and the opacity they produce, often persist for months or years after the injury. Transparency is subsequently restored if the EBM is fully regenerated, myofibroblasts are deprived of TGF-ß and undergo apoptosis, and keratocytes reoccupy the anterior stroma and reabsorb the disordered extracellular matrix.

Opioids for Ocular Pain - A Narrative Review.

BACKGROUND: Refractive surgery is a common procedure, but may be associated with severe post-operative pain. OBJECTIVES: To describe studies addressing the use of opioids for control of pain after ocular surgery, with an emphasis on refractive surgery. STUDY DESIGN: This is a narrative review of relevant articles on the physiology of corneal pain and the use of opioids for its treatment after surgery. SETTING: Single tertiary center. METHODS: A PubMed search was conducted for studies published from January 1985 to May 2015 on the physiopathology of corneal pain and opioid treatment of post-refractive surgical pain. Reviews, meta-analyses, and randomized clinical trials were included. Inclusion criteria focused on photorefractive keratectomy (PRK) and laser in situ keratomileusis (LASIK). RESULTS: Authors found 109 articles through the search strategies. A total of 75 articles were included based on the inclusion criteria. DISCUSSION: Pain after ocular surgery is likely to be a multifactorial phenomenon. A combination of topical and systemic analgesics is used to treat post-operative pain after refractive surgery. Pain may be severe during the first 72 to 96 hours, depending on the surgical procedure. No studies were found that directly analyze the benefits of opioids after PRK, although they are routinely prescribed in some centers. LIMITATIONS: This is a narrative review in contrast to a systematic review and did not include studies indexed in databases other than PubMed. CONCLUSIONS: Although opioids are used for the short-term treatment of post-operative pain in refractive surgery, their benefits and risks should be properly evaluated in randomized clinical trials before their use can be safely advised. KEY WORDS: Photorefractive keratectomy, in situ keratomileusis, pain, analgesia, opioid, codeine, review.

Injury and defective regeneration of the epithelial basement membrane in corneal fibrosis: A paradigm for fibrosis in other organs?

Myofibroblast-mediated fibrosis is important in the pathophysiology of diseases in most organs. The cornea, the transparent anterior wall of the eye that functions to focus light on the retina, is commonly affected by fibrosis and provides an optimal model due to its simplicity and accessibility. Severe injuries to the cornea, including infection, surgery, and trauma, may trigger the development of myofibroblasts and fibrosis in the normally transparent connective tissue stroma. Ultrastructural studies have demonstrated that defective epithelial basement membrane (EBM) regeneration after injury underlies the development of myofibroblasts from both bone marrow- and keratocyte-derived precursor cells in the cornea. Defective EBM permits epithelium-derived transforming growth factor beta, platelet-derived growth factor, and likely other modulators, to penetrate the stroma at sustained levels necessary to drive the development of vimentin+ alpha-smooth muscle actin+ desmin+ (V+A+D+) mature myofibroblasts and promote their persistence. Defective versus normal EBM regeneration likely relates to the severity of the stromal injury and a resulting decrease in fibroblasts (keratocytes) and their contribution of EBM components, including laminin alpha-3 and nidogen-2. Corneal fibrosis may resolve over a period of months to years if the inciting injury is eliminated through keratocyte-facilitated regeneration of normal EBM, ensuing apoptosis of myofibroblasts, and reorganization of disordered extracellular matrix by repopulating keratocytes. We hypothesize the corneal model of fibrosis associated with defective BM regeneration and myofibroblast development after epithelial or parenchymal injury may be a paradigm for the development of fibrosis in other organs where chronic injury or defective BM underlies the pathophysiology of disease.

Regeneration of Defective Epithelial Basement Membrane and Restoration of Corneal Transparency After Photorefractive Keratectomy.

PURPOSE: To study regeneration of the normal ultrastructure of the epithelial basement membrane (EBM) in rabbit corneas that had -9.00 D photorefractive keratectomy (PRK) and developed late haze (fibrosis) with restoration of transparency over 1 to 4 months after surgery and in corneas that had incisional wounds. METHODS: Twenty-four rabbits had one of their eyes included in one of the two procedure groups (-9.00 D PRK or nearly full-thickness incisional wounds), whereas the opposite eyes served as the unwounded control group. All corneas were evaluated with slit-lamp photographs, transmission electron microscopy, and immunohistochemistry for the myofibroblast marker alpha-smooth muscle actin and collagen type III. RESULTS: In the -9.00 D PRK group, corneas at 1 month after surgery had dense corneal haze and no evidence of regenerated EBM ultrastructure. However, by 2 months after surgery small areas of stromal clearing began to appear within the confluent opacity (lacunae), and these corresponded to small islands of normally regenerated EBM detected within a larger area of the excimer laser-ablated zone with no evidence of normal EBM. By 4 months after surgery, the EBM was fully regenerated and the corneal transparency was completely restored in the ablated zone. In the incisional wound group, the two dense, linear corneal opacities were observed at 1 month after surgery and progressively faded by 2 and 3 months after surgery. The EBM ultrastructure was fully regenerated at the site of the incisions, including around epithelial plugs that extended into the stroma, by 1 month after surgery in all eyes. CONCLUSIONS: In the rabbit model, spontaneous resolution of corneal fibrosis (haze) after high correction PRK is triggered by regeneration of EBM with normal ultrastructure in the excimer laser-ablated zone. Conversely, incisional wounds heal in rabbit corneas without the development of myofibroblasts because the EBM regenerates normally by 1 month after surgery. [J Refract Surg. 2017:33(5):337-346.].

EBM regeneration and changes in EBM component mRNA expression in stromal cells after corneal injury.

PURPOSE: To investigate the production of the epithelial basement membrane (EBM) component mRNAs at time points before lamina lucida and lamina densa regeneration in anterior stromal cells after corneal injury that would heal with and without fibrosis. METHODS: Rabbit corneas were removed from 2 to 19 days after -4.5D or -9.0D photorefractive keratectomy (PRK) with the VISX S4 IR laser. Corneas were evaluated with transmission electron microscopy (TEM) for full regeneration of the lamina lucida and the lamina densa. Laser capture microdissection (LCM) based quantitative real-time (RT)-PCR was used to quantitate the expression of mRNAs for laminin α-3 (LAMA3), perlecan, nidogen-1, and nidogen-2 in the anterior stroma. RESULTS: After -4.5D PRK, EBM was found to be fully regenerated at 8 to 10 days after surgery. At 4 days after PRK, the nidogen-2 and LAMA3 mRNAs levels were detected at statistically significantly lower levels in the anterior stroma of the -9.0D PRK corneas (where the EBM would not fully regenerate) compared to the -4.5D PRK corneas (where the EBM was destined to fully regenerate). At 7 days after PRK, nidogen-2 and LAMA3 mRNAs continued to be statistically significantly lower in the anterior stroma of the -9.0D PRK corneas compared to their expression in the anterior stroma of the -4.5D PRK corneas. CONCLUSIONS: Key EBM components LAMA3 and nidogen-2 mRNAs are expressed at higher levels in the anterior stroma during EBM regeneration in the -4.5D PRK corneas where the EBM is destined to fully regenerate and no haze developed compared to the -9.0D PRK corneas where the EBM will not fully regenerate and myofibroblast-related stromal fibrosis (haze) will develop.

Corneal Collagen Cross-linking in Advanced Keratoconus: A 4-Year Follow-up Study.

PURPOSE: To analyze the safety and efficacy of standard corneal collagen cross-linking (CXL) in advanced cases of progressive keratoconus after 4 years of follow-up. METHODS: A retrospective case series of patients with advanced progressive keratoconus (stages 3 and 4 of Amsler-Krumeich classification) underwent standard CXL treatment. The parameters examined were changes in uncorrected visual acuity (UDVA), corrected visual acuity (CDVA), keratometry values (mean, flat, steep, and apical), pachymetry, and endothelial cell count at the baseline and at 12, 24, and 48 months postoperatively. RESULTS: Forty eyes of 40 patients were enrolled in the study. The mean patient age was 22.5 years (range: 15 to 37 years). Both mean UDVA and CDVA remained stable during the time points; no statistically significant change was noted. Although a slight reduction was observed in all keratometric readings, a statistically significant reduction was only reached in the apical keratometry (P = .037) at 4 years after CXL. A significant reduction in the corneal thickness was also found (ultrasonic: 388 ± 49 to 379 ± 48 µm; slit-scanning: 362 ± 48 to 353 ± 51 µm); however, this change was likely not clinically meaningful. Endothelial cell count was not significantly different at the end of the study. Treatment failure or progression was noted in two patients (5%) over the follow-up period. CONCLUSIONS: Standard CXL treatment was safe and able to stabilize both visual acuity and topographic parameters at 4 years of follow-up in eyes with advanced keratoconus. [J Refract Surg. 2016;32(7):459-464.].

Intraocular straylight before and after low myopic photorefractive keratectomy with and without mitomycin C.

PURPOSE: To evaluate ocular straylight before and after photorefractive keratectomy (PRK) for low myopia with and without topical mitomycin (MMC) treatment. METHODS: Patients who underwent PRK for low myopia were enrolled into the study. PRK without MMC was performed in 21 eyes (12 patients), whereas PRK with topical 0.02% MMC was performed in 25 eyes (14 patients). Both groups were treated using the NIDEK EC5000 excimer laser. Measurements were performed using the C-Quant straylight meter preoperatively and at two and four months postoperatively. RESULTS: The mean patient age was 30 ± 4 years, and the mean spherical equivalent refractive error was -2.2 ± 0.75 D. The mean preoperative intraocular straylight values were 1.07 ± 0.10 in the PRK without MMC group and 1.07 ± 0.11 log(s) in the PRK with topical MMC group. At two months after surgery, there was a decrease in mean intraocular straylight values in both groups. However, a significant difference was only reached in the PRK with MMC group [0.98 ± 0.09 log(s), p=0.002] compared with preoperative values, which was likely due to a greater scatter of measurements in the PRK without MMC group [1.03 ± 0.13 log(s), p=0.082]. At four months postoperatively, ocular straylight values were not significantly different compared with those at baseline in either the PRK without MMC group [1.02 ± 0.14 log(s), p=0.26] or in the PRK with topical MMC group [1.02 ± 0.11 log(s), p=0.13]. CONCLUSION: PRK for low myopia decreases ocular straylight, and MMC application further reduces straylight in the early postoperative period. However, ocular straylight values do not significantly differ at four months after surgery compared with those at baseline.

Predictors of Early Postoperative Pain After Photorefractive Keratectomy.

PURPOSE: To compare the profiles of postoperative photorefractive keratectomy (PRK) pain between both eyes under the same conditions and to verify the preoperative predictors of pain such as gender, anxiety, knowledge of the procedure, and spherical equivalent refractive error (SERE). METHODS: This prospective study included 86 eyes of 43 patients with myopia who underwent PRK in both eyes at an interval of 14 days between the procedures. Before surgery, subjects answered the State Anxiety Inventory. After surgery, usual PRK pain treatment was given. Subjects answered the Visual Analog Scale, the Brief Pain Inventory (BPI), and the McGill Pain Questionnaire at 1, 24, 48, 72, and 96 hours after surgery. Pain scores and anxiety were compared between each eye using the Wald test and paired Student t test, respectively. The Wald test was performed for gender and SERE for each eye separately. RESULTS: There were no statistically significant differences between both eyes for all time points regarding the Visual Analog Scale, BPI, and McGill Pain Questionnaire-Pain Rating Index pain scores. Subjects were less anxious on average before the second surgery compared with before the first surgery (P < 0.001); however, it was not related to pain ratings after surgery. Gender did not significantly affect any scale of pain, and the SERE between -3 diopters (D) and -5 D (P = 0.035) revealed effects on the BPI. CONCLUSIONS: The profiles of postoperative pain after PRK were similar between both eyes under the same conditions. In this study, a high SERE was the only predictor for increased pain after PRK.

Intraocular straylight before and after low myopic photorefractive keratectomy with and without mitomycin C / Dispersão de luz intraocular antes e depois da ceratectomia fotorrefrativa para baixa miopia com e sem mitomicina C

ABSTRACT Purpose: To evaluate ocular straylight before and after photorefractive keratectomy (PRK) for low myopia with and without topical mitomycin (MMC) treatment. Methods: Patients who underwent PRK for low myopia were enrolled into the study. PRK without MMC was performed in 21 eyes (12 patients), whereas PRK with topical 0.02% MMC was performed in 25 eyes (14 patients). Both groups were treated using the NIDEK EC5000 excimer laser. Measurements were performed using the C-Quant straylight meter preoperatively and at two and four months postoperatively. Results: The mean patient age was 30 ± 4 years, and the mean spherical equivalent refractive error was -2.2 ± 0.75 D. The mean preoperative intraocular straylight values were 1.07 ± 0.10 in the PRK without MMC group and 1.07 ± 0.11 log(s) in the PRK with topical MMC group. At two months after surgery, there was a decrease in mean intraocular straylight values in both groups. However, a significant difference was only reached in the PRK with MMC group [0.98 ± 0.09 log(s), p=0.002] compared with preoperative values, which was likely due to a greater scatter of measurements in the PRK without MMC group [1.03 ± 0.13 log(s), p=0.082]. At four months postoperatively, ocular straylight values were not significantly different compared with those at baseline in either the PRK without MMC group [1.02 ± 0.14 log(s), p=0.26] or in the PRK with topical MMC group [1.02 ± 0.11 log(s), p=0.13]. Conclusion: PRK for low myopia decreases ocular straylight, and MMC application further reduces straylight in the early postoperative period. However, ocular straylight values do not significantly differ at four months after surgery compared with those at baseline.

RESUMO Objetivo: Avaliar a dispersão de luz intraocular antes e depois da ceratectomia fotorrefrativa (PRK) para baixa miopia com e sem a aplicação tópica de mitomicina C. Métodos: Pacientes submetidos à PRK para baixa miopia foram selecionados para o estudo. PRK sem MMC foi realizado em 21 olhos (12 pacientes) e PRK com MMC tópica a 0,02% foi realizado em 25 olhos (25 pacientes). Ambos os grupos foram tratados com o excimer laser da Nidek EC5000. Avaliações foram realizadas usando o medidor de dispersão de luz C-Quant no pré-operatório e com 2 e 4 meses de pós-operatório. Resultados: A média de idade dos pacientes foi 30 ± 4 anos e a média do equivalente esférico foi -2,2 ± 0,75 D. As médias da dispersão de luz intraocular no pré-operatório foram 1,07 ± 0,10 no grupo PRK sem MMC e 1,07 ± 0,11 log(s) no grupo PRK com MMC tópica. Após 2 meses da cirurgia houve uma diminuição na média da dispersão de luz intraocular em ambos os grupos. Entretanto uma diferença estatisticamente significante, comparado com os valores pré-operatórios, foi observada apenas no grupo PRK com MMC (0,98 ± 0,09 log(s), p=0,002), provavelmente devido as medidas com maior espalhamento de luz no grupo sem MMC (1,03 ± 0,13 log(s), p=0,082). Após 4 meses de pós-operatório, os valores de dispersão de luz não apresentavam diferença estatisticamente significantes quando comparados com os valores iniciais, tanto no grupo sem MMC (1,02 ± 0,14 log(s), p=0,26) quanto no grupo com MMC tópica (1,02 ± 0,11 log(s), p=0,13). Conclusão: PRK para baixa miopia diminui a dispersão de luz ocular e a aplicação de MMC contribui para uma ainda menor dispersão de luz no período pós-operatório inicial. Entretanto, quatro meses após a cirurgia a dispersão de luz intraocular não é significantemente diferente das medidas pré-operatórias.

Corneal Molecular and Cellular Biology for the Refractive Surgeon: The Critical Role of the Epithelial Basement Membrane.

PURPOSE: To provide an overview of the recent advances concerning the corneal molecular and cellular biology processes involved in the wound healing response after excimer laser surface ablation and LASIK surgery. METHODS: Literature review. RESULTS: The corneal wound healing response is a complex cascade of events that impacts the predictability and stability of keratorefractive surgical procedures such as photorefractive keratectomy and LASIK. The generation and persistence of corneal myofibroblasts (contractile cells with reduced transparency) arise from the interaction of cytokines and growth factors such as transforming growth factor beta and interleukin 1 produced by epithelial and stromal cells in response to the corneal injury. Myofibroblasts, and the opaque extracellular matrix they secrete into the stroma, disturb the precise distribution and spacing of collagen fibers related to corneal transparency and lead to the development of vision-limiting corneal opacity (haze). The intact epithelial basement membrane has a pivotal role as a structure that regulates corneal epithelial-stromal interactions. Thus, defective regeneration of the epithelial basement membrane after surgery, trauma, or infection leads to the development of stromal haze. The apoptotic process following laser stromal ablation, which is proportional to the level of attempted correction, leads to an early decrease in anterior keratocyte density and the diminished contribution of these non-epithelial cells of components such as perlecan and nidogen-2 required for normal regeneration of the epithelial basement membrane. Haze persists until late repair of the defective epithelial basement membrane. CONCLUSIONS: Defective regeneration of the epithelial basement membrane has a critical role in determining whether a cornea heals with late haze after photorefractive keratectomy or with scarring at the flap edge in LASIK.

Femtosecond Laser-Assisted LASIK Flap Complications.

PURPOSE: To discuss intraoperative and postoperative femtosecond laser-assisted LASIK flap complications and their management. METHODS: Review of published literature. RESULTS: Flap creation is a critical step in LASIK. The femtosecond laser has improved the overall predictability and safety of the lamellar incision, but complications can still occur during or after flap creation. Although many complications (eg, epithelial ingrowth and flap striae) were reduced with the femtosecond laser application, other specific complications have emerged, such as vertical gas breakthrough, opaque bubble layer, and transient light-sensitivity syndrome. CONCLUSIONS: The application of femtosecond laser technology to LASIK flap creation has increased greatly since its introduction. These lasers have improved the safety and predictability of the lamellar incision step. The majority of the femtosecond laser-assisted flap complications can be well managed without significant effects on refractive outcomes.

Improved Evaluation of Postoperative Pain After Photorefractive Keratectomy.

PURPOSE: Postoperative pain remains an important limiting factor to the selection of photorefractive keratectomy (PRK). There is a consensus in neurology pain research that pain should be evaluated as a multidimensional concept, which differs from current practice in ophthalmology. The purpose of this paper was to validate the use of multidimensional questionnaires, such as the Brief Pain Inventory (BPI) and the McGill Pain Questionnaire (MPQ), to provide an improved analysis of pain after PRK and to better describe its temporal profile. METHODS: This prospective study included 43 eyes of 43 myopic patients who underwent unilateral PRK. After surgery, usual pain treatment was administered. All of the participants responded to the Visual Analogue Scale (VAS), the BPI and the MPQ 1, 24, 48, 72, and 96 hours after surgery. The internal consistency was evaluated, different postoperative periods were compared, and convergent validity was assessed using correlation testing. RESULTS: The Cronbach alpha test showed high internal consistency for each of the questionnaire subscales. Patients reported higher postoperative pain values at the first measurement of the VAS (4.93 ± 2.38), MPQ-pain rating index (26.95 ± 10.58), BPI-pain severity index (14.53 ± 7.36), and BPI-pain interference index (22.30 ± 15.13). Almost all of the scales and subscales showed a statistically significant direct correlation with the VAS at all of the evaluation periods. CONCLUSIONS: This study validated the utility of multidimensional questionnaires to expand the assessment of the PRK postoperative pain profile, including intensity and other qualitative aspects.

The corneal fibrosis response to epithelial-stromal injury.

The corneal wound healing response, including the development of stromal opacity in some eyes, is a process that often leads to scarring that occurs after injury, surgery or infection to the cornea. Immediately after epithelial and stromal injury, a complex sequence of processes contributes to wound repair and regeneration of normal corneal structure and function. In some corneas, however, often depending on the type and extent of injury, the response may also lead to the development of mature vimentin+ α-smooth muscle actin+ desmin+ myofibroblasts. Myofibroblasts are specialized fibroblastic cells generated in the cornea from keratocyte-derived or bone marrow-derived precursor cells. The disorganized extracellular matrix components secreted by myofibroblasts, in addition to decreased expression of corneal crystallins in these cells, are central biological processes that result in corneal stromal fibrosis associated with opacity or "haze". Several factors are associated with myofibroblast generation and haze development after PRK surgery in rabbits, a reproducible model of scarring, including the amount of tissue ablated, which may relate to the extent of keratocyte apoptosis in the early response to injury, irregularity of stromal surface after surgery, and changes in corneal stromal proteoglycans, but normal regeneration of the epithelial basement membrane (EBM) appears to be a critical factor determining whether a cornea heals with relative transparency or vision-limiting stromal opacity. Structural and functional abnormalities of the regenerated EBM facilitate prolonged entry of epithelium-derived growth factors such as transforming growth factor ß (TGF-ß) and platelet-derived growth factor (PDGF) into the stroma that both drive development of mature myofibroblasts from precursor cells and lead to persistence of the cells in the anterior stroma. A major discovery that has contributed to our understanding of haze development is that keratocytes and corneal fibroblasts produce critical EBM components, such as nidogen-1, nidogen-2 and perlecan, that are essential for complete regeneration of a normal EBM once laminin secreted by epithelial cells self-polymerizes into a nascent EBM. Mature myofibroblasts that become established in the anterior stroma are a barrier to keratocyte/corneal fibroblast contributions to the nascent EBM. These myofibroblasts, and the opacity they produce, often persist for months or years after the injury. Transparency is subsequently restored when the EBM is completely regenerated, myofibroblasts are deprived of TGFß and undergo apoptosis, and the keratocytes re-occupy the anterior stroma and reabsorb disordered extracellular matrix. The aim of this review is to highlight factors involved in the generation of stromal haze and its subsequent removal.

Accelerated Corneal Collagen Cross-linking for Postoperative LASIK Ectasia: Two-Year Outcomes.

PURPOSE: To evaluate the effectiveness and safety of accelerated corneal collagen cross-linking for postoperative LASIK ectasia after 2 years. METHODS: A prospective, single-center case series was performed with patients treated for postoperative LASIK ectasia. All eyes underwent accelerated corneal collagen cross-linking (CCL-Vario Crosslinking; Peschke Meditrade GmbH, Zurich, Switzerland) at 9 mW/cm(2) for 10 minutes. The main outcome measures were changes in uncorrected distance visual acuity, corrected distance visual acuity, central corneal thickness, corneal topography, and endothelial cell density. These parameters were assessed at baseline and at the 6-month and 1- and 2-year follow-up visit. RESULTS: The study enrolled 40 eyes of 24 patients (15 male and 9 female) with a mean age of 33.8 ± 7.5 years (range: 24 to 52 years) that attained at least 2 years of follow-up. The surgical procedure was uneventful in all cases. All eyes stabilized after treatment without any further signs of progression and no statistically significant changes in the mean uncorrected distance visual acuity (P = .649), corrected distance visual acuity (P = .616), mean keratometry (P =.837), steep keratometry (P = .956), ultrasonic pachymetry (P = .135), slit-scanning pachymetry (P = .276), and endothelial cell density (P = .523). In addition, 72.5% of the patients presented stable or gains of Snellen lines over time. CONCLUSIONS: Accelerated corneal collagen cross-linking seems to be safe and effective in halting postoperative LASIK ectasia progression after 2 years of follow-up. However, a longer follow-up period with a larger cohort is needed to validate these findings.

Epithelial basement membrane proteins perlecan and nidogen-2 are up-regulated in stromal cells after epithelial injury in human corneas.

The epithelial basement membrane (BM) is a specialized extracellular matrix that has been shown to have a critical role in corneal development, wound healing, and disease. Although the epithelial BM contributes to corneal homeostasis, relatively little is know about non-epithelial production of its components that may be important in defective regeneration of the epithelial basement membrane associated with opacity after photorefractive keratectomy. The purpose of the current study was to investigate stromal production of corneal epithelial BM proteins in wounded human corneas using immunohistochemistry. A total of five unwounded control eyes and five 30-min epithelial-wounded corneas were obtained from fresh corneoscleral buttons removed from human eyes enucleated due to choroidal melanoma with normal anterior segments. In the wounded corneas, an eight mm patch of central corneal epithelium and epithelial BM was removed with a Beaver blade when the patient was under general anesthesia. Immunohistochemical analyses were performed to detect perlecan and nidogen-2 proteins-important components of the epithelial BM lamina lucida and lamina densa zones. Perlecan and nidogen-2 proteins were detected in the BM itself and at low levels in keratocytes in all unwounded corneas. After epithelial injury, both perlecan and nidogen-2 were expressed at high levels in stromal keratocytes, including superficial keratocytes in the early phases of apoptosis. Thus, after epithelial and epithelial BM injury, stromal keratocytes contribute important perlecan and nidogen-2 components to the regenerating epithelial BM.

Topical cyclosporine a treatment in corneal refractive surgery and patients with dry eye.

PURPOSE: To evaluate preoperative and postoperative dry eye and the effect of cyclosporine A treatment in patients screened for corneal refractive surgery and treated with photorefractive keratectomy (PRK) or LASIK. METHODS: A consecutive case series of 1,056 patients screened for corneal refractive surgery from 2007 to 2012 was retrospectively analyzed. The level of preoperative and postoperative dry eye and the responsiveness to topical cyclosporine A treatment were assessed. RESULTS: One eye of each patient was randomly selected. A total of 642 eyes progressed to surgery: 524 (81.6%) and 118 (18.4%) underwent LASIK and PRK, respectively. Of 81 (7.7%) diagnosed as having dry eye, 55 were deemed potential candidates and optimized for refractive surgery. Thirty-seven patients with moderate dry eye were treated with topical cyclosporine A prior to surgery (mean duration: 3.2 ± 2.1 months; range: 1 to 12 months). After cyclosporine A treatment, 28 (75.7%) eyes underwent LASIK, 4 (10.8%) eyes underwent PRK, and 5 (13.5%) eyes were not operated on due to failed treatment of dry eye. Postoperative refractive surgery-induced neurotrophic epitheliopathy (LINE in LASIK) was noted in 132 (27.3%) and 12 (11.1%) eyes that underwent LASIK and PRK, respectively. Topical cyclosporine A was prescribed in 79 LASIK-induced and 3 PRK-induced dry eyes. After 12 months or more of cyclosporine A treatment, 5 (6.1%) eyes continued to have dry eye symptoms or signs. CONCLUSIONS: Topical cyclosporine A treatment is effective therapy for optimizing patients for refractive surgery and treatment of new onset or worsened dry eye after surgery.

Cellular and extracellular matrix modulation of corneal stromal opacity.

Stromal transparency is a critical factor contributing to normal function of the visual system. Corneal injury, surgery, disease and infection elicit complex wound healing responses that serve to protect against insults and maintain the integrity of the cornea, and subsequently to restore corneal structure and transparency. However, in some cases these processes result in prolonged loss of corneal transparency and resulting diminished vision. Corneal opacity is mediated by the complex actions of many cytokines, growth factors, and chemokines produced by the epithelial cells, stromal cells, bone marrow-derived cells, lacrimal tissues, and nerves. Myofibroblasts, and the disorganized extracellular matrix produced by these cells, are critical determinants of the level and persistence of stromal opacity after corneal injury. Decreases in corneal crystallins in myofibroblasts and corneal fibroblasts contribute to cellular opacity in the stroma. Regeneration of a fully functional epithelial basement membrane (BM) appears to have a critical role in the maintenance of corneal stromal transparency after mild injuries and recovery of transparency when opacity is generated after severe injuries. The epithelial BM likely has a regulatory function whereby it modulates epithelium-derived growth factors such as transforming growth factor (TGF) ß and platelet-derived growth factor (PDGF) that drive the development and persistence of myofibroblasts from precursor cells. The purpose of this article is to review the factors involved in the maintenance of corneal transparency and to highlight the mechanisms involved in the appearance, persistency and regression of corneal opacity after stromal injury.

Screening of refractive surgery candidates for LASIK and PRK.

PURPOSE: The aim of this study was to evaluate exclusion criteria in screening patients for refractive surgery. METHODS: Patients screened for initial refractive surgery by a single surgeon at the Cole Eye Institute (Cleveland Clinic) between 2007 and 2012 were reviewed. Exclusion criteria for patients who were not offered refractive surgery based on history and/or examination parameters were analyzed. RESULTS: A total of 1067 refractive candidates were enrolled in the study. Five hundred nineteen (48.6%) were male and 548 (51.4%) were female with a mean age of 39 ± 12 (range, 17-78) years. Refractive surgery was performed in 657 (61.6%) patients, and photorefractive keratectomy was considered the best option for 106 (9.9%) patients. Four hundred ten (38.4%) of all screened patients did not have refractive surgery, and 134 of these patients (12.6%) were considered to have contraindications for laser in situ keratomileusis and photorefractive keratectomy. Among the excluded patients, 69 (51.5%) were male and 65 (48.5%) were female with a mean age of 40 ± 14 (range, 18-78) years. Abnormal corneal topography (34.3%) and low or insufficient corneal thickness (23.1%) were the most common reasons for exclusion. High myopia (10.5%) and (insipient or definite) cataract (9.7%) were also common reasons for exclusion. Other common factors for exclusion were high hyperopia (3.7%), need to wear reading glasses after surgery (3.7%), and severe dry eye unresponsive to treatment (3.7%). CONCLUSIONS: Abnormal corneal topography and low, or insufficient, corneal thickness remain the most common exclusion factors for corneal refractive surgery. Factors such as cataract, too high of correction, and severe dry eye are also common reasons for exclusion of patients.

TGFß and PDGF-B signaling blockade inhibits myofibroblast development from both bone marrow-derived and keratocyte-derived precursor cells in vivo.

Myofibroblasts, the primary cells associated with corneal stromal haze (opacity), can be derived from both cornea-derived and bone marrow-derived precursor cells. In the present study, the role of TGFß or PDGF blockage on bone marrow-derived myofibroblast development was investigated using a green fluorescent protein (GFP) chimeric bone marrow mouse model and plasmid vectors that blocked TGFß or PDGF signaling. At the peak of corneal haze one month after irregular phototherapeutic keratectomy the central stroma had significantly less alpha-smooth muscle actin (α-SMA)-positive cells derived from GFP+ bone marrow-derived cells or GFP- keratocyte/corneal fibroblast-derived cells when corneas were treated with the TGFß blocking vector pGFPC1.TGFRBKDEL or the PDGF blocking vector pCMV.PDGFRB.23KDEL compared with the corresponding empty vector treated or untreated control groups. In individual animals, 30-60% of myofibroblasts were derived from bone marrow-derived precursor cells and 40-70% of myofibroblasts were derived from keratocyte-derived precursor cells. TGFß and PDGF regulate corneal myofibroblast development from bone marrow-derived precursor cells and keratocyte/corneal fibroblast-derived precursor cells.