Farhad Hafezi

Corneal collagen crosslinking with riboflavin and ultraviolet A to treat induced keratectasia after laser in situ keratomileusis

PURPOSE: To determine whether riboflavin and ultraviolet‐A (UVA) corneal crosslinking can be used as an alternative therapy to prevent the progression of keratectasia. SETTING: Institute for Refractive and Ophthalmic Surgery, Zurich, Switzerland, and a private clinic, Athens, Greece. METHODS: Corneal crosslinking was performed in 10 patients with formerly undiagnosed forme fruste keratoconus or pellucid marginal corneal degeneration who had laser in situ keratomileusis (LASIK) for myopic astigmatism and subsequently developed iatrogenic keratectasia. Surgery was performed in 1 eye per patient. RESULTS: Crosslinking induced by riboflavin and UVA arrested and/or partially reversed keratectasia over a postoperative follow‐up of up to 25 months as demonstrated by preoperative and postoperative corneal topography and a reduction in maximum keratometric readings. CONCLUSION: Riboflavin–UVA corneal crosslinking increased the biomechanical stability of the cornea and may thus be a therapeutic means to arrest and partially reverse the progression of LASIK‐induced iatrogenic keratectasia.

Corneal cross-linking-induced stromal demarcation line.

Purpose: Corneal collagen cross-linking by UVA/riboflavin (X-linking) represents a new method for the treatment of progressive keratoconus and currently is under clinical study. To avoid UVA irradiation damage to the corneal endothelium, the parameters for X-linking are set in a way that effective treatment occurs only in the first 300 μm of the corneal stroma. Here, X-linking not only strengthens the biomechanical properties of the cornea but also induces keratocyte apoptosis. To date, the effectiveness of treatment could be monitored only indirectly by postoperative follow-up corneal topographies or using corneal confocal microscopy. Here we describe a corneal stromal demarcation line indicating the transition zone between cross-linked anterior corneal stroma and untreated posterior corneal stroma. The demarcation line is biomicroscopically detectable in slit-lamp examination as early as 2 weeks after treatment. Methods: X-linking was performed in 16 cases of progressive keratoconus, and corneas were examined biomicroscopically and by means of corneal topography and pachymetry before and after treatment. Results: In 14 of 16 cases, a thin stromal demarcation line was visible at a depth of approximately 300 μm over the whole cornea after X-linking treatment. Conclusion: This newly observed demarcation line may result from differences in the refractive index and/or reflection properties of untreated versus X-linked corneal stroma and represents an effective tool to biomicroscopically easily monitor the depth of effective X-linking treatment in keratoconus.

Collagen crosslinking with ultraviolet-A and hypoosmolar riboflavin solution in thin corneas

&NA; Corneal collagen crosslinking (CXL) with riboflavin and ultraviolet‐A light is a method for treating progressive keratectasia. The currently accepted treatment parameters induce collagen crosslinking in the anterior 250 to 350 μm of corneal stroma. To protect the endothelium, CXL inclusion criteria require a minimum corneal thickness of 400 μm after removal of the epithelium. In advanced keratoconus, however, progressive corneal thinning often leads to a remaining stromal thickness of less than 400 μm. We have therefore modified the current treatment protocol by preoperatively swelling thin corneas to a stromal thickness of at least 400 μm using hypoosmolar riboflavin solution. This treatment protocol was performed in a case series of 20 patients, and no complications were observed. Preoperative swelling of the cornea safely broadens the spectrum of CXL indications to thin corneas that would otherwise not be eligible for treatment.

Apoptotic cell death in retinal degenerations.

Apoptosis is a regulated mode of single cell death that involves gene expression in many instances and occurs under physiological and pathological conditions in a large variety of systems. We briefly summarize major features of apoptosis in general and describe the occurrence of apoptosis in the retina in different situations that comprise animal models of retinitis pigmentosa, light-induced lesions, histogenesis during development, and others. Apoptosis can be separated into several phases: the induction by a multitude of stimuli, the effector phase in which the apoptotic signal is transmitted to the cellular death machinery, the excecution period when proteolytic cascades are activated, and the phagocytic removal of cellular remnants. Control mechanisms for retinal apoptosis are only beginning to be clarified. Potential apoptotic signal transducers were investigated in our laboratory, including metabolites of arachidonic acid and downstream mediators of signaling molecules such as transcription factors. Work in our laboratory revealed an essential role of the immediate-early gene product c-Fos in light-induced apoptosis. c-Fos is a member of the AP-1 family of transcription factors and, together with other members of this family, it may regulate apoptosis in the central nervous system. Expression of the c-fos gene in the retina can be evoked by light exposure and follows a diurnal rhythm. Future studies will have to clarify how light can control the expression of specific genes, and specifically, the role of c-fos and other genes of retinal apoptosis including potential target genes and signaling pathways.

Protection of Rpe65-deficient mice identifies rhodopsin as a mediator of light-induced retinal degeneration

Light-induced apoptosis of photoreceptors represents an animal model for retinal degeneration. Major human diseases that affect vision, such as age-related macular degeneration (AMD) and some forms of retinitis pigmentosa (RP), may be promoted by light. The receptor mediating light damage, however, has not yet been conclusively identified; candidate molecules include prostaglandin synthase, cytochrome oxidase, rhodopsin, and opsins of the cones and the retinal pigment epithelium (PE). We exposed to bright light two groups of genetically altered mice that lack the visual pigment rhodopsin (Rpe65−/− and Rho−/−). The gene Rpe65 is specifically expressed in the PE and essential for the re-isomerization of all-trans retinol in the visual cycle and thus for the regeneration of rhodopsin after bleaching. Rho−/− mice do not express the apoprotein opsin in photoreceptors, which, consequently, do not contain rhodopsin. We show that photoreceptors lacking rhodopsin in these mice are completely protected against light-induced apoptosis. The transcription factor AP-1, a central element in the apoptotic response to light, is not activated in the absence of rhodopsin, indicating that rhodopsin is essential for the generation or transduction of the intracellular death signal induced by light.

Ultraviolet A/riboflavin corneal cross-linking for infectious keratitis associated with corneal melts.

Purpose: To evaluate the efficacy of ultraviolet-corneal cross-linking (CXL) for treating infectious melting keratitis. Methods: Five patients with infectious keratitis associated with corneal melting were treated with CXL at the outpatient departments of the Institut für Refraktive und Ophthalmo-Chirurgie and the eye hospital at the University of Zurich. CXL was performed when the infection did not respond to systemic and topical antibiotic therapy. Follow-up after cross-linking ranged from 1 to 9 months. Results: In all cases, the progression of corneal melting was halted after CXL treatment. Emergency keratoplasty was not necessary in any of the 5 cases presented. Conclusions: CXL is a promising option for treating patients with therapy-refractory infectious keratitis to avoid emergency keratoplasty.

Contralateral eye study of corneal collagen cross-linking with riboflavin and UVA irradiation in patients with keratoconus

PURPOSE To assess the progression of keratoconus in patients treated with collagen cross-linking with riboflavin and ultraviolet A (UVA) irradiation. METHODS Thirty-eight eyes of 19 patients with progressive keratoconus were enrolled in a prospective comparative study. Average follow-up was 9 +/- 2 months (range: 5 to 12 months). The worse eye was treated with collagen cross-linking, and the fellow eye served as the control. Corneal epithelium was mechanically removed. Riboflavin 0.1% solution in dextran T-500 20% solution was applied every 2 to 3 minutes for 30 minutes throughout the irradiation. Ultraviolet A irradiation (370 nm) was performed using a commercially available UVA lamp for 30 minutes. RESULTS The group treated with collagen crosslinking demonstrated a mean decrease (less myopic) in spherical equivalent refraction and cylinder of 1.03 +/- 2.22 diopters (D) (range: -5.25 to +3.75 D) and 1.04 +/- 1.44 D (range: -2.00 to +4.00 D), respectively (P < .01), and an increase in uncorrected visual acuity (UCVA) and best spectacle-corrected visual acuity (BSCVA) of 0.06 +/- 0.05 (range: 0.00 to 0.20) and 0.10 +/- 0.14 (range: -0.10 to 0.34), respectively (P < .01). The maximal curvature decreased by 1.57 +/- 1.14 D (range: 0.00 to 3.90 D), and intraocular pressure increased by 2 +/- 2 mmHg (range: -1 to 6 mmHg), which was statistically significant. No statistical difference was noted regarding central corneal thickness (P = .06) and endothelial cell count (P = .07). The untreated group showed no statistical difference for any of the clinical parameters, apart from UCVA and BSCVA, which decreased by 0.08 +/- 0.12 (range: -0.40 to 0.10) and 0.06 +/- 0.09 (range: -0.20 to 0.10), respectively (P < .01). CONCLUSIONS Riboflavin/UVA collagen cross-linking appears to be efficacious in inhibiting the progression of keratoconus by reducing the corneal curvature, spherical equivalent refraction, and refractive cylinder in eyes with progressive keratoconus at average 9-month follow-up.

Scheimpflug imaging of corneas after collagen cross-linking.

Purpose: To compare geometrical shape factors of keratoconus corneas after cross-linking (CXL) by means of Scheimpflug imaging with those of untreated fellow eyes. Setting: Institut für Refraktive und Ophthalmo-Chirurgie, Zürich, Switzerland. Methods: Scheimpflug imaging of the anterior segments was performed with the Pentacam (Oculus, Wetzlar, Germany) in 21 patients with progressive keratectasia before and after CXL. Only 1 eye per patient was treated with corneal cross-linking using the riboflavin/UV-A approach, the fellow eye serving as control. The following corneal parameters and their postoperative evolution during 1 year after treatment have been evaluated: minimal curvature radius and its location, thickness at the thinnest point, location of the thinnest point, anterior and posterior elevation, conoid asphericity constants of the anterior and posterior surface, and 7 keratoconus indices. Statistical comparison was performed by means of the Wilcoxon test. Results: None of the treated eyes showed topographic progression in contrast to the untreated group where 8 eyes experienced significant progression. Minimal curvature radius increased significantly after 1 year compared with preoperative (6.14-6.21 mm), whereas in the untreated fellow eye, it significantly decreased (6.94-6.86 mm). Minimal corneal thickness was significantly reduced after treatment (P < 0.002 at 12 months). The cornea showed an evolution toward a more regular shape as indicated by a significant reduction in 4 of 7 keratoconus indices. No complications of CXL occurred in this small study group. Conclusions: After cross-linking, the corneal shape undergoes a process of regularization. This process is active during the first year after treatment and may continue. Longer follow-up is warranted to estimate the full amount of regression of the keratectasia after CXL.

Q-factor customized ablation profile for the correction of myopic astigmatism

PURPOSE: To compare the results of the Q‐factor customized aspheric ablation profile with the wavefront‐guided customized ablation pattern for the correction of myopic astigmatism. SETTING: Institute for Refractive and Ophthalmic Surgery, Zurich, Switzerland. METHODS: Thirty‐five patients were enrolled in a controlled study in which the nondominant eye was treated with the Q‐factor customized profile (custom‐Q study group) and the dominant eye was treated with wavefront‐guided customized ablation (control group). Preoperative and 1‐month postoperative high‐contrast visual acuity, low‐contrast visual acuity, and glare visual acuity, as well as aberrometry and asphericity of the cornea, were compared between the 2 groups. All eyes received laser in situ keratomileusis surgery, and the laser treatment was accomplished with the Wavelight Eye‐Q 400 Hz excimer laser. RESULTS: For corrections up to −9 diopters (D) of myopia, there were no statistically significant differences between the 2 groups regarding any visual or optical parameter except coma‐like aberrations (3rd Zernike order), where the wavefront‐guided group was significantly better 1 month after surgery (P = .002). For corrections up to −5 D (spherical equivalent), the Q‐factor optimized treated eyes had a significantly smaller shift toward oblate cornea: ΔQ15 = 0.25 in Q‐factor customized versus ΔQ15 = 0.38 in wavefront‐guided treatment (P = .04). CONCLUSIONS: Regarding safety and refractive efficacy, custom‐Q ablation profiles were clinically equivalent to wavefront‐guided profiles in corrections of myopia up to –9 D and astigmatism up to 2.5 D. Corneal asphericity was less impaired by the custom‐Q treatment up to −5 D of myopia.

Effect of treatment sequence in combined intrastromal corneal rings and corneal collagen crosslinking for keratoconus.

PURPOSE: To compare 2 sequences of combined intrastromal corneal ring segment (ICRS) implantation and ultraviolet/riboflavin–mediated corneal collagen crosslinking (CXL) in progressive keratoconus. SETTING: Dunya Eye Hospital, Istanbul, Turkey. METHODS: In this prospective comparative randomized consecutive study, CXL was followed by ICRS implantation (Group 1) or ICRS implantation was followed by CXL (Group 2). Uncorrected (UDVA) and corrected (CDVA) distance visual acuities, spherical equivalent (SE), manifest cylinder (cylinder), and mean keratometry (K) were compared preoperatively and postoperatively. RESULTS: The mean interval between treatments was 7 months ± 2 (SD) (mean follow‐up, 13 ± 1 months). The mean UDVA and CDVA improved in both groups (UDVA: 0.07 ± 0.09 to 0.25 ± 0.12, Group 1, and 0.11 ± 0.09 to 0.32 ± 0.21, Group 2; CDVA: 0.24 ± 0.11 to 0.41 ± 0.20 and 0.22 ± 0.16 to 0.55 ± 0.2, respectively). The mean SE, cylinder, and mean K values decreased in both groups (SE: −7.13 ± 3.34 D to −2.98 ± 2.33 D, Group 1, and −7.05 ± 5.54 D to −2.81 ± 4.08 D, Group 2; cylinder: −4.38 ± 2.03 D to −2.62 ± 1.93 D and −4.68 ± 2.60 D to −2.20 ± 1.67 D, respectively; mean K: 52.47 ± 4.01 D to 48.31 ± 3.65 D and 52.06 ± 4.93 D to 48.08 ± 4.13 D, respectively). Overall, there was more improvement in CDVA, SE, and mean K in Group 2 than in Group 1. CONCLUSION: Implantation of ICRS followed by CXL resulted in greater improvement of keratoconus.