Virgilio Galvis

Keratoconus: an inflammatory disorder?

Keratoconus has been classically defined as a progressive, non-inflammatory condition, which produces a thinning and steepening of the cornea. Its pathophysiological mechanisms have been investigated for a long time. Both genetic and environmental factors have been associated with the disease. Recent studies have shown a significant role of proteolytic enzymes, cytokines, and free radicals; therefore, although keratoconus does not meet all the classic criteria for an inflammatory disease, the lack of inflammation has been questioned. The majority of studies in the tears of patients with keratoconus have found increased levels of interleukin-6 (IL-6), tumor necrosis factor-α(TNF-α), and matrix metalloproteinase (MMP)-9. Eye rubbing, a proven risk factor for keratoconus, has been also shown recently to increase the tear levels of MMP-13, IL-6, and TNF-α. In the tear fluid of patients with ocular rosacea, IL-1α and MMP-9 have been reported to be significantly elevated, and cases of inferior corneal thinning, resembling keratoconus, have been reported. We performed a literature review of published biochemical changes in keratoconus that would support that this could be, at least in part, an inflammatory condition.

Laser in situ keratomileusis to correct post-keratoplasty astigmatism: 1-step versus 2-step procedure☆☆☆

Purpose: To investigate the correction of post‐penetrating keratoplasty (PKP) astigmatism using laser in situ keratomileusis (LASIK). Visual and refractive outcomes were evaluated after LASIK was performed in 1 step (lamellar cut and ablation in 1 procedure) or 2 steps (lamellar cut then ablation in 2 successive procedures). Setting: Department of Cornea and Refractive Surgery, Vissum–Instituto Oftalmológico de Alicante, University of Miguel Hernández, Alicante, Spain. Methods: In this prospective observational study, 22 consecutive eyes were divided into 2 groups depending on the LASIK procedure performed to correct post‐PKP astigmatism. Group 1 (1‐step LASIK) included 11 eyes and Group 2 (2‐step LASIK), 11 eyes. The patients were followed for 6 months. Results: A statistically significant improvement was obtained in Group 2 with a mean vector analysis result of the cylinder of –4.37 diopters (D) ± 1.79 (SD) (P = .018). In Group 1, the mean astigmatism correction was 2.38 ± 1.71 D. The number of reoperations and residual refractive defects were significantly better in Group 2. Conclusion: The 2‐step technique improved the accuracy of excimer laser correction of post‐PKP astigmatism.

Penetration of topically administered prednisolone acetate into the human aqueous humor.

A single standardized drop of 1.0% prednisolone acetate labeled with tritiated thymidine was administered topically to one eye of 58 patients shortly before elective cataract extraction. An aqueous humor sample was aspirated at varying intervals and its corticosteroid content was determined. Peak drug concentration in aqueous humor was 1.13 mug/ml, which occurred 30 to 45 minutes after instillation of the medication. Substantial quantitites of corticosteroid were found in the aqueous humor five minutes after drug administration. The area under the drug concentration in aqueous humor-vs-time curve (a measure of the drugs bioavailability in aqueous humor) was 88 mug min/ml, and its half-life in human aqueous humor was 28 minutes. None of these values were significantly different from the comparable values in rabbit eyes.

Cohort Study of Intracameral Moxifloxacin in Postoperative Endophthalmitis Prophylaxis

We conducted a cohort study to evaluate post-cataract surgery endophthalmitis rates in relation to prophylactic intracameral moxifloxacin administration. A total of 2332 patients (2674 eyes) who underwent phacoemulsification by a single surgeon from January 2007 through December 2012 were included in the study. A total of 1056 eyes did not receive intracameral prophylactic moxifloxacin and the antibiotic was injected in 1618 eyes. The incidence of presumed postoperative endophthalmitis in the 2 groups was calculated. The rate of presumed infectious endophthalmitis after cataract surgery between January 2007 and June 2009 (without intracameral moxifloxacin) was 0.094%. The rate in the second period, from July 2009 to December 2012 (with prophylactic intracameral moxifloxacin), was 0%. In our patients, a decline in the incidence of presumed infectious postoperative endophthalmitis appeared to be associated with the application of intracameral moxifloxacin.

Corneal Transplantation at an Ophthalmological Referral Center in Colombia: Indications and Techniques (2004-2011)

Purpose: To analize changing trends in indications and surgical techniques of corneal transplantation at an ophthalmological tertiary referral center in Colombia over a 7 year period. Methods: A retrospective analysis was performed of medical records from patients who underwent corneal transplantation surgeries at Fundación Oftalmológica de Santander (FOSCAL) in Bucaramanga, Colombia, between August 2004 and August 2011. Results: During this period from a total of 450 corneal transplants performed, we had access to 402 medical records (89.4%). The patients’ mean age was 55. Leading indications were: pseudophakic/aphakic bullous kerathopathy (PBK/ABK) (34.6%), corneal scar (15.7%), active infectious keratitis (14.4%) and keratoconus (12.7%). During the first period (2004-2007) PBK/ABK was the leading indication, followed by stromal opacities and keratoconus. During the second period (2008-2011) PBK/ABK remained the leading indication. Infectious keratitis, however, became the second most common indication. Stromal opacities and keratoconus, moved to third and fourth, respectively. All transplants performed in the first period (2004-2007) were penetrating keratoplasties. In the second period (2008-2011) 18.7% of the procedures were performed using the Descemet’s stripping automated endothelial keratoplasty technique (DSAEK). Conclusions: Similar to other international results, PBK/ABK was the leading indication for corneal transplantation at our institution. Keratoconus is becoming a less common indication for keratoplasty in our institution. Infectious keratitis remains a frequent indication for corneal transplantation in this geographical area. In our institution we started performing DSAEK in 2009, and it is emerging as the procedure of choice in corneal diseases that involve only the endothelial layers.

Human corneal endothelium regeneration: effect of ROCK inhibitor.

We read with great interest the article by Okumura et al., in the April 2013 issue, on Rho-associated protein kinase (ROCK)inhibitor eye drops’ effect on corneal endothelium. As clinicians, knowing only some very basic concepts of molecular biology and regenerative medical procedures, but very interested in the field of human corneal endothelial regeneration, we dare to make some comments. During the last 17 years, in many articles, the group headed by Joyce at Schepens Eye Research Institute has identified various mechanisms causing in vivo human corneal endothelial cells to be arrested in G1-phase of the cell cycle: cell–cell contact inhibition (possibly mediated by the cyclin-dependent kinase inhibitor p27Kip1); deficiency or absence of positive growth factor stimulation; age-related increased expression of G1-phase inhibitors (cyclin-dependent kinase inhibitor p21Cip1, and p16INK4a) that lastly leads the cells to stressinduced premature senescence; and finally, the presence of transforming growth factor-b 2 (TGF-b 2) that suppresses Sphase entry (possibly involving its effects on p27Kip1 and prostaglandin E2 levels). However, evidence of mitosis in humans in vivo has been reported since 1982. Treffers studied it in two patients: a wound was created by a central transcorneal freeze, and after removing the cornea from the enucleated eye, using tritiated thymidine showed evidence of both migration and proliferation of endothelial corneal cells. Studies from more than a decade ago by Wollensak and Green and, more recently, works by Lagali et al. have shown that, in corneal grafts, a partial or total replacement of the donor endothelial corneal cells by recipient endothelium frequently occurs, proving the ability of peripheral recipient endothelial cells to migrate to the central cornea. Although a complete donor cell replacement in the graft by the recipient’s endothelial cells is possible without needing cell proliferation (leading to a reduction of the cell density by approximately 50%), in vivo mitotic division, in addition to migration, might contribute to the repopulation of graft endothelium in those cases, as suggested by both groups of authors. We also suggested that in vivo corneal endothelial cell proliferation might have been a factor in spontaneous repopulation of the posterior bare stroma with endothelial cells in both eyes of a patient who underwent Descemet’s stripping without endothelial replacement, reported by Shah et al. In that patient, the right eye underwent Descemet’s stripping endothelial keratoplasty and had graft failure. Later a regraft was performed, but the second posterior corneal lenticule detached. Surgeons decided to remove the donor tissue, but it was not replaced. Finally, the cornea gained transparency, and the patient reached a corrected visual acuity of 20/20. That eye’s confocal microscopy image prior to the original surgery showed a very irregular endothelial mosaic pattern with apparently lower cell density than shown in final postoperative images after removing the donor lenticule, which, in our opinion, favors cellular replication in addition to migration. We think descemetorhexis played a role in releasing contact inhibition at least in a group of recipient endothelial cells. Studies by Whikehart et al. and McGowan and coauthors, which reported telomerase activity at the peripheral endothelium in unwounded human tissues and specific stem cell markers in the trabecular meshwork and the transition zone between the trabecular meshwork and the outer edge of the corneal endothelium, suggest that endothelial stem cells reside in the posterior human limbus and respond to corneal wounding by initiating an endothelial repair process, and may also contribute to a normal, slow replacement of corneal endothelial cells. Recently, He et al. published additional evidence that in vivo human corneal endothelial cell proliferation exists. Cell organization in clusters of two or three layers and radial rows in the extreme periphery of human corneas supports the hypothesis that corneal endothelial cells continuously migrate centripetally from peripherally located stem cells. These authors suggest a model of human corneal endothelium homeostasis: in the periphery of the cornea, cells divide very slowly within a renewal zone and then migrate toward the center but probably desquamate, while the density of the central cells remains stable. They suggest that the cell clusters located in the extreme periphery may be stem cell niches or emerging points for progenitors migrating from deeper niches and that the contact with aqueous humor leads the cells to lose their proliferating capacity, but not their migrating potential. Also recently, Hirata-Tominaga and coauthors (including several of the authors of the article published in the April 2013 issue of IOVS, which is the motive of this letter) found that leucine-rich repeat-containing G-protein– coupled receptor 5 (LGR5), reportedly a marker of multiple tissue stem cells in mice, is expressed in the peripheral region of human corneal endothelial cells and that those LGR5(þ) cells show some stem/progenitor cell characteristics. The presence of stem cells supports the hypothesis about the in vivo proliferative activity of human corneal endothelial cells. Okumura et al., in the present study in both a corneal endothelial dysfunction primate model and a human clinical case series of corneal endothelial dysfunction, used a model injuring endothelial cells by transcorneal freezing. Primary effects of that procedure were lysis of the cells affected by the freezing and the release of contact inhibition of at least a fraction of the remaining cells. In the primate model, noncontact specular microscopy revealed that corneal endothelial cell density was significantly higher in the ROCK inhibitor (Y-27632) group compared with the controls at 4 weeks (3000 cells/mm vs. 1500 cells/mm), which suggested a positive effect of the substance. Although the authors did not verify that the treatment did not alter the karyotype of endothelial cells, by evaluating the frequency of cells having an abnormal chromosome number (i.e., aneuploid), they determined histologic phenotypes in the primate corneal endothelial wound model, and they found that the percentages of tight junction protein ZO-1 and Naþ/KþATPase–positive cells in the central area were significantly higher in the ROCK-inhibitor treated eyes than those in the control eyes, suggesting that the intervention rapidly enhances functional recovery as well as morphologic recovery. In the series of patients, however, results were less definitive. A point to bear in mind is that pachymetry measurements made with various techniques have a range of intra-individual variability, which should be considered when analyzing changes in corneal thickness. It is also important to know exactly which measurement technique was used, since some techniques, such as ultrasound pachymetry, have proven to be more operator dependent (by the difference in the exact location of the probe and the corneal indentation caused by examiner when applying the probe). The patient in case 2 underwent Descemet’s stripping automated endothelial keratoplasty apparently before the 6-month follow-up, and data of pachymetry or visual acuity before the corneal graft are not

Artisan Aphakic Lens for Cataract Surgery in Anterior Megalophthalmos

A 44-year-old man with anterior megalophthalmos arrived at the clinic presenting a cataract in the right eye. The corneal diameter was 13 mm. Iridodonesis and phacodonesis were evident during slit lamp examination. Anterior chamber depth was 5.89 mm, and the diameter of the capsular bag was approximately 14.45 mm. Due to the large capsular bag, a standard posterior chamber intraocular lens was considered inadequate because of potential instability. Phacoemulsification and an implantation of an iris-claw lens (Artisan for aphakia®, Ophtec) in the posterior chamber were performed with good results. In the fourth postoperative month, uncorrected distance visual acuity was 20/30, and 20/20 was achieved with +0.75 –1.25 × 10°. We consider retropupillary aphakic iris-claw intraocular lenses to be a worthwhile option in these cases of megalophthalmos and cataract, since instability is avoided and the procedure is less challenging than suturing the lens.

Post-LASIK edema-induced keratopathy (PLEK), a new name based on pathophysiology of the condition

A 33-year-old man who underwent uneventful laser in situ keratomileusis (LASIK) developed pressure-induced stromal edema resulting in an interface haze in both eyes and a pocket of fluid under the flap of the right eye 10 days after surgery, while receiving topical fluorometholone. Intraocular pressure by applanation tonometry was 16 mm Hg in his right eye (erroneous result due to the fluid in the interface) and 34 mm Hg in his left eye. After discontinuation of steroids and addition of ocular hypotensive medication, interface fluid collection disappeared in his right eye. Visual acuity improved and haze diminished in both eyes. This case illustrates that in the same patient a post-LASIK edema induced syndrome may be present with or without fluid in the interface, suggesting that both clinical pictures could be manifestations of a broad spectrum of the same condition. We suggest a new name for this non-inflammatory disorder: post-LASIK edema-induced keratopathy (PLEK).

Is myopia another clinical manifestation of insulin resistance

Myopia is a multifactorial visual refraction disease, in which the light rays from distant objects are focused in front of retina, causing blurry vision. Myopic eyes are characterized by an increased corneal curvature and/or ocular axial length. The prevalence of myopia has increased in recent decades, a trend that cannot be attributed exclusively to genetic factors. Low and middle income countries have a higher burden of refractive error, which we propose could be a consequence of a shorter exposure time to a westernized lifestyle, a phenomenon that may also explain the rapid increase in cardiometabolic diseases, such as diabetes, among those populations. We suggest that interactions between genetic, epigenetic and a rapidly changing environment are also involved in myopia onset and progression. Furthermore, we discuss several possible mechanisms by which insulin resistance may promote abnormal ocular growth and myopia to support the hypothesis that insulin resistance and hyperinsulinemia are involved in its pathogenesis, providing a link between trends in myopia and those of cardiometabolic diseases. There is evidence that insulin have direct ocular growth promoting effects as well an indirect effect via the induction of insulin-like growth factors leading to decreases insulin-like growth factor-binding protein, also implicated in ocular growth.

Retropupillary iris-claw intraocular lens in aphakic eyes.

Reply : I agree with Dr. Peposes suggestion that this was a study designed to look at the real world performance of accommodating IOLs available and approved for use at the time of the study. Although the refractive target for the Crystalens HD may have been amended to “select the first available plus for the dominant eye and the first available minus for the nondominant eye,” this was not the recommendation at the time of the study. The A constant had been adjusted by the manufacturers as the study was being planned, and the recommendation was to target C0.25 D. Dr. Pepose comments that “despite this 1.0 D advantage for the mini-monovision nonaccommodating monofocal and Tetraflex groups, the mean near visual acuity for the Crystalens HD was 1.5 lines (ie, 7.7 letters) better than the monofocal minimonovision and equivalent to the Tetraflex set for mini-monovision.” He fails to take into account that the CrystalensHDhas a bispheric designwith a central 1.50 mm zone that is 3 mm thicker. This modification of the optic provides an increaseddepth of focus of 1.50D, as stated in the paper. Thus, the Crystalens HD underperforms since it has a 0.50 D advantage, and the near visual performance should be that much better. Dr. Pepose is correct that this study was underpowered todetect a 7.5-letter difference innearvisual acuity, as it was designed to detect a 10-letter difference in acuity. Given the design of the study, no significant difference was found in the performance of the IOLs for near vision. It would be inappropriate to draw conclusions on a difference taken in isolation without considering the standard deviation and without increasing the size of cohorts to possibly detect the lower difference. I look forward to the publication of a controlled prospective comprehensive study incorporating a protocol that evaluates not only the visual performance but also the subjective assessment of accommodating IOLs.dGeorge Beiko, BM, BCh, FRCS