A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease

Corneal transplantation for Fuchs´ endothelial dystrophy: A comparison of three surgical techniques concerning 10 year graft survival and visual function.

OBJECTIVE:Comparison of conventional Penetrating Keratoplasty (PKP), posterior mushroom PKP and Descemet's Stripping Automated Endothelial Keratoplasty (DSAEK) regarding overall graft survival of primary corneal transplants for Fuchs´ endothelial dystrophy (FED), best spectacle-corrected visual acuity (BSCVA) and astigmatism. METHODS:Single centre study using prospectively collected data from the national database for follow-up of corneal transplants. Main outcome parameters: 10 years graft survival, astigmatism at 24 months, pre- and post-operative BSCVA. RESULTS:In total, 721 cases were included: PKP, n = 171; posterior mushroom PKP, n = 91; and DSAEK, n = 459. There was no significant difference in graft survival between PKP, posterior mushroom PKP and the DSAEK technique (log-rank test, P = 0.12). The overall post-operative BSCVA improvement in all treatment groups was significant (paired t-test, P<0.001). Pre-operative BSCVA was better for the DSAEK group (0.68 ± 0.41 logMAR) as compared to the PKP (0.89 ± 0.53) and posterior mushroom PKP group (0.90 ± 0.58); ANOVA, P<0.001. After 24 months, BSCVA was significantly better for the DSAEK group (0.25 ± 0.26 logMAR) compared to the PKP (0.35 ± 0.29) and posterior mushroom PKP group (0.41 ± 0.42); ANOVA, P<0.001. A significant difference in astigmatism was found (median test, P<0.001) between the DSAEK (1.7 ± 1.1 D), PKP (4.6 ± 2.7 D) and posterior mushroom PKP group (4.5 ± 3.3 D). The significantly lower DSAEK-induced astigmatism was confirmed by vector analysis. CONCLUSION:There was no difference in graft survival and BSCVA improvement between conventional PKP, inverted mushroom PKP and DSAEK in this study. The significantly lower changes in astigmatism, wound stability and faster visual rehabilitation with DSAEK surgery are favourable aspects of this technique. The benefits of posterior lamellar keratoplasty warrant earlier intervention, which may contribute to preserve better vision for a prolonged period of remaining lifetime

Age-related risk factors, culture outcomes, and prognosis in patients admitted with infectious keratitis to two Dutch tertiary referral centers

PURPOSE: To assess age-related risk factors (RFs), microbiologic profile, and prognosis of infectious keratitis and create guidelines for prevention and treatment. METHODS: Retrospective review of patients with infectious keratitis admitted to 2 Dutch tertiary referral centers from January 2002 to December 2004. RESULTS: Forty-nine patients were admitted to the Academic Medical Center (Amsterdam) and 107 to the Rotterdam Eye Hospital. Mean age was 56.6 +/- 24.4 (SD) years; 49.4% were >or=60 years of age. The most common RFs among the elderly were systemic illness (36.4%), ocular surgery (33.8%), topical steroids (26%), blepharitis (20.8%), and herpetic eye disease (28.6%). This was significantly different from the most common RFs among younger patients (contact lens wear, 62.7%; chi2, P = 0.000). Gram-negative infections predominated (52.3%) and were more prevalent among younger patients (chi2, P = 0.000). Gram-positive infections prevailed among the elderly. Untreated patients had higher culture positive rates (68.7%) than patients treated with antibiotics before culturing (41.3%; chi2, P = 0.001). Elderly patients had a higher risk of perforations than younger patients (27.6% vs. 9.9%), a worse prognosis (mean VA, 6/30 vs. 6/10), and more often needed surgery (57.1% vs. 23.4%; P < 0.005 in all cases). CONCLUSIONS: Infectious keratitis is a more severe disease in elderly than in younger patients with more complications and a worse prognosis. Elderly patients have multiple and more diverse risk factors, making prevention difficult. Prevention should aim at minimizing topical steroid use and controlling blepharitis, ocular surface disease, and herpetic eye disease. Initial antibiotic treatment should include sufficient coverage of Gram-positive pathogen

Prevalence of Myopic Macular Features in Dutch Individuals of European Ancestry with High Myopia

Importance: High myopia incidence and prevalence is increasing worldwide, and the visual burden caused by myopia is expected to rise accordingly. Studies investigating the occurrence of myopic complications in individuals of European ancestry with high myopia are scarce, hampering insights into the frequency of myopic retinal complications in European individuals and their visual burden. Objective: To assess the frequency of myopic macular features in individuals of European ancestry with high myopia. Design, Setting, and Participants: This cross-sectional analysis of the Dutch Myopia Study (MYST) and individuals with high myopia from the Rotterdam Study (RS) included 626 patients with high myopia (spherical equivalent of refractive error [SER] ≤-6 diopters [D] or axial length [AL] ≥26 mm) who underwent an extensive ophthalmic examination including multimodal retinal imaging. In addition to this combination of a population-based cohort study and mix-based high myopia study, a systematic literature review was also performed to compare findings with studies of individuals of Asian ancestry. Exposures: High myopia, age, and AL. Main Outcomes and Measures: Frequency of myopic macular and optic disc features: tessellated fundus, myopic macular degeneration (MMD), staphyloma, peripapillary intrachoroidal cavitation, peripapillary atrophy (PPA), and "plus" lesions (choroidal neovascularization, Fuchs spot, and lacquer cracks). Results: The mean (SD) SER of the combined study population (MYST and RS) was -9.9 (3.2) D; the mean (SD) age was 51.4 (15.1) years, and 387 (61.8%) were women. The prevalence of MMD was 25.9% and increased with older age (P for trend <.001), lower SER (odds ratio [OR], 0.70; 95% CI, 0.65-0.76; P <.001), and higher AL (OR, 2.53; 95% CI, 2.13-3.06; P <.001). Choroidal neovascularization or Fuchs spot was present in 2.7% (n = 17), both lesions in 0.3% (n = 2), and lacquer cracks in 1.4% (n = 9). Staphyloma, PPA, and MMD were highly prevalent in visual impaired and blind eyes (frequency was 73.9% [20 of 27], 90.5% [19 of 21], and 63.0% [17 of 27] of unilateral blind eyes for MMD, staphyloma, and PPA, respectively). Seven previous studies in Asian populations reported a variable MMD frequency ranging from 8.3% to 64%, but frequencies were similar for comparable risk profiles based on age and SER. Conclusions and Relevance: In this cross-sectional study of a highly myopic Dutch population of European ancestry, myopic retinal features were frequent; were associated with age, SER, and AL; and occurred in all visually severely impaired eyes. The absence of treatment options for most of these retinal complications emphasizes the need for effective strategies to prevent high myopia

A machine learning approach to explore predictors of graft detachment following posterior lamellar keratoplasty: a nationwide registry study

Machine learning can be used to explore the complex multifactorial patterns underlying postsurgical graft detachment after endothelial corneal transplantation surgery and to evaluate the marginal effect of various practice pattern modulations. We included all posterior lamellar keratoplasty procedures recorded in the Dutch Cornea Transplant Registry from 2015 through 2018 and collected the center-specific practice patterns using a questionnaire. All available data regarding the donor, recipient, surgery, and practice pattern, were coded into 91 factors that might be associated with the occurrence of a graft detachment. In this research, we used three machine learning methods; a regularized logistic regression (lasso), classification tree analysis (CTA), and random forest classification (RFC), to select the most predictive subset of variables for graft detachment. A total of 3647 transplants were included in our analysis and the overall prevalence of graft detachment was 9.9%. In an independent test set the area under the curve for the lasso, CTA, and RFC was 0.70, 0.65, and 0.72, respectively. Identified risk factors included: a Descemet membrane endothelial keratoplasty procedure, prior graft failure, and the use of sulfur hexafluoride gas. Factors with a reduced risk included: performing combined procedures, using pre-cut donor tissue, and a pre-operative laser iridotomy. These results can help surgeons to review their practice patterns and generate hypotheses for empirical research regarding the origins of graft detachments

A multi-ethnic genome-wide association study implicates collagen matrix integrity and cell differentiation pathways in keratoconus.

Keratoconus is characterised by reduced rigidity of the cornea with distortion and focal thinning that causes blurred vision, however, the pathogenetic mechanisms are unknown. It can lead to severe visual morbidity in children and young adults and is a common indication for corneal transplantation worldwide. Here we report the first large scale genome-wide association study of keratoconus including 4,669 cases and 116,547 controls. We have identified significant association with 36 genomic loci that, for the first time, implicate both dysregulation of corneal collagen matrix integrity and cell differentiation pathways as primary disease-causing mechanisms. The results also suggest pleiotropy, with some disease mechanisms shared with other corneal diseases, such as Fuchs endothelial corneal dystrophy. The common variants associated with keratoconus explain 12.5% of the genetic variance, which shows potential for the future development of a diagnostic test to detect susceptibility to disease