N-Glycosylation Patterns across the Age-Related Macular Degeneration Spectrum.

The pathogenesis of age-related macular degeneration (AMD) remains elusive, despite numerous research studies. Therefore, we aimed to investigate the changes of plasma and IgG-specific N-glycosylation across the disease severity spectrum. We examined 2835 subjects from the 10.001 Dalmatians project, originating from the isolated Croatian islands of Vis and Korcula. All subjects were classified into four groups, namely (i) bilateral AMD, (ii) unilateral AMD, (iii) early-onset drusen, and (iv) controls. We analysed plasma and IgG N-glycans measured by HPLC and their association with retinal fundus photographs. There were 106 (3.7%) detected cases of AMD; 66 of them were bilateral. In addition, 45 (0.9%) subjects were recorded as having early-onset retinal drusen. We detected several interesting differences across the analysed groups, suggesting that N-glycans can be used as a biomarker for AMD. Multivariate analysis suggested a significant decrease in the immunomodulatory bi-antennary glycan structures in unilateral AMD (adjusted odds ratio 0.43 (95% confidence interval 0.22-0.79)). We also detected a substantial increase in the pro-inflammatory tetra-antennary plasma glycans in bilateral AMD (7.90 (2.94-20.95)). Notably, some of these associations were not identified in the aggregated analysis, where all three disease stages were collapsed into a single category, suggesting the need for better-refined phenotypes and the use of disease severity stages in the analysis of more complex diseases. Age-related macular degeneration progression is characterised by the complex interplay of various mechanisms, some of which can be detected by measuring plasma and IgG N-glycans. As opposed to a simple case-control study, more advanced and refined study designs are needed to understand the pathogenesis of complex diseases.

The analysis of the glaucoma screening event results obtained during the World Glaucoma Week in Zagreb, Croatia.

PURPOSE: To report the prevalence of undiagnosed glaucoma, as well as demographic characteristics and risk factors among glaucoma suspects who were detected in a publicly promoted intraocular pressure (IOP) based glaucoma screening event. METHODS: A total of 2468 subjects older than 18 years participated in the glaucoma screening event in Zagreb, in 2014, which included a medical interview and IOP measurement using Icare tonometer. 256 subjects (10.37%) were identified as glaucoma suspects, out of which 125 (5.06%) subjects underwent further detailed ophthalmic examination and were classified into five diagnostic groups. RESULTS: The prevalence of all types of newly diagnosed glaucoma was 1.175%, while the prevalence of ocular hypertension (OH), primary open-angle glaucoma (POAG), primary angle closure (PAC) and secondary glaucoma (SG) was 0.16%, 0.89%, 0.16% and 0.12%, respectively. The prevalence of newly diagnosed glaucoma in glaucoma suspects was 23.2%. 17.60% of glaucoma suspects were diagnosed as POAG. Older age was statistically significantly associated with POAG (p = 0.001) and PAC (p = 0.029). At the univariate level, refractive errors were a statistically significant predictor of POAG, and those with hyperopia had more than three times larger odds for POAG. At the multivariate level, none of the predictors reached statistical significance. CONCLUSION: Successful cooperation between healthcare institutions and media can be a useful way of increasing awareness and detection of individuals at an increased risk for developing glaucoma.

SUBCONJUNCTIVAL FRAGMENTATION OF A PREVIOUSLY EFFICIENT XEN GEL STENT IMPLANTATION AND SUCCESSFUL BLEB FORMATION: A CASE REPORT.

The XEN gel stent is one of the available minimally invasive glaucoma surgery devices, a new generation implant, which is designed to reduce intraocular pressure in patients with primary open angle glaucoma if past medical treatments have failed. This report presents a case of subconjunctival fragmentation of the XEN gel stent after a three-month follow-up of successful XEN gel implantation. A 70-year-old male patient was treated for primary open angle glaucoma. He underwent successful phacoemulsification and intraocular lens implantation two years before. Due to medical therapy failure in controlling glaucoma, XEN gel stent implantation was suggested to the patient. The implant was successfully placed in both eyes, and extended bleb and drainage aqueous humor from the anterior chamber to the subconjunctival space was obtained. Three months after the surgery, at a regular follow-up visit, three fragments of the subconjunctival part of the XEN gel implant were found in his left eye. Neither serious complications nor intraocular pressure increase were detected. A new potential complication of the XEN gel implant is described.

Association Between Serum Vitamin D Level and Glaucoma in Women.

The aim of the study was to determine whether serum vitamin D level is lower in female patients with glaucoma as compared with control group. The mechanism by which vitamin D reduces intraocular pressure is not fully clarified. Almost all tissues possess vitamin D receptor (VDR). The mice lacking VDR (VDR knockout mice) have greatly contributed to the understanding of the general vitamin D physiologic function. VDR has been found in some ganglion layer cells, external and internal nuclear layers of retina, and in retinal pigment epithelium, while VDR epitopes have also been found in the ciliary body epithelium, pointing to the role of this protein in eye physiology. The 1,25(OH)2D3 modulates expression of the genes involved in the regulation of intraocular pressure in non-human primates. Extracellular matrix can be remodeled by 1,25(OH)2D3 treatment. Actin disruption can lead to cell morphology alteration, trabecular meshwork relaxation and intraocular pressure reduction. This observational cross-sectional study included 90 female glaucoma subjects aged 45-55 and 50 glaucoma free female subjects as control group. Results of a pilot study conducted in 20 glaucoma subjects and 20 control subjects are presented below. All study subjects underwent history taking, complete ophthalmologic examination and serum vitamin D determination. The mean serum vitamin D level was 32.31 nmol/L in glaucoma patients and 64.17 nmol/L in control subjects. Serum vitamin D level was statistically significantly lower in glaucoma patients as compared with control group (p<0.05).

The Resident Surgeon Phacoemulsification Learning Curve at Clinical Department of Ophthalmology, Sestre Milosrdnice University Hospital Center

The aim of the study was to analyze the resident learning process of phacoemulsification cataract surgery and to assess the resident phacoemulsification learning curve. This prospective study comprised 86 consecutive cases of phacoemulsification performed using standard technique by eight residents over a one-year period at Clinical Department of Ophthalmology, Sestre milosrdnice University Hospital Center in Zagreb. Operative data on each case included resident and attending surgeon, date of operation, step-by-step success questionnaire, and intraoperative complications. Postoperative data included visual acuity at one-month postoperative visit and postoperative complications. Eighty-six operations were performed under the supervision of attending surgeon. The mean best-corrected visual acuity improved from 0.47±0.25 to 0.8±0.25 postoperatively. Intraoperative complications occurred in 13 (15.12%) cases and continued to decrease throughout residency training. The mean number of individually performed steps per operation increased throughout residency (from 7.6 to 9.0). There was one early postoperative complication, endophthalmitis, which was successfully treated, and no other postoperative complications occurred. Resident surgical competency can be improved by maximizing the number of cataract procedures since the complication rates and the number of individually performed steps improved continuously with increasing surgical experience.

Genome-wide association study identifies genetic risk underlying primary rhegmatogenous retinal detachment.

Rhegmatogenous retinal detachment (RRD) is an important cause of vision loss and can potentially lead to blindness. The underlying pathogenesis is complex and incompletely understood. We applied a two-stage genetic association discovery phase followed by a replication phase in a combined total of 2833 RRD cases and 7871 controls. The discovery phase involved a genome-wide association scan of 867 affected individuals and 1953 controls from Scotland, followed by genotyping and testing 4347 highest ranking or candidate single nucleotide polymorphisms (SNPs) in independent sets of cases (1000) and controls (2912) of Dutch and British origin. None of the SNPs selected reached a Bonferroni-corrected threshold for significance (P < 1.27 × 10(-7)). The strongest association, for rs12960119 (P = 1.58 × 10(-7)) located within an intron of the SS18 gene. Further testing was carried out in independent case-control series from London (846 cases) and Croatia (120 cases). The combined meta-analysis identified one association reaching genome-wide significance for rs267738 (OR = 1.29, P = 2.11 × 10(-8)), a missense coding SNP and eQTL for CERS2 encoding the protein ceramide synthase 2. Several of the top signals showing suggestive significance in the combined meta-analysis encompassed genes with a documented role in cell adhesion or migration, including SS18, TIAM1, TSTA3 and LDB2, which warrant further investigation. This first genetic association study of RRD supports a polygenic component underlying RRD risk since 27.4% of the underlying RRD liability could be explained by the collective additive effects of the genotyped SNP from the discovery genome-wide scan.

Genetic influences on plasma CFH and CFHR1 concentrations and their role in susceptibility to age-related macular degeneration.

It is a longstanding puzzle why non-coding variants in the complement factor H (CFH) gene are more strongly associated with age-related macular degeneration (AMD) than functional coding variants that directly influence the alternative complement pathway. The situation is complicated by tight genetic associations across the region, including the adjacent CFH-related genes CFHR3 and CFHR1, which may themselves influence the alternative complement pathway and are contained within a common deletion (CNP147) which is associated with protection against AMD. It is unclear whether this association is mediated through a protective effect of low plasma CFHR1 concentrations, high plasma CFH or both. We examined the triangular relationships of CFH/CFHR3/CFHR1 genotype, plasma CFH or CFHR1 concentrations and AMD susceptibility in combined case-control (1256 cases, 1020 controls) and cross-sectional population (n = 1004) studies and carried out genome-wide association studies of plasma CFH and CFHR1 concentrations. A non-coding CFH SNP (rs6677604) and the CNP147 deletion were strongly correlated both with each other and with plasma CFH and CFHR1 concentrations. The plasma CFH-raising rs6677604 allele and raised plasma CFH concentration were each associated with AMD protection. In contrast, the protective association of the CNP147 deletion with AMD was not mediated by low plasma CFHR1, since AMD-free controls showed increased plasma CFHR1 compared with cases, but it may be mediated by the association of CNP147 with raised plasma CFH concentration. The results are most consistent with a regulatory locus within a 32 kb region of the CFH gene, with a major effect on plasma CFH concentration and AMD susceptibility.

Meta-analysis of genome-wide association studies in five cohorts reveals common variants in RBFOX1, a regulator of tissue-specific splicing, associated with refractive error.

Visual refractive errors (REs) are complex genetic traits with a largely unknown etiology. To date, genome-wide association studies (GWASs) of moderate size have identified several novel risk markers for RE, measured here as mean spherical equivalent (MSE). We performed a GWAS using a total of 7280 samples from five cohorts: the Age-Related Eye Disease Study (AREDS); the KORA study ('Cooperative Health Research in the Region of Augsburg'); the Framingham Eye Study (FES); the Ogliastra Genetic Park-Talana (OGP-Talana) Study and the Multiethnic Study of Atherosclerosis (MESA). Genotyping was performed on Illumina and Affymetrix platforms with additional markers imputed to the HapMap II reference panel. We identified a new genome-wide significant locus on chromosome 16 (rs10500355, P = 3.9 × 10(-9)) in a combined discovery and replication set (26 953 samples). This single nucleotide polymorphism (SNP) is located within the RBFOX1 gene which is a neuron-specific splicing factor regulating a wide range of alternative splicing events implicated in neuronal development and maturation, including transcription factors, other splicing factors and synaptic proteins.

Masqueraded sebaceous gland carcinoma of the lower eyelid in a young pregnant patient.

The purpose of this case report is to present misdiagnosed sebaceous gland carcinoma of the lower eyelid with rapid growth in a young woman during pregnancy. Eyelid sebaceous gland carcinoma is a relatively rare tumor and a disease primarily of older patients. It occurs more commonly in oriental populations and with a predilection for the upper eyelid. Early diagnosis and appropriate treatment may help improve disease control and patient survival.

Solitary Clear Cell Renal Cell Carcinoma Metastasis to the Eyelid: A Case Report.

Introduction: This study is a case of solitary clear cell renal cell carcinoma (ccRCC) eyelid metastasis in a 66-year-old man as the first sign of a primary tumor. ccRCC usually spreads to the lungs, mediastinum, bones, liver, and brain, while ocular metastases are rare. Case Presentation: Solitary metastasis presented as a solid mass in the central third of the upper eyelid, which has been growing for 3 weeks. Treatment included tumor removal and blepharoplasty. Histopathological examination showed metastasis of clear cell renal carcinoma. A thorough examination revealed a primary tumor on the lower pole of the right kidney. A right nephrectomy was performed, and histopathology showed ccRCC. Postoperative examinations showed no signs of local or systemic disease. Sunitinib malate was administered to the patient. Conclusion: The eyelid metastasis in this case was still solitary and had been discovered before the existence of the primary tumor was known. Ocular metastasis of renal carcinoma is a rare initial manifestation of the disease and therefore requires a multidisciplinary approach in the treatment of these patients.

Correlation between Structural and Functional Changes in Patients with Raised Intraocular Pressure Due to Graves' Orbitopathy.

This study explores the complication of secondary intraocular pressure (IOP) elevation and consequent glaucoma development in Graves' orbitopathy (GO), an autoimmune disorder associated with hyperthyroidism. Utilizing Octopus 900 visual field testing and optical coherence tomography (OCT), the research established correlations between functional and structural changes in optic nerve regions in patients with GO and patients with GO with elevated IOP (GO IOP) groups. A comparison with primary open-angle glaucoma (POAG) was conducted in a cohort of 182 subjects. The study identifies optic nerve head parameters that effectively differentiate changes in GO and GO IOP groups. In the GO group, the strongest correlation between structural and functional changes was observed in sector 7, while in the GO IOP group, it was in sectors 1 and 7. For POAG, correlation was found in six sectors. Elevated IOP in GO correlates with structural and functional impairments similarly to early glaucoma. Risk factors for GO-related elevated IOP included older age, longer duration of thyroid disease, and higher anti-thyroglobulin values. The study highlights the significance of regular IOP measurements, visual field assessments, and OCT examinations in GO patients. Early antiglaucoma intervention is warranted when characteristic structural and functional changes and/or risk factors are identified.

One Incremental Stride for Doxycycline, One Substantial Advancement for Thyroid Eye Disease.

The aim of this study is to assess the effectiveness of a 12-week doxycycline treatment for thyroid eye disease (TED), an autoimmune condition associated with thyroid dysfunction. In this randomized controlled clinical trial, 82 patients were randomly assigned at a 1:1 ratio to receive doxycycline (50 mg) or to undergo no treatment. Various metrics, including margin reflex distance (MRD1 and MRD2), eyelid aperture, levator muscle function, lagophthalmos, proptosis, ocular motility, diplopia, and Graves' ophthalmopathy-specific quality-of-life (GO-QOL) scale scoring were assessed. Exclusion criteria were uncontrolled systemic diseases, tetracycline allergies, pregnancy, lactation, or age below 18. The mean age was 51.6 years (SD), 87.8% of participants were female, and all were Caucasians. By week 12, the doxycycline group exhibited a significant improvement rate based on MRD2 (from 4 to 15 participants with physiological findings), clinical activity score (from 7 to 35 participants with non-active disease), and GO-QOL (from 51.22% to 70.73% of participants with a good life quality). Doxycycline showcased anti-inflammatory and immunomodulatory effects in treating TED, suggesting its potential efficacy for TED and other orbit inflammatory conditions. However, these results warrant further validation through future research involving extended follow-up periods and larger cohorts.

Macular thickness after glaucoma filtration surgery.

The aim of present study was to analyze early postoperative changes in the macular area using optical coherence tomography (OCT) after uncomplicated glaucoma filtration surgery. This prospective study included 32 patients (34 eyes) with open-angle glaucoma, which underwent trabeculectomy with or without use of mitomycin C. Exclusion criteria were macular edema, uveitis, age-related macular degeneration, blurred optical media, secondary glaucoma and angle-closure glaucoma. All standard clinical examinations were made before surgery, at the 2nd day, 1 week and 1 month after surgery. Tomography of the macula was performed during every examination using Cirrus HD OCT for the analysis of central subfield thickness. Results show that thickening of the macula was slightly higher 1 week and 1 month after operation in comparison with baseline end 2nd day postoperativelly. There was no significant difference in the change of macular thickness in patients who have used topical prostaglandins compared with those who have used other topical medications. Also, there was no difference in macular changes between patients treated with or without mitomycin C. In conclusion, we found a slight subclinical increase in macular thickness after uncomplicated trabeculectomy, for which we considered that was the result in reduction of intraocular pressure after glaucoma surgery. Macular thickening after glaucoma filtering surgery could be a physiological reaction to the stress of the retina caused by a sudden reduction of intraocular pressure and it is the consequence of altered relationship between capillary pressure and interstitial fluid pressure.

Bilateral Acute Iris Transillumination (BAIT): A Rare Syndrome Possibly Associated with COVID-19 and Moxifloxacin Use. A Report of 2 Cases.

Bilateral acute iris transillumination (BAIT) is a rare clinical entity, presumed to be associated with preceding upper respiratory tract infection and/or use of certain antibiotics, marked by bilateral acute loss of iris pigment epithelium with pigment dispersion in the anterior chamber and trabecular meshwork, which can cause elevated intraocular pressure and glaucoma, and with iris transillumination and sphincter paralysis which lead to photophobia and blurry vision. We report the first two cases of BAIT in our center which both had a history of preceding COVID-19 (coronavirus disease 2019) and moxifloxacin use. With more awareness, ophthalmologists might diagnose more cases, and thus gain more information regarding the link between COVID-19 and BAIT, which might be underdiagnosed since it is rare or easily misdiagnosed as some more common diseases with similar features.

Gender- and Age-Related Differences of Ocular Biometric Parameters in Patients Undergoing Cataract Surgery in Bosnia and Herzegovina.

Purpose: The aim of the study is to determine the distribution and mutual relationship of ocular biometric parameters, as well as to evaluate gender- and age-related differences in patients undergoing cataract surgery in Bosnia and Herzegovina. Materials and Methods: It was a retrospective cross-sectional study of consecutive patients who underwent cataract surgery between January 2017 and December 2021 in a tertiary care clinic. All biometric measurements were performed using the optical biometer OA-2000 (Tomey, Nagoya, Japan). Results: The study evaluated 1278 eyes from 1278 consecutive cataract patients. The average age of all included patients was 69.4 ± 9.98 (range 40-96). A total of 672 eyes (52.58%) were from females. The mean axial length (AL), anterior chamber depth (ACD), lens thickness (LT), and mean keratometry were 23.46 ± 1.18 mm, 3.17 ± 0.40 mm, 4.54 ± 0.48 mm, and 43.42 ± 1.55D, respectively. Corneal astigmatism of ≥1D, >2D and >3D was found in 33.4%, 7.8% and 2.5% patients, respectively. Females were found to have shorter AL (p < 0.0001), shallower ACD (p < 0.0001) and steeper corneas (p < 0.0001). In both genders, AL, ACD and with the rule astigmatism showed a decreasing trend (p = 0.0001), while keratometry, the average cylinder, and against the rule astigmatism showed an increasing trend (p = 0.0001) with increasing age. Furthermore, in both genders, there was an increasing trend in ACD (p = 0.0001), and a decreasing trend in keratometry (p = 0.0001) and LT (p = 0.0001) with increasing AL. Conclusions: This study provides useful reference data on ocular biometry for cataract surgeons in Bosnia and Herzegovina. Female patients tend to have steeper corneas, shorter AL and shallower AC than males, and these differences are independent of age or AL.

The Role of Thermal Camera in the Assessment of Thyroid Eye Disease Activity.

Background: Thyroid eye disease (TED; also known as thyroid - associated orbitopathy, Graves ophthalmopathy) is an autoimmune inflammatory disease which presents in typical signs and symptoms such as deep orbital pain, chemosis with or without caruncular edema, unilateral or bilateral proptosis, eyelid retraction, eyelid edema or erythema, restrictive strabismus and compressive optic neuropathy. Objective: The aim of this study was to investigate the role of thermal camera in the assessment of thyroid eye disease (TED) activity compared to the Clinical Activity Score (CAS) scale, exophthalmometry values, and thyroid hormone and antibody levels. Methods: A total of 50 patients participated in this cross-sectional study of whom 29 were in the active phase of TED according to the sum on CAS scale and 21 patients in the inactive phase. The Flir E8® thermal camera was used to measure the temperature of the orbital area and the values were compared with the CAS scale, exophthalmometry values and thyroid hormone and antibody levels. Results: Higher values of temperature (p>0.0001), CAS score (p>0.0001), exophthalmometry (p=0.022), FT4 (p=0.0176) and TRAb (p=0.0091) were found in patients in the active phase of TED. Temperature of orbital area showed statistically significant positive correlation with CAS scale (p=0.0001), exophthalmometry values (p=0.0022) and anti-TPO levels (p=0.019). Conclusion: Thermal camera showed higher values of the temperature of the orbital area in patients in the active phase of the disease and positively correlated with the CAS scale, exophthalmometry findings and anti-TPO levels.

New loci associated with central cornea thickness include COL5A1, AKAP13 and AVGR8.

Central corneal thickness (CCT) is a highly heritable trait, which has been proposed to influence disorders of the anterior segment of the eye. A genome-wide association study (GWAS) of CCT was performed in 2269 individuals from three Croatian and one Scottish population. In the discovery set (1445 individuals), two genome-wide significant associations were identified for single nucleotide polymorphisms rs12447690 (ß = 0.23 SD, P = 4.4 × 10(-9)) and rs1536482 (ß = 0.22 SD, P = 7.1 × 10(-8)) for which the closest candidate genes (although ≥90 kb away) were zinc finger 469 (ZNF469) on 16q24.2 and collagen 5 alpha 1 (COL5A1) on 9q34.2, respectively. Only the ZNF469 association was confirmed in our replication set (824 individuals, P = 8.0 × 10(-4)) but COL5A1 remained a suggestive association in the combined sample (ß = 0.16 SD, P = 1.1 × 10(-6)). Following a larger meta-analysis including recently published CCT GWAS summary data, COL5A1 was genome-wide significant (ß = 0.13 SD, P = 5.1 × 10(-8)), together with two additional novel loci. The second new locus (defined by rs1034200) was 5 kb from the AVGR8 gene, encoding a putative transcription factor with typical ZNF and KRAB domains, in chromosomal region 13q12.11 (ß = 0.14 SD, P = 3.5 × 10(-9)). The third new locus (rs6496932), on 15q25.3 (ß = 0.13, P = 1.4 × 10(-8)), was within a wide linkage disequilibrium block extending into the 5' end of the AKAP13 gene, encoding a scaffold protein concerned with signal transduction from the cell surface. These associations offer mechanistic insights into the regulation of CCT and offer new candidate genes for susceptibility to common disorders in which CCT has been implicated, including primary open-angle glaucoma and keratoconus.

Diplopia, COVID-19 and Vaccination: Results from a Cross-Sectional Study in Croatia.

The aim of this study was to explore diplopia as a symptom of undetected COVID-19 infection or as a possible side effect of COVID-19 vaccination. We examined 380 patients with diplopia admitted to the Department of Ophthalmology of the University Hospital Centre Sestre milosrdnice in Zagreb, Croatia, from July 2020 to June 2022. After excluding patients with confirmed organic underlying diplopia causes or monocular diplopia, we linked the patient information with the national COVID-19 and vaccination registries. Among the 91 patients included in this study, previously undetected COVID-19 infection as the possible cause of diplopia was confirmed in five of them (5.5%). An additional nine patients (9.9%) were vaccinated within one month from the onset of their symptoms, while the remaining 77 had neither and were therefore considered as controls. The breakdown according to the mechanism of diplopia showed no substantial difference between the vaccinated patients and the controls. We detected marginally insignificant excess abducens nerve affection in the COVID-positive group compared with that in the controls (p = 0.051). Post-vaccination diplopia was equally common in patients who received vector-based or RNA-based vaccines (21.4 vs. 16.7%; p = 0.694). COVID-19 testing should be performed for all cases of otherwise unexplained diplopia. The risk of post-vaccination diplopia was similar in both types of vaccines administered, suggesting a lack of evidence linking specific vaccine types to diplopia.