Evaluation of the effects of environmental factors and eating habits on exfoliation syndrome and glaucoma in a Turkish population.

PURPOSE: This study aimed to assess the possible effect of environmental factors and eating habits on patients with the exfoliation syndrome (XFS) and exfoliative glaucoma (XFG) in a Turkish population. METHODS: A questionnaire was applied to 1,000 individuals, including 290 patients with XFS, 210 patients with XFG, and 500 age- and sex-matched healthy control participants. Sociodemographic characteristics, home type and warming methods, living and working conditions (indoor-outdoor), dietary habits based on the the guidance of Turkey Dietary Guidelines, (Determination of Nutritional Status Report and Turkey National Nutrition and Health Survey) and using sunglasses were evaluated. The chi-square test, Student t test, and analysis of variance were used for the statistical analysis with SPSS v. 23.0 software. RESULTS: The case-control groups were matched during data collection, and age and sex distribution in groups was analyzed; however, no difference was found. The average years and hours spent outdoor were statistically different between case and control groups (P < 0.05). The disease risk among individuals wearing sunglasses was 2.74 times less than that among those who did not wear sunglasses. Individuals born in the city had 1.46 times lower risk. Also, living out of the city until the age of 12 years increased the risk of getting the disease 1.36 times. In addition, while living in an apartment decreased the risk of disease, using a stove increased. The control groups had more healthy eating habits than the case groups. CONCLUSION: This case-control study showed that time spent outdoors, wearing sunglasses, home type, heating method, and eating habits might be associated with XFS and XFG.

Evaluation of the corneal thickness and endothelial changes following uncomplicated phacoemulsification in diabetic and non-diabetic patients with pseudo-exfoliation syndrome by specular microscopy.

PURPOSE: To evaluate corneal endothelial cell changes following uncomplicated phacoemulsification in diabetic patients with PEX, compared with diabetic patients and non-diabetic patients with PEX. METHODS: This prospective, comparative, non-randomized cohort study included 61 eyes of 61 patients who were diagnosed as having senile cataract. Patients were divided into three groups: Group (1) included 19 eyes of patients with DM and PEX, group (2) included 22 eyes of diabetic patients, and group (3) included 20 eyes of patients with PEX. All included patients had uncomplicated phacoemulsification with IOL implantation. Patients were examined by non-contact specular microscopy (NIDEK, CEM-530, Japan), preoperatively and postoperatively at regular follow-up periods (one, three, and six months postoperatively) with analysis of the endothelial cell density, percentage of hexagonal cells, CV, and CCT. RESULTS: By the end of follow-up period, there was a statistically significant reduction in ECD and HEX with a significant increase in CV and CCT in group one (DM-PEX). In group two (DM), a statistically significant decrease in ECD and HEX with a significant increase in CCT was reported, while in group three (PEX), the only significant difference was found in the form of ECD reduction. CONCLUSION: Patients with DM and PEX had significant changes regarding ECD, CV, HEX, and CCT which were more pronounced than in patients with DM only or PEX only. More attention should be paid while operating on diabetic patients with PEX to save corneal endothelium and decrease postoperative complications. STUDY REGISTRATION NUMBER: The study was retrospectively registered (16 July 2021) on ClinicalTrials.gov (NCT04965168).

Coexistence of MRCS syndrome, extremely long axis and exfoliation syndrome: a case report and literature review.

BACKGROUND: The coexistence of MRCS (microcornea, retinal dystrophy, cataract, and posterior staphyloma) syndrome and extremely long axis is rare since microcornea frequently accompanies with diminution of entire anterior segment and occasionally the whole globe. In the case presented here, combination of these two elements were identified, together with XFS (exfoliation syndrome). CASE PRESENTATION: A 66-year-old Han Chinese woman presented for consultation due to impaired vision which accompanied throughout her entire life span and worsened during the last 2 years. Combination of MRCS syndrome and extremely long axial length was evidently diagnosed in both eyes, with XFS confirmed in her right eye, but mutation screening failed to identify disease-causing sequence variants in some specific genes reported previously, including BEST1 and ARL2. However, likely pathogenic mutations in FBN2 gene were identified. Bilateral cataract phacoemulsification without intraocular lens implantation was performed using scleral tunnel incision and under general anesthesia. At 3-month follow-up, ocular recovery of the patient was satisfactory. CONCLUSIONS: The case presented here exhibited rare coexistence of MRCS syndrome, extremely long axis and XFS. The complexity of her ocular abnormalities brought challenges to surgical management, in which multidisciplinary collaboration is often required. Furthermore, the genetic analysis in this case yielded a possible novel candidate gene for MRCS syndrome and provided evidence in support of genetic heterogeneity in this phenotype.

Analysis of genetically determined gene expression suggests role of inflammatory processes in exfoliation syndrome.

BACKGROUND: Exfoliation syndrome (XFS) is an age-related systemic disorder characterized by excessive production and progressive accumulation of abnormal extracellular material, with pathognomonic ocular manifestations. It is the most common cause of secondary glaucoma, resulting in widespread global blindness. The largest global meta-analysis of XFS in 123,457 multi-ethnic individuals from 24 countries identified seven loci with the strongest association signal in chr15q22-25 region near LOXL1. Expression analysis have so far correlated coding and a few non-coding variants in the region with LOXL1 expression levels, but functional effects of these variants is unclear. We hypothesize that analysis of the contribution of the genetically determined component of gene expression to XFS risk can provide a powerful method to elucidate potential roles of additional genes and clarify biology that underlie XFS. RESULTS: Transcriptomic Wide Association Studies (TWAS) using PrediXcan models trained in 48 GTEx tissues leveraging on results from the multi-ethnic and European ancestry GWAS were performed. To eliminate the possibility of false-positive results due to Linkage Disequilibrium (LD) contamination, we i) performed PrediXcan analysis in reduced models removing variants in LD with LOXL1 missense variants associated with XFS, and variants in LOXL1 models in both multiethnic and European ancestry individuals, ii) conducted conditional analysis of the significant signals in European ancestry individuals, and iii) filtered signals based on correlated gene expression, LD and shared eQTLs, iv) conducted expression validation analysis in human iris tissues. We observed twenty-eight genes in chr15q22-25 region that showed statistically significant associations, which were whittled down to ten genes after statistical validations. In experimental analysis, mRNA transcript levels for ARID3B, CD276, LOXL1, NEO1, SCAMP2, and UBL7 were significantly decreased in iris tissues from XFS patients compared to control samples. TWAS genes for XFS were significantly enriched for genes associated with inflammatory conditions. We also observed a higher incidence of XFS comorbidity with inflammatory and connective tissue diseases. CONCLUSION: Our results implicate a role for connective tissues and inflammation pathways in the etiology of XFS. Targeting the inflammatory pathway may be a potential therapeutic option to reduce progression in XFS.

Evaluation of the Effect of Duration on Retinal Nerve Fiber Layer Thickness and Choroidal Thickness in Exfoliation Syndrome and Exfoliative Glaucoma.

Aims: To compare retinal nerve fiber layer (RNFL) thickness and choroidal thickness in patients with exfoliation syndrome (XFS) and exfoliative glaucoma (XFG) for 1−5 years or 6−10 years compared to healthy volunteers. Methods and Material: Seventy-eight eyes of 78 patients with XFG, 78 eyes of 78 patients with XFS, and 83 eyes of 83 healthy individuals were included in this prospective study. SD-OCT data for choroid thickness and RNFL were recorded. Results: RNFL thickness was statistically significantly lower in eyes with XFG and XFS than in the control group (p < 0.001). Macular choroidal thickness decreased significantly in the XFG group compared to the XFS and control groups (p < 0.001). No significant difference was observed between the XFS and control groups (p > 0.05). In terms of choroidal and RNFL thicknesses by years in XFG and XFS patients, values were lower in the patients diagnosed 6−10 years previously than in those diagnosed 1−5 years previously. However, the difference was not statistically significant (p > 0.05). Conclusions: Thinning of both choroidal and RNLF thickness in XFG and XFS patients may mean that PEX material is an important risk factor for the progression of XFS to XFG. In addition, thinner choroid and RNLF thickness in the 6−10 years groups show the effect of PEX material and the importance of time.

Hearing Loss in Exfoliation Syndrome: Systematic Review and Meta-Analysis.

OBJECTIVE: To determine if exfoliation syndrome (XFS) is associated with hearing loss (HL) or vestibular dysfunction. DATA SOURCES: PubMed, Scopus, CINAHL, and Cochrane Library through April 1, 2022. REVIEW METHODS: Two reviewers independently screened abstracts, selected articles for inclusion, and extracted data. Studies included for qualitative analysis conducted audiometric, tympanometric, or vestibular evaluations on all subjects. RESULTS: Twenty-one publications (1148 patients with XFS and 1212 controls) were included in the systematic review, and 16 publications (968 patients with XFS and 1147 controls) in the meta-analysis. Greater severity of HL was seen for patients with XFS compared to controls across all frequencies (odds ratio [OR] 8.8 [7.3-10.2]). Patients with XFS were more likely to have moderate to profound sensorineural HL (OR 1.8 [1.3-2.5]), and less likely to have none to mild HL (OR 0.34 [0.17-0.67]) or no HL (OR 0.37 [0.28-0.50]). Three studies found patients with XFS had lower tympanometric peaks. Two studies found that abnormal vestibular testing results could be more common for patients with XFS. CONCLUSIONS: HL is associated with XFS. A sensorineural component to HL is confirmed, and mixed HL is possible. Given the high prevalence and infrequent diagnosis of XFS, the authors hypothesize that the current understandings of presbycusis might be improved by further investigation in XFS. Laryngoscope, 133:1025-1035, 2023.

Abdominal aortic aneurysm and exfoliation syndrome: A literature review comparing single site findings.

Several studies have suggested a possible relationship between exfoliation syndrome (XFS) and abdominal aortic aneurysm (AAA). A systematic literature review was undertaken to investigate this potential association. The systematic literature review was performed according to the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. Clear definitions of XFS and AAA were used to identify eligible studies via an unrestricted search of the PubMed interface from 1979 to October 31st, 2021. After review, 876 citations were gathered and evaluated for inclusion, from which 22 articles were included. Of these 22, 16 were excluded because they did not assess the relationship between AAA and XFS or provide primary data. Ultimately, six studies were included in this literature review. Half of the studies explored AAA prevalence in a population with or without XFS, and the other half explored the opposite. Three studies supported XFS as a risk factor for the development of AAA, and the other three found this relationship to be inconclusive. This systematic review revealed inconsistent results regarding an association between AAA and XFS. A large database study including XFS and AAA patients would be useful in further determining if an association does in fact exist.

Abdominal aortic aneurysm and exfoliation syndrome in Utah.

PURPOSE: A pilot study of electronic medical records (EMR) in Utah was undertaken to investigate exfoliation syndrome and exfoliation glaucoma (XFS/XFG) in abdominal aortic aneurysm (AAA) patients. In a subsequent retrospective cohort study of Utah XFS/XFG patients and population controls, the risk of AAA was examined. METHODS: EMR of a statewide healthcare population were obtained from the Utah Population Database (UPDB) which links decades of medical records with Utah demographic and vital records data. In a pilot study, 7167 patients ages ≥40 years identified with AAA diagnosed from 1996 to 2015, based on International Classification of Diseases (ICD) version 9/10 codes, were included. A univariable hazards model was used to determine the risk of XFS/XFG in AAA patients. An XFS/XFG outcome based on ICD 9/10 codes in AAA patients and in 5:1 sex- and age-matched non-AAA controls was determined. A retrospective cohort of 3412 XFS/XFG patients ages ≥50 years diagnosed from 1996 to 2020 and 10 227 3:1 sex- and age-matched controls who underwent ≥1 dilated eye examination(s) were recently identified and updated diagnoses of AAA were obtained. Multivariable logistic regression was used to estimate AAA risk in XFS/XFG patients compared with controls. In a subset of XFS/XFG patients, chart reviews were conducted to confirm clinically diagnosed AAA. RESULTS: In the AAA pilot, 20 patients (0.3%) and 118 controls (0.3%) developed XFS/XFG, respectively. We observed no increased risk of XFS/XFG in AAA patients compared with non-AAA-matched controls (HR = 0.99, 95% CI 0.6-1.6). Among XFS/XFG study patients and controls, 122 patients (3.6%) and 376 controls (3.7%) had an AAA diagnosis. We likewise observed no increased risk of AAA in XFS/XFG patients (OR = 0.97, 95% CI 0.8-1.2). In 14 XFS/XFG patients with an ICD 9/10 diagnosis of AAA who underwent chart review, a clinical diagnosis of AAA was confirmed in 9 patients (64.3%). CONCLUSION: Our findings do not support an association between AAA and XFS/XFG.

Evaluation of the segmented inner retinal layers in exfoliation glaucoma.

PURPOSE: To investigate the macular spectral domain optical coherence tomography (SD-OCT) measurements of the segmented inner retinal layers in patients with exfoliation syndrome (XFS), exfoliation glaucoma (XFG). METHODS: This prospective cross-sectional study included 28 eyes with XFS, 47 eyes with XFG, and 29 healthy controls. Thickness of the inner retinal layers, including retinal nerve fiber layer (RNFL), ganglion cell layer (GCL), and inner plexiform layer (IPL) was obtained from the horizontal SD-OCT scans. Functional correlation of structural parameters was analyzed using the mean sensitivity (MS) values on 10-2 visual fields. RESULTS: The RNFL, GCL, and IPL were thinnest in eyes with XFG. Among these retinal layers, IPL was significantly thinner in eyes with XFS than healthy controls (p = 0.02) and the IPL thickness was significantly correlated with the corresponding MS scores on 10-2 visual fields (r = 0.492, p = 0.02) in eyes with XFS. Neither GCL nor RNFL thickness values demonstrated significant correlations with functional parameters in eyes with XFS (r = 0.377, p = 0.08; r = 0.212, p = 0.34). In eyes with XFG, the IPL thickness correlated with the visual field MS scores (r = 0.572, p = 0.0007), similar to the correlation of GCL (r = 0.585, p = 0.0005) thickness with visual field scores. CONCLUSIONS: Segmented analysis of the macular IPL thickness presented a significant correlation with the 10-2 visual field scores not only in eyes with XFG but also in eyes with XFS. With respect to early dendritic/synaptic alterations in animal models, larger and longitudinal studies are encouraged to determine the predictive value of the IPL thickness for conversion of XFS to XFG.

A new method of arterial stiffness measurement in pseudoexfoliation syndrome: cardio-ankle vascular index / Um novo método para medição da rigidez arterial na síndrome de pseudoesfoliação: índice vascular cardíaco-tornozelo

ABSTRACT Purpose: To investigate whether pseudoexfoliation syndrome affects arterial stiffness by using cardio-ankle vascular index measurement. Methods: This cross-sectional case-control study included 55 patients with pseudoexfoliation syndrome and 106 age- and gender-matched healthy control subjects. All subjects underwent a complete ophthalmic exa mination of both eyes and cardio-ankle vascular index measu rements. Echocardiographic and body mass index measurements were performed in all patients, and the results were recorded. A binary regression model was used to determine the relationship between cardio-ankle vascular index and pseudoexfoliation. Results: There were no significant differences between the pseudoexfoliation and control groups in baseline clinical and demographic characteristics, echocardiographic measurements of left ventricular ejection fraction, and body mass index. The mean cardio-ankle vascular index value was significantly higher in the pseudoexfoliation group than in the controls (9.47 ± 1.23 vs. 8.33 ± 1.50, p<0.001). Intraocular pressure was significantly higher in the pseudoexfoliation group than in the controls (18.31 ± 1.78 vs. 15.24 ± 2.42 mm Hg, p<0.05). Although the logistic regression analysis showed that mean cardio-ankle vascular index and IOP values were positively associated with pseudoexfoliation syndrome (Odds ratios (OR) = 1.973, 95% CI, 1.051-3.706, p=0.035; OR=3.322, 95% CI = 2.000-5.520, p<0.001, respectively), the Pearson correlation analysis revealed a borderline significant positive correlation between age and mean cardio-ankle vascular index and a significant positive correlation between dyslipidemia and intraocular pressure and mean cardio-ankle vascular index (r=0.265, p=0.050; r=0.337, p=0.012; r=0.433, p=0.001, respectively). Conclusion: Our findings demonstrated that cardio-ankle vascular index values increased in patients with pseudoexfoliation syndrome.

RESUMO Objetivo: Investigar se a síndrome de pseudoesfoliação afeta a rigidez arterial, usando a medição do índice vascular cardíaco-tornozelo. Métodos: Este estudo transversal caso-controle incluiu 55 pacientes com síndrome de pseudoesfoliação e 106 controles saudáveis, pareados por idade e gênero. Todos os indivíduos foram submetidos a um exame oftalmológico completo de ambos os olhos e à medição do índice vascular cardíaco-tornozelo. Medidas ecocardiográficas e do índice de massa corporal também foram feitas em todos os pacientes, e os resultados foram registrados. Usou-se um modelo de regressão binária para avaliar uma possível relação entre o índice vascular cardíaco-tornozelo e a pseudoesfoliação. Resultados: Não houve diferença significativa entre os grupos com pseudoesfoliação e de controle em relação às características clínicas e demográficas basais, às medidas ecocardiográficas da fração de ejeção do ventrículo esquerdo e ao índice de massa corporal. Os valores médios do índice vascular cardíaco-tornozelo foram significativamente maiores no grupo com pseudoesfoliação do que no de controle (9,47 ± 1,23 contra 8,33 ± 1,50, p<0,001). Os valores da pressão intraocular no grupo com pseudoesfoliação excederam significativamente os do grupo de controle (18,31 ± 1,78 mmHg contra 15.24 ± 2.42 mmHg, p<0.05). A análise de regressão logística demonstrou uma associação positiva das médias do índice vascular cardíaco-tornozelo e da pressão intraocular com a síndrome de pseudoesfoliação (respectivamente, OR=1,973, IC 95%: 1,051-3,706, p=0,035 e OR=3,322, IC 95%: 2,000-5,520, p<0,001). Já a análise de correlação de Pearson revelou uma correlação positiva de significância limítrofe entre a idade e a média do índice vascular cardíaco-tornozelo, e uma correlação positiva significativa entre a dislipidemia, a pressão intraocular e a média do índice vascular cardíaco-tornozelo (respectivamente, r=0,265, p=0,050; r=0,337, p=0,012; e r=0,433, p=0,001). Conclusão: Nossos achados demonstraram que os valores do índice vascular cardíaco-tornozelo se encontram aumentados em pacientes com síndrome de pseudoesfoliação.

Genome-Wide RNA Sequencing of Human Trabecular Meshwork Cells Treated with TGF-ß1: Relevance to Pseudoexfoliation Glaucoma.

Pseudoexfoliation glaucoma (XFG) is an aggressive form of secondary open angle glaucoma, characterised by the production of exfoliation material and is estimated to affect 30 million people worldwide. Activation of the TGF-ß pathway by TGF-ß1 has been implicated in the pathogenesis of pseudoexfoliation glaucoma. To further investigate the role of TGF-ß1 in glaucomatous changes in the trabecular meshwork (TM), we used RNA-Seq to determine TGF-ß1 induced changes in the transcriptome of normal human trabecular meshwork (HTM) cells. The main purpose of this study was to perform a hypothesis-independent RNA sequencing analysis to investigate genome-wide alterations in the transcriptome of normal HTMs stimulated with TGF-ß1 and investigate possible pathophysiological mechanisms driving XFG. Our results identified multiple differentially expressed genes including several genes known to be present in exfoliation material. Significantly altered pathways, biological processes and molecular functions included extracellular matrix remodelling, Hippo and Wnt pathways, the unfolded protein response, oxidative stress, and the antioxidant system. This cellular model of pseudoexfoliation glaucoma can provide insight into disease pathogenesis and support the development of novel therapeutic interventions.

Towards preventing exfoliation glaucoma by targeting and removing fibrillar aggregates associated with exfoliation syndrome.

Exfoliation syndrome presents as an accumulation of insoluble fibrillar aggregates that commonly correlates with age and causes ocular complications, most notably open-angle glaucoma. Despite advances in understanding the pathogenesis and risk factors associated with exfoliation syndrome, there has been no significant progress in curative pharmacotherapy of this disease. It is thought that the ability to target the fibrillar aggregates associated with exfoliation may offer a new therapeutic approach, facilitating their direct removal from affected tissues. Phage display techniques yielded two peptides (LPSYNLHPHVPP, IPLLNPGSMQLS) that could differentiate between exfoliative and non-affected regions of the human lens capsule. These peptides were conjugated to magnetic particles using click chemistry to investigate their ability in targeting and removing exfoliation materials from the anterior human lens capsule. The behavior of the fibrillar materials upon binding to these magnetic particles was assessed using magnetic pins and rotating magnetic fields of various strengths. Ex vivo studies showed that the magnetic particle-peptide conjugates could generate enough mechanical force to remove large aggregates of exfoliation materials from the lens capsule when exposed to a low-frequency rotating magnetic field (5000 G, 20 Hz). Biocompatibility of targeting peptides with and without conjugated magnetic particles was confirmed using MTT cell toxicity assay, live/dead cell viability assay, and DNA fragmentation studies on primary cultured human trabecular meshwork cells. This is a novel, minimally invasive, therapeutic approach for the treatment of exfoliation glaucoma via the targeting and removal of exfoliation materials that could be applied to all tissues within the anterior segment of the eye.

Exfoliation Syndrome and Exfoliation Glaucoma in the Navajo Nation.

(1) Background: Exfoliation syndrome (XFS) is a common cause of secondary open angle glaucoma. In 1971, Faulkner et al. estimated the prevalence of XFS among 50 Navajo Nation residents as 38%. Given that XFS can cause irreversible blindness secondary to glaucoma (XFG), this study aims to identify the current prevalence of XFS among Navajo Nation residents within the Four Corners region of the U.S. (2) Methods: A retrospective chart review was conducted from 2016 to 2021 for patients aged 18 and older. All patients with XFS or XFG diagnosed by slit lamp exam were identified through chart review. (3) Results: Of the 1152 patient charts available for review, eight patients (11 eyes) were diagnosed with XFS with three patients (4 eyes) demonstrating concomitant XFG. Within this XFS population, 50% of the patients identified as male, with a mean age of 73 years. The overall prevalence of XFS was 0.7% and the overall prevalence of XFG was found to be 0.26%. The rate of XFG among patients with XFS was 37.5%. (4) Conclusion: Compared to Faulkner's study of Navajo Nation residents in 1971, our findings show a considerably lower prevalence of XFS at 0.7%. We present the largest study to date of XFS among this population.

Role of Mitochondrial Mutations in Ocular Aggregopathy.

Background Mitochondria are essential cellular organelles that are responsible for oxidative stress-induced damage in age-dependent neurodegenerations such as glaucoma. Previous studies have linked mitochondrial DNA (mtDNA) mutations to cellular energy shortages that result in eye degeneration. Methodology To look for nucleotide variations in mtDNA in exfoliation syndrome/glaucoma (XFS/XFG), we performed a polymerase chain reaction (PCR) to amplify the entire coding region of the mitochondrial genome from peripheral blood of XFS/XFG (n = 25) patients and controls (n = 25). Results This study identified a total of 65 variations in XFS/XFG patients, of which 25 (38%) variations were non-synonymous single-nucleotide polymorphism (nsSNPs). Out of 25 nsSNPs, seven (five nsSNP in MT-ND4 and two in MT-ATP6 gene) were predicted as pathogenic using four different software, namely, SIFT, Polyphene2, mutation taster, and MutPred2. The pathogenic nsSNPs were then subjected to structural change analysis using online tools. Conclusions The pathogenic nsSNPs were found in both proteins' transmembrane domains and were expected to be conserved, but with lower protein stability (ΔΔG <- 0.5), indicating a possibly harmful effect in exfoliation. However, three-dimensional protein analysis indicated that the predicted mutations in MT-ND4 and MT-ATP6 were unlikely to alter the protein function.

Fellow-eye asymmetry on optical coherence tomography angiography and thickness parameters in unilateral pseudoexfoliation syndrome / Assimetria do olho oposto na angiografia por tomografia de coerência óptica e parâmetros de espessura na síndrome de pseudoexfoliação unilateral

ABSTRACT Purpose: To investigate inter-eye retinal vessel density and thickness asymmetry in unilateral pseudoexfoliation syndrome and understand its use for the early detection of glaucoma. Methods: Thirty patients with unilateral pseudoexfoliation syndrome were enrolled in our study. Optical coherence tomography angiography macular scans were used measure the retinal vessel density, and optical coherence tomography scans were used to assess the thickness parameters of the peripapillary retinal nerve fiber layer and the macular ganglion cell complex. Inter-eye asymmetry was determined by taking the absolute value of the difference in the vessel density and thickness parameters between the pseudoexfoliation syndrome eye and fellow eye. Results: The mean patient age was 64.20 ± 7.05 y in the study group. Inter-eye asymmetry in the peripapillary retinal nerve fiber layer thickness and macular ganglion cell complex measurements were significant in the study group (p=0.03 and p=0.001, respectively). The vessel density of the macular superficial inner region was significantly lower in eyes with pseudoexfoliation syndrome than in fellow eyes (p=0.035). However, there was no inter-eye asymmetry in the central and full region macular superficial vessel density of eyes with pseudoexfoliation syndrome and fellow eyes (p>0.05). Conclusion: Retinal vessel density can be evaluated using optical coherence tomography angiography measurements. There was inter-eye asymmetry in the inner region macular superficial vessel density, peripapillary retinal nerve fiber layer, and macular ganglion cell complex thickness of the unilateral pseudoexfoliation syndrome eyes and fellow eyes. Further studies on a larger number of subjects might provide more clarity regarding the relationship between the inter-eye asymmetry of the retinal vessel density and thickness parameters with early detection of glaucomatous damage.

RESUMO Objetivo: Investigar a densidade dos vasos interoculares da retina e assimetria na espessura na síndrome de pseudoexfoliação unilateral e o seu uso para a detecção precoce de glaucoma. Métodos: Trinta pacientes com síndrome de pseudoexfoliação unilateral foram incluídos no estudo. As varreduras maculares de angiografia por tomografia de coerência óptica mediram a densidade dos vasos da retina, e as varreduras por tomografia de coerência óptica obtiveram parâmetros de espessura da camada de fibras nervosas da retina peripapilar e do complexo macular de célula ganglionar. A assimetria interocular foi determinada tomando o valor absoluto da diferença entre o olho da síndrome de pseudoexfoliação e o olho oposto nos parâmetros de densidade e espessura dos vasos. Resultados: A média de idade foi 64,20 ± 7,05 anos no grupo de estudo. A assimetria interocular na espessura da camada de fibra nervosa da retina peripapilar e as medidas do complexo macular de célula ganglionar foram estatisticamente significativas no grupo de estudo (p=0,03 e p=0,001, respectivamente). Para os olhos com síndrome de pseudoexfoliação, a densidade do vaso da região macular superficial interna foi significativamente menor do que em olhos opostos (p=0,035). No entanto, não houve assimetria interocular estatisticamente significativa na densidade macular dos vasos superficiais da região central e completa entre os olhos da síndrome de pseudoexfoliação e os olhos opostos (p>0,05). Conclusões: A densidade dos vasos da retina pode ser avaliada por medidas de angiografia por tomografia de coerência óptica. Houve assimetria interocular na densidade macular do vaso superficial da região interna, camada de fibra nervosa da retina peripapilar e espessura do complexo macular de célula ganglionar entre olhos com síndrome de pseudoexfoliação unilateral e olhos opostos. Novos estudos com um número maior de indivíduos podem fornecer a relação entre a assimetria interocular da densidade do vaso da retina e os parâmetros de espessura com detecção precoce de dano glaucomatoso.

Prevalence of risk alleles in the lysyl oxidase-like 1 gene in pseudoexfoliation glaucoma patients in India.

Purpose: The purpose of this study was to genotype two previously identified SNPs (rs1048661:R141L, and rs3825942:G153D) in the lysyl oxidase-like 1 (LOXL1) gene and determine their association with pseudoexfoliation glaucoma (XFG) in patients from Pune, India. Methods: All subjects underwent detailed phenotyping, and DNA extraction was performed on blood samples by using standardized techniques. Exon 1 of the LOXL1 gene containing the SNPs (rs3825942:G153D; rs1048661:R141L) were Sanger sequenced, and the results were analyzed using sequence analysis software SeqScape 2.1.1. Results: Data were analyzed from 71 patients with XFG and 81 disease-negative, age-matched controls. There was a strong association between the G allele of rs3825942 and XFG with an odds ratio of 10.2 (CI: 3.92-26.6; P < 0.001). The G allele of rs1048661 also showed an increase in risk relative to the T allele (OR = 1.49; CI: 0.88-2.51; P = 0.13), but this was not significant. Haplotype combination frequencies were estimated for rs1048661 and rs3825942; the GG haplotype was associated with a significant increase in risk (OR = 3.91; CI: 2.27-6.73; P < 0.001). Both the GA and TG haplotypes were associated with decreased XFG risk, although the latter was not significant (GA: OR = 0.08; CI: 0.03-0.21; P < 0.001; TG: OR = 0.67; CI: 0.40-1.13; P = 0.13). Conclusion: The risk G allele in rs3852942 (G153D) is strongly associated with the development of XFG in the Western Indian population. Genetic screening strategies to identify LOXL1 risk alleles in the population can assist in case definition and early diagnosis, targeting precious resources to high-risk patients.

Head and Neck Region Dermatological Ultraviolet-Related Cancers are Associated with Exfoliation Syndrome in a Clinic-Based Population.

OBJECTIVE: We assessed the relationship between ultraviolet (UV)-associated dermatological carcinomas (basal cell carcinoma [BCC] and squamous cell carcinoma [SCC]) and exfoliation syndrome (XFS) or exfoliation glaucoma (XFG). DESIGN: Case-control study. PARTICIPANTS: Between 2019 and 2021, 321 participants and control subjects (XFS or XFG = 98; primary open-angle glaucoma [POAG] = 117; controls = 106; ages 50-90 years) were recruited. METHODS: A cross-sectional survey assessing medical history, maximum known intraocular pressure, cup-to-disc ratio, Humphrey visual field 24-2, the propensity to tan or burn in early life, history of BCC or SCC, and XFS or XFG diagnosis. The multivariable models adjusted for age, sex, medical history, eye color, hair color, and likeliness of tanning versus burning at a young age. MAIN OUTCOME MEASURES: History of diagnosed XFS or XFG. RESULTS: Any history of BCC or SCC in the head and neck region was associated with a 2-fold higher risk of having XFS or XFG versus having POAG or being a control subject (odds ratio [OR], 2.01; 95% confidence interval [CI], 1.04-3.89) in a multivariable-adjusted analysis. We observed a dose-response association in which the chance of having XFS or XFG increased by 67% per head and neck BCC or SCC occurrence (OR, 1.67; 95% CI, 1.09-2.56). When we excluded POAG participants, head and neck BCC or SCC was associated with a 2.8-fold higher risk of XFS or XFG (OR, 2.80; 95% CI, 1.12-7.02), and each additional occurrence had a 2-fold higher risk of XFS or XFG (OR, 1.97; 95% CI, 1.09-3.58). The association between head and neck region BCC or SCC and POAG compared with the control subjects was null (OR, 1.42; 95% CI, 0.58-3.48). With BCC or SCC located anywhere on the body, there was a nonsignificantly higher risk of having XFS or XFG compared with having POAG or being a control subject (OR, 1.65; 95% CI, 0.88-3.09). CONCLUSIONS: Head and neck region BCCs or SCCs are associated with a higher risk of having XFS or XFG. These findings support prior evidence that head and neck UV exposure may be a risk factor for XFS.

Refractive Outcomes of Uneventful Cataract Surgery in Pseudoexfoliation Syndrome and Pseudoexfoliation Glaucoma.

PURPOSE: To compare the refractive outcomes after cataract surgery between patients with and without pseudoexfoliation, and to evaluate the risk factors of refractive error. METHODS: Retrospective review of 210 eyes with pseudoexfoliation (study group) and 510 normal eyes (control group) that underwent uneventful phacoemulsification with intraocular lens implantation. The study group included pseudoexfoliation syndrome and pseudoexfoliation glaucoma (PXG) subgroups. The main outcome measure was refractive error, defined as the difference between the target refraction and postoperative refraction in diopter (D). A refractive error >±1.0 D was identified as a large-magnitude refractive error. The frequency of the large-magnitude refractive error was compared between study and control groups, and also between each subgroup and normal eyes. The factors influencing refractive error were analyzed by logistic regression. RESULTS: There was a significantly higher frequency of a refractive error >± 1.0 D and hyperopic error >1.0 D in the study group than in the control group (p = 0.001 and p = 0.003, respectively). In the multivariate logistic regression analysis, PXG and poor preoperative visual acuity were related with a large-magnitude refractive error (p = 0.001 and p = 0.02, respectively) Refractive error >± 1.0 D and hyperopic error >1.0 D were noted more often in PXG eyes that had an intraocular pressure spike >25 mmHg at postoperative first 24 hours (p = 0.01 and p=0.03, respectively). CONCLUSIONS: The eyes with pseudoexfoliation were at a high risk for refractive error, especially in the presence of glaucoma. In PXG, the only significant risk factor for refractive error was observed to be the presence of an intraocular pressure spike.

Association of the CYP39A1 G204E Genetic Variant with Increased Risk of Glaucoma and Blindness in Patients with Exfoliation Syndrome.

PURPOSE: Carriers of functionally deficient mutations in the CYP39A1 gene have been recently reported to have a 2-fold increased risk of exfoliation syndrome (XFS). The aim of this study was to evaluate the risk of blindness and related clinical phenotypes of XFS patients carrying the loss-of-function CYP39A1 G204E mutation in comparison with XFS patients without any CYP39A1 mutation. DESIGN: Retrospective case study. PARTICIPANTS: A total of 35 patients diagnosed with XFS carrying the CYP39A1 G204E mutation and 150 XFS patients without any CYP39A1 mutation who were randomly selected from the Japanese XFS cohort. METHODS: Two-sided Fisher exact test with an alpha level < 0.05 was used to estimate the significance of the calculated odds ratio (OR) for all categorical measures. Comparisons between groups of subjects were performed using linear mixed effect models with group as random effect and taking possible dependence between eyes within a subject into account. MAIN OUTCOME MEASURES: Primary analysis compared the incidence of blindness (defined as visual acuity [VA] < 0.05 decimal), prevalence of exfoliation glaucoma (XFG), history of glaucoma surgery, and indices of glaucoma severity such as visual field (VF) mean deviation (MD), intraocular pressure (IOP), and vertical cup-disc ratio (CDR) between CYP39A1 G204E carriers and those without any CYP39A1 mutation. RESULTS: The overall risk for blindness was significantly higher in XFS patients carrying the CYP39A1 G204E variant (10/35 [28.6%]) compared with XFS patients without any CYP39A1 mutations (8/150 [5.4%]; odds ratio [OR], 7.1; 95% confidence interval [CI], 2.7-20.2]; P < 0.001). A higher proportion of XFS patients with the CYP39A1 G204E mutation (23/35 [65.7%]) had evidence of XFG in at least 1 eye compared with the comparison group (41/150 [27.3%]; OR, 5.1; 95% CI, 2.4-11.4]; P < 0.0001). Significantly higher peak IOP, larger vertical CDR, and worse VF MD were also found in CYP39A1 G204E variant carriers (P < 0.001). Additionally, patients with the CYP39A1 G204E mutation (18/35 [51.4%]) required more laser or glaucoma surgical interventions compared with those without any CYP39A1 mutation (32/150 [21.3%], P < 0.001). CONCLUSIONS: Patients with XFS carrying the CYP39A1 G204E mutation had significantly increased risk of blindness, higher occurrence of XFG, and more severe glaucoma compared with patients with XFS without any CYP39A1 mutation.

Zonular defects in loxl1-deficient zebrafish.

BACKGROUND: To investigate the roles of the lysyl oxidase-like 1 (loxl1) gene in zebrafish eye development and the potency of loxl1 deficiency in mimicking the ocular manifestations of exfoliation syndrome (XFS). METHODS: CRISPR/Cas9 technology was used to generate a frameshift coding deletion in zebrafish loxl1. Expression profiles and ocular manifestations of the wildtype, heterozygous mutant (loxl1+/- ) and homozygous mutant (loxl1-/- ) zebrafish were analysed in a range of developmental stages from zebrafish larvae to dissected adult zebrafish eyes. RESULTS: The loxl1 deficiency caused zonular bundling disorders in juvenile zebrafish and accumulation of pearl-like particles adhering to the adult zebrafish zonule. The bundles appeared to lack form and were thinner in both loxl1+/- and loxl1-/- zebrafish compared with the wildtype (p < 0.01 for all Bonferroni post-hoc analyses). The zonule of loxl1-/- zebrafish appeared stretched, ragged and torn, with isolated fibres also detected. The particles in loxl1-/- zebrafish were more numerous (counts: 92.33 ± 10.02/100 µm2 vs. 58.33 ± 5.03/100 µm2 , p = 0.006), but smaller in size (diameter: 0.21 ± 0.03 µm vs. 0.43 ± 0.04 µm, p = 0.002) compared with those in loxl1+/- . Transmission electron microscopy revealed thinning or even loss of elastic lamina in loxl1+/- Bruch's membrane (BM) (thickness of elastic lamina: 92.94 ± 18.19 nm in the wildtype vs 35.65 ± 14.76 nm in loxl1+/- , p = 0.003). The breakage of BM was observed in loxl1-/- . CONCLUSIONS: The loxl1-/- zebrafish is a promising animal model of XFS zonular pathology.