Exfoliation Syndrome Glaucoma Research Articles

Mass cytometry and transcriptomic profiling reveal body-wide pathology induced by Loxl1 deficiency.

ObjectiveThe loss of LOXL1 expression reportedly leads to the prolapse of pelvic organs or to exfoliation syndrome glaucoma. Increasing evidence suggests that LOXL1 deficiency is associated with the pathogenesis of several other diseases. However, the characterization of the systemic functions of LOXL1 is limited by the lack of relevant investigative technologies.Materials and MethodsTo determine the functions of LOXL1, a novel method for body‐wide organ transcriptome profiling, combined with single‐cell mass cytometry, was developed. A body‐wide organ transcriptomic (BOT) map was created by RNA‐Seq of tissues from 17 organs from both Loxl1 knockout (KO) and wild‐type mice.ResultsThe BOT results indicated the systemic upregulation of genes encoding proteins associated with the immune response and proliferation processes in multiple tissues of KO mice, and histological and immune staining confirmed the hyperplasia and infiltration of local immune cells in the tissues of KO mice. Furthermore, mass cytometry analysis of peripheral blood samples revealed systemic immune changes in KO mice. These findings were well correlated with results obtained from cancer databases. Patients with tumours had higher Loxl1 mutation frequencies, and patients with Loxl1‐mutant tumours showed the upregulation of immune processes and cell proliferation and lower survival rates.ConclusionThis study provides an effective strategy for the screening of gene functions in multiple organs and also illustrates the important biological roles of LOXL1 in the cells of multiple organs as well as in systemic immunity.

A Comparison of Resource Use and Costs of Caring for Patients With Exfoliation Syndrome Glaucoma Versus Primary Open-Angle Glaucoma

To characterize differences in resource utilization and cost of managing enrollees with exfoliation glaucoma (XFG) compared to primary open-angle glaucoma (POAG). Retrospective utilization and cost comparison using Medicare claims data. We identified Medicare beneficiaries with XFG or POAG and ≥5 years of continuous enrollment from January 2008 to December 2014. We distinguished newly diagnosed cases from those with preexisting disease. We compared ophthalmic resource utilization and costs over 2 years of follow-up for persons with newly diagnosed and preexisting XFG vs those with POAG. Main outcome measures were number of clinic visits, diagnostic procedures, medication fills, laser and incisional surgery, and mean eye care costs per beneficiary. Among 192 eligible enrollees (median age 77.6 years) with newly diagnosed XFG and 7339 enrollees (median age 77.3 years) with newly diagnosed POAG, those with XFG had more office visits (mean, 9.1 vs 7.9; P= .001), cataract surgery (34.9% vs 19.0%; P < .0001), and glaucoma surgery (28.7% vs 19.7%, P= .002). They also experienced 27% higher mean total eye care costs ($3260 vs $2562, P=.0001) over 2 years of follow-up. Among 2745 enrollees (median age 80.5 years) with preexisting XFG and 89 036 persons (median age 79.5) with preexisting POAG, persons with XFG had more office visits (mean 9.3 vs 7.3; P < .0001), perimetry (85.3% vs 79.8%; P < .0001), cataract surgery (23.4% vs 12.3%; P<.0001), laser trabeculoplasty (18.6% vs 9.6%; P< .0001), and trabeculectomy (8.1 vs 1.8%; P<.0001) and experienced 37% higher total mean eye care costs ($3764 vs $2739; P < .0001). Healthcare resource utilization and costs are substantially higher for managing patients with XFG compared to POAG.

Medical Management of Glaucoma in Exfoliation Syndrome.

The treatment of glaucoma in exfoliation syndrome is similar to primary open-angle glaucoma. Frequently, exfoliation glaucoma (XFG) patients require early polytherapy with topical medications. Little emphasis has been placed on tailoring treatment specifically to XFG. New outflow enhancing agents with novel mechanisms of action, such as Rho Kinase inhibition, NO signaling (both recently FDA-approved drugs) and adenosine α1-receptor stimulation, act directly on the trabecular meshwork. These agents may prove to be effective in lowering intraocular pressure and perhaps altering the pathogenesis of XFG aid in the long-term management of this disease.

Mechanisms of Glaucoma in Exfoliation Syndrome.

The most important characteristic of exfoliation syndrome (XFS) is that it involves a greater risk of developing glaucoma. In comparison with other forms of open-angle glaucoma, exfoliation glaucoma is more resistant to medical therapy and progresses faster. Possible pathologic mechanisms of glaucoma development in XFS comprise: (1) elevated intraocular pressure (IOP) caused by functional impairment of aqueous humor outflow due to deposition of exfoliation material in the trabecular meshwork and trabecular cell dysfunction, (2) XFS-associated connective tissue elastosis leading to structural and functional alterations of the lamina cribrosa which increases the vulnerability toward elevated IOP and development of glaucomatous optic neuropathy, (3) elevated IOP due to closure of the anterior chamber angle accompanied by forward displacement of the crystalline lens due to zonular weakness, (4) presumable primary functional impairment of retinal ganglion cells. In addition to the discovery of lysyl oxidase-like 1, further genetic associations have been identified and knowledge related to XFS etiology and pathophysiology has markedly increased over the past 10 years. Further cell biological investigations navigated by the molecular genetics underlying XFS will eventually lead to a better understanding of the complex mechanisms of exfoliation glaucoma.

Recent Advances in the Surgical Management of Glaucoma in Exfoliation Syndrome.

Surgical and laser procedures traditionally used in the management of exfoliation glaucoma (XFG) include laser trabeculoplasty, trabeculectomy, and glaucoma drainage implant surgery. Having demonstrated similar safety and efficacy in XFG compared with primary open-angle glaucoma, trabeculectomy remains the most commonly performed surgery in XFG. Recent trends in practice patterns in developed nations demonstrate a shift towards glaucoma drainage implant surgery, which is currently the procedure of choice in XFG for many, particularly in developed nations. In addition, cataract surgery alone may significantly decrease intraocular pressure in patients with XFG, may prevent glaucoma development in patients with exfoliation syndrome, and is recommended to be performed early in the course of the disease. With the relatively recent introduction of nonpenetrating glaucoma surgery and the ongoing evolution of minimally invasive glaucoma surgery, several other surgical procedures have now become part of the glaucoma surgeon's armamentarium when treating XFG, including the Ex-PRESS shunt, deep sclerectomy, viscocanalostomy, Trabectome, as well as angle procedures. These techniques have demonstrated promising results in various types of glaucoma. More research is, however, needed to establish the safety and efficacy of these procedures in XFG.

Laser Management of Glaucoma in Exfoliation Syndrome.

Argon laser trabeculoplasty as well as selective laser trabeculoplasty can be used in patients with exfoliation syndrome with similar safety and efficacy. However, treatment effect may abruptly reverse and patients need to be followed regularly to monitor intraocular pressure control. Newer laser treatment modalities including micropulse laser trabeculoplasty, titanium sapphire laser trabeculoplasty and pattern scanning trabeculoplasty show promising results but need to be studied in exfoliation patients. For exfoliation patients with angle closure, peripheral iridectomy, iridoplasty or cataract extraction can be very helpful. For refractory exfoliation glaucoma, transscleral diode laser cyclophotocoagulation offers a reasonable option to lower intraocular pressure. Other approaches to cyclophotocoagulation such as micropulse transcleral diode laser need to be studied further in exfoliation patients.

Is Autophagy Dysfunction a Key to Exfoliation Glaucoma?

In this short report we review previous work toward the identification of the protein and cellular sources of exfoliation glaucoma and described our recent finding on dysfunction of autophagy in Tenon capsule fibroblasts obtained from exfoliation syndrome glaucoma patients at the time of surgery and discuss the potential implications of these findings for understanding the cellular sources of the disease.

Evaluation of LOXL1 polymorphisms in exfoliation syndrome in the Uygur population

In this study, we evaluate the association profiles of the lysyl oxidase-like 1 ( LOXL1) gene polymorphisms with exfoliation syndrome in XFS Uygur population. Case-control study. Sixty-four unrelated Uygur patients with XFS (including 7 patients with Exfoliation Syndrome Glaucoma) and 127 Uygur control subjects were included. All of control subjects were selected from the same area, passed through the same ophthalmic checks and confirmed without any expressions of XFS. Most of them suffered from cataract and other ophthalmic disease.Genotypes of the three single nucleotide polymorphisms (SNPs) of LOXL1 (rs1048661, rs2165241 and rs3825942) were analyzed by direct sequencing following PCR amplification, and a case-control association study was performed and judged by odd ratio (OR) with (95% confidential interval). G allele of rs1048661 [OR:1.92 (1.14-3.22)], G of rs3825942 [OR:4.86 (2.02-11.68)], and T of rs2165241[OR:3.98 (2.54-6.25)] were risk alleles for the disorder. The genotypes TT for rs2165241 [OR:2.20 (1.04-4.65)] were risk genotypes for the disease. LOXL1 is a susceptibility gene of XFS in the Uygur populations. The risk alleles of rs1048661, rs3825942 and rs2165241 in Uygur subjects were identified to be significantly associated with XFS individually.

Common variants at 9p21 and 8q22 are associated with increased susceptibility to optic nerve degeneration in glaucoma.

Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10−18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10−11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10−12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10−10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.

Combined exfoliation and pigment dispersion : Paradigm of an overlap syndrome

Objective To describe a series of patients with combined pigment dispersion syndrome (PDS) and exfoliation syndrome (XFS) and to introduce a concept, the overlap syndrome, to aid in assessing multiple risk factors for glaucomatous damage. Design Clinic-based, cross-sectional study. Setting New York Eye and Ear Infirmary. Participants Twenty-six patients identified from the glaucoma database as having combined pigment dispersion syndrome–glaucoma and exfoliation syndrome–glaucoma. Main outcome measures Quantification of patients with both pigment dispersion syndrome–glaucoma (PDS/PG) and exfoliation syndrome–glaucoma (XFS/XFG) and its clinical implications. Results Among the 26 patients (all white) having both XFS/XFG and PDS/PG, the average age was 64.3 ± 9.8 years and 19 of 26 were men. All patients had bilateral PDS/PG. Bilateral XFS/XFG was present in 9 of 26 patients and, of the 17 patients with unilateral involvement, the left eye was affected in 13. Conclusions Both XFS and PDS are common. Middle-aged patients with known PDS/PG should be suspected of having the onset of XFS if one eye escapes intraocular pressure control. Patients with unilateral XFG at presentation may also have signs of PDS/PG, often remitted. We define the term overlap syndrome to describe the sequential appearance over time of two or more risk factors for glaucomatous damage. The appearance of a new risk factor in a patient whose condition has been stable can alter the course and prognosis of the disease. This concept should prove useful in dealing with secondary and normal-tension glaucomas.

Factors Affecting the Results of Argon Laser Trabeculoplasty in Open-Angle Glaucoma

Argon laser trabeculoplasty (ALT) was performed in 232 eyes of 180 patients affected by uncontrolled primary open-angle glaucoma (POAG), exfoliation syndrome glaucoma (ESG) or pigment dispersion syndrome glaucoma (PDSG). Mean follow-up was 9 months (3-22). Mean IOP change was -21.6% (+/- 19) from the initial value. The effect of IOP was larger in patients with ESG, PDSG, and in POAG cases with more pigmented trabecular meshwork. No relationship was found between IOP changes and age or refraction of patients; the association with iridoplasty did not influence final results. An Octopus computerized perimeter was used for pre and post-treatment visual field tests. In 113 eyes Octopus exams met the requirements for quantitative analysis. In this group 17% of visual field improved, 64% remained stable and 19% worsened. A good functional response was more frequent among the eyes with less advanced disease.

Argon laser trabeculoplasty in exfoliation syndrome.

A retrospective study of the effects of argon laser trabeculoplasty on a consecutive series of 44 phakic patients (55 eyes) with exfoliation syndrome glaucoma is reported. The follow-up was 12 to 23 months, mean 15 months. At an individual level laser trabeculoplasty was successful in 70% of the patients and 40% were able to reduce or stop their medication. Two patients showed 'late failure' at 15 months after initial control. An early rise of intraocular pressure was fairly common in the exfoliation group, and perhaps these patients need particularly careful monitoring during the initial hours following argon laser trabeculoplasty. A beneficial effect was noted on diurnal curve fluctuations and peak intraocular pressures.