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Kang JH, Loomis SJ, Rosner BA, Wiggs JL, Pasquale LR. Comparison of risk factor profiles for primary open angle glaucoma subtypes defined by pattern of visual field loss: a prospective study. Invest Ophthalmol Vis Sci 2015;Abstract

PURPOSE: We explored whether risk factor associations differed by primary open-angle glaucoma (POAG) subtypes defined by visual field (VF) loss pattern (i.e., paracentral or peripheral). METHODS: We included 77,157 women in the Nurses Health Study and 42,773 men in the Health Professionals Follow-up Study (1986-2010) and incident medical-record confirmed cases of paracentral (n=440) and peripheral (n=865) POAG subtypes. We evaluated African-heritage, glaucoma family history, body mass index (BMI), mean arterial blood pressure, diabetes mellitus, physical activity, smoking, caffeine and alcohol intakes. We used competing risk Cox regression analyses modeling age as the metameter and stratified by age, cohort and event type. We sequentially identified factors with the least significant differences in associations with POAG subtypes ("stepwise down" approach with P for heterogeneity [P-het]<0.10 as threshold). RESULTS: BMI was more inversely associated with the POAG paracentral VF loss subtype than the peripheral VF loss subtype (per 10 kg/m2; hazard ratio [HR]=0.67 [95% Confidence Interval [CI]: 0.52, 0.86] vs. HR=0.93 [95% CI: 0.78, 1.10]; P-het=0.03) as was smoking (per 10 pack-years; HR=0.92 [95% CI: 0.87, 0.98] vs. HR=0.98 [95% CI: 0.94, 1.01]; P-het=0.09). These findings were robust in sensitivity analyses using a "stepwise up" approach (identify factors that showed the most significant differences). Non-heterogeneous (p-het>0.10) adverse associations with both POAG subtypes were observed with glaucoma family history, diabetes, African-heritage, greater caffeine intake and higher mean arterial pressure. CONCLUSIONS: These data indicate that POAG with early paracentral VF loss has distinct as well as common determinants compared to POAG with peripheral VF loss.

Aung T, Ozaki M, Mizoguchi T, Allingham RR, Li Z, Haripriya A, Nakano S, Uebe S, Harder JM, Chan ASY, Lee MC, Burdon KP, Astakhov YS, Abu-Amero KK, Zenteno JC, Nilgün Y, Zarnowski T, Pakravan M, Safieh LA, Jia L, Wang YX, Williams S, Paoli D, Schlottmann PG, Huang L, Sim KS, Foo JN, Nakano M, Ikeda Y, Kumar RS, Ueno M, Manabe S-I, Hayashi K, Kazama S, Ideta R, Mori Y, Miyata K, Sugiyama K, Higashide T, Chihara E, Inoue K, Ishiko S, Yoshida A, Yanagi M, Kiuchi Y, Aihara M, Ohashi T, Sakurai T, Sugimoto T, Chuman H, Matsuda F, Yamashiro K, Gotoh N, Miyake M, Astakhov SY, Osman EA, Al-Obeidan SA, Owaidhah O, Al-Jasim L, Shahwan SA, Fogarty RA, Leo P, Yetkin Y, Oğuz Ç, Kanavi MR, Beni AN, Yazdani S, Akopov EL, Toh K-Y, Howell GR, Orr AC, Goh Y, Meah WY, Peh SQ, Kosior-Jarecka E, Lukasik U, Krumbiegel M, Vithana EN, Wong TY, Liu Y, Koch AAE, Challa P, Rautenbach RM, Mackey DA, Hewitt AW, Mitchell P, Wang JJ, Ziskind A, Carmichael T, Ramakrishnan R, Narendran K, Venkatesh R, Vijayan S, Zhao P, Chen X, Guadarrama-Vallejo D, Cheng CY, Perera SA, Husain R, Ho S-L, Welge-Luessen U-C, Mardin C, Schloetzer-Schrehardt U, Hillmer AM, Herms S, Moebus S, Nöthen MM, Weisschuh N, Shetty R, Ghosh A, Teo YY, Brown MA, Lischinsky I, Lischinsky I, Lischinsky I, Crowston JG, Coote M, Zhao B, Sang J, Zhang N, You Q, Vysochinskaya V, Founti P, Chatzikyriakidou A, Lambropoulos A, Anastasopoulos E, Coleman AL, Wilson RM, Rhee DJ, Kang JH, May-Bolchakova I, Heegaard S, Mori K, Alward WLM, Jonas JB, Xu L, Liebmann JM, Chowbay B, Schaeffeler E, Schwab M, Lerner F, Wang N, Yang Z, Frezzotti P, Kinoshita S, Fingert JH, Inatani M, Tashiro K, Reis A, Edward DP, Pasquale LR, Kubota T, Wiggs JL, Pasutto F, Topouzis F, Dubina M, Craig JE, Yoshimura N, Sundaresan P, John SWM, Ritch R, Hauser MA, Khor C-C. A common variant mapping to CACNA1A is associated with susceptibility to exfoliation syndrome. Nat Genet 2015;47(4):387-92.Abstract

Exfoliation syndrome (XFS) is the most common recognizable cause of open-angle glaucoma worldwide. To better understand the etiology of XFS, we conducted a genome-wide association study (GWAS) of 1,484 cases and 1,188 controls from Japan and followed up the most significant findings in a further 6,901 cases and 20,727 controls from 17 countries across 6 continents. We discovered a genome-wide significant association between a new locus (CACNA1A rs4926244) and increased susceptibility to XFS (odds ratio (OR) = 1.16, P = 3.36 × 10(-11)). Although we also confirmed overwhelming association at the LOXL1 locus, the key SNP marker (LOXL1 rs4886776) demonstrated allelic reversal depending on the ancestry group (Japanese: ORA allele = 9.87, P = 2.13 × 10(-217); non-Japanese: ORA allele = 0.49, P = 2.35 × 10(-31)). Our findings represent the first genetic locus outside of LOXL1 surpassing genome-wide significance for XFS and provide insight into the biology and pathogenesis of the disease.

Bunker S, Holeniewska J, Vijay S, Dahlmann-Noor A, Khaw P, Ng Y-S, Shima D, Foxton R. Experimental glaucoma induced by ocular injection of magnetic microspheres. J Vis Exp 2015;(96)Abstract

Progress in understanding the pathophysiology, and providing novel treatments for glaucoma is dependent on good animal models of the disease. We present here a protocol for elevating intraocular pressure (IOP) in the rat, by injecting magnetic microspheres into the anterior chamber of the eye. The use of magnetic particles allows the user to manipulate the beads into the iridocorneal angle, thus providing a very effective blockade of fluid outflow from the trabecular meshwork. This leads to long-lasting IOP rises, and eventually neuronal death in the ganglion cell layer (GCL) as well as optic nerve pathology, as seen in patients with the disease. This method is simple to perform, as it does not require machinery, specialist surgical skills, or many hours of practice to perfect. Furthermore, the pressure elevations are very robust, and reinjection of the magnetic microspheres is not usually required unlike in some other models using plastic beads. Additionally, we believe this method is suitable for adaptation for the mouse eye.

Wu H, de Boer JF, Chen L, Chen TC. Correlation of localized glaucomatous visual field defects and spectral domain optical coherence tomography retinal nerve fiber layer thinning using a modified structure-function map for OCT. Eye (Lond) 2015;29(4):525-33.Abstract

PurposeTo study the correlation between glaucomatous visual field (VF) defects assessed by standard automated perimetry (SAP) and peripapillary retinal nerve fiber layer (RNFL) thinning measured by spectral domain optical coherence tomography (OCT) using a modified OCT-based peripapillary RNFL structure-function map.Patients and methodsPerimetric glaucoma patients and age-matched normal control subjects were recruited from a university hospital clinic. All eyes underwent testing with the Spectralis spectral domain OCT and SAP on the same day. An OCT-based correspondence map, which correlated VF areas with peripapillary RNFL sectors was created to evaluate the relationship between glaucomatous RNFL thinning and VF loss in six nerve fiber layer bundle areas. Correlations of RNFL thinning with corresponding VF defects were examined using Spearman rank-order correlations. To demonstrate the association between localized VF defects and RNFL thickness, the theoretical curves were made according to an established log-linear model. The measured RNFL thickness values and VF defects were presented in the same scatterplot for each sector.ResultsFifty-six glaucoma patients and 85 normal subjects were included in the study. Significant association between localized VF loss and RNFL thinning was found in corresponding areas. Data from the current study fit well with established log-linear models, which compare RNFL thickness values with VF defects.ConclusionAnalysis of RNFL thinning in eyes with localized glaucomatous VF defects showed good structure-function correlation in a new OCT-based structure-function correspondence map.

Marra KV, Wagley S, Omar A, Kinoshita T, Kovacs KD, Silva P, Kuperwaser MC, Arroyo JG. Case-matched comparison of vitrectomy, peripheral retinal endolaser, and endocyclophotocoagulation versus standard care in neovascular glaucoma. Retina 2015;35(6):1072-83.Abstract

PURPOSE: To evaluate the efficacy of combination pars plana vitrectomy, endoscopic peripheral panretinal photocoagulation, and endocyclophotocoagulation (ECP) as compared with standard care in patients with neovascular glaucoma. METHODS: This age-matched case-controlled retrospective series of 54 eyes compared the clinical outcomes between a consecutive series of combination pars plana vitrectomy/panretinal photocoagulation/ECP (n = 27) versus the current standard of care (n = 27) for patients with neovascular glaucoma. "Standard" treatments for patients with neovascular glaucoma include panretinal photocoagulation, intravitreal bevacizumab, filtration surgery, pars plana vitrectomy, and Ahmed valve placement. RESULTS: After 1 year, mean intraocular pressure reduced from 40.7 ± 12.40 mmHg preoperatively to 12.3 ± 4.84 mmHg (P < 0.001) in the ECP group and from 34.7 ± 12.38 mmHg to 23.2 ± 12.34 mmHg in the control group (P = 0.002). Compared with controls, the mean drop in intraocular pressure in the ECP group was significantly greater at all postoperative visits. Logarithm of the minimal angle of resolution visual acuity outcomes were similar in both groups. There were 2 cases (7.4%) of postoperative phthisis bulbi in each group. CONCLUSION: Endoscopic pars plana vitrectomy, panretinal photocoagulation, and ECP seem to control intraocular pressure to a greater extent than standard glaucoma treatments in patients with neovascular glaucoma. In this aged-matched comparative case series, there was no significant difference between the two treatments' effects on visual acuity.

Liu Y, Simavli H, Que CJ, Rizzo JL, Tsikata E, Maurer R, Chen TC. Patient characteristics associated with artifacts in Spectralis optical coherence tomography imaging of the retinal nerve fiber layer in glaucoma. Am J Ophthalmol 2015;159(3):565-76.e2.Abstract

PURPOSE: To determine patient factors and eye conditions associated with artifacts in Spectralis optical coherence tomography (OCT) retinal nerve fiber layer (RNFL) scans. DESIGN: Retrospective cross-sectional study. METHODS: The prevalence of 12 artifact types were described in this review of 2313 eye scans from 1188 patients who underwent a complete eye examination with Spectralis OCT scanning during the period of September 2009 to July 2013. The generalized estimating equations model was used to analyze associations between increased artifact prevalence and 10 patient characteristics, which included age, sex, race, visual acuity, refractive error, astigmatism, cataract status, glaucoma staging, visual field reliability, and glaucoma diagnosis. RESULTS: A total of 1070 or 46.3% of the 2313 eye scans had at least 1 artifact. Decentration error was the most common artifact (27.8%), followed by posterior vitreous detachment artifacts (14.4%). Visual acuity of less than 20/40 (P < .0001), presence of moderate to severe cataracts (P < .0001), advanced stage of glaucoma (P < .0001), and a diagnosis of open-angle glaucoma (P = .0003) were associated with increased prevalence of artifacts. CONCLUSIONS: Clinicians should first assess scans for artifacts before making therapeutic decisions based on RNFL thickness measurements.

Simavli H, Que CJ, Akduman M, Rizzo JL, Tsikata E, de Boer JF, Chen TC. Diagnostic capability of peripapillary retinal thickness in glaucoma using 3D volume scans. Am J Ophthalmol 2015;159(3):545-56.e2.Abstract

PURPOSE: To determine the diagnostic capability of spectral-domain optical coherence tomography (SD OCT) peripapillary retinal thickness (RT) measurements from 3-dimensional (3D) volume scans for primary open-angle glaucoma (POAG). DESIGN: Cross-sectional study. METHODS: setting: Institutional. study population: 156 patients (89 POAG and 67 normal subjects). observation procedures: One eye of each subject was included. SD OCT peripapillary RT values from 3D volume scans were calculated for 4 quadrants of 3 different sized annuli. Peripapillary retinal nerve fiber layer (RNFL) thickness values were also determined. main outcome measures: Area under the receiver operating characteristic curve (AUROC) values, sensitivity, specificity, positive and negative predictive values, and positive and negative likelihood ratios. RESULTS: The top 5 RT AUROCs for all glaucoma patients and for a subset of early glaucoma patients were for the inferior quadrant of outer circumpapillary annulus of circular grid (OCA) 1 (0.959, 0.939), inferior quadrant of OCA2 (0.945, 0.921), superior quadrant of OCA1 (0.890, 0.811), inferior quadrant of OCA3 (0.887, 0.854), and superior quadrant of OCA2 (0.879, 0.807). Smaller RT annuli OCA1 and OCA2 consistently showed better diagnostic performance than the larger RT annulus OCA3. For both RNFL and RT measurements, best AUROC values were found for inferior RT OCA1 and OCA2, followed by inferior and overall RNFL thickness. CONCLUSION: Peripapillary RT measurements from 3D volume scans showed excellent diagnostic performance for detecting both glaucoma and early glaucoma patients. Peripapillary RT values have the same or better diagnostic capability compared to peripapillary RNFL thickness measurements, while also having fewer algorithm errors.

Qian CX, Hassanaly S, Harissi-Dagher M. Anterior Segment Optical Coherence Tomography in the Long-Term Follow-up andDetection of Glaucoma in Boston TypeIKeratoprosthesis. Ophthalmology 2015;122(2):317-25.Abstract

PURPOSE: To evaluate the role of anterior segment (AS) optical coherence tomography (OCT) as a standardized method of imaging Boston type I keratoprosthesis (KPro) after surgery, particularly in the visualization of iris and angle structures. DESIGN: Prospective case series. PARTICIPANTS: Twenty patients who underwent KPro implantation in 1 eye. METHODS: Patients underwent AS OCT imaging before surgery. After KPro implantation, patients were imaged using the AS single, dual, and quad scans to obtain transverse images of the eye every 15° over 360°. High-resolution, corneal quad, and anterior chamber scans were also obtained. This imaging protocol allowed juxtaposition and comparison of the same imaging coordinates obtained before surgery and 3, 6, and 12 months after surgery. MAIN OUTCOME MEASURES: Postoperative visual acuity (VA), glaucoma progression on clinical examination and formal visual field testing, and anatomic angle changes on AS OCT defined by angle closure, peripheral anterior synechiae (PAS), iris-KPro backplate touch, and graft-host interface changes over time. RESULTS: Mean follow-up was 18.8±3.2 months. The average preoperative VA was 1.9±0.5 logarithm of the minimum angle of resolution. After surgery, VA improved to 1.0±0.9 at last follow-up (P = 0.002). Fourteen of 20 patients had glaucoma before surgery. After surgery, 5 of these patients deteriorated clinically and 1 de novo diagnosis of glaucoma was made. On OCT, the average total degrees of angle closure for all patients increased from 158.5±158.9° before surgery to 205.4±154.0° after surgery (P = 0.04). The number of eyes with 360° of PAS increased from 6 of 20 before surgery to 9 of 20 after surgery. Iris-backplate touch was demonstrated in 5 of 20 patients, with an average area of involvement of 24.2±36.2°. Overall, of the 12 of 20 patients with clear signs of anatomic angle narrowing and synechiae progression on imaging, 3 had glaucoma deterioration detected by clinical examination. In the other 9 patients, angle changes on OCT were not accompanied by any detectable clinical signs of glaucomatous deterioration. CONCLUSIONS: Anterior segment OCT can be used to observe anatomic changes after KPro implantation that cannot be detected otherwise. We were unable to demonstrate a correlation between anatomic features and clinical progression.

Radcliffe NM, Smith SD, Syed ZA, Park SC, Ehrlich JR, De Moraes CG, Liebmann JM, Ritch R. Retinal blood vessel positional shifts and glaucoma progression. Ophthalmology 2014;121(4):842-8.Abstract
PURPOSE: To determine the characteristics and significance of retinal blood vessel (RBV) positional shifts over time in a cohort of patients with progressive glaucoma. DESIGN: Retrospective cohort study. PARTICIPANTS: Baseline and serial stereophotographs from 1 eye of 125 patients with open-angle glaucoma with ≥8 reliable Swedish interactive threshold algorithm standard visual fields (VFs) were included. On the basis of global rates of threshold sensitivity change, patients with glaucoma were divided into groups of minimal (<-0.02 decibels [dB]/year), moderate (-0.02 to -0.65 dB/year), or fast (≥-0.65 dB/year) progression. To determine whether graders' assessments of RBV positional shifts were false-positives, a control group consisting of 33 patients with glaucoma with 2 sets of photographs taken on the same day was included. METHODS: Masked graders reviewed serial photographs aligned with automated alternation flicker (EyeIC, Narbeth, PA) and assessed them for the presence of any discrete RBV positional shifts (2 graders) and for traditional measures of structural progression (2 graders), including neuroretinal rim loss, parapapillary atrophy progression, and disc hemorrhage (DH). MAIN OUTCOME MEASURES: Presence or absence of RBV positional shifts, rates of VF progression, and presence or absence of traditional measures of structural progression. RESULTS: A total of 158 image sets (125 longitudinal and 33 same-day controls) from patients with glaucoma were included. Retinal blood vessel shifts were noted in 33 of 125 (26.4%) longitudinally followed glaucomatous eyes and 2 of 33 (6%) same-day control patients (P = 0.01). Agreement between graders I and II was 90.4% (kappa=0.77; P< 0.001). Eyes with RBV positional change progressed more rapidly than those without (-0.55 vs. -0.29 dB/year; 95% confidence interval [CI], 0.03-0.48); P = 0.03). Retinal blood vessel shift was present in 12.1% of minimal progressors versus 31.5% of moderate and fast progressors (P = 0.04). Rate of VF progression was statistically associated with RBV shift (odds ratio [OR], 2.2; 95% CI, 1.1-4.5; P = 0.03). Other variables significantly associated with RBV shift included neuroretinal rim loss (OR, 21.9; 95% CI, 5.7-83.6; P< 0.001) and DH (OR, 4.6; 95% CI, 1.5-15.5; P< 0.01). A multivariable model revealed that rim loss and DH, but not rate of functional change, were significantly associated with RBV shift. CONCLUSIONS: Retinal blood vessel positional shifts occurred in eyes with functionally progressive glaucoma, neuroretinal rim loss, and DH. This is a novel clinical finding that could help identify glaucoma progression or individuals at higher risk for future progression.
Kang JH, Loomis SJ, Yaspan BL, Bailey JC, Weinreb RN, Lee RK, Lichter PR, Budenz DL, Liu Y, Realini T, Gaasterland D, Gaasterland T, Friedman DS, McCarty CA, Moroi SE, Olson L, Schuman JS, Singh K, Vollrath D, Wollstein G, Zack DJ, Brilliant M, Sit AJ, Christen WG, Fingert J, Forman JP, Buys ES, Kraft P, Zhang K, Allingham RR, Pericak-Vance MA, Richards JE, Hauser MA, Haines JL, Wiggs JL, Pasquale LR. Vascular tone pathway polymorphisms in relation to primary open-angle glaucoma. Eye (Lond) 2014;28(6):662-71.Abstract
AIMS: Vascular perfusion may be impaired in primary open-angle glaucoma (POAG); thus, we evaluated a panel of markers in vascular tone-regulating genes in relation to POAG. METHODS: We used Illumina 660W-Quad array genotype data and pooled P-values from 3108 POAG cases and 3430 controls from the combined National Eye Institute Glaucoma Human Genetics Collaboration consortium and Glaucoma Genes and Environment studies. Using information from previous literature and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we compiled single-nucleotide polymorphisms (SNPs) in 186 vascular tone-regulating genes. We used the 'Pathway Analysis by Randomization Incorporating Structure' analysis software, which performed 1000 permutations to compare the overall pathway and selected genes with comparable randomly generated pathways and genes in their association with POAG. RESULTS: The vascular tone pathway was not associated with POAG overall or POAG subtypes, defined by the type of visual field loss (early paracentral loss (n=224 cases) or only peripheral loss (n=993 cases)) (permuted P≥0.20). In gene-based analyses, eight were associated with POAG overall at permuted P<0.001: PRKAA1, CAV1, ITPR3, EDNRB, GNB2, DNM2, HFE, and MYL9. Notably, six of these eight (the first six listed) code for factors involved in the endothelial nitric oxide synthase activity, and three of these six (CAV1, ITPR3, and EDNRB) were also associated with early paracentral loss at P<0.001, whereas none of the six genes reached P<0.001 for peripheral loss only. DISCUSSION: Although the assembled vascular tone SNP set was not associated with POAG, genes that code for local factors involved in setting vascular tone were associated with POAG.
Kang JH, Wiggs JL, Pasquale LR. Relation between time spent outdoors and exfoliation glaucoma or exfoliation glaucoma suspect. Am J Ophthalmol 2014;158(3):605-14.e1.Abstract
PURPOSE: To evaluate the relation between time spent outdoors at various life periods and risk of exfoliation glaucoma or exfoliation glaucoma suspect. DESIGN: Retrospective cohort study in the United States. METHODS: Participants (49 033 women in the Nurses Health Study and 20 066 men in the Health Professionals Follow-up Study) were 60+ years old, were free of glaucoma and cataract, reported eye examinations, and completed questions about time spent outdoors in direct sunlight at midday at 3 life periods: high school to age 24 years, age 25-35 years, and age 36-59 years (asked in 2006 in women and 2008 in men). Participants were followed biennially with mailed questionnaires from 1980 women/1986 men to 2010. Incident cases (223 women and 38 men) were confirmed with medical records. Cohort-specific multivariable-adjusted rate ratios from Cox proportional hazards models were estimated and pooled with meta-analysis. RESULTS: Although no association was observed with greater time spent outdoors in the ages of 25-35 or ages 36-59 years, the pooled multivariable-adjusted rate ratios for ≥11 hours per week spent outdoors in high school to age 24 years compared with ≤5 hours per week was 2.00 (95% confidence interval = 1.30, 3.08; P for linear trend = .001). In women, this association was stronger in those who resided in the southern geographic tier in young adulthood (P for interaction = .07). CONCLUSIONS: Greater time spent outdoors in young adulthood was associated with risk of exfoliation glaucoma or exfoliation glaucoma suspect, supporting an etiologic role of early exposures to climatic factors.
Villarreal G, Chatterjee A, Oh SS, Oh D-J, Rhee DJ. Pharmacological regulation of SPARC by lovastatin in human trabecular meshwork cells. Invest Ophthalmol Vis Sci 2014;55(3):1657-65.Abstract
PURPOSE: Statins have been shown to increase aqueous outflow facility. The matricellular protein SPARC (secreted protein acidic and rich in cysteine) is a critical mediator of aqueous outflow and intraocular pressure (IOP). Here, we examine the effects of lovastatin on SPARC expression in trabecular meshwork (TM) cells, exploring the molecular mechanisms involved. METHODS: Primary cultured human TM cells were incubated for 24, 48, and 72 hours with 10 μM lovastatin. In separate cultures, media was supplemented with either farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP) for the duration of the 72-hour time point experiment. Trabecular meshwork cells were also pretreated for 24 hours with lovastatin followed by 24-hour stimulation with 3 ng/mL TGF-β2. Cell lysates and media were harvested and relative mRNA and protein level changes were determined. Krüppel-like factor 4 (KLF4) localization in normal human anterior segments was examined by immunofluorescence. Adenovirus expressing human KLF4 was used and relative changes in SPARC mRNA and protein levels were assessed. RESULTS: Incubating TM cells with lovastatin suppressed SPARC mRNA and protein levels. This effect was reversed upon media supplementation with GGPP but not FPP. Pretreating cells with lovastatin inhibited TGF-β2 induction of SPARC. The KLF4 transcription factor was expressed throughout the TM and the inner and outer walls of Schlemm's canal. Lovastatin treatment upregulated KLF4 mRNA and protein levels. Overexpression of KLF4 downregulated SPARC expression. CONCLUSIONS: Collectively, our data identify lovastatin as an important pharmacological suppressor of SPARC expression in TM cells, and provide further insight into the molecular mechanisms mediating statin enhancement of aqueous outflow facility.
Wiggs JL, Pawlyk B, Connolly E, Adamian M, Miller JW, Pasquale LR, Haddadin RI, Grosskreutz CL, Rhee DJ, Li T. Disruption of the blood-aqueous barrier and lens abnormalities in mice lacking lysyl oxidase-like 1 (LOXL1). Invest Ophthalmol Vis Sci 2014;55(2):856-64.Abstract
PURPOSE: Exfoliation syndrome (ES) is commonly associated with glaucoma, premature cataracts, and other ocular and systemic pathologies. LOXL1 gene variants are significantly associated with ES; however, the role of the protein in ES development remains unclear. The purpose of this study was to characterize the ocular phenotype in Loxl1(-/-) (null) mice. METHODS: Loxl1 null mice and strain-matched controls (C57BL) were evaluated by clinical and histologic analyses. RESULTS: Anterior segment histology showed a pronounced vesiculation of the anterior lens in the null mice. The lesions were subcapsular and in direct apposition with the posterior iris surface. Fluorescein angiography showed increased diffusion of fluorescein into the anterior chamber of the null mice compared with age-matched controls (P = 0.003, two-tailed, unequal variance t-test), suggesting compromise of the blood-aqueous barrier. Intraocular pressure measurements were within the normal range (16.5 ± 2.0 mm Hg) in null mice up to 1 year of age. Immunohistochemistry showed decreased elastin in the iris and ciliary body in the null mouse compared with controls. CONCLUSIONS: Elimination of LOXL1 in mice impairs the blood-aqueous humor barrier in the ocular anterior segment and causes lens abnormalities consistent with cataract formation, but does not result in deposition of macromolecular material or glaucoma. These results show that mice lacking LOXL1 have some ES features but that complete disease manifestation requires other factors that could be genetic and/or environmental.
Turalba AV, Shah AS, Andreoli MT, Andreoli CM, Rhee DJ. Predictors and outcomes of ocular hypertension after open-globe injury. J Glaucoma 2014;23(1):5-10.Abstract
PURPOSE: Evaluate predictors and outcomes of ocular hypertension after open-globe injury. PATIENTS AND METHODS: This is a retrospective, case-control study reviewing records of consecutive patients with open-globe injuries treated at Massachusetts Eye and Ear Infirmary between February 1999 and January 2007. Of 658 patients treated, 382 had at least 2 months of follow-up and sufficient data to be included. Main outcome measures are visual acuity, intraocular pressure (IOP), and type of glaucoma intervention employed. RESULTS: Sixty-five (17%) patients developed ocular hypertension defined as IOP≥22 mm Hg at >1 visit or requiring treatment. Increased age (P<0.001), hyphema (0.025), lens injury (P<0.0001), and zone II injury (P=0.0254) are risk factors for developing ocular hypertension after open-globe injury. Forty-eight (74%) patients with ocular hypertension were treated medically, 8 (12%) underwent filtering or glaucoma drainage device surgery, 5 (8%) had IOP normalization with observation, while 4 (6%) required anterior chamber washout with no other glaucoma surgery. Patients with ocular hypertension had an average maximum IOP=33.4 mm Hg at a median follow-up of 21 days, with most patients maintaining normal IOP at all follow-up time points. Visual acuity improved over time with median acuity of hand motions preoperatively, and 20/60 at 12 and 36 months. CONCLUSIONS: Ocular hypertension is a significant complication after open-globe injury that sometimes requires surgical intervention. Predictive factors can alert physicians to monitor for elevated IOP in the first month after trauma. Most patients with traumatic ocular hypertension had improved visual acuity and IOP normalization over time.
Truong TN, Li H, Hong Y-K, Chen L. Novel characterization and live imaging of Schlemm's canal expressing Prox-1. PLoS One 2014;9(5):e98245.Abstract
Schlemm's canal is an important structure of the conventional aqueous humor outflow pathway and is critically involved in regulating the intraocular pressure. In this study, we report a novel finding that prospero homeobox protein 1 (Prox-1), the master control gene for lymphatic development, is expressed in Schlemm's canal. Moreover, we provide a novel in vivo method of visualizing Schlemm's canal using a transgenic mouse model of Prox-1-green fluorescent protein (GFP). The anatomical location of Prox-1⁺ Schlemm's canal was further confirmed by in vivo gonioscopic examination and ex vivo immunohistochemical analysis. Additionally, we show that the Schlemm's canal is distinguishable from typical lymphatic vessels by lack of lymphatic vessel endothelial hyaluronan receptor (LYVE-1) expression and absence of apparent sprouting reaction when inflammatory lymphangiogenesis occurred in the cornea. Taken together, our findings offer new insights into Schlemm's canal and provide a new experimental model for live imaging of this critical structure to help further our understanding of the aqueous humor outflow. This may lead to new avenues toward the development of novel therapeutic intervention for relevant diseases, most notably glaucoma.

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