Neovascular glaucoma (NVG) is a secondary ocular pathological condition resulting from a myriad of ocular and systemic conditions with retinal ischemia as a mediator in over 95% of cases. NVG is caused by the growth of a fibrovascular membrane secondary to a local angiogenic stimulus over the trabecular meshwork obstructing aqueous outflow. This results in an initial secondary open-angle glaucoma stage that may be amenable to intraocular pressure (IOP)-lowering medications and modulation of the underlying ischemic process, often in combination with panretinal photocoagulation and adjunctive use of vascular endothelial growth factor inhibitors. In the more advanced stages of neovascularization, connective tissue myofibroblasts associated with new vessel growth contract causing progressive synechial closure of the anterior-chamber angle. Elevation of IOP, once significant secondary angle closure is established, tends to be refractory to topical and oral IOP-lowering medications and often requires glaucoma surgical interventions.

Glaucoma is a leading cause of blindness worldwide. Primary open-angle glaucoma (POAG) is the most common subtype and is a complex trait with multigenic inheritance. Genome-wide association studies have previously identified a significant association between POAG and the SIX6 locus (rs10483727, odds ratio (OR) = 1.32, p = 3.87×10−11). SIX6 plays a role in ocular development and has been associated with the morphology of the optic nerve. We sequenced the SIX6 coding and regulatory regions in 262 POAG cases and 256 controls and identified six nonsynonymous coding variants, including five rare and one common variant, Asn141His (rs33912345), which was associated significantly with POAG (OR = 1.27, p = 4.2×10−10) in the NEIGHBOR/GLAUGEN datasets. These variants were tested in an in vivo Danio rerio (zebrafish) complementation assay to evaluate ocular metrics such as eye size and optic nerve structure. Five variants, found primarily in POAG cases, were hypomorphic or null, while the sixth variant, found only in controls, was benign. One variant in the SIX6 enhancer increased expression of SIX6 and disrupted its regulation. Finally, to our knowledge for the first time, we have identified a clinical feature in POAG patients that appears to be dependent upon SIX6 genotype: patients who are homozygous for the SIX6 risk allele (His141) have a statistically thinner retinal nerve fiber layer than patients homozygous for the SIX6 non-risk allele (Asn141). Our results, in combination with previous SIX6 work, lead us to hypothesize that SIX6 risk variants disrupt the development of the neural retina, leading to a reduced number of retinal ganglion cells, thereby increasing the risk of glaucoma-associated vision loss.

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PurposeThis study was designed to evaluate the changes in aqueous humor dynamics (AHD) produced by selective laser trabeculoplasty (SLT) and to explore if baseline AHD parameters are predictive of IOP response to SLT.MethodsThirty-one consecutive subjects diagnosed with ocular hypertension or primary open-angle glaucoma scheduled to undergo SLT as their primary IOP-lowering therapy were enrolled in this prospective observational study. Subjects underwent baseline assessment of AHD in both eyes. Variables assessed were IOPs at 9 AM and noon, aqueous humor flow rate (fluorophotometry), episcleral venous pressure (EVP, venomanometry), outflow facility (pneumatonography and fluorophotometry) and uveoscleral outflow (calculated using modified Goldmann equation). All subjects underwent 360 degrees SLT and AHD measurements were repeated 3 months later.ResultsCompared with baseline, IOPs after SLT were significantly lower at 9 AM (22.9 ± 5.1 vs. 19.7 ± 3.0 mm Hg; P = 0.001) and noon (23.4 ± 4.6 vs. 20.0 ± 3.5 mm Hg; P < 0.001). Outflow facility by fluorophotometry was significantly increased from 0.17 ± 0.11 μL/min/mm Hg at baseline to 0.24 ± 0.14 μL/min/mm Hg at 3 months (P = 0.008). Outflow facility by tonography (baseline: 0.16 ± 0.07 μL/min/mm Hg vs. 3 months: 0.22 ± 0.16 μL/min/mm Hg; P = 0.046) was similarly increased. No change in aqueous flow or EVP was observed. There were no changes in IOP or AHD in the contralateral untreated eye. Using multiple linear regression models, higher baseline aqueous flow, lower baseline outflow facility, and possibly lower uvescleral outflow were associated with more IOP lowering with SLT.ConclusionsThe IOP-lowering effect of SLT is mediated through an increase in outflow facility. There is no contralateral effect. Higher aqueous flow and lower outflow facility may be predictive of better response to SLT.

Y-27632 and H-1152 lower IOP in rabbits and hypertensive eyes of NHPs for at least 6 h after single doses. The Y-27632 effect on IOP in hypertensive NHP eyes is caused by increases in outflow facility and uveoscleral outflow. An increase in aqueous humor formation attenuates but does not prevent an IOP decrease.