Steady-State Pattern Electroretinography in Eyes with Glaucoma and High Myopia.

PURPOSE: To investigate features of the steady-state pattern electroretinogram (ssPERG) in subjects with glaucoma (G), high myopia (HM; spherical equivalent ≤-6D) and glaucoma with high myopia (GHM). PATIENTS AND METHODS: Our study included 48 participants divided into 3 groups (G, HM, and GHM) who each underwent monocular ssPERG testing with Diopsys NOVA PERG protocols. The ConStim protocol detects distinct topographic patterns of dysfunction 16° and 24° around the central macula. MagD is the amplitude of the average signal and MagD/Mag ratio indicates the consistency of the response. ssPERG indices were compared between groups and correlated with functional (ie, visual field mean deviation (VFMD)) and structural (ie, average retinal nerve fibre layer (RNFL) thickness; Cirrus optical coherence tomography) features. RESULTS: Participants had an average age of 59.4±7.6 years. Mean Humphrey VFMD was -14.22 ± 2.88dB, -2.62 ± 1.18dB and -12.80 ± 2.60dB for G, HM and GHM groups, respectively. Mean RNFL thickness was 63.0 ± 8.20µm, 69.5 ± 15.7µm and 60.6 ± 5.0µm for G, HM and GHM groups, respectively. For the 24° setting, no significant differences were noted for any of the parameters. For the 16° setting, MagD was lower in the GHM group compared to the HM group (0.29µV vs 0.52µV; p = 0.02). Significant differences were noted for the MagD/Mag ratio between HM and G groups (0.58 vs 0.40; p = 0.02) and between HM and GHM groups (0.58 vs 0.35; p = 0.002). There were positive correlations between both MagD 16° and MagD/Mag ratio 16° with VFMD (correlation coefficient [r]=0.37, p = 0.009; and r = 0.44, p = 0.002, respectively) and RNFL (r = 0.43, p = 0.002; and r = 0.48, p = 0.001, respectively). CONCLUSION: MagD/Mag ratio at 16° was significantly lower in glaucomatous eyes (with or without high myopia) compared to those with high myopia without glaucoma, suggesting that glaucoma has a distinct impact on MagD/Mag ratio at 16° irrespective of the presence of myopia.

Spatio-Temporal In Vivo Imaging of Ocular Drug Delivery Systems using Fiberoptic Confocal Laser Microendoscopy.

Subconjunctival injection is an attractive route to administer ocular drugs due to easy trans-scleral access that bypasses anterior ocular barriers, such as the cornea and conjunctiva. While therapeutic effects and pharmacokinetics of the drugs upon subconjunctival injection have been described in some studies, very few assess the ocular distribution of drugs or drug delivery systems (DDS). The latter is critical for the optimization of intraocular DDS design and drug bioavailability to achieve the desired ocular localization and duration of action (e.g., acute versus. prolonged). This study establishes the use of fiberoptic confocal laser microendoscopy (CLM) to qualitatively study the ocular distribution of fluorescent liposomes in real-time in live mice after sub-conjunctival injection. Being designed for in vivo visual inspection of tissues at the microscopic level, this is also the first full description of the CLM imaging method to study spatio-temporal distribution of injectables in the eye after subconjunctival injection.

In vivo fate of liposomes after subconjunctival ocular delivery.

Subconjunctival administration of nanocarriers presents an alternative drug delivery strategy to overcome blood-ocular barriers to enhance drug bioavailability to specific parts of the eye. Using fiberoptic Confocal Laser Microendoscopy (CLM) and radiotracing, we describe the effects of charge, size, cholesterol content and lipid saturation on the ocular and corporal distribution of liposome nanocarriers in live mouse models. Positively charged or large (>250 nm) liposomes exhibit sustained ocular residence times in and around the injection site; cholesterol loading slows down this clearance, whereas lipid saturation accelerates clearance. Neutral, negatively charged, or smaller sized liposomes distribute to the limbus, rich in stem cells and blood capillaries. Differential lymphatic and systemic clearance from the eye to corporeal tissues was also observed across formulations. These results demonstrate the need to optimize liposome design for control over temporal and spatial nanocarrier bioavailability and clearance from the eye for improved efficacy and safety of ocular therapeutics.

Inhibition of Monocyte Chemoattractant Protein 1 Prevents Conjunctival Fibrosis in an Experimental Model of Glaucoma Filtration Surgery.

Purpose: To evaluate the effect of treatment with monocyte chemoattractant protein-1 receptor inhibitor (MCP-Ri) to maintain bleb survival and prevent fibrosis in an experimental model of glaucoma filtration surgery (GFS). Methods: GFS was performed on one eye of C57/Bl6 mice (n = 36) that was treated with MCP-Ri, mitomycin-C (MMC), or vehicle at the time of surgery. Real-time polymerase chain reaction was used to evaluate conjunctival expression of monocyte chemoattractant protein-1 (MCP-1), TGFB1, TGFB2, collagen 1a1 (Col1a1), sparc (Sparc), and fibronectin at 2 and 7 days following surgery. Anterior segment slit-lamp examination, optical coherence tomography, and confocal microscopy were performed in vivo at day 14. Eyes were processed for immunohistochemical staining of F4/80, a monocyte-macrophage marker, at day 2. In vitro experiments were also performed to compare the effect of MMC, MCP-Ri, and vehicle on the viability of mouse Tenon's fibroblasts. Results: Treatment with MCP-Ri results in a greater reduction in the percentage of F4/80-positive cells in conjunctival blebs and lesser MCP-1 gene expression following experimental GFS than MMC or control. Both MMC and MCP-Ri reduced Col1a1 and Sparc expression, but not fibronectin. TGFB1 decreased with MCP-Ri but not MMC; MMC but not MCP-Ri reduced TGFB2. MMC and MCP-Ri treatment resulted in the preservation of bleb height at day 14, as compared to control. MCP-Ri was less toxic to mouse Tenon's fibroblasts in comparison with MMC. Conclusions: Targeting MCP-1 results in prolonged bleb survival following experimental GFS with less cellular toxicity as compared to MMC. MCP inhibition could provide a safer alternative to conventional antifibrotic adjunctive treatments in GFS.

Ocular lubricant use in medically and surgically treated glaucoma: a retrospective longitudinal analysis.

BACKGROUND: Chronic use of intraocular pressure-lowering medications is associated with ocular surface disease (OSD). In this study, we assess the incidence of topical lubricant use as a surrogate marker for underlying OSD, in medically and surgically treated glaucoma patients. METHODS: Retrospective chart review was performed for newly diagnosed glaucoma patients who were started on topical medications in 2007 and followed up over a 5-year period. Primary outcome measure was the incidence of topical lubricant use in these patients and a subset of these patients who required glaucoma or cataract surgery during follow-up. RESULTS: Charts of 505 newly diagnosed glaucoma patients with no prior history of ocular lubricant use were analyzed. Mean age was 63.9 years (SD 11.1), 42.8% were women. One hundred one (20.0%) patients underwent phacoemulsification surgery, 80 underwent mitomycin C (MMC) augmented phacotrabeculectomy, 16 underwent MMC-augmented trabeculectomy and 3 underwent tube surgery during the course of follow-up as their only type of surgery. Five-year incidence of lubricant use was 59% in all glaucoma subjects; 54.1% of patients were on medical treatment and 74.0% of patients who underwent phacotrabeculectomy or trabeculectomy were started on lubricants, respectively (P=0.0011); 60.4% of glaucoma subjects who underwent phacoemulsification surgery were started on lubricants. Incidence of lubricant use increased from 17.7% preoperatively to 74.0% postoperatively in subjects who required trabeculectomy or phacotrabeculectomy. Incidence of lubricant use was similar in patients on one or multiple glaucoma medications, with the mean onset of lubricant use being 10 months after starting glaucoma medication in both groups. Females were more likely to use artificial tears compared with males (P=0.002). CONCLUSION: Both medical and surgical management of glaucoma have an adverse effect on the ocular surface. Chronic use of glaucoma medications was associated with a high incidence of ocular lubricant use. MMC-augmented trabeculectomy was associated with an even higher incidence of ocular lubricant use.

Randomized, controlled trial of a sustained delivery formulation of 5-fluorouracil for the treatment of failing blebs.

PURPOSE: To determine the efficacy of a subconjunctival injection of hyaluronic acid (HA) with 5-fluorouracil (5FU) formulation as an adjunct in reviving bleb function by needling. DESIGN: Prospective, randomized, controlled trial. PARTICIPANTS: Fifty patients with previous trabeculectomy and scheduled by the managing physician for a needling intervention. METHODS: One eye of each patient was randomized to receive needling with HA-5FU mixture or needling with subconjunctival injection of 5FU solution alone. MAIN OUTCOME MEASURES: The primary outcome was the percentage of subjects with an intraocular pressure (IOP) <15 mmHg without any medications at 3 months. Secondary outcomes included the need for additional needling procedures and changes in bleb morphology. RESULTS: Forty-nine subjects (25 in the HA-5FU group and 24 in the 5FU group) completed 3 months of follow-up. At baseline, there was no significant difference between the groups in terms of demographic features, subtype of glaucoma, vertical cup-to-disc ratio, or visual field indices. The mean number of glaucoma medications at baseline was higher in the 5FU group (0.8±1.1 [mean ± standard deviation] vs. 0.2±0.6, P = 0.04). An IOP <15 mmHg without medications was reached in 48.0% of subjects in the HA-5FU group and in 33.3% of subjects in the 5FU group (P = 0.2). At 3 months, both groups demonstrated a significant decrease in IOP from baseline (HA-5FU: decrease of 5.9 mmHg [95% confidence interval, 3.4-8.4]; 5FU: decrease of 6.0 mmHg [95% confidence interval, 3.2-8.2]; P<0.001 for both). Intergroup comparisons for IOP change from baseline was not significant (P = 0.9). However, repeat needling was required more frequently in the 5FU group compared with the HA-5FU group (50.0% vs. 12.0%; P = 0.004). There were no significant differences in the number of reported adverse events, bleb vascularity, or morphology between the 2 groups. CONCLUSIONS: Subconjunctival injection of HA-5FU to revive bleb function after bleb needling is as effective as 5FU solution. Fewer repeat needlings were required after treatment with HA-5FU, suggesting that the use of a combined formulation of HA-5FU may improve the overall outcomes of bleb needlings.