VEGF-A-induced changes in distal outflow tract structure and function.

PURPOSE: To investigate changes in distal outflow tract vessels caused by VEGF-A and their impact on outflow. METHODS: We compared VEGF-A perfused porcine anterior segments with and without trabecular meshwork (TM) to control eyes. In the first experiment (n=48), we analyzed live changes of the outflow tract with spectral-domain optical coherence tomography (SD-OCT) over 3 h and reconstructed them in 3D. In a second experiment (n=32), we measured the intraocular pressure (IOP) variation in response to VEGF-A over 48 h and computed the outflow facility. RESULTS: VEGF-A increased the vessel volume of the distal outflow tract by 16.8±10.6% while control eyes remained unchanged (0.5±6.8%). Volume changes occurred within the first 100 min before plateauing at 140 min. VEGF-A enhanced the outflow facility in eyes without TM by 38.6±25.5% at 24 h as compared to controls (p<0.05). CONCLUSION: VEGF-A dilated vessels of the distal outflow tract and increased the outflow facility even after TM removal, pointing to a regulatory mechanism independent of proximal structures.

[Continuous Optimisation of Experimental Models - an Example from Glaucoma Research]. / Die kontinuierliche Optimierung von experimentellen Modellen ­ Darstellung an einem Beispiel aus der Glaukomforschung.

BACKGROUND: There is a great demand for suitable models to test novel surgical and therapeutic approaches in glaucoma therapy. To address this need and to provide further alternatives to in vivo animal models, we aimed at modifying an established in vitro porcine eye perfusion model. METHODS: Two weaknesses of the previously established porcine anterior segment model include media leakage during perfusion and setup disintegration due to mechanical instability. To overcome these, we slightly modified the previously used custom-made perfusion dishes and incorporated new components into the model setup. To prevent fluid leakage, we secured the anterior segments more firmly to the perfusion trays using a compression ring, steel screws, and nuts. Customised mounts were used to stabilise the perfusion dish and pressure transducer as a single unit. The mounts were made of polylactide (PLA) and printed using a 3D printer. RESULTS: The use of steel screws and nuts allowed tighter clamping of the anterior segments and prevented medium leakage. Our PLA custom mounts stabilised the entire assembly and facilitated handling during experiments and improved comparability between tested eyes. They also prevented accidental detachment of the pressure transducers, which resulted in more stable pressure curves. Our PLA mounts tolerated incubation temperatures of up to 37 °C and disinfection with enzymatic detergents and 70% ethanol without showing signs of deformation or degradation after four months of regular usage. CONCLUSION: Modifications introduced to an established in vitro perfusion model improved its efficacy and reproducibility. Our adjusted model is an example of how many models can be optimised through critical analysis, thereby saving resources and providing reliable results in the long run.

Tissue-engineered anterior segment eye cultures demonstrate hallmarks of conventional organ culture.

BACKGROUND: Glaucoma is a blinding disease largely caused by dysregulation of outflow through the trabecular meshwork (TM), resulting in elevated intraocular pressure (IOP). We hypothesized that transplanting TM cells into a decellularized, tissue-engineered anterior segment eye culture could restore the outflow structure and function. METHODS: Porcine eyes were decellularized with freeze-thaw cycles and perfusion of surfactant. We seeded control scaffolds with CrFK cells transduced with lentiviral vectors to stably express eGFP and compared them to scaffolds seeded with primary TM cells as well as to normal, unaltered eyes. We tracked the repopulation behavior, performed IOP maintenance challenges, and analyzed the histology. RESULTS: Transplanted cells localized to the TM and progressively infiltrated the extracellular matrix, reaching a distribution comparable to normal, unaltered eyes. After a perfusion rate challenge to mimic a glaucomatous pressure elevation, transplanted and normal eyes reestablished a normal intraocular pressure (transplanted = 16.5 ± 0.9 mmHg, normal = 16.9 ± 0.9). However, eyes reseeded with eGFP-expressing CrFK cells could not regulate IOP, remaining high and unstable (27.0 ± 6.2 mmHg) instead. CONCLUSION: Tissue-engineered anterior segment scaffolds can serve as readily available, scalable ocular perfusion cultures. This could reduce dependency on scarce donor globes in outflow research and may allow engineering perfusion cultures with specific geno- and phenotypes.

Inter-eye correlation analysis of 24-h IOPs and glaucoma progression.

PURPOSE: To determine whether 24-h IOP monitoring can be a predictor for glaucoma progression and to analyze the inter-eye relationship of IOP, perfusion, and progression parameters. METHODS: We extracted data from manually drawn IOP curves with HIOP-Reader, a software suite we developed. The relationship between measured IOPs and mean ocular perfusion pressures (MOPP) to retinal nerve fiber layer (RNFL) thickness was analyzed. We determined the ROC curves for peak IOP (Tmax), average IOP(Tavg), IOP variation (IOPvar), and historical IOP cut-off levels to detect glaucoma progression (rate of RNFL loss). Bivariate analysis was also conducted to check for various inter-eye relationships. RESULTS: Two hundred seventeen eyes were included. The average IOP was 14.8 ± 3.5 mmHg, with a 24-h variation of 5.2 ± 2.9 mmHg. A total of 52% of eyes with RNFL progression data showed disease progression. There was no significant difference in Tmax, Tavg, and IOPvar between progressors and non-progressors (all p > 0.05). Except for Tavg and the temporal RNFL, there was no correlation between disease progression in any quadrant and Tmax, Tavg, and IOPvar. Twenty-four-hour and outpatient IOP variables had poor sensitivities and specificities in detecting disease progression. The correlation of inter-eye parameters was moderate; correlation with disease progression was weak. CONCLUSION: In line with our previous study, IOP data obtained during a single visit (outpatient or inpatient monitoring) make for a poor diagnostic tool, no matter the method deployed. Glaucoma progression and perfusion pressure in left and right eyes correlated weakly to moderately with each other.

Exact matching of trabectome-mediated ab interno trabeculectomy to conventional trabeculectomy with mitomycin C followed for 2 years.

PURPOSE: We used exact matching for a highly balanced comparison of ab interno trabeculectomy (AIT) with the trabectome to trabeculectomy with mitomycin C (TRAB). METHODS: A total of 5485 patients who underwent AIT were exact-matched to 196 TRAB patients by baseline intraocular pressure (IOP), number of glaucoma medications, and glaucoma type. Nearest-neighbor-matching was applied to age. Success was defined as a final IOP of less than 21 mmHg, IOP reduction of at least 20% reduction from baseline, and no secondary surgical interventions. Outcomes were measured at 1, 3, 6, 12, 18, and 24 months. RESULTS: A total of 165 AIT could be matched to 165 TRAB. The mean baseline IOP was 22.3 ± 5.6 mmHg, and the baseline number of glaucoma medications was 2.7 ± 1.1 in both groups. At 24 months, IOP was reduced to 15.8 ± 5.2 mmHg in AIT and 12.4 ± 4.7 mmHg in TRAB. IOP was lower than baseline at all visits (p < 0.01) and lower in TRAB than AIT (p < 0.01). Glaucoma medications were reduced to 2.1 ± 1.3 in AIT and 0.2 ± 0.8 in TRAB. Compared to baseline, patients used fewer drops postoperatively (p < 0.01) and more infrequently in TRAB than in AIT (p > 0.01). Secondary surgical interventions had the highest impact on success and became necessary in 15 AIT and 59 TRAB patients. Thirty-two challenging events occurred in TRAB and none in AIT. CONCLUSION: Both AIT and TRAB reduced IOP and medications. This reduction was more significant in TRAB but at the expense of four times as many secondary interventions.

Comparison of a second-generation trabecular bypass (iStent inject) to ab interno trabeculectomy (Trabectome) by exact matching.

PURPOSE: To achieve a highly balanced comparison of trabecular bypass stenting (IS2, iStent inject) with ab interno trabeculectomy (T, Trabectome) by exact matching. METHODS: Fifty-three IS2 eyes were matched to 3446 T eyes. Patients were matched using exact matching by baseline intraocular pressure (IOP), the number of glaucoma medications, and glaucoma type, and using nearest neighbor matching by age. Individuals without a close match were excluded. All surgeries were combined with phacoemulsification. RESULTS: A total of 78 eyes (39 in each group) could be matched as exact pairs with a baseline IOP of 18.3 ± 5.1 mmHg and glaucoma medications of 2.7 ± 1.2 in each. IOP in IS2 was reduced to 14.6 ± 4.2 mmHg at 3 months and in T to a minimum of 13.1 ± 3.2 mmHg at 1 month. In IS2, IOP began to rise again at 6 months, eventually exceeding baseline. At 24 months, IOP in IS2 was 18.8 ± 9.0 mmHg and in T 14.2 ± 3.5 mmHg. IS2 had a higher average IOP than T at all postoperative visits (p < 0.05 at 1, 12, 18 months). Glaucoma medications decreased to 2.0 ± 1.5 in IS2 and to 1.5 ± 1.4 in T. CONCLUSION: T resulted in a larger and sustained IOP reduction compared with IS2 where a rebound occurred after 6 months to slightly above preoperative values.

Dose-dependent effects of netarsudil, a Rho-kinase inhibitor, on the distal outflow tract.

PURPOSE: To characterize the effects of netarsudil on the aqueous humor outflow tract distal to the trabecular meshwork (TM). We hypothesized that netarsudil increases outflow facility in eyes with and without circumferential ab interno trabeculectomy (AIT) that removes the TM. METHODS: Sixty-four porcine anterior segment cultures were randomly assigned to groups with (n = 32) and without circumferential AIT (n = 32). Cultures were exposed to 0.1, 1, and 10 µM netarsudil (N = 8 eyes per concentration). For each concentration, IOP and vessel diameters were compared with their respective pretreatment baselines. Outflow tract vessel diameters were assessed by spectral-domain optical coherence tomography (SDOCT) and rendered in 4D (XYZ time series). RESULTS: Netarsudil at 1 µM reduced IOP both in eyes with TM (- 0.60 ± 0.24 mmHg, p = 0.01) and in eyes without TM (- 1.79 ± 0.42 mmHg, p < 0.01). At this concentration, vessels of the distal outflow tract dilated by 72%. However, at 0.1 µM netarsudil elevated IOP in eyes with TM (1.59 ± 0.36 mmHg, p < 0.001) as well as in eyes without TM (0.23 ± 0.32 mmHg, p < 0.001). Vessels of the distal outflow tract constricted by 31%. Similarly, netarsudil at a concentration of 10 µM elevated IOP both in eyes with TM (1.91 ± 0.193, p < 0.001) and in eyes without TM (3.65 ± 0.86 mmHg, p < 0.001). At this concentration, outflow tract vessels constricted by 27%. CONCLUSION: In the porcine anterior segment culture, the dose-dependent IOP changes caused by netarsudil matched the diameter changes of distal outflow tract vessels. Hyper- and hypotensive properties of netarsudil persisted after TM removal.

SALT Trial: Steroids after Laser Trabeculoplasty: Impact of Short-Term Anti-inflammatory Treatment on Selective Laser Trabeculoplasty Efficacy.

PURPOSE: This study examined whether short-term use of topical nonsteroidal anti-inflammatory drug (NSAID) or steroid therapy affected the efficacy of selective laser trabeculoplasty (SLT). DESIGN: Double-masked, randomized, placebo-controlled, dual-center, multisurgeon trial. PARTICIPANTS: Patients older than 18 years with intraocular pressure (IOP) of more than 18 mmHg for whom the clinician decided SLT was the appropriately indicated therapy were randomized to 1 of 3 groups in a ratio of 1:1:1 as follows: ketorolac 0.5%, prednisolone 1%, or saline tears. METHODS: After SLT, patients randomized into each group were instructed to use an unmarked drop 4 times daily starting the day of SLT and continuing for 4 additional days. The Kruskal-Wallis test and Wilcoxon rank-sum test were used for continuous variables when comparing 2 or 3 treatment groups, respectively. The Fisher exact test was used for categorical variables. MAIN OUTCOME MEASURES: The primary outcome of this study was IOP at 12 weeks. Secondary outcome measures included IOP at 1 and 6 weeks, patient-reported pain, and detectable anterior chamber inflammation. RESULTS: Ninety-six eyes of 85 patients fit inclusion criteria and were enrolled between the 2 sites. The NSAID, steroid, and placebo groups were similar in baseline demographics and baseline IOP (mean, 23.3±3.9 mmHg; P = 0.57). There was no statistically significant difference in IOP decrease among groups at week 6. Both the NSAID and steroid groups showed a statistically significantly greater decrease in IOP at week 12 compared with the placebo group (mean, -6.2±3.1 mmHg, -5.2±2.7 mmHg, and -3±4.3 mmHg, respectively; P = 0.02 [analysis of variance] and P = 0.002 [t test] for NSAID vs. placebo groups; P = 0.02 for steroid vs. placebo groups). CONCLUSIONS: Significantly better IOP reduction at 12 weeks was measured in eyes treated with steroid or NSAID drops after SLT. Short-term postoperative use of NSAID or steroid drops may improve IOP reduction after SLT. Longer-term follow-up studies are indicated.

RKI-1447, a Rho kinase inhibitor, causes ocular hypotension, actin stress fiber disruption, and increased phagocytosis.

PURPOSE: This study investigated the hypotensive effect of RKI-1447, a Rho kinase inhibitor, in a porcine ex vivo pigmentary glaucoma model. METHODS: Twenty-eight porcine anterior chambers were perfused with medium supplemented with 1.67 × 107 pigment particles/ml for 48 h before treatment with RKI-1447 (n = 16) or vehicle control (n = 12). Intraocular pressure (IOP) was recorded and outflow facility was calculated. Primary trabecular meshwork cells were exposed to RKI-1447 or vehicle control; effects on the cytoskeleton, motility, and phagocytosis were evaluated. RESULT: Compared to baseline, the perfusion of pigment caused a significant increase in IOP in the RKI-1447 group (P = 0.003) at 48 h. Subsequent treatment with RKI-1447 significantly reduced IOP from 20.14 ± 2.59 to 13.38 ± 0.91 mmHg (P = 0.02). Pigment perfusion reduced the outflow facility from 0.27 ± 0.03 at baseline to 0.18 ± 0.02 at 48 h (P < 0.001). This was partially reversed with RKI-1447. RKI-1447 caused no apparent histological changes in the micro- or macroscopic TM appearance. RKI-1447-treated primary TM cells showed significant disruption of the actin cytoskeleton both in the presence and absence of pigment (P < 0.001) but no effect on TM migration was observed. Pigment-treated TM cells exhibited a reduction in TM phagocytosis, which RKI-1447 reversed. CONCLUSION: RKI-1447 significantly reduces IOP by disrupting TM stress fibers and increasing TM phagocytosis. These features may make it useful for the treatment of secondary glaucomas with an increased phagocytic load.

Five-year clinical outcomes of combined phacoemulsification and trabectome surgery at a single glaucoma center.

PURPOSE: To analyze the 5-year results of trabectome ab interno trabeculectomy of a single glaucoma center. METHOD: In this retrospective interventional single-center case series, data of 93 patients undergoing ab interno trabeculotomy between September 2010, and December 2012 were included. Kaplan-Meier analysis was performed using success criteria defined as postoperative intraocular pressure (IOP) ≤ 21 mmHg, and > 20% reduction from preoperative IOP, and no need for further glaucoma surgery. Risk factors for failure were identified using Cox proportional hazards ratio (HR). RESULTS: The retention rate for 5-year follow-up was 66%. The cumulative probability of success at 1, 2, 3, 4, and 5 years was 82.6%, 76.7%, 73.9%, 72.3%, and 67.5%. Risk factors for failure were lower baseline IOP (HR = 0.27, P = 0.001), younger age (HR = 0.25, P = 0.02), and higher central corneal thickness (HR = 0.18, P = 0.01). Exfoliative glaucoma was associated with a higher success rate (HR = 0.39, P = 0.02). IOP was decreased significantly from 20.0 ± 5.6 mmHg at baseline to 15.6 ± 4.6 mmHg at 5-year follow-up (P = 0.001). The baseline number of glaucoma medications was 1.8 ± 1.2, which decreased to 1.0 ± 1.2 medications at 5 years. CONCLUSION: Trabectome surgery was associated with a good long-term efficacy and safety profile in this single-center case series with a high retention rate.

Impact of pigment dispersion on trabecular meshwork cells.

PURPOSE: Dysfunction of the trabecular meshwork (TM) in pigmentary glaucoma contributes to increased aqueous humor outflow resistance and intraocular pressure. In this study, we investigated the effect of pigment dispersion on trabecular meshwork cells. METHODS: Porcine TM cells from ab interno trabeculectomy specimens were exposed to pigment dispersion, then, analyzed for changes in morphology, immunostaining, and ultrastructure. Their abilities to phagocytose migrate, and contraction was quantified. An expression microarray, using 23,937 probes, and a pathway analysis were performed. RESULTS: Stress fiber formation was increased in the pigment dispersion group (P) (60.1 ± 0.3%, n = 10) compared to control (C) (38.4 ± 2.5%, n = 11, p < 0.001). Phagocytosis declined (number of cells with microspheres in P = 37.0 ± 1.1% and in C = 68.7 ± 1.3%, n = 3, p < 0.001) and migration was reduced after 6 h (cells within the visual field over 6 h in P = 28.0.1 ± 2.3 (n = 12) and in C = 40.6 ± 3.3 (n = 13), p < 0.01). Pigment induced contraction at 24 h onwards (p < 0.01). Microarray analysis revealed that Rho signaling was central to these responses. CONCLUSION: Exposure of TM cells to pigment dispersion resulted in reduced phagocytosis and migration, as well as increased stress fiber formation and cell contraction. The Rho signaling pathway played a central and early role, suggesting that its inhibitors could be used as a specific intervention in treatment of pigmentary glaucoma.

Outflow facility and extent of angle closure in a porcine model.

PURPOSE: To establish the extent of anterior chamber angle circumference needed to maintain a physiological outflow facility (C). This could create a model to investigate focal outflow regulation. METHODS: Twenty anterior segments of porcine eyes were assigned to five groups, each with a different degree of cyanoacrylate-mediated angle closure: 90° (n = 4), 180° (n = 4), 270° (n = 4), 360° (n = 4), and four unoccluded control eyes. The outflow facility was measured at baseline, 3, 12, 24, and 36 h after angle closure. Outflow patterns were evaluated with canalograms and the histomorphology was compared. RESULTS: Baseline outflow facilities of the five groups were similar (F = 0.922, p = 0.477). Occlusion of 360° induced a significant decrease in facility from baseline at all time-points (p ≤ 0.023 at 3, 12, 24, and 36 h). However, no difference from baseline was found in any of the partially occluded (0-270°) groups (F ≥ 0.067, p ≥ 0.296 at 3, 12, 24, and 36 h). The canalograms confirmed the extent of occlusion with flow through the unblocked regions. Histology revealed no adverse effects of blockage on the TM or aqueous plexus in the unoccluded angle portions. The unoccluded TM appeared normal. CONCLUSION: Cyanoacrylate-mediated angle occlusion created a reproducible angle closure model. Ninety degrees of unoccluded anterior chamber angle circumference was sufficient to maintain physiological outflow. This model may help understand how outflow can be regulated in healthy, nonglaucomatous TM.

Factors associated with lamina cribrosa displacement after trabeculectomy measured by optical coherence tomography in advanced primary open-angle glaucoma.

PURPOSE: To investigate the relationship of lamina cribrosa displacement to corneal biomechanical properties and visual function after mitomycin C-augmented trabeculectomy. METHOD: Eighty-one primary open-angle eyes were imaged before and after trabeculectomy using an enhanced depth spectral domain optical coherence tomography (SDOCT). Corneal biomechanical properties were measured with the ocular response analyzer before the surgery. The anterior lamina cribrosa (LC) was marked at several points in each of the six radial scans to evaluate LC displacement in response to intraocular pressure (IOP) reduction. A Humphrey visual field test (HVF) was performed before the surgery as well as 3 and 6 months, postoperatively. RESULTS: Factors associated with a deeper baseline anterior lamina cribrosa depth (ALD) were cup-disc ratio (P = 0.04), baseline IOP (P = 0.01), corneal hysteresis (P = 0.001), and corneal resistance factor (P = 0.001). After the surgery, the position of LC became more anterior (negative), posterior (positive), or remained unchanged. The mean LC displacement was - 42 µm (P = 0.001) and was positively correlated with the magnitude of IOP reduction (regression coefficient = 0.251, P = 0.02) and negatively correlated with age (regression coefficient = - 0.224, P = 0.04) as well as baseline cup-disk ratio (Regression coefficient = - 0.212, P = 0.05). Eyes with a larger negative LC displacement were more likely to experience an HVF improvement of more than a 3 dB gain in mean deviation (P = 0.002). CONCLUSION: A larger IOP reduction and younger age was correlated with a larger negative LC displacement and improving HVF. The correlation between lower SDOCT cup-disc ratio and postoperative negative LC displacement was borderline (P = 0.05). Corneal biomechanics did not predict LC displacement.

Outflow enhancement by three different ab interno trabeculectomy procedures in a porcine anterior segment model.

PURPOSE: To evaluate three different microincisional ab interno trabeculectomy procedures in a porcine eye perfusion model. METHODS: In perfused porcine anterior segments, 90° of trabecular meshwork (TM) was ablated using the Trabectome (T; n = 8), Goniotome (G; n = 8), or Kahook device (K; n = 8). After 24 h, additional 90° of TM was removed. Intraocular pressure (IOP) and outflow facility were measured at 5 and 10 µl/min perfusion to simulate an elevated IOP. Structure and function were assessed with canalograms and histology. RESULTS: At 5 µl/min infusion rate, T resulted in a greater IOP reduction than G or K from baseline (76.12% decrease versus 48.19% and 47.96%, P = 0.013). IOP reduction between G and K was similar (P = 0.420). Removing another 90° of TM caused an additional IOP reduction only in T and G but not in K. Similarly, T resulted in the largest increase in outflow facility at 5 µl/min compared with G and K (first ablation, 3.41 times increase versus 1.95 and 1.87; second ablation, 4.60 versus 2.50 and 1.74) with similar results at 10 µl/min (first ablation, 3.28 versus 2.29 and 1.90 (P = 0.001); second ablation, 4.10 versus 3.01 and 2.01 (P = 0.001)). Canalograms indicated circumferential flow beyond the ablation endpoints. CONCLUSIONS: T, G, and K significantly increased the outflow facility. In this model, T had a larger effect than G and K.

Low iris and anterior chamber volume is associated with deepening after laser peripheral iridotomy in primary angle closure suspects.

PURPOSE: To evaluate the association between baseline ocular variables and the widening of the anterior chamber angle by laser peripheral iridotomy (LPI) in primary angle closure suspects (PACS) using a new Fourier-domain swept-source anterior segment optical coherence tomography (FD-ASOCT). METHOD: Sixty-six PACS eyes of 41 individuals were enrolled in this prospective interventional case series. An FD-ASOCT (Casia SS-1000 OCT; Tomey, Nagoya, Japan) was used to measure biometric baseline variables and at 1 month after the LPI. Paired t test was used to compare the difference between pre-and post-LPI measurements. Multivariate regression analysis was used to test for an association between baseline iris thickness and volume, anterior chamber depth and volume, and lens vault with a widening of the angle after an LPI. Changes in trabecular iris space area and angle opening distance after the LPI were main outcome measures. RESULTS: The mean age of participants was 58.6 ± 8.7 years, 68.2% of whom were female. The angle opening distance, recess area, and trabecular iris surface area at 500 µm increased by 48 to 73% (all P < 0.001). Lens vault and iris volume did not change. A low anterior chamber volume and low iris volume were associated with angle greater deepening by LPI. CONCLUSION: Eyes with a shallow anterior chamber and thinner irises are more likely to experience angle opening from an LPI.

Impact of same-session trabectome surgery on Ahmed glaucoma valve outcomes.

PURPOSE: To evaluate the efficacy and survival rates of same session ab interno trabeculectomy with the trabectome and Ahmed glaucoma valve implant (AT) in comparison to the Ahmed glaucoma valve alone (A). METHOD: A total of 107 eyes undergoing primary glaucoma surgery were enrolled in this retrospective comparative case series, including 48 eyes which underwent AT and 59 eyes which received A alone. Participants were identified using the procedural terminology codes, and their medical records were reviewed. The primary outcome measure was success defined as IOP > 5 mmHg, ≤ 21 mmHg and ≥ 20% reduction of IOP from baseline at two consecutive visits after 3 months, and no need for glaucoma reoperation. Secondary outcome measures were IOP, the number of glaucoma medications, incidence of a hypertensive phase, and best corrected visual acuity (BCVA). RESULTS: The cumulative probability of success at 1 year was 70% in AT, and 65% in A (p = 0.85). IOP decreased significantly from 26.6 ± 10.1 mmHg at baseline to 14.7 ± 3.3 mmHg at the final follow-up in AT (p = 0.001). The corresponding numbers for A were 27.8 ± 10.2 and 16.7 ± 4.9, respectively (p = 0.001). The final IOP was significantly lower in AT (p = 0.022). The number of medications at baseline was comparable in both groups (2.6 ± 1.2 in AT and 2.5 ± 1.3 in A, p = 0.851). Corresponding number at 1 year visit was 1.2 ± 2 in AT and 2.8 ± 1.8 in A (p = 0.001). The incidence of a hypertensive phase was 18.7% in AT and 35.5% in A (p = 0.05). HP resolved in only 30% of eyes. The criteria for HP resolution were fulfilled in 9 eyes (30%). There was no difference in the rate of resolution of the hypertensive phase between AT and A (33.3 and 28.5%, respectively, p = 0.67). CONCLUSION: Ahmed glaucoma valve implant with same session trabectome surgery significantly decreased the rate of the hypertensive phase and postoperative IOP as well as the number of glaucoma medications.

Gene transfer to the outflow tract.

Elevated intraocular pressure is the primary cause of open angle glaucoma. Outflow resistance exists within the trabecular meshwork but also at the level of Schlemm's canal and further downstream within the outflow system. Viral vectors allow to take advantage of naturally evolved, highly efficient mechanisms of gene transfer, a process that is termed transduction. They can be produced at biosafety level 2 in the lab using protocols that have evolved considerably over the last 15-20 years. Applied by an intracameral bolus, vectors follow conventional as well as uveoscleral outflow pathways. They may affect other structures in the anterior chamber depending on their transduction kinetics which can vary among species when using the same vector. Not all vectors can express long-term, a desirable feature to address the chronicity of glaucoma. Vectors that integrate into the genome of the target cell can achieve transgene function for the life of the transduced cell but are mutagenic by definition. The most prominent long-term expressing vector systems are based on lentiviruses that are derived from HIV, FIV, or EIAV. Safety considerations make non-primate lentiviral vector systems easier to work with as they are not derived from human pathogens. Non-integrating vectors are subject to degradation and attritional dilution during cell division. Lentiviral vectors have to integrate in order to express while adeno-associated viral vectors (AAV) often persist as intracellular concatemers but may also integrate. Adeno- and herpes viral vectors do not integrate and earlier generation systems might be relatively immunogenic. Nonviral methods of gene transfer are termed transfection with few restrictions of transgene size and type but often a much less efficient gene transfer that is also short-lived. Traditional gene transfer delivers exons while some vectors (lentiviral, herpes and adenoviral) allow transfer of entire genes that include introns. Recent insights have highlighted the role of non-coding RNA, most prominently, siRNA, miRNA and lncRNA. SiRNA is highly specific, miRNA is less specific, while lncRNA uses highly complex mechanisms that involve secondary structures and intergenic, intronic, overlapping, antisense, and bidirectional location. Several promising preclinical studies have targeted the RhoA or the prostaglandin pathway or modified the extracellular matrix. TGF-ß and glaucoma myocilin mutants have been transduced to elevate the intraocular pressure in glaucoma models. Cell based therapies have started to show first promise. Past approaches have focused on the trabecular meshwork and the inner wall of Schlemm's canal while new strategies are concerned with modification of outflow tract elements that are downstream of the trabecular meshwork.

Longer-term Baerveldt to Trabectome glaucoma surgery comparison using propensity score matching.

PURPOSE: To apply propensity score matching to compare Baerveldt glaucoma drainage implant (BGI) to Trabectome-mediated ab interno trabeculectomy (AIT). Recent data suggests that AIT can produce results similar to BGI which is traditionally reserved for more severe glaucoma. METHODS: BGI and AIT patients with at least 1 year of follow-up were included. The primary outcome measures were intraocular pressure (IOP), number of glaucoma medications, and a Glaucoma Index (GI) score. GI reflected glaucoma severity based on visual field, the number of preoperative medications, and preoperative IOP. Score matching used a genetic algorithm consisting of age, gender, type of glaucoma, concurrent phacoemulsification, baseline number of medications, and baseline IOP. Patients with neovascular glaucoma, with prior glaucoma surgery, or without a close match were excluded. RESULTS: Of 353 patients, 30 AIT patients were matched to 29 BGI patients. Baseline characteristics including, IOP, the number of glaucoma medications, type of glaucoma, the degree of VF loss and GI were not significantly different between AIT and BGI. BGI had a preoperative IOP of 21.6 ± 6.3 mmHg compared to 21.5 ± 7.4 for AIT on 2.8 ± 1.1 medications and 2.5 ± 2.3 respectively. At 30 months, the mean IOP was 15.0 ± 3.9 mmHg for AIT versus 15.0 ± 5.7 mmHg for BGI (p > 0.05), while the number of drops was 1.5 ± 1.3 for AIT (change: p = 0.001) versus 2.4 ± 1.2 for BGI (change: p = 0.17; AIT vs BGI: 0.007). Success, defined as IOP < 21 mmHg, < 20% reduction and no reoperation, was achieved at 1 year in 56% of AIT versus 55% of BGI (p > 0.05) and 50% versus 52% at 2.5 years. CONCLUSIONS: A propensity score matched comparison of AIT and BGI demonstrated a similar IOP reduction through 1 year. AIT required fewer medications.

Stratification of phaco-trabectome surgery results using a glaucoma severity index in a retrospective analysis.

BACKGROUND: To stratify the outcomes of phacoemulsification combined with trabectome surgery using a new glaucoma severity index. METHODS: This is a retrospective, observational cohort study that included open angle glaucoma patients with visually significant cataract that had phacoemulsification combined with trabectome surgery. Exclusion criteria were follow-up less than 12 months, any other surgeries or diagnosis of neovascular or active uveitic glaucoma. Patients were stratified into four groups according to the Glaucoma Index (GI) that incorporated preoperative intraocular pressure (IOP), number of medications and visual field status. The primary outcome measures were IOP reduction and the success rate at 12 months. We examined the relationship between GI group and IOP and medications at one year with a linear regression analysis and survival with log-rank testing. RESULTS: Of 1374 patients, a total of 498 cases with 12 month follow-up were included in the study after applying the exclusion criteria. At one year, IOP of GI groups 1 through 4 was reduced by 2.9 ± 4.4, 3.6 ± 5.0, 3.9 ± 5.3, and 9.2 ± 7.6 mmHg for. Individuals in the next higher GI group had a 1.69 ± 0.2 mmHg larger IOP decrease. The success rate was 98%, 93%, 96% and 88% at one year for GI groups 1 to 4 (p < 0.05). CONCLUSIONS: A substantial IOP reduction was seen in subjects with more advanced glaucoma suggesting that the trabecular meshwork is the primary impediment to outflow and its ablation benefits those eyes relatively more than in mild glaucoma. A larger IOP reduction can be expected in individuals with a higher GI group that indicates a clinically more challenging glaucoma.

Repeatability of selective laser trabeculoplasty for open-angle glaucoma.

BACKGROUND: To analyze the results of repeat selective laser trabeculoplasty (SLT). INCLUSION CRITERIA: participants with primary or secondary open-angle glaucoma (excluding uveitic) who had undergone SLT 360° (SLT 1) with diminution of response over time followed by repeat SLT 360° (SLT 2). Six months of follow-up were required and at least 6 months in between SLT 1 and 2. The main outcome measures were IOP reduction at 6 and 12 months and a comparison of the response between SLT 1 and 2. RESULTS: One hundred thirty-seven patients met the inclusion criteria. If only one eye had repeat treatment, that eye was chosen; if both eyes qualified, one was chosen at random. The baseline intraocular pressure (IOP) for SLT 1 = 20.3+/- 5.2 mmHg and SLT 2 = 19.4 +/- 5.0 was reduced to 16.4 +/- 3.9 and 16.7 +/- 4.7 at 1 year, respectively (p < .001). Medication use was not significantly changed, and was 2.2 +/- 1.2 at baseline for SLT 1 and 2.1 +/- 1.3 for SLT 2, and at 1 year was 1.9 +/- 1.3 and 2.2 +/- 1.2, respectively. A subanalysis of 62 patients matched for equivalent baselines showed a baseline IOP = 18.7 +/- 3.8 for SLT 1 and 18.7 +/- 3.5 for SLT 2, reduced to 16.0 +/- 4.3 and 15.3 +/- 3.8 at 1 year (p < .001). CONCLUSION: Repeat SLT laser (360-degree treatment, followed by a loss of effect over time, then a second 360-degree treatment) in this population resulted in IOP lowering similar to that of the initial treatment.