Vikas Gulati

A Novel 8-mm Schlemm's Canal Scaffold Reduces Outflow Resistance in a Human Anterior Segment Perfusion Model

PURPOSE To study the effect on outflow facility and outflow resistance of a nitinol microstent implanted into Schlemms canal. METHODS Using a constant pressure perfusion method, outflow facility and outflow resistance were measured in 26 pairs of dissected anterior segments from donated human eyes. Measurements were made at perfusion pressures of 10, 20, 30 and 40 mm Hg. The Hydrus Microstent was placed in Schlemms canal of one eye and the contralateral eye underwent a sham procedure. Outflow facility and outflow resistance were measured again after the microstent implantation or sham procedure. RESULTS The Hydrus Microstent significantly increased outflow facility from 0.33 ± 0.17 μL/min/mm Hg to 0.52 ± 0.19 μL/min/mm Hg (P < 0.001). Outflow resistance was significantly reduced from 4.38 ± 3.03 mm Hg/μL/min at baseline to 2.34 ± 1.04 mm Hg/μL/min (P < 0.001) with the microstent. There was a linear correlation between outflow resistance at baseline and decrease in outflow resistance with the microstent (R(2) = 0.89, P < 0.0001). CONCLUSIONS The increase in outflow facility and decrease in resistance supports the potential use of the Hydrus Microstent as a surgical option to reduce intraocular pressure (IOP). The IOP-lowering effect may be higher in eyes with higher outflow resistance (and IOP) as compared with eyes with lower outflow resistance (and IOP).

Improvement in Outflow Facility by Two Novel Microinvasive Glaucoma Surgery Implants

PURPOSE To determine improvement in outflow facility (C) in human anterior segments implanted with a novel Schlemms canal scaffold or two trabecular micro-bypasses. METHODS Human anterior segments were isolated from 12 pairs of eyes from donors with no history of ocular disease and then perfused at 50, 40, 30, 20, and 10 mm Hg pressures for 10 minutes each. Baseline C was calculated from perfusion pressures and flow rates. The scaffold was implanted into Schlemms canal of one anterior segment, and two micro-bypasses were implanted three clock-hours apart in the contralateral anterior segment. Outflow facility and resistance were compared at various standardized perfusion pressures and between each device. RESULTS Compared to baseline, C increased by 0.16 ± 0.12 μL/min/mm Hg (74%) with the scaffold, and 0.08 ± 0.12 μL/min/mm Hg (34%) with two micro-bypasses. The scaffold increased C at perfusion pressures of 50, 40, 30, and 20 mm Hg (P < 0.005). Two micro-bypasses increased C at a perfusion pressure of 40 mm Hg (P < 0.05). CONCLUSIONS Both implants effectively increased C in human eyes ex vivo. The scaffold increased C by a greater percentage (73% vs. 34%) and at a greater range of perfusion pressures (20 to 50 mm Hg vs. 40 mm Hg) than the two micro-bypasses, suggesting that the 8-mm dilation of Schlemms canal by the scaffold may have additional benefits in lowering the outflow resistance. The Hydrus Microstent scaffold may be an effective therapy for increasing outflow facility and thus reducing the IOP in patients with glaucoma.

Correlations between parameters of aqueous humor dynamics and the influence of central corneal thickness

PURPOSE The individual parameters of aqueous humor dynamics may influence each other to maintain intraocular pressure (IOP) homeostasis. Central corneal thickness (CCT) is known to be associated with onset and progression of glaucoma and can potentially influence the individual parameters of aqueous humor dynamics that maintain IOP. This study investigates the correlation between parameters of aqueous humor dynamics and the influence of CCT in healthy volunteers and compares it with the correlations seen in patients with ocular hypertension. METHODS Aqueous humor dynamics (aqueous flow, outflow facility, and uveoscleral outflow), IOP, and pachymetry data from 94 healthy ocular normotensive (ONT) volunteers and 63 ocular hypertensive (OHT) patients was analyzed retrospectively. Linear correlations between individual aqueous humor dynamics parameters and pachymetry were evaluated using scatter plots and the Spearman correlation coefficient where appropriate. RESULTS In both groups, a significant (P < 0.05) negative correlation was found between corneal thickness and aqueous flow (ONT, R(2) = 0.14; OHT, R(2) = 0.10) and between corneal thickness and uveoscleral outflow (ONT and OHT, R(2) = 0.10). A significant (P < 0.05) positive correlation was found between aqueous flow and outflow facility (ONT, R (2) = 0.24; OHT, R(2) = 0.10). In healthy controls, but not OHT patients, a significant (P < 0.001) positive correlation was found between aqueous flow and uveoscleral outflow (R(2) = 0.15). CONCLUSIONS Thicker corneas may be associated with lower aqueous production and lower uveoscleral outflow. The interplay between parameters of aqueous humor dynamics suggests possible autoregulatory mechanisms in the eye. OHT may differ from ONT subjects in their inability to increase the uveoscleral outflow with increases in aqueous inflow.

Mechanism of Action of Selective Laser Trabeculoplasty and Predictors of Response

Purpose This 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. Methods Thirty-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. Results Compared 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. Conclusions The 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.

Assumption constraints of fluorophotometry in human eyes

We read with great interest the article entitled “Fluorophotometric Study of the Effect of the Glaukos Trabecular Microbypass Stent on Aqueous Humor Dynamics” by Fernández-Barrientos et al. The authors examined aqueous humor dynamics before and after surgery in eyes undergoing cataract surgery and the implantation of the bypass stent (group 1) and in eyes undergoing cataract surgery alone (group 2). They reported a significant increase in outflow facility in both groups, with the combined procedure group having the highest values. Outflow facility was calculated with aqueous flow assessed by fluorophotometry, a standard value of 10 mm Hg for episcleral venous pressure, and negligible uveoscleral outflow in the Goldmann equation. Fluorophotometry is a useful technique for assessment of aqueous humor dynamics, but it does have several assumptions that must be met for the technique to be valid. The anterior chamber fluorescein disappearance technique of Jones and Maurice requires the presence of an intact iridolenticular diaphragm, which is compromised in eyes undergoing cataract surgery with a lens implant. Most investigators familiar with the technique exclude from study any subject with prior ocular surgeries. In pseudophakic eyes, one can no longer assume that there is minimal loss of fluorescein into the vitreous cavity. Such a loss would manifest itself on fluorophotometry as an apparent increase in aqueous inflow. This can be seen from the results of Fernández-Barrientos et al. where aqueous flow values as high as 4.05 1.8 L/min (compared to a baseline of 1.78 0.44 L/min) were reported in group 1 at 6 months after the surgical procedure. The apparent increase in aqueous flow was found to be statistically significant in both groups at all but one measurement time in the postoperative period. There is no reason to believe that cataract surgery or the bypass stent itself would increase aqueous flow several months after the procedure is performed. Hence, it is likely that the higher values of aqueous flow obtained by the authors after surgery are the result of a systematic error introduced by the pseudophakic state of the eyes undergoing the measurement. This apparent increase in aqueous flow does seem to resolve spontaneously with time, as seen in their Table 4. At 1 year after surgery, the apparent increase in aqueous flow in group 2 was reduced to a level that differed by a statistically insignificant amount from baseline. Hence, it may be possible to obtain valid aqueous flow measurements in pseudophakic eyes with intact capsules a year or more after the cataract surgery. Fernández-Barrientos et al. also made the assumption that the pressure-independent outflow (uveoscleral outflow) is a negligible component in aqueous humor dynamics. More recent work has shown uveoscleral outflow to be a more significant contributor than the 10% cited in 1971 by Bill and Phillips. Since the purpose of Fernández-Barrientos et al. was to evaluate the effects on pressure-dependent outflow alone, it can be argued that uveoscleral outflow, even though a significant contributor to aqueous outflow, could have been ignored, because it was not expected to change with time and with any of the procedures performed in the study. However, this assumption may not be valid, as any surgical procedure on the anterior chamber angle has a very high probability of disturbing the supraciliary space and altering uveoscleral outflow. Making multiple attempts at proper device placement or implanting multiple devices would make inadvertent communication with the supraciliary space even more likely. An increase in uveoscleral outflow would be expected to lower the intraocular pressure (IOP). However, if the uveoscleral outflow is assumed to be negligible and unchanged, this decrease in IOP could be erroneously attributed to an improvement in the outflow facility. Further, the artifact in aqueous inflow measurements introduces a systematic error in the calculation of outflow facility that makes the improvement in outflow facility look better than it may have been. As can be seen from the formula used to calculate the outflow facility, [CT F/(IOP Pev)], any errors in measurement of aqueous flow (F) would directly influence the calculated outflow facility (CT). We feel that the only valid aqueous flow measurement that satisfies the prerequisite of a fluorophotometric assessment is the one obtained before surgery. Since cataract surgery with or without the microbypass stent should not be expected to change the aqueous humor production rate at the time of the measurement, these values may be used for the calculation of outflow facility after the procedure. The effects of an erroneous F in the outflow facility calculation can be seen in Table 1. The IOP data (after washout of ocular medications) at the time of fluorophotometry is not provided in the article; however, the mean IOP gradient can be calculated readily by using the reported means of F and CT as IOP gradient F/CT. As can be seen from the table, at 1 year, the mean CT of 0.27 L/min/mm Hg in group 1 versus 0.16 L/min/mm Hg in group 2 is more likely to be representative of outflow facility at these times. These values also are more consistent with the values obtained by Bahler et al., who reported an 84% increase in outflow facility after placement of the bypass stent in cultured human anterior segments.

Comparison of aqueous outflow facility measurement by pneumatonography and digital schiøtz tonography

Purpose It is not known if outflow facilities measured by pneumatonography and Schiøtz tonography are interchangeable. In this study we compared outflow facility measured by pneumatonography to outflow facility measured by digital Schiøtz tonography. Methods Fifty-six eyes from 28 healthy participants, ages 41 to 68 years, were included. Intraocular pressure (IOP) was measured in the sitting and supine positions with a pneumatonometer. With the subject in the supine position, IOP was recorded for 2 minutes by using a pneumatonometer with a 10-g weight and for 4 minutes by using a custom digital Schiøtz tonometer. Outflow facility was determined from the changes in pressure and intraocular volume and a standard assumed ocular rigidity coefficient for each instrument, respectively, and by using an ocular rigidity coefficient calculated by measuring pressure without and with a weight added to the pneumatonometer tip. Results The outflow facility was 0.29 ± 0.09 μL/min/mm Hg by Schiøtz tonography and 0.24 ± 0.08 μL/min/mm Hg by pneumatonography (P < 0.001) when using the standard assumed constant ocular rigidity coefficient. Mean calculated ocular rigidity coefficient was 0.028 ± 0.01 μL−1, and outflow facility determined by using this coefficient was 0.23 ± 0.08 μL/min/mm Hg by Schiøtz tonography and 0.21 ± 0.07 μL/min/mm Hg by pneumatonography (P = 0.003). Outflow facilities measured by the two devices were correlated when the ocular rigidity was assumed (r = 0.60, P < 0.001) or calculated (r = 0.70, P < 0.001). Conclusions Outflow facilities measured by pneumatonography were correlated with those measured by Schiøtz tonography, but Schiøtz tonography reported approximately 10% to 20% higher facilities when using the standard method. When ocular rigidity was determined for each eye, differences were smaller. Measurements from these devices cannot be compared directly.

High-resolution adaptive optics findings in talc retinopathy

Talc retinopathy is a recognized ocular condition characterized by the presence of small, yellow, glistening crystals found inside small retinal vessels and within different retinal layers. These crystals can be associated with retinal vascular occlusion and ischemia. Different diagnostic modalities have been used previously to characterize the retinal lesions in talc retinopathy. Adaptive optics, a high resolution imaging technique, is used to evaluate the location, appearance and distribution of talc crystals in a case of talc retinopathy.

The Water-Drinking Test Revisited: An Analysis of Test Results in Subjects with Glaucoma

ABSTRACT Purpose: The Water-Drinking Test (WDT) has been shown to predict the diurnal IOP change. This study evaluates the factors that may affect the WDT results. Methods: This study was conducted on 203 glaucoma patients who had undergone trabeculectomy (53) or tube surgery (31), or had a medically controlled open-angle (82) or closed-angle (37) glaucoma. IOP was measured at baseline and then every 15 minutes over a one-hour period after drinking water. The main outcome measures were IOP change (increase in IOP from baseline) at all measurement time points, IOP peak (highest IOP after drinking water), IOP fluctuation (difference between IOP peak and baseline), and assessing the association of these IOPs with a patient’s demographic and management modalities. Results: The mean age of the participants was 54±18 years, and 113 (56%) were male. Female patients showed greater IOP fluctuation than males (7.28 vs. 5.92 mm Hg; P=0.016), and a greater IOP peak (22.7 vs. 20.1 mm Hg; P=0.001). The observed associations between gender and IOP changes were only significant in <50 years. IOP at 60 minutes was greater in tube than trabeculectomy (5.6 vs. 3.1 mm Hg; P=0.007). The number of topical medications showed a direct independent association with IOP changes (P<0.001). Compared to other classes of topical medications, latanoprost showed lower WDT-IOP profile (P=0.0003). Conclusions: WDT-IOP change was diminished in subjects on latanoprost, and was greater in females <50 years, and those on greater number of medications.

Age at natural menopause genetic risk score in relation to age at natural menopause and primary open-angle glaucoma in a US-based sample

Objective: Several attributes of female reproductive history, including age at natural menopause (ANM), have been related to primary open-angle glaucoma (POAG). We assembled 18 previously reported common genetic variants that predict ANM to determine their association with ANM or POAG. Methods: Using data from the Nurses’ Health Study (7,143 women), we validated the ANM weighted genetic risk score in relation to self-reported ANM. Subsequently, to assess the relation with POAG, we used data from 2,160 female POAG cases and 29,110 controls in the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (NEIGHBORHOOD), which consists of 8 datasets with imputed genotypes to 5.6+ million markers. Associations with POAG were assessed in each dataset, and site-specific results were meta-analyzed using the inverse weighted variance method. Results: The genetic risk score was associated with self-reported ANM (P = 2.2 × 10–77) and predicted 4.8% of the variance in ANM. The ANM genetic risk score was not associated with POAG (Odds Ratio (OR) = 1.002; 95% Confidence Interval (CI): 0.998, 1.007; P = 0.28). No single genetic variant in the panel achieved nominal association with POAG (P ≥0.20). Compared to the middle 80 percent, there was also no association with the lowest 10th percentile or highest 90th percentile of genetic risk score with POAG (OR = 0.75; 95% CI: 0.47, 1.21; P = 0.23 and OR = 1.10; 95% CI: 0.72, 1.69; P = 0.65, respectively). Conclusions: A genetic risk score predicting 4.8% of ANM variation was not related to POAG; thus, genetic determinants of ANM are unlikely to explain the previously reported association between the two phenotypes.

Genetic correlations between intraocular pressure, blood pressure and primary open-angle glaucoma: A multi-cohort analysis

Primary open-angle glaucoma (POAG) is the most common chronic optic neuropathy worldwide. Epidemiological studies show a robust positive relation between intraocular pressure (IOP) and POAG and modest positive association between IOP and blood pressure (BP), while the relation between BP and POAG is controversial. The International Glaucoma Genetics Consortium (n=27 558), the International Consortium on Blood Pressure (n=69 395), and the National Eye Institute Glaucoma Human Genetics Collaboration Heritable Overall Operational Database (n=37 333), represent genome-wide data sets for IOP, BP traits and POAG, respectively. We formed genome-wide significant variant panels for IOP and diastolic BP and found a strong relation with POAG (odds ratio and 95% confidence interval: 1.18 (1.14–1.21), P=1.8 × 10−27) for the former trait but no association for the latter (P=0.93). Next, we used linkage disequilibrium (LD) score regression, to provide genome-wide estimates of correlation between traits without the need for additional phenotyping. We also compared our genome-wide estimate of heritability between IOP and BP to an estimate based solely on direct measures of these traits in the Erasmus Rucphen Family (ERF; n=2519) study using Sequential Oligogenic Linkage Analysis Routines (SOLAR). LD score regression revealed high genetic correlation between IOP and POAG (48.5%, P=2.1 × 10−5); however, genetic correlation between IOP and diastolic BP (P=0.86) and between diastolic BP and POAG (P=0.42) were negligible. Using SOLAR in the ERF study, we confirmed the minimal heritability between IOP and diastolic BP (P=0.63). Overall, IOP shares genetic basis with POAG, whereas BP has limited shared genetic correlation with IOP or POAG.