Tear Exchange, Intraocular Pressure, and Wear Characteristics of Quadrant-specific Versus Spherical Haptic Scleral Lenses.

OBJECTIVES: To compare scleral lenses (SLs) with a quadrant-specific (study lens) or a spherical (habitual lens) landing zone in a crossover study. METHODS: Seven participants (eight eyes) wore each of two lenses for 2 weeks before measurements. We measured visual acuity, contrast sensitivity, intraocular pressure (IOP), fluid reservoir clearance, corneal thickness, tear exchange, and lens experience. Variables were compared between lenses and before and after 2 hr of wear. RESULTS: The visual acuity was not different between the study lens, 0.12 logarithm of the minimum angle of resolution (logMAR), and habitual lens, 0.18 logMAR (median, P = 1.0). Contrast sensitivity was 1.3% under the study lens and 1.6% under the habitual lens ( P = 0.94). IOP did not change after 2 hr of wear for either lens (study lens, P = 0.33 and habitual lens, P = 0.74), and corneal thickness did not change during wear of either lens ( P = 0.44). The fluorescein concentration under the study lens did not change after 2 hr (99% of initial concentration; P = 0.84) but decreased to 46% of initial concentration under the habitual lens ( P = 0.008). Lens comfort was slightly better with the study lens (5.0 vs. 4.0, respectively; P = 0.05). CONCLUSIONS: SLs with spherical or quadrant-specific landing zones provide good vision and do not affect IOP or corneal thickness. However, tear exchange is greater under spherical lenses than under quadrant-specific lenses. The quadrant-specific lens provides greater patient comfort.

Unconventional aqueous humor outflow: A review.

Aqueous humor flows out of the eye primarily through the conventional outflow pathway that includes the trabecular meshwork and Schlemm's canal. However, a fraction of aqueous humor passes through an alternative or 'unconventional' route that includes the ciliary muscle, supraciliary and suprachoroidal spaces. From there, unconventional outflow may drain through two pathways: a uveoscleral pathway where aqueous drains across the sclera to be resorbed by orbital vessels, and a uveovortex pathway where aqueous humor enters the choroid to drain through the vortex veins. We review the anatomy, physiology and pharmacology of these pathways. We also discuss methods to determine unconventional outflow rate, including direct techniques that use radioactive or fluorescent tracers recovered from tissues in the unconventional pathway and indirect methods that estimate unconventional outflow based on total outflow over a range of pressures. Indirect methods are subject to a number of assumptions and generally give poor agreement with tracer measurements. We review the variety of animal models that have been used to study conventional and unconventional outflow. The mouse appears to be a promising model because it captures several aspects of conventional and unconventional outflow dynamics common to humans, although questions remain regarding the magnitude of unconventional outflow in mice. Finally, we review future directions. There is a clear need to develop improved methods for measuring unconventional outflow in both animals and humans.

Descemet Stripping Endothelial Keratoplasty for Fuchs' Endothelial Corneal Dystrophy: Five-Year Results of a Prospective Study.

PURPOSE: To determine 5-year outcomes of Descemet stripping endothelial keratoplasty (DSEK) for Fuchs' endothelial corneal dystrophy (FECD). DESIGN: Prospective cohort study. PARTICIPANTS: Fifty-two eyes of 45 subjects with FECD undergoing primary DSEK. METHODS: Subjects were examined before and at fixed intervals through 60 months after DSEK. At each visit, graft survival was determined by slit-lamp examination; best spectacle-corrected visual acuity (BSCVA) was measured using the electronic Early Treatment Diabetic Retinopathy Study (ETDRS) protocol; total anterior corneal higher-order aberrations (HOAs) were derived from corneal topography; and corneal backscatter, corneal thickness, and endothelial cell density were measured from confocal microscopy images. Corneal thickness also was measured by ultrasonic pachymetry. Changes after DSEK were analyzed using generalized estimating equation models. MAIN OUTCOME MEASURES: Best-corrected visual acuity, HOAs, endothelial cell loss, corneal thickness, and corneal backscatter. RESULTS: Complete 60-month follow-up was possible in 34 eyes. Mean BSCVA±standard deviation improved from 0.45±0.19 logarithm of the minimum angle of resolution (logMAR) (Snellen equivalent, 20/56) before DSEK to 0.09±0.13 logMAR (Snellen equivalent, 20/25) at 5 years (P < 0.001). Between 1 and 5 years, BSCVA improved by 0.06 logMAR (or 3 ETDRS letters; 95% confidence interval, 0.05-0.07 logMAR) per year (P < 0.001), and 56% of eyes were 0.1 logMAR (20/25) or better at 5 years. Graft thickness (approximately 155 µm) and corneal thickness (approximately 700 µm) did not change after surgery. Anterior corneal HOAs and backscatter decreased between 1 and 5 years (P ≤ 0.002). Six grafts failed, of which 4 were primary (iatrogenic); mean endothelial cell loss±standard deviation was 55±15% at 5 years. CONCLUSIONS: Between 1 and 5 years after DSEK, BSCVA continues to improve such that at 5 years, more than half of eyes see better than 20/25 with a mean total corneal thickness of 700 µm. Improvement in vision is accompanied by continued reduction in corneal haze and aberrations, suggesting ongoing remodeling of the cornea after restoration of endothelial function.

Intraocular Pressure After 2 Hours of Small-Diameter Scleral Lens Wear.

OBJECTIVES: Compression of episcleral veins or deformation of tissue in the Schlemm's canal beneath the landing zone of scleral lenses could elevate intraocular pressure (IOP). We examined the effect of 2 hr of small-diameter scleral lens wear on IOP. METHODS: Twenty-nine participants, 29 ± 6 years old (mean ± SD) who experienced no history of eye disease or scleral lens wear, were included in the study. Each participant was fitted with a 15-mm Jupiter scleral lens on one eye (study eye). Intraocular pressure was measured in both eyes by pneumatonometry centrally on the cornea and peripherally on the sclera. The lens was then placed on one eye and was worn for 2 hr. Intraocular pressure was remeasured immediately after lens placement, at 1 and 2 hr of lens wear, and immediately after lens removal. Intraocular pressure after removal of the scleral lens was compared with IOP before placing the lens and to IOP in the control eye using paired t tests. RESULTS: Immediately after removing the scleral lens, mean central IOP in the study eye (13.9 ± 3.1 mm Hg) was not different from mean central IOP in the control eye (13.5 ± 2.2 mm Hg, P = 0.4) or in the same eye before lens wear (13.6 ± 1.9 mm Hg, P = 0.6). There were also no differences in IOP measured peripherally at 2 hr of lens wear (P = 0.8). CONCLUSIONS: Neophyte scleral lens wear of a 15-mm scleral lens for 2 hr does not increase IOP in healthy eyes.

Corneal High-Order Aberrations and Backscatter in Fuchs' Endothelial Corneal Dystrophy.

PURPOSE: Suboptimal visual acuity after endothelial keratoplasty has been attributed to increased anterior corneal high-order aberrations (HOAs). In this study, we determined anterior and posterior corneal HOAs over a range of severity of Fuchs' endothelial corneal dystrophy (FECD). DESIGN: Cross-sectional study. PARTICIPANTS: A total of 108 eyes (62 subjects) with a range of severity of FECD and 71 normal eyes (38 subjects). METHODS: All corneas were examined by using slit-lamp biomicroscopy to determine the severity of FECD versus normality. Fuchs' endothelial corneal dystrophy corneas were categorized as mild, moderate, or advanced according to the area and confluence of guttae and the presence of clinically visible edema. Normal corneas were devoid of any guttae. Wavefront errors from the anterior and posterior corneal surfaces were derived from Scheimpflug images and expressed as Zernike polynomials through the sixth order over a 6-mm diameter optical zone. Backscatter from the anterior 120 µm and posterior 60 µm of the cornea also was measured from Scheimpflug images and was standardized to a fixed scatter source. Variables were compared between FECD and control eyes by using generalized estimating equation models to adjust for age and correlation between fellow eyes. MAIN OUTCOME MEASURES: High-order aberrations, expressed as root mean square of wavefront errors, and backscatter of the anterior and posterior cornea. RESULTS: Total anterior corneal HOAs were increased in moderate (0.61±0.27 µm, mean ± standard deviation; P = 0.01) and advanced (0.66±0.28 µm; P = 0.01) FECD compared with controls (0.47±0.16 µm). Total posterior corneal HOAs were increased in mild (0.22±0.09 µm; P = 0.017), moderate (0.22±0.08 µm; P < 0.001), and advanced (0.23±0.09 µm; P < 0.001) FECD compared with controls (0.16±0.03 µm). Anterior and posterior corneal backscatter were higher for all severities of FECD compared with controls (P ≤ 0.02, anterior; P ≤ 0.001, posterior). CONCLUSIONS: Anterior and posterior corneal HOAs and backscatter are higher than normal even in early stages of FECD. The early onset of HOAs in FECD might contribute to the persistence of HOAs and incomplete visual rehabilitation after endothelial keratoplasty.

Corneal abnormalities early in the course of Fuchs' endothelial dystrophy.

PURPOSE: Corneas with advanced Fuchs' endothelial dystrophy that require endothelial keratoplasty manifest anterior corneal structural and cellular abnormalities that have been associated with visual deficits before and after endothelial keratoplasty. In this study, we determined the onset of these abnormalities in the course of the disease. DESIGN: Cross-sectional study. PARTICIPANTS: Sixty-three eyes (39 subjects) with a range of severity of Fuchs' dystrophy and 25 eyes (13 subjects) with normal corneas. METHODS: All corneas were examined using slit-lamp biomicroscopy, ultrasonic pachymetry, and confocal microscopy. The clinical grade of Fuchs' dystrophy was assessed according to the presence and extent of guttae and clinically evident edema and was categorized as mild (grades 1 and 2), moderate (grades 3 and 4), or advanced (grades 5 and 6). Normal corneas were devoid of any central guttae (grade 0). Corneal backscatter (haze) was measured from the confocal image light intensity profile. Stromal cell density and number and the presence of abnormal subepithelial cells were determined from confocal images. Comparisons between groups were made by using generalized estimating equation models. MAIN OUTCOME MEASURES: Anterior corneal backscatter, stromal cell density and number, presence of subepithelial cells, and central corneal thickness. RESULTS: Anterior corneal backscatter was 18% to 67% higher in eyes with moderate and advanced Fuchs' dystrophy compared with normal eyes (P ≤ 0.003); a similar trend was noted in mild Fuchs' dystrophy eyes compared with normal eyes (P = 0.08). Stromal cell density and the absolute number of stromal cells in the anterior 10% of the stroma were approximately 20% and 27% lower, respectively, in Fuchs' dystrophy (regardless of severity) compared with normal (P < 0.001). Abnormal subepithelial cells were visible in 9%, 19%, and 30% of corneas with mild, moderate, and advanced Fuchs' dystrophy, respectively. Only corneas with advanced Fuchs' dystrophy were thicker than normal (P < 0.001). CONCLUSIONS: Anterior corneal cellular and structural abnormalities begin early in the course of Fuchs' dystrophy, before the onset of clinically evident edema. The chronicity of these changes can explain their incomplete resolution after endothelial keratoplasty, and understanding the onset of these may help to determine the optimal time to intervene to achieve best outcomes.

Fuchs' endothelial corneal dystrophy: subjective grading versus objective grading based on the central-to-peripheral thickness ratio.

PURPOSE: To assess interobserver agreement between 2 corneal specialists grading Fuchs' dystrophy clinically and to determine if the corneal central-to-peripheral thickness ratio (CPTR) may be an alternative and objective metric of disease severity. DESIGN: Cross-sectional study. PARTICIPANTS: Forty-five eyes (26 subjects) with mild and moderate Fuchs' dystrophy, 73 eyes (60 subjects) with advanced Fuchs' dystrophy, and 267 eyes (142 subjects) with normal corneas. METHODS: Corneas with Fuchs' dystrophy were graded by 2 corneal specialists based on the confluence and area of guttae and the presence or absence of edema. Central corneal thickness (CCT) and peripheral corneal thickness at 4 mm from the center (PCT4) were measured by using scanning-slit pachymetry. The value of CPTR4 was the quotient of CCT and PCT4. MAIN OUTCOME MEASURES: Interobserver agreement for clinical grade and CPTR4. RESULTS: Interobserver agreement for clinical grading of Fuchs' dystrophy was moderate (κ = 0.32; 95% confidence interval, 0.19-0.45). In normal corneas, CCT was not correlated with age (r = -0.10; P = 0.28; n = 267), PCT4 decreased with age (r = -0.33; P<0.001; n = 254), and CPTR4 increased with age (r = 0.59; P<0.001; n = 254). Central corneal thickness was higher in Fuchs' dystrophy (652 ± 61 µm; n = 118) than in normal corneas (559 ± 31 µm; n = 267; P<0.001). Also, PCT4 was higher in Fuchs' dystrophy (650 ± 51 µm; n = 107) than in normal corneas (643 ± 43 µm; n = 254; P<0.001 after adjusting thickness for age). Furthermore, CPTR4 was higher in advanced Fuchs' dystrophy (1.03 ± 0.07; n = 65) than in mild and moderate Fuchs' dystrophy (0.95 ± 0.07; n = 42; age-adjusted P<0.001), which in turn was higher than in normal corneas (0.87 ± 0.05; n = 254; age-adjusted P<0.001). Finally, CPTR4 was highly correlated with clinical grade of Fuchs' dystrophy (r = 0.77; P<0.001; n = 361), was repeatable (median coefficient of variation, 1.3%), and provided excellent discrimination between Fuchs' dystrophy and normal corneas (area under the receiver operator characteristic curve, 0.93). CONCLUSIONS: Agreement between corneal specialists for the subjective and morphologic clinical grading of Fuchs' dystrophy is only moderate. The corneal CPTR is an objective, repeatable, and possibly functional, metric of severity of Fuchs' dystrophy that warrants further investigation to determine its role in monitoring disease progression and predicting the need for keratoplasty.

Eye Dynamics and Engineering Network Consortium: Baseline Characteristics of a Randomized Trial in Healthy Adults.

PURPOSE: To improve understanding of intraocular pressure (IOP) and its variance, this project identifies systemic and ocular characteristics of healthy eyes of adult volunteers including IOP variation, ocular biometrics, and aqueous humor dynamics (AHDs). These data serve as baseline controls for further studies from the Eye Dynamics and Engineering Network (EDEN) Consortium. DESIGN: Multicenter open-label clinical trial in healthy adults randomized to 1 week treatment with 2 approved glaucoma drugs in a crossover design. PARTICIPANTS: Among 135 healthy participants, 122 participants (aged 55.2 ± 8.8 years; 92 females, 30 males) completed the protocol. METHODS: Participants from the University of Michigan, Mayo Clinic, and University of Nebraska Medical Center underwent measurements of ocular biometrics, AHD, and IOP using 4 tonometers. Intraocular pressure data during 3 study visits without glaucoma medications were used in the analysis. The PhenX Toolkit survey acquired standardized data on medical history, surgical history, medications, smoking and alcohol exposures, and physical measures. MAIN OUTCOME MEASURES: The variability of IOP measurements within eyes was assessed as visit-to-visit IOP variation, within-visit IOP variation, and within-visit positional IOP variation. The concordance (or correlation) between eyes was also assessed. RESULTS: Average positional change of > 4.7 mmHg was detected with a range of 0.5-11.0 mmHg. Pearson correlation of IOP between eyes within a visit was 0.87 (95% confidence interval [CI], 0.82-0.91) for Goldmann applanation tonometry, 0.91 (95% CI, 0.88-0.94) for Icare rebound tonometry, and 0.91 (95% CI, 0.88-0.94) for pneumatonometry. There was a 4% to 12% asymmetric fluctuation of 3 mmHg or more between eyes between visits using rebound tonometry, 9% with Goldmann applanation tonometry, and 3% to 4% by pneumotonometry. The coefficient of variation between visits for the same eye ranged from 11.2% to 12.9% for pneumatonometry, from 13.6% to 17.4% for rebound tonometry, and 15.8% to 16.2% for Goldmann applanation tonometry. CONCLUSIONS: The current study from the EDEN Consortium describes measurement methods and data analyses with emphasis on IOP variability. Future papers will focus on changes in ocular biometrics and AHD with timolol or latanoprost treatment. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Anterior corneal aberrations after Descemet's stripping endothelial keratoplasty for Fuchs' endothelial dystrophy.

PURPOSE: To determine the change in anterior corneal high-order aberrations (HOAs) after Descemet's stripping endothelial keratoplasty (DSEK) for Fuchs' dystrophy, and to compare the HOAs with those of age-matched controls. DESIGN: Prospective cohort and cross-sectional study. PARTICIPANTS AND CONTROLS: Forty-eight eyes with Fuchs' dystrophy were examined before and after DSEK, and were compared with 52 eyes of age-matched controls with normal corneas. METHODS: Corneas of patients with Fuchs' dystrophy were examined prospectively before and at intervals through 2 years after DSEK. Wavefront errors from the anterior corneal surface were derived from corneal topograms and were expressed as Zernike polynomials through the sixth order. Best-corrected visual acuity (BCVA) was measured by the electronic Early Treatment of Diabetic Retinopathy Study protocol, and subepithelial haze was measured from the brightness of confocal images. Total HOAs were compared before and after DSEK, and with those of age-matched controls, by using generalized estimating equation models. Relationships between HOAs, BCVA, subepithelial haze, and recipient age were determined. MAIN OUTCOME MEASURES: Anterior corneal HOAs, BCVA, and subepithelial haze (backscattered light). RESULTS: In Fuchs' dystrophy before DSEK, total HOAs (4 mm optical zone) from the anterior corneal surface (0.29±0.13 µm) were higher than those of controls (0.17±0.08 µm; P<0.001). At 2 years after DSEK, total HOAs (0.26±0.13 µm) did not differ from preoperative aberrations (P = 0.99), and remained higher than in controls (P<0.001). At 2 years, total HOAs were correlated with BCVA (r = 0.59; P<0.001; n = 27), with subepithelial haze (r = 0.41; P = 0.01; n = 25), and with recipient age (r = 0.59; P<0.001; n = 27). CONCLUSIONS: Anterior corneal HOAs are higher in Fuchs' dystrophy than in controls, and remain higher through 2 years after DSEK. The aberrated anterior surface might be related to anterior corneal ultrastructural changes and haze formation in Fuchs' dystrophy, and should not be ignored as a source of decreased visual acuity after DSEK.

Measurement of episcleral venous pressure.

Episcleral venous pressure (EVP) is an important determinant of intraocular pressure (IOP) and can be measured by using various techniques. It has been measured non-invasively by estimating the pressure required to compress an episcleral vein to a predetermined endpoint. However, the lack of objective endpoints makes EVP measurement in humans uncertain, and a wide range of mean EVP has been reported in the literature. We review the evidence for physiologic regulation of EVP and its role in glaucoma therapy, techniques that have been used to measure EVP and the need for objective measurements, and reported values for EVP. We also review recent progress toward developing an objective technique for EVP measurement.

A novel method for computerized measurement of episcleral venous pressure in humans.

Episcleral venous pressure (EVP) is an important determinant of intraocular pressure (IOP) and can be estimated by the pressure required to compress an episcleral vein. However, the lack of objective measurement endpoints makes EVP measurements in humans uncertain. To address this issue, we developed a new method to measure EVP objectively and reproducibly, and demonstrated its utility on a group of normal subjects. Our system for pressure chamber based venomanometry included a computer-controlled motor drive to increase pressure automatically, a transducer to record pressure, and a high-definition video camera to record vein collapse. Pressure measurements were synchronized with the video stream to determine the pressure required to collapse the vein to a specific pre-determined degree. This system was used to measure EVP in 10 eyes from 5 young healthy volunteers. Episcleral veins were selected in each of 4 quadrants. EVP was calculated to be the pressure in the chamber that compressed the vein by 0% (by back-projection), 10% or 50% as determined by using image analysis of the video stream. For this group of subjects, mean EVP was 6.3 ± 2.8 mmHg (mean ± SD, n = 40 measurements), 7.0 ± 2.6 mmHg, and 9.6 ± 2.6 mmHg using the 0%, 10% and 50% reduction endpoints, respectively. Pressures and standard deviations determined from these endpoints were significantly different from each other (p < 0.001). Coefficients of variation between right and left eyes were 12.7%, 10.2%, and 6.8% using the 0%, 10% and 50% endpoints, respectively. Based on previous research and theoretical considerations, the 0% endpoint is assumed to provide the most accurate estimate of baseline EVP, and can only be estimated by analyzing the brightness profiles of the vessels in the video stream. Objective measurement of EVP is important for understanding normal aqueous humor dynamics and its changes in disease states and with therapies. EVP has typically been assumed to be constant because of the lack of a convenient means of its measurement. This new method provides a precise means to assess EVP based on specific endpoints of vessel collapse, and enables, for the first time, objective and non-invasive measurements of EVP changes.

Prostaglandin pathway gene therapy for sustained reduction of intraocular pressure.

Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme in prostaglandin (PG) biosynthesis. In the eye, loss of COX-2 expression in aqueous humor-secreting cells has been associated with primary open-angle glaucoma (POAG). Reduction of intraocular pressure (IOP) is the main treatment goal in this disease. We used lentiviral vectors to stably express COX-2 and other PG biosynthesis and response transgenes in the ciliary body epithelium and trabecular meshwork (TM), the ocular suborgans that produce aqueous humor and regulate its outflow, respectively. We show that robust ectopic COX-2 expression and PG production require COX-2 complementary DNA (cDNA) sequence optimization. When COX-2 expression was coupled with a similarly optimized synthetic PGF2alpha receptor transgene to enable downstream signaling, gene therapy produced substantial and sustained reductions in IOP in a large animal model, the domestic cat. This study provides the first gene therapy for correcting the main cause of glaucoma.

Endothelial image quality after descemet stripping with endothelial keratoplasty: a comparison of three microscopy techniques.

PURPOSE: To determine corneal endothelial image quality after descemet stripping with endothelial keratoplasty (DSEK) as recorded by three different microscopy techniques: noncontact specular microscopy, noncontact confocal microscopy, and contact confocal microscopy. METHODS: The corneal endothelium of 52 eyes after DSEK and 20 normal eyes was photographed by the three microscopy techniques during a single encounter. Image quality was graded by two masked observers according to the proportion of countable contiguous cells visible in the image; disagreements in grading were adjudicated by a third observer. Endothelial cell density was compared among the three techniques. RESULTS: After DSEK, image quality was better with contact confocal microscopy than with noncontact confocal microscopy (P = 0.01) and better with noncontact confocal microscopy than with noncontact specular microscopy (P < 0.001). With noncontact specular microscopy, 42% of images after DSEK were uncountable. In normal corneas, all images were countable, and although image quality was better with contact confocal microscopy than with noncontact confocal (P = 0.03) and noncontact specular (P < 0.001) microscopy, the difference was not clinically important. For countable images, the mean differences in endothelial cell density between microscopy methods were close to zero after DSEK and in normal corneas. CONCLUSIONS: Confocal optics enable better image quality of the corneal endothelium in corneas with high backscatter, such as those after DSEK. When images were countable, there was a good agreement for endothelial cell density measured by the three microscopy techniques.

Effect of Topical Phenylephrine 2.5% on Episcleral Venous Pressure in Normal Human Eyes.

Purpose: Phenylephrine has been shown to affect intraocular pressure (IOP) but the mechanism of action is poorly understood. However, its action as a vasoconstrictor suggests possible effects on episcleral venous pressure (EVP). In this study, we evaluated the effect of phenylephrine on EVP and IOP in healthy subjects. Methods: Forty eyes of 20 subjects were included. Each subject received 3 drops of phenylephrine 2.5% in one eye at 1-minute intervals. The fellow eye served as control. Blood pressure, heart rate, and IOP and EVP of both eyes were measured at baseline, 15 minutes, and 60 minutes after instillation of phenylephrine. IOP was measured by pneumatonometry. EVP was assessed by using a computer-controlled episcleral venomanometer. Changes in IOP, EVP, blood pressure, and heart rate at 15 and 60 minutes were analyzed by paired t-tests. Results: IOP increased 15 minutes after instillation of phenylephrine in both treated (P = 0.001) and control eyes (P = 0.01) and returned to baseline at 60 minutes. The change in IOP at 15 minutes was not significantly different between the 2 groups. EVP in treated eyes was unchanged at 15 minutes (P = 0.8) but decreased significantly at 60 minutes (P < 0.001). In control eyes, there was no change in EVP at any time (P > 0.6). There were no significant changes from baseline in systolic and diastolic blood pressure and heart rate after instillation of phenylephrine. Conclusions: IOP elevation associated with topical phenylephrine is not caused by an increase in EVP in healthy subjects. Instead, EVP decreases with phenylephrine, but the mechanism remains to be determined.

Measurement of aqueous humor flow.

Aqueous humor flow, one of the primary determinants of intraocular pressure, has been measured non-invasively in the human eye since the early 1950s. Other than sleep, which decreases flow rate to approximately half of what it is during alert wakefulness, few conditions affect flow rate. Three classes of medication can suppress flow and have been used therapeutically, beta-adrenergic antagonists, alpha(2)-adrenergic agonists, and carbonic anhydrase inhibitors. Studies of the production and circulation of aqueous humor have provided a basis for understanding the fundamental dynamics of the eye as well as understanding treatments for glaucoma.

Effect of Timolol on Aqueous Humor Outflow Facility in Healthy Human Eyes.

PURPOSE: Hyposecretion of aqueous humor has been postulated to adversely affect the health of the trabecular meshwork and outflow resistance. However, the effect of medications that reduce aqueous humor production on outflow facility in living human eyes is unclear. This study evaluated the effect of timolol, an aqueous humor flow suppressant, on outflow facility in healthy eyes. DESIGN: Prospective, before-and-after study. METHODS: In a multicenter study, 113 healthy participants over 40 years of age were included. Intraocular pressure (IOP) was measured with the participant in the sitting position by using a pneumatonometer. The outflow facility was measured with the participant in the supine position by 2-minute pneumatonography. After participants self-administered drops of timolol 0.5% for 1 week, twice daily in each eye, both measurements were repeated. RESULTS: Mean IOP decreased from 15.1 ± 3.0 mm Hg at baseline to 12.4 ± 2.4 mm Hg (P < 0.001) after 1 week of timolol use. Mean outflow facility decreased from 0.23 ± 0.08 µL/min/mm Hg at baseline to 0.18 ± 0.08 µL/min/mm Hg (P < 0.001) after timolol. The change in outflow facility was negatively correlated with baseline outflow facility (r = -0.51; P < 0.001). CONCLUSIONS: Timolol reduces outflow facility in healthy human eyes, and this effect is greater in eyes with higher baseline outflow facility. This phenomenon may be related to reduced aqueous humor flow, but the precise mechanism remains to be determined.

Circadian variation of aqueous dynamics in young healthy adults.

PURPOSE: Recent research indicates that intraocular pressure (IOP) does not decrease significantly during the nocturnal period, although aqueous humor flow decreases by 50% or more at night. This study was undertaken to investigate whether changes in outflow facility, episcleral venous pressure, or uveoscleral flow at night could account for the nocturnal IOP. METHODS: Sixty-eight eyes of 34 healthy subjects (age, 18-44 years; mean, 29) were studied. Aqueous humor flow rate, IOP, and outflow facility were measured with pneumatonometry, anterior chamber fluorophotometry, and Schiotz tonography respectively, in each eye during the mid-diurnal (2-4 PM) and mid-nocturnal (2-4 AM) periods. Nocturnal IOP, flow rate, and outflow facility were compared to the same variables during the diurnal period. Mathematical models based on the modified Goldmann equation were used to assess the conditions under which these results could be reconciled. RESULTS: Supine IOP decreased slightly from 18.9 +/- 2.7 mm Hg in the mid-diurnal period to 17.8 +/- 2.5 mm Hg in the mid-nocturnal period (mean +/- SD, P = 0.001). Aqueous flow rate decreased from 2.26 +/- 0.73 to 1.12 +/- 0.75 microL/min (mean +/- SD, P < 0.001). There was a nonsignificant trend toward a nocturnal decrease of outflow facility (diurnal, 0.27 +/- 0.11 microL/min/mm Hg; nocturnal, 0.25 +/- 0.08 microL/min/mm Hg; mean +/- SD, P = 0.13). CONCLUSIONS: Outflow facility measured by tonography does not decrease enough during the nocturnal period to compensate for the decreased aqueous humor flow rate. Modeling results indicate that the experimental results could be reconciled only if nocturnal changes in episcleral venous pressure and/or uveoscleral flow occurred.

Mechanism of action of bimatoprost, latanoprost, and travoprost in healthy subjects. A crossover study.

PURPOSE: To study the effects of 3 prostaglandin analogs, bimatoprost, latanoprost, and travoprost, on aqueous dynamics in the same subjects and to compare techniques of assessing outflow facility. DESIGN: Experimental study (double-masked, placebo-controlled, randomized paired comparison, 4-period crossover). PARTICIPANTS: Thirty healthy adult subjects. METHODS: Bimatoprost, latanoprost, travoprost, or a placebo was administered to the left eye once a day in the evening for 7 days, after a minimum 4-week washout period between each session. Tonographic outflow facility was measured by Schiøtz tonography and pneumatonography on day 7. On day 8, the aqueous humor flow rate and fluorophotometric outflow facility were measured by fluorophotometry. Uveoscleral outflow was calculated from the aqueous humor flow rate and outflow facility using the Goldmann equation. MAIN OUTCOME MEASURES: Facility of outflow, aqueous humor flow rate, intraocular pressure (IOP), and calculation of uveoscleral outflow. RESULTS: All medications lowered IOP relative to a placebo. None of the drugs affected aqueous humor production. All medications increased outflow facility compared with placebo when measured by Schiøtz and 2-minute pneumatonography (P< or =0.02); the apparent increase of outflow facility measured with fluorophotometry and 4-minute pneumatonography did not reach statistical significance. In contrast, uveoscleral outflow was significantly increased by all medications when calculated from 4-minute pneumatonography data, and fluorophotometry and Schiøtz data at higher episcleral venous pressures. The apparent increase found with 2-minute pneumatonography did not reach statistical significance. These differing results in the same patients indicate that differences in measurement techniques, and not differences in mechanism of action, explain previous conflicting published reports on the mechanism of action of the prostaglandins. CONCLUSIONS: Bimatoprost, latanoprost, and travoprost have similar mechanisms of action. All 3 drugs reduce IOP without significantly affecting the aqueous production rate. All drugs increase aqueous humor outflow, either by enhancing the pressure-sensitive (presumed trabecular) outflow pathway or by increasing the pressure-insensitive (uveoscleral) outflow, but the assessment of the amount of flow through each pathway depends upon the measurement technique.

Scattered light and visual function in a randomized trial of deep lamellar endothelial keratoplasty and penetrating keratoplasty.

PURPOSE: To compare vision, intraocular forward light scatter and corneal backscatter between deep lamellar endothelial keratoplasty (DLEK) and penetrating keratoplasty (PK) for endothelial dysfunction. DESIGN: A randomized clinical trial. METHODS: Thirteen eyes (12 patients) were randomized to DLEK with a 9 mm scleral incision, and 15 eyes (14 patients) were randomized to PK. The primary outcome was high-contrast best spectacle-corrected visual acuity (BSCVA) at 12 months after surgery; intraocular forward light scatter and corneal backscatter were measured at one, three, six, and 12 months after surgery. RESULTS: BSCVA at 12 months was 0.34 +/- 0.16 logMAR (logarithm of the minimum angle of resolution) for DLEK and 0.25 +/- 0.21 logMAR for PK (P = .23; minimum detectable difference at 12 months was 0.23 logMAR). The change in postoperative forward light scatter after DLEK correlated with the change in BSCVA (r = -0.66; P < .001; n = 11). Corneal backscatter was higher after DLEK than after PK at three and six months in the anterior third (P < or = .005), at one through 12 months in the middle third (P < .001), and at one through six months in the posterior third (P < or = .02) of the cornea. Backscatter after DLEK did not return to normal through 12 months (P < .001). CONCLUSIONS: BSCVA was similar at one year after DLEK and PK. Improvement in BSCVA after DLEK correlated with decreasing forward light scatter. Increased backscatter after DLEK originated not only from the posterior cornea (interface) but also from the host cornea, which might limit visual outcomes after posterior lamellar keratoplasty.