Central serous chorioretinopathy treatment with a systemic PDE5 and PDE6 inhibitor (sildenafil).

PURPOSE: Examine the use of systemic phosphodiesterase inhibition (sildenafil) to clear central serous chorioretinopathy (CSCR). OBSERVATIONS: In a long-standing CSCR patient, sildenafil produced a rapid resolution. When discontinued (dechallenge) the CSCR returned. When rechallenged, the CSCR again rapidly disappeared and did not recur in 5 months of continued therapy. CONCLUSIONS: AND IMPORTANCE: Systemic sildenafil can cause rapid clearance of CSCR and can augment or replace other treatments.

Treatment of Macular Degeneration with Sildenafil: Results of a Two-Year Trial.

OBJECTIVE: To evaluate PDE5/6 inhibition with sildenafil to reduce choroidal ischemia and treat age-related macular degeneration. METHODS: Sildenafil was prescribed to treat participants with macular degenerations or macular dystrophies measured by spectral-domain optical coherence tomography, color fundus photography, enhanced depth imaging, and best-corrected visual acuity. RESULTS: No change in calcified drusen was noted. Vitelliform-type soft drusen were not substantially changed. A participant with Best vitelliform macular dystrophy had a significant improvement in vision as well as in photoreceptor and ellipsoid layers. CONCLUSIONS: Our research supports sildenafil as a safe treatment for age-related and vitelliform macular degenerations. Thickened Bruch's membrane reduces the beneficial effect of perfusion increase, but all eyes appear to benefit from PDE6. Notably, maintenance or improvement in the photoreceptor layer may be the most significant result of sildenafil and is consistent with PDE6 inhibition. Thus, sil-denafil treatment of macular degeneration offers significant potential for vision retention and recovery.

Age-related macular degeneration: choroidal ischaemia?

AIM: Our aim is to use ultrasound to non-invasively detect differences in choroidal microarchitecture possibly related to ischaemia among normal eyes and those with wet and dry age-related macular degeneration (AMD). DESIGN: Prospective case series of subjects with dry AMD, wet AMD and age-matched controls. METHODS: Digitised 20 MHz B-scan radiofrequency ultrasound data of the region of the macula were segmented to extract the signal from the retina and choroid. This signal was processed by a wavelet transform, and statistical modelling was applied to the wavelet coefficients to examine differences among dry, wet and non-AMD eyes. Receiver operating characteristic (ROC) analysis was used to evaluate a multivariate classifier. RESULTS: In the 69 eyes of 52 patients, 18 did not have AMD, 23 had dry AMD and 28 had wet AMD. Multivariate models showed statistically significant differences between groups. Multiclass ROC analysis of the best model showed an excellent volume-under-curve of 0.892±0.17. The classifier is consistent with ischaemia in dry AMD. CONCLUSIONS: Wavelet augmented ultrasound is sensitive to the organisational elements of choroidal microarchitecture relating to scatter and fluid tissue boundaries such as seen in ischaemia and inflammation, allowing statistically significant differentiation of dry, wet and non-AMD eyes. This study further supports the association of ischaemia with dry AMD and provides a rationale for treating dry AMD with pharmacological agents to increase choroidal perfusion. ClinicalTrials.gov registration: NCT00277784.

Pulse-encoded ultrasound imaging of the vitreous with an annular array.

The vitreous body is nearly transparent both optically and ultrasonically. Conventional 10- to 12-MHz diagnostic ultrasound can detect vitreous inhomogeneities at high gain settings, but has limited resolution and sensitivity, especially outside the fixed focal zone near the retina. To improve visualization of faint intravitreal fluid/gel interfaces, the authors fabricated a spherically curved 20-MHz five-element annular array ultrasound transducer, implemented a synthetic-focusing algorithm to extend the depth-of-field, and used a pulse-encoding strategy to increase sensitivity. The authors evaluated a human subject with a recent posterior vitreous detachment and compared the annular array with conventional 10-MHz ultrasound and spectral-domain optical coherence tomography. With synthetic focusing and chirp pulse-encoding, the array allowed visualization of the formed and fluid components of the vitreous with improved sensitivity and resolution compared with the conventional B-scan. Although optical coherence tomography allowed assessment of the posterior vitreoretinal interface, the ultrasound array allowed evaluation of the entire vitreous body.

Epithelial, stromal, and total corneal thickness in keratoconus: three-dimensional display with artemis very-high frequency digital ultrasound.

PURPOSE: To characterize the epithelial, stromal, and total corneal thickness profile in a population of eyes with keratoconus. METHODS: Epithelial, stromal, and total corneal thickness profiles were measured in vivo by Artemis very high-frequency (VHF) digital ultrasound scanning (ArcScan) across the central 6- to 10-mm diameter of the cornea on 54 keratoconic eyes. Maps of the average, standard deviation, minimum, maximum, and range of epithelial, stromal, and total corneal thickness were plotted. The average location of the thinnest epithelium, stroma, and total cornea were found. The cross-sectional semi-meridional stromal and total corneal thickness profiles were calculated using annular averaging. The absolute stromal and total corneal thickness progressions relative to the thinnest point were calculated using annular averaging as well as for 8 semi-meridians individually. RESULTS: The mean corneal vertex epithelial, stromal, and total corneal thicknesses were 45.7+/-5.9 microm, 426.4+/-38.5 microm, and 472.2+/-41.4 microm, respectively. The average epithelial thickness profile showed an epithelial doughnut pattern characterized by localized central thinning surrounded by an annulus of thick epithelium. The thinnest epithelium, stroma, and total cornea were displaced on average by 0.48+/-0.66 mm temporally and 0.32+/-0.67 mm inferiorly, 0.31+/-0.45 mm temporally and 0.54+/-0.37 mm inferiorly, and 0.31+/-0.43 mm temporally and 0.50+/-0.35 mm inferiorly, respectively, with reference to the corneal vertex. The increase in semi-meridional absolute stromal and total corneal thickness progressions was greatest inferiorly and lowest temporally. CONCLUSIONS: Three-dimensional thickness mapping of the epithelial, stromal, and total corneal thickness profiles characterized thickness changes associated with keratoconus and may help in early diagnosis of keratoconus.

High-resolution photoacoustic imaging of ocular tissues.

Optical coherence tomography (OCT) and ultrasound (US) are methods widely used for diagnostic imaging of the eye. These techniques detect discontinuities in optical refractive index and acoustic impedance, respectively. Because these both relate to variations in tissue density or composition, OCT and US images share a qualitatively similar appearance. In photoacoustic imaging (PAI), short light pulses are directed at tissues, pressure is generated due to a rapid energy deposition in the tissue volume and thermoelastic expansion results in generation of broadband US. PAI thus depicts optical absorption, which is independent of the tissue characteristics imaged by OCT or US. Our aim was to demonstrate the application of PAI in ocular tissues and to do so with lateral resolution comparable to OCT. We developed two PAI assemblies, both of which used single-element US transducers and lasers sharing a common focus. The first assembly had optical and 35-MHz US axes offset by a 30 degrees angle. The second assembly consisted of a 20-MHz ring transducer with a coaxial optics. The laser emitted 5-ns pulses at either 532 nm or 1064 nm, with spot sizes at the focus of 35 microm for the angled probe and 20 microm for the coaxial probe. We compared lateral resolution by scanning 12.5 microm diameter wire targets with pulse/echo US and PAI at each wavelength. We then imaged the anterior segment in whole ex vivo pig eyes and the choroid and ciliary body region in sectioned eyes. PAI data obtained at 1064 nm in the near infrared had higher penetration but reduced signal amplitude compared to that obtained using the 532 nm green wavelength. Images were obtained of the iris, choroid and ciliary processes. The zonules and anterior cornea and lens surfaces were seen at 532 nm. Because the laser spot size was significantly smaller than the US beamwidth at the focus, PAI images had superior resolution than those obtained using conventional US.

Epithelial thickness after hyperopic LASIK: three-dimensional display with Artemis very high-frequency digital ultrasound.

PURPOSE: To characterize the epithelial thickness profile in a population of eyes after LASIK for hyperopia or hyperopic astigmatism. METHODS: The epithelial thickness profile was measured in vivo by Artemis very high-frequency (VHF) digital ultrasound scanning (ArcScan Inc) across the central 10-mm diameter of the cornea on 65 eyes at least 3 months after hyperopic LASIK using a 7-mm ablation zone with the MEL 80 excimer laser (Carl Zeiss Meditec). Maps of the average, standard deviation, minimum, maximum, and range of epithelial thickness were plotted. The cross-sectional hemi-meridional epithelial thickness profile was calculated using annular averaging. Linear regression analysis was performed to evaluate correlations between epithelial thickness, spherical equivalent refraction treated, and maximum simulated keratometry. RESULTS: The mean thinnest epithelial thickness was 39.7 +/- 5.6 microm and the mean thickest epithelial thickness was 89.3 +/- 14.6 microm. The average epithelial thickness profile showed an epithelial doughnut pattern characterized by localized central thinning within the 4-mm diameter zone surrounded by an annulus of thick epithelium, with the thickest epithelium at the 3.4-mm radius. The epithelium was on average 10-microm thicker temporally than nasally at the 3.4-mm radius. Central epithelium was thinner and paracentral epithelium was thicker for higher hyperopic corrections and steeper maximum simulated keratometry. CONCLUSIONS: Three-dimensional high-resolution ultrasound mapping of epithelial thickness profile after LASIK for hyperopia demonstrated thinner epithelium centrally and thicker epithelium paracentrally. Presumably, the paracentral epithelial thickening compensated in part for the stromal tissue removed by the hyperopic ablation, whereas the central epithelial thinning compensated for the localized increase in corneal curvature.

Repeatability of layered corneal pachymetry with the artemis very high-frequency digital ultrasound arc-scanner.

PURPOSE: To assess the three-dimensional repeatability of thickness measurements for epithelium, stroma, cornea, flap, and residual stromal bed using the Artemis very high-frequency (VHF) digital ultrasound arc-scanner (ArcScan Inc). METHODS: Five consecutive measurements were obtained for 10 eyes of 10 patients 1 year after LASIK using the Artemis VHF digital ultrasound arc-scanner across the central 10-mm diameter of the cornea. Repeatability analysis was performed for thickness measurements for each corneal layer-epithelium, stroma, cornea, flap, and residual stromal bed. The standard deviation of repeated measurements (point-repeatability) was calculated for each measurement location in 0.1-mm steps for the 10×10-mm matrix. The pooled standard deviation of the point-repeatability for each measurement location within the central 1-, 2-, and 3-mm radius was calculated (region-repeatability). The corneal thickness of the baseline scan set was compared to that of subsequent scan sets within the same session and plotted over time to assess any possible hydration effects of the immersion technique. RESULTS: The repeatability at the corneal vertex was 0.58 µm for epithelium, 1.78 µm for stroma, 1.68 µm for cornea, 1.68 µm for flap, and 2.27 µm for residual stromal bed. The region-repeatability within the central 1-mm radius was 1.01 µm for epithelium, 3.44 µm for stroma, 3.35 µm for cornea, 2.81 µm for flap, and 3.97 µm for residual stromal bed. The mean difference in corneal thickness from the baseline value was within 1.25 µm for each of the subsequent four scan sets over a 5-minute immersion period. CONCLUSIONS: Layered pachymetry of the epithelium, stroma, cornea, flap, and residual stromal bed showed high repeatability with the Artemis VHF digital ultrasound arc-scanner. The high repeatability validates the use of the Artemis for in vivo layered pachymetry.

Stromal thickness in the normal cornea: three-dimensional display with artemis very high-frequency digital ultrasound.

PURPOSE: To characterize the stromal thickness profile in a population of normal eyes. METHODS: Stromal thickness profile was measured in vivo by Artemis very high-frequency digital ultrasound scanning (ArcScan, Morrison, Colo) across the central 10-mm corneal diameter on 110 normal eyes. Maps of the average, standard deviation, minimum, maximum, and range of stromal thickness were plotted. The average location of the thinnest stroma was found. The cross-sectional hemi-meridional stromal thickness profile was calculated using annular averaging. The absolute stromal thickness progression relative to the thinnest point was calculated using annular averaging as well as for 8 hemi-meridians individually. RESULTS: The mean stromal thickness at the corneal vertex and at the thinnest point were 465.4+/-36.9 mum and 461.8+/-37.3 mum, respectively. The thinnest stroma was displaced on average 0.17+/-0.31 mm inferiorly and 0.33+/-0.40 mm temporally from the corneal vertex. The average absolute stromal thickness progression from the thinnest point could be described by the quadratic equation: stromal thickness = 6.411 x radius(2) + 2.444 x radius (R(2) = 0.999). Absolute stromal thickness progression was independent of stromal thickness at the thinnest point. The increase in hemi-meridional absolute stromal thickness progression was greatest superiorly and lowest temporally. CONCLUSIONS: Three-dimensional thickness mapping of the corneal stroma and stromal thickness progression in a population of normal eyes represent a normative data set, which may help in early diagnosis of corneal abnormalities such as keratoconus and pellucid marginal degeneration. Absolute stromal thickness progression was found to be independent of stromal thickness.

Epithelial thickness profile changes induced by myopic LASIK as measured by Artemis very high-frequency digital ultrasound.

PURPOSE: To characterize changes in the corneal epithelial thickness profile induced by myopic LASIK. METHODS: This was a prospective study of 37 eyes of 19 myopic LASIK patients. Eyes were divided into three groups according to sphere in the maximum myopic meridian: low (-1.00 to -4.00 diopters [D]), moderate (-4.25 to -6.00 D), and high myopia (-6.25 to -13.50 D). The epithelial thickness profile was measured by prototype Artemis very high-frequency (VHF) digital ultrasound scanner (ArcScan Inc) across the central 10-mm corneal diameter preoperatively and between 3 and 6 months postoperatively. The epithelial thickness profile was determined by averaging the epithelial thickness within annular bands centered on the corneal vertex. The change in epithelial thickness profile was calculated as the difference between the preoperative and postoperative epithelial thickness profiles. RESULTS: The corneal epithelium thickened after myopic LASIK across the central 6 mm with maximum thickening centrally and progressively less thickening centrifugally in low myopia, and a more homogenous thickening in moderate and high myopia within the 5-mm diameter. The mean epithelial thickening at the corneal vertex was 7.41 +/- 1.09 microm, 9.29 +/- 1.22 microm, and 12.33 +/- 1.05 microm for low, moderate, and high myopia, respectively. The rate of epithelial thickening at the corneal vertex per diopter of myopia treated decreased with increasing myopia. CONCLUSIONS: Although the magnitude of epithelial thickening increased with increasing ablation depth, in accordance with Barraquer's Law of Thicknesses, the myopic refractive shift due to epithelial thickness profile changes was paradoxically more significant in low myopia than in high myopia.

Effect of corneal hydration on ultrasound velocity and backscatter.

The cornea's acoustic properties (speed-of-sound, backscatter, attenuation) are related to its state of hydration. Our aim was to determine these properties as a function of corneal hydration using high-frequency ultrasound. Bovine corneas were suspended in a Dexsol-equivalent corneal preservation medium at 33 degrees C and then immersed successively in 75%, 50% and 25% medium and distilled water. Using a 38-MHz focused ultrasound transducer, we measured speed-of-sound and corneal thickness (n = 8) and stromal backscatter (n = 6) after 45-min immersion in each medium. Corneal speed-of-sound was modeled as a function of corneal thickness. We found the mean speed-of-sound to be 1605.4 +/- 2.9 m/s in normotensive medium. The maximum observed speed-of-sound was 1616 m/s. As we decreased medium tonicity, the cornea swelled and the speed-of-sound decreased, reaching 1563.0 +/- 2.2 m/s in water. Average corneal thickness increased from 969 +/- 93 microm in 100% medium to 1579 +/- 104 microm in water. Going from 100% medium to water, stromal backscatter (midband-fit) increased from -60.0 +/- 0.8 dBr to -52.5 +/- 3.5 dBr, spectral slope increased from -0.119 +/- 0.021 to -0.005 +/- 0.030 dB/MHz and attenuation coefficient decreased from 0.927 +/- 0.434 to 0.010 +/- 0.581 dB/cm-MHz. The observed correlation between acoustic backscatter and attenuation with the speed-of-sound offers a potential means for more accurate determination of speed-of-sound and, hence, thickness in edematous corneas.

Correlation of anterior chamber angle and ciliary sulcus diameters with white-to-white corneal diameter in high myopes using artemis VHF digital ultrasound.

PURPOSE: To determine whether horizontal angle diameter and sulcus diameter can be accurately estimated by conventional external measurements in high myopic eyes. METHODS: Ten horizontal anterior segment scans were obtained with the Artemis 1 very high-frequency (VHF) digital ultrasound arc-scanner in 40 eyes of 20 patients. Angle and sulcus diameters were measured and descriptive statistics and within-eye repeatability were calculated. Linear regression was performed between each permutation of white-to-white, angle diameter, and sulcus diameter. Multivariate regression also included anterior chamber depth (ACD), age, manifest refraction, keratometry, and central corneal thickness (CCT). The standard deviation and 95% confidence interval (CI) of the residuals were calculated. RESULTS: The population mean +/-standard deviation (95% CI) was 12.88 +/- 0.42 mm [12.74, 13.02] for angle diameter and 12.85 +/- 0.69 mm [12.63, 13.07] for sulcus diameter. Within-eye repeatability was 0.13 mm for angle diameter and 0.23 mm for sulcus diameter. A weak correlation was noted between white-to-white and angle diameter (r2=0.59) with a 95% CI of +/-0.53 mm. Multivariate regression found white-to-white, CCT, and minimum keratometry predicted angle diameter (r2=0.69) with a 95% CI of +/-0.46 mm. For predicting sulcus diameter, there were weak correlations between white-to-white (r2=0.32) with a 95% CI of +/-1.11 mm and angle diameter (r2=0.46) with a 95% CI of +/-0.99 mm. Multivariate regression found angle diameter and ACD predicted sulcus diameter (r2=0.57) with 95% CI of +/-0.88 mm. CONCLUSIONS: Regression modeling found weak correlations among all combinations of white-to-white, angle diameter, and sulcus diameter. Given the relative accuracy of direct measurement of angle and sulcus diameter compared to the potential accuracy of these regression equations, it appears that direct measurement would increase the safety of anterior and posterior chamber phakic intraocular lens sizing.

Central corneal thickness measured by the Orbscan II system, contact ultrasound pachymetry, and the Artemis 2 system.

PURPOSE: To compare central corneal thickness (CCT) measurements by the Orbscan II device, contact ultrasound (US) pachymetry, and the noncontact Artemis 2 scanning US system. SETTING: Department of Ophthalmology, Weill Cornell Medical College, New York, New York, USA. METHODS: The CCT in 40 eyes (20 normal subjects) was measured by the Orbscan II followed by contact US pachymetry and then the Artemis 2. Results were compared using analysis of variance (ANOVA), paired t tests, and Bland-Altman plots. RESULTS: There was a significant difference in CCT measurements between the 3 modes (F = 32.84, P = .0001, 1-way ANOVA). Artemis 2 and US pachymetry measurements were highly correlated (r2 = 0.963, P < .0001), although Artemis 2 values were a mean of 11.2 microm +/- 6.6 (SD) thinner than pachymetry values. Artemis 2 and Orbscan II measurements were less well correlated (r2 = 0.851, P < .001); Orbscan II values were a mean of 7.5 +/- 15.7 microm thinner than Artemis 2 values. Orbscan II values showed a trend toward increasing underestimation of CCT in thinner corneas. CONCLUSIONS: Ultrasound pachymetry and Artemis 2 CCT measurements were highly correlated; the 11 microm mean difference in measurements may be attributed to decentration, oblique incidence of the probe to the cornea, or possibly the effect of topical anesthesia with contact pachymetry. Although the mean difference between Orbscan II and Artemis 2 values was 7.5 microm, Orbscan values were less correlated than Artemis 2 values with contact US pachymetry and were prone to underestimation of the CCT in thinner corneas.

Improved high-resolution ultrasonic imaging of the eye.

Currently, virtually all clinical diagnostic ultrasound systems used in ophthalmology are based on fixed-focus, single-element transducers. High-frequency (> or = 20-MHz) transducers introduced to ophthalmology during the last decade have led to improved resolution and diagnostic capabilities for assessment of the anterior segment and the retina. However, single-element transducers are restricted to a small depth of field, limiting their capacity to image the eye as a whole. We fabricated a 20-MHz annular array probe prototype consisting of 5 concentric transducer elements and scanned an ex vivo human eye. Synthetically focused images of the bank eye showed improved depth of field and sensitivity, allowing simultaneous display of the anterior and posterior segments and the full lens contour. This capability may be useful in assessment of vitreoretinal pathologies and investigation of the accommodative mechanism.

High-frequency ultrasonic imaging of the anterior segment using an annular array transducer.

OBJECTIVE: Very high-frequency ultrasound (VHFU; >35 megahertz [MHz]) allows imaging of anterior segment structures of the eye with a resolution of less than 40 microm. The low focal ratio of VHFU transducers, however, results in a depth of field (DOF) of less than 1 mm. The aim was to develop a high-frequency annular array transducer for ocular imaging with improved DOF, sensitivity, and resolution compared with conventional transducers. DESIGN: Experimental study. PARTICIPANTS: Cadaver eyes, ex vivo cow eyes, in vivo rabbit eyes. METHODS: A spherically curved annular array ultrasound transducer was fabricated. The array consisted of 5 concentric rings of equal area, had an overall aperture of 6 mm, and a geometric focus of 12 mm. The nominal center frequency of all array elements was 40 MHz. An experimental system was designed in which a single array element was pulsed and echo data were recorded from all elements. By sequentially pulsing each element, echo data were acquired for all 25 transmit-and-receive annuli combinations. The echo data then were focused synthetically and composite images were produced. Transducer operation was tested by scanning a test object consisting of a series of 25-microm diameter wires spaced at increasing range from the transducer. Imaging capabilities of the annular array were demonstrated in ex vivo bovine, in vivo rabbit, and human cadaver eyes. MAIN OUTCOME MEASURES: Depth of field, resolution, and sensitivity. RESULTS: The wire scans verified the operation of the array and demonstrated a 6.0-mm DOF, compared with the 1.0-mm DOF of a conventional single-element transducer of comparable frequency, aperture, and focal length. B-mode images of ex vivo bovine, in vivo rabbit, and cadaver eyes showed that although the single-element transducer had high sensitivity and resolution within 1 to 2 mm of its focus, the array with synthetic focusing maintained this quality over a 6-mm DOF. CONCLUSIONS: An annular array for high-resolution ocular imaging has been demonstrated. This technology offers improved DOF, sensitivity, and lateral resolution compared with single-element fixed focus transducers currently used for VHFU imaging of the eye.