Thermally tuned VCSEL at 850†nm as a low-cost alternative source for full-eye SS-OCT.

Swept-source optical coherence tomography (SS-OCT) demonstrates superior performance in comparison to spectral domain OCT with regard to depth ranging. The main driver of cost for SS-OCT systems is, however, the price of the source. Here we show a low-cost alternative swept source that uses a thermally tuned vertical-cavity surface-emitting laser (VCSEL) at 850 nm. Its center wavelength can be tuned by adjusting the operating temperature through modulation of the injection current. At 2 kHz sweep rate, the depth range of the system was 5 cm, with a sensitivity roll-off of under -3 dB across this range. The system achieved a sensitivity of 97 dB with a sample beam power of 0.3 mW and an axial resolution of 50 µm in air. To demonstrate the system performance in vivo, an eye of a healthy volunteer was measured, and full-eye scans were acquired at 25 and 50 kHz from the cornea to the retina. Based on our results, we believe that this technology can be used as a cost-effective alternative OCT for point-of-care diagnostics.

Optical coherence tomography-measured retinal nerve fiber layer thickness values compensated with a multivariate model and discrimination between stable and progressing glaucoma suspects.

PURPOSE: Our previously introduced multivariate model, compensating for intersubject variability, was applied to circumpapillary retinal nerve fiber layer (RNFL) values measured with optical coherence tomography in glaucoma suspects with or without prior progressive optic disc (OD) change in a series of confocal scanning laser tomography (CSLT, HRT III) measurements. METHODS: In this prospective study, OD change during CSLT follow-up was determined with strict, moderate, and liberal criteria of the topographic change analysis (TCA). Model compensation (MC) as well as age compensation (AC) was applied to RNFL sectors (RNFLMC vs. RNFLAC). Diagnostic performance of RNFLMC vs. RNFLAC was tested with an area under the receiver operating characteristic (AUROC) and was compared between methods. RESULTS: Forty-two glaucoma suspects were included. Patients without prior progressive OD change during the CSLT follow-up (= stable) had thicker RNFL thickness values in most areas and for all progression criteria. RNFLMC AUROC for the global RNFL (0.719) and the inferior quadrant (0.711) performed significantly better compared with RNFLAC AUROC (0.594 and 0.631) to discriminate between stable and progressive glaucoma suspects as defined by the moderate criteria of CSLT progression analysis (p = 0.028; p = 0.024). CONCLUSION: MC showed a slight but significant improvement in detection of subjects with prior progressive OD change among a group of glaucoma suspects, when compared to AC, which is the compensation method commonly used during OCT data evaluation in daily routine. Further studies are warranted to validate the present results.

Retinal Oxygen Extraction in Patients with Primary Open-Angle Glaucoma.

Objective: To compare total retinal oxygen extraction between patients with primary open-angle glaucoma (POAG) and healthy control subjects. Design: A prospective, single-center, cross-sectional, case−control study performed at the Medical University of Vienna. Subjects: Forty patients with POAG and 40 age- and sex-matched control subjects. Methods: Total retinal blood flow was measured using Doppler optical coherence tomography (OCT). Retinal arterial and venous oxygen saturation was measured using reflectance spectroscopy. From these parameters, oxygen content in the retinal arterial and venous circulation as well as total retinal oxygen extraction were calculated. Results: Total retinal blood flow was lower in POAG (25.2 ± 6.7 µL/min) as compared to healthy control subjects (35.6 ± 8.3 µL/min, p < 0.001). Retinal arterial oxygen content was not different between the two groups (0.18 ± 0.01 mL(O2)/mL in both groups, p < 0.761), but retinal venous oxygen content was higher in POAG (0.15 ± 0.01 mL(O2)/mL) than in healthy controls (0.14 ± 0.01 mL(O2)/mL p < 0.001). Accordingly, retinal oxygen extraction was reduced in POAG (0.8 ± 0.3 µL(O2)/min as compared to healthy controls: 1.4 ± 0.4 µL(O2)/min, p < 0.001). There was a significant association between total retinal blood flow and total retinal oxygen extraction with measures of structural and functional damage (p < 0.001 each). Conclusions: This study indicates that POAG is associated with a reduction in total retinal oxygen extraction linked to structural and functional damage of the disease. Since the technology is non-invasive, it allows for longitudinal studies investigating to which degree low retinal oxygen extraction is linked to the progression of the disease.

Needling and open filtering bleb revision after XEN-45 implantation-a retrospective outcome comparison.

PURPOSE: To compare efficacy and safety of needling and open bleb revision after XEN-45 surgery. METHODS: This retrospective study represents real-life data of patients who underwent XEN-45 surgery between November 2014 and June 2018 in the Vienna General Hospital. The following groups were formed for data evaluation: (PSEA) primary surgery secondary intervention allowed (n = 268); (PS) primary surgery until secondary intervention (n = 268); (N) first needling until additional secondary intervention (n = 55); (BR) first bleb revision until additional secondary intervention (n = 105). Main outcome measures were pre- and postoperative intraocular pressure (IOP), number of glaucoma medication (GM), Kaplan-Meier success rates, and secondary intervention rates. Success was defined as postoperative IOP < 21 mmHg and < 18 mmHg together with ≥ 20% IOP reduction with medication allowed. RESULTS: IOP (and GM) was lowered from 23.5 ± 8.0 (GM 3.1 ± 1.0) to 14.9 ± 8.2 mmHg (1.2 ± 1.4) in group PSEA and 18.1 ± 8.2 mmHg (1.5 ± 1.4) in group PS, in group N from 23.2 ± 10.1 (1.5 ± 1.0) to 19.3 ± 8.5 mmHg (2.2 ± 1.3) and in group BR from 22.0 ± 8.0 mmHg (2.5 ± 1.1) to 15.5 ± 6.4 mmHg (1.3 ± 1.5) after a median follow-up of 16.0, 8.4, 4.8, and 7.3 months, respectively. Success rates at 1 year were significantly higher in group BR (50.7%) compared to PS (37.7%, p = 0.019) and N (24.3%; p = 0.015). An additional intervention was required less frequently in group BR (17.1%) compared to group PS (49.6%, p < 0.001) and group N (54.5%, p < 0.001). CONCLUSION: Our data appear to indicate favorable outcomes for open XEN bleb revision in terms of Kaplan-Meier success rates and secondary intervention rate compared to the needling procedure.

Comparison of Spectralis and Cirrus spectral domain optical coherence tomography for the objective morphometric assessment of the neuroretinal rim width.

PURPOSE: The assessment of cup-disc ratio as a surrogate parameter for the neuroretinal rim width (NRW) of the optic nerve is well established, but prone to human error and imprecision. Objective assessment of the NRW is provided by spectral domain optical coherence tomography (SD-OCT). This study is the first to systematically compare NRW measurements acquired with the Carl Zeiss Meditech Cirrus HD-OCT 5000 and the Heidelberg Engineering Spectralis SD-OCT. METHODS: In this cross-sectional study, 20 eyes of each 20 glaucoma patients and 20 age-matched healthy controls underwent ophthalmic examination, SD-OCT imaging, and computer perimetry. Regression analyses were performed for the NRW comparability and the effect of the rotational alignment disconcordance (RAD), receiver-operating characteristics (ROC) for NRW-based healthy glaucoma discrimination capability, and Pearson's correlation for covariate association. RESULTS: Mean NRW differences were 8 ± 48 µm (p = 0.4528), 91 ± 80 µm (p < 0.01), and 49 ± 77 µm (p < 0.001) in the glaucoma, healthy, and whole group. On average, the Cirrus showed higher NRW values (+ 50 µm) than the Spectralis, this difference increased with values starting with 159 µm. Discrimination ROC were 1.0 (Spectralis) and 0.9675 (Cirrus). RAD showed very little effect on NRW (R2 = 0.9661, p < 0.001). NRW-covariate correlation was highly significant (p < 0.001) with both devices for clinical cup/disc ratio, calculated rim width, visual field mean, and pattern deviations. CONCLUSIONS: Our results suggest to only cautiously compare Spectralis and Cirrus NRW measurements only in patients with morphologically manifest glaucoma. For morphological progression analysis, we recommend the continuous usage of the same device.

PRESERFLO™ Microshunt: 1-Year Results of a 25-Gauge vs. 27-Gauge Needle Tract.

Background: The purpose of this study was to evaluate the effectiveness and safety of the PreserFlo™ microshunt (PMS) using a 25-Gauge vs. 27-Gauge needle tract. Methods: This is a prospective postoperative examination of 60 glaucoma eyes that received a PMS. The main outcome measures were intraocular pressure (IOP), glaucoma drug score (GDS), Kaplan-Meier success rates, complications, and secondary intervention rates. Two subgroups were formed for data comparison: 27-Gauge (27G), and 25-Gauge (25G). Success was defined as IOP < 18 mmHg together with ≥20% IOP reduction with medication allowed (qualified success = QS18) or not (full success = FS18). Results: IOP and GDS were reduced from baseline to the 1-year study visit as follows: All eyes from 23.4 ± 8.6 mmHg (3.1 ± 0.9) to 15.1 ± 5.9 mmHg (0.8 ± 1.1); 25G from 24.2 ± 7.3 mmHg (3.0 ± 0.8) to 12.7 ± 2.7 mmHg (0.5 ± 0.8); and 27G from 23.1 ± 9.2 mmHg (3.1 ± 1.0) to 16.2 ± 6.7 mmHg (0.9 ± 1.2). IOP at one year was lower in the 25G group compared to the 27G group (p = 0.035). Bleb needling was required in eight (13.3%) eyes and open bleb revisions in three (5.0%). Transient hypotony occurred in 21% and choroidal effusion in 8% of all eyes. Choroidal effusions were more frequent in the 25G group (21%) compared to the 27G group (2%, p = 0.031). One-year success rates were significantly higher in the 25G group compared to the 27G group for both QS18 (25G: 67.9% vs. 27G: 35.7%, p = 0.002) and FS18 (25G: 63.6% vs. 27G: 29.2%, p = 0.007). Conclusions: The PreserFlo microshunt is an effective and safe glaucoma surgery with a low rate of bleb revisions or needlings. We show that the 25G needle tract might be more efficient for IOP control at the cost of increased IOP-related complications compared to 27G.

Birefringent Properties of the Peripapillary Retinal Nerve Fiber Layer in Healthy and Glaucoma Subjects Analyzed by Polarization-Sensitive OCT.

Purpose: To study the circumpapillary retinal nerve fiber layer (RNFL) birefringence (BIR) of early glaucoma and age-matched healthy eyes using polarization-sensitive optical coherence tomography (PS-OCT). Methods: In this prospective cross-sectional study, we compared virtual circular PS-OCT B-scans with a diameter of 3.5 mm centered on the optic disc (OD) acquired with a PS-OCT prototype (860 nm center wavelength). Early glaucoma was defined by the glaucomatous appearance of the OD and a pathologic visual field test with a mean deviation (MD) better than -6 dB. The main outcome parameters were BIR, RNFL-thickness (RNFL-T), and phase retardation (RET). The BIR value at each virtual A-scan position was the quotient of the RET measured at the inner segment/outer segment junction divided by the RNFL-T. Results: The dataset comprised 49 early glaucoma patients (mean ± standard deviation [SD]: 64 ± 10 years) and 49 healthy control subjects (61 ± 9 years). Glaucomatous eyes showed a statistically significant lower BIR globally (mean ± SD: 0.108 ± 0.008°/µm vs. 0.112 ± 0.009°/µm, P = 0.033), superiorly (0.116 ± 0.017°/µm vs. 0.126 ± 0.013°/µm, P = 0.0001), and inferiorly (0.112 ± 0.011°/µm vs. 0.121 ± 0.011°/µm, P < 0.0001), and increased BIR in the temporal quadrant (0.088 ± 0.015°/µm vs. 0.078 ± 0.014°/µm, P = 0.0001) compared to healthy eyes. Conclusions: We report a reduced BIR of the RNFL in early perimetric glaucoma, which can be interpreted as a sign of loss or change of intracellular microtubules and may contribute to a better understanding of early disease development. Prospective longitudinal studies are needed to determine whether BIR is altered in pre-perimetric human glaucoma before RNFL-T decline.

Automatic retinal nerve fiber bundle tracing based on large field of view polarization sensitive OCT data.

A technique to accurately estimate trajectories of retinal nerve fiber bundles (RNFB) in a large field of view (FOV) image covering 45° is described. The method utilizes stitched projections of polarization-sensitive optical coherence tomography (PS-OCT) data, as well as a mathematical model of average RNFB trajectories as prior. The fully automatic process was applied to data recorded in healthy subjects and glaucoma patients and automatically detected individual RNFB trajectories are compared to manual traces.

Effect of regular smoking on flicker induced retinal vasodilatation in healthy subjects.

BACKGROUND: Habitual smoking is a risk factor for a variety of vascular diseases, including ocular pathologies. In the current study, we set out to investigate whether the regulation of retinal vascular tone is impaired in habitual smokers. For this purpose, vascular reactivity was tested during flicker light induced vasodilatation in smokers and in a non-smoking control group. METHODS: In this prospective, balanced, parallel group study 24 chronic smokers (28.1 ± 3.3 years) and 24 age-matched never-smoking volunteers (28.2 ± 4.0 years) were included. Flicker induced vasodilatation was measured in major retinal arteries and veins using a retinal vessel analyzer and flicker induced changes in retinal blood velocities were assessed in retinal veins by laser Doppler velocimetry. Three flicker periods of 60s were scheduled. Blood cotinine concentration was determined and a Fagerstrom questionnaire was performed to evaluate nicotine dependency. RESULTS: In non-smoking subjects, stimulation with flicker light increased retinal venous diameter by +7.7 ± 3.1%, +6.9 ± 2.9% and +7.1 ± 2.8% during the three flicker periods, respectively. Flicker induced vasodilatation in veins was significantly diminished in chronic smokers (+4.9 ± 2.4%, +6.3 ± 3.1% and +5.7 ± 3.4%, ANOVA between groups, p=0.032) as compared to the non-smoking control group. Calculated retinal blood flow in the measured veins increased by a maximum of +54 ± 21%, +43 ± 18% and +46 ± 19% during the three stimulation periods in the non-smoking subjects, respectively. The flicker induced increase in retinal blood flow as assessed in the veins was significantly reduced in chronic smokers as compared to the non-smoking control group (+19 ± 16%, +26 ± 14%, +24 ± 13%, ANOVA between groups, p=0.013). In retinal arteries, flicker stimulation increased retinal arterial diameters by 5.2 ± 3.8%, 5.8 ± 4.8% and 5.5 ± 5.6% during the three flicker periods in the non-smoking group. In smokers, the flicker induced arterial vasodilatation was not significantly different compared to non-smokers (4.6 ± 4.1%, 3.8 ± 3.7% and 4.8 ± 3.4%, ANOVA between groups, p=0.4). CONCLUSION: Our data indicate that the flicker induced hemodynamic response of retinal veins is reduced in chronic smokers as compared to age matched healthy volunteers. This supports the hypothesis that chronic smoking leads to vascular dysfunction in the eye.

Generating large field of view en-face projection images from intra-acquisition motion compensated volumetric optical coherence tomography data.

A technique to generate large field of view projection maps of arbitrary optical coherence tomography (OCT) data is described. The technique is divided into two stages - an image acquisition stage that features a simple to use fast and robust retinal tracker to get motion free retinal OCT volume scans - and a stitching stage where OCT data from different retinal locations is first registered against a reference image using a custom pyramid-based approach and finally stitched together into one seamless large field of view (FOV) image. The method is applied to data recorded with a polarization sensitive OCT instrument in healthy subjects and glaucoma patients. The tracking and stitching accuracies are quantified, and finally, large FOV images of retinal nerve fiber layer retardation that contain the arcuate nerve fiber bundles from the optic nerve head to the raphe are demonstrated.

Acute effects of intravenously administered ethanol on retinal vessel diameters and flicker induced vasodilatation in healthy volunteers.

There is evidence from several vascular beds that acute alcohol consumption causes ocular hypotension and peripheral vasodilatation. The current study investigated the effects of intravenously administered ethanol on retinal vessel diameters and on flicker induced retinal vasodilatation. For this purpose, ethanol (0.35 g/kg) or placebo (physiologic saline solution) was administered intravenously for 40 min in a randomized, double masked, two way cross-over design to 12 healthy male volunteers. Retinal vessel diameters and flicker induced vasodilatation were measured before administration of ethanol as well as 30, 50, 90 and 130 min after the start of infusion with a retinal vessel analyzer. Intraocular pressure, systemic blood pressure and blood ethanol concentration were determined at the same time points. Intravenous administration of ethanol increased blood ethanol concentration from 0.0 g/l to 0.56+/-0.10 g/l. Ethanol reduced IOP, but did not change ocular perfusion pressure. After cessation of the infusion blood ethanol concentration started to drop reaching a blood ethanol concentration of 0.22+/-0.06 g/l 130 min after the start of infusion. Retinal arterial diameters increased significantly after administration of ethanol by a maximum of +4.2+/-4.0%, whereas no change was observed in retinal veins. Neither arterial nor venous diameters were influenced by administration of placebo. Flicker stimulation induced a significant dilatation in both arterial and venous diameters. Ethanol did not change flicker responses in arteries or in retinal veins. In conclusion, intravenous administration of ethanol increases retinal arterial diameters, whereas venous diameters remained unchanged. Whether this is related to a direct vasodilator effect or to a hitherto unidentified mechanism remains to be clarified.

Strategies for reducing variance in laser Doppler flowmetry measurements.

BACKGROUND: Scattering of blood flow data as assessed with laser Doppler flowmetry (LDF) in humans is a problem in many studies using this technique. We set out to reduce variability in LDF data by eliminating the effect of the total returning light level (DC) on LDF parameters in the choroid through partial regression analysis. METHODS: In 20 healthy subjects, choroidal blood flow parameters were measured at different DC values using a portable confocal LDF device. We used two different strategies to reduce scattering of data eliminating the effect of yield, which is defined as DC/gain. On the one hand, we used a previously described method based on a third-order polynomial fit, which combines all obtained data. On the other hand, we applied a new method based on a linear fit for each individual subject. RESULTS: Variability of data during changes in DC is higher for LDF parameters volume and flow than for velocity. Both methods were successful in reducing scattering of LDF parameters with varying DC. CONCLUSIONS: The present study indicates that both methods to correct for changes in yield were successful in reducing the variability of LDF measurements. When systematic changes in DC occur after an intervention, one needs to be careful in interpreting the obtained data and it remains to be shown if either of the two techniques is capable of correcting for this effect. The approach presented here may, however, represent an effective, easily applicable and valid approach to reduce scattering of data from using LDF to assess blood flow in the posterior pole of the human eye.

Optic nerve head blood flow regulation during changes in arterial blood pressure in patients with primary open-angle glaucoma.

PURPOSE: Abnormal autoregulation of optic nerve head blood flow (ONHBF) has been postulated to play an important role in primary open-angle glaucoma (POAG). We used laser Doppler flowmetry (LDF) to estimate quantitatively the ONHBF and compared ONHBF autoregulation between glaucoma patients and healthy controls during isometric exercise. METHODS: Forty patients with POAG and 40 healthy age- and sex-matched subjects underwent three periods of isometric exercise, each consisting of 2 min of handgripping. Optic nerve head blood flow (ONHBF) was measured continuously using LDF. Systemic blood pressure, intraocular pressure and ocular perfusion pressure were assessed in all participants. RESULTS: Isometric exercise was associated with an increase in ocular perfusion pressure during all handgripping periods in both groups (p < 0.001). However, there was no change in ONHBF in either group. Three of the glaucoma patients and two of the healthy subjects showed a consistent 10% decrease in blood flow during isometric exercise, in spite of an increase in their blood pressure. This difference between groups was not significant (p = 0.61). Four other glaucoma subjects showed a consistent increase in blood flow of more than 10% during isometric exercise, whereas this was not seen in healthy subjects (p = 0.035). CONCLUSION: This study suggests that abnormal ONHBF autoregulation is more often seen in patients with POAG than healthy control subjects. The relationship to the glaucoma disease process is currently unknown and requires further investigation.

Effect of unspecific inhibition of cyclooxygenase by indomethacin on retinal and choroidal blood flow.

PURPOSE: Animal studies suggest that retinal and choroidal blood flow decrease after administration of indomethacin, a nonspecific cyclooxygenase inhibitor. Cyclooxygenase is the key enzyme involved in the arachidonic pathway and regulates the production of vasoactive substances such as prostaglandins and thromboxans. The aim of the present study was to investigate the short-term effects of indomethacin on ocular blood flow in healthy humans. METHODS: A randomized, double-masked, placebo-controlled, two-way crossover study in 12 healthy, male, nonsmoking subjects was performed. Indomethacin was administered as a bolus injection of 0.4 mg/kg followed by continuous infusion of 0.4 mg/kg/h over 120 minutes. Ocular hemodynamic parameters were measured at baseline and up to 3 hours after start of the infusion. Subfoveal choroidal blood flow and fundus pulsation amplitude were measured with laser Doppler flowmetry and laser interferometry, respectively. Retinal vessel diameters were assessed using a retinal vessel analyzer. Retinal blood flow was calculated based on retinal vessel diameters, and red blood cell velocity was measured with laser Doppler velocimetry. RESULTS: Administration of indomethacin decreased retinal arterial diameters up to -4.3% +/- 3.4% and reduced retinal blood velocity by a maximum of -29% +/- 20% (P < 0.05). Calculated retinal blood flow decreased by -27% +/- 21% (P < 0.05), reaching the maximal decrease 60 minutes after administration. Choroidal blood flow and fundus pulsation amplitude (FPA) also decreased during the infusion of indomethacin with maximum effects of -17% +/- 13% (P < 0.05, vs. placebo) and -7% +/- 4% (P < 0.05, vs. placebo), respectively. CONCLUSIONS: Results showed a marked decrease in retinal and choroidal blood flow after short-term administration of indomethacin. Whether this decrease can be attributed to a reduced production of prostaglandins or an unknown mechanism has yet to be clarified. Further studies appear to be indicated to investigate whether the long-term intake of indomethacin is associated with an increased risk for vascular eye disease.

Optic nerve head morphology in primary open-angle glaucoma and nonarteritic anterior ischaemic optic neuropathy measured with spectral domain optical coherence tomography.

PURPOSE: Optic nerve head (ONH) parameters as well as circumpapillary retinal nerve fibre layer (RNFL) thickness values measured with two different spectral domain optical coherence tomography (SD-OCT) machines (Spectralis® and Cirrus® OCT) have been compared between two patient groups, primary open-angle glaucoma (POAG), nonarteritic anterior ischaemic optic neuropathy (NAION) and healthy controls. A comparison of the performance of the two OCT machines was made. METHODS: Twenty healthy controls, 20 POAG and 20 NAION patients with comparable visual field defects were included. Comparison between groups was made using anova and post hoc t-tests. To evaluate the diagnostic power of OCT to differentiate POAG from NAION, a stepwise linear regression analysis of the rim-RNFL correlation with adjusting covariates (optic disc area and age) was performed. Based on the regression formula, the area under the receiver operator characteristic (AUROC) was calculated. RESULTS: Both glaucoma and NAION patients showed significantly smaller global RNFL thickness values compared to healthy subjects in t-tests (p < 0.001), while only patients with glaucoma showed significantly smaller global ONH parameters for both devices compared to healthy subjects (p < 0.001). Correlation between global ONH parameters was highly statistically significant (r = 0.93), whereas in t-test a statistically significant difference between the two machines was detected (p < 0.001). Area under the receiver operator characteristic revealed a similarly good discrimination between glaucoma and NAION for Spectralis® (0.980) and Cirrus® OCT (0.945). CONCLUSION: NAION patients have similar RNFL thickness values as do glaucomatous eyes, whereas ONH parameters in NAION eyes were similar to those seen in healthy controls. This difference might help discriminating between these two different disease conditions in a chronic disease stadium, and in this regard, none of the two OCT machines performed better.

A Functional Regression Model of the Retinal Nerve Fiber Layer Thickness in Healthy Subjects.

PURPOSE: A new functional regression model is presented to explain the intersubject variability of the circumpapillary retinal nerve fiber layer (RNFL) thickness in healthy subjects. METHODS: To evaluate the functional regression approach we used data from 202 healthy volunteers, divided equally into training samples (TS) and validation samples (VS). Covariates included RNFL, fovea distance, fovea angle, optic disk ratio, orientation and area provided by Fourier-domain-optical coherence tomography, age, and refractive error. Root mean square errors (RMSE) were calculated for each of the 256 sectors and for the 12 clock-hour sectors in the TS and VS and were compared to the RMSE of the previous model and the standard deviation of the raw data. RESULTS: With the functional regression approach, we were able to explain on average 27.4% of the variation in the TS and 25.1% of the variation in the VS. The new model performed better compared to a multivariate linear regression model. It performed best in the superior-temporal and inferior-temporal clock-hour sectors where the percentage of RMSE reduction ranged between 26.3% and 44.1% for the TS and between 20.6% and 35.4% for the VS. CONCLUSIONS: The new functional regression approach improves on the multivariate linear regression model and allows an even larger reduction of the amount of intersubject variability, while at the same time using a substantially smaller number of parameters to be estimated. TRANSLATIONAL RELEVANCE: The demonstrated reduction of interindividual variation is expected to translate into an improved diagnostic separation between healthy and glaucomatous subjects, but this remains to be demonstrated in further studies.

Effects of pentoxifylline and alprostadil on ocular hemodynamics in healthy humans.

PURPOSE: Alprostadil, a prostaglandin (PG)E(1) analogue and pentoxifylline, an alkylxanthine derivate, have been shown to exert vasodilatory effects in several vascular beds. The purpose of the present study was to investigate the effect of PGE(1) and pentoxifylline on the ocular circulation. METHODS: A placebo-controlled, double-masked, three-way, crossover study was performed in 15 healthy male subjects. Subjects received pentoxifylline (300 mg), PGE(1) (alprostadil 60 mug), or placebo intravenously over 2 hours on three trial days. Choroidal red blood cell flow was assessed with laser Doppler flowmetry and pulsatile choroidal blood flow with laser interferometric measurement of fundus pulsation amplitude (FPA). Retinal blood cell flow was calculated based on the measurements of maximum erythrocyte velocity in a retinal vein assessed with bidirectional laser Doppler velocimetry, and diameter measurements of retinal vessels were obtained with a retinal vessel analyzer. RESULTS: Pentoxifylline increased FPA by 15.4% +/- 1.1% (P < 0.001 versus placebo and baseline). Alprostadil tended to increase FPA, but this effect did not reach the level of significance (P = 0.07 versus placebo). Choroidal blood flow as measured with laser Doppler flowmetry tended to increase during pentoxifylline and PGE(1) infusion by 8.9% +/- 2.9% (P = 0.062) and 4.5% +/- 6.2% (P = 0.29), respectively, but none of these effects was significant. The drugs under study had no effect on mean red blood cell velocity in retinal veins, on retinal vessel diameters, intraocular pressure, blood pressure, or pulse rate. CONCLUSIONS: PGE(1) did not alter the parameters of retinal or choroidal circulation in healthy subjects. Pentoxifylline increased FPA, but did not change choroidal blood flow as measured with laser Doppler flowmetry and did not affect retinal blood flow parameters. Accordingly, neither pentoxifylline nor PGE(1) appears to be suitable to improve ocular blood flow in healthy subjects. Whether long-term treatment with alprostadil would improve choroidal blood flow in patients with vascular disease remains to be established.

Effects of topical clonidine versus brimonidine on choroidal blood flow and intraocular pressure during squatting.

PURPOSE: Clonidine and brimonidine, two alpha-2 agonists, have been shown to reduce intraocular pressure (IOP) in patients with glaucoma. Little is known, however, about the exact role of alpha receptors in the control of ocular blood flow in the posterior pole of the eye. Hence, the study was conducted to investigate the effects of topical clonidine versus topical brimonidine on choroidal blood flow and intraocular pressure during squatting. METHODS: This was a randomized, double-masked, controlled, two-way crossover study. Twelve healthy male nonsmoking volunteers, aged between 19 and 35 years were included in the study. Two drops of clonidine or brimonidine were administered in the subjects' study eyes. Continuous measurement using the compact laser Doppler flowmeter was performed during a 6-minute squatting period, to assess choroidal blood flow regulation during an increase in ocular perfusion pressure. RESULTS: Both substances induced a pronounced but comparable (P = 0.8) decrease in IOP. Squatting increased mean arterial pressure (MAP) and ocular perfusion pressure (P < 0.01). This increase was comparable between the clonidine and the brimonidine study day (P = 0.88). Squatting induced an increase in choroidal blood flow that was less pronounced than the increase in ocular perfusion pressure. Compared with baseline the alpha-2 agonists decreased choroidal blood flow during squatting (P = 0.0026) to a comparable degree (P = 0.86). Vascular resistance increased at baseline and during squatting after administration of the alpha-2 agonists (P < 0.01) in both groups to a comparable degree (P = 0.56). CONCLUSIONS: Topical alpha-2 agonists may induce changes in choroidal blood flow, even after a single administration. Long-term studies are needed to study potential effects of brimonidine and clonidine in the clinical setting.

Intravenous administration of clonidine reduces intraocular pressure and alters ocular blood flow.

AIM: To evaluate the effect of intravenously administered clonidine on ocular blood flow in healthy volunteers. METHODS: A randomised, double-masked, placebo-controlled, two-way crossover study was performed in 12 healthy young volunteers. Clonidine (0.2 microg/kg/min) or placebo was administered intravenously over 10 minutes. The effects of clonidine were studied at baseline and up to 150 minutes after infusion. Ocular haemodynamics were measured using laser Doppler flowmetry, laser Doppler velocimetry and a retinal vessel analyser. RESULTS: Clonidine significantly decreased mean arterial pressure (MAP) and intraocular pressure (IOP). Calculated ocular perfusion pressure decreased significantly by -8.7+/-8.7% after infusion of clonidine (p<0.01 vs placebo). Retinal arterial diameters increased by +4.4+/-2.7% (p = 0.012 vs placebo), whereas no significant change was observed in retinal veins. Red blood cell velocity decreased by -16+/-14% (p<0.01 vs placebo) after infusion of clonidine. Hence, calculated retinal blood flow decreased by -14+/-12% (p = 0.033 vs placebo). Choroidal blood flow increased by +18+/-19% (p<0.01 vs placebo) and optic nerve head blood flow increased by +16+/-23% (p = 0.046 vs placebo) 30 minutes after administration of clonidine but both returned to baseline thereafter. CONCLUSION: The short-time increase in choroidal and optic nerve head blood flow indicates a transient vasodilatory effect of clonidine due to an unknown mechanism. The decrease in retinal blood flow indicates clonidine-induced vasoconstriction in the retinal microvasculature.

Intravenous administration of diphenhydramine reduces histamine-induced vasodilator effects in the retina and choroid.

PURPOSE: Intravenous administration of histamine causes an increase in choroidal blood flow (ChBF) and retinal vessel diameters in healthy subjects. The receptor mediating this response has not yet been identified. The present study was undertaken to clarify whether H1 receptor blockade with diphenhydramine affects the hemodynamic response of histamine in the choroid and the retina. METHODS: A randomized, double-masked, placebo-controlled, two-way crossover study was performed in 18 healthy, male, nonsmoking subjects. Histamine (0.32 microg/kg per minute over 30 minutes) was infused intravenously in the absence (NaCl as placebo) or presence of the H1 blocker diphenhydramine (1.0 mg/min over 50 minutes). Ocular hemodynamic parameters, blood pressure, and intraocular pressure were measured before drug administration, after infusion of diphenhydramine or placebo, and after co-infusion of histamine. Subfoveal ChBF and fundus pulsation amplitude (FPA) were measured with laser Doppler flowmetry and laser interferometry, respectively. Retinal arterial and venous diameters were measured with a retinal vessel analyzer. Retinal blood velocity was assessed with bidirectional laser Doppler velocimetry. RESULTS: Administration of histamine caused a decrease in mean arterial pressure by -4% +/- 9% (ANOVA P = 0.01). This effect was blunted by coadministration of diphenhydramine (ANOVA, P = 0.04). Histamine significantly increased FPA and subfoveal ChBF. Coadministration of diphenhydramine significantly reduced this effect (ANOVA; FPA P = 0.001, ChBF P = 0.049). Histamine significantly increased retinal arterial diameter by +3.5% +/- 4.5% and retinal venous diameter by +3.7% +/- 2.8%. Again, coadministration of diphenhydramine significantly reduced the vasodilative effect to +0.3% +/- 5.5% in retinal arteries (ANOVA, P = 0.00006) and to +0.9% +/- 2.5% in retinal veins (ANOVA, P = 0.004). CONCLUSIONS: The present data confirm that histamine increases ChBF and retinal vessel diameters in healthy subjects. Administration of the H1 receptor blocker diphenhydramine significantly reduced histamine-induced changes in ocular perfusion parameters. These results strongly indicate that in the retina and choroid, H1 receptors are involved in the histamine-mediated hemodynamic effects in vivo.