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.

A pilot study to assess the effect of a three-month vitamin supplementation containing L-methylfolate on systemic homocysteine plasma concentrations and retinal blood flow in patients with diabetes.

Purpose: The aim of the present study was to investigate the effect of a three-month dietary supplementation with a methylfolate formulation on homocysteine plasma concentrations and ocular blood flow parameters in patients with diabetes. Methods: Twenty-four patients with diabetes received a dietary supplement (Oculofolin, Aprofol AG, Switzerland) containing 900 µg L­methylfolate (levomefolate calcium or [6S]-5-methyltetrahydrofolic acid, calcium salt), methylcobalamin, and other ingredients for three consecutive months. The patients' plasma homocysteine concentration and retinal blood flow were assessed at baseline and after three months of folate intake. Retinal blood flow was measured using a custom-built dual-beam Doppler optical coherence tomography (OCT) system. In addition, flicker-induced retinal vasodilatation was assessed by means of a commercially available dynamic vessel analyzer (IMEDOS, Jena, Germany). Results: Supplementation was well tolerated by all patients. After three months, plasma homocysteine concentration significantly decreased from 14.2 ± 9.3 to 9.6 ± 6.6 µmol/L (p < 0.001). In addition, a tendency toward an increased total retinal blood flow from 36.8 ± 12.9 to 39.2 ± 10.8 µl/min was observed, but this effect did not reach the level of significance (p = 0.11). Supplementation had no effect on retinal vessel diameter or flicker-induced vasodilatation. Conclusions: The present data show that a three-month intake of a dietary supplement containing methylfolate can significantly reduce blood homocysteine levels in patients with diabetes. This is of importance because higher homocysteine plasma levels have been found to be associated with an increased risk of vascular associated systemic diseases and eye diseases. Whether systemic methylfolate supplementation affects retinal perfusion must be studied in a larger population.

Retinal oxygen extraction in individuals with type 1 diabetes with no or mild diabetic retinopathy.

AIMS/HYPOTHESIS: The aim of this study was to compare retinal oxygen extraction in individuals with diabetes with no or mild non-proliferative diabetic retinopathy and healthy age- and sex-matched volunteers. METHODS: A total of 24 participants with type 1 diabetes and 24 healthy age- and sex-matched volunteers were included in this cross-sectional study. Retinal oxygen extraction was measured by combining total retinal blood flow measurements using a custom-built bi-directional Doppler optical coherence tomography system with measurements of oxygen saturation using spectroscopic reflectometry. Based on previously published mathematical modelling, the oxygen content in retinal vessels and total retinal oxygen extraction were calculated. RESULTS: Total retinal blood flow was higher in diabetic participants (46.4 ± 7.4 µl/min) than in healthy volunteers (40.4 ± 5.3 µl/min, p = 0.002 between groups). Oxygen content in retinal arteries was comparable between the two groups, but oxygen content in retinal veins was higher in participants with diabetes (0.15 ± 0.02 ml O2/ml) compared with healthy control participants (0.13 ± 0.02 ml O2/ml, p < 0.001). As such, the arteriovenous oxygen difference and total retinal oxygen extraction were reduced in participants with diabetes compared with healthy volunteers (total retinal oxygen extraction 1.40 ± 0.44 vs 1.70 ± 0.47 µl O2/min, respectively, p = 0.03). CONCLUSIONS/INTERPRETATION: Our data indicate early retinal hypoxia in individuals with type 1 diabetes with no or mild diabetic retinopathy as compared with healthy control individuals. Further studies are required to fully understand the potential of the technique in risk stratification and treatment monitoring. TRIAL REGISTRATION: ClinicalTrials.gov NCT01843114.

Measuring optic nerve head perfusion to monitor glaucoma: a study on structure-function relationships using laser speckle flowgraphy.

PURPOSE: We aimed to describe the global and localized correlations among visual field (VF) sensitivity, optic nerve head (ONH) perfusion measured by laser speckle flowgraphy (LSFG) and neural structure measured by optical coherence tomography (OCT) in open-angle glaucoma (OAG) and to compare the floor effect for LSFG and OCT. METHODS: Cross-sectional, multicenter study including one eye each from fifty OAG patients (mean age 69.3 years; average VF mean deviation, MD, -8.5 dB, range -25.17 to 0.85 dB) and fifty-one controls. Patients underwent SITA standard 24-2 automated perimetry and measurement of ONH perfusion, peripapillary retinal nerve fibre layer thickness (RNFLT) and macular ganglion cell-inner plexiform layer thickness (GCIPLT). We tested the presence of a significant change (breakpoint) in the correlation slope with VF sensitivity to assess floor effect. RESULTS: The correlation between the LSFG parameter Mean All (MA) of the global disc area and MD (r = 0.56, p < 0.001) did not show a breakpoint, in contrast to the correlations between MD and OCT global parameters, which showed breakpoints at -8.53 and -4.05 dB for RNFLT and GCIPLT, respectively. Global and localized correlations with VF sensitivity were stronger for LSFG compared to OCT. In particular, LSFG outperformed OCT in the correlation with the central VF sector (r = 0.50, p < 0.001 and r = 0.06, p = 0.67 for MA and RNFLT, respectively). CONCLUSION: The global and sectoral correlations with VF sensitivity and the favourable floor effect compared to OCT indicate LSFG as a promising tool to monitor progression particularly in late-stage glaucoma. Further longitudinal studies are warranted.

Influence of Perfluorohexyloctane Eye Drops on Tear Film Thickness in Patients with Mild to Moderate Dry Eye Disease: A Randomized Controlled Clinical Trial.

Purpose: The aim of this mechanistic clinical study was to explore the effect of water-free perfluorohexyloctane eye drops on tear film thickness (TFT) in patients with dry eye disease (DED). Methods: Forty-eight patients with mild to moderate DED participated in this randomized, single-masked, observer-blinded parallel group study in a 1:1 ratio to receive either perfluorohexyloctane or unpreserved 0.9% saline solution (Hydrabak®, Thea, France) eye drops 4 times daily in both eyes for 4 weeks. A custom-built ultrahigh-resolution optical coherence tomography system was used to measure TFT. Furthermore, evaluation of lipid layer thickness (LLT) and noninvasive tear film breakup time, as well as standard clinical tests for signs and symptoms of DED were performed. Results: Mean TFT and LLT at baseline were comparable between the 2 treatment groups. After a single drop instillation, perfluorohexyloctane eye drops temporarily increased TFT immediately. After multiple dosing, perfluorohexyloctane eye drops gradually increased TFT over time with a maximum effect at the end of the study (least square mean difference: 6.42%; P = 0.0142 at week 4). LLT values measured before drop instillation showed a more prominent increase in LLT for perfluorohexyloctane eye drops (13.36% ± 26.33% vs. 3.21% ± 28.65%). All other parameters got better in both treatment groups with no statistical difference between groups. Conclusions: These results demonstrate that perfluorohexyloctane eye drops increase TFT as well as LLT over time. These tear film reestablishing attributes are in line with the mode of action of perfluorohexyloctane eye drops to avoid evaporation through stabilization of the lipid layer.

Cervical spine injuries in American football.

American football is a high-energy contact sport that places players at risk for cervical spine injuries with potential neurological deficits. Advances in tackling and blocking techniques, rules of the game and medical care of the athlete have been made throughout the past few decades to minimize the risk of cervical injury and improve the management of injuries that do occur. Nonetheless, cervical spine injuries remain a serious concern in the game of American football. Injuries have a wide spectrum of severity. The relatively common 'stinger' is a neuropraxia of a cervical nerve root(s) or brachial plexus and represents a reversible peripheral nerve injury. Less common and more serious an injury, cervical cord neuropraxia is the clinical manifestation of neuropraxia of the cervical spinal cord due to hyperextension, hyperflexion or axial loading. Recent data on American football suggest that approximately 0.2 per 100,000 participants at the high school level and 2 per 100,000 participants at the collegiate level are diagnosed with cervical cord neuropraxia. Characterized by temporary pain, paraesthesias and/or motor weakness in more than one extremity, there is a rapid and complete resolution of symptoms and a normal physical examination within 10 minutes to 48 hours after the initial injury. Stenosis of the spinal canal, whether congenital or acquired, is thought to predispose the athlete to cervical cord neuropraxia. Although quite rare, catastrophic neurological injury is a devastating entity referring to permanent neurological injury or death. The mechanism is most often a forced hyperflexion injury, as occurs when 'spear tackling'. The mean incidence of catastrophic neurological injury over the past 30 years has been approximately 0.5 per 100,000 participants at high school level and 1.5 per 100,000 at the collegiate level. This incidence has decreased significantly when compared with the incidence in the early 1970s. This decrease in the incidence of catastrophic injury is felt to be the result of changes in the rules in the mid-1970s that prohibited the use of the head as the initial contact point when blocking and tackling. Evaluation of patients with suspected cervical spine injury includes a complete neurological examination while on the field or the sidelines. Immobilization on a hard board may also be necessary. The decision to obtain radiographs can be made on the basis of the history and physical examination. Treatment depends on severity of diagnosed injury and can range from an individualized cervical spine rehabilitation programme for a 'stinger' to cervical spine decompression and fusion for more serious bony or ligamentous injury. Still under constant debate is the decision to return to play for the athlete.

Age-Related Decline of Retinal Oxygen Extraction in Healthy Subjects.

Purpose: To investigate the age-dependence of total retinal blood flow and total retinal oxygen extraction in healthy subjects and determine their possible correlations with structural optical coherence tomography (OCT) parameters. Methods: This observational cross-sectional study consisted of 68 healthy subjects (mean ± SD age, 45.6 ± 16.3 years; 47% female). Total retinal oxygen extraction was calculated based on measurement of total retinal blood flow using bi-directional Doppler OCT and measurement of oxygen saturation using spectroscopic reflectometry. Retinal nerve fiber layer thickness was measured using OCT, and the total number of retinal ganglion cells was estimated based on a previous published model. Correlation of these parameters with age was studied and the association between structural OCT parameters and hemodynamic vascular parameters was calculated. Results: Both structural and vascular parameters showed a significant decline with increasing age. The correlation coefficients were between r = -0.25 and r = -0.41. Furthermore, structural and vascular parameters were significantly correlated with each other. The strongest association was found between the level of total retinal oxygen extraction and the number of retinal ganglion cells (r = 0.75, P < 0.001). Conclusions: We showed that there was an age-related decline of retinal oxygen extraction. Levels of retinal oxygen extraction are correlated to retinal nerve fiber layer thickness and number of retinal ganglion cells. Our data partially explain the wide inter-individual variability in retinal blood flow values in healthy subjects. Longitudinal studies are required to study the time course of vascular and neuronal loss in humans.

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.

Distinguishing Keratoconic Eyes and Healthy Eyes Using Ultrahigh-Resolution Optical Coherence Tomography-Based Corneal Epithelium Thickness Mapping.

PURPOSE: To find differences in epithelial thickness (ET) maps of eyes with keratoconus (KC) and healthy eyes. DESIGN: Institutional cross-sectional study. METHODS: In this study 40 keratoconic eyes and 76 healthy eyes were scanned using a custom-built ultrahigh-resolution optical coherence tomography system. Automated segmentation ET maps with 17 subsectors were calculated (central, temporal inferior, temporal superior, nasal inferior, and nasal superior area). The thinnest point of the epithelium (minET), the thickest point of the epithelium (maxET), and the thinnest point diagonally opposing the thickest point (ETmax/op) were additional parameters. Ratios were calculated as follows: minET/diagonally opposing point (R1), maxET/diagonally opposing point (R2), inferior temporal area/superior nasal area (RTI/NS), and inferior/superior hemisphere (RI/S). Furthermore, collected parameters were analyzed regarding their diagnostic accuracy (area under the curve; AUC). RESULTS: Statistically significant differences were as follows: central ET, 46.25 ± 2.56/50.91 ± 1.66; minET, 38.50 ± 2.10/46.79 ± 1.27; ETmax/op, 47.14 ± 2.45/49.60 ± 1.57; temporal inferior area: 43.93 ± 2.95/51.04 ± 1.51 (all mean ± standard deviation, µm); R1, 0.76 ± 0.09/0.93 ± 0.04; R2, 1.08 ± 0.04/1.21 ± 0.16; RTI/NS, 0.85 ± 0.08/1.02 ± 0.04; RI/S: 0.92 ± 0.07/0.99 ± 0.02. AUC values were R1: 0.979 (confidence interval [CI]: 0.957-1.000), RTI/NS: 0.977 (CI: 0.951-1.000), and minET: 0.928 (CI: 0.880-0.977). CONCLUSIONS: Epithelial thickness maps could clearly visualize different ET patterns. Parameters with the highest potential of diagnostic discrimination between eyes with KC and healthy eyes were, in descending order, R1, RTI/NS, and minET. Consequently, epithelial thickness irregularity and asymmetry seem to be the most promising diagnostic factor in terms of discriminating between keratoconic eyes and healthy eyes.

Effect of changing from preserved prostaglandins to preservative-free tafluprost in patients with glaucoma on tear film thickness.

PURPOSE: Long-term glaucoma therapy with preservative-containing eye drops may impact ocular surface health. This study was performed to investigate whether a switch from preserved topical prostaglandin therapy to preservative-free tafluprost therapy improves precorneal tear film thickness in patients with glaucoma or ocular hypertension. METHODS: A total of 30 patients who were under topical preservative-containing prostaglandin monotherapy for at least 6 months were included. Patients were then switched from preserved prostaglandin therapy to unpreserved tafluprost drops once daily. Tear film thickness was measured at baseline and 4 and 12 weeks after therapy change with an ultrahigh-resolution optical coherence tomography system. Furthermore, clinical measures of ocular surface disease were determined and symptoms were assessed using the Dry Eye-Related Quality-of-Life Score. RESULTS: After switching to unpreserved tafluprost, tear film thickness significantly increased from 4.7 ± 0.5 to 5.0 ± 0.6 µm 4 weeks after therapy change and still tended to be increased after 12 weeks (4.8 ± 0.7 µm). Breakup time significantly increased from 5.1 ± 2.3 to 7.2 ± 3.4 s and to 10.1 ± 3.6 s after therapy change. In addition, a significant decrease in corneal staining score from 1.8 ± 0.7 to 1.4 ± 0.8 after 4 weeks and to 0.7 ± 0.7 after 12 weeks treatment was observed. Switching to preservative-free drops reduced Dry Eye-Related Quality-of-Life Score from 11.4 ± 11.0 to 5.7 ± 6.4 and to 4.7 ± 7.5. CONCLUSION: Our data show that switching to preservative-free tafluprost leads to an increase in tear film thickness, breakup time, and an improvement of Dry Eye-Related Quality-of-Life Score. Our results therefore indicate that a switch to unpreserved tafluprost is beneficial for ocular surface health in patients under long-term preserved prostaglandin eye drops.

Effect of Hyaluronic Acid/Trehalose in Two Different Formulations on Signs and Symptoms in Patients with Moderate to Severe Dry Eye Disease.

PURPOSE: This randomized, observer-masked, crossover study investigated the effect of two hyaluronic acid/trehalose-based containing formulations, with different physical properties, on the signs and symptoms in patients with moderate to severe dry eye disease (DED). METHODS: In one group, patients received a mixture of sodium hyaluronate and trehalose (HT, Thealoz Duo®) for use during the day. In the other group, patients received a more viscous formulation consisting of hyaluronic acid, trehalose, and carbomer (HTC-gel, Thealoz Duo Gel) to use pro re nata. Both groups used HTC-gel before going to bed. Clinical standard tests for DED were performed at the beginning and end of each one-week period. Further, patient satisfaction including quality of sleep was assessed using a visual analogue scale. RESULTS: Corneal fluorescein and conjunctival lissamine green staining scores decreased, and tear breakup time (BUT) increased for both groups (p < 0.001 each). Mean instillation frequency was 3.1 ± 2.6 drops/day when using HT and 1.9 ± 2.2 drops/day when using HTC-gel (p=0.02). A significant improvement in the quality of sleep was observed with both treatments (p=0.01). CONCLUSIONS: Our results show improvement in signs and symptoms of DED in both groups. While instillation of HTC-gel resulted in a lower instillation frequency, both formulations of trehalose showed good clinical efficacy. This trial is registered with NCT02980913.

Assessment of choroidal blood flow using laser speckle flowgraphy.

BACKGROUND/AIMS: There is considerable interest in novel techniques to quantify choroidal blood flow (CBF) in humans. In the present study, we investigated a novel technique to measure CBF based on laser speckle flowgraphy (LSFG) in healthy subjects. METHODS: This study included 31 eyes of 31 healthy, non-smoking subjects aged between 19 and 74 years. A commercial LSFG instrument was used to measure choroidal vessel diameter (CVD) and relative flow volume (RFV) in choroidal vessels that were identified on fundus photos, an approach that was used previously only for retinal vessels. The reproducibility and the effect of isometric exercise on these parameters were investigated. The latter was compared with measurement of subfoveal CBF using laser Doppler flowmetry (LDF). RESULTS: Intraclass correlation coefficients for CVD and RFV were higher than 0.8 indicating excellent reproducibility. During isometric exercise, we observed an increase in ocular perfusion pressure of approximately 60% (P<0.001). The increase in RFV and CBF was lower, but also highly significant versus baseline (at minute 6 of isometric exercise: RFV 10.5%±4.2%, CBF 8.3%±3.6%; P<0.001 each) indicating choroidal autoregulation. CONCLUSION: LSFG may be a novel approach to study blood flow in choroidal vessels. Data are reproducible and show good agreement with LDF data. TRIAL REGISTRATION NUMBER: NCT02102880, Results.

Evaluation of flicker induced hyperemia in the retina and optic nerve head measured by Laser Speckle Flowgraphy.

PURPOSE: The coupling between neural activity and blood flow is a physiological key principle of ocular blood flow regulation. The current study was performed to investigate whether Laser speckle flowgraphy (LSFG), a commercially available technique for measuring blood flow, is capable to assess flicker-induced haemodynamic changes in the retinal and optic nerve head (ONH) circulation. METHODS: Twenty healthy subjects were included in this cross sectional study. A commercial LSFG instrument was used to measure blood flow at the ONH as well as in retinal vessels before and during stimulation with flickering light. Mean blur rate (MBR), a measure of relative blood flow velocity, was obtained for the ONH and relative flow volume (RFV) a measure of relative blood flow of the respective retinal vessels. RESULTS: Stimulation with flicker light increased ONH MBR by +17.5%±6.6% (p<0.01). In retinal arteries, flicker stimulation led an increase of +23.8±10.0% (p<0.05) in total RFV. For retinal veins, an increase of +23.1%±11.0 (p<0.05) in total RFV was observed during stimulation. A higher response was observed in nasal RFV compared to temporal RFV in retinal arteries (nasal: +28.9%±20.0%; temporal: +20.4%±17.6%, p<0.05) and veins (nasal: +28.3%±19.6%; temporal +17.8%±18.9%, p<0.05). CONCLUSION: As shown previously with other techniques, flicker stimulation leads to an increase in retinal and optic nerve head blood flow. Our results indicate that LSFG is an appropriate method for the quantification of retinal and ONH blood flow during visual stimulation and may be used as a non-invasive, easy to use tool to assess neuro-vascular coupling in humans.

Effect of Single Instillation of Two Hyaluronic Acid-Based Topical Lubricants on Tear Film Thickness in Patients with Dry Eye Syndrome.

PURPOSE: This study investigated the effect of single administration of 2 different hyaluronic acid-based topical lubricants on tear film thickness (TFT) in patients with moderate-to-severe dry eye disease (DED). METHODS: Sixty patients were randomized to receive eye drops containing unpreserved sodium hyaluronate, triglycerides, and phospholipids (HTP), unpreserved sodium hyaluronate (HA), or unpreserved sodium chloride (NaCl). TFT and lipid layer thickness (LLT) were assessed before and at defined time points after single instillation with a custom-built ultrahigh-resolution optical coherence tomography system and a white light interferometer. Standard tests for DED such as a visual analogue scale (VAS), corneal fluorescein staining (CFS), Schirmer I test, and tear break-up time (BUT) were performed. RESULTS: The time course in TFT was significantly different between the 3 administered agents (P < 0.001). Single administration of HTP significantly increased TFT over a period of 40 min, an increase in TFT over 20 min was observed after instillation of HA, whereas NaCl had no effect. No significant difference in the change in BUT, CFS, or LLT was observed between the 3 groups (P = 0.57, 0.97, and 0.86, respectively). A significant improvement in subjective symptoms (VAS) was found after single instillation of HTP (P = 0.03 vs. baseline) and HA, but not after administration of NaCl (P = 0.03, P < 0.01, and P = 0.08 vs. baseline, respectively, P = 0.57 between groups). CONCLUSIONS: Single administration of HTP and HA significantly increased TFT showing a longer residence time and improved subjective symptoms, whereas instillation of NaCl had no effect. Long-term studies with multiple instillations will be necessary to further investigate the effect of the tested products on the clinical outcome. ClinicalTrials.gov ID: NCT03161080.

Effect of different lubricant eye gels on tear film thickness as measured with ultrahigh-resolution optical coherence tomography.

PURPOSE: To compare the effect of a single drop of different lubricant eye gels on tear film thickness (TFT) as measured with ultrahigh-resolution optical coherence tomography (UHR-OCT) in patients with mild-to-moderate dry eye disease (DED). METHODS: The study followed a randomized, single-masked, observer-blinded parallel group design. Patients received a single dose of either unpreserved trehalose 3% + hyaluronic acid 0.15% (TH), hyaluronic acid 0.2% (HA) or polyethylene glycol 0.4% + propylene glycol 0.3% (PP) eye drops. In total, 60 patients were included and TFT was measured using a custom-built UHR-OCT system. RESULTS: The mean TFT at baseline was 3.5 ± 0.7 µm. There was a significant difference in the time-course of TFT between the three groups (p = 0.001 between groups). Ten minutes after instillation, TFT increased by 155.8 ± 86.6%, 65.7 ± 71.5% and 33.4 ± 19.6% in the PP, TH and HA group, respectively (p < 0.001 between groups). Thirty minutes after instillation, the effect of all three different agents on TFT was comparable. Sixty and 120 min after administration, a significant increase in TFT was only seen for the TH group, but not for the other products (60 min: p < 0.021 between groups; 120 min: p < 0.037 between groups). CONCLUSION: In conclusion, we observed differences in TFT after administration of the lubricant gels. Ten minutes after instillation, a pronounced increase in TFT was observed in all groups. As compared to the other products, the combination of trehalose 3% + hyaluronic acid 0.15% offers a significantly longer increase in TFT indicating for a longer residence time.

Optic nerve head and retinal blood flow regulation during isometric exercise as assessed with laser speckle flowgraphy.

The aim of the present study was to investigate regulation of blood flow (BF) in the optic nerve head (ONH) and a peripapillary region (PPR) during an isometric exercise-induced increase in ocular perfusion pressure (OPP) using laser speckle flowgraphy (LSFG) in healthy subjects. For this purpose, a total of 27 subjects was included in this study. Mean blur rate in tissue (MT) was measured in the ONH and in a PPR as well as relative flow volume (RFV) in retinal arteries (ART) and veins (VEIN) using LSFG. All participants performed isometric exercise for 6 minutes during which MT and mean arterial pressure were measured every minute. From these data OPP and pressure/flow curves were calculated. Isometric exercise increased OPP, MTONH and MTPRR. The relative increase in OPP (78.5 ± 19.8%) was more pronounced than the increase in BF parameters (MTONH: 18.1 ± 7.7%, MTPRR: 21.1 ± 8.3%, RFVART: 16.5 ±12.0%, RFVVEIN: 17.7 ± 12.4%) indicating for an autoregulatory response of the vasculature. The pressure/flow curves show that MTONH, MTPRR, RFVART, RFVVEIN started to increase at OPP levels of 51.2 ± 2.0%, 58.1 ± 2.4%, 45.6 ± 1.9% and 45.6 ± 1.9% above baseline. These data indicate that ONHBF starts to increase at levels of approx. 50% increase in OPP: This is slightly lower than the values we previously reported from LDF data. Signals from the PPR may have input from both, the retina and the choroid, but the relative contribution is unknown. In addition, retinal BF appears to increase at slightly lower OPP values of approximately 45%. LSFG may be used to study ONH autoregulation in diseases such as glaucoma. TRIAL REGISTRATION: ClinicalTrials.gov NCT02102880.

Measurement of Retinal Vascular Caliber From Optical Coherence Tomography Phase Images.

PURPOSE: To compare retinal vessel calibers extracted from phase-sensitive optical coherence tomography (OCT) images with vessel calibers as obtained from the Retinal Vessel Analyzer (RVA). METHODS: Data from previously published studies in 13 healthy subjects breathing room air (n = 214 vessels) and 7 subjects breathing 100% oxygen (n = 101 vessels) were used. Vessel calibers from OCT phase images were measured vertically along the optical axis by three independent graders. The data from RVA fundus images were corrected for magnification to obtain absolute values. RESULTS: The average vessel diameter as obtained from OCT images during normoxia was lower than from RVA images (83.8 ± 28.2 µm versus 86.6 ± 28.0 µm, P < 0.001). The same phenomenon was observed during 100% oxygen breathing (OCT: 81.0 ± 22.4 µm, RVA: 85.5 ± 26.0 µm; P = 0.001). Although the agreement between the two methods was generally high, the difference in individual vessels could be as high as 40%. These differences were neither dependent on absolute vessel size nor preferably found in specific subjects. Interobserver differences between OCT evaluators were much lower than differences between the techniques. CONCLUSIONS: Extracting vessel calibers from OCT phase images may be an attractive approach to overcome some of the problems associated with fundus imaging. The source of differences in vessel caliber between the two methods remains to be investigated. In addition, it remains unclear whether OCT-based vessel caliber measurement is superior to fundus camera-based imaging in risk stratification for systemic or ocular disease. (ClinicalTrials.gov numbers, NCT00914407, NCT02531399.).

Ocular Blood Flow Measurements in Healthy White Subjects Using Laser Speckle Flowgraphy.

PURPOSE: To assess the feasibility and reliability of Laser Speckle Flowgraphy (LSFG) to measure ocular perfusion in a sample of healthy white subjects and to elucidate the age-dependence of the parameters obtained. METHODS: This cross-sectional study included 80 eyes of 80 healthy, non-smoking white subjects of Western European descent between 19 and 79 years of age. A commercial LSFG instrument was applied to measure ocular blood flow at the optic nerve head (ONH) three successive times before and after pharmacological pupil dilation. The mean blur rate (MBR), a measure of relative blood flow velocity, was obtained for different regions of the ONH. Eight parameters of ocular perfusion derived from the pulse-waveform analysis of MBR including blowout time (BOT) and falling rate (FR) were also recorded. RESULTS: Artifact-free LSFG images meeting the quality criteria for automated image analysis were obtainable in 93.8% without pupil dilation and in 98.8% with pharmacological pupil dilation. Measurements of MBR showed excellent repeatability with intraclass correlation coefficients ≥ 0.937 and were barely affected by pupil dilation. The majority of pulse-waveform derived variables exhibited equally high repeatability. MBR-related blood flow indices exhibited significant age dependence (p<0.001). FR (r = 0.747, p<0.001) and BOT (r = -0.714, p<0.001) most strongly correlated with age. CONCLUSIONS: LSFG represents a reliable method for the quantitative assessment of ocular blood flow in white subjects. Our data affirms that the LSFG-derived variables FR and BOT may be useful biomarkers for age-related changes in ocular perfusion.

Measurements of Retinal Perfusion Using Laser Speckle Flowgraphy and Doppler Optical Coherence Tomography.

PURPOSE: This study evaluated the validity of retinal perfusion measurements using laser speckle flowgraphy (LSFG) by means of in vitro experiments and direct comparison with dual-beam Doppler optical coherence tomography (D-OCT) in a healthy Caucasian population. METHODS: The flow velocity of scattering solution pumped through a glass capillary was measured at 17 different flow velocities (range, 0.5-47 mm/s) using LSFG. The flow within the glass capillary was produced by a computer-controlled infusion pump. In vivo, three consecutive LSFG scans were obtained in 20 eyes of 20 healthy Caucasian subjects before and after pharmacological pupil dilation. Relative flow volume (RFV), the primary output parameter of LSFG, was comparatively validated relative to absolute measurements of retinal blood flow and velocity as obtained from D-OCT. RESULTS: In the in vitro experiments, RFV was found to saturate at a level of approximately 700 arbitrary units (au) or 23.5 mm/s of actual velocity. In vivo, RFV was in significant agreement with absolute blood flow measurements as obtained from D-OCT in arteries (r = 0.69, P = 0.001) and veins (r = 0.74, P < 0.001). However, linear regression analysis revealed significant positive zero offset values for RFV of 223.4 and 282.7 au in arteries and veins, respectively. CONCLUSIONS: Measurements of RFV were successfully obtainable, reproducible, and not influenced by pharmacological pupil dilation. Nevertheless, our data revealed flaws in the LSFG method of measuring retinal perfusion in Caucasians. Adjustment to the technique is required to address apparent issues with RFV, especially saturation effects with higher arterial flow rates. The present dataset may provide a valuable tool to do so. (Clinicaltrials.gov number NCT02582411).

Effect of a Matrix Therapy Agent on Corneal Epithelial Healing After Standard Collagen Cross-linking in Patients With Keratoconus: A Randomized Clinical Trial.

IMPORTANCE: Corneal abrasions are frequent after standard (epithelium-off [epi-off]) corneal collagen cross-linking (CXL) in patients with progressive keratoconus. A new matrix therapy agent (ReGeneraTing Agent [RGTA]) has been developed to promote corneal wound healing. OBJECTIVE: To assess the effect of the new type of matrix therapy agent on corneal wound healing after epi-off CXL in patients with keratoconus. DESIGN, SETTING, AND PARTICIPANTS: This double-masked randomized clinical trial enrolled 40 patients with keratoconus undergoing epi-off CXL from July 18, 2014, to October 21, 2015, when the last follow-up was completed. The analysis of the intention-to-treat population was performed at the Department of Clinical Pharmacology in cooperation with the Center for Medical Physics and Biomedical Engineering and the Department of Ophthalmology and Optometry of the Medical University of Vienna. INTERVENTIONS: Patients were randomized to receive the matrix therapy agent or hyaluronic acid-containing eyedrops, 0.1%, every other day starting immediately after surgery. The size of the corneal defect was measured using ultrahigh-resolution optical coherence tomography (OCT) and slitlamp photography (SLP) with fluorescein staining. MAIN OUTCOMES AND MEASURES: Corneal wound healing rate, defined as the size of the defect over time. RESULTS: Among the 40 patients undergoing epi-off CXL (31 men; 9 women; mean [SD] age, 31 [10] years), wound healing was significantly faster in the matrix therapy agent group compared with the hyaluronic acid group (4.4 vs 6.1 days; mean difference, 1.7 days; 95% CI, 0.25-3.15 days; P = .008). The defect size was smaller in the matrix therapy agent group than in the hyaluronic acid group as measured with OCT (12.4 vs 23.9 mm2; mean difference, 11.6 mm2; 95% CI, 0.8-23.5 mm2; P = .045) and SLP (11.9 vs 23.5 mm2; mean difference, 11. 6 mm2; 95% CI, 1.3-22.9 mm2; P = .03). A correlation between the defect size measured with OCT and SLP was found (r = 0.89; P < .001). No ocular or serious adverse events occurred. CONCLUSIONS AND RELEVANCE: Use of a new matrix therapy agent appears to improve corneal wound healing after CXL in patients with keratoconus. Monitoring of corneal wound healing using ultrahigh-resolution OCT might be an attractive alternative to SLP because OCT provides an objective and 3-dimensional evaluation of the corneal defect. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT02119039.