Retinal vascular structure independently predicts the initial treatment response in neovascular age-related macular degeneration.

PURPOSE: Prediction of the early treatment response is important in neovascular age-related macular degeneration (nAMD). Hence, we aimed to test if non-invasive measurements of the retinal vascular structure were able to predict a successful outcome of initial intravitreal treatment. METHODS: In 58 eyes of 58 patients with treatment-naïve nAMD, advanced markers of retinal vascular structure were measured by Singapore I Vessel Assessment prior to initial intravitreal treatment with three monthly injections of aflibercept with subsequently categorization of patients as full treatment responders (FTR) or non/partial treatment responders (N/PR), with the former defined as loosing fewer than five Early Treatment Diabetic Retinopathy Study letters and having no residual intra- or subretinal fluid or macular haemorrhage. RESULTS: Of 54 eyes attending follow-up, 44.4% were categorized as FTR. Patients with FTR were older (81.5 vs. 77 years, p = 0.04), and prior to treatment those eyes had a lower retinal arteriolar fractal dimension (Fd) (1.21 vs. 1.24 units, p = 0.02) and venular length-diameter ratio (LDR) (7.3 vs. 15.9 units, p = 0.006), but did not differ with respect to other retinal vascular parameters. In multiple logistic regression models, a lower chance of FTR was independently predicted by a higher retinal venular LDR (odds ratio [OR] 0.91, 95% CI 0.82-0.99, p = 0.03, for each 1 unit increment) and marginally by a higher retinal arteriolar Fd (OR 0.83, 95% CI 0.68-1.00, p = 0.05, for each 0.01 unit increment). CONCLUSION: Retinal venular LDR independently predicted the initial treatment response in nAMD. If confirmed by long-term, prospective studies, this might help to guide treatment.

Retinal arteriolar calibre and venular fractal dimension predict progression of proliferative diabetic retinopathy 6 months after panretinal photocoagulation: a prospective, clinical interventional study.

OBJECTIVE: We examined the hypothesis that baseline retinal vascular geometry in patients with proliferative diabetic retinopathy (PDR) predicts disease activity 6 months after panretinal photocoagulation (PRP). METHODS AND ANALYSIS: We included 47 eyes from 40 patients with treatment-naïve PDR in a 6-month prospective study. Diagnosis of PDR and disease activity was evaluated by wide-field fluorescein angiography (Optomap, Optos, Dunfermline, Scotland, UK). At baseline and 6-month follow-up, the retinal vessel geometry was measured on optic disc centred images using semiautomated software Vessel Assessment and Measurement Platform for Images of the Retina (VAMPIRE, Dundee, Scotland). RESULTS: At baseline, mean age and duration of diabetes was 51.6 and 21.4 years, and 62.5% were men. Seventeen eyes (36.2%) had progression of PDR during follow-up. At baseline, we found higher retinal arteriolar calibre (31.3±0.8 vs 28.8±0.8 pixels, p=0.02) and venous fractal dimension (FD) (1.257±0.011 vs 1.222±0.011, p=0.02) in eyes with progression of PDR as compared with eyes with non-progression. In a multiple logistic regression model, both higher retinal arteriolar calibre (OR 1.34, 95% CI, 1.09 to 1.64, p<0.01) and venular FD (OR 1.15, 95% CI, 1.04 to 1.27, p<0.01) predicted progression of PDR. Venular calibre was seen to increase from baseline to month six regardless of disease progression (non-progression 45.0±0.7 vs 52.7±1.8 pixels, p<0.01; progression 46.2±0.8 vs 51.0±1.7 pixels, p<0.01). CONCLUSION: Our prospective study showed that arteriolar calibre and venular FD at baseline were predictive of disease activity 6 months after PRP treatment in patients with treatment-naïve PDR.

Retinal vascular oxygen saturation in response to a less extensive laser treatment in proliferative diabetic retinopathy.

PURPOSE: The purpose of this study was to evaluate the association between retinal laser burden and vascular oxygen saturation in patients with proliferative diabetic retinopathy (PDR) treated with different extent of retinal laser. METHODS: The study was a prospective, interventional study of patients with treatment-naïve PDR. Patients were treated with navigated retinal laser (Navilas® , OD-OS GmbH, Teltow, Germany) in different doses. Retinal oximetry was obtained at baseline (BL) prior to laser and after 6 months (M6). Patients were divided into three groups according to total laser spots applied: <1500 spots (Group 1), 1500-2000 spots (Group 2), and >2000 spots (Group 3). RESULTS: We included 33 eyes of 28 patients with treatment-naïve PDR. The groups did not differ according in BL characteristics. Between BL and M6, retinal arteriolar oxygen saturation did not change but retinal venular oxygen saturation (median with interquartile range) decreased in Groups 1 and 2 (1: 65.5 ± 8.8% versus 60.5 ± 9.5%, p = 0.04; 2: 65.3 ± 7.3% versus 63.0 ± 13.5%, p = 0.04). Focal retinal venular oxygen saturation, located to quadrants with retinal neovascularization, decreased in Group 2 from BL to M6 (67.5 ± 13.3% versus 61.5 ± 8.8%, p = 0.04). Retinal venular diameter decreased from BL to M6 in Group 1 (174.5 ± 15.3 µm versus 165.1 ± 28.7 µm, p = 0.01). CONCLUSIONS: In this study of patients with treatment-naïve PDR, we showed that a less extensive laser treatment caused a reduction in retinal venular oxygen saturation and diameter 6 months after treatment. Our results suggest that less extensive laser treatment may be sufficient to improve the retinal metabolic environment conducive to PDR regression.

Optical coherence tomography angiography measured area of retinal neovascularization is predictive of treatment response and progression of disease in patients with proliferative diabetic retinopathy.

BACKGROUND: The purpose of this study was to evaluate the area of retinal neovascularization in patients with treatment-naïve proliferative diabetic retinopathy (PDR) as measured by optical coherence tomography angiography (OCT-A) as a marker of subsequent treatment response after panretinal photocoagulation (PRP), and to examine if this area correlated with area of retinal neovascularization as measured by fluorescein angiography (FA). METHODS: En face OCT-A scans (4.5 × 4.5 mm) of neovascularizations were obtained at baseline (BL) before PRP and at month (M) 3 and M6 after treatment. Progression of PDR were defined as lesion growth (assessed by ophthalmoscopy and wide-field fundus photo) or increasing leakage by Optos ultra-widefield FA, and patients were divided into two groups; progression or non-progression. Mann-Whitney U test and Wilcoxon signed-rank test were used to analyse differences between groups and between time points. Areas of retinal neovascularizations (OCT-A and FA) were calculated by algorithms developed in Python (version 3.6.8, The Python Software Foundation, USA). RESULTS: Of 21 eyes included, 14 had progression of disease. Median OCT-A area did not differ between the two groups (progression vs. non-progression) at BL (76.40 ± 162.03 vs. 72.62 ± 94.15, p = 0.43) but were statistically significantly larger in the progression group at M6 (276.69 ± 168.78 vs. 61.30 ± 70.90, p = 0.025). Median FA area did not differ in the progression vs. the non-progression group at BL (111.42 ± 143.08 vs. 60.80 ± 54.83, p = 0.05) or at M6 (200.12 ± 91.81 vs. 123.86 ± 162.16, p = 0.62). Intraclass correlation between area by OCT-A and FA was -5.99 (95% CI: -35.28-0.993), p = 0.71. CONCLUSIONS: In this study of patients with treatment-naïve PDR, we showed that increasing area of retinal neovascularizations measured by OCT-A at M6 indicated progression of disease after PRP treatment. Our results suggest that area by OCT-A reflects disease activity and that it can be used as an indicator to monitor the progression of PDR over time, and to evaluate treatment response six months after PRP. Trial registration https://clinicaltrials.gov (identifier: NCT03113006). Registered April 13, 2017.

Retinal oximetry: Metabolic imaging for diseases of the retina and brain.

Retinal oximetry imaging of retinal blood vessels measures oxygen saturation of hemoglobin. The imaging technology is non-invasive and reproducible with remarkably low variability on test-retest studies and in healthy cohorts. Pathophysiological principles and novel biomarkers in several retinal diseases have been discovered, as well as possible applications for systemic and brain disease. In diabetic retinopathy, retinal venous oxygen saturation is elevated and arteriovenous difference progressively reduced in advanced stages of retinopathy compared with healthy persons. This correlates with pathophysiology of diabetic retinopathy where hypoxia stimulates VEGF production. Laser treatment and vitrectomy both improve retinal oximetry values, which correlate with clinical outcome. The oximetry biomarker may allow automatic measurement of severity of diabetic retinopathy and predict its response to treatment. Central retinal vein occlusion is characterized by retinal hypoxia, which is evident in retinal oximetry. The retinal hypoxia seen on oximetry correlates with the extent of peripheral ischemia, visual acuity and thickness of macular edema. This biomarker may help diagnose and measure severity of vein occlusion and degree of retinal ischemia. Glaucomatous retinal atrophy is associated with reduced oxygen consumption resulting in reduced arteriovenous difference and higher retinal venous saturation. The oximetry findings correlate with worse visual field, thinner nerve fiber layer and smaller optic disc rim. This provides an objective biomarker for glaucomatous damage. In retinitis pigmentosa, an association exists between advanced atrophy, worse visual field and higher retinal venous oxygen saturation, lower arteriovenous difference. This biomarker may allow measurement of severity and progression of retinitis pigmentosa and other atrophic retinal diseases. Retinal oximetry offers visible light imaging of systemic and central nervous system vessels. It senses hypoxia in cardiac and pulmonary diseases. Oximetry biomarkers have been discovered in Alzheimer's disease and multiple sclerosis and oxygen levels in the retina correspond well with brain.

Peripheral capillary non-perfusion in treatment-naïve proliferative diabetic retinopathy associates with postoperative disease activity 6 months after panretinal photocoagulation.

BACKGROUND/AIMS: With the perspective to provide individualised panretinal laser photocoagulation (PRP) for proliferative diabetic retinopathy (PDR), we evaluated if retinal peripheral capillary non-perfusion (PCNP) and oximetry, as non-invasive markers of retinal metabolism and function, could predict disease activity 6 months after PRP. METHODS: We performed a prospective, interventional study of patients with treatment-naïve PDR. Retinal oximetry and ultra-widefield fluorescein angiography were performed at baseline (BL) and three (3M) and 6 months (6M) after PRP by a navigated laser system. At 6M follow-up, patients were divided according to disease activity: active or inactive. RESULTS: We included 33 eyes, and 69.6% were men. At BL, the median age and duration of diabetes (with IQRs) were 51.6±23.4 and 20.0±15.0 years. Haemoglobin A1c was 63.0±17.0 mmol/mol and blood pressure was 152±37/82±24 mm Hg. At BL and M6, patients with postoperative disease activity (30.3.%, n=10) had a larger area with PCNP than those with inactive PDR (BL: 51%-75% vs 26%-50%, p=0.03; 6M: 51%-75% vs 26%-50%, p=0.03). The area of PCNP did not change from BL to 6M in either group (inactive PDR: p=0.38, active PDR: p=0.87). Changes in retinal oxygen saturation were not found to be clinical relevant. CONCLUSION: We found the area of PCNP at all timepoints to be statistically larger in patients with active PDR 6 months after PRP treatment. Therefore, the area of PCNP, at baseline, may serve as a potential predictive marker for PDR activity after treatment.

Changes in retinal venular oxygen saturation predict activity of proliferative diabetic retinopathy 3 months after panretinal photocoagulation.

BACKGROUND/AIMS: Proliferative diabetic retinopathy (PDR) is a severe blinding condition. We investigated whether retinal metabolism, measured by retinal oximetry, may predict PDR activity after panretinal laser photocoagulation (PRP). METHODS: We performed a prospective, interventional, clinical study of patients with treatment-naive PDR. Wide-field fluorescein angiography (OPTOS, Optomap) and global and focal retinal oximetry (Oxymap T1) were performed at baseline (BL), and 3 months (3M) after PRP. Angiographic findings were used to divide patients according to progression or non-progression of PDR after PRP. We evaluated differences in global and focal retinal oxygen saturation between patients with and without progression of PDR after PRP treatment. RESULTS: We included 45 eyes of 37 patients (median age and duration of diabetes were 51.6 and 20 years). Eyes with progression of PDR developed a higher retinal venous oxygen saturation than eyes with non-progression at 3M (global: +5.9% (95% CI -1.5 to 12.9), focal: +5.4%, (95% CI -4.1 to 14.8)). Likewise, progression of PDR was associated with a lower arteriovenular (AV) oxygen difference between BL and 3M (global: -6.1%, (95% CI -13.4 to -1.4), focal: -4.5% (95% CI -12.1 to 3.2)). In a multiple logistic regression model, increment in global retinal venular oxygen saturation (OR 1.30 per 1%-point increment, p=0.017) and decrement in AV oxygen saturation difference (OR 0.72 per 1%-point increment, p=0.016) at 3M independently predicted progression of PDR. CONCLUSION: Development of higher retinal venular and lower AV global oxygen saturation independently predicts progression of PDR despite standard PRP and might be a potential non-invasive marker of angiogenic disease activity.

Temporal changes in retinal vascular parameters associated with successful panretinal photocoagulation in proliferative diabetic retinopathy: A prospective clinical interventional study.

PURPOSE: We aimed to investigate changes in retinal vascular geometry over time after panretinal photocoagulation (PRP) in patients with proliferative diabetic retinopathy (PDR). METHODS: Thirty-seven eyes with PDR were included. Wide-field fluorescein angiography (Optomap, Optos PLC., Dunfermline, Scotland, UK) was used to diagnose PDR at baseline and to assess activity at follow-up month three and six. At each time-point, a trained grader measured retinal vessel geometry on optic disc (OD) centred images using semiautomated software (SIVA, Singapore I Vessel Assessment, National University of Singapore, Singapore) according to a standardized protocol. RESULTS: At baseline, the mean age and duration of diabetes were 52.8 and 22.3 years, and 65% were male. Mean HbA1c was 69.9 mmol/mol, and blood pressure was 155/84 mmHg. Of the 37 eyes with PDR, eight (22%) eyes had progression at month three and 13 (35%) progressed over six months. Baseline characteristics, including age, sex, duration of diabetes, HbA1c, blood pressure, vessel geometric variables and total amount of laser energy delivered did not differ by progression status. However, compared to patients with progression of PDR, patients with favourable treatment outcome had alterations in the retinal arteriolar structures from baseline to month six (calibre, 154.3 µm versus 159.5 µm, p = 0.04, tortuosity 1.12 versus 1.10, p = 0.04) and in venular structures from baseline to month three (fractal dimension 1.490 versus 1.499, p = 0.04, branching coefficient (BC) 1.32 versus 1.37, p = 0.01). CONCLUSION: In patients with PDR, successful PRP leads to alterations in the retinal vascular structure. However, baseline retinal vascular geometry characteristics did not predict treatment outcome.

Noninvasive Retinal Markers in Diabetic Retinopathy: Advancing from Bench towards Bedside.

The retinal vascular system is the only part of the human body available for direct, in vivo inspection. Noninvasive retinal markers are important to identity patients in risk of sight-threatening diabetic retinopathy. Studies have correlated structural features like retinal vascular caliber and fractals with micro- and macrovascular dysfunction in diabetes. Likewise, the retinal metabolism can be evaluated by retinal oximetry, and higher retinal venular oxygen saturation has been demonstrated in patients with diabetic retinopathy. So far, most studies have been cross-sectional, but these can only disclose associations and are not able to separate cause from effect or to establish the predictive value of retinal vascular dysfunction with respect to long-term complications. Likewise, retinal markers have not been investigated as markers of treatment outcome in patients with proliferative diabetic retinopathy and diabetic macular edema. The Department of Ophthalmology at Odense University Hospital, Denmark, has a strong tradition of studying the retinal microvasculature in diabetic retinopathy. In the present paper, we demonstrate the importance of the retinal vasculature not only as predictors of long-term microvasculopathy but also as markers of treatment outcome in sight-threatening diabetic retinopathy in well-established population-based cohorts of patients with diabetes.

Retinal oximetry in patients with ischaemic retinal diseases.

The retinal oximeter is a new tool for non-invasive measurement of retinal oxygen saturation in humans. Several studies have investigated the associations between retinal oxygen saturation and retinal diseases. In the present systematic review, we examine whether there are associations between retinal oxygen saturation and retinal ischaemic diseases. We used PubMed and Embase to search for retinal oxygen saturation and retinal ischaemic diseases. Three separate searches identified a total of 79 publications. After two levels of manual screening, 10 studies were included: six about diabetic retinopathy (DR) and four about retinal vein occlusion. No studies about retinal artery occlusion were included. In diabetes, all studies found that increases in retinal venous oxygen saturation (rvSatO2 ) were associated with present as well as increasing levels of DR. Four of six studies also found increased retinal arterial oxygen saturation (raSatO2 ) in patients with DR. In patients with central retinal vein occlusion (CRVO), all studies found that rvSatO2 was reduced, but raSatO2 remained unchanged. Branch retinal vein occlusion was not associated with changes in retinal oxygen saturation, but this was based on a single study. In conclusion, DR is associated with increased rvSatO2 and might also be related to increased raSatO2 . Central retinal vein occlusion (CRVO) is correlated with increased rvSatO2 but unrelated to raSatO2 . Prospective studies are needed to expand these findings. These would tell whether retinal oximetry could be a potential tool for screening or a biomarker of treatment outcome in patients with ischaemic retinal diseases.

Graft flow unaffected by full occlusion of left anterior descending artery during coronary artery bypass grafting in a porcine model.

BACKGROUND: We investigated in a porcine model whether measuring both the flow distal to an anastomosis and the graft transit time flow (TTF) gives a more accurate picture of the true blood flow in the left anterior descending artery (LAD) than graft TTF measurement alone. METHODS: We performed off-pump coronary artery bypass grafting (CABG)-left internal mammary artery (LIMA) to the LAD-on 5 Yorkshire-Landrace pigs. Snares were placed both proximal and distal to the anastomosis. Flow was measured with ultrasound and TTF. This was carried out on the LIMA and at 2 locations on the LAD. Measurements were performed at the following times: baseline, during proximal snaring, after proximal snare loosening, during distal snaring, after distal snare loosening, and during both proximal and distal snaring. RESULTS: During distal snaring, the TTF dropped (P = .047), and the pulsatile index (PI) increased (P = .025), while the ultrasound flow in the LAD dropped (P = .002). During proximal and distal snaring, the ultrasound flow dropped (P = .005), but the TTF value did not change significantly, compared with baseline. CONCLUSION: A high flow and a low PI were seen in the graft, both proximal and distal to the anastomosis, despite a fully occluded LAD. This result suggests that graft TTF measurement alone is not sufficient when performing CABG, and measurement of flow distal to the anastomosis is also necessary to determine the true blood flow in the LAD.