Factors Associated with Changes in Peripapillary Retinal Nerve Fibre Layer Thickness in Healthy Myopic Eyes

Myopic people face an elevated risk of primary open angle glaucoma. Changes in the fundus in people with high myopia often lead to misdiagnosis of glaucoma, as this condition has many clinical signs in common with myopia, making the diagnosis of glaucoma more challenging. Compared to reduction of the visual field, a decrease in retinal nerve fibre layer (RNFL) thickness occurs earlier in glaucoma, which is widely considered useful for distinguishing between these conditions. With the development of optical coherence tomography (OCT), RNFL thickness can be measured with good reproducibility. According to previous studies, this variable is not only affected by axial length but also related to the patient’s age, gender, ethnicity, optic disc area, and retinal blood flow in myopia. Herein, we intend to summarize the factors relevant to the RNFL in myopia to reduce the false-positive rate of glaucoma diagnosis and facilitate early prevention of myopia.

Fractalkine-induced microglial vasoregulation occurs within the retina and is altered early in diabetic retinopathy

Local blood flow control within the central nervous system (CNS) is critical to proper function and is dependent on coordination between neurons, glia, and blood vessels. Macroglia, such as astrocytes and Müller cells, contribute to this neurovascular unit within the brain and retina, respectively. This study explored the role of microglia, the innate immune cell of the CNS, in retinal vasoregulation, and highlights changes during early diabetes. Structurally, microglia were found to contact retinal capillaries and neuronal synapses. In the brain and retinal explants, the addition of fractalkine, the sole ligand for monocyte receptor Cx3cr1, resulted in capillary constriction at regions of microglial contact. This vascular regulation was dependent on microglial Cx3cr1 involvement, since genetic and pharmacological inhibition of Cx3cr1 abolished fractalkine-induced constriction. Analysis of the microglial transcriptome identified several vasoactive genes, including angiotensinogen, a constituent of the renin-angiotensin system (RAS). Subsequent functional analysis showed that RAS blockade via candesartan abolished microglial-induced capillary constriction. Microglial regulation was explored in a rat streptozotocin (STZ) model of diabetic retinopathy. Retinal blood flow was reduced after 4 wk due to reduced capillary diameter and this was coincident with increased microglial association. Functional assessment showed loss of microglial–capillary response in STZ-treated animals and transcriptome analysis showed evidence of RAS pathway dysregulation in microglia. While candesartan treatment reversed capillary constriction in STZ-treated animals, blood flow remained decreased likely due to dilation of larger vessels. This work shows microglia actively participate in the neurovascular unit, with aberrant microglial–vascular function possibly contributing to the early vascular compromise during diabetic retinopathy.

Diabetic mice have retinal and choroidal blood flow deficits and electroretinogram deficits with impaired responses to hypercapnia

Purpose The purpose of this study was to investigate neuronal and vascular functional deficits in the retina and their association in a diabetic mouse model. We measured electroretinography (ERG) responses and choroidal and retinal blood flow (ChBF, RBF) with magnetic resonance imaging (MRI) in healthy and diabetic mice under basal conditions and under hypercapnic challenge. Methods Ins2Akita diabetic (Diab, n = 8) and age-matched, wild-type C57BL/6J mice (Ctrl, n = 8) were studied under room air and moderate hypercapnia (5% CO2). Dark-adapted ERG a-wave, b-wave, and oscillatory potentials (OPs) were measured for a series of flashes. Regional ChBF and RBF under air and hypercapnia were measured using MRI in the same mice. Results Under room air, Diab mice had compromised ERG b-wave and OPs (e.g., b-wave amplitude was 422.2±10.7 μV in Diab vs. 600.1±13.9 μV in Ctrl, p < 0.001). Under hypercapnia, OPs and b-wave amplitudes were significantly reduced in Diab (OPs by 30.3±3.0% in Diab vs. -3.0±3.6% in Ctrl, b-wave by 17.9±1.4% in Diab vs. 1.3±0.5% in Ctrl). Both ChBF and RBF had significant differences in regional blood flow, with Diab mice having substantially lower blood flow in the nasal region (ChBF was 5.4±1.0 ml/g/min in Diab vs. 8.6±1.0 ml/g/min in Ctrl, RBF was 0.91±0.10 ml/g/min in Diab vs. 1.52±0.24 ml/g/min in Ctrl). Under hypercapnia, ChBF increased in both Ctrl and Diab without significant group difference (31±7% in Diab vs. 17±7% in Ctrl, p > 0.05), but an increase in RBF was not detected for either group. Conclusions Inner retinal neuronal function and both retinal and choroidal blood flow were impaired in Diab mice. Hypercapnia further compromised inner retinal neuronal function in diabetes, while the blood flow response was not affected, suggesting that the diabetic retina has difficulty adapting to metabolic challenges due to factors other than impaired blood flow regulation.

The effect of systemic factors on retinal blood flow in patients with carotid stenosis: an optical coherence tomography angiography study

Carotid artery stenosis (CAS) is among the leading causes of mortality and permanent disabilities in the Western world. CAS is a consequence of systemic atherosclerotic disease affecting the majority of the aging population. Optical coherence tomography angiography (OCTA) is a novel imaging technique for visualizing retinal blood flow. It is a noninvasive, fast method for qualitative and quantitative assessment of the microcirculation. Cerebral and retinal circulation share similar anatomy, physiology, and embryology; thus, retinal microvasculature provides a unique opportunity to study the pathogenesis of cerebral small vessel disease in vivo. In this study, we aimed to analyze the effect of systemic risk factors on retinal blood flow in the eyes of patients with significant carotid artery stenosis using OCT angiography. A total of 112 eyes of 56 patients with significant carotid stenosis were included in the study. We found that several systemic factors, such as decreased estimated glomerular filtration rate (eGFR), hypertension, and carotid occlusion have a significant negative effect on retinal blood flow, while statin use and carotid surgery substantially improve ocular microcirculation. Neither diabetes, clopidogrel or acetylsalicylic acid use, BMI, serum lipid level, nor thrombocyte count showed a significant effect on ocular blood flow. Our results demonstrate that a systematic connection does exist between certain systemic risk factors and retinal blood flow in this patient population. OCTA could help in the assessment of cerebral circulation of patients with CAS due to its ability to detect subtle changes in retinal microcirculation that is considered to represent changes in intracranial blood flow.

Quantitative analysis and clinical application of iris circulation in ischemic retinal disease

Background To evaluate quantitative changes in iris blood circulation in patients with ischemic risk. Methods This observational case-control study included 79 patients with diabetic retinopathy (DR) and retinal vein occlusion (RVO). The RVO group included 21 patients; the monocular proliferative diabetic retinopathy (PDR) group included 19 patients; the nondiabetic retinopathy (NDR) group included 18 patients; and the healthy control group included 21 healthy controls. In the RVO group, we analyzed RVO affected eyes, RVO contralateral eyes, and healthy control eyes. We also compared eyes with PDR and contralateral eyes without PDR, patients with diabetes mellitus (DM) without DR, and healthy control eyes. The microvascular networks of the iris and retina were analyzed using optical coherence tomography angiography. The analysis included vessel area density (VAD) and vessel skeleton density (VSD) of iris and retina. Results In the RVO group, the VAD and VSD of iris in the affected eye were higher than those in contralateral and healthy control eyes, and the VAD and VSD of contralateral eyes were higher than those of healthy control eyes. The retinal blood flow of the RVO eyes was less than that of the contralateral and healthy control eyes, but there were no difference between the contralateral eyes and healthy control eyes. The VAD and VSD of iris in PDR were larger than nonproliferative diabetic retinopathy (NPDR) and the NPDR were larger than NDR. There were no differences between NDR and healthy control eyes. Also, there were no differences among the four groups with respect to retinal blood flow. Conclusions Compared with the retina, iris blood circulation quantitative analysis data seem to be more sensitive to ischemia and may be used as a new predictor of ischemic disease, even if further research is needed to better understand the clinical value and importance of this analysis. Trial registration The trial is registered with the clinical trial registration number nct03631108.

Retinal Vascular Implications of Ocular Hypertension

In this chapter, we review the basics of retinal vascular anatomy and discuss the physiologic process of retinal blood flow regulation. We then aim to explore the relationship between intraocular pressure and retinal circulation, taking into account factors that affect retinal hemodynamics. Specifically, we discuss the concepts of ocular perfusion pressure, baro-damage to the endothelium and transmural pressure in relation to the intraocular pressure. Finally, we demonstrate the inter-relationships of these factors and concepts in the pathogenesis of some retinal vascular conditions; more particularly, through examples of two common clinical pathologies of diabetic retinopathy and central retinal vein occlusion.

Retinal Oxygen Metabolism and Haemodynamics in Patients With Multiple Sclerosis and History of Optic Neuritis

Vascular changes and alterations of oxygen metabolism are suggested to be implicated in multiple sclerosis (MS) pathogenesis and progression. Recently developed in vivo retinal fundus imaging technologies provide now an opportunity to non-invasively assess metabolic changes in the neural retina. This study was performed to assess retinal oxygen metabolism, peripapillary capillary density (CD), large vessel density (LVD), retinal nerve fiber layer thickness (RNFLT) and ganglion cell inner plexiform layer thickness (GCIPLT) in patients with diagnosed relapsing multiple sclerosis (RMS) and history of unilateral optic neuritis (ON). 16 RMS patients and 18 healthy controls (HC) were included in this study. Retinal oxygen extraction was modeled using O2 saturations and Doppler optical coherence tomography (DOCT) derived retinal blood flow (RBF) data. CD and LVD were assessed using optical coherence tomography (OCT) angiography. RNFLT and GCIPLT were measured using structural OCT. Measurements were performed in eyes with (MS+ON) and without (MS-ON) history for ON in RMS patients and in one eye in HC. Total oxygen extraction was lowest in MS+ON (1.8 ± 0.2 μl O2/min), higher in MS-ON (2.1 ± 0.5 μl O2/min, p = 0.019 vs. MS+ON) and highest in HC eyes (2.3 ± 0.6 μl O2/min, p = 0.002 vs. MS, ANOVA p = 0.031). RBF was lower in MS+ON (33.2 ± 6.0 μl/min) compared to MS-ON (38.3 ± 4.6 μl/min, p = 0.005 vs. MS+ON) and HC eyes (37.2 ± 4.7 μl/min, p = 0.014 vs. MS+ON, ANOVA p = 0.010). CD, LVD, RNFLT and GCIPL were significantly lower in MS+ON eyes. The present data suggest that structural alterations in the retina of RMS patients are accompanied by changes in oxygen metabolism, which are more pronounced in MS+ON than in MS-ON eyes. Whether these alterations promote MS onset and progression or occur as consequence of disease warrants further investigation.Clinical Trial Registration:ClinicalTrials.gov registry, NCT03401879.

Acute and subacute macular and peripapillary angiographic changes in choroidal and retinal blood flow post-intravitreal injections

Whether post injectional acute intraocular pressure (IOP) increase is associated with decreased peripapillary and macular perfusion is still under debate. Here, we investigated early changes in the choroidal and retinal blood flow using OCTA imaging in a cohort of patients undergoing anti-VEGF intravitreal injections (IVI) for macular edema following retinal vein occlusion and diabetic retinopathy. In this prospective single-center, observational study, the pre- and post-IVI changes in retinal perfusion were examined via assessment of vessel length density (VLD) and vessel density (VD) in deep and superficial capillary segmentations (DCP and SCP), foveal avascular zone (FAZ) in SCP, as well as flow signal deficits in the choriocapillaris segmentation. Mean IOP significantly changed over the study course (p = 0.000; ANOVA). Measurements at 5 min post-IVI (33.48 ± 10.84 mmHg) differed significantly from baseline (17.26 ± 2.41 mmHg, p = 0.000), while measurements from one day, one week, and one-month post-IVI did not (p = 0.907, p = 1.000 and p = 1.000 respectively). In comparison to baseline, no changes in OCTA parameters, including FAZ, VD, VLD, and FV, were detected 5 min post-IVI. No significant alterations in OCTA parameters were observed during study course. Increased IOP spikes were detected post-IVI; however, no potential permanent ischemic retinal damage was suspected.

Retinal oxygen delivery and extraction in ophthalmologically healthy subjects with different blood pressure status

Purpose: To compare retinal oxygen delivery (DO2) and extraction (VO2) in ophthalmologically healthy subjects with different blood pressure (BP) status. Methods: In this case-control study, we prospectively included 93 eyes of 93 subjects (age 50-65) from a large-scale population-based Dutch cohort (n=167,000) and allocated them to four groups (low BP, normal BP [controls], treated arterial hypertension [AHT], untreated AHT). We estimated vascular calibers from fundus images and fractal dimension (FD) from optical coherence tomography angiography scans. We combined calibers, FD, BP, and intraocular pressure measurements in a proxy of total retinal blood flow (RBF), using a validated Poiseuille-based model. We measured arterial and venous oxygen saturations (SaO2, SvO2) with a two-wavelength scanning laser ophthalmoscope. We calculated DO2 and VO2 from RBF, SaO2, and SvO2. We compared DO2 and VO2 between groups and investigated the DO2-VO2 association. Results: DO2 and VO2 were different between groups (P=0.009, P=0.036, respectively). In post hoc analysis, the low BP group had lower DO2 than the untreated AHT group (P=4.9⋅10-4), while both the low BP group and the treated AHT group had lower VO2 than the untreated AHT group (P=0.021, P=0.034, respectively). There was a significant DO2-VO2 correlation (R[obs]=0.65, b[obs]=0.51, P=2.4⋅10-12). After correcting for shared measurement error, the slope was no longer significant (b[cor]=0.19, P=0.29), while the correlation coefficient could not be calculated. Conclusions: DO2 and VO2 were altered in ophthalmologically healthy subjects with different BP status. Future studies could elucidate whether these changes can explain the increased risk of several ophthalmic pathologies in those subjects.