Retinal artery to vein ratio is associated with cerebral microbleeds in individuals with type 1 diabetes.

OBJECTIVES: A third of asymptomatic individuals with type 1 diabetes (T1D) show signs of cerebrovascular disease in brain MRI. These signs associate with advanced stages of diabetic retinal disease, but not in mild or moderate retinopathy. We aimed to evaluate a wider spectrum of retinal changes by exploring the relationship between quantitative measures of retinal vessel parameters (RVP) and cerebrovascular changes in T1D. METHODS: We included 146 neurologically asymptomatic individuals with T1D [51% women, median age 40 (33.0-45.1) years] and 24 healthy, sex-matched and age-matched controls. All individuals underwent a clinical and biochemical work-up and brain MRI, which was evaluated for cerebral microbleeds (CMBs), white matter hyperintensities, and lacunar infarcts. RVPs, including central retinal arteriole (CRAE) and central retinal vein (CRVE) equivalents and the ratio of the two variables (arteriovenous ratio, AVR) were assessed quantitatively by a computer-assisted method (IVAN software, version 3.2.6) from fundus images. RESULTS: Among T1D participants, those with CMBs had a lower arteriovenous ratio (AVR) compared with those without CMBs ( P  = 0.023). AVR was inversely associated with the amount of CMBs ( r  = -0.063, P  = 0.035). CMB prevalence was higher in those with AVR below the median (31%) compared with above the median (16%, P  < 0.001), and this difference was significant also after individuals with only no-to-mild retinopathy were included (28 vs. 16%, P  = 0.005). A correlation between blood pressure and CRAE ( r  = -0.19, P  = 0.025) appeared among those with T1D. CONCLUSION: Regardless of the severity of diabetic retinopathy, AVR is associated with the existence of CMBs in T1D.

Early remodeling and loss of light-induced dilation of retinal small arteries in CADASIL.

A major hurdle to therapeutic development in cerebral small vessel diseases is the lack of in-vivo method that can be used repeatedly for evaluating directly cerebral microvessels. We hypothesised that Adaptive Optics (AO), which allows resolution images up to 1-2 µm/pixel at retinal level, could provide a biomarker for monitoring vascular changes in CADASIL, a genetic form of such condition. In 98 patients and 35 healthy individuals, the wall to lumen ratio (WLR), outer and inner diameter, wall thickness and wall cross-sectional area were measured in a parapapillary and/or paramacular retinal artery. The ratio of vessel diameters before and after light flicker stimulations was also calculated to measure vasoreactivity (VR). Multivariate mixed-model analysis showed that WLR was increased and associated with a larger wall thickness and smaller internal diameter of retinal arteries in patients. The difference was maximal at the youngest age and gradually reduced with aging. Average VR in patients was less than half of that of controls since the youngest age. Any robust association was found with clinical or imaging manifestations of the disease. Thus, AO enables the detection of early functional or structural vascular alterations in CADASIL but with no obvious link to the clinical or imaging severity.

Impairment of central retinal artery hemodynamics in affected and fellow eyes in giant cell arteritis patients with unilateral vision loss.

OBJECTIVES: Permanent visual impairment is a major complication of giant cell arteritis (GCA). We investigated the added value of color Doppler imaging (CDI) of the central retinal artery (CRA) in patients with suspected GCA for early risk evaluation before temporal artery biopsy (TAB) results become available. METHODS: We conducted a non-interventional observational study of 30 consecutive patients hospitalized for suspected GCA, including a comprehensive analysis of clinical, laboratory, imaging, CDI and pathology data. GCA was diagnosed or excluded (GCA+, GCA-, respectively) according to American College of Rheumatology (ACR) criteria and TAB findings. Three patients not meeting ACR criteria were excluded secondarily. The GCA- group contained ten patients, and the GCA+ group contained 17 patients, including eight with unilateral, transient or permanent clinical visual impairment (CVI). RESULTS: Mean blood flow velocity (mBFV) in the CRA was impaired in the affected eyes of GCA + CVI+ patients (1.9 ± 0.9 cm.s-1, p < 0.001) relative to controls (4.1 ± 1.0 cm.s-1), GCA- patients (3.6 ± 0.7 cm.s-1) and GCA + CVI- patients (3.8 ± 0.8 cm.s-1). The mBFVs of the CRA was similar for affected and fellow eyes (right or left). CRA mBFV measurements effectively differentiated between patients with and without CVI (ROC-curve analysis, AUC = 0.925 [95%CI: 0.700 to 0.996], p < 0.0001, 88% sensitivity, 89% specificity, and cutoff of ≤2.7 cm.s-1 for affected eyes; 75% sensitivity, 100% specificity and cutoff of ≤2.2 cm.s-1 for fellow eyes). CONCLUSION: CDI facilities the early detection of visual ischemia risk in GCA+ patients, justifying urgent high-dose corticosteroid administration to save at least the fellow eye before pathology results become available.

DETECTION AND CHARACTERISTICS OF UNRUPTURED RETINAL ARTERIAL MACROANEURYSMS.

PURPOSE: To determine the presence of unruptured retinal arterial macroaneurysms (RAMs) and to examine the characteristics of the detected lesions. METHODS: This retrospective observational study included the affected and contralateral eyes of 50 patients (100 eyes) with symptomatic, unilateral, ruptured RAMs who visited the Department of Ophthalmology at the Kyoto University Hospital (April 2014-April 2020) and were followed up for at least 6 months after the onset. The presence and characteristics of unruptured RAMs were examined by reviewing the findings of color fundus photography and infrared scanning laser ophthalmoscopy performed before the onset or during the follow-up period. RESULTS: Unruptured RAMs were detected in six of the 50 patients. Some patients had bilateral or multiple unruptured RAMs, and a total of 12 unruptured RAMs were detected in eight eyes of the six patients. Among the detected lesions, eight exhibited a longitudinal increase in their diameter during the follow-up period, whereas six exhibited ruptures. CONCLUSION: Unruptured RAM is not an uncommon retinal vascular abnormality and can enlarge and progress to ruptured RAM.

Elevated retinal artery vascular resistance determined by novel visualized technique of laser speckle flowgraphy in branch retinal vein occlusion.

We aimed to investigate the increase in resistivity of the retinal artery in the branch retinal vein occlusion (BRVO)-affected area, and to visualize it. Thirty-two eyes of 32 patients with BRVO were measured by laser speckle flowgraphy (LSFG). The retinal artery and vein running to the BRVO-affected area and vertically symmetrical vessels in the unaffected area were examined. We applied the LSFG parameter beat strength over mean blur rate (BOM), calculated using a similar method to the pulsatility index used in Doppler flowmetry to evaluate resistivity of the vessels. Our results showed that the BOM map could clearly visualize the increase of resistivity in the retinal artery as a two-dimensional map. The BOM of the arteries in the affected area was significantly higher than that of the unaffected area (P = 0.001). Multiple regression analysis showed that the ratio of BOM in retinal arteries of the affected area to the unaffected was significantly associated with the extent of retinal hemorrhage (ß = 0.447, P = 0.009). In conclusion, the index of resistivity of the retinal artery in the BRVO-affected area was higher and could be visualized in a two-dimensional map. These findings and techniques would contribute to elucidate the pathophysiology of BRVO.

The Relationship Between Optic Disc and Retinal Artery Position and Glaucomatous Visual Field Progression.

Purpose: To investigate whether retinal structural parameters, including positions of the optic disc and major retinal arteries, affect glaucomatous progression of the visual field (VF). Methods: In this cohort study, 116 eyes of 73 patients with primary open angle glaucoma (POAG) were included. VFs were measured using the Humphrey Field Analyzer 24-2 program and the VF was divided into seven sectors according to the corresponding optic disc angle. Average total deviation (TD) was calculated in each sector. Positions of major retinal arteries in the superotemporal and inferotemporal areas were decided by identifying the points where the retinal artery intersected the 3.4-mm-diameter circle around the optic disc. The relationship between sectorial TD VF progression rate and eight variables (age, mean and standard deviation of intraocular pressure during the observation period, baseline sectorial TD value, papillomacular bundle tilt angle, and axial length, along with superior/inferior arterial angle) was investigated. Results: The main outcome measures were the association between retinal structural parameters and glaucomatous progression of VF. The superior retinal artery angular position was positively associated with sectorial TD progression rates in two central sectors in the inferior hemifield, which suggests faster VF progression where superior retinal artery angles are narrow. Papillomacular bundle tilt was not associated with TD progression rate in any sector. Conclusions: Progression of the inferior VF was associated with the superior retinal artery angular position in this study of POAG.

Retinal arteriolar tortuosity and fractal dimension are associated with long-term cardiovascular outcomes in people with type 2 diabetes.

AIMS/HYPOTHESIS: Our aim was to determine whether quantitative retinal traits in people with type 2 diabetes are independently associated with incident major cardiovascular events including CHD and stroke. METHODS: A total of 1066 men and women with type 2 diabetes, aged 65-74 years, were followed up over 8 years in the population-based Edinburgh Type 2 Diabetes Study. Using retinal photographs taken at baseline and specialist software, a number of quantitative retinal traits were measured, including arteriolar and venular widths and tortuosity as well as fractal dimension (a measure of the branching pattern complexity of the retinal vasculature network). Incident CHD events occurring during follow-up included fatal and non-fatal myocardial infarction, first episodes of angina and coronary interventions for CHD. Incident cerebrovascular events included fatal and non-fatal stroke or transient ischaemic attack. Cox proportional hazard regression analyses were performed to identify the association of the retinal traits with cardiovascular events in the population with retinal data available (n = 1028). RESULTS: A total of 200 participants had an incident cardiovascular event (139 CHD and 61 cerebrovascular events). Following adjustment for age and sex, arteriolar tortuosity and fractal dimension were associated with cerebrovascular events (HR 1.27 [95% CI 1.02, 1.58] and HR 0.74 [95% CI 0.57, 0.95], respectively), including with stroke alone (HR 1.30 [95% CI 1.01, 1.66] and HR 0.73 [95% CI 0.56, 0.97], respectively). These associations persisted after further adjustment for established cardiovascular risk factors (HR 1.26 [95% CI 1.01, 1.58] and HR 0.73 [95% CI 0.56, 0.94], respectively). Associations generally reduced in strength after a final adjustment for the presence of diabetic retinopathy, but the association of fractal dimension with incident cerebrovascular events and stroke retained statistical significance (HR 0.73 [95% CI 0.57, 0.95] and HR 0.72 [95% CI 0.54, 0.97], respectively). Associations of retinal traits with CHD were generally weak and showed no evidence of statistical significance. CONCLUSIONS/INTERPRETATION: Arteriolar tortuosity and fractal dimension were associated with incident cerebrovascular events, independent of a wide range of traditional cardiovascular risk factors including diabetic retinopathy. These findings suggest potential for measurements of early retinal vasculature change to aid in the identification of people with type 2 diabetes who are at increased risk from stroke.

Effect of ECG-gating Retinal Photographs on Retinal Vessel Caliber Measurements in Subjects with and without Type 2 Diabetes.

Purpose/Aim of this study: Retinal vessel caliber is an independent risk marker of cardiovascular disease risk. However, variable mechanical delays in capturing retinal photographs and cardiac cycle-induced retinal vascular changes have been shown to reduce the accuracy of retinal vessel caliber measurements, but this has only ever been investigated in healthy subjects. This cross-sectional study is the first study to investigate this issue in type 2 diabetes. The aim of this study was to determine whether ECG-gating retinal photographs reduce the variability in retinal arteriolar and venular caliber measurements in controls and type 2 diabetes.Materials and Methods: Fifteen controls and 15 patients with type 2 diabetes were arbitrarily recruited from Westmead Hospital, Sydney, Australia. A mydriatic fundoscope connected to our novel ECG synchronization unit captured 10 ECG-gated (at the QRS) and 10 ungated digital retinal photographs of the left eye in a randomized fashion, blinded to study participants. Two independent reviewers used an in-house semi-automated software to grade single cross-sectional vessel diameters across photographs, between 900 and 1800 microns from the optic disc edge. The coefficient of variation compared caliber variability between retinal arterioles and venules.Results: Our ECG synchronization unit reported the smallest time delay (33.1 ± 48.4 ms) in image capture known in the literature. All 30 participants demonstrated a higher reduction in retinal arteriolar (ungated: 1.02, 95%CI 0.88-1.17% vs ECG-gated: 0.39, 95%CI 0.29-0.49%, p < .0001) than venular (ungated 0.62, 95%CI 0.53-0.73% vs ECG-gated: 0.26, 95%CI 0.19-0.35%, p < .0001) coefficient of variation by ECG-gating photographs. Intra-observer repeatability and inter-observer reproducibility analysis reported high interclass correlation coefficients ranging from 0.80 to 0.86 and 0.80 to 0.93 respectively.Conclusion: ECG-gating photographs at the QRS are recommended for retinal vessel caliber analysis in controls and patients with type 2 diabetes as they refine measurements.

Associating the biomarkers of ocular blood flow with lamina cribrosa parameters in normotensive glaucoma suspects. Comparison to glaucoma patients and healthy controls.

PURPOSE: To evaluate association between ocular blood flow biomarkers and lamina cribrosa parameters in normotensive glaucoma suspects compared to glaucoma patients and healthy controls. METHODS: A total of 211 subjects (72 normotensive glaucoma suspects, 70 with primary open-angle glaucoma and 69 controls) were included. Ocular blood flow biomarkers in ophthalmic artery, central retinal artery, as well as in nasal and temporal short posterior ciliary arteries were measured using colour Doppler imaging. Lamina cribrosa position was assessed by measuring its depth, deflection depth, lamina cribrosa shape index and its horizontal equivalent (LCSIH) on B-scan images obtained using optical coherence tomography. RESULTS: Ocular blood flow biomarkers in glaucoma patients were statistically significantly reduced when compared to healthy controls in peak systolic velocity (PSV) (P = 0.001 in ophthalmic artery and P<0.001 in central retinal artery) and mean flow velocity (Vm) (P = 0.008 in ophthalmic artery and P = 0.008 in central retinal artery), but not statistically significantly different to that of glaucoma suspects except for PSV in central retinal artery (P = 0.011). Statistically significant correlations corrected for age, central corneal thickness and intraocular pressure were found in glaucoma patients between LCSIH and end diastolic velocity of central retinal artery (P = 0.011), and of nasal short posterior ciliary artery (P = 0.028), and between LCSIH and Vm of central retinal artery (P = 0.011) and of nasal short posterior ciliary artery (P = 0.007). No significant correlations were observed between these parameters in glaucoma suspects and healthy controls. CONCLUSIONS: Impaired ocular blood flow associated with the deformation of lamina cribrosa was found in glaucoma patients, whereas glaucoma suspects had similar lamina cribrosa shape to glaucoma patients but that deformation was not associated with ocular blood flow biomarkers.

Different retinopathy phenotypes in type 2 diabetes predict retinopathy progression.

PURPOSE: To characterize the progression in retinopathy severity of different phenotypes of mild nonproliferative diabetic retinopathy (NPDR) in patients with type 2 diabetes. DESIGN AND METHODS: Patients with type 2 diabetes and mild NPDR (ETDRS 20 or 35) were followed in a 5-year longitudinal study. Examinations, including color fundus photography (CFP) and optical coherence tomography (OCT and OCTA), were performed at baseline, 6 months and then annually. Phenotype classification was performed based on microaneurysm turnover (MAT, on CFP) and central retinal thickness (CRT, on OCT). Phenotype A is characterized by low MAT (< 6) and normal CRT; Phenotype B by low MAT (< 6) and increased CRT; and Phenotype C by higher MAT (≥ 6) with or without increased CRT. ETDRS grading of seven fields CFP was performed at the initial and last visits. RESULTS: Analysis of ETDRS grade step changes showed significant differences in diabetic retinopathy (DR) progression between the different phenotypes (p < 0.001). Of the 66 participants with phenotype A only 2 eyes (3%) presented 2-or-more-step worsening. None of the 50 participants characterized as phenotype B developed 2-step worsening, whereas 13 eyes (23.2%) characterized as phenotype C had 2-or-more-steps worsening. Phenotype C presents the higher risk for 2-or-more step worsening (OR: 15.94 95% CI: 3.45-73.71; p < 0.001) and higher sensitivity, correctly identifying 86.7% of cases at risk (AUC: 0.84 95% CI: 0.72-0.96; p < 0.001). Diabetic retinopathy severity progression was associated with HbA1c (p = 0.019), LDL levels (p = 0.043), and ocular factors as MAT (p = 0.010), MA formation rate (p = 0.014) and MA disappearance rate (p = 0.005). Capillary closure at 5-year follow-up, identified by lower vessel density (VD) on OCTA, was also associated with diabetic DR severity progression (p = 0.035). CONCLUSIONS: Different DR phenotypes in type 2 diabetes show different risks of retinopathy progression. Phenotype C is associated with increased HbA1c values and presents a higher risk of a 2-or-more-step worsening of the ETDRS severity score.

Site of Origin of the Ophthalmic Artery Influences the Risk for Retinal Versus Cerebral Embolic Events.

BACKGROUND: Embolic events leading to retinal ischemia or cerebral ischemia share common risk factors; however, it has been well documented that the rate of concurrent cerebral infarction is higher in patients with a history of transient ischemic attack (TIA) than in those with monocular vision loss (MVL) due to retinal ischemia. Despite the fact that emboli to the ophthalmic artery (OA) and middle cerebral artery share the internal carotid artery (ICA) as a common origin or transit for emboli, the asymmetry in their final destination has not been fully explained. We hypothesize that the anatomic location of the OA takeoff from the ICA may contribute to the differential flow of small emboli to the retinal circulation vs the cerebral circulation. METHODS: We report a retrospective, comparative, case-control study on 28 patients with retinal ischemia and 26 patients with TIA or cerebral infarction caused by embolic events. All subjects underwent either computed tomography angiography or MRA. The location of the ipsilateral OA origin off the ICA was then graded in a blinded fashion and compared between cohorts. Vascular risk factors were collected for all patients, including age, sex, hypertension, hyperlipidemia, arrhythmia, diabetes, coronary artery disease, and smoking. RESULTS: We find that in patients with retinal ischemia of embolic etiology, the ipsilateral OA takeoff from the ICA is more proximal than in patients with cerebral infarcts or TIA (P = 0.0002). We found no statistically significant differences in demographic, vascular, or systemic risk factors. CONCLUSIONS: We find that the mean anatomical location of the OA takeoff from the ICA is significantly more proximal in patients with MVL due to retinal ischemia compared with patients with TIA or cerebral ischemia. This finding contributes significantly to our understanding of a long observed but poorly understood phenomenon that patients with MVL are less likely to have concurrent cerebral ischemia than are patients with TIA.

Multimodal imaging in pediatric arterial macroaneurysm: A case report.

Our aim is to report a case of asymptomatic retinal arterial macroaneurysm in a 9-year-old female patient. She was referred to our Ophthalmology clinic for a routine ophthalmologic examination and, after the detection of a juxtafoveal saccular vascular enlargement in indirect ophthalmoscopy, underwent a multimodal imaging assessment. Optical coherence tomography-angiography and fluorescein angiography were important to determine the nature of the lesion, identified as a congenital retinal arterial macroaneurysm. Retinal vascular abnormalities represent a rare finding in pediatric patients and must be carefully explored to establish the correct diagnosis. A multimodal imaging approach was very useful to thoroughly reach this target. Vascular abnormalities represent a rare finding in pediatric patients and must be carefully explored to establish the correct diagnosis. A multimodal imaging approach is very useful to study in deep the reported arterial macroaneurysm in a non-invasive way.

Paracentral acute middle maculopathy associated with hypoperfusion of the cilioretinal artery and impending central retinal vein occlusion.

BACKGROUND: Paracentral acute middle maculopathy is defined as ischemia of the deep retinal layers. We report an unusual case of paracentral acute middle maculopathy associated with hypoperfusion of the cilioretinal artery and impending central retinal vein occlusion in a young male with no previous comorbidities. CASE REPORT: The patient was a 22-year-old male complaining about a sudden loss of vision in his right eye upon awakening. Fundus examination showed optic disk edema, and increased tortuosity of the retinal veins and a few retinal hemorrhages. Swept-source optical coherence tomography found a hyperreflective band that was more pronounced at the level of the inner nuclear layer of the retina. These findings led us to a diagnosis of paracentral acute middle maculopathy associated with hypoperfusion of the cilioretinal artery. CONCLUSION: The finding of paracentral acute middle maculopathy on optical coherence tomography demands a proper investigation of its cause, because it has an intimate association with vascular diseases and is not an isolated entity. In our case, we could not identify the etiology of the unilateral event in this young male, although dehydration due to alcohol consumption and subsequent hypotension might have played a role in this ischemic event.

RAP study, report 1: novel subtype of macular neovascularisation type III, cilioretinal MNV3.

PURPOSE: To report on patients with macular neovascularisation type III (MNV3) arising from cilioretinal arteries (CRAs) (cilioretinal macular neovascularisation type III (cMNV3)). METHODS: We reviewed baseline examinations of patients with neovascular age-related macular degeneration using multimodal imaging. We determined the type and distribution of MNV lesions in each cMNV3 case, the range of distances from the fovea, existence of exudative maculopathy, intraretinal haemorrhage and other morphological characteristics. 50 consecutive eyes with usual MNV3 without CRA were included as a control group. RESULTS: 102 eyes of 102 patients were identified with MNV3 lesions. Among these, we found 12 eyes (12%) with cMNV3, 84 eyes (82%) with usual MNV3 without CRA and 6 eyes (6%) with usual MNV3 with CRA. Ten cases of cMNV3 had one lesion, and two cases had two lesions. The lesions were distributed equally between the superior and inferior halves of the macula, whereas in the nasal and temporal halves, there were 8 (57%) and 6 (43%) lesions, respectively. All cMNV3 lesions were located between 500 and 1500 µm from the central fovea except one, which was located between 1500 and 3000 µm. None of the lesions had macular neovascularisation type I (MNV1) or macular neovascularisation type II (MNV2) elsewhere in both groups. Exudative maculopathy and intraretinal haemorrhage were found in seven (88%) and five (63%) of the eight pure cMNV3 cases, respectively. CONCLUSION: cMNV3 can be solitary or multiple, isolated or accompanied with usual MNV3 lesions, but not with concurrent MNV1 or MNV2. It is frequently associated with extensive exudative maculopathy, intraretinal haemorrhage and subretinal fluid.

Decreased Vascular Patterning in the Retinas of Astronaut Crew Members as New Measure of Ocular Damage in Spaceflight-Associated Neuro-ocular Syndrome.

Purpose: Ocular structural and functional changes, collectively termed spaceflight-associated neuro-ocular syndrome (SANS), have been described in astronauts undergoing long-duration missions in the microgravity environment of the International Space Station. We tested the hypothesis that retinal vascular remodeling, particularly by smaller vessels, mediates the chronic headward fluid shifts associated with SANS. Methods: As a retrospective study, arterial and venous patterns extracted from 30° infrared Heidelberg Spectralis retinal images of eight crew members acquired before and after six-month missions were analyzed with NASA's recently released VESsel GENeration Analysis (VESGEN) software. Output parameters included the fractal dimension and overall vessel length density that was further classified into large and small vascular branching generations. Vascular results were compared with SANS-associated clinical ocular measures. Results: Significant postflight decreases in Df, Lv, and in smaller but not larger vessels were quantified in 11 of 16 retinas for arteries and veins (P value for Df, Lv, and smaller vessels in all 16 retinas were ≤0.033). The greatest vascular decreases occurred in the only retina displaying clinical evidence of SANS by choroidal folds and optic disc edema. In the remaining 15 retinas, decreases in vascular density from Df and Lv ranged from minimal to high by a custom Subclinical Vascular Pathology Index. Conclusions: Together with VESGEN, the Subclinical Vascular Pathology Index may represent a new, useful SANS biomarker for advancing the understanding of SANS etiology and developing successful countermeasures for long duration space exploration in microgravity, although further research is required to better characterize retinal microvascular adaptations.

Optical Coherence Tomography Angiography and Multifocal Electroretinogram Findings in Paracentral Acute Middle Maculopathy.

Paracentral acute middle maculopathy (PAMM) is an optical coherence tomography (OCT) finding seen in patients with retinal capillary ischemia. In this case report, we present a case of PAMM after a transient central retinal artery occlusion and the multifocal electroretinogram (mfERG) and other multimodal imaging findings. Clinical examination, OCT angiography, OCT en face, fluorescein angiography, and visual fields were performed at the baseline and follow-up examinations. As a result, we identified in this PAMM case evidence of hypoperfusion in both the choriocapillaris as well as the deep capillary plexus. To the best of our knowledge, the involvement of choriocapillaris has not been reported previously in the literature. Moreover, we concluded that mfERG constitutes a useful investigation in PAMM and this is the first mfERG findings to be presented for a PAMM case specifically.