Neuronal activity-dependent regulation of retinal blood flow.

Blood flow in the retina is intrinsically regulated to meet the metabolic demands of its constituent cells. Flickering light or stationary contrast reversals induce an increase in blood flow within seconds of the stimulus onset. This phenomenon is thought to compensate for an increase in ganglion cell activity and energy consumption. Ganglion cell activity is in turn dependent on signals from photoreceptors, bipolar cells, horizontal cells and amacrine cells. The physiological properties of these neurons determine how each type is affected by a particular light characteristic. Neuronal activity then triggers the release of signalling molecules that dilate local blood vessels and increase blood flow. Nitric oxide has been implicated as an important mediator, but metabolites of arachidonic acid may also be involved. Detailed elucidation of these mechanisms, together with advances in imaging technology, may facilitate the use of neurovascular tests to improve the detection of retinal damage in pathological conditions.

Associations of retinal oximetry in persons with diabetes.

BACKGROUND: There are limited data available on the variables that might affect retinal vessel oxygen saturation (SO2) in diabetes. Therefore, the aim of this study is to assess factors associated with retinal oximetry values in persons with diabetes. DESIGN: Clinic-based cross-sectional study. PARTICIPANTS: Fifty-eight persons with diabetes aged 18+ years, recruited from the University of Melbourne, the Royal Victorian Eye and Ear Hospital, and St. Vincent's Hospital (Melbourne), Australia. METHODS: Retinal oximetry was performed using the oximetry module of the Vesselmap system (Imedos UG, Jena, Germany) in 92 diabetic eyes. Generalized estimating equation models were used to estimate the associations between candidate variables (age; gender; retinal capillary flow; duration of diabetes; hypertension; smoking status; presence of diabetic retinopathy [DR]; glycated haemoglobin; triglyceride; total cholesterol; finger SO2 and ocular perfusion pressure) with retinal oximetry measures. MAIN OUTCOME MEASURE: Arteriolar SO2, venular SO2 and the arterio-venous (A-V) difference. RESULTS: Of the candidate factors assessed, only the presence of DR was significantly associated with increased venular SO2 and decreased A-V difference in unadjusted analyses. In models adjusting for age and gender and significant variables from unadjusted analyses, compared with no DR, the presence of DR was significantly associated with greater retinal venular SO2 values (ß = 3.65%, 95% confidence interval: 0.67-6.63%) and decreased A-V difference (ß = -2.00%, 95% confidence interval: -3.46 to -0.53%). CONCLUSION: In patients with diabetes, eyes with DR were associated with increased venular SO2 and decreased A-V difference compared with eyes without DR, suggesting an altered metabolic state in DR.

Peripheral Ophthalmic Artery Aneurysm Associated with Multifocal Intracranial and Extracranial Aneurysms: Case Report and Literature Review.

Peripheral ophthalmic artery aneurysm is a rare disease entity. We review the relevant literature and report a case of fusiform aneurysm involving the entire intraorbital ophthalmic artery in association with multiple intracranial and extracranial aneurysms, diagnosed on digital subtraction angiography. The patient suffered irreversible blindness secondary to compressive optic neuropathy which did not improve after a 3-day trial of intravenous methylprednisolone. Autoimmune screen was normal. The underlying cause is unknown.

Flicker-induced retinal arteriole dilation is reduced by ambient lighting.

PURPOSE: To investigate the impact of ambient room lighting on the magnitude of flicker light-induced retinal vasodilations in healthy individuals. METHODS: Twenty healthy nonsmokers participated in a balanced 2 × 2 crossover study. Retinal vascular imaging was performed with the dynamic vessel analyzer under reduced or normal ambient lighting, then again after 20 minutes under the alternate condition. Baseline calibers of selected arteriole and venule segments were recorded in measurement units. Maximum percentage dilations from baseline during 20 seconds of luminance flicker were calculated from the mean of three measurement cycles. Within-subject differences were assessed by repeated measures analysis of variance with the assumption of no carryover effects and pairwise comparisons from the fitted model. RESULTS: Mean (SD) maximum arteriole dilations during flicker stimulation under reduced and normal ambient lighting were 4.8% (2.3%) and 4.1% (1.9%), respectively (P = 0.019). Maximum arteriole dilations were (mean ± 95% confidence interval) 0.7% ± 0.6% lower under normal ambient lighting compared with reduced lighting. Ambient lighting had no significant effect on maximum venular dilations during flicker stimulation or on the baseline calibers of arterioles or venules. CONCLUSIONS: Retinal arteriole dilation in response to luminance flicker stimulation is reduced under higher ambient lighting conditions. Reduced responses with higher ambient lighting may reflect reduced contrast between the ON and OFF flicker phases. Although it may not always be feasible to conduct studies under reduced lighting conditions, ambient lighting levels should be consistent to ensure that comparisons are valid.

Flicker light-induced retinal vasodilation is unaffected by inhibition of epoxyeicosatrienoic acids and prostaglandins in humans.

PURPOSE: To investigate the role of epoxyeicosatrienoic acids (EETs) and prostaglandins (PGs) in retinal blood vessel calibers and vasodilation during flicker light stimulation in humans. METHODS: Twelve healthy nonsmokers participated in a balanced crossover study. Oral fluconazole 400 mg and dispersible aspirin 600 mg were used to inhibit production of EETs and PGs, respectively. Retinal imaging was performed 1 hour after drug ingestion with the Dynamic Vessel Analyzer. Resting calibers of selected vessel segments were recorded in measurement units (MU). Maximum percentage dilations during flicker stimulation were calculated from baseline calibers. We then studied six participants each after fluconazole and aspirin ingestions at 30-minute intervals for 2 hours. Within-subject differences were assessed by ANOVA and Dunnett-adjusted pairwise comparisons with significance taken at P < 0.05. RESULTS: In crossover study participants, mean (SD) arteriole and venule dilations without drug administration were 4.4% (2.0%) and 4.6% (1.7%), respectively. Neither drug affected vasodilation during flicker stimulation. Mean (SD) resting arteriole and venule calibers on no-drug visits were 119.6 (10.6) MU and 145.7 (17.0) MU, respectively. Fluconazole reduced mean (±95% CI) resting venule calibers by 5.1 (4.3) MU. In repeated measures participants, neither drug affected vasodilations, but fluconazole reduced resting venule calibers over 2 hours (P < 0.001). CONCLUSIONS: Epoxyeicosatrienoic acids and prostaglandins are unlikely to be primary mediators of flicker light-induced retinal vasodilation in humans. However, EETs may play a role in the regulation of retinal vascular tone and blood flow under resting physiological conditions.

Decreased retinal capillary flow is not a mediator of the protective myopia-diabetic retinopathy relationship.

PURPOSE: The mechanisms supporting the protective relationship between a longer axial length (AL) and a decreased risk of diabetic retinopathy (DR) remain unclear. Previous studies have demonstrated reduced retinal blood flow in axial myopia, and it has been suggested that the compromised retinal capillaries in diabetes are less likely to leak and rupture as a result of this decreased flow. In this study, we therefore investigated if reduced retinal capillary flow (RCF) is a potential mechanism underpinning this protective relationship. METHODS: Retinal capillary flow was assessed using the Heidelberg Retinal Flowmeter in 150 eyes of 85 patients with diabetes aged 18+ years from the Royal Victorian Eye and Ear Hospital and St. Vincent's Hospital (Melbourne), Australia. Axial length was measured using the Intraocular Lens Master. Diabetic retinopathy was graded from two-field retinal photographs into none, mild, moderate, and severe DR using the modified Airlie House classification system. RESULTS: A total of 74 out of 150 eyes (49.3%) had DR. A longer AL was associated with decreased odds of DR presence (per mm increase in AL, odds ratio [OR] 0.61, 95% confidence interval [CI] 0.41-0.91) and DR severity (OR: 0.65; 95% CI: 0.44-0.95). However, no association was found between AL and RCF (per mm increase in AL, regression coefficient [ß] -1.80, 95% CI -13.50 to 9.50) or between RCF and DR (per unit increase in RCF, OR 1.00; 95% CI 0.99-1.00). CONCLUSIONS: Our finding suggests that diminished RCF may not be a major factor underlying the protective association between axial elongation and DR.

Quantitative measurement of hard exudates in patients with diabetes and their associations with serum lipid levels.

PURPOSE: To describe a reproducible method of quantifying macular hard exudates (HEs) in diabetic maculopathy and determine the associations of HEs with systemic risk factors. METHODS: Patients with diabetes were recruited from a tertiary eye hospital in Melbourne, Australia. Total macular area covered by HEs (total HE area) and the distance from the foveal center to the nearest HE were measured in a semi-automated manner. Associations between HE parameters and diabetic complication risk factors were examined using multiple linear regression models. RESULTS: Of 593 participants (mean age 60.5-years old), 97 (16.4%) had HEs in at least one eye, due to diabetic maculopathy. The intraclass correlation coefficients (ICC) for inter- and intra-observer agreements were 0.982 and 0.999, respectively. Total HE area was positively associated with qualitative HE severity scale determined by photographic graders. The median of total HE area was 0.089 mm(2) (interquartile range, 0.027-0.246). The median distance between foveal center and the nearest HE was 791.1 µm (431.9-1385.4). After adjusting for age, sex, duration of diabetes, glycated hemoglobin, mean arterial pressure, diabetic retinopathy level, and use of lipid-lowering medication, low density lipoprotein (LDL) cholesterol (P = 0.009), and triglyceride levels (P = 0.036) were positively associated with total HE area. Higher triglyceride levels were associated with central involvement (P = 0.023). CONCLUSIONS: Quantitative measurement of HEs in patients with diabetes is associated with lipid levels, and higher triglyceride levels are associated with a higher risk of central involvement. Quantitative information may be useful to monitor HE progression or treatment response in persons with diabetic maculopathy.

An update on the molecular actions of fenofibrate and its clinical effects on diabetic retinopathy and other microvascular end points in patients with diabetes.

The drug fenofibrate has received major attention as a novel medical treatment for diabetic retinopathy (DR) and other diabetes-induced microvascular complications. This interest stems from two recent large, well-designed clinical trials that demonstrated large reductions in the progression of DR and the need for laser intervention, in addition to a reduction in renal and neurological outcomes, in patients with type 2 diabetes. In both trials, the greatest benefit on DR progression was observed in those patients with DR at baseline. Originally considered a lipid-modifying drug, it now appears that multiple mechanisms may underpin the benefit of fenofibrate on diabetic microvascular end points. Fenofibrate regulates the expression of many different genes, with a range of beneficial effects on lipid control, inflammation, angiogenesis, and cell apoptosis. These factors are believed to be important in the development of DR regardless of the underlying diabetes etiology. Cell experiments have demonstrated improved survival of retinal endothelial and pigment epithelial cells in conjunction with reduced stress signaling under diabetic conditions. Further, fenofibrate improves retinal outcomes in rodent models of diabetes and retinal neovascularization. Given the results of these preclinical studies, further clinical trials are needed to establish the benefits of fenofibrate in other forms of diabetes, including type 1 diabetes. In DR management, fenofibrate could be a useful adjunctive treatment to modifiable risk factor control and regular ophthalmic review. Its incorporation into clinical practice should be continually revised as more information becomes available.

Retinal arteriolar dilation to flicker light is reduced on short-term retesting.

PURPOSE: To investigate the impact of retesting frequency over a short period on flicker light-induced retinal vasodilation. METHODS: Twenty healthy participants were included. The retinal vascular response to flicker light stimulation was assessed three times (at baseline and after 5 and 30 minutes of rest [tests 1, 2, and 3, respectively]) in each participant using the Dynamic Vessel Analyzer. Relative dilations of selected arteriole and venule segments during flicker stimulation and resting diameters were measured automatically. The mean vessel dilations and resting diameters were compared using repeated-measures analysis of variance. RESULTS: Participants were young (mean [SD] age, 33.1 [5.7] years) and mostly female (70%). The mean (SD) maximum arteriolar dilations during flicker stimulation were 3.23% (2.06%), 2.44% (1.62%), and 3.36% (2.11%) in tests 1, 2, and 3, respectively. The mean (SD) venular dilations were 4.26% (1.28%), 3.81% (1.61%), and 4.43% (1.73%) in tests 1, 2, and 3, respectively. The mean arteriolar dilations were significantly different across the three tests (P < 0.001). Compared with test 1, arteriolar dilations were significantly reduced after 5 minutes (P = 0.008) but not 30 minutes (P = 0.437) of rest. No significant differences were found over time for the mean venular dilations (P = 0.128). Resting diameters of selected vessels were not significantly different between tests. CONCLUSIONS: Retinal arteriolar dilation during flicker stimulation is reduced on short-term retesting, without a significant change in baseline vessel diameter, indicating decreased responsiveness to the flicker stimulus. Researchers should allow at least 30 minutes between consecutive tests to minimize suppression of the flicker response.

Axial length, retinal function, and oxygen consumption: a potential mechanism for a lower risk of diabetic retinopathy in longer eyes.

PURPOSE: To determine the relationship between axial length (AL), retinal function, and relative oxygen (O2) consumption to better understand the protective effect of axial elongation on diabetic retinopathy development. METHODS: Measurements of AL, multifocal electroretinogram (mfERG), and relative O2 consumption (difference between arteriolar and venular O2 saturation levels or A-V difference) were performed on 50 healthy individuals. The relationships between AL, mfERG amplitude, and A-V difference were analyzed using linear regression models. Path analysis was performed to determine the direct and indirect effects (via mfERG amplitude) of AL on A-V difference. RESULTS: mfERG P1 amplitude was positively associated with A-V difference (ß = 0.33; 95% confidence interval [CI]: 0.23-0.42). Increased AL was significantly associated with a decrease in A-V difference (ß = -1.08; 95% CI: -1.52 to -0.65) as well as a decrease in retinal function (ß = -3.14, 95% CI: -4.07 to -2.20). Path analysis models including AL (study factor), retinal function (intermediate variable), and A-V difference (outcome variable) showed that AL had little direct association with A-V difference (ß(p) = -0.002), while the indirect effect of AL on A-V difference via changes in retinal function were substantial (ß(p) = -0.51). CONCLUSIONS: In eyes with longer AL, the reduction in A-V difference is explained by the parallel reduction in retinal function. These findings suggest that longer eyes have decreased retinal function and O2 consumption, and thus are relatively less hypoxic in the presence of diabetes, which may partly explain the reduced risk of DR in these eyes.