Ischemic Diabetic Retinopathy Research Articles

Prevalence of venous loops and association with retinal ischemia in diabetic retinopathy using widefield swept-source OCT angiography.

To investigate the prevalence and clinical characteristics of diabetic patients with retinal venous loops (RVLs) and to assess the association with retinal ischemia using widefield swept-source optical coherence tomography angiography (WF SS-OCTA). In this retrospective, cross-sectional study, a total of 195 eyes of 132 diabetic patients (31 eyes with no diabetic retinopathy (DR), 76 eyes with nonproliferative DR (NPDR), and 88 eyes with proliferative DR (PDR)) were imaged with WF SS-OCTA using Angio 6 × 6mm and Montage 15 × 15mm scans. Quantitative ischemia-related parameters, including ischemia index (ratio of nonperfusion area to total retinal area), foveal avascular zone (FAZ), and neovascularization features, were evaluated. RVLs were classified as type I or type II according to the branching level of the feeder vessel. A multivariate generalized estimating equations (GEE) logistic regression model was used to analyze the association of systemic parameters and ischemia-related metrics with RVLs in PDR eyes. Forty-eight RVLs were identified in 22 eyes (11.28%). The prevalence of RVLs was higher in PDR compared to NPDR eyes (21.59% vs. 3.95%, P < 0.05). Type II RVLs accounted for a higher proportion than type I (89.58% vs. 10.42%, P < 0.001). RVLs were more likely to originate from superior (vs. inferior) and temporal (vs. nasal) veins (P < 0.05). The GEE model showed that neovascularization (NV) flow area and diastolic blood pressure were associated with RVLs in the PDR group (P < 0.05). WF SS-OCTA is useful for the identification of RVLs in patients with DR. NV flow area and diastolic blood pressure were associated with the presence of RVLs in eyes with PDR. Ischemia index, FAZ, and other WF SS-OCTA parameters were not associated with RVLs. Further longitudinal studies are needed to identify the role of RVLs in DR progression.

Sensitivity and Specificity of the Optical Coherence Tomography Angiography for Detection of Neovascularization and Evaluation of Peripheral Ischemia in Diabetic Retinopathy.

The purpose of this study was to identify the sensitivity and specificity of optical coherence tomography angiography (OCTA) parameters for the presence of neovascularization elsewhere (NVE) and to investigate the relationship between ischemic areas. This study included 59 eyes with non-proliferative diabetic retinopathy (NPDR) and 36 eyes with proliferative diabetic retinopathy (PDR). The foveal avascular zone (FAZ), vessel density (VD) for the superficial and the deep capillary plexus (DCP), choriocapillaris flow area (CCP), and non-perfusion area (unit²) were recorded. The area under the curve (AUC) under the receiver operating characteristic curves, sensitivity and specificity were calculated for statistically significant outcomes. Later, based on visual acuity, PDR group was subdivided into group 2A: PDR eyes with VA ≤0.2 logMAR and group 2B: PDR eyes with VA>0.2 logMAR. Non-perfusion area and OCTA features were compared between the subgroups. The VD in DCP was significantly lower, FAZ and non-perfusion area were larger in PDR group (p=0.001, p<0.001, and p<0.001). The AUC for presence of NVE, for the VD, was 0.710 (p=0.012) with sensitivity and specificity of 64% and 65%, for the FAZ was 0.746 (p<0.001) with sensitivity and specificity of 72% and 72.7%. There was a significant positive correlation between the FAZ and non-perfusion area (For NPDR, p=0.025, for PDR p<0.001). There was a significant negative correlation between the VD in DCP and ischemic area in PDR group. (p<0.001) In group 2B, non-perfusion area and FAZ were larger than group 2A. The VD and CCP flow area were also lower in group 2B (All, p<0.05). In cases with decreased VD in DCP and increased FAZ, the probability of PDR increases. Despite the sensitivity and specificity of the OCTA indices for the prediction of NVE being moderate, the OCTA is very useful in evaluating the microvascular structure in DR.

Robust non-perfusion area detection in three retinal plexuses using convolutional neural network in OCT angiography.

Non-perfusion area (NPA) is a quantitative biomarker useful for characterizing ischemia in diabetic retinopathy (DR). Projection-resolved optical coherence tomographic angiography (PR-OCTA) allows visualization of retinal capillaries and quantify NPA in individual plexuses. However, poor scan quality can make current NPA detection algorithms unreliable and inaccurate. In this work, we present a robust NPA detection algorithm using convolutional neural network (CNN). By merging information from OCT angiograms and OCT reflectance images, the CNN could exclude signal reduction and motion artifacts and detect the avascular features from local to global with the resolution preserved. Across a wide range of signal strength indices, and on both healthy and DR eyes, the algorithm achieved high accuracy and repeatability.

Three-dimensional structural and angiographic evaluation of foveal ischemia in diabetic retinopathy: method and validation.

Optical coherence tomography angiography (OCTA) allows us to noninvasively investigate foveal ischemia, a key feature of diabetic retinopathy (DR). However, the sizes of the foveal avascular zone (FAZ) have a significant variation in normal population, preventing the objective assessment of pathological enlargement of FAZ due to capillary dropout. Based on the relationship between FAZ and ganglion cell complex (GCC) thickness in normal eyes, we defined a theoretical baseline FAZ (tbFAZ) on structural OCT and measured 2D and 3D vessel density in its vicinity on the simultaneously acquired OCTA in normal and diabetic eyes. We found that the structure-based tbFAZ was a reliable reference to identify foveal ischemia and that the 3D vessel density demonstrated ischemia more effectively than the 2D method. The proposed 3D para-FAZ vessel density correlates well with DR severity and potentially is a useful diagnostic biomarker, especially in the early stages of DR.

Central retinal thickness following panretinal photocoagulation using a multispot semi-automated pattern-scanning laser to treat ischaemic diabetic retinopathy: Treatment in one session compared with four monthly sessions.

To compare central retinal thickness (CRT) after panretinal photocoagulation (PRP) with a multispot semi-automated PAttern-SCAnning Laser (PASCAL) in one session (SS-PRP) versus four monthly sessions (MS-PRP) in diabetic retinopathy. Multicentre, prospective, randomized, single-blinded, controlled trial evaluating the noninferiority of SS-PRP versus MS-PRP for CRT measured with macular spectral-domain optical coherence tomography (SD-OCT), with a 9-month follow-up in patients presenting severe nonproliferative diabetic retinopathy (DR) or mild proliferative DR without macular oedema (ME) at baseline. Ninety-seven eyes of 97 participants with a mean age of 57.0±14.2years wereincluded. The mean change of CRT from baseline to 9months was not statistically different in SS-PRP or in MS-PRP: +16.9±28.3μm versus +24.7±31.8μm, respectively (p=0.224). The variation in mean best-corrected visual acuity (BCVA) from baseline to 9months was similar in both groups: -1.1±6.5 letters versus -0.6±6.2 letters (p=0.684). The number of patients with stabilization of DR was not statistically different between the two groups. No severe complication was recorded in either group. This study showed the noninferiority of PRP performed in one session versus four monthly sessions with a PASCAL concerning central retinal thickness for treating mild proliferative or severe nonproliferative DR without ME at baseline.

CHARACTERIZATION OF THE MIDDLE CAPILLARY PLEXUS USING OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY IN HEALTHY AND DIABETIC EYES.

To assess the ability of optical coherence tomography angiography to image the retinal middle capillary plexus (MCP), and to characterize the MCP as a unique vascular network separate from the superficial and deep capillary plexus (DCP). Healthy and diabetic eyes were imaged using the Avanti XR optical coherence tomography angiography instrument (Optovue Inc, Fremont, CA). Using manual segmentation of the retinal layers, the authors generated en face angiograms to distinguish the three capillary plexuses (superficial capillary plexus, MCP, DCP). In healthy eyes, arterioles gave rise to distinct branches in the MCP, and venules gave rise to prominent vortex like branches in the DCP. The foveal avascular zone was most well-defined at the level of the MCP, and had a larger area in the DCP. In diabetic eyes, the three capillary plexuses showed varying degrees of nonperfusion, including variable shapes and extent of the foveal avascular zone, with loss of border integrity at the MCP. Microaneurysms appeared in all the three capillary plexuses. Using customized segmentation analysis in optical coherence tomography angiography, the authors demonstrate that the MCP is qualitatively and functionally distinct from the superficial capillary plexus and DCP, which may help clarify the pathogenesis of different middle retinal ischemic entities and provide new insights into retinal ischemia in diabetic retinopathy.

A Computational Model of Peripheral Photocoagulation for the Prevention of Progressive Diabetic Capillary Occlusion.

We developed a computational model of the propagation of retinal ischemia in diabetic retinopathy and analyzed the consequences of various patterns and sizes of burns in peripheral retinal photocoagulation. The model addresses retinal ischemia as a phenomenon of adverse local feedback in which once a capillary is occluded there is an elevated probability of occlusion of adjacent capillaries resulting in enlarging areas of retinal ischemia as is commonly seen clinically. Retinal burns of different sizes and patterns, treated as local oxygen sources, are predicted to have different effects on the propagation of retinal ischemia. The patterns of retinal burns are optimized with regard to minimization of the sum of the photocoagulated retina and computer predicted ischemic retina. Our simulations show that certain patterns of retinal burns are effective at preventing the spatial spread of ischemia by creating oxygenated boundaries across which the ischemia does not propagate. This model makes no statement about current PRP treatment of avascular peripheral retina and notes that the usual spot sizes used in PRP will not prevent ischemic propagation in still vascularized retinal areas. The model seems to show that a properly patterned laser treatment of still vascularized peripheral retina may be able to prevent or at least constrain the propagation of diabetic retinal ischemia in those retinal areas with intact capillaries.

Ischemic diabetic retinopathy as a possible prognostic factor for chronic kidney disease progression

To assess the value of diabetic retinopathy (DR) severity as a possible predictive prognostic factor for the progression of chronic kidney disease (CKD). Retrospective cohort study. Patients (51) who were initially diagnosed with DR and CKD were enrolled and their medical records were evaluated. The following ophthalmic factors were assessed by fluorescein angiography at the initial visit: area of capillary nonperfusion, presence of neovascularization and vitreous hemorrhage, and DR grade. The effect of these factors on CKD progression over the 2-year period of the study, defined as doubling of serum creatinine or the development of end-stage renal disease requiring dialysis or renal transplant, was evaluated. The study included 51 patients with DR and CKD; of these, 11 patients (21.6%) were found to have proliferative DR (PDR) and seven patients (13.7%) had high-risk PDR at baseline. Patients with ischemic DR, who showed extensive capillary nonperfusion (≥ 10 optic disc areas) in the retina, had a greater risk for CKD progression (hazard ratio = 6.64; P = 0.002). We found that extensive capillary nonperfusion in the retina greatly increased the risk of progression of CKD in patients with DR. This suggests that the retina and the kidney may have shared risk factors for microvascular disease secondary to diabetes mellitus, and emphasizes the need for a team approach to diabetes care.

Patterns of Peripheral Retinal and Central Macula Ischemia in Diabetic Retinopathy as Evaluated by Ultra-widefield Fluorescein Angiography

To investigate the association between peripheral and central ischemia in diabetic retinopathy. Retrospective, cross-sectional. Consecutive ultra-widefield fluorescein angiography images were collected from patients with diabetes over a 12-month period. Parameters quantified include the foveal avascular zone (FAZ) area, peripheral ischemic index, peripheral leakage index, and central retinal thickness measurements, as well as visual acuity. The peripheral ischemia or leakage index was calculated as the area of capillary nonperfusion or leakage, expressed as a percentage of the total retinal area. Forty-seven eyes of 47 patients were included. A moderate correlation was observed between the peripheral ischemia index and FAZ area (r = 0.49, P = .0001). A moderate correlation was also observed between the peripheral leakage index and FAZ area, but only in eyes that were laser naïve (r = 0.44, P = .02). A thinner retina was observed in eyes with macular ischemia (217 ± 81.8 μm vs 272 ± 36.0 μm) (P = .02), but not peripheral ischemia (258 ± 76.3 μm vs 276 ± 68.0 μm) (P = .24). The relationships between different patterns of peripheral and central macular pathology and visual acuity were evaluated in a step-wise multivariable regression model, and the variables that remained independently associated were age (r = 0.33, P = .03), FAZ area (r = 0.45, P = .02), and central retinal thickness (r = 0.38, P = .01), (R(2)-adjusted = 0.36). Ultra-widefield fluorescein angiography provides an insight into the relationships between diabetic vascular complications in the retinal periphery and central macula. Although we observed relationships between ischemia and vascular leakage in the macula and periphery, it was only macular ischemia and retinal thinning that was independently associated with a reduced visual function.

Preserve the (intraocular) environment: the importance of maintaining normal oxygen gradients in the eye

Oxygen levels in the eye are generally low and tightly regulated. Oxygen enters the eye largely by diffusion from retinal arterioles and through the cornea. In intact eyes, oxygen from the retinal arterioles diffuses into the vitreous body. There is a decreasing oxygen gradient from the retina to the lens, established by oxygen consumption by ascorbate in the vitreous fluid and lens metabolism. Age-related degeneration of the vitreous body or removal during vitrectomy exposes the posterior of the lens to increased oxygen, causing nuclear sclerotic cataracts. Lowering oxygen in the vitreous, as occurs in patients with ischemic diabetic retinopathy, protects against cataracts after vitrectomy. Vitrectomy and cataract surgery increase oxygen levels at the trabecular meshwork and with it the risk of open angle glaucoma. Two additional risk factors for glaucoma, African heritage and having a thinner cornea, are also associated with increased oxygen in the anterior chamber angle. Preservation of the vitreous body and the lens, two important oxygen consumers, would protect against nuclear sclerotic cataracts and open angle glaucoma. Delaying removal of the lens for as long as possible after vitrectomy would be an important step in delaying ocular hypertension and glaucoma progression.

Zytokinbestimmung aus Glaskörperproben bei retinalen Gefäßerkrankungen

The aim of this study was to determine cytokine levels from vitreous samples of treatment-naive patients with diabetic retinopathy (DRP), retinal vein occlusion (RVO) and exudative age-related macular degeneration (ARMD). In this study 187 patients (median age 67 years, 101 males) were treated with a combined drug therapy including a 23-gauge core vitrectomy. Interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) and intravitreal vascular endothelial growth factor (VEGF-A) levels were determined a using cytometric bead assay (CBA) and compared to those of the control group. Compared to the control group all diseases had significantly elevated cytokine levels, except VEGF in ARMD. In DRP samples of patients with diffuse diabetic macula edema (DME) higher VEGF-A and MCP-1 levels were found than in patients with focal DME. Ischemic DRP had higher VEGF levels than non-ischemic DRP. All measured cytokines were significantly higher in central retinal vein occlusion (CRVO) than in branch retinal vein occlusion (BRVO). Differences in intravitreal cytokine levels in DRP, RVO and ARMD could be demonstrated. The knowledge of depicted specific characteristic dysregulation of cytokines could allow more targeted future therapies.

ISCHEMIC DIABETIC RETINOPATHY MAY PROTECT AGAINST NUCLEAR SCLEROTIC CATARACT

ISCHEMIC DIABETIC RETINOPATHY MAY PROTECT AGAINST NUCLEAR SCLEROTIC CATARACT

Ischemic Diabetic Retinopathy May Protect against Nuclear Sclerotic Cataract

To determine whether diabetes mellitus is protective for nuclear sclerotic cataract at baseline and 6 and 12 months after vitrectomy surgery. Prospective, interventional cohort study. Phakic diabetic and nondiabetic patients undergoing vitrectomy surgery for a variety of retinal conditions underwent Scheimpflug lens photography in the operated and fellow eye at baseline and at 6 and 12 months after vitrectomy surgery. Of 52 eyes included in the analysis, 23 eyes were from diabetic patients, 14 of which had surgery for ischemic retinopathy. At baseline, eyes with ischemic diabetic retinopathy had less nuclear sclerotic cataract than nonischemic diabetic and nondiabetic eyes. This was true for eyes undergoing vitrectomy surgery (P = .0001) and for fellow eyes (P = .003). Nuclear sclerotic cataract developed after vitrectomy surgery in nonischemic diabetic eyes and nondiabetic eyes at the same rate. Diabetic eyes with ischemic retinopathy showed no significant progression of nuclear opacification, and therefore had significantly less postvitrectomy nuclear cataract at 6 months (P < 1 × 10(-6)) and at 12 months (P < .001) than nondiabetic or nonischemic diabetic eyes. Normalizing to baseline opacity and adjusting for age and other comorbidities did not alter this result. Ischemic diabetic retinopathy, not just systemic diabetes mellitus, protected against nuclear sclerotic cataract at baseline and after vitrectomy surgery. These findings are consistent with the hypothesis that increased exposure to oxygen is responsible for nuclear cataract formation.

Ultrastructure of Rapidly Proliferating Preretinal Membrane of Very Extensive Ischemic Diabetic Retinopathy

Purpose: Using transmission electron microscopy (TEM), we studied the ultrastructures of rapidly proliferating preretinal membranes of young patients with very extensive ischemic proliferative diabetic retinopathy and diabetes with uncontrollable blood sugar level. Methods: Nine cases of preretinal membranes were obtained from six eyes of five patients with rapidly progressed proliferative diabetic retinopathy (mean age, 35 years) during vitrectomy. We obtained each preretinal membrane bimanually as one single sheet membrane using intraocular scissors and forceps. Each tissue was fixed in 3% glutaraldehyde in the operating room. All specimens were prepared and studied using TEM. Results: The preretinal membranes were composed of blood vessels and some interstitial cells. The blood vessels within the preretinal membranes varied in developmental stages, from the immature stage to the mature stage. The blood vessels were highly active, in that primitive cells showed a large nucleus and prominent chromatin clumping with abundant cytoplasm. Highly active fibroblast-like cells were also noted. Conclusions: We observed highly active angiogenesis in preretinal membranes, which rapidly proliferated in cases of severe retinal ischemia in young diabetes patients. This is the first report of such a finding, which may help to explain the poor prognosis of this disease modality.

Regulation of Pigment Epithelium–Derived Factor Production and Release by Retinal Glial (Müller) Cells under Hypoxia

To assess the regulation of pigment epithelium-derived factor (PEDF) production by retinal Müller glial cells, especially under ischemic or hypoxic conditions. PEDF was determined in surgically excised retinal tissue originating from patients with ischemic diabetic retinopathy and in primary guinea pig Müller cell cultures exposed to the protein synthesis inhibitor cycloheximide (CHX) and to hypoxia. PEDF production and secretion were studied by immunohistochemistry, quantitative RT-PCR, ELISA, fluorescence-activated cell sorter analysis, and Western blotting. Gliotic Müller cells displayed decreased PEDF immunoreactivity in fibrovascular tissue from patients with diabetes compared with tissue from subjects with pathologic myopia. In Müller cell cultures, CHX treatment resulted in an increase, whereas mild hypoxia (2.5%-10% O(2)) induced a decrease, of PEDF mRNA and protein levels. However, strong hypoxia (0.2% O(2)) induced an upregulation of PEDF mRNA expression and resulted in only slightly reduced PEDF levels after 24 hours, detected as either a released, soluble, or cell surface-linked protein. These results suggest that under certain conditions including mild hypoxia, Müller cells synthesize a protein factor that downregulates PEDF expression or its turnover. Generally, the cells appear to generate a biphasic response to hypoxia. In moderate hypoxia, PEDF is downregulated such that the VEGF-to-PEDF ratio increases (and angiogenesis is facilitated). During severe (or chronic) oxygen deficiency, however, the PEDF decline is arrested or even reversed; thus, the neurotrophic effects of PEDF remain available.

Serum Inflammatory Markers in Diabetic Retinopathy

To evaluate the association of serum factors with the severity of diabetic retinopathy and to assess their presence in retinal tissue obtained at autopsy. The following serum factors of 93 subjects were examined at the National Eye Institute (NEI) clinical center: the chemokines regulated on activation, normal T-cell expressed and presumably secreted (RANTES)/CCL5, epithelial neutrophil activator (ENA)-78/CXCL5, interferon-induced protein (IP)-10/CXCL10, stromal cell-derived factor (SDF)-1alpha/CXCLl2, monocyte chemoattractant protein (MCP)-1/CCL2, macrophage inflammatory protein (MIP)-1alpha/CCL3, interleukin (IL)-8/CXCL8; the cytokine IL-6; the cell adhesion molecules intercellular adhesion molecule (ICAM-1/CD54) and vascular cell adhesion molecule (VCAM/CD106); and the growth factor vascular endothelial growth factor (VEGF). Logistic regression was performed to assess the association of these factors with age, sex, severity of retinopathy, hemoglobin A(1C), total cholesterol, creatinine, duration of diabetes, and presence of macular edema. The outcome assessed was severity of retinopathy. Frozen sections of two donor eyes obtained at autopsy from a donor with documented severe nonproliferative diabetic retinopathy and diabetic macular edema and of a normal nondiabetic eye were processed by immunoperoxidase staining with primary antibodies against RANTES, MCP-1, ICAM-1, and LFA-1alpha/CD11a. The levels of RANTES and SDF-1alpha were significantly elevated in patients with at least severe nonproliferative diabetic retinopathy compared with those with less severe diabetic retinopathy (P < 0.001 and 0.007, respectively). Positive immunostaining was observed in the inner retina for MCP-1 and RANTES of the patient with diabetes. Staining was strongly positive throughout the diabetic retina for ICAM-1. Normal retinal tissues showed little reactivity. Serum chemokines were significantly elevated in patients with at least severe nonproliferative diabetic retinopathy compared with those who had less severe retinopathy. Elevated levels of the chemokines and cell adhesion molecules were also identified in eyes of a donor with ischemic diabetic retinopathy. These findings provide evidence to support the role of inflammation in the pathogenesis of diabetic retinopathy.

Effect of camonagrel, a selective thromboxane synthase inhibitor, on retinal vascularization in experimental diabetes

Platelet hyperactivity accompanied by an increased synthesis of thromboxane and/or a decreased prostacyclin production are important factors in ischemic diabetic retinopathy. We studied the effect of camonagrel and dazoxiben, two thromboxane synthase inhibitors, on retinal vascularization in a model of streptozotocin-induced diabetes in rats. Ten nondiabetic rats, 10 diabetic animals treated with saline (i.e., not treated), and 60 diabetic animals treated with dazoxiben or camonagrel (10, 50 or 100 mg kg −1 day −1 p.o.) were studied. All treatments lasted for 90 days. Dazoxiben and camonagrel produced a dose-dependent reduction in platelet aggregation and thromboxane synthesis. Dazoxiben increased prostacylin synthesis by 78% at 100 mg kg −1 day −1, and camonagrel by 154%. Dazoxiben increased retinal vascularity by 74%, and by 183% after camonagrel treatment. Prostacyclin synthesis showed a direct linear correlation with the degree of retinal vascularization ( r 2=0.6733, P<0.00001). We conclude that an increased prostacyclin synthesis may have a greater influence than the inhibition of thromboxane synthesis in preventing ischemic diabetic retinopathy in experimental diabetes. Camonagrel may be an alternative treatment in the prevention of these lesions.

Retinal Oxygenation and Laser Treatment in Patients With Diabetic Retinopathy

The oxygen tension in the preretinal vitreous cavity was measured in human patients undergoing vitreous operations for proliferative diabetic retinopathy. The oxygen tension was significantly higher (P = .004) over areas of retina that had been treated with panretinal photocoagulation than it was over untreated areas in the same retina. This confirmed previous results in animals that showed that panretinal photocoagulation increases the inner retinal oxygen tension. We concluded that panretinal photocoagulation improves the oxygen supply to the inner retina and thereby minimizes the influence of retinal ischemia in diabetic retinopathy.

Severe diabetic retinopathy at presentation in a young man

A 22 year old man presented with a severe ischaemic diabetic retinopathy and, in spite of photocoagulation therapy, was blind in one eye 16 months after diagnosis. Four similar cases of aggressive diabetic retinopathy are reviewed. There is increasing evidence that a small group of young men with insulin dependent diabetes (IDD) may develop severe diabetic retinopathy at, or soon after, diagnosis.

Relationship between retinal ischemia and cardiovascular autonomic damage in diabetes.

In order to investigate the relationship between ischemic diabetic retinopathy and cardiac autonomic dysfunction we studied 40 diabetic patients (mean age +/- SEM: 48 +/- 2 years). Retinopathy was evaluated by fluorescein angiography and patients were divided into three groups: a) with ischemic retinopathy (15 patients), b) with edematous retinopathy (13 patients) and c) without retinopathy (12 patients). Cardiac autonomic function was assessed by 4 tests based on cardiovascular reflexes (heart rate response to Valsalva maneuver and to deep breathing; systolic blood pressure fall after standing and diastolic blood pressure rise during handgrip) and by the cross-correlation test, a computerized technique for the analysis of respiratory sinus arrhythmia based on spectral analysis of electrocardiographic and respiratory signals. Abnormalities of cardiac autonomic tests were present in 26/40 patients (65%); considering the retinal angiographic classification, autonomic test abnormalities were found in 13/15 (86.6%) patients with ischemic retinopathy, in 7/13 (53.9%) patients with edematous retinopathy and in 6/12 (50%) patients without retinopathy. The prevalence of cardiac autonomic dysfunction was significantly higher (p less than 0.005) in the ischemic retinopathy group compared to the other groups. These results show a strong association between ischemic retinopathy and cardiac autonomic dysfunction.