Oftalmologia
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- Pathophysiology of diabetic retinopathyPublication . Cunha-Vaz, JGAfter a brief analysis of the pathological picture of diabetic retinopathy, of which only the topographical distribution of the vascular lesions appears to be specific, the results obtained with 2 new methods of study of the retinal circulation, are presented. These methods are vitreous fluorophotometry and fluorometric determination of segmental retinal blood flow. Vitreous fluorophotometry has shown that a disturbance of the blood-retinal barrier, possibly functional, appears in diabetic eyes before any lesion is clinically visible in the fundus, and that there is a close correlation between the severity of the vascular lesions and higher vitreous fluorophotometry readings. Blood flow studies have shown that in diabetes the retinal blood flow increases markedly with progress of background retinopathy, decreasing finally where proliferative retinopathy, with marked arteriolar narrowing, is present. On the basis of these findings a working hypothesis for the pathogenesis of diabetic retinopathy is presented.
- Microperfusion studies on the permeability of retinal vessels. A new model demonstrating organic anion transport and a reabsorptive fluid fluxPublication . Murta, JN; Cunha-Vaz, JG; Sabo, CA; Jones, CW; Laski, MEWe developed an experimental model to study the permeability of individual retinal vessels in vitro using microperfusion techniques adapted from kidney tubule studies. The retinal vessels were isolated by freehand dissection and mounted on a microperfusion apparatus. When inulin was perfused luminally, it was diluted to 80.2 +/- 2.3% of its initial concentration. However, no radioactive leak into the bath side was observed, suggesting that the dilution was due to fluid flux from bath to lumen. The dilution of fluorescein (81.9 +/- 3.8%) was in the same range as that of inulin, the reference marker. The extremely low lumen-to-bath fluorescein flux, 0.5 +/- 0.9 X 10(-12) mol/min/mm, increased by 68% when probenecid was added to the perfusate and by 210% when probenecid was placed in the bath. The effect was concentration-dependent. When placed in the bath, fluorescein moved rapidly across the retinal vessel walls, accumulating in the lumen to concentrations 40 times higher than in the bath. This movement from bath to lumen, which was much higher (13.6 +/- 0.3 X 10(-12) mol/min/mm) than the lumen-to-bath fluorescein flux for the same fluorescein concentration, decreased by adding probenecid to the bath. The kinetics of this unidirectional movement of fluorescein were consistent with a saturable active transport process. The fluid flux from bath to lumen across the retinal vessels, which was 6.3 +/- 1.0 nl/min/mm for perfusion rates of 6.6 +/- 0.2 nl/min, was temperature-dependent and was coupled to the fluorescein transport. Fluorescein stimulated the fluid flux by 17% when added to the perfusate and by 60% when added to the bath, and this effect could be reversed by probenecid. Our results showed an active transport of fluorescein in the rabbit retinal vessels coupled with net fluid flux from outside the vessels into the lumen.
- Studies on the pathophysiology of diabetic retinopathy. The blood-retinal barrier in diabetesPublication . Cunha-Vaz, JGA review of the pathologic picture of diabetic retinopathy shows that available clinical methods of examination demonstrate the alteration of the blood-retinal barrier (leakage), microaneurysms, capillary closure, preferential channels, preretinal neovascularization and gross extravascular lesions. All of these changes may be shown by fluorescein angiography. The value of this method, however, is fundamentally related to the morphologic demonstration of these lesions and not their quantification. Quantitative evaluation of retinal involvement in diabetes is needed in order to delineate more clearly its natural history, criteria for prognosis, and effect of treatment. Vitreous fluorophotometry, a quantitative and sensitive method of evaluating the permeability of the blood-retinal barrier, has opened new perspectives for the evaluation of retinal involvement in diabetes. Vitreous fluorophotometry has shown that a disturbance of the blood-retinal barrier, possibly functional, appears in diabetic eyes before any lesion is clinically visible in the fundus, and that there is a close correlation between the severity of the vascular lesions and higher vitreous fluorophotometry readings. Recent studies also indicate an interesting correlation with metabolic control, particularly, glycosylated hemoglobin levels and insulin treatment. Finally, on the basis of these findings a working hypothesis for the pathogenesis of diabetic retinopathy is presented.
- Blood-retinal barrier permeability and its relation to progression of retinopathy in patients with type 2 diabetes. A four-year follow-up study.Publication . Cunha-Vaz, JG; Leite, E; Sousa, JC; Faria de Abreu, JRForty patients with late-onset diabetes (age at diagnosis 30 years or more) and minimal retinopathy as found by fundus photography were followed prospectively by repeated examination (baseline, 1 year, and 4 years). The study shows that early retinopathy changes are not permanent or invariably progressive. In the 1st year of follow-up microaneurysms worsened in 25%, improved in 10%, and remained stabilized in 65%. Vitreous fluorometry was able to detect an overall increase of 0.84 +/- 1.06 x 10(-6) min-1 in blood-retinal barrier (BRB) penetration ratios. After 4 years, 16 of the 40 patients had undergone photocoagulation (focal photo-coagulation in 11 and pan retinal photocoagulation in 5). The eyes that needed photocoagulation were the eyes that had higher fluorometry penetration ratios at the patient's entry into the study and showed a higher rate of deterioration during the 1st year of the study (5.54 +/- 1.97 vs 3.11 +/- 1.22 x 10(-6) min-1, P < 0.001, initial values; 1.52 +/- 0.76 vs 0.45 +/- 0.99 x 10(-6) min-1, P < 0.001, annual increase in leakage). The eyes that did not need photocoagulation, 24 out of 40, showed stable fluorometry readings within the 4-year period of follow-up (+0.02 +/- 0.98 10(-6) min-1). Abnormally high vitreous fluorometry values and their rapid increase over time appear to be good indicators of rapid progression and worsening of the retinopathy.
- Cholesterol oxides accumulate in human cataractsPublication . Girão, H; Mota, MC; Ramalho, J; Pereira, PHuman lens membranes contain the highest cholesterol content of any known biological membrane. Although cholesterol is prone to oxidation, the presence of its oxidation products in human cataract has not been shown before. This study was designed to investigate the presence of cholesterol oxides in human cataractous lenses. Human clear lenses (n = 48) were obtained from Coimbra University Hospital Eye Bank. Human cataracts (n = 54) were obtained by routine extracapsular surgery. Cholesterol oxides were isolated by solid-phase extraction on a C18 cartridge and quantified as TMS-ether derivatives by gas chromatography. The extraction procedure allows for an efficient recovery of the major cholesterol oxides, while retaining virtually all cholesterol. Exposure of membranes isolated from transparent human lenses to the free radical generator 2,2'-Azobis(2-amidinopropane) dihydrochloride (AAPH) produced 7 alpha-hydroxycholesterol (6%), 7 beta-hydroxycholesterol (19%), 5 alpha, 6 alpha-epoxycholestanol (1%) and 7-ketocholesterol (74%) as major oxidation products. Cataractous lenses contained quantifiable amounts of 7 beta-hydroxycholesterol (7.3 +/- 0.74 mmol mol-1 cholesterol), 7-ketocholesterol (4.2 +/- 0.32 mmol mol-1 cholesterol), 5 alpha, 6 alpha-epoxycholestanol (0.9 +/- 0.16 mmol mol-1 cholesterol), 20 alpha-hydroxycholesterol (0.6 +/- 0.13 mmol mol-1 cholesterol) and 25-hydroxycholesterol (0.1 +/- 0.02 mmol mol-1 cholesterol), whereas clear lenses contained no detectable amounts of cholesterol oxides. We have shown, for the first time, that oxysterols accumulate in human cataracts. Although the total amount of oxidized cholesterol in cataracts is not likely to be high it may account for much of the membrane damage associated with cataract formation.
- Diabetic macular edemaPublication . Cunha-Vaz, JGRetinal edema is defined as any increase of water in retinal tissue resulting in an increase in its volume. This increase may be initially intracellular or extracellular. In the first case, there is cytotoxic edema. In the second, vasogenic edema, directly associated with an alteration of the blood-retinal barrier (BRB). Retinal thickness can now be measured, using the retinal thickness analyser (RTA). Similarly, local breakdown of the BRB can now be mapped using the retinal leakage analyser (RLA). The application of these methods to diabetic macular edema has shown that both types of retinal retinopathy edema occur in the initial stages of diabetic retinal disease. These observations suggest a role for neuroprotective and vasoprotective agents in the management of diabetic retinal disease.
- Progression of retinopathy and alteration of the blood-retinal barrier in patients with type 2 diabetes: a 7-year prospective follow-up studyPublication . Cunha-Vaz, JG; Lobo, CL; Sousa, JC; Leite, E; Faria de Abreu, JRBACKGROUND: The study was carried out to evaluate the correlation between blood-retinal barrier (BRB) permeability and the progression of diabetic retinopathy (DR), defined by development of "need for photocoagulation", over a 7-year period by means of vitreous fluorometry (VF). METHODS: Forty type 2 diabetic patients with minimal or no retinopathy, aged 40-65 years (mean 53.9 + 7.3 years), were followed up prospectively for 7 years. Investigations including standard ophthalmological examination, fundus photography, fluorescein angiography and VF were performed at entry and 1, 4, 5 and 7 years later. Only one eye per patient was included in the study. Need for photocoagulation was based on Early Treatment Diabetic Retinopathy Study protocols and decided by the attending ophthalmologist. RESULTS: After 7 years of follow-up a total of 22 of the 40 eyes had received photocoagulation. The eyes that needed photocoagulation were those that had higher VF values at the entry of the study and showed higher rates of deterioration (initial values 5.1 + 1.9 vs 2.8 + 1.5 x 10(-6) min-1, P < 0.001; annual increase in leakage for the first year, 1.5 + 0.8 vs 0.5 + 1.0 x 10(-6) min-1, P < 0.001,). The eyes that did not need photocoagulation during the 7 years of follow-up showed stable VF readings (-0.1 + 1.2 x 10(-6) min-1, difference between initial values and 7 years later). CONCLUSIONS: Abnormally high VF values and their rapid increase over time are good indicators of progression and worsening of the retinopathy in diabetes type 2.
- Novel imaging techniques for diabetic macular edemaPublication . Lobo, CL; Bernardes, RC; Faria de Abreu, JR; Cunha-Vaz, JGRetinal edema should be defined as any increase of water of the retinal tissue resulting in an increase in its volume. It may be of cytotoxic or vasogenic origin. Development of vasogenic macular edema is dependent on a series of factors such as blood pressure, blood-retinal barrier permeability, retinal cell damage, retinal tissue osmotic pressure and retinal tissue compliance. Objective measurements of retinal thickness are now possible using the Retinal Thickness Analyser. Localised measurements of blood-retinal barrier permeability may also be obtained using the Retinal Leakage Analyser, a modified confocal scanning laser fluorometer, while obtaining simultaneously angiographic images of the choroid and retina. These new imaging techniques show that cytotoxic and vasogenic retinal edema may occur independently in the early stages of diabetic retinopathy. These findings offer new perspectives for designing novel therapeutic strategies.
- Alterations of the blood-retinal barrier and retinal thickness in preclinical retinopathy in subjects with type 2 diabetesPublication . Lobo, CL; Bernardes, RC; Cunha-Vaz, JGOBJECTIVE: To identify alterations of the blood-retinal barrier by mapping retinal fluorescein leakage into the vitreous and changes in retinal thickness occurring in the macular region in preclinical diabetic retinopathy. METHODS: Ten eyes from 10 patients with type 2 diabetes and no lesions visible on fundus photography (level 10 of Wisconsin grading) were examined with the retinal leakage analyzer (RLA) (Confocal Scanning Laser Ophthalmoscope [modified]; Carl Zeiss Inc, Thornwood, NY) and the retinal thickness analyzer (RTA) (Talia Technology, Mevaseret Zion, Israel). The maps of retinal leakage and retinal thickness were aligned and integrated in the same image to correlate leakage with thickness. Data from the group of individuals with diabetes were compared with those of a healthy control population (N = 14; mean age, 48 years; range, 42-55 years) and used to establish reference maps for the RLA and RTA. RESULTS: Areas of abnormally increased fluorescein leakage were detected in 9 of 10 eyes examined. The increased leakage in 6 (67%) of 9 eyes reached values higher than 40% more than the mean +2 SD RLA control value. Areas of abnormally increased thickness were found in 7 of 10 eyes examined. For the most part, the increases in retinal thickness were not severe (ie, <15% increase in 5 eyes and an 18% increase in 1 eye). The eyes with the most extensive leakage (cases 1, 3, and 9) showed relatively good coincidence between the location of the areas of increased leakage and the location of the areas of increased thickness. In 4 eyes (cases 2, 5, 7, and 8), no such correlation was apparent. The 3 remaining eyes showed little coincidence between these locations. Characteristically, the latter 3 eyes had areas of abnormally increased thickness that were much larger than the areas of increased fluorescein leakage, which were relatively moderate or absent of any leakage. CONCLUSIONS: Localized sites of increased fluorescein leakage and zones of increased retinal thickness were found in most eyes in a series of 10 eyes in the preretinopathy stage from 10 patients with type 2 diabetes. Increases in retinal thickness may be observed that do not coincide with sites of retinal leakage. Two types of increased retinal thickness may, therefore, be present in the preretinopathy stage of diabetic retinopathy, one directly associated with an alteration of the blood-retinal barrier, and another occurring without apparent breakdown of blood-retinal barrier.
- One-year follow-up of blood-retinal barrier and retinal thickness alterations in patients with type 2 diabetes mellitus and mild nonproliferative retinopathyPublication . Lobo, CL; Bernardes, RC; Faria de Abreu, JR; Cunha-Vaz, JGOBJECTIVE: To examine the 1-year alterations of the blood-retinal barrier and changes in retinal thickness occurring in the macular region in patients with type 2 diabetes mellitus and mild nonproliferative retinopathy. METHODS: We classified 12 eyes of 12 patients with type 2 diabetes mellitus and mild nonproliferative retinopathy by 7-field stereoscopic fundus photography, levels 20 and 35 of Wisconsin grading, and examined them 3 times, at 6-month intervals, by fluorescein angiography, retinal leakage analyzer (RLA) (modified confocal scanning laser ophthalmoscope), and retinal thickness analyzer. The maps of retinal leakage and retinal thickness were aligned and integrated into one image. Data from the group of individuals with diabetes were compared with those from a healthy control population (n = 14; mean age, 48 years; age range, 42-55 years) to establish reference maps for the RLA and the retinal thickness analyzer. RESULTS: Areas of abnormally increased fluorescein sodium leakage and increased thickness were detected in all eyes examined at baseline. The sites of increased fluorescein leakage reached values as high as 483% above normal, but in 10 of the total 36 examinations performed, fluorescein leakage returned to normal levels. A statistically significant correlation was found between changes in hemoglobin A(1c) values and variations in percentage of abnormal fluorescein leakage between the 6- and 12-month examinations (P<.001). When comparing the RLA-leaking sites among the 3 examinations, a good correlation was seen among the location of these sites of maximum leakage, but there was a clear fluctuation in the percentage of increases. A correlation was noted between the location of the RLA-leaking sites and the location of areas of increased retinal thickness in subsequent examinations, either 6 or 12 months later. Microaneurysms showed relatively little leakage and leaked progressively less in successive examinations. CONCLUSIONS: The dominant alteration in the retina of patients with type 2 diabetes mellitus and mild nonproliferative retinopathy is the presence of RLA-leaking sites, indicating spotty retinal vascular damage characterized by alteration of the blood-retinal barrier. This damage appears to be reversible and directly associated with variations in glycemic metabolic control. Retinal edema appears to develop mainly as a result of retinal vascular leakage.