Joan DuPont

Retinal haemodynamics in patients with early diabetes mellitus.

AIMS/BACKGROUND: The retinal circulation was investigated in a group of 19 patients with insulin dependent diabetes mellitus with less than 4 years of disease duration and no evidence of diabetic retinopathy. Results of these patients were compared with those of 16 age-matched normal controls. METHODS: Venous diameter (D) was measured from monochromatic fundus photographs. Maximum erythrocyte velocity (Vmax) was assessed by bidirectional laser Doppler velocimetry in the major retinal veins of one eye of each subject. Total volumetric blood flow rate (QT) was calculated by adding the flow rates of the major retinal veins. RESULTS: Average QT was 12% larger than normal in diabetic patients (one tailed, non-paired Students t test, p < 0.05). A statistically significant correlation was observed between QT and disease duration (r = 0.35, p < 0.04). Patients with longer disease duration tended to have somewhat larger QT. The average retinal vascular regulatory responses to hyperoxia were not significantly different from normal in diabetic patients. In these patients, however, higher blood glucose levels were associated with decreased regulatory responses to hyperoxia. CONCLUSIONS: Patients with diabetes mellitus of relatively short duration have mildly increased QT, suggesting that increased blood flow may play an early role in the development of diabetic retinal microangiopathy.

Optic nerve blood flow is diminished in eyes of primary open-angle glaucoma suspects.

PURPOSE The purpose of this study was to evaluate optic nerve blood flow in primary open-angle glaucoma suspect eyes with normal automated visual fields, in an attempt to elucidate how early in the glaucomatous disease process changes in optic nerve blood flow become apparent. METHODS Twenty-one eyes (21 patients) suspected of having primary open-angle glaucoma were studied prospectively and compared with a previously reported cohort of 22 eyes (22 patients) with primary open-angle glaucoma and 15 eyes (15 subjects) of age-matched controls. Primary open-angle glaucoma suspect eyes had untreated intraocular pressure greater than 21 mm Hg and normal visual fields using Humphrey program 24-2 or 30-2 with a full threshold strategy. Laser Doppler flowmetry was used to measure optic nerve head blood velocity, volume, and flow at four quadrants in the optic nerve, in the cup, and in the foveola of one eye of each patient. The mean flow from the superotemporal rim, inferotemporal rim, and cup was calculated (Flow(3)) and identified as the main outcome measure. Measurements from primary open-angle glaucoma suspect eyes were compared with corresponding measurements from controls and eyes with primary open-angle glaucoma; a Student t test was employed with a Bonferroni corrected P value of.025 to account for comparisons of primary open-angle glaucoma suspects both to controls and to eyes with primary open-angle glaucoma. RESULTS Compared with controls, Flow(3) was 24% lower in primary open-angle glaucoma suspect eyes (P <.0003). In primary open-angle glaucoma suspect eyes, flow was 16% lower in the superotemporal rim (P <.007), 35% lower in the cup (P <.007), and 22% lower in the inferotemporal neuroretinal rim (P <.029) compared with controls. No significant difference between primary open-angle glaucoma suspect and control eyes was seen in the inferonasal rim, superonasal rim, or foveola. No significant difference was detected at any location between primary open-angle glaucoma suspect eyes and eyes with primary open-angle glaucoma. CONCLUSIONS Laser Doppler flowmetry detected circulatory abnormalities in primary open-angle glaucoma suspects who did not have any manifest visual field defect. Decreases in flow in glaucoma suspects were similar in magnitude to those of subjects with primary open-angle glaucoma. These data suggest that impaired optic nerve blood flow develops early in the glaucomatous process and does not develop solely as a result of glaucoma damage.

Foveolar Choroidal Circulation and Choroidal Neovascularization in Age-Related Macular Degeneration

PURPOSE To investigate in a longitudinal study whether foveolar choroidal blood flow changes are associated with the development of choroidal neovascularization (CNV) in AMD. METHODS Relative foveolar choroidal blood velocity (ChBVel), volume (ChBVol), and flow (ChBFlow) were assessed in 135 patients with AMD, at baseline and then annually with laser Doppler flowmetry. All study eyes had visual acuity of 20/40 or better and no CNV at the time of enrollment. Comparison of foveolar choroidal circulatory measurements at baseline and their change before the development of CNV was made between eyes that had CNV and those that did not. RESULTS CNV developed in 28 eyes during the study. Baseline average foveolar ChBVol and ChBFlow in these eyes were 24% (P < 0.0001) and 20% (P = 0.0007) lower than that observed in the 165 eyes in which CNV did not develop. In the eyes with CNV, foveolar ChBVol and ChBFlow decreased by 9.6% and 11.5% before the formation of CNV, whereas in the eyes that did not, they increased by 6.7% (P = 0.006) and 2.8% (P = 0.004), respectively. Eyes with lower baseline foveolar ChBFlow were more likely (risk ratio = 3.47, 95% CI: 1.24-8.70) to show visual loss of three or more lines than were eyes with a higher baseline ChBFlow (P = 0.005). CONCLUSIONS The development of CNV and visual loss are associated with lower choroidal circulatory parameters at baseline. In addition, the results suggest that decreases in the foveolar choroidal circulation precede the development of CNV in AMD and may play some role in its development.

Retinal Hemodynamics in Retinitis Pigmentosa

PURPOSE To investigate the retinal hemodynamic changes occurring in patients with retinitis pigmentosa (RP). METHODS Bidirectional laser Doppler velocimetry and monochromatic fundus photography were used to determine retinal venous diameter (D), maximum erythrocyte velocity (Vmax), and volumetric blood flow (Q) in the major retinal veins of eight patients with RP and eight age-matched normal controls. The retinal vascular regulatory responses to hyperoxia, defined as the percent decreases in D (RD), Vmax (RVmax), and Q (RQ) at four to six minutes of breathing 100% oxygen, were determined in eight normal subjects and five RP patients. RESULTS Average D, Vmax, and Q +/- S.D. in the largest retinal vein of each subject were 106 +/- 14 microns, 1.01 +/- 0.20 cm/sec, and 3.5 +/- 1.3 microliters/min, respectively, in RP patients, and 166 +/- 12 microns, 1.79 +/- 0.14 cm/sec, and 14.7 +/- 2.6 microliters/min, respectively, in normal subjects. This corresponded to significant decreases from normal of 36% in D, 44% in Vmax, and 76% in Q in RP patients (Wilcoxons rank sum test, P < .001). Average total retinal volumetric blood flow rate was 8.2 +/- 2.9 microliters/min in RP patients and 37 +/- 4.9 microliters/min in normal subjects, corresponding to a significant decrease from normal of 78% (Wilcoxons rank sum test, P < .001). In RP patients, the regulatory responses to hyperoxia (RD, RVmax, and RQ) were similar to those observed in normal subjects. RESULTS Retinal blood flow is significantly decreased in patients with RP, probably as a result of vascular remodeling in response to reduced metabolic demand. The regulatory responses to hyperoxia are similar to those of normal subjects. Measurements of retinal blood flow may help assess the progression of the disease and the effects of treatment.

Effect of sildenafil citrate (viagra) on the ocular circulation

PURPOSE Sildenafil citrate induces vasodilation by enhancing the smooth muscle relaxant effects of nitric oxide. We have previously reported that nitrate compounds, a different group of nitric oxide-mediated vasodilators used mainly for the treatment of ischemic cardiac diseases, produce an increase in optic nerve head circulation and retinal venous vasodilation. The purpose of the present investigation was to evaluate the effect of sildenafil on ocular circulation. METHODS In a double-blind, randomized, crossover trial, 15 healthy male volunteers received 100-mg doses of sildenafil citrate (Viagra; Pfizer, Inc, New York, New York) or matching placebo on 2 separate days. Laser Doppler flowmetry was used to assess foveolar choroidal and optic nerve rim circulatory parameters. Measurements were obtained in one eye at baseline, 1 hour, and 5 hours after dosing. Blood pressure and intraocular pressure were monitored, and perfusion pressure was calculated. RESULTS Mean optic nerve head blood flow measurements at baseline, 1 hour, and 5 hours were 11.6 +/- 2.2 arbitrary units (+/- SD), 12.5 +/- 2.8, and 12.1 +/- 2.4 after sildenafil and 11.9 +/- 2.5, 12.6 +/- 3.1, and 13.0 +/- 3.0 after placebo, respectively. When compared with placebo, no significant change in mean blood pressure, intraocular pressure, perfusion pressure, or choroidal or optic nerve circulatory parameters were observed after sildenafil treatment. The power to detect a 20% change in optic nerve head and choroidal blood flow after sildenafil was approximately 90%. CONCLUSIONS In comparison with placebo, no significant change in optic nerve rim or foveolar choroidal blood flow was observed after treatment with sildenafil. This suggests that nitrate compounds and sildenafil may differentially affect ocular circulation. Furthermore, no significant effects on intraocular pressure, systemic blood pressure, or ocular perfusion pressure were detected after sildenafil treatment.

Submacular surgery trials randomized pilot trial of laser photocoagulation versus surgery for recurrent choroidal neovascularization secondary to age-related macular degeneration: I. Ophthalmic outcomes. Submacular Surgery Trials Pilot Study report number 1

PURPOSE To report complications and changes in vision during 2 years of follow-up of patients with age-related macular degeneration assigned randomly to surgical removal or to laser photocoagulation of subfoveal recurrent neovascular lesions in a pilot trial designed to test methods, to refine estimates of outcome rates, and to project patient accrual rates for a larger multicenter randomized trial to evaluate submacular surgery. PATIENTS AND METHODS Eligible patients with previous laser photocoagulation of extrafoveal or juxtafoveal choroidal neovascularization secondary to age-related macular degeneration were enrolled at 15 collaborating clinical centers. Assignments to treatment arm were made by personnel at a central coordinating center. Adherence to eligibility criteria and treatment assignment was assessed centrally at a photograph reading center. Patients were examined at 3, 6, 12, and 24 months after treatment for data collection purposes. Outcome measures reported include treatment complications, adverse events, requirements for additional treatment, and 2-year changes in visual acuity from baseline. RESULTS Of 70 patients enrolled, 36 were assigned to laser photocoagulation and 34 to submacular surgery; all were treated as assigned. One patient in each group died before the 2-year examination. Visual acuity was measured at the 2-year examination for 31 of the surviving patients (89%) in the laser arm and for 28 of the surviving patients (85%) in the surgery arm. The 2-year measurements for 36 of the 59 patients (61%) were made by an examiner masked to treatment assignment and to the identity of the study eye. Improvements and losses of visual acuity were observed in both treatment arms; 20 of 31 study eyes (65%) in the laser arm and 14 of 28 study eyes (50%) in the surgery arm had visual acuity 2 years after enrollment that was better than or no more than 1 line worse than the baseline level. Changes in visual acuity and the size of the central macular lesions from baseline to the 2-year examination were similar in the treatment arms. Few serious complications were observed in either arm at the time of initial treatment; serious adverse events were rare. During follow-up, 11 laser-treated eyes and 18 surgically treated eyes had additional intraocular procedures. CONCLUSIONS The data from this pilot trial suggest no reason to prefer submacular surgery over laser photocoagulation for treatment of patients with age-related macular degeneration who have lesions similar to those studied in this pilot trial. Any clinical trial designed to compare submacular surgery with laser photocoagulation in eyes with age-related macular degeneration and subfoveal recurrent neovascular lesions must enroll several hundred patients in order to reach a statistically valid conclusion regarding differences between these two methods of treatment with respect to either changes in visual acuity or complication rates.

Association of Risk Factors for Choroidal Neovascularization in Age-Related Macular Degeneration With Decreased Foveolar Choroidal Circulation

PURPOSE To investigate the relationship between known risk factors for age-related macular degeneration (AMD) progression and foveolar choroidal circulation in eyes with nonexudative AMD. DESIGN Cross-sectional study of nonexudative AMD. METHODS Laser Doppler flowmetry measurements of relative choroidal blood velocity, choroidal blood volume (ChBVol), and choroidal blood flow (ChBFlow) were obtained in the center of the fovea of 273 study eyes of 204 AMD patients investigated at the Scheie Eye Institute, University of Pennsylvania Medical School. All study eyes had visual acuity of 20/40 or better, good fixation, no other intraocular pathologic features, and no evidence of choroidal neovascularization. RPE hypertrophy was determined from color fundus photographs by trained masked graders at the Scheie Image Reading Center. Correlation analysis and multivariate linear regression analysis with adjustments for significant covariates were carried out. RESULTS A significant inverse correlation was observed between age and ChBFlow (r = -0.36; P < .0001), and ChBVol (r = -0.28; P < .0001), but not for choroidal blood velocity. A significant inverse correlation was observed between spherical equivalent and ChBFlow (r = -0.21; P = .006) and ChBVol (r = -0.14; P = .04), but not for choroidal blood velocity. ChBFlow and ChBVol were significantly lower in patients with a history of hypertension (P < or = .003) and in eyes with retinal pigment epithelium hypertrophy (P < or = .04), respectively. CONCLUSIONS All the above-described risk factors for AMD development and progression are associated with decreased choroidal circulatory parameters, suggesting that decreases in choroidal circulatory parameters may be involved in the development of AMD.

The Association Between Drusen Extent and Foveolar Choroidal Blood Flow in Age-Related Macular Degeneration

Purpose: To investigate the relationship between drusen extent and foveolar choroidal blood flow in nonexudative age-related macular degeneration. Methods: Total drusen area, average druse area, and total drusen number were determined using a computer program developed to quantify the extent of manually outlined drusen from fundus photographs of 157 patients (239 eyes) with nonexudative age-related macular degeneration. Laser Doppler flowmetry was used to assess relative choroidal blood velocity (ChBVel), volume (ChBVol), and flow (ChBFlow) in the center of the fovea. Results: We found a significant inverse relationship between total drusen area and ChBVol or ChBFlow. For every 1-mm2 increase in total drusen area, ChBVol decreased by 0.0061 arbitrary units (P = 0.03) and ChBFlow decreased by 0.23 arbitrary units (P = 0.049). Average druse area was also significantly inversely related to ChBVol and ChBFlow. For every 0.01-mm2 increase in average druse area, the ChBVol decreased by 0.0149 arbitrary units (P = 0.001) and the ChBFlow decreased by 0.4951 arbitrary units (P = 0.003). Adjustment for age weakened the significance, although it remained strong for average druse area versus ChBFlow (P = 0.017) and ChBVol (P = 0.004). The computer-aided quantification of drusen used in this study showed high intra- and intergrader agreement. Conclusion: In patients with nonexudative age-related macular degeneration, there is an association between increased drusen extent and decreased ChBVol and ChBFlow. This suggests the presence of ischemia and possibly the reason why patients with high-risk drusen are prone to advanced disease.

Foveolar Choroidal Hemodynamics in Proliferative Diabetic Retinopathy

Purpose: We studied the choroidal circulation in patients with proliferative diabetic retinopathy (PDR) to assess whether choroidal hemodynamic abnormalities may exist in PDR. Methods: Eighteen eyes of 18 patients with PDR and high-risk characteristics for visual loss were included in this study. Mean duration of diabetes was 20 ± 9 years (mean ± SD), hemoglobin A1c was 8.9 ± 2.3%, and blood glucose at the time of blood flow measurement was 188 ± 90 mg/dl. Choroidal circulatory parameters obtained in these patients were compared to those of 35 eyes of 35 age and blood pressure matched, healthy controls using a Wilcoxon rank sum test. Laser Doppler flowmetry (Oculix) was used to calculate relative choroidal blood velocity (Chvel), volume (Chvol), and flow (Chflow) in the center of the foveola. Results: No significant differences in average age, mean blood pressure (BPm), or perfusion pressure (PP) were observed between diabetic patients and control subjects. In diabetic patients, Chvol was 0.29 ± 0.08 (mean ± 1 SD) arbitrary units (AU); this value was 15% lower than that of control subjects, 0.34 ± 0.10 AU (p = 0.04). In contrast, average Chvel was not significantly different between subjects with PDR (0.39 ± 0.07 AU) and control subjects (0.41 ± 0.07 AU). The average Chflow in subjects with PDR (9.4 ± 2.9 AU) was 27% lower than that of control subjects (12.8 ± 4.2 AU; p = 0.003). No significant correlation was detected between the circulatory measurements and age, BPm, or PP. There was a statistically significant negative correlation between duration of diabetes and Chvel (R = −0.55; p = 0.03). Conclusions: Our results suggest that Chvol and Chflow are significantly reduced in patients with PDR.

The effect of pregnancy on retinal hemodynamics in diabetic versus nondiabetic mothers.

PURPOSE To investigate retinal circulatory changes that occur during the third trimester of pregnancy in diabetic patients and control subjects. METHODS Bidirectional laser Doppler velocimetry and monochromatic fundus photography were used to assess the retinal circulation in seven pregnant diabetic patients and 13 age-matched pregnant control subjects. Retinal venous diameter (D), maximum erythrocyte velocity (Vmax), and retinal volumetric blood flow rate (Q) were measured in one eye of each subject during the third trimester of pregnancy (DPREG, VmaxPREG, and QPREG, respectively). These measurements were repeated during the postpartum period for both diabetic patients (11+/-7 weeks postpartum) and control subjects (16+/-6 weeks postpartum; P = .203; DPOST, VmaxPOST, and QPOST). RESULTS In control subjects, DPREG was significantly reduced by -4.5%+/-4.4% (mean percent difference +/-1 standard deviation; paired t test, P =.006) relative to DPOST. In diabetic women, DPREG was also significantly reduced by -8.1%+/-3.2% compared with DPOST (P = .001), a change that was significantly larger than that seen in control subjects (unpaired t test; P = .035). Compared with QPOS T, QPREG was reduced by -7.1%+/-14.2% (P = .123), in control subjects. In diabe tic women, QPREG was significantly decreased by -18.4%+/-9.3% compared with QPOST (P = .012). This reduction in QPREG was significantly greater in diabetic patients than in nondiabetic control subjects (unpaired t test, P = .040). No significant differences between VmaxPREG and VmaxPOST were observed in either diabetic patients (-3.1%+/-12.9%; P =.400) or control subjects (+1.9%+/-14.4%; P = .787). CONCLUSIONS Retinal venous diameter is decreased during the third trimester of pregnancy in both diabetic and nondiabetic mothers. This decrease is significantly larger in diabetic than in nondiabetic mothers. In addition, we observed a reduction in retinal volumetric blood flow in diabetic patients during pregnancy that was significantly larger than that present in nondiabetic women. This fall in retinal volumetric blood flow in diabetic patients may exacerbate retinal ischemia and hypoxia and thus may be associated with the progression of diabetic retinopathy.