Foveolar choroidal blood flow in age-related macular degeneration.

PURPOSE: To compare measurements of the foveolar choroidal blood circulation in subjects with nonexudative, age-related macular degeneration (AMD) with those of control subjects. METHODS: Laser Doppler flowmetry was used to assess relative choroidal blood velocity (ChBVel), volume (ChBVol), and flow (ChBFlow) in the center of the fovea. Measurements were obtained in 20 eyes of 20 subjects with 10 or more large drusen, visual acuity of 20/32 or better, and no evidence of choroidal neovascularization. Findings obtained in these subjects were compared with those of 10 eyes of 10 age- and blood pressure-matched control subjects with no large drusen. Foveolar choroidal blood flow measurements were obtained by asking the study participants to fixate on a probing laser beam. RESULTS: No significant differences in average age, blood pressure, or intraocular pressure were observed between subjects with AMD and control subjects. In subjects with AMD, average ChBVol was 0.24 +/- 0.08 (+/- 1 SD) arbitrary units (AU); this value was 33% lower than that of control subjects (0.36 +/- 0.11 AU; two-tailed, independent Student's t-test, P = 0.005). Average ChBVel, conversely, was not significantly different from normal (0.44 +/- 0.07 AU) in subjects with AMD (0.44 +/- 0.10 AU). Average ChBFlow in subjects with AMD (8.7 +/- 3.1 AU) was 37% lower than that of control subjects (13.7 +/- 3.5 AU) (P = 0.0005). Average blood flow pulsatility was 6% higher in subjects with AMD (0.71 +/- 0.15) than in control subjects (0.66 +/- 0.14), but this difference was not statistically significant (P = 0.42). CONCLUSIONS: Average ChBFlow in the nonexudative stages of AMD is lower than that of age-matched controls, and the effect is caused mainly by a decrease in ChBVol. Further studies are needed to elucidate whether decreased ChBFlow plays a role in the development of choroidal neovascularization, and whether ChBFlow measurements may help identify subjects with AMD at risk for developing choroidal neovascularization.

Psychophysical evidence for rod vulnerability in age-related macular degeneration.

PURPOSE: To determine whether there is rod system dysfunction in the central retina of patients with age-related macular degeneration (AMD). METHODS: Dark-adapted sensitivity (500-nm stimulus) and light-adapted sensitivity (600 nm) were measured psychophysically at 52 loci in the central 38 degrees (diameter) of retina in 80 patients with AMD, and results were compared with those from older adult normal controls. All dark-adapted data were corrected for preretinal absorption. RESULTS: Mean field dark-adapted sensitivity was significantly lower in AMD patients as a group than in normal subjects. Within the AMD group were subsets of patients with normal mean dark- and light-adapted sensitivities; reduced dark-adapted sensitivities without detectable light-adapted losses; both types of losses; and, least commonly, only light-adapted losses. Regional retinal analyses of the dark-adapted deficit indicated the greatest severity was 2 degrees to 4 degrees or approximately 1 mm from the fovea, and the deficit decreased with increasing eccentricity. CONCLUSIONS: These psychophysical results are consistent with histopathologic findings of a selective vulnerability for parafoveal rod photoreceptors in AMD. The different patterns of rod and cone system losses among patients at similar clinical stages reinforces the notion that AMD is a group of disorders with underlying heterogeneity of mechanism of visual loss. Dark-adapted macula-wide testing may be a useful complement to the more traditional outcome measures of fundus pathology and foveal cone-based psychophysics in future AMD trials.

Pseudoxanthoma elasticum: high calcium intake in early life correlates with severity.

The characteristic histopathologic lesion of pseudoxanthoma elasticum (PXE) is calcification of the central core of elastic fibers in affected organs; it is correlated with clinical severity. One hypothesis holds that lowering dietary calcium might reduce or prevent tissue injury and minimize clinical effects. This hypothesis would be supported by demonstrating that clinical expression is positively associated with previous calcium intake. We studied 32 unrelated PXE patients (20 men and 12 women, mean age 43 years, SE = 14.2, range = 13-71) by grading their clinical severity and their presumed calcium intake during childhood, adolescence, and adulthood. Overall severity in the study group varied greatly and correlated positively with age (P less than 0.001). Overall severity correlated positively with calcium ingestion as an adolescent (P less than 0.001, with the other predictor variables held constant). Overall cardiovascular and eye severity were a function of age (P less than 0.000001 for both), whereas skin severity was not. These results confirm that PXE is a highly variable condition that generally worsens with age and support the rationale for a clinical trial to determine the effects of different levels of dietary calcium ingestion in young PXE patients on their subsequent clinical course.

Age-related macular degeneration and blindness due to neovascular maculopathy.

Age-related macular degeneration (AMD) is one of the four most common causes of blindness in the United States. Retinal manifestations of AMD can be categorized as either atrophic or neovascular/exudative. To the best of our knowledge, the proportion of patients legally blind due to the neovascular/exudative manifestations of this disease has not been previously reported. Data from two studies, the Framingham Eye Study and a large case-control study, demonstrate that the vast majority of patients with legal blindness due to AMD have the neovascular/exudative form of the disease. Seventy-nine percent of eyes legally blind due to AMD in the Framingham population and 90% of eyes legally blind due to AMD in the case-control study had neovascular/exudative retinopathy. This is in spite of the fact that neovascular/exudative retinopathy is a relatively infrequent complication of AMD.

The second eye of patients with senile macular degeneration.

Patients with senile macular degeneration and exudative maculopathy in one eye and drusen in the second eye have a 3% to 7% risk per year of exudative maculopathy developing in the second eye during the first three years following their initial presentation. The risk is the same for patients with new vessel membranes or other types of exudative maculopathy in the first eye. Second eyes in which exudative changes develop are more likely to have larger numbers of drusen or greater confluence of drusen (or both) initially. The data from this study were analyzed using the Kaplan-Meier technique of estimation, a method (to our knowledge) not previously employed by other investigators. The demographic features of the overall study population, as well as the photographic features associated with increased risk of development of exudative maculopathy, were in agreement with those previously reported.

Central serous chorioretinopathy and pregnancy.

BACKGROUND AND OBJECTIVE: Fourteen cases of central serous chorioretinopathy in pregnancy had been reported before this study was conducted. These cases have suggested a nonwhite predominance. Subretinal fibrinous exudates have been seen in 90% of the patients, compared with fewer than 20% of patients in typical (nonpregnant) central serous chorioretinopathy. No case has recurred outside of pregnancy, to our knowledge, and there have been no reports of subsequent pregnancies uninvolved by this disorder. These findings led us to collect our cases of central serous retinopathy in pregnancy because our experience differed from that of previous reports and provides additional new information. DESIGN: Case series. SETTING: The Wilmer Institute Retinal Vascular Center, Baltimore, Md. PATIENTS: Questionnaires sent to retinal faculty and fellows and a review of files revealed four patients, all included herein, with central serous chorioretinopathy presenting during pregnancy. RESULTS: All four patients were white. Three patients had subretinal fibrinous exudates and/or precipitates. All experienced resolution of the serous detachment near the end of the pregnancy or within the first few months after delivery. Only one patient had a subsequent pregnancy, and this was not complicated by the presence of central serous chorioretinopathy. One other patient experienced a recurrence 2 1/2 years after her last pregnancy. CONCLUSIONS: There may be no racial predominance in the development of central serous chorioretinopathy in pregnancy. Subretinal fibrinous exudates are quite common, independent of race. The uninvolved subsequent pregnancy suggests that recurrence in the context of pregnancy is not inevitable. This disorder may recur outside of pregnancy.

Presumed ocular histoplasmosis syndrome. A clinicopathologic correlation of a treated case.

A patient with bilateral presumed ocular histoplasmosis had been successfully treated in his symptomatic right eye with laser photocoagulation for subretinal neovascularization in two areas of the macula. The left eye also showed neovascularization clinically and histopathologically but was not treated because there was no detectable leakage and the vision was not affected. There was no change in the left eye over a two-year period. Clinicopathologic correlation of the treated and untreated macular lesions and the peripapillary and peripheral lesions is presented.

Flicker fusion thresholds in Best macular dystrophy.

Flicker fusion threshold intensities were measured as a function of flicker frequency for patients with Best macular dystrophy having normal or near-normal Snellen visual acuity. These data were found to differ from normal in ways that may be interpreted to be an abnormal elevation of the foveal cone threshold, a loss of cone temporal resolution, or both. The results led to the conclusion that Best macular dystrophy affects the neurosensory retina even when Snellen visual acuity is normal.

A histopathologic study of Best's macular dystrophy.

Light and transmission electron microscopic examinations of two postmortem eyes from an 80-year-old woman with clinically well-documented Best's macular dystrophy disclosed striking abnormalities in the retinal pigment epithelium (RPE), photoreceptors, and sub-RPE area. The RPE cells were flattened, with displacement of the nuclei toward the apex and diffuse deposition of abnormal lipofuscin and pleomorphic melanolipofuscin granules. A PAS-positive, acid-mucopolysaccharide-negative, electron-dense, finely granular material was deposited in the inner segments of the degenerating photoreceptors and the Mueller cells. An abnormal fibrillar material was present underneath and in close association with the RPE cells, just beneath the area of photoreceptor cell loss. The choriocapillaris was normal. Breaks in Bruch's membrane and neovascularization were noted in the foveolar region. There is evidence that the sensory-retinal changes are primary and that the RPE changes are secondary.

A model of the incidence and consequences of choroidal neovascularization secondary to age-related macular degeneration. Comparative effects of current treatment and potential prophylaxis on visual outcomes in high-risk patients.

OBJECTIVE: To describe the comparative impact of current and preventive treatments on incidence of choroidal neovascularization (CNV) and severe vision loss in patients with bilateral soft drusen (BSD). DESIGN: Stochastic model. SETTING: US population. PATIENTS: Prevalence cohort of white patients 43 years or older with BSD. INTERVENTIONS: Application of prophylaxis of 10% to 50% efficacy to 1 or both eyes of patients with BSD, application of laser photocoagulation to eligible CNV lesions, or both. MAIN OUTCOME MEASURES: Proportion of patients with BSD after 10 years with unilateral and bilateral CNV and resultant unilateral and bilateral vision loss to visual acuity of 20/200 or worse. RESULTS: The natural history of patients with BSD generated by the model shows that 12.40% of these patients develop either unilateral or bilateral CNV within 10 years of their entry into the BSD prevalence cohort. Bilateral disease occurs in 3.86% of patients with BSD within 10 years. The proportion of patients with BSD becoming legally blind from CNV within 10 years is 2.54% if no treatment is performed. Current laser treatment for CNV decreases the proportion with legal blindness within 10 years to 2.24%. The addition of a preventive treatment of 10% efficacy applied bilaterally to the current laser treatment regimen decreases the proportion with legal blindness to 1.86%; a 25% effective preventive treatment decreases it to 1.34%. Comparatively, preventive treatment of 10% and 25% efficacy given to the fellow eye only after the first eye has developed CNV decreases the proportion of legally blind patients at 10 years only to 2.06% and 1.77%, respectively. All outcomes vary with sex and age at entry into the BSD cohort. CONCLUSIONS: Patients with BSD face a 12.40% risk of developing CNV within 10 years. The addition of even a modest (10% effective) bilateral preventive treatment to the current regimen for CNV would more than double the prevention of legal blindness in the BSD population relative to current laser treatment; a preventive treatment of 33% efficacy more than halves the rate of legal blindness caused by CNV. Preventive treatment given to the fellow eye only after the first develops CNV has substantially less impact.

Contrast sensitivity in age-related macular degeneration.

Low-contrast charts were used to investigate the possibility that patients with drusen have visual deficits not detected by standard Snellen charts. We compared performance on Regan letter charts between 52 eyes with drusen and Snellen acuity of 20/20 and 27 control eyes. The drusen group read fewer letters than the control group on all of the charts tested. This difference increased as the contrast of the charts decreased. The loss of performance on all of the Regan charts correlated with drusen severity. Twenty-one eyes with drusen and normal Snellen acuity also were tested with a Ginsburg contrast sensitivity chart and compared with age-matched normal controls. The results showed a loss of contrast sensitivity at high spatial frequencies and a loss of peak contrast sensitivity with increasing drusen severity. These results suggest that in patients with drusen, low-contrast charts may be useful for measuring visual loss not detected by standard Snellen charts.

Loculated fluid. A previously undescribed fluorescein angiographic finding in choroidal neovascularization associated with macular degeneration. Macular Photocoagulation Study Reading Center.

The Foveal Photocoagulation Study, a component of the Macular Photocoagulation Study, is designed to evaluate whether laser treatment can reduce the risk of severe visual loss in eyes with well-defined choroidal neovascular membranes associated with macular degeneration that extend through the foveal center. On one third of the 554 baseline angiograms of study patients enrolled in and whose eyes were graded in the study as of January 31, 1990, the Reading Center staff has noted an unusual pattern of hyperfluorescence in the late-transit frames that has not been described previously. This pattern, which we call "loculated fluid," consists of a well-demarcated area of hyperfluorescence that appears to represent pooling of fluorescein in a compartmentalized space anterior to the choroidal neovascular leakage. Although the loculated fluid may conform to a pattern of typical cystoid macular edema, it can also pool within an area deep to the sensory retina in a shape that does not bear any resemblance to cystoid macular edema. This pattern is important to recognize because it (1) should not be confused with the angiographic pattern or extent of choroidal neovascularization and (2) should be differentiated from a serous detachment or tear of the retinal pigment epithelium.

Peripheral retinal function in age-related macular degeneration.

Aging changes are seen histopathologically outside the central retina, but have not been correlated with the presence of age-related macular degeneration (AMD). We studied 21 patients with drusen and AMD to see if peripheral retinal function changes are correlated with changes in the central retina. Electrooculogram Arden ratios were normal. Intensity-response analysis of dark-adapted electroretinogram b-waves and analysis of flicker electroretinograms were normal except for a small sensitivity loss presumed to reflect aging and lens yellowing. There was no difference between patients' severely involved AMD eye and their fellow eye with only drusen. Static perimetry showed sensitivity loss in the central 20 degrees, but normal thresholds peripheral to this. These results suggest that retinal function abnormalities in AMD are confined to the central retina, and the small age-related peripheral changes found do not correlate with the degree of AMD.

Simulated treatment of recurrent choroidal neovascularization in primate retina. Comparative histopathologic findings.

We simulated the treatment of recurrent choroidal neovascular membranes (CNVM) by applying two courses of laser treatment to monkey retinas. Argon green, argon blue-green, and krypton red lasers (KRLs) were used in juxtafoveal, papillomacular bundle, and nonmacular areas. The effects were examined clinically and histopathologically. Results of once-treated control eyes were consistent with those of previous studies. Repeat treatment, however, resulted in full-thickness retinal destruction or necrosis with all laser modalities and in all fundus locations. These results are consistent with the absorptive characteristics of xanthophyll and melanin and suggest only limited advantages to the KRL when treatment of recurrent CNVM is performed in a previously treated area of the fundus. However, treatment of recurrent CNVM is still probably most successful with a KRL, because recurrent CNVM is usually at a border of a photocoagulation scar, where the retina is still untreated, and because histologic studies have demonstrated inner retinal sparing with a KRL in juxtafoveal areas.

The risk of cerebrovascular and cardiovascular disease in patients with anterior ischemic optic neuropathy.

Of 217 patients in whom anterior ischemic optic neuropathy (AION) was diagnosed during the period from 1975 to 1985, verifiable medical information was obtained for 212 (98%). Over a median follow-up period of three years, no group of patients had an increased mortality rate over that of age-, sex-, and race-matched controls; however, patients with "idiopathic" AION and patients with systemic hypertension who developed nonarteritic AION had a statistically significant increased risk of experiencing cerebrovascular events and myocardial infarctions compared with appropriately matched control groups. In view of the findings of our study, we suggest that patients with idiopathic AION and hypertensive patients who develop nonarteritic AION undergo a complete physical examination, cardiac evaluation, tests of carotid artery patency, and careful medical follow-up to attempt to prevent subsequent cerebrovascular or cardiovascular events.

Parafoveal telangiectasis and diabetic retinopathy.

Five patients with mild nonproliferative diabetic retinopathy had visual loss associated with parafoveal telangiectasis. Minimal macular edema with characteristic parafoveal plaques of subretinal pigment epithelial hyperplasia was seen in all patients. Fluorescein angiography revealed the presence of ectatic, dilated, leaking perifoveal capillaries. The occurrence of parafoveal telangiectasis in patients with diabetic retinopathy has, to our knowledge, not been previously described. One previous clinicopathologic report described the histologic appearance of parafoveal telangiectasis in a nondiabetic patient to be similar to that seen in diabetic patients. The association of parafoveal telangiectasis and diabetic retinopathy raises interesting speculations into the pathogenesis of the entity of parafoveal telangiectasis. In addition, the importance of obtaining fluorescein angiography prior to therapy of diabetic macular edema is emphasized.

Natural course of poorly defined choroidal neovascularization associated with macular degeneration.

We obtained follow-up data on 84 eyes with age-related macular degeneration and poorly defined angiographic leakage presumed to represent choroidal neovascularization. A poorly defined neovascular membrane was presumed to be present when subsensory retinal fluid was present in association with choroidal leakage on fluorescein angiography and in which the extent of leakage was not well defined. Among the 84 eyes, the average initial visual acuity was 20/80. In 75 (89%) of 84 eyes, the leakage involved the foveal center at initial presentation. At follow-up (average, 28 months; range, six to 53 months), the average visual acuity was 20/250; the final acuity declined at least three but less than six lines in 18 eyes (21%) and six or more lines in 35 eyes (42%). There was a statistically significant difference in the percentage of eyes that developed moderate or severe visual loss among eyes that progressed to disciform scarring compared with eyes that continued to manifest poorly defined leakage without evidence of scarring. Given that most severe visual loss associated with macular degeneration can be attributed to consequences of neovascular membranes and that many membranes associated with age-related macular degeneration are poorly defined, our study results support the possibility that poorly defined neovascular membranes represent a major cause of severe visual loss among the elderly in the United States.

Relationship of drusen and abnormalities of the retinal pigment epithelium to the prognosis of neovascular macular degeneration. The Macular Photocoagulation Study Group.

We graded macular features of 127 fellow eyes of participants in the Macular Photocoagulation Study who had an extrafoveal choroidal neovascular membrane secondary to age-related macular degeneration in the first eye and no initial evidence of the neovascular form of age-related macular degeneration in the fellow eye. Our aims were to determine the relationship of drusen characteristics and retinal pigment epithelial abnormalities to the risk of subsequent development of neovascularization in the fellow eye and the risk of subsequent development of recurrent neovascular membranes after photocoagulation in the first eye. Regression analysis demonstrated that the presence of large drusen and focal hyperpigmentation of the retinal pigment epithelium were independent risk factors for the subsequent development of neovascularization in the fellow eye (relative risk, 2.4 and 2.5, respectively). Only 10% of eyes with no large drusen or any retinal pigment epithelial hyperpigmentation compared with 58% of eyes with both large drusen and retinal pigment epithelial hyperpigmentation developed neovascularization in the fellow eye within 5 years. Using multivariate Cox regression analysis, we noted that the risk of developing recurrent neovascular membranes in the first eye was significantly increased when large drusen (relative risk, 2.8) were noted in the fellow eye at the time of laser treatment in the first eye. Fundus features in the fellow eye appear to help identify patients at high risk of developing visual loss from recurrent neovascular membranes following laser treatment in the first eye and from development of a neovascular membrane in the fellow eye.

The evolution of argon laser photocoagulation scars in patients with the ocular histoplasmosis syndrome.

In 34 patients (35 eyes) with successfully treated histoplasmic choroidal neovascular membranes with a mean follow-up of 10.1 years, neither the neovascular membrane size nor the distance to the center of the foveal avascular zone (FAZ) affected final visual acuity. For a subgroup of 18 patients who had a two-year follow-up visit, the average chorioretinal scar expanded in area 50.1% per year for the first two years and 4.6% per year thereafter. This corresponded to a migration rate toward the FAZ of 152 micron/y for the first two years and 22 micron/y thereafter. After ten years, the average scar was 3.23 times larger than the initial treatment area and 480 micron closer to the FAZ than the initial treatment edge. Of the eight patients whose scars expanded to involve the center of the FAZ, six had final visual acuities either equal to or better than the initial visual acuities.

Choroidopathy in systemic lupus erythematosus.

Choroidopathy in association with systemic lupus erythematosus (SLE) is a clinically unusual manifestation, previously described in only six patients, to our knowledge. We have followed up six patients with SLE and choroidopathy manifested by multifocal, serous elevations of the retinal pigment epithelium and sensory retina. In four patients, macular involvement was present, and they suffered visual loss. Two eyes of two patients progressed to large, bullous, exudative retinal detachments. In the three patients in whom control of the systemic disease was achieved, the serous detachments resolved. The pathogenesis is most likely related to choroidal vascular disease with resultant pigment epithelial damage and serous fluid leakage beneath the retina.