Nutritional AMD treatment phase I (NAT-1): feasibility of oral DHA supplementation in age-related macular degeneration.

PURPOSE: To create a pilot study in order to evaluate the feasibility of a prospective case-control study of oral supplementation with fish oil (docosahexaenoic acid [DHA]; eicosapentaenoic acid [EPA]) in a population with age-related macular degeneration (AMD). METHODS: A homogeneous group of 38 patients with drusenoid pigment epithelial detachment in one eye (PED) without choroidal new vessels (CNV) was selected. A complete ophthalmologic examination, and a complete profile of fatty acids in serum (S) and in red blood cell membranes (RBCM), were recorded at day 0 and month 6. In group 1, 22 patients were orally supplemented with EPA (720 mg/day) and DHA (480 mg/day) during 6 months. In group 2, 16 patients were followed as controls. Nutritional recommendations on fish consumption were given to both groups. RESULTS: In group 1, after 6 months supplementation we observed a significant blood enrichment in EPA (EPA-S: 2.20 vs 0.79, p<0.0001 and EPA-RBCM: 2.24 vs 0.85, p<0.0001) and in DHA (DHA-S: 2.47 vs 1.56, p<0.0001 and DHA-RBCM: 6.47 vs 4.67, p<0.0001). No change was observed in group 2 despite nutritional recommendations. In this short followup, no evolution to CNV was noted in either of the two groups. Neither side effects nor dropouts were observed in either of the groups. DISCUSSION: This study supports the feasibility of a long-term double-masked prospective case-control study in an AMD population in order to evaluate a potential benefit from oral supplementation with DHA.

Correlation of visual function impairment and OCT findings in patients with Stargardt disease and fundus flavimaculatus.

PURPOSE: To investigate the relationship between morphologic lesions of the retina and functional abnormalities in patients with Stargardt disease (STGD) and fundus flavimaculatus (FFM). DESIGN. Case-controlled, prospective, comparative observational study. METHODS: A complete ophthalmologic examination, including best-corrected visual acuity (BCVA) and optical coherence tomography (OCT), was performed in 61 eyes of 32 consecutive patients with STGD/FFM and in 60 eyes of 30 matched healthy control subjects. Furthermore, fundus-related perimetry was performed in 12 of the affected eyes. RESULTS: The age ranged from 21 to 71 years in STGD/FFM patients and from 21 to 72 years in controls. BCVA ranged from 20/20 to 20/400 and from 20/20 to 20/32, respectively, in STGD/FFM patients and in controls. A foveal thinning was found by OCT Stratus in almost all cases (average 160 microm) compared with controls (average 210 microm) (p<0.001). BCVA impairment significantly correlated to the degree of foveal thinning (r2=0.16; p=0.0014). Moreover, in STGD/FFM patients the authors observed two types of hyperreflective deposits which were not correlated with BCVA impairment or foveal thinning. In addition, fundus-related perimetry revealed a stable fixation in 8/12 eyes, that was predominantly central in only 4 of these eyes. A smaller degree of foveal thinning correlated to a more stable fixation (p=0.0108), even if not predominantly central (p=0.0218). CONCLUSIONS: In this series, lower visual acuity and unstable fixation correlated with a greater transverse foveal thinning. OCT and fundus-related perimetry may be useful tools in STGD/FFM patients.

Retinal photocoagulation for proliferative sickle cell retinopathy: a prospective clinical trial with new sea fan classification.

PURPOSE: To compare the clinical outcome of stage III proliferative sickle cell retinopathy (PSR) treated by peripheral retinal scatter photocoagulation to natural course disease. METHODS: Long-term follow-up of 101 patients enrolled in a prospective trial of photocoagulation for PSR has been completed. Among 202 eyes of 101 patients enrolled at the University Eye Clinic of Créteil, 73 eyes showed a stage III PSR, which the authors further divided into five new grades (A, B, C, D, E) considering size, hemorrhage, fibrosis, and visible vessels. Grading was based on a three-mirror fundus examination, 360 degrees color photographs, and fluorescein angiography. Mean follow- up was 4 years. RESULTS: Thirty-eight treated eyes and 35 untreated eyes were included in this study. The evolution was not statistically significant between treated and untreated groups concerning flat sea fan <1 MPS disc area (grade A) or elevated sea fan with partial fibrosis (grade C). Progression and regression were compared between the two groups for grade B, resulting statistically significant (p<0.05). Nine complications (13%) were observed, which only occurred in untreated patients with elevated sea fan and hemorrhage (grade B) or complete fibrosed sea fan with well defined vessels (grade E) (p<0.05). CONCLUSIONS: These data suggest that patients with grade A or C new sea fan classification should not be initially treated but observed.

Indocyanine green angiography features of Malattia leventinese.

BACKGROUND/AIM: Malattia leventinese (ML) is an inherited macular degeneration characterised by the presence of small radial drusen. Despite extensive descriptions of this study of the fundus, angiographic features of ML have been inadequately described. The aim is to describe the indocyanine green angiography (ICG) features observed in ML. METHODS: 10 eyes from five consecutive ML patients (aged 27-44 years) were prospectively included. A complete ophthalmological examination including colour fundus photographs, autofluorescence, fluorescein angiography (FA), and ICG was performed. RESULTS: ICG differentiated two types of drusen. Large round aggregated drusen were consistently hypofluorescent in the early phases and presented as hyperfluorescent spots surrounded by halos of hypofluorescence in the late phases. Conversely, small radial drusen were mostly hyperfluorescent in the early phases with decreased fluorescence in the late phases of the ICG sequence. FA also showed differences in staining between the two types of drusen. CONCLUSIONS: ICG angiography revealed marked differences between the large round and small radial drusen observed in ML. The large central drusen presented with an unusual pustuliform feature on the late phases of the ICG sequence. This distinct feature may be useful in the diagnosis of late stage disease when drusen consolidation could obscure the radial drusen.

[Macular pigment and age-related macular degeneration. Clinical implications]. / Pigment maculaire et dégénérescence maculaire liée à l'âge. Implications cliniques.

The potential impact of macular pigment on the development of age-related macular degeneration (AMD) is currently a major research avenue. The role of oxidative damage in the pathogenesis of AMD has been recently confirmed by the results of a large randomized clinical trial, the AREDS (Age-Related Eye Disease Study). This study has established that high-dose supplementation with vitamins C and E, beta carotene, and zinc might prevent AMD progression and visual acuity loss in a large but determined subset of patients. Macular pigment components (mainly lutein and zeaxanthin) are highly resistant to free radicals. Moreover, extensive data from clinical, epidemiological and experimental studies suggest that lutein and zeaxanthin might protect against the development of AMD. Furthermore, an additional intake of lutein and/or zeaxanthin seems to induce an increase of the density of the macular pigment. However, a careful review of the available data suggest that only future randomized clinical trials will allow to determine the exact role of lutein and zeaxanthin in the prevention of AMD.

Quantitative evaluation of fluorescein angiograms: microaneurysm counts.

This study describes a method for quantifying microaneurysms (MA) from fluorescein angiograms. The method was validated by the reproducibility of the number of MA in 30 angiograms read twice each by two independent observers; and by the absolute difference in MA counts between two readings by the same observer, and difference in numbers counted by two different observers. The precise location of each MA on two readings was also studied and the reproducibility of location varied from 60 to 71%, depending on the quality of the angiograms. Clinicians and technicians working in the same or in different centers obtained similar results. The coefficient of correlation between observers and between readings was satisfactory, r greater than 0.9. The method is easy to learn and the reproducibility allows for its use in clinical trials.

ABCR gene analysis in familial exudative age-related macular degeneration.

PURPOSE: Identification of genetic factors in the pathogenesis of age-related macular degeneration (AMD) is of crucial importance in this common cause of blindness. Mutations in the Stargardt disease gene (ABCR) were previously reported in patients with atrophic forms of AMD. The purpose of this study was to analyze familial segregation of ABCR gene mutations in 52 unrelated multiplex cases of exudative AMD. METHODS: A complete ophthalmological examination including visual acuity measurement, fundus examination, and fluorescein angiography (FA) was performed on each exudative AMD patient. The entire coding sequence of the ABCR gene was analyzed using a combination of single-strand conformation polymorphism and confirmatory sequencing of the exons showing an abnormal pattern of migration. RESULTS: Six heterozygous missense changes were identified. A lack of familial segregation was observed in 4 of 6 codon changes (Arg943Gln, Val1433Ile, Pro1948Leu, and Ser2255Ile). Conversely, 2 codon changes cosegregated with the disease in 2 small families: Pro940Arg and Leu1970Phe. CONCLUSIONS: The authors believe that segregation of the ABCR gene mutations with familial cases of AMD has not yet been shown. The analysis of familial segregation allowed the authors to exclude 4 of 6 codon changes as disease-causing mutations. Furthermore, it was shown here that the ABCR gene may be rarely involved in exudative AMD, with at best 2 of 52 familial cases (4%) related to this susceptibility factor.

A novel ABCR nonsense mutation responsible for late-onset fundus flavimaculatus.

PURPOSE: To report the ophthalmologic features of a novel truncating mutation in the ABCR gene in a patient affected with late-onset fundus flavimaculatus (FFM). METHODS: A complete ophthalmologic examination was performed in a 70-year-old patient, including best-corrected visual acuity measurement, slit lamp and fundus examination, fundus photographs, frequent fluorescein and indocyanine green angiographies, visual field testing, color vision analysis, electroretinogram, and electro-oculogram. The 50 exons of the ABCR gene were analyzed using direct sequencing. RESULTS: Fluorescein and indocyanine green angiographies confirmed the diagnosis of FFM. A heterozygous base change was found, resulting in the substitution of an arginine to a stop at codon 152 of the ABCR gene. CONCLUSIONS: A heterozygous nonsense ABCR gene mutation was found in a patient affected with FFM. No other mutation has been identified in the entire coding sequence and the promoter region, suggesting that a heterozygous severe ABCR mutant may be responsible for a mild and delayed FFM phenotype, different from that of age-related macular degeneration.

Binding of basic fibroblast growth factor to normal and neovascularized rabbit cornea.

The labeling pattern of frozen sections of rabbit cornea incubated with radioiodinated basic fibroblast growth factor (bFGF) was investigated in normal corneas and prostaglandin-induced neovascularized corneas by autoradiography followed by image analysis. 125I-bFGF binds to Bowman's, Descemet's, and vascular basement membranes in a dose-dependent manner. The specificity of the binding of bFGF to basement membrane was demonstrated by the following experiments: 1) an excess of unlabeled growth factor displaced the labeling; 2) histones did not modify the labeling; and 3) 2 M NaCl washing and enzymatic treatment with heparitinase prevented binding of labeled growth factor without apparent destruction of the overall structure of the basement membrane. Our results suggest that bFGF binds to the heparan sulfate proteoglycan of basement membranes. Both normal limbal vessels and the newly formed corneal vessels exhibited the same type of labeling but with different intensities, according to the degree of maturation of the new vessels. bFGF binding also is located clearly on the endothelial cells in both types of vessels. This second binding site could correspond to the high affinity receptors on the cell surface and suggests a direct interaction of bFGF with endothelial cells during new vessel formation.

The pretear characteristics of pigment epithelial detachments. A study of 40 eyes.

Retinal pigment epithelial tears are a major complication of pigment epithelial detachment (PED) in the elderly. We observed the pretear process of PED in 38 patients (40 eyes) to identify characteristic angiographic changes. Before the tear occurred, the filling pattern of the PED underwent alterations, including an increase in the size and a modification in the shape of the PED (27 eyes); the development of notches (14 eyes); and the onset or increase of subretinal fluid, hard exudates, and/or hemorrhages (30 eyes). The most noteworthy feature was the uneven filling of the PED, with a remarkably hypofluorescent central area that remained dark until the late angiographic frames (24 eyes). Conversely, hyperfluorescence appeared early at the margins of the PED, increased progressively, and sometimes demonstrated a crenated edge. The high risk of tearing indicates that laser treatment of the retina should be considered carefully in the presence of these angiographic features.

Perifoveal laser treatment for subfoveal choroidal new vessels in age-related macular degeneration. Results of a randomized clinical trial.

In a controlled clinical trial, 160 eyes underwent "perifoveal" laser photocoagulation. All patients had age-related macular degeneration and subfoveal neovascularization (0.5 to 2.5 disc diameters), without detectable fibrous tissue, and visual acuity from 20/100 to 20/1000. At least 1 year of follow-up has been completed in 127 eyes. Visual acuity was maintained or improved in 12 (20.3%) of 59 untreated eyes vs 28 (41.1%) of 68 treated eyes (P = .04). Reading visual acuity (J4) with the use of low-vision aids was retained in 28 untreated eyes (47.4%) vs 50 treated eyes (73.5%) (P less than .01). Automated static perimetry showed an increased scotomatous area and/or depth with eccentric fixation in all but four patients. A flat atrophic scar was achieved in 53 of 68 treated eyes. Statistical analysis indicated that perifoveal photocoagulation has been effective in the short-term preservation of visual acuity.

Imaging of chorioretinal anastomoses in vascularized retinal pigment epithelium detachments.

OBJECTIVE: To identify specific features of pigment epithelium detachments with limited hyperfluorescent lesions (hot spots). DESIGN: One hundred eighty-two consecutive patients (186 eyes) who had vascularized pigment epithelium detachments and recent onset of symptoms were examined with indocyanine green and fluorescein videoangiography using the scanning laser ophthalmoscope. The choroidal neovascularization complex and macular retinal vessels were studied. The natural history and the effect of laser treatment were evaluated. RESULTS: Fifty-four eyes had hot spots on indocyanine green angiography. In 50 of these 54 eyes, the video analysis showed an anastomosis of one or more retinal vessels, with the choroidal neovascularization within the hot spot. One or two retinal veins or arteries or both filled with both dyes and were seen to enter into the hot spot. Results of indocyanine green-guided photocoagulation of the hot spot in 28 eyes were disappointing. CONCLUSION: Continuous recording of the early phases of fluorescein and indocyanine green angiography allowed identification of chorioretinal anastomoses in vascularized pigment epithelium detachments with hot spots at an early exudative stage of age-related macular degeneration in 50 (26.8%) of 186 eyes. The poor outcome of laser photocoagulation could be related not only to the development of an overlying pigment epithelium detachment, but also to the retinal and choroidal vascularization of the lesion.

Antiphospholipid antibodies in retinal vascular occlusions. A prospective study of 75 patients.

OBJECTIVE: To assess the prevalence of antiphospholipid antibodies in patients with occlusive retinal vascular disorders. PATIENTS: Seventy-five consecutive patients (44 with central retinal vein occlusions, 24 with branch venous occlusions, five with vasculitis plus branch venous occlusion, and two with arterial occlusions) were screened for antiphospholipid antibodies and compared with a control group composed of outpatients with similar systemic vascular disorders. RESULTS: The antibody assay for one patient was positive for lupus anticoagulant and the antibody assay for three other patients was positive for anticardiolipin antibodies. These four patients had central or branch retinal vein occlusion and presented with several vascular risk factors. Comparison of the retinal vascular occlusion and the control groups showed no difference in the levels of anticardiolipin antibodies or lupus anticoagulant. CONCLUSIONS: Antiphospholipid antibodies did not seem to be a feature of retinal vein occlusion, but in rare cases (5%) they may contribute to the occlusive phenomenon. A systematic screening does not seem to be justified, but it may be valuable to test for antiphospholipid antibodies in patients without conventional risk factors and in patients with clotting screen abnormalities, particularly if associated with lupus-like syndrome or other elements of the primary antiphospholipid syndrome.

Ocular fluorophotometric and angiographic findings in toxemia of pregnancy.

Ocular fluorophotometry was performed in 24 patients with hypertension due to toxemia of pregnancy and in ten normal subjects. Patients showing features of accelerated hypertension in the fundus (eg, hemorrhage, cotton-wool spots, and disc edema) were excluded from the study. Fluorescein concentrations in the aqueous and posterior vitreous increased significantly in toxemic patients compared with those in normal subjects; the blood-aqueous barrier was disrupted earlier than the blood-retinal barrier. Nevertheless, these barriers were only disrupted when the arterial diameter was altered. Ocular fluorometric abnormalities disappeared after delivery in all but two cases.

Natural course of nonaphakic cystoid macular edema.

We evaluated the longterm natural history of nonaphakic cystoid macular edema (CME) in a retrospective study of 130 out of 557 CME cases recorded in the past ten years. A listing of causes was provided and the cases divided into two groups: those with perifoveal leakage and those with deep subretinal leakage. In cases of diabetic retinopathy, 60 patients who were followed up for more than three years had noncystoid or cystoid macular edema. The occurrence and persistence of a large central foveal cyst usually resulted in a severe decrease in visual acuity. Hard exudates, present in 60% of cases, seemed to influence visual prognosis when they were inside the foveal avascular zone. In cases of venous occlusion, chronic CME increased the risk of a central cyst and was the major cause of a macular scar. In cases of uveitis and vasculitis, the restoration of macular capillary wall competence was possible when inflammation decreased. Disturbances in the macular pigment epithelium were also shown to produce poor visual acuity.

An international classification and grading system for age-related maculopathy and age-related macular degeneration. The International ARM Epidemiological Study Group.

A common detection and classification system is needed for epidemiologic studies of age-related maculopathy (ARM). Such a grading scheme for ARM is described in this paper. ARM is defined as a degenerative disorder in persons > or = 50 years of age characterized on grading of color fundus transparencies by the presence of the following abnormalities in the macular area: soft drusen > or = 63 microns, hyperpigmentation and/or hypopigmentation of the retinal pigment epithelium (RPE), RPE and associated neurosensory detachment, (peri)retinal hemorrhages, geographic atrophy of the RPE, or (peri)retinal fibrous scarring in the absence of other retinal (vascular) disorders. Visual acuity is not used to define the presence of ARM. Early ARM is defined as the presence of drusen and RPE pigmentary abnormalities described above; late ARM is similar to age-related macular degeneration (AMD) and includes dry AMD (geographic atrophy of the RPE in the absence of neovascular AMD) or neovascular AMD (RPE detachment, hemorrhages, and/or scars as described above). Methods to take and grade fundus transparencies are described.

Retinal detachment after choroidal ischemia.

Injection of a 15-micron microsphere suspension through one or two vortex veins of nine monkey eyes caused various degrees of sectorial choroidal ischemia, which were documented by fluorescein angiography and electron microscopy. The severity of the lesions to the fundus depended on the volume of microspheres injected (0.4 to 1.6 ml of a suspension of 600,000 microspheres/ml). Three hours after embolization white patches appeared in the retinal pigment epithelium as well as a posterior pole serous retinal detachment in five eyes. Delayed choroidal filling was noted in the quadrant involved, but a few choriocapillaris units slowly perfused, leading to fluorescein leakage in the serous retinal detachments. Histologic examination showed various types of damage to the retinal pigment epithelium, including vacuolization and cell membrane rupture.

Late developing lesions in birdshot retinochoroidopathy.

Birdshot retinochoroidopathy is characterized by depigmented spots radiating from the optic disk in association with mild vitritis, retinal vasculitis, and involvement of the optic nerve head. In two patients, we traced the long-term course of uveitis with vitritis, retinal vasculitis, and papillitis that resulted in the typical cream-colored spots of birdshot retinochoroidopathy after seven and eight years, respectively, of follow-up. These observations suggest that in long-standing inflammation of the retinal vasculature and uveal tract, the HLA-A29 antigen should be assessed, because the development of typical lesions of birdshot retinochoroidopathy may be delayed in some patients.

Choroidal ischemia.

Nine patients, seven women and two men, ranging in age from 21 to 86 years, had generalized vascular disease and significant deficits in choroidal perfusion but no retinal vascular changes. Because these perfusion abnormalities can be identified only by fluorescein angiography and the fundus appears to be normal, choroidal ischemia may be more common than has been realized. Infarction of the choroid, retinal pigment epithelium, and outer retina are usually unassociated with retinal detachment; even ischemia severe enough to induce retinal detachment seldom produces significant atrophy.

Acute sectorial choroidal ischemia.

Four eyes (of three patients) with sectorial choroidal ischemia by temporal arteritis or carotid obstruction underwent fluorescein angiography during and after the acute phase. In all cases hypoperfusion affected the whole temporal choroid; however, disturbance of retinal pigment epithelium was much less extensive. In two cases the retinal pigment epithelium became necrotic and scarred within a limited area that was typically triangular in shape; in the third case scarring was limited to some pigmented streaks, and in the fourth case, retinal pigment epithelium remained normal. The triangular scar that appeared after episodes of choroidal hypoperfusion did not seem to be a true reflection of the extent of the choroidal artery obstruction in the acute phase. Our observations suggest that the deficient choroidal perfusion involved more than the choroidal artery supplying the triangular area of pigment epithelium disturbance. Several mechanisms (for example, retrograde venous filling, restoration of perfusion) reduce the deleterious effects of ischemia. Thus the necrosis of the retinal pigment epithelium would appear in only those sectors where ischemia was particularly severe or prolonged.