Common variant in VEGFA and response to anti-VEGF therapy for neovascular age-related macular degeneration.

Age-related macular degeneration (AMD) is a leading cause of visual impairment in aging populations in industrialized countries. Here we investigated whether the genotype of vascular endothelial growth factor A (VEGFA) gene is associated with response to anti-VEGF therapy. 223 eyes with neovascular AMD were treated with intravitreal anti-VEGF therapy. Responders were defined as patients who had an improvement in best corrected visual acuity (BCVA) of at least 5 letters or one line on the EDTRS visual acuity chart along with resolution of intraretinal or subretinal fluid over 12 months. Patients who did not meet the definition of responders were classified as poor-responders. The vision of responders (n = 148) improved while the vision of poor-responders (n = 75) worsened (P<0.001). Responders on average had a decrease in central foveal thickness (CFT), while poor-responders had an increase in CFT (P <0.001). Compared with the responder group, the poor-responder group had a higher frequency of the risk (T) allele (Allelic P = 0.019) and TT genotype (P = 0.002 under a recessive model) for the VEGFA-rs943080 polymorphism. VEGFA expression was 1.8-fold higher in cells with the VEGFA rs943080 TT genotype than in cells with the VEGFA rs943080 CC genotype (P = 0.012). Age, gender, smoking, diabetes mellitus, and hypertension did not play a significant role in treatment response, but BMI was found to be significantly different between responders and poorresponders (P = 0.033). In conclusion, we demonstrated a potential pharmacogenetic relationship between the VEGFA gene and treatment response to anti-VEGF therapy.The studies are registered at ClinicalTrials.gov under the identifiers NCT00474695 (http://clinicaltrials. gov/ct2/show/NCT00474695) and NCT01464723 (http://clinicaltrials.gov/ct2/show/NCT01464723).

Association of LIPC and advanced age-related macular degeneration.

PURPOSE: To determine whether there is an association between hepatic lipase (LIPC) and age-related macular degeneration (AMD) in two independent Caucasian cohorts. METHODS: A discovery cohort of 1626 patients with advanced AMD and 859 normal controls and a replication cohort of 2159 cases and 1150 controls were genotyped for two single-nucleotide polymorphisms (SNPs) in the promoter region of LIPC. The associations between the SNPs and AMD were examined by χ(2) tests. RESULTS: In the discovery cohort, rs493258 and rs10468017 were both associated with advanced AMD (P=9.63E-3 and P=0.048, respectively). The association was corroborated in the replication cohort (P=4.48E-03 for rs493258 and P=0.015 for rs10468017). Combined analysis resulted in even more significant associations (P=1.21E-04 for rs493258 and P=1.67E-03 for rs10468017). CONCLUSION: The LIPC promoter variants rs493258 and rs10468017 were associated with advanced AMD in two independent Caucasian populations, confirming that LIPC polymorphisms may be a genetic risk factor for AMD in the Caucasian population.

Pegaptanib sodium for neovascular age-related macular degeneration: third-year safety results of the VEGF Inhibition Study in Ocular Neovascularisation (VISION) trial.

AIMS: To evaluate the safety of up to 3 years of pegaptanib sodium therapy in the treatment of neovascular age-related macular degeneration (NV-AMD). METHODS: Two concurrent, prospective, multicentre, double-masked studies randomised subjects with all angiographic lesion compositions of NV-AMD to receive intravitreous pegaptanib sodium (0.3, 1 and 3 mg) or sham injections every 6 weeks for 54 weeks. Those initially assigned to pegaptanib were rerandomised to continue or discontinue therapy for 48 more weeks; sham-treated subjects continued sham, discontinued or received pegaptanib. At 102 weeks, subjects receiving pegaptanib 0.3 mg or 1 mg in years 1 or 2 continued; those receiving pegaptanib 3 mg or who did not receive treatment in years 1 and 2 were rerandomised to 0.3 mg or 1 mg for year 3. RESULTS: As in years 1 and 2, pegaptanib was well tolerated in year 3. Adverse events were mainly ocular in nature, mild, transient and injection-related. Serious adverse events were rare. No evidence of systemic safety signals attributed to vascular endothelial growth factor inhibition arose in year 3. There were no findings in relation to vital signs or electrocardiogram results suggesting a relationship to pegaptanib treatment. CONCLUSION: The 3-year safety profile of pegaptanib sodium was favourable in patients with NV-AMD.

Comparison of 4 mg versus 20 mg intravitreal triamcinolone acetonide injections.

AIMS: To compare the non-decanted (standard) 4 mg versus the decanted 20 mg intravitreal triamcinolone acetonide (IVTA) injections and to assess their effect on intraocular pressure (IOP). METHODS: We retrospectively reviewed the records of 92 consecutive eyes, which received an intravitreal injection of either dose of triamcinolone acetonide, at a single retina centre. The change in IOP (elevation of at least 5 mm Hg from baseline or above 21 mm Hg) was analysed with a multivariate logistic analysis. The mean follow-up period in both groups was 27 weeks. A subgroup analysis comparing vitrectomised to non-vitrectomised eyes in both groups was also performed. RESULTS: Of the 92 eyes, 46% (23 of 51) in the 4 mg group versus 30% (12 of 41) in the 20 mg group had an IOP >21 mm of Hg (p = 0.14) after a mean follow-up period of 27 weeks. The vitrectomised eyes (3 of 24) in the 20 mg group had a significantly lower rate of IVTA induced IOP elevation than the non-vitrectomised eyes (9 of 17) (p = 0.013). The IOP elevation occurred significantly earlier in the 4 mg group (vitrectomised eyes 27 (SD 43) days and non-vitrectomised eyes 61 (52) days) than in the 20 mg group (vitrectomised eyes 104 (56) days and non-vitrectomised eyes 119 (82) days), independent of the vitreous status (vitrectomised p = 0.05 and non-vitrectomised p = 0.04). The mean value of initial high IOP in the non-vitrectomised eyes was higher in the 4 mg group than in the corresponding 20 mg group (p = 0.048). CONCLUSION: Decanted 20 mg IVTA may not pose a significantly greater risk of IOP elevation than the 4 mg non-decanted IVTA.

Year 2 efficacy results of 2 randomized controlled clinical trials of pegaptanib for neovascular age-related macular degeneration.

OBJECTIVE: To evaluate the efficacy of a second year of pegaptanib sodium therapy in patients with neovascular age-related macular degeneration (AMD). DESIGN: Two concurrent, multicenter, randomized, double-masked, sham-controlled studies (V.I.S.I.O.N. [Vascular Endothelial Growth Factor Inhibition Study in Ocular Neovascularization] trials). PARTICIPANTS: Patients with all angiographic neovascular lesion compositions of AMD were enrolled. In combined analyses, 88% (1053/1190) were re-randomized at week 54, and 89% (941/1053) were assessed at week 102. INTERVENTIONS: At week 54, those initially assigned to pegaptanib were re-randomized (1:1) to continue or discontinue therapy for 48 more weeks (8 injections). Those initially assigned to sham were re-randomized to continue sham, discontinue sham, or receive 1 of 3 pegaptanib doses. MAIN OUTCOME MEASURES: Mean change in visual acuity (VA) over time and mean change in the standardized area under the curve of VA and proportions of patients experiencing a loss of > or =15 letters from week 54 to week 102; losing <15 letters (responders) from baseline to week 102; gaining > or =0, > or =1, > or =2, and > or =3 lines of VA; and progressing to legal blindness (20/200 or worse). RESULTS: In combined analysis, mean VA was maintained in patients continuing with 0.3-mg pegaptanib compared with those discontinuing therapy or receiving usual care. In patients who continued pegaptanib, the proportion who lost >15 letters from baseline in the period from week 54 to week 102 was half (7%) that of patients who discontinued pegaptanib or remained on usual care (14% for each). Kaplan-Meier analysis showed that patients continuing 0.3-mg pegaptanib for a second year were less likely to lose > or =15 letters than those re-randomized to discontinue after 1 year (P<0.05). The proportion of patients gaining vision was higher for those assigned to 2 years of 0.3-mg pegaptanib than receiving usual care. Progression to legal blindness was reduced for patients continuing 0.3-mg pegaptanib for 2 years. CONCLUSIONS: Continuing visual benefit was observed in patients who were randomized to receive therapy with pegaptanib in year 2 of the V.I.S.I.O.N. trials when compared with 2 years' usual care or cessation of therapy at year 1.

The prevalence of multiple sclerosis in the city of São Paulo, Brazil, 1997.

July 1, 1997 was stipulated as the day for estimating the prevalence of multiple sclerosis within the city of São Paulo. The patients were identified via various sources, including associated universities and magnetic resonance services of the city of São Paulo. The area covered by the study has a population of 9,380,000, mainly white and of European origin, with a large number of immigrants from Spain and Portugal. The patients were classified in accordance with the criteria of Poser et al. (1983), and only those with defined multiple sclerosis were registered. The study gave a prevalence of 15.0/10(5) inhabitants, or three times the value obtained in a similar study in 1990. This increase reveals the larger number of cases encompassed by the study, and is attributed to the use of more detailed recording methods, improvements in diagnosis, and better conditions for treatment.

Locating blood vessels in retinal images by piecewise threshold probing of a matched filter response.

We describe an automated method to locate and outline blood vessels in images of the ocular fundus. Such a tool should prove useful to eye care specialists for purposes of patient screening, treatment evaluation, and clinical study. Our method differs from previously known methods in that it uses local and global vessel features cooperatively to segment the vessel network. We evaluate our method using hand-labeled ground truth segmentations of 20 images. A plot of the operating characteristic shows that our method reduces false positives by as much as 15 times over basic thresholding of a matched filter response (MFR), at up to a 75% true positive rate. For a baseline, we also compared the ground truth against a second hand-labeling, yielding a 90% true positive and a 4% false positive detection rate, on average. These numbers suggest there is still room for a 15% true positive rate improvement, with the same false positive rate, over our method. We are making all our images and hand labelings publicly available for interested researchers to use in evaluating related methods.

Polypoidal choroidal vasculopathy masquerading as central serous chorioretinopathy.

OBJECTIVE: To differentiate polypoidal choroidal vasculopathy (PCV) from central serous chorioretinopathy (CSC). DESIGN: A retrospective, observational case series. PARTICIPANTS: Thirteen patients originally diagnosed with CSC proved to have PCV after more extensive evaluation and follow-up. METHODS: A clinical and angiographic review of patients with manifestations of CSC, including macular detachment. MAIN OUTCOME MEASURES: Demographic data, funduscopic examination, and fluorescein and indocyanine green (ICG) angiographic findings. RESULTS: Thirteen patients initially suspected of having CSC were ultimately diagnosed as having PCV. These eyes had exudative macular detachments secondary to a small caliber, polypoidal choroidal vascular abnormality or so-called polypoidal choroidal neovascularization. The clinical manifestations in the fundus varied. They included multiple, variably sized serous pigment epithelial detachments, neurosensory retinal detachment, lipid deposition, patchy atrophy of the pigment epithelium and indistinct staining from decompensation of the posterior blood-retinal barrier on fluorescein angiography. In reality, the suspected PEDs proved to be polypoidal lesions of PCV when imaged with ICG angiography. CONCLUSIONS: The clinical diagnosis of CSC or PCV generally poses little challenge to the experienced retinal specialist. However, in CSC with persistent and/or recurrent exudation, a myriad of retinal pigment epithelial changes may evolve that make it difficult to differentiate these two entities. In such patients, ICG angiography is useful in differentiating CSC from PCV. An accurate clinical diagnosis is important since each of these entities, CSC and PCV, may differ in terms of their risk factors, natural course, and visual prognosis.

Polypoidal choroidal vasculopathy and neovascularized age-related macular degeneration.

OBJECTIVE: To determine the nature and frequency of polypoidal choroidal vasculopathy (PCV) in a series of patients suspected of having neovascularized age-related macular degeneration (AMD). METHODS: A prospective analysis of 167 consecutive, newly diagnosed patients aged 55 years or older with presumed neovascularized AMD was performed. All patients were examined with fundus biomicroscopy as well as fluorescein and indocyanine green angiography. RESULTS: Choroidal neovascularization secondary to AMD was diagnosed in 154 (92.2%) of 167 patients; 13 (7.8%) patients had PCV. The patients affected by PCV were younger than those with AMD (P = .01). Peripapillary choroidal neovascularization was seen in 3 (1.9%) of 154 patients with AMD and 3 (23.1%) of 13 patients with PCV (P = .006). Significant drusen were present in 63 (70%) of 90 fellow eyes with unilateral AMD compared with only 1 (16.7%) of 6 eyes with PCV (P = .02). Only 5 patients with AMD (3.2%) were nonwhite compared with 3 patients with PCV (23.1%) (P = .02). CONCLUSIONS: A measurable number of elderly patients with findings suggestive of neovascularized AMD and serosanguineous macular manifestations will instead have PCV. Polypoidal choroidal vasculopathy can occur in any sex or race, but is more commonly seen in the peripapillary area, without associated drusen, and in nonwhite patients. It is important to differentiate AMD from PCV because there are significant differences in the demographic risk profile, natural course, visual prognosis, and management of these patients.

Measurement and classification of retinal vascular tortuosity.

Automatic measurement of blood vessel tortuosity is a useful capability for automatic ophthalmological diagnostic tools. We describe a suite of automated tortuosity measures for blood vessel segments extracted from RGB retinal images. The tortuosity measures were evaluated in two classification tasks: (1) classifying the tortuosity of blood vessel segments and (2) classifying the tortuosity of blood vessel networks. These tortuosity measures were able to achieve a classification rate of 91% for the first problem and 95% on the second problem, which confirms that they capture much of the ophthalmologists' notion of tortuosity. Finally, we discuss how the accuracy of these measures can be influence by the method used to extract the blood vessel segments.

Silicone oil tamponade to seal macular holes without position restrictions.

OBJECTIVE: The authors performed a study to determine the effectiveness and safety of silicone oil as a substitute for gas to fill the vitreous cavity to treat macular holes. DESIGN: Multicenter, nonrandomized, interventional trial. PARTICIPANTS: Thirty-seven consecutive patients chose vitrectomy with silicone tamponade instead of gas to treat 40 eyes with stage-2 to stage-4 idiopathic age-related macular holes. Stage-2 holes constituted 40% of the holes, and stage-3 and stage-4 holes made up 60%. INTERVENTION: All eyes were treated with vitrectomy, manual detachment of the posterior vitreous face (not done for stage-4 holes), autologous serum instillation, and silicone fill of the vitreous cavity. After insertion of the oil, the patients resumed normal activity with no restriction of head or eye position except to avoid faceup position. The oil was removed after approximately 6 weeks. MAIN OUTCOME MEASURES: The authors considered the seal of the macular hole and the preoperative and postoperative logarithm of the minimum angle of resolution (logMAR) visions the most significant measures for comparison to other studies. RESULTS: Eighty percent of all holes and 86% of holes not treated previously were sealed with a single silicone tamponade of the vitreous cavity. The logMAR value of visual acuity improved an average of 0.26 (2.6 lines) to 0.61 (20/81) for all eyes and 0.34 (3.4 lines) to 0.52 (20/66) when the macular hole sealed. Completeness of fill of the vitreous cavity with silicone affected seal of the macular hole. Three of eight eyes in which open holes developed after oil removal had less than 90% fill of the vitreous cavity by silicone. Sixty-nine percent of lenses increased opacity one grade or were removed after silicone tamponade. There were no significant adverse effects arising from silicone tamponade. CONCLUSIONS: Silicone oil tamponade of macular holes is effective and safe. Silicone may be optimal for the treatment of macular holes in persons who must travel, who cannot maintain facedown positioning, or who have monocular vision. The most important factor in the successful closure of the macular hole was the completeness of fill of the vitreous cavity with silicone oil.

Imaging the microvasculature of choroidal melanomas with confocal indocyanine green scanning laser ophthalmoscopy.

OBJECTIVE: To image the microvasculature of choroidal melanoma with a new confocal scanning laser ophthalmoscope. METHODS: Eighteen consecutive patients, each with a unilateral choroidal melanoma, were examined prospectively. Indocyanine green angiography was performed with a new confocal scanning laser ophthalmoscope that enabled serial optical sectioning through the tumor. Two additional patients were studied with indocyanine green angiography and confocal scanning laser ophthalmoscopy just before enucleation for posterior choroidal melanomas. The histologic identification of microvasculature patterns was compared with the angiograms for these patients. RESULTS: In the series of 18 patients, 16 (89%) indocyanine green angiograms with optical sectioning revealed tubular structures within the melanoma that were identified as tumor vessels based on their angiographic appearance. The microvasculature patterns identified by indocyanine green angiography correlated well with the histologic appearance of these microvasculature patterns in both patients for whom histologic verification was available. CONCLUSIONS: This preliminary study suggests that indocyanine green angiography with confocal scanning laser ophthalmoscopy images the microvasculature of choroidal melanomas and may be capable of detecting microvasculature patterns that have been shown to be prognostically significant from histopathological studies.

Locating blood vessels in retinal images by piece-wise threshold probing of a matched filter response.

We describe an automated method to locate and outline blood vessels in images of the ocular fundus. Such a tool should prove useful to eyecare specialists for purposes of patient screening, treatment evaluation, and clinical study. Our method differs from previously known methods in that it uses local and global vessel features cooperatively to segment the vessel network. A comparison of our method against hand-labeled ground truth segmentations of five images yielded 65% sensitivity and 81% specificity. A previously known technique yielded 69% sensitivity and 63% specificity. For a baseline, we also compared the ground truth against a second hand labeling, yielding 80% sensitivity and 90% specificity. These numbers indicate our method improves upon the previously known technique, but that further improvement is still possible.

[Production of scientific articles about health in six Latin American countries, 1973-1992]. / Producción de artículos científicos sobre salud en seis países de América Latina, 1973 a 1992.

The production of articles resulting from biomedical, clinical, and public health studies that originated in Argentina, Brazil, Chile, Cuba, Mexico, and Venezuela from 1973 through 1992 was analyzed to discover trends in health research in Latin America. From the database of the Institute for Scientific Information (ISI), 41,238 articles with first authors who resided in those countries were extracted. These articles were analyzed by subject area, type of study, country, number of authors and institutions that participated in the investigation, and citations received by each article. Also analyzed were 95 articles in epidemiology selected from a pool of 570 published by authors from the six countries in 11 public health journals that enjoy international prestige. The results showed that the number of published works increased by 117% between the first and last five-year periods within the study period. Clinical research was distributed the most evenly among the countries, and public health research was the most concentrated (60.7% originated in Brazil). The numbers of biomedical and public health research articles showed relatively more growth than those reporting on clinical research throughout the period. A relative decrease was found in articles by only one author, which suggests a greater frequency of team efforts, and an increase was seen in articles with authors tied to two or more national or foreign institutions, which indicates greater cooperation between institutions and countries. The average number of citations received by each article was 3, which was less than half the number received by the articles in the ISI database (7.78). Regarding the subset of 95 articles in epidemiology, the great majority (96%) dealt with infectious diseases or maternal and child health, while in the international literature 78% of such articles were about chronic diseases. This group of articles gave evidence of more cooperation with international institutions and had a citation index of 4.36 per article. It is concluded that, despite the inherent limitations, this type of study reveals some general trends in the development of research in the six Latin American countries with the greatest scientific production and makes it possible to formulate hypotheses on the factors that influence these trends. Taken with the paper caution, the results of studies like this one can be of great value in defining health science and technology policies.

Automated measurement of retinal vascular tortuosity.

Automatic measurement of blood vessel tortuosity is a useful capability for automatic ophthalmological diagnostic tools. We describe a suite of automated tortuosity measures for blood vessel segments extracted from RGB retinal images. The tortuosity measures were evaluated in two classification tasks: (1) classifying the tortuosity of blood vessel segments and (2) classifying the tortuosity of blood vessel networks. These tortuosity measures were able to achieve a classification rate of 91% for the first problem and 95% on the second problem, which confirms that they capture much of the ophthalmologists' notion of tortuosity.