Protective coding variants in CFH and PELI3 and a variant near CTRB1 are associated with age-related macular degeneration†.

Although numerous common age-related macular degeneration (AMD) alleles have been discovered using genome-wide association studies, substantial disease heritability remains unexplained. We sought to identify additional common and rare variants associated with advanced AMD. A total of 4,332 cases and 25,268 controls of European ancestry from three different populations were genotyped using the Illumina Infinium HumanExome BeadChip. We performed meta-analyses to identify associations with common variants, and single variant and gene-based burden tests to identify rare variants. Two protective, low-frequency, non-synonymous variants were significantly associated with a decrease in AMD risk: A307V in PELI3 (odds ratio [OR] = 0.14, P = 4.3 × 10-10) and N1050Y in CFH (OR = 0.76, P = 6.2 × 10-12). The new variants have a large effect size, similar to some rare mutations we reported previously in a targeted sequencing study, which remain significant in this analysis: CFH R1210C (OR = 18.82, P = 3.5 × 10-07), C3 K155Q (OR = 3.27, P = 1.5 × 10-10) and C9 P167S (OR = 2.04, P = 2.8 × 10-07). We also identified a strong protective signal for a common variant (rs8056814) near CTRB1 associated with a decrease in AMD risk (logistic regression: OR = 0.71, P = 1.8 × 10-07). Suggestive protective loci were identified in the COL4A3 and APOH genes. Our results support the involvement of common and low-frequency protective variants in this vision-threatening condition. This study expands the roles of the innate immune pathway as well as the extracellular matrix and high-density lipoprotein pathways in the aetiology of AMD.

Primary intraocular lymphoma: improving the diagnostic procedure.

OBJECTIVE: To analyze the clinical features of primary intraocular lymphoma (PIOL) and to describe cytochemical and immunocytochemical findings of the vitreous specimens as well as the reasons for delayed diagnosis of PIOL. DESIGN: Prospective noncomparative study. PARTICIPANTS: Eleven patients referred to the uveitis or medical retina units, Department of Ophthalmology, University of Helsinki, were diagnosed as having PIOL between 2000 and 2005. The median follow-up of the patients was 32 months. METHODS: Clinical features and diagnostic workup of uveitis were described. Twelve vitrectomies were performed on 9 patients. The first 5 biopsies were fixed in an equal volume of 50% alcohol. The specimens of the next 7 vitrectomies were handled without alcohol, and tissue culture medium was added to the samples. MAIN OUTCOME MEASURES: Clinical features of PIOL, intervals from ocular symptoms and from first ophthalmological examination to diagnosis, and the role of a proper handling of the vitreous sample in the diagnosis of PIOL. RESULTS: Six females (54%) and 5 males (46%) (median age, 61 years) were included. Ten patients had ocular symptoms for 1 to 30 months (median, 8) before the first contact with an ophthalmologist. Uveitis was bilateral in 9 patients. Vitreitis was seen in all patients, and it was severe in 8. Fundus lesions dominated in 3 patients. Six patients lost useful vision in one eye before the diagnosis of PIOL. Cytologic and immunohistochemical stainings prepared of the unfixed vitreous specimens showed PIOL in 6 patients. The samples fixed in alcohol were nondiagnostic in 4 patients, and in them, verification of diagnosis was based on brain biopsy (3) or cerebrospinal fluid (1) findings. Seven patients died due to primary nervous system lymphoma. CONCLUSIONS: Diagnosis of PIOL is difficult but can be improved. Severe bilateral vitreitis in an elderly patient is a characteristic finding of PIOL. Alcohol fixation may jeopardize the identification of PIOL cells in the vitreous sample. Optimal handling of the vitreous specimens and examination of the slides by an experienced cytopathologist are critical in the diagnostic workup of PIOL.

The insulin-like growth factor system and Type 1 diabetic retinopathy during pregnancy.

AIMS/HYPOTHESIS: To find out whether the levels of insulin-like growth factor-I (IGF-I), IGF binding protein-1 (IGFBP-1), highly phosphorylated IGFBP-1 (hpIGFBP-1), and IGF binding protein-3 (IGFBP-3) are related to the progression of diabetic retinopathy (DR) during pregnancy and postpartum. METHODS: In a prospective study of 42 pregnant women with Type 1 diabetes and 9 nondiabetic controls, DR was graded from fundus photographs. Levels of serum total IGF-I and two different phosphoisoform patterns of IGFBP-1 and IGFBP-3 were measured during the first and third trimester of pregnancy and 3 months postpartum. RESULTS: Both the levels of serum total IGF-I (P<.0001) and IGFBP-3 (P=.003) were lower in the diabetic than in the nondiabetic women during pregnancy and postpartum (repeated-measures ANOVA between the groups). Additionally, the IGF-I and IGFBP-3 levels tended to be lower in the diabetic women with more severe DR at baseline than in those with less severe DR. There were no statistically significant differences in the levels of IGF-I and IGFBP-3 in the diabetic women with progression of DR compared with those without. No statistical differences appeared in the IGFBP-1 phosphoisoform patterns between the groups. CONCLUSIONS/INTERPRETATION: In diabetic women, mean serum levels of IGF-1 and IGFBP-3 are lower than in nondiabetic controls during pregnancy and/or postpartum. Because there was no clear connection between the IGF system and progression of DR during pregnancy, it is unlikely that these substances mediate the tendency of DR to progress during pregnancy.

Predictors of structural findings in old disciform lesions.

PURPOSE: To analyze the baseline findings predictive of the size and type of the late exudative age-related macular degeneration (AMD) lesions. DESIGN: Observational case series. METHODS: Retrospective study. SETTING: University clinic referral practice. STUDY POPULATION: The records of 167 consecutive patients initially diagnosed with recent choroidal neovascularization (CNV) related to AMD were analyzed 4.8 to 9.2 (mean 6.8) years after baseline. Of 121 patients still living, 74 attended the reexamination. After exclusions, data from 61 patients were analyzed. OBSERVATION PROCEDURES: From the fundus photographs and fluorescein angiographic images taken at baseline and at follow-up the size and components of AMD lesion were measured. The presence of hemorrhage, pigment epithelial detachment (PED), classic CNV, laser treatment, and involvement of the fellow eye were recorded at baseline. MAIN OUTCOME MEASURES: Lesion size, increase in lesion size, persistent exudative process, subretinal fibrosis, and chorioretinal anastomosis at the follow-up examination. RESULTS: Large lesion (P <.001) and CNV (P =.003) sizes, and the presence of occult, no classic CNV (P =.013) at baseline predict a large lesion at follow-up. Other factors predicting a large lesion were subfoveal (P =.019) and bilateral lesions (P =.017) and the presence of hemorrhage (P =.012) at baseline. A large (P =.040) and bilateral lesion (P =.040) and hemorrhage (P =.011) at baseline were correlated with subretinal fibrosis at follow-up. Occult lesions (P =.002) at baseline were correlated with chorioretinal anastomosis at follow-up. CONCLUSION: The type and size of the late AMD lesion can partly be predicted from baseline characteristics.

Corneal innervation, corneal mechanical sensitivity, and tear fluid secretion after transscleral contact 670-nm diode laser cyclophotocoagulation.

PURPOSE: To examine the effect of 670-nm diode laser cyclophotocoagulation on corneal morphology, density of corneal subbasal nerves, corneal mechanical sensitivity, and the rate of tear fluid secretion in human eyes. PATIENTS AND METHODS: Transscleral contact cyclophotocoagulation was performed in 10 eyes of 10 consecutive patients on 180 degrees of the pars plicata of the ciliary body, using a 670-nm diode laser (power = 430 mW, application time = 10 seconds). In vivo confocal microscopy, with special attention to corneal morphology and the density of the subbasal nerves in the central and inferior perilimbal cornea, was performed preoperatively, and at 3 days and 1 month postoperatively. Corneal mechanical sensitivity was tested preoperatively, and at 3 days and 1 month postoperatively, using a Cochet-Bonnet esthesiometer. The rate of tear fluid secretion was measured preoperatively and 1 month postoperatively, using the Schirmer basic secretion tear test with topical anesthesia. RESULTS: After cyclophotocoagulation, in vivo confocal microscopy did not reveal any changes in any of the corneal layers or in the corneal subbasal nerves. After treatment, as compared with baseline (paired samples test, > 0.05), there was no statistically significant change in the mechanical sensitivity values in any part of the cornea or in the Schirmer basic secretion tear test result. CONCLUSION: The results of this preliminary study suggest that cyclophotocoagulation with the 670-nm diode laser does not impair corneal innervation.

Cyclophotocoagulation with the transscleral contact red 670-nm diode laser in the treatment of glaucoma.

PURPOSE: To retrospectively evaluate the results of cyclophotocoagulation (CPC) with the transscleral contact red 670-nm diode laser in treating glaucoma. METHODS: Cyclophotocoagulation was performed in 60 eyes of 60 patients with a mean age of 74 +/- 11 years (range 49-90 years). The treatment was delivered via a fibre-optic probe. The power per application was 430 mW. Exposure time was 10 seconds. RESULTS: The mean overall follow-up time after the initial CPC was 26 +/- 20 months (range 3-75 months). Preoperative intraocular pressure (IOP) was 27 +/- 11 mmHg (n = 60). After one or more CPC treatments, mean IOP decreased to 20 +/- 7 mmHg (n = 51) at 1 month, 19 +/- 5 mmHg (n = 45) at 3 months, 18 +/- 5 mmHg (n = 29) at 6 months, 19 +/- 7 mmHg (n = 22) at 1 year, 18 +/- 7 mmHg (n = 16) at 2 years, 14 +/- 4 mmHg (n = 8) at 3 years, and 18 +/- 6 mmHg (n = 60) at the last follow-up. An IOP of 8-21 mmHg or a > 30% decrease in IOP was obtained in 33 of 41 eyes (80%) with baseline IOP > 21 mmHg at the last follow-up. Hypotonia (IOP < 8 mmHg) did not develop in any of the eyes studied. CONCLUSIONS: Cyclophotocoagulation with the red 670-nm diode laser is an effective and well tolerated means of treating glaucoma.

Transscleral red-laser cyclophotocoagulation combined with limited anterior retinal cryocoagulation in neovascular glaucoma.

PURPOSE: To evaluate transscleral contact red-laser cyclophotocoagulation (CPC), using a visible red 647-nm krypton or 670-nm diode laser and limited transscleral anterior retinal cryocoagulation in neovascular glaucoma. METHODS: In a retrospective case series, 35 eyes of 35 consecutive patients treated during a period of 6 years were included in the study. Inclusion was dependent on follow-up of at least 1 month. Patients who had undergone previous cyclodestructive procedures and patients who received an additional glaucoma operation in conjunction with CPC were excluded. In the combined procedure, the power per CPC application was 370-450 mW and exposure time was 10 seconds. One to two rows of cryoapplications were given to 360 degrees of the anterior retina. RESULTS: The success rate in terms of intraocular pressure (IOP of 8-21 mmHg or a decrease in IOP > 30%) was 89% at the last follow-up (17 +/- 15 months). Iris neovascularization regressed in 51% of eyes. Hypotonia developed in one (3%) eye (IOP of 5 mmHg). No cases of phthisis bulbi were seen. Visual acuity (VA) declined in 49% of eyes. CONCLUSIONS: A combination of transscleral contact red-laser CPC with limited anterior retinal cryocoagulation is efficient in lowering IOP in neovascular glaucoma and is well tolerated. During follow-up, a decrease in VA occurs in a significant proportion of patients.

Vasoactive mediators and retinopathy during type 1 diabetic pregnancy.

PURPOSE: To evaluate the role of various vasoactive hormones in the evolution of diabetic retinopathy during pregnancy and postpartum. METHODS: Retinopathy was graded from fundus photographs of 45 pregnant women with type 1 diabetes and seven pregnant women without diabetes in a prospective study. Markers of renin-angiotensin-system (RAS), plasma renin activity (PRA), angiotensin II (AngII), aldosterone, natriuretic peptides (ANP, BNP, CNP) and adreonomedullin (AM) were measured during the first and third trimesters and at 3 months postpartum. The women with diabetes were grouped by progression of retinopathy during pregnancy and postpartum. RESULTS: Levels of PRA (p = 0.001) and ANP (p = 0.03) were significantly lower in diabetes than in non-diabetes subjects throughout pregnancy and postpartum. No significant differences appeared in levels of AngII, aldosterone, AM, BNP or CNP between the two groups. In multivariate logistic regression analyses with retinopathy progression by the third trimester as the dependent variable, only duration of diabetes qualified in the model (p = 0.027, R = 0.227, Exp(B) = 1.28). CONCLUSIONS: Diabetic pregnancy is associated with lower levels of PRA and ANP compared to non-diabetic pregnancy. Lowered RAS activity may contribute to the hyperdynamic blood flow and progression of DR during diabetic pregnancy. Within the power of this study no clear associations between the vasoactive hormones and progression of retinopathy could be detected.

Topographic change in the central macula coupled with contrast sensitivity loss in diabetic pregnancy.

PURPOSE: To study macular topography and contrast sensitivity (CS) in diabetic and nondiabetic women during pregnancy and post partum. METHODS: A prospective study of 46 pregnant women with insulin-dependent diabetes and 11 nondiabetic pregnant controls. Macular surface topography was analyzed by Heidelberg Retinal Tomograph. Volume above the reference plane (VARP) was measured with 1.0-, 1.5-, 2.0-, and 3.0-mm-diameter circles. CS was measured with the Vistech 6500 Contrast Test System. RESULTS: The diabetic women had greater VARP than the controls measured with the 1.5-mm diameter circle. In diabetic women, the mean VARP was 0.084+/-0.064 mm(3) (mean +/- SD) in the first trimester, 0.080 +/- 0.056 mm(3) in the third trimester, and 0.087 +/- 0.067 mm(3) 3 months post partum compared with the values of 0.069+/-0.043, 0.054+/-0.024, and 0.036+/-0.020 mm(3) in the controls ( P=0.036 between groups). In diabetic women requiring laser treatment, the difference from controls was more significant ( P<0.001). CS at 3 cpd and 6.0 cpd was lower in diabetic women than in controls throughout pregnancy and post partum ( P=0.012 and P=0.043). A statistically significant negative correlation appeared between macular topography and CS during the third trimester; between cpd 6 and VARP 1.5 mm ( r=-0.471, P=0.001), and between cpd 6 and VARP 2.0 mm ( r=-0.446, P=0.002). CONCLUSIONS: In the diabetic women, especially in those with clear progression of retinopathy during pregnancy and post-partum, the macula seemed to be slightly more elevated than in the controls, and CS was lower at mid-range spatial frequencies. CS loss in the diabetic women correlated with macular elevation during the third trimester.