María R. Sanabria

A Strong Genetic Association between the Tumor Necrosis Factor Locus and Proliferative Vitreoretinopathy: The Retina 4 Project

OBJECTIVE To assess the genetic contribution to proliferative vitreoretinopathy (PVR) and report the strong association observed in the tumor necrosis factor (TNF) locus. DESIGN As a component of The Retina 4 Project, a case-controlled, candidate gene association study in the TNF locus was conducted. PARTICIPANTS AND CONTROLS Blood from 450 patients with (138 cases) and without (312 controls) post-rhegmatogenous retinal detachment (RD) PVR was genotyped to determine polymorphisms located in the TNFα gene. METHODS Single nucleotide polymorphisms (SNPs) with correlation coefficients of ≥ 0.8 and a minor allelic frequency of ≥ 10% were studied. Functional SNPs or SNPs previously described in association with other inflammatory diseases were also added for analysis. The SNPlex Genotyping System (Applied Biosystems, Foster City, CA) was used for genotyping. Single nucleotide polymorphism and haplotype analyses were performed. Bioinformatic tools were used to evaluate those SNPs that were significantly associated. MAIN OUTCOME MEASURES Single and haplotypic significant associations with PVR. RESULTS A total of 11 common tag SNPs in the following genes were analyzed: lymphotoxin alpha (LTA), TNFα, leukocyte-specific transcript 1 (LST1), and the activating natural killer receptor p30 (NCR3). After permutation, there was a significant association in the non-synonymous polymorphism rs2229094(T→C) in the LTA gene (P = 0.0283), which encodes a cysteine to arginine change in the signal peptide. This marker was also present in all significant haplotypic associations and was not observed in any nonsignificant associations. When this SNP was analyzed using bioinformatic tools, the hydropathy profile changed, as well as the transmembrane region and the splicing site predictions. CONCLUSIONS The strong association found in the rs2229094(T→C) of the LTA gene may indicate an important role of this polymorphism in the development of PVR. If supported in extended studies, the rs2229094(T→C) may have significant implications regarding the genetic risk of the retinal repairing process.

Non-complicated retinal detachment management: variations in 4 years. Retina 1 project; report 1

Aims: To assess variations in the characteristics and management of two series of non-complicated rhegmatogenous retinal detachments (RD) carried out 4 years apart in Spain. Methods: Prospective, multicentric, non-randomised comparative study. 339 consecutive cases of RD treated in five hospitals were included. Group 1 (G1) (n = 186) included cases operated on from 1999 to 2001; group 2 (G2) (n = 153) included cases from 2004 to 2006. 83 variables related to preoperative characteristics of RD, surgical management and postoperative evolution were recorded. Surgeons were allowed to treat patients following their personal criteria. Differences in preoperative characteristics, rate of vitrectomy and anatomical outcome were studied. Quantitative variables were compared by Mann–Whitney U test and qualitative variables by standard contingency tables. Multivariate analysis was carried out by logistic regression analysis. Results: G1 showed a significantly longer delay in performing surgery, since the first symptoms appeared (G1: 29 (SD 50) days; G2: 22 (55); p<0.001) and more RD without visible retinal break than G2 (G1: 17.4%; G2: 9.2%; p = 0.028). In G2, cases with multiple retinal breaks (G1: 31.6%; G2: 44.6%) were more frequent (p = 0.022). No significant differences in other preoperative variables were observed. Vitrectomy was performed in 30.1% in G1 and in 78.4% in G2 as a primary surgical approach (p<0.001). Regardless of the characteristics of the RD, the rate of vitrectomy was higher in G2. The reattachment rate was over 94% in both groups (p = 0.833). Pseudophakic RD showed better anatomical outcomes in G2 (G1: 83.9%; G2: 96.4%; p = 0.028). Conclusion: There is an increasing tendency to treat RD with primary vitrectomy, which is related to neither a higher complexity of cases nor better anatomical results.

Oct findings in torpedo maculopathy.

BACKGROUND Torpedo maculopathy, also called solitary hypopigmented nevus, is a rare though benign disorder. To our knowledge, there are no previous optical coherence tomography (OCT) descriptions in the literature. METHODS Results of ophthalmologic examinations (including retinography, OCT, and visual field testing) for 2 girls aged 12 years and 13 years throughout 5 years of follow-up were reviewed. RESULTS In both cases, anterior and posterior segment evaluation was unremarkable except for the presence of a flat, fishtail-shaped, hypopigmented lesion temporal to the macula, pointing to the fovea. In case 1, OCT disclosed faint thinning of the retina above the lesion especially in the outer retina and hyperreflectivity of the retinal pigment epithelium (RPE) associated with a posterior hyperreflective signal deep in the choroids. In case 2, OCT showed an atrophic retina with reduced thickness probably due to the absence of the photoreceptor layer. Shallow serous neurosensory detachment, increased RPE reflectivity, and higher penetration of light to the choroid were also evident. CONCLUSION In both cases of torpedo maculopathy studied by OCT, we found a variable amount of retinal degeneration, and a serous retinal detachment was found in one case.

Ocular pain after intravitreal injection.

Abstract Purpose: To evaluate the efficacy of different anesthetics and topical anti-inflammatory treatment in patients undergoing intravitreal injections (IVI). Methods: Prospective, randomized, double masked, comparative study. Patients undergoing 0.05 mL IVI were randomized to two different preoperative anesthetic regimes (regime A [0.5% tetracaine + naphazoline] versus regime B [5% lidocaine]) and two different post-injection topical protocols (protocol 1 [tobramycin qid] versus protocol 2 [tobramycin qid + diclofenac qid]). Patients were trained to score pain using a numerical rating pain scale from 0 (no pain) to 10 (excruciating pain) immediately after the injection, 30 min and 24 h later. Patients were instructed to take oral paracetamol (650–1000 mg, adjusted to the patient’s weight) every six hours ad lib if necessary. Results: A total of 156 patients were enrolled; 86 patients were randomized to regime A and 70 to regime B; 78 patients were assigned to each of the post-injection topical protocols. The average pain score immediately after the IVI was 2.77 (SD 2.12) for the whole group (2.85, SD 2.23 with tetracaine and 2.67, SD 2.00 with lidocaine; p = 0.73, Mann–Whitney U-test). Twenty-four hours later, the average pain score was 1.84, SD 2.45 (topical diclofenac + tobramycin) versus 1.75, SD 1.83 (topical tobramycin; p = 0.46, Mann–Whitney U-test). Forty-seven patients (30%) required oral paracetamol (average 3.3 and range 1–5 tablets). Conjunctival hemorrhage 30 min after the injection was less frequent and severe in eyes treated with topical naphazoline (p = 0.055, Mann–Whitney U-test). Conclusions: Topical tetracaine and lidocaine provide similar anesthesia before IVI. Topical diclofenac does not seem to reduce pain scores after IVI.

PRPH2 (Peripherin/RDS) mutations associated with different macular dystrophies in a Spanish population: a new mutation.

Purpose. To assess the occurrence of PRPH2 mutations in patients presenting macular dystrophies and to describe their phenotype-genotype correlation. Methods. A total of 32 sporadic cases and 13 individuals from 5 families were studied. The patients presented early onset drusen, suspected pattern dystrophy (including adult-onset foveomacular vitelliform dystrophy [AOFVD]), or any presumed macular dystrophy producing neovascularization or atrophic changes documented before patients reached 50 years of age. In case of atrophy, this could be confined to the macula, which was considered to be central areolar choroidal dystrophy (CACD), or extend to the midperiphery of the retina, which we called diffuse macular dystrophy (DMD). Clinical workup and analysis of PRPH2, EFEMP1, and TIMP3 genes were done. Results. Four mutations of the PRPH2 gene were found in 3 sporadic cases and 3 families (n=11). A p.R46X mutation, previously described in CACD, was found in 3 members of a family with AOFVD and in a sporadic case with DMD. A p.L45F mutation, described before in retinitis pigmentosa, was found in a sporadic case of AOFVD. A p.R195L mutation previously described in CACD was found in 2 members of a family with CACD. The latter was found in a family and a sporadic case (from the same village as the family) and all of them presented DMD. A new p.V209l mutation was found in a patient with AOFVD. Conclusions. New phenotypes were found for known mutations. No phenotype variation was observed in the members of the 3 families. A new mutation in PRPH2 gene was found.

Efficacy of intravitreal and periocular triamcinolone associated with photodynamic therapy for treatment of retinal angiomatous proliferation

Aims: To compare the relative efficacy of photodynamic therapy (PDT), PDT associated with intravitreal triamcinolone (PDT–IT) and PDT associated with periocular triamcinolone (PDT–PT) for treatment of retinal angiomatous proliferation (RAP) stage III. Methods: Retrospective, interventional, non-randomised multicentric study. The files, optical coherence tomography scans, indocyanine green and fluorescein angiograms of patients with RAP stage III who had been referred to a regional centre for PDT were retrospectively examined. Final visual acuity and chorioretinal atrophy were considered to be the main outcome indicators. The need to re-treat and recurrences were also considered. Results: Forty-two eyes were treated by PDT as monotherapy, 18 eyes by PDT–PT, and 19 eyes by PDT–IT. The mean (SD) age in each group was 79.1 (5.2), 77.0 (5.9) and 80.2 (5.1) years, respectively. The mean (SD) initial best corrected visual acuity (BCVA) was 0.17 (0.19), 0.21 (0.20) and 0.20 (0.18), respectively. Mean BCVA was 0.14 (0.19), 0.17 (0.15) and 0.17 (0.23), respectively, at 6 months (p = 0.27, 0.33 and 0.21, respectively) and 0.12 (0.18), 0.10 (0.10) and 0.17 (0.26), respectively, at 12 months (p = 0.12, 0.05 and 0.60, respectively, comparing vision at 6 months and 12 months with baseline; Student t test for paired data). Retinal pigment epithelium rips appeared in three eyes in group 1, in one eye in group 2, and in two eyes in group 3. Conclusion: Combined PDT–IT may offer better results than PDT monotherapy or PDT–PT in patients with RAP stage III.

External validation of existing formulas to predict the risk of developing proliferative vitreoretinopathy: the Retina 1 Project; report 5.

Purpose: To externally validate the accuracy of previously published formulas for predicting proliferative vitreoretinopathy development after retinal detachment surgery. Methods: Clinical variables from consecutive retinal detachment patients (n = 1,047) were collected from the Retina 1 Project conducted in 17 Spanish and Portuguese centers. These data were used for external validation of four previously published formulas, F1 to F4. Receiver-operating characteristic curves were used to validate the quality of formulas, and measures of discrimination, precision, and calibration were calculated for each. Concordance among the formulas was determined by Cohen kappa index. Results: The areas under the receiver-operating characteristic curves were as follows: F1, 0.5809; F2, 0.5398; F3, 0.5964; and F4, 0.4617. F1 had the highest accuracy, 74.21%. Almost 19% of proliferative vitreoretinopathy cases were correctly classified by F1 compared with 13%, 15%, and 10% for F2, F3, and F4, respectively. There was moderate concordance between F2 and F3 but little between the other formulas. Conclusion: After external validation, none of the formulas were accurate enough for routine clinical use. To increase its usefulness, other factors besides the clinical ones considered here should be incorporated into future formulas for predicting risk of developing proliferative vitreoretinopathy.

Variations in Functional and Anatomical Outcomes and in Proliferative Vitreoretinopathy Rate along a Prospective Collaborative Study on Primary Rhegmatogenous Retinal Detachments: The Retina 1 Project—Report 4

Purpose. To analyse variations in the anatomical and functional outcomes and in proliferative vitreoretinopathy (PVR) rate of a prospective multicentric study that was primarily designed for identification of clinical risk factors for PVR. Methods. 1,046 retinal detachment (RD) cases were analysed. Cases were divided into two series based upon variation in PVR rate determined by logistic regression analysis. Series 1 (S1) included RD treated during 2004-2005 (n = 481) and Series 2 (S2) during 2006–2008 (n = 565). Pre-, intra-, and postoperative characteristics were recorded. Results. There were few differences in the preoperative characteristics. S2 had more vitrectomies and scleral bands and fewer explants and associated cataract extractions than S1. Anatomic reattachment improved from 87.9% to 92.9% in S1 and S2, respectively, (P = 0.006). Visual acuity at 3 months ≥20/40 increased from 36.5% of S1 to 44.2% in S2 (P = 0.049). PVR rate diminished from 14.1% in S1 to 8.1% in S2 (P = 0.002). Centres with higher rates of PVR in S1 showed the greatest reductions in S2. Conclusion. An improvement in anatomical and functional outcome and PVR rate occurred in participating centres cannot be attributed to the learning curve of surgeons. We speculated that it could be an effect of their participation in the study.

A propensity score matching application: indications and results of adding scleral buckle to vitrectomy: The Retina 1 Project: Report 3.

Purpose To identify the indications and differences in outcomes for adding a scleral buckle (SB) to pars plana vitrectomy (PPV) in a prospective series of rhegmatogenous retinal detachment (RD) by using propensity score matching (PSM) to analyze causal effects in observational studies. Methods Data were collected from the Retina 1 Project, a prospective, interventional, nonrandomized study of consecutive RDs. Case selection was based upon treatment with PPV or PPV+SB. Surgeons followed personal criteria for the inclusion of SB in the PPV. Propensity score matching corrected for selection biases. Outcomes were assessed by anatomic and visual criteria and the development of proliferative vitreoretinopathy. Results Of 523 patients analyzed, 251 had PPV and 272 had PPV+SB. Surgeons used PPV+SB more frequently in younger patients with RD, in those with posterior or unidentified breaks, in phakic eyes, in eyes with the posterior vitreous attached, and for more extended RDs. Overall single surgery anatomic success rate was 86.4%. Based on PSM, there were no difference in reattachment rates of the PPV group, 86.9%, and the PPV+SB group, 85.93%. The incidence of PVR was similar in both groups, with 8.5% in the PPV group and 10.5% in the PPV+SB group. Conclusions Data from the Retina 1 Project established the indications for adding SB to PPV in treating primary RD in this series. No anatomic or visual differences between PPV and PPV+SB were found.

Loss of Visual Acuity after Successful Surgery for Macula-On Rhegmatogenous Retinal Detachment in a Prospective Multicentre Study

Purpose. To quantify the frequency of visual loss after successful retinal detachment (RD) surgery in macula-on patients in a multicentric, prospective series of RD. Methods. Clinical variables from consecutive macula-on RD patients were collected in a prospective multicentric study. Visual loss was defined as at least a reduction in one line in best corrected visual acuity (VA) with Snellen chart. The series were divided into 4 subgroups: (1) all macula-on eyes (n = 357); (2) macula-on patients with visual loss at the third month of follow-up (n = 53) which were further subdivided in (3) phakic eyes (n = 39); and (4) pseudophakic eyes (n = 14). Results. Fifty-three eyes (14.9%) had visual loss three months after surgery (n = 39 phakic eyes; n = 14 pseudophakic eyes). There were no statistically significant differences between them regarding their clinical characteristics. Pars plana vitrectomy (PPV) was used in 67.2% of cases, scleral buckle in 57.7%, and scleral explant in 11.9% (36.1% were combined procedures). Conclusions. Around 15% of macula-on RD eyes lose VA after successful surgery. Development of cataracts may be one cause in phakic eyes, but vision loss in pseudophakic eyes could have other explanations such as the effect of released factors produced by retinal ischemia on the macula area. Further investigations are necessary to elucidate this hypothesis.