Yashin Ramkissoon

A genetic case-control study confirms the implication of SMAD7 and TNF locus in the development of proliferative vitreoretinopathy.

PURPOSE Proliferative vitreoretinopathy (PVR) is still the major cause of failure of retinal detachment (RD) surgery and although the risk for developing this complication is associated with some clinical characteristics, the correlation is far from absolute, raising the possibility of genetic susceptibility. The objective of this study was to analyze the genetic contribution to PVR in patients undergoing RD surgery, the Retina 4 Project. METHODS A candidate gene association study was conducted in 2006 in a Spanish population of 450 patients suffering from primary rhegmatogenous RD. Replication was carried out in a larger population undergoing RD surgery at several European centers among 546 new patients. Single nucleotide polymorphism (SNP) of 30 genes known to be involved with inflammation were analyzed. For replication stage, those genes previously detected as significantly associated with PVR were genotyped. Distribution of allelic and haplotypic frequencies in case and control group were analyzed. Single and haplotypic analysis were assessed. The Rosenberg two-stage method was used to correct for single and multiple analyses. RESULTS After correction for multiple comparisons, four genes were significantly associated with PVR: SMAD7 (P = 0.004), PIK3CG (P = 0.009), TNF locus (P = 0.0005), and TNFR2 (P = 0.019) In the European sample, replication was observed in SMAD7 (P = 0.047) and the TNF locus (P = 0.044). CONCLUSIONS These results confirm the genetic contribution to PVR and the implication of SMAD7 and TNF locus in the development of PVR. This finding may have implications for understanding the mechanisms of PVR and could provide a potential new therapeutic target for PVR prophylaxis.

The p53 codon 72 polymorphism (rs1042522) is associated with proliferative vitreoretinopathy: the Retina 4 Project.

PURPOSE To compare the distribution of a p53 gene polymorphism among European subjects undergoing primary retinal detachment (RD) surgery in relation to the development of proliferative vitreoretinopathy (PVR). DESIGN Case-controlled gene association study conducted as a component of the Retina 4 Project (a European multicenter study). PARTICIPANTS AND CONTROLS Five hundred fifty DNA samples, 134 with PVR secondary to primary RD and 416 with RD without PVR. METHODS The p53 codon 72 polymorphism (rs1042522) was analyzed using allele-specific primer polymerase chain reaction. Proportions of genotypes and the proline (Pro-P) homozygote groups between subsamples from different countries were analyzed in 2 phases. In the first, subsamples from Spain and Portugal were analyzed. After significant results were found, samples from the United Kingdom (UK) and The Netherlands were analyzed (second phase). Genotypic and allelic frequencies were compared between cases and controls in the global sample. MAIN OUTCOME MEASURES Single significant associations with PVR. RESULTS A significant difference (P<0.05, Fisher exact test) was observed regarding the p53 genotype frequencies at codon 72 between the PVR cases and the non-PVR controls in Spain and Portugal (phase I), but not in the UK or The Netherlands (phase II). Analysis of Pro homozygote carriers between cases and controls revealed differences in Spain (29.01-42.18 and 2.29-10.20, respectively), Portugal (10.49-29.50 and 1.35-8.89, respectively), and The Netherlands (16.49-31.70 and 4.51-15.09, respectively), but no differences in the UK (7.68-18.1 and 4.85-13.94, respectively). The odds ratio of Pro carriers from Spain and Portugal together was 8.12 (95% confidence interval [CI], 3.72-17.69; P<0.05), whereas the odds ratio of Pro carriers from the UK and The Netherlands was 2.12 (95% CI, 0.96-4.68; P = 0.07). All control samples were in Hardy-Weinberg equilibrium. Considering the entire sample, significant differences were found in genotype frequencies between cases (RR, 30.59%; RP, 43.28%; PP, 26.11% [R = Arg; P = Pro]) and controls (RR, 39.66%; RP, 52.64%; PP, 7.69%) and in Pro homozygote carriers between controls (Pro homozygote 95% CI, 18.67-33.52) and cases (Pro homozygote 95% CI, 5.1-10.2). CONCLUSIONS Results indicate that the Pro variant of p53 codon 72 polymorphism is associated with a higher risk of PVR developing after a primary RD. Further studies are necessary to understand the role of this polymorphism in the development of PVR.

The T309G MDM2 gene polymorphism is a novel risk factor for proliferative vitreoretinopathy.

Proliferative vitreoretinopathy (PVR) is still the major cause of failure in retinal detachment (RD) surgery. It is believed that down-regulation in the p53 pathway could be an important key in PVR pathogenesis. The purpose was to evaluate the impact of T309G MDM2 polymorphism (rs2279744) in PVR. Distribution of T309G MDM2 genotypes among European subjects undergoing RD surgery was evaluated. Proportions of genotypes between subsamples from different countries were analyzed. Also, a genetic interaction between rs2279744 in MDM2 and rs1042522 in p53 gene was analyzed. Significant differences were observed comparing MDM2 genotype frequencies at position 309 of intron 1 between cases (GG: 21.6%, TG: 54.5%, TT: 23.8%) and controls (GG: 7.3%, TG: 43.9%, TT: 48.7%). The proportions of genotypes between sub-samples from different countries showed a significant difference. Distribution of GG genotype revealed differences in Spain (35.1–53.0)/(22.6–32.9), Portugal (39.0–74.4)/(21.4–38.9), Netherlands (40.6–66.3)/(25.3–38.8) and UK (37.5–62.4)/(23.3–34.2). The OR of G carriers in the global sample was 5.9 (95% CI: 3.2 to 11.2). The OR of G carriers from Spain and Portugal was 5.4 (95% CI: 2.2–12.7), whereas in the UK and the Netherlands was 7.3 (95% CI: 2.8–19.1). Results indicate that the G allele of rs2279744 is associated with a higher risk of developing PVR in patients undergoing a RD surgery. Further studies are necessary to understand the role of this SNP in the development of PVR.

Predicting proliferative vitreoretinopathy: temporal and external validation of models based on genetic and clinical variables

Purpose To validate three models for predicting proliferative vitreoretinopathy (PVR) based on the analysis of genotypic data and relevant clinical characteristics. Methods The validation series consisted of data from 546 patients operated on from primary rhegmatogenous retinal detachment (RRD) coming from centres in the Netherlands, Portugal, Spain and the UK. Temporal and geographical validation was performed. The discrimination capability of each model was analysed and compared with the original series, using a receiver operating curve. Then, clinical variables were combined in order to improve the predictive capability. A risk reclassification analysis was performed with and without each one of the variables. Reclassification of patients was compared and models were readjusted in the original series. Readjusted models were further validated. Results One of the models showed good predictability in the temporal sample as well as in the original series (area under the curve (AUC) original=0.7352; AUC temporal=0.6457, 95% CI 50.17 to 78.97). When clinical variables were included, only pre-existent PVR improves the predictability of this model in the validation series (temporal and geographical samples) (AUC original=0.7940 vs AUC temporal=0.7744 and AUC geographical=0.7152). The other models showed acceptable AUC values when clinical variables were included although they were less accurate than in the original series. Conclusions Genetic profiling of patients with RRD can improve the predictability of PVR in addition to the well-known clinical biomarkers. This validated formula could be a new tool in our current clinical practice in order to identify those patients at high risk of developing PVR.

BAX and BCL-2 polymorphisms, as predictors of proliferative vitreoretinopathy development in patients suffering retinal detachment: the Retina 4 project.

To compare the distribution of BCL‐2 ‐938C>A (rs2279115) and BAX ‐248G>A (rs4645878) genotypes among European subjects undergoing rhegmatogenous retinal detachment (RRD) surgery in relation to the further development of proliferative vitreoretinopathy (PVR).

Bilateral infiltrative disease of the extraocular muscles: a rare clinical presentation of early stage chronic lymphocytic leukemia.

Orbital involvement in chronic lymphocytic leukemia (CLL) is highly unusual and most commonly involves hemorrhage or soft tissue infiltration in advanced disease. We report a case of rapid onset bilateral orbital muscle infiltration as the presenting feature of early stage CLL. In addition, we demonstrate clinico-pathological correlation with an identical chronic B-cell lymphocytic infiltrate in both orbit and bone marrow, with good response of the orbital disease to local radiotherapy.

Use of hydroxypropylmethylcellulose 2% for removing adherent silicone oil from silicone intraocular lenses

Background/aims: To investigate the effect of hydroxypropylmethylcellulose (HPMC) on the physical interaction (contact angle) between silicone oil and a silicone intraocular lens (IOL). Methods: In vitro experiments were performed, to determine the effect of HPMC (0.5%, 1% or 2%), with or without an additional simple mechanical manoeuvre, on the contact angle of silicone oil at the surface of both silicone and acrylic (control) IOLs. A balanced salt solution chamber was used. The study group comprised 21 silicone and nine acrylic IOLs. Results: The median contact angle of silicone oil on silicone IOL was 99°. The addition of HPMC 2% alone did not significantly alter the contact angle. HPMC 2% combined with an additional single mechanical manoeuvre increased the contact angle to 180° (greater non-wetting), with complete separation of silicone oil from silicone IOL within 1 min. The manoeuvre alone, or in conjunction with a lower concentration of HPMC (0.5 or 1%), was ineffective in increasing the contact angle. Conclusion: We present a novel, non-toxic technique of using hydroxypropylmethylcellulose 2% combined with a simple mechanical manoeuvre, for the removal of adherent silicone oil droplets from silicone intraocular lenses.

Arterial occlusion after scleral buckling

We present a report of a young man with bilateral retinal dialyses in whom surgery, in the form of scleral buckling, was initially performed only to one eye. Post-operatively, he developed features of combined central retinal and distal choroidal artery occlusions in the operated eye. Postulated mechanisms for this complication included a period of systemic hypotension during surgery, and previously undiagnosed polycythaemia and activated protein-C resistance which were found on subsequent haematological investigations, these being risk factors for thrombosis. This case serves to highlight the need for caution in performing simultaneous bilateral scleral buckling surgery without routine haematological screening, due to the extremely rare but potentially devastating effects of bilateral vascular occlusion.