A systematic review and meta-analysis of the effect of intravitreal VEGF inhibitors on cardiorenal outcomes.

BACKGROUND: Vascular endothelial growth factor inhibitors (VEGFis) have transformed the treatment of many retinal diseases, including diabetic maculopathy. Increasing evidence supports systemic absorption of intravitreal VEGFi and development of significant cardiorenal side effects. METHODS: We conducted a systematic review and meta-analysis (PROSPERO: CRD42020189037) of randomised controlled trials of intravitreal VEGFi treatments (bevacizumab, ranibizumab and aflibercept) for any eye disease. Outcomes of interest were cardiorenal side effects (hypertension, proteinuria, kidney function decline and heart failure). Fixed effects meta-analyses were conducted where possible. RESULTS: There were 78 trials (81 comparisons; 13 175 participants) that met the criteria for inclusion: 47% were trials in diabetic eye disease. Hypertension (29 trials; 8570 participants) was equally common in VEGFi and control groups {7.3 versus 5.4%; relative risk [RR] 1.08 [95% confidence interval (CI) 0.91-1.28]}. New or worsening heart failure (10 trials; 3384 participants) had a similar incidence in VEGFi and control groups [RR 1.03 (95% CI 0.70-1.51)]. Proteinuria (5 trials; 1902 participants) was detectable in some VEGFi-treated participants (0.2%) but not controls [0.0%; RR 4.43 (95% CI 0.49-40.0)]. Kidney function decline (9 trials; 3471 participants) was similar in VEGFi and control groups. In participants with diabetic eye disease, the risk of all-cause mortality was higher in VEGFi-treated participants [RR 1.62 (95% CI 1.04-2.46)]. CONCLUSION: In trials of intravitreal VEGFi, we did not identify an increased risk of cardiorenal outcomes, although these outcomes were reported in only a minority of cases. There was an increased risk of death in VEGFi-treated participants with diabetic eye disease. Additional scrutiny of post-licensing observational data may improve the recognition of safety concerns in VEGFi-treated patients.

Mutations in TSPAN12 cause autosomal-dominant familial exudative vitreoretinopathy.

Familial exudative vitreoretinopathy (FEVR) is an inherited blinding disorder of the retinal vascular system. Although mutations in three genes (LRP5, FZD4, and NDP) are known to cause FEVR, these account for only a fraction of FEVR cases. The proteins encoded by these FEVR genes form part of a signaling complex that activates the Norrin-beta-catenin signaling pathway. Recently, through a large-scale reverse genetic screen in mice, Junge and colleagues identified an additional member of this signaling complex, Tspan12. Here, we report that mutations in TSPAN12 also cause autosomal-dominant FEVR. We describe seven mutations identified in a cohort of 70 FEVR patients in whom we had already excluded the known FEVR genes. This study provides further evidence for the importance of the Norrin-beta-catenin signaling pathway in the development of the retinal vasculature and also indicates that more FEVR genes remain to be identified.

Null mutations in LTBP2 cause primary congenital glaucoma.

Primary congenital glaucoma (PCG) is an autosomal-recessive condition characterized by high intraocular pressure (IOP), usually within the first year of life, which potentially could lead to optic nerve damage, globe enlargement, and permanent loss of vision. To date, PCG has been linked to three loci: 2p21 (GLC3A), for which the responsible gene is CYP1B1, and 1p36 (GLC3B) and 14q24 (GLC3C), for which the genes remain to be identified. Here we report that null mutations in LTBP2 cause PCG in four consanguineous families from Pakistan and in patients of Gypsy ethnicity. LTBP2 maps to chromosome 14q24.3 but is around 1.3 Mb proximal to the documented GLC3C locus. Therefore, it remains to be determined whether LTBP2 is the GLC3C gene or whether a second adjacent gene is also implicated in PCG. LTBP2 is the largest member of the latent transforming growth factor (TGF)-beta binding protein family, which are extracellular matrix proteins with multidomain structure. It has homology to fibrillins and may have roles in cell adhesion and as a structural component of microfibrils. We confirmed localization of LTBP2 in the anterior segment of the eye, at the ciliary body, and particularly the ciliary process. These findings reveal that LTBP2 is essential for normal development of the anterior chamber of the eye, where it may have a structural role in maintaining ciliary muscle tone.

Familial exudative vitreoretinopathy and DiGeorge syndrome: a new locus for familial exudative vitreoretinopathy on chromosome 22q11.2?

PURPOSE: To describe a patient with DiGeorge syndrome in association with familial exudative vitreoretinopathy (FEVR). DESIGN: Observational case report. PARTICIPANTS: A newborn female and her parents. METHODS: Family members were examined by slit-lamp biomicroscopy and indirect ophthalmoscopy. Deletion mapping was performed by fluorescent in situ hybridization and genotyping. Mutation screening was undertaken by direct sequencing. MAIN OUTCOME MEASURES: The presence or absence of a microdeletion on chromosome 22q11.2 in the patient and her parents and mutation screening of FZD4 and LRP5 in the patient. RESULTS: The patient had classical features of DiGeorge syndrome and FEVR. A de novo microdeletion on chromosome 22q11.2 was found in the patient, confirming the diagnosis of DiGeorge syndrome. No mutations were identified in the known FEVR genes. CONCLUSIONS: Patients with DiGeorge syndrome should have a dilated retinal examination to look for signs of FEVR. Chromosome 22q11.2 may represent a novel locus for FEVR.

Photodynamic Therapy for Circumscribed Choroidal Haemangioma in a Scottish Cohort.

PURPOSE: The aim of this study was to evaluate the safety and efficacy of photodynamic therapy (PDT) with verteporfin as a treatment for circumscribed choroidal haemangioma (CCH). PROCEDURES: This is a retrospective cohort study of all treatment-naïve patients undergoing PDT with verteporfin for CCH in a single centre between April 1, 2007, and September 30, 2016. Best corrected visual acuity (BCVA; using ETDRS letter score), optical coherence tomography (OCT) measurements and a subjective measurement of visual function were recorded before treatment, at 3-month follow-up and at each annual follow-up. RESULTS: Seventeen Caucasian patients with CCH received PDT, with a re-treatment rate of 23.5% (n = 4). Mean (±SD) follow-up was 36.5 (±32.6) months (range 2-106). Mean (±SD) pre-PDT BCVA was 58.5 (±15.5) letters, with a mean improvement from baseline of 8.2 letters at 3 months, of 13.8 letters at 1 year, of 21.1 letters at 2 years and of 19.5 letters at 3 years of follow-up. Subjective visual improvement was noted in 67% at 3 months, in 93% at 1 year, in 86% at 2 years and in 100% at 3 years of follow-up. OCT demonstrated no intraretinal/subretinal fluid in 63% at 3 months, in 77% at 1 year, in 86% at 2 years and in 100% at 3 years of follow-up. No complications of PDT were noted during the study. CONCLUSIONS: PDT is a safe and effective treatment for CCH which results in both structural and functional improvements, and these findings are particularly applicable to patients of Caucasian ethnicity. OCT provides a useful and readily available option to monitor CCH disease activity and its response to PDT.

Recessive mutations in TSPAN12 cause retinal dysplasia and severe familial exudative vitreoretinopathy (FEVR).

PURPOSE: Familial exudative vitreoretinopathy (FEVR) is an inherited disorder that disrupts the development of the retinal vasculature and can result in blindness. FEVR is genetically heterogeneous and mutations in four genes, NDP, FZD4, LRP5, and TSPAN12, encoding components of a novel ligand-receptor complex that activates the Norrin-ß-catenin signaling pathway, account for approximately 50% of cases. We recently identified mutations in TSPAN12 as a cause of dominant FEVR. The purpose of this study was to identify recessive TSPAN12 mutations in FEVR patients. METHODS: Mutation screening was performed by directly sequencing PCR products generated from genomic DNA with primers designed to amplify the coding sequence of TSPAN12. Splicing defects were verified by reverse transcriptase PCR of leukocyte cDNA. RESULTS: TSPAN12 screening in a large dominant FEVR family unexpectedly led to the identification of homozygous mutations in severely affected family members, whereas mildly affected family members were heterozygous. Further screening in a cohort of 10 retinal dysplasia/severe FEVR patients identified an additional three cases with recessive TSPAN12 mutations. In all examined cases, single mutation carriers were mildly affected compared to patients harboring two TSPAN12 mutations. CONCLUSIONS: We report for the first time recessive mutations in TSPAN12 and describe the first genetic cause for the clinical variation seen in FEVR families. Our data raise the possibility that patients with severe FEVR actually may harbor two mutant alleles, derived either from the same gene or potentially from other genes encoding components of the Norrin-ß-catenin signaling pathway.