Wendelin Dailey

Effects of anti-VEGF treatment on the recovery of the developing retina following oxygen-induced retinopathy.

PURPOSE Inhibition of VEGF is widely used in patients to control neovascularization and decrease vascular permeability. To date, the effect of VEGF inhibition has not been evaluated in the developing retina such as that seen in premature infants. The goal of this study was to address the effect of anti-VEGF treatment on retinal development of a mouse model of retinopathy. METHODS C57BL/6J mice were evaluated using a model of oxygen-induced retinopathy. Test animals were treated at postnatal day (P) 14 with intravitreal injections of the VEGF inhibitor aflibercept (2.5 or 10 μg) in one eye. Control animals were treated with injection of PBS in one eye. The noninjected fellow eyes were used as internal controls. Areas of avascular retina and neovascular tufts in injected (treated) eyes and noninjected fellow eyes were determined at P17, and the difference related to these characteristics was obtained among them. To evaluate the effect of VEGF inhibition on neurogenesis, focal ERG was performed at P21 and P42. Histologic evaluation of the retinal structure was also evaluated at P42. RESULTS Aflibercept treatment reduced the amount of neovascular tufts but significantly increased the area of avascular retina (low dose and high dose) at P17. The delayed vascular growth corresponded to decreased ERG amplitudes (at P21 and P42) and structural changes in the retinal layers that persisted (at P42), despite vascular recovery. CONCLUSIONS Inhibition of VEGF in developing eyes has the short-term effect of delayed vascular growth and the long-term effects of decreased function with persistent changes in the neuroretinal structures.

Clinical presentation and genetic correlation of patients with mutations affecting the FZD4 gene.

OBJECTIVE To correlate the ophthalmic findings of patients with pediatric vitreoretinopathies with mutations occurring in the FZD4 gene. METHODS A total of 123 patients diagnosed with autosomal-dominant familial exudative vitreoretinopathy (AdFEVR) or retinopathy of prematurity (ROP) and 42 control patients were enrolled in the study. Diagnoses were based on retinal findings at each patients first examination or during ROP screening. Genomic DNA was isolated and polymerase chain reaction and direct sequencing of the FZD4 gene performed. RESULTS FZD4 gene mutations were discovered in 13 of the 123 (10.6%) patients. Nine of the 63 patients with AdFEVR (14.3%) has mutations in the FZD4 gene. Four heterozygous mutations were identified: C117R, C181Y, Q505X, and P33S/P168S. Four of the 60 patients with ROP (6.7%) have a double missense mutation P33S/P168S that was also found in the patients with FEVR. No other FZD4 mutations were found in the patients with ROP. Additionally, patients expressing the double mutation had clinical presentations that overlapped, making it difficult to assign a definitive diagnosis. None of the mutations found in the patients with FEVR or ROP were seen in the control chromosomes. CONCLUSION Mutations occurring in the FZD4 gene affect patients diagnosed with both FEVR and ROP. The clinical picture often overlaps and may require a detailed birth and family history for diagnosis. Genetic testing confirms inherited vitreoretinopathy and helps direct clinical management. Clinical Relevance Patients diagnosed with ROP may have a mutation in the FZD4 gene and display characteristics consistent with FEVR. Analysis of the FZD4 gene should be considered.

Elevated levels of cystatin C and tenascin-C in schisis cavities of patients with congenital X-linked retinoschisis.

Purpose: To describe the finding of tenascin C and cystatin-C in the intraschisis cavities of pediatric patients with intraretinal schisis cavities. Methods: Three patients with congenital X-linked retinoschisis (CXLRS) and one girl with clinical retinoschisis underwent vitrectomy for vision-threatening schisis cavities. At the time of surgery undiluted samples of intraschisis fluid and vitreous fluid from four eyes (three male and one female) were obtained and analyzed by gel electrophoresis and protein sequencing for the presence of tenascin C and cystatin-C. Results: Tenascin C and cystatin-C were found in all four samples of fluid from the intraschisis cavities, including a girl with a clinical presentation of CXLRS. The vitreous samples did not have detectable levels of either protein as determined by gel electrophoresis. Conclusions: Tenascin C and cystatin-C levels are elevated in intraschisis cavity fluid. Interestingly, this was also found in a girl not carrying a mutation in the retinoschisin gene, indicating that elevated concentrations of tenascin C and cystatin-C result from pathologic changes in the retina and not from the presence of aberrant retinoschisin.