Yannek I. Leiderman

Rapid response of retinal pigment epithelial detachments to intravitreal aflibercept in neovascular age-related macular degeneration refractory to bevacizumab and ranibizumab

PurposeThe aim of this study is to report the short-term efficacy of aflibercept in the treatment of neovascular age-related macular degeneration (AMD) with associated retinal pigment epithelial detachment (PED) which is refractory or develops tachyphylaxis to bevacizumab and ranibizumab.MethodsThe method comprised a retrospective review of the medical records of patients with neovascular AMD and associated PEDs recently treated with aflibercept and previously treated with bevacizumab and ranibizumab.ResultsThree eyes of three female patients of ages 49, 55, and 65 years old with large serous PEDs and subretinal fluid (SRF) associated with occult choroidal neovascularization and neovascular AMD were treated with aflibercept after intravitreal bevacizumab and/or ranibizumab failed to resolve the lesions. All had complete resolution of SRF and complete or near-complete resolution of the PEDs after aflibercept injections over a 3-month period. Visual acuity improved in all three eyes.ConclusionIntravitreal aflibercept may be an effective treatment option for serous PED in neovascular AMD patients after bevacizumab and ranibizumab have previously failed. Larger studies with longer follow-up are required to determine the role of aflibercept in treatment of PED in neovascular AMD.

Molecular genetics of RB1--the retinoblastoma gene.

Thirty-seven years ago Alfred Knudson proposed his “two-hit” theory of the molecular etiology of retinoblastoma, establishing an elegant conceptual paradigm for tumorigenesis in general. A great body of work has subsequently elucidated the structure and function of the RB1 gene and the biology of its protein product, pRB. Multiple categories of mutations have been characterized and correlated with phenotypic expression, including translocations, deletions, insertions, and point mutations. The purpose of this review is to provide a concise overview of the molecular genetics and genotype-phenotype correlations in retinoblastoma.

Proliferative Vitreoretinopathy: Pathobiology and Therapeutic Targets

The cell biology and molecular mediators of proliferative vitreoretinopathy continue to be elucidated. The purpose of this review is to summarize contemporary findings in the visual and neurosciences relevant to the pathophysiology of proliferative vitreoretinopathy, with an emphasis on the biologic mediators that represent potential therapeutic targets.

Diagnosis, classification, and treatment of retinoblastoma.

Retinoblastoma represents approximately 4% of all pediatric malignancies and is the most common primary intraocular cancer in children. Worldwide, it is estimated that there are 5000 to 8000 newly diagnosed cases of retinoblastoma yearly. In the United States, approximately 250 to 350 cases are diagnosed each year. The first description of a child successfully treated with radiation for retinoblastoma was reported in 1903. Since that time, improvement in survival of retinoblastoma has been faster than any other cancer in children or adults. In 2003, retinoblastoma was the pediatric cancer with the highest survival. In the Western world, 99% of children will survive this cancer and over 90% will retain normal vision in at least 1 eye. Unfortunately, primarily to late detection of advanced retinoblastoma, in medically underdeveloped nations survival drops to approximately 50%. A genetic basis for the development of retinoblastoma was recognized over 70 years ago. In 1971, after noting differences in tumor development in patients with unilateral versus bilateral retinoblastoma, Knudson proposed his now famous two-hit model of tumorgenesis. The retinoblastoma gene (RB1) was the first human cancer gene cloned and was the first of a whole new class of human tumor-suppressor genes. The protein responsible for intraocular retinoblastoma is vital for terminal differentiation of many cell lineages, including differentiation of retinal progenitor cells. It is now recognized that the loss of normal functioning RB1 is an important step in the development of many adult nonocular cancers.

Diffusion-weighted magnetic resonance imaging of bilateral simultaneous optic nerve infarctions

AN 85-YEAR-OLD MAN presentedwithcomplete loss of vision. Duringtheweekprior topresentation,hereportedgraduallyprogressiveblurred anddarkvisioninbotheyeswithdramaticworseningonthedayofpresentation.Hehadnoothersymptoms,includingheadache.Hismedicalhistory was significant for hypertension and peripheral vascular disease. On examination, his blood pressure was elevated. There was no cranial artery tenderness. He was alert withintactlanguageandmemory.Visual acuity was light perception OU. Both pupils were 4 mm and nonreactive to light. Eye movements were normal,andcornealreflexeswereintactandsymmetric.Funduscopicexamination showed bilateral optic nerve head edema with right optic nervesectoralpallorandaleftmacularinfarction(Figure,AandB).The remainderoftheneurologicalexamination was normal. Magnetic resonanceimagingshowedrestricteddiffusion (Figure, C and D) with a reduced apparent diffusion coefficient signal (not shown) within the leftintraorbitalopticnerveandatthe right anterior optic nerve. The platelet count was 1134/µL, the erythrocytesedimentationratewas40mm/h, and the C-reactive protein level was 17.7 mg/L (to convert to nanomoles per liter, multiply by 9.524). COMMENT

Recurrent isolated sixth nerve palsy after consecutive annual influenza vaccinations in a child

Recurrent sixth nerve palsy in children in the absence of structural or other neurological abnormality is a rare occurrence. We report the case of recurrent isolated sixth (abducens) nerve palsy after consecutive annual influenza vaccinations in an otherwise-healthy 2-year-old boy. Investigations including magnetic resonance imaging of the brain and orbits after each episode failed to reveal any abnormality. The temporal relation to the immunizations supports but does not prove that the influenza immunization regimen was responsible.

TGFβ signaling induces expression of Gadd45b in retinal ganglion cells.

PURPOSE Growth arrest and DNA damage protein 45b (Gadd45b) functions as an intrinsic neuroprotective molecule protecting retinal ganglion cells (RGCs) from injury. This study was performed to elucidate further the induction pathway of Gadd45b expression in RGCs. METHODS The induction of Gadd45b expression in response to TGFβNFκB signaling was investigated in RGC5 cultures in vitro and murine retina in vivo. Gadd45b mRNA and protein expression were detected by quantitative real-time RT-PCR, immunoblot assay, immunohistochemistry, and immunocytochemistry. Activation of NFκB and TGFβ/Gadd45b signaling were assessed by measuring phosphorylation of NFκB and using specific inhibitors. Gadd45b siRNA was transfected into RGC5 to silence Gadd45b mRNA expression. RESULTS Expression of TGFβ receptors I and II was detected in RGC5 in vitro and RGCs in vivo. TGFβ induced abundant Gadd45b mRNA and protein expression, exhibiting a dose-dependent response in vitro. Exogenous TGFβ1 induced upregulation of Gadd45b expression in RGCs in murine retina in vivo. TGFβ stimulated phosphorylation of NFκB, and inhibition of NFκB phosphorylation blocked induction of Gadd45b by TGFβ in RGC5 cells. Induction of Gadd45b by TGFβ increased the resistance of RGC5 cells against TNFα cytotoxicity and paraquat oxidative stress. CONCLUSIONS TGFβ signaling induced Gadd45b expression in RGCs. Modulation of the TGFβ/NFκB/Gadd45b signaling pathway may provide a means to enhance the neuroprotective effect of Gadd45b in RGCs.

Retinal Oximetry and Vessel Diameter Measurements With a Commercially Available Scanning Laser Ophthalmoscope in Diabetic Retinopathy

Purpose To test the hypothesis that retinal vascular diameter and hemoglobin oxygen saturation alterations, according to stages of diabetic retinopathy (DR), are discernible with a commercially available scanning laser ophthalmoscope (SLO). Methods One hundred eighty-one subjects with no diabetes (No DM), diabetes with no DR (No DR), nonproliferative DR (NPDR), or proliferative DR (PDR, all had photocoagulation) underwent imaging with an SLO with dual lasers (532 nm and 633 nm). Customized image analysis software determined the diameters of retinal arteries and veins (DA and DV) and central retinal artery and vein equivalents (CRAE and CRVE). Oxygen saturations of hemoglobin in arteries and veins (SO2A and SO2V) were estimated from optical densities of vessels on images at the two wavelengths. Statistical models were generated by adjusting for effects of sex, race, age, eye, and fundus pigmentation. Results DA, CRAE, and CRVE were reduced in PDR compared to No DM (P ≤ 0.03). DV and CRVE were similar between No DM and No DR, but they were higher in NPDR than No DR (P ≤ 0.01). Effect of stage of disease on SO2A differed by race, being increased relative to No DM in NPDR and PDR in Hispanic participants only (P ≤ 0.02). Relative to No DM, SO2V was increased in NPDR and PDR (P ≤ 0.05). Conclusions Alterations in retinal vascular diameters and SO2 by diabetic retinopathy stage can be detected with a widely available SLO, and covariates such as race can influence the results.

The effects of diabetic retinopathy stage and light flicker on inner retinal oxygen extraction fraction

Purpose We determined the effects of light flicker and diabetic retinopathy (DR) stage on retinal vascular diameter (D), oxygen saturation (SO2), and inner retinal oxygen extraction fraction (OEF). Methods Subjects were categorized as nondiabetic control (NC, n = 42), diabetic with no clinical DR (NDR; n = 32), nonproliferative DR (NPDR; n = 42), or proliferative DR (PDR; n = 14). Our customized optical imaging system simultaneously measured arterial and venous D (DA, DV) and SO2 (SO2A, SO2V) before and during light flicker. Inner retinal OEF was derived from SO2 values. Light flicker–induced ratios of metrics (DAR, DVR, SO2AR, SO2VR, OEFR) were calculated. Results Arterial D was larger in NPDR compared to NC (P = 0.01) and PDR (P = 0.002), whereas DV was similar among groups (P ≥ 0.16). Light flicker increased DA and DV (P ≤ 0.004), but DAR and DVR were similar among groups (P ≥ 0.09). Arterial SO2 was higher in all groups compared to NC (P ≤ 0.02) and higher in PDR compared to NDR and NPDR (P<0.001). Arterial SO2 did not change with light flicker (P ≥ 0.1). Venous SO2 was higher in NPDR and PDR compared to NC and NDR (P ≤ 0.02). Light flicker increased SO2V in NC, NDR, and PDR (P ≤ 0.003), and SO2VR was lower in NPDR compared to NC and NDR (P ≤ 0.05). Inner retinal OEF was lower in NPDR compared to NDR and PDR (P ≤ 0.02). Light flicker decreased OEF (P ≤ 0.03), but OEFR was greater in NPDR compared to NC and NDR (P ≤ 0.03). Conclusions The findings of alterations in retinal D, SO2, OEF, and their light flicker–induced responses at stages of DR may be useful to elucidate the pathophysiology of DR.

PARS PLANA VITRECTOMY COMBINED WITH CATARACT EXTRACTION: A Comparison of Surgical Outcomes Using Single-Piece and Multipiece Foldable Intraocular Lenses.

Purpose: To assess whether complication rates are comparable between phacovitrectomy using multipiece lenses versus single-piece foldable intraocular lenses. Methods: Single-center, multisurgeon retrospective comparative consecutive interventional case series. Two hundred and seventy-one patients undergoing combined phacovitrectomy performed during a single session at a university-based ophthalmology practice from 2004 to 2013 were identified, of whom 184 met study inclusion criteria; 56.4% patients had diabetes mellitus. Results: There was no difference in the total incidences of postoperative complications between combined surgery using single-piece and multipiece intraocular lenses (P = 0.80) or among individual complications between the 2 groups, including synechiae (2.7 vs. 5.3%; P = 0.61), pupillary capture (0.7 and 2.6%; P = 0.36), and lens subluxation (1.4 and 0%; P > 0.99). There was no difference in the incidences of complications in patients with diabetes mellitus compared with nondiabetic patients undergoing phacovitrectomy (P = 0.13). Complication rates did not differ between single-piece and multipiece lenses with the use of postoperative intravitreal tamponade (P = 0.67). Conclusion: Single-piece, acrylic intraocular lenses are associated with a low rate of surgical complications after combined phacovitrectomy and represent an acceptable alternative to multipiece foldable intraocular lenses under the circumstances and using the surgical techniques implemented in this study.