David N. Zacks

Retinal pigment epithelium tears after intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration.

Background: Intravitreal bevacizumab (Avastin, Genentech, Inc., South San Francisco, CA) treatment of neovascular age-related macular degeneration (AMD) has become an important part of clinical retinal practice. We describe retinal pigment epithelium (RPE) tears that were noted after intravitreal injection of bevacizumab. Methods: In this multimember, retrospective case series, data on eyes that developed RPE tears after intravitreal bevacizumab injection were collected and analyzed. Previous treatments, type of lesion, time to tear, and preinjection and final visual acuities were all compared. The total numbers of bevacizumab injections were available from all four institutions and compiled to estimate the incidence rate. Results: Four retina centers administered a total of 1,455 intravitreal 1.25-mg bevacizumab injections for neovascular AMD during the 9-month study period. Twelve patients presented with RPE tears within 4 days to 8 weeks of injection (mean ± SD, 24.3 ± 15.2 days from injection to tear). In each case, the RPE tear was preceded by an RPE detachment, and all had a component of serous sub-RPE fluid. On the basis of our collective data, we estimate an incidence rate of ≈0.8%. Conclusions: RPE tears can occur after intravitreal injection of bevacizumab. The low incidence of this adverse event should not preclude anti–vascular endothelial growth factor therapy counseling for patients with neovascular AMD, but eyes with serous RPE detachments appear to be most vulnerable to this adverse event.

Interleukin-6 as a photoreceptor neuroprotectant in an experimental model of retinal detachment.

PURPOSE To test the hypothesis that interleukin (IL)-6 prevents photoreceptor cell death during periods of retinal separation from the retinal pigment epithelium (RPE). METHODS Retinal-RPE separation was created in wild-type C57BL mice, IL-6(-/-) mice, and Brown Norway rats by subretinal injection of 1% hyaluronic acid. In some animals, anti-IL-6 neutralizing antibody (NAB) or exogenous IL-6 was administered into the subretinal space at the time of separation or at specified times afterward. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) was performed 3 days after separation to detect apoptotic photoreceptors. Photoreceptor cell counts were performed after 1 and 2 months. RESULTS Loss of IL-6 function through genetic ablation (IL-6(-/-) mice) or injection of anti-IL-6 NAB resulted in significantly increased levels of TUNEL-positive staining 3 days after retinal-RPE separation. One month after separation, outer nuclear layer (ONL) cell counts were significantly lower in IL-6(-/-) mice or in animals injected with anti-IL-6 NAB than in controls. Gain of IL-6 function through the addition of exogenous IL-6 resulted in significantly increased ONL counts at 1 month but not at 2 months. Reinjection of IL-6 at 1 month led to continued preservation of ONL counts compared with controls. A window of opportunity for treatment was detected because delaying injection of exogenous IL-6 to 2 weeks after retinal-RPE separation still resulted in significantly greater ONL cell counts compared with controls. CONCLUSIONS IL-6 may serve as a photoreceptor neuroprotectant in the setting of retinal-RPE separation.

Combined intravitreal injection of triamcinolone acetonide and panretinal photocoagulation for concomitant diabetic macular edema and proliferative diabetic retinopathy

Purpose: To present our results of intravitreal injection of triamcinolone acetonide (IVTA) combined with panretinal photocoagulation (PRP) for patients with concomitant clinically significant diabetic macular edema and proliferative diabetic retinopathy. Methods: Charts of patients undergoing combined IVTA and PRP were reviewed. Outcome measures included visual acuity, presence of macular edema, and response of proliferative disease to laser photocoagulation. Results: Four patients were included in this study. All patients maintained stable visual acuity during the treatment period. All patients had improvement in the amount of macular edema, despite the application of PRP, as well as complete regression of their proliferative disease. There were no short-term complications associated with IVTA or PRP. Conclusion: Combination treatment with IVTA and PRP may provide benefit in patients with diffuse diabetic macular edema who require urgent PRP for proliferative diabetic retinopathy by preventing exacerbation of macular edema.

Autophagy Activation in the Injured Photoreceptor Inhibits Fas-Mediated Apoptosis

PURPOSE To examine the activation of autophagy and its relationship to Fas-mediated photoreceptor apoptosis during experimental retinal detachment. METHODS Retina-retinal pigment epithelium (RPE) separation was created in Brown-Norway rats by subretinal injection of 1% hyaluronic acid and the intraretinal levels of the autophagy proteins LC3 and Atg5, the time course of LC3-I to LC3-II conversion, and the activation of cathepsins B and D were assayed with Western blot analysis and immunohistochemistry. We measured the ability of a Fas-activating antibody to induce LC3-I to LC3-II conversion in 661W cells, and the in vivo effect of Met12, a small molecule inhibitor of the Fas receptor, on LC3-I to LC3-II conversion and Atg5 expression. Autophagy activation was inhibited using 3-methyladenine (3-MA) or siRNA knockdown of Atg5 and the effect on apoptosis was measured using a caspase 8 activity assay, caspase 8 immunoblots, and photoreceptor TUNEL staining. RESULTS Retina-RPE separation resulted in a Fas-dependent activation of autophagy, with increased Atg5 levels and intraphotoreceptor conversion of LC3-I to LC3-II. Detached retinas had increased levels of autophagosome-associated lysosomal proteases, cathepsins B and D. Inhibition of autophagy by 3-MA or siAtg5 accelerated the time course of caspase 8 activation and photoreceptor TUNEL staining. CONCLUSIONS Autophagy activation occurs in the photoreceptors after retina-RPE separation. This appears to be, at least in part, dependent on Fas receptor activation, and plays a role in regulating the level of photoreceptor apoptosis.

Inhibition of Retinal Detachment-Induced Apoptosis in Photoreceptors by a Small Peptide Inhibitor of the Fas Receptor

Purpose. To test the effect of a small peptide inhibitor (Met12) of the Fas receptor on the activation of extrinsic and intrinsic apoptosis pathways after retinal detachment. Methods. Retinal-RPE separation was created in Brown Norway rats by subretinal injection of 1% hyaluronic acid. Met12, derived from the Fas-binding extracellular domain of the oncoprotein Met, was injected into the subretinal space at the time of separation. A mutant peptide and vehicle administered in a similar fashion acted as inactive controls. The extrinsic apoptotic pathway was induced in 661W cells using a Fas-activating antibody in the presence or absence of Met12. Caspase 3, caspase 8, and caspase 9 activities were measured with calorimetric and luminescent assays in retinal extracts and cell lysates. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) was performed in retinal sections 3 days after separation. Histology was performed in retinal sections 2 months after retinal detachment. Results. Met12 inhibited Fas-induced caspase 8 activation in 661W cells. Similarly, administration of Met12 into the subretinal space inhibited the activation of caspase 3, caspase 8, and caspase 9 after retinal detachment. This corresponded to a decreased level of TUNEL-positive staining of photoreceptors after retinal-RPE separation in animals that received Met12, but not inactive mutant, peptide treatment. After 2 months, the outer nuclear layer was significantly thicker, and the photoreceptor count was higher in animals treated with subretinal Met12. Conclusions. The small peptide Met12 may serve as a photoreceptor-protective agent in the setting of retinal-RPE separation.

Switching To Less Expensive Blindness Drug Could Save Medicare Part B

The biologic drugs bevacizumab and ranibizumab have revolutionized treatment of diabetic macular edema and neovascular age-related macular degeneration, leading causes of blindness. Ophthalmologic use of these drugs has increased and now accounts for roughly one-sixth of the Medicare Part B drug budget. The two drugs have similar efficacy and potentially minor differences in adverse-event rates; however, at

18 Billion Over A Ten-Year Period

2,023 per dose, ranibizumab costs forty times more than bevacizumab. Using modeling methods, we predict ten-year (2010-20) population-level costs and health benefits of using bevacizumab and ranibizumab. Our results show that if all patients were treated with the less expensive bevacizumab instead of current usage patterns, savings would amount to

Melanoma-associated retinopathy and recurrent exudative retinal detachments in a patient with choroidal melanoma

18 billion for Medicare Part B and nearly

XIAP Therapy Increases Survival of Transplanted Rod Precursors in a Degenerating Host Retina

5 billion for patients. With an additional

Adverse Events After Pars Plana Vitrectomy Among Medicare Beneficiaries

6 billion savings in other health care expenses, the total savings would be almost