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Diabetic retinopathy is the leading cause of visual impairment and preventable blindness, and represents a significant socioeconomic cost for health care systems worldwide. Therefore, new approaches beyond current standards of diabetes care are needed. Based on the crucial pathogenic role of vascular endothelial growth factor (VEGF) in the development of diabetic macular edema (DME), intravitreal anti-VEGF agents have emerged as new treatments. To provide an understanding of the rationale for use and clinical efficacy of anti-VEGF treatment, we examine this topic in a two-part Bench to Clinic narrative. In the Bench narrative, we provide an overview of the role of VEGF in the pathogenesis of diabetic retinopathy, the molecular characteristics of anti-VEGF agents currently used, and future perspectives and challenges in this area. In the Clinic narrative that follows our contribution, Cheung et al. provide an overview of the current evidence from clinical trials on anti-VEGF therapy for diabetic retinopathy.

Aim: This study was conducted to evaluate the possible clinical and genetic indicators for an early response to intravitreal ranibizumab (IVR) in exudative age-related macular degeneration (AMD)., Patients & Methods: The records of 120 eyes from 120 Japanese patients with treatment-naive exudative AMD were retrospectively reviewed. Three consecutive IVR treatments were performed every month. Achievement of anatomical resolution was evaluated by ophthalmoscopy and optical coherence tomography. Multivariable logistic regression analysis was conducted by analyzing SNPs in the ARMS2 locus (A69S) and in the CFH gene (I62V and Y402H), in addition to clinical factors., Results: The mean central retinal thickness of overall patients was significantly decreased (-120.1 ± 122.8 µm, p = 2.7 × 10(-19)) at 3 months after the initial treatment. In the logistic regression analysis, the poor anatomical resolution of the lesion at 3 months was associated with the combination of CFH I62V + CFH Y402H variants (p = 0.0021), and the polypoidal choroidal vasculopathy lesions (p = 0.044)., Conclusion: The CFH variants and the polypoidal choroidal vasculopathy lesion may influence the early anatomical resolution with IVR in exudative AMD.

Symptomatic choroidal metastasis (SCM) is an uncommon manifestation of lung cancer (LC). Treatment of SCM usually includes a combination of systemic therapy (chemotherapy and/or targeted therapy) for the primary tumor as well as local therapy (ocular radiation) for CM. Intravitreal bevacizumab (IV-Bev) is a newer modality being tried for local control of SCM. We describe here two patients with LC who presented with CM and were treated with IV-Bev. We performed a systematic literature review of previously reported patients with CM from LC who were treated with IV-Bev. Six reports (involving seven patients) in which IV-Bev was used as primary treatment modality for CM from LC were identified in the systematic literature review. A total of nine patients (seven previously reported and two index cases) were analyzed further. Along with individual case descriptions of index patients, pooled analysis of demographic profile, histology and outcomes with treatment (systemic and ocular) for the nine patients identified in this systematic review are described. A majority (n = 7) had non-small-cell lung cancer (NSCLC) histology, CM as presenting manifestation (n = 6) and unilateral ocular involvement (n = 8). IV-Bev was used in a dose of either 1.25 mg/cycle (n = 5) or 2.5 mg/cycle (n = 4) with number of cycles varying from 2 to 14 and duration between cycles varying from 2 to 8 weeks. Of the nine patients treated with IV-Bev as the primary ocular treatment modality, six (all non-squamous NSCLC) had favorable ocular response. No short-term ocular complications related to therapy were noted. We suggest that IV-Bev is a promising and safe alternative to ocular radiation for initial treatment of CM from non-squamous NSCLC. However, we recommend against using it for patients with small-cell lung cancer.

Introduction: Wet or exudative age-related macular degeneration (AMD) is the leading cause of blindness in the United States for individuals over the age of 65 years. Wet AMD is characterized by the formation of choroidal neovascularization, which can lead to edema, hemorrhage and scarring of the macula. This leads to metamorphopsia and vision loss. Without treatment, the loss of vision is permanent. The current gold standard treatment of wet AMD consists of intravitreal injections of anti-vascular endothelial growth factor (VEGF) medications., Areas Covered: Numerous new therapies in the drug pipeline aim at addressing limitations of current treatments. Future therapies involve novel compounds that attack different parts of the VEGF cascade, novel delivery systems aimed at reducing the frequency of intraocular injections, combination therapies and the use of radiation in conjunction with intravitreal therapies., Expert Opinion: Limitations of current treatments include the need for repeated injections, the high financial costs and treatment burdens of repeated injections, the risk of adverse ocular and systemic adverse events, and the inability to completely reverse the disease process of wet AMD. There are many new therapies and approaches in the pipeline which hold promise for improving the treatment of wet AMD.

Purpose: To describe 1-year clinical results of intravitreal ranibizumab treatment in patients with choroidal neovascularization secondary to exudative age-related macular degeneration (AMD) and to evaluate whether early treatment is a predictive value for prognosis of the disease., Materials and Methods: Clinical records were retrospectively reviewed of 104 eyes that underwent intravitreal ranibizumab therapy for exudative AMD. Patients were divided into two groups according to their symptom duration: group 1, <1 month; and group 2, 1-3 months. After three monthly injections, patients were examined monthly, and subsequent injections were performed as needed., Results: There were 43 female (48.9%) and 45 males (51.1%). The follow-up time was 13.7±1.9 (12-19) months. The mean logarithm of minimum angle of resolution best-corrected visual acuity (BCVA) improved significantly, from 0.45±0.639 at baseline to 0.08±0.267 at 12 months in group 1, and from 1.06±0.687 at baseline to 0.75±0.563 at 12 months in group 2. The increase in BCVA was statistically significant in group 1 (P=0.009). The mean central retinal thickness (CRT) decreased significantly, from 355.13±119.93 μm at baseline to 250.85±45.48 μm at 12 months in group 1, and from 371.88±91.047 μm at baseline to 268.61±53.51 μm at 12 months in group 2. The decrease in CRT was statistically significant in group 1 (P=0.001)., Conclusion: Intravitreal ranibizumab therapy was effective in significantly increasing mean BVCA and reducing CRT. Shorter duration of AMD, as measured by the subjective duration of visual symptoms, is associated with better visual outcome after treatment.

Terminology of persistent diabetic macular edema has been initially reserved to cases unresponsive to conventional laser photocoagulation according to ETDRS criteria. While knowledge about pathophysiology of macular edema evolved and new drugs became available, the terminology of persistent diabetic macular edema expanded to include resistance to most current therapies. The purpose of this paper is to review medical and surgical options in the treatment of such difficult cases according to literature data and personal experience.

We report the case of a patient with congenital toxoplasmosis and submacular hemorrhage caused by a neovascular membrane who underwent an intravitreal injection of C3F8 and bevacizumab, and had a good visual recovery.

Retinitis pigmentosa denotes a heterogeneous group of rare genetic diseases in which both rods and cones eye are damaged. It is a disease of poor prognosis. We describe the case of a 22 years old woman successfully treated with intravitreal implant of dexamentasone (OZURDEX®, Allergan, USA) for the treatment of macular edema due to retinitis pigmentosa.

Intravitreal injection is widely used for easy control of drug levels in posterior segment of the eye by injecting the drug directly with hypodermic needles. Patients, however, often experience complications from intravitreal injection due to repeated injections, increased intraocular pressure, and infection. In addition, injected drug reflux after intravitreal injection makes it challenging to maintain predetermined drug dose due to the drug loss through backward effusions. Here, we described that the Tower Microneedle can reduce initial reflux and bleb formation due to its smaller outer diameter compared to a traditional hypodermic needle. Furthermore, we use phenylephrine hydrochloride for pupil expansion and demonstrated that Tower Microneedle induced similar pupil expansions using only half the drug volume, in the same period of time, compared to the 31 Gauge hypodermic needle. Consequently, Tower Microneedle achieves the same therapeutic effect in the vitreous body using fewer drugs than a traditional hypodermic needle due to the decreased backward drug effusion. Tower Microneedle described herein holds great promise for intravitreal injection with less reflux and lower drug dosage.

Purpose: To describe an alternative technique for avoiding contact with the lids and eyelashes without the use of a metal lid speculum along with the results in clinical practice., Methods: Retrospective review of the medical records of all patients undergoing intravitreal injections of bevacizumab and ranibizumab with lid retraction achieved by bimanual assisted eyelid retraction between November 2010 and December 2011., Results: A total of 10,164 consecutive intravitreal injections were performed, of which 3,834 were bevacizumab and 6,330 were ranibizumab. In this cohort of patients, 3 suspected cases of endophthalmitis developed (2 culture-negative), corresponding to a rate of 0.03%., Conclusion: The technique of bimanual assisted eyelid retraction for intravitreal injection has a low rate of infection similar to the reported rates using a metal lid speculum.

The purpose of this research was to investigate the possibility of dexamethasone (DEX)-loaded PLGA-TPGS nanoparticles (NPs) in rabbits after intravitreal administration for the treatment of posterior segment diseases. The DEX-loaded PLGA-TPGS NPs were fabricated and characterized in terms of surface morphology, particle size and size distribution, entrapment efficiency, and in vitro drug release. The animals were classified randomly into two groups: experimental group with thirty rabbits, and control group with eighteen rabbits. Rabbits in the experimental group received intravitreal injections of 0.1 mL of DEX-loaded PLGA-TPGS NPs suspension and the control rabbits received intravitreal injection of 0.1 mL DEX (20 g/L in saline). The DEX concentrations in plasma and the ocular tissues such as the cornea, aqueous humor, lens, iris, vitreous humor, and chorioretina were determined by HPLC. The DEX-loaded PLGA-TPGS nanoparticle suspension were transparent and maintained a sustained release of DEX for about 45 days in vitreous and provided relatively constant DEX levels for more than 30 days with a mean concentration of 3.93 mg/L. Based on the area-under-the-curve (AUC), the bioavailability of DEX in the experimental group was significantly higher than that in the control group administrated with regular DEX. These results suggest that intravitreal administration of DEX-loaded PL.3A-TPGS NPs leads to a sustained release of DEX with a high bioavailability, providing a basis for a novel approach to treat posterior segment diseases.

Intravitreal injection is a common procedure performed by ophthalmologists. It is a quick and targeted treatment for a number of ophthalmic conditions. Despite this, the potential to cause serious complications and patient discomfort cannot be ignored. This article presents the level of evidence in the scientific literature supporting common practices such as location of the procedure, anaesthetic choice, sterile procedure techniques, comparison of some common pharmaceutical agents and the use of antibiotics., (© 2012 The Authors. Clinical and Experimental Ophthalmology © 2012 Royal Australian and New Zealand College of Ophthalmologists.)

Background: The number of patients treated with intravitreal injections has increased significantly over the past few years, mainly following the introduction of anti-vascular endothelial growth factor antibody intraocular drugs. Bevacizumab is mostly used in this group of medications., Objectives: To describe persistent elevation of intraocular pressure (IOP) following intravitreal injection of bevacizumab., Methods: We reviewed consecutive cases of persistent IOP elevation after intravitreal bevacizumab injection for exudative age-related macular degeneration (AMD). A total of 424 patients (528 eyes) met the inclusion criteria and received 1796 intravitreal injections of bevacizumab. Persistent IOP elevation was found in 19 eyes (3.6%, 19/528) of 18 patients (4.2%, 18/424) with IOP elevated 30-70 mmHg 3-30 days after injection., Results: Mean IOP was 42.6 mmHg (range 30-70); IOP elevations occurred after an average of 7.8 injections of bevacizumab (range 3-13). Injected eyes (19/528) had a significantly higher incidence of elevated IOP than uninjected eyes (fellow eyes), 1/328, P < 0.001., Conclusions: Like other anti-vascular endothelial growth factor (VEGF) substances reported in a few recent studies, intravitreal injection of bevacizumab for neovascular AMD may be associated with persistent IOP elevation. Providers should be aware that significant IOP elevation might occur after repeated treatments.

Purpose: We recently demonstrated that direct subretinal (SR) injection of adeno-associated virus (AAV) type 8 (AAV8) into photoreceptor cells and retinal pigment epithelium (RPE) is a highly efficient model of gene delivery. The current study compared transduction efficiency and expression patterns associated with various routes of vector administration., Method: The efficacy of intravitreal (VT), SR and subconjunctival (SC) injections for delivery of AAV8-derived vectors, i.e. those expressing luciferase (Luc) and enhanced green fluorescent protein (GFP) - AAV8/Luc and AAV8/GFP, respectively - were compared in an animal (mouse) model (n = 8 mice/group). Transduction efficiency and expression patterns were examined at post-injection weeks 1 and 2, and months 1, 3, 6 and 12 via in vivo imaging., Results: One year after AAV injection, AAV8/Luc-treated mice exhibited stable and sustained high expression of vector in the VT and SR groups, but not in the SC group (VT:SR:SC = 3,218:2,923:115; 1 × 10(5 )photons/s). Histological analysis showed that GFP expression was observed in the inner retina of VT group mice, and in photoreceptor cells and RPE of SR group mice, whereas no GFP expression was noted in the SC group. Electroretinography (ERG) revealed adverse effects following SR delivery., Conclusions: Results suggest that both SR and VT injections of AAV8 vectors are useful routes for administering ocular gene therapy, and stress the importance of selecting an appropriate administration route, i.e. one that targets specific cells, for treating ocular disorders.

Congenital cytomegalovirus (CMV) infection is a major cause of birth defects and childhood disorders in the United States. Retinitis occurs in 25% of infants with severely symptomatic congenital CMV and in ∼1% of asymptomatic infants. Intravitreal ganciclovir is recommended in adults with CMV retinitis (CMVR) refractory or noncompliant to intravenous therapy. No literature is available discussing the use of intravitreal ganciclovir for CMVR in neonates. We report a term neonate who received intravenous and intravitreal ganciclovir for treatment of CMVR. Three doses of intravitreal ganciclovir (2 mg per dose in each eye) were administered. Intravitreal injections of ganciclovir appeared to be well tolerated and improvement of the retinitis was appreciated. Intravitreal ganciclovir is an effective treatment of CMVR in adult acquired immunodeficiency syndrome (AIDS) patients. We report one case of intravitreal ganciclovir in a term neonate with promising results.

Purpose: Cystoid macular edema (CME) is a rarely reported side effect of nanoparticle albumin bound (nab)-paclitaxel therapy-an antimitotic agent used for breast cancer. We describe a patient with bilateral CME secondary to Abraxane that was minimally responsive to intravitreal bevacizumab. To our knowledge, this is the first reported case of the use of intravitreal bevacizumab for this condition. A previous report has described the ineffectiveness of concurrent intravenous bevacizumab with Abraxane. This lack of efficacy and knowledge of the mechanism of paclitaxel may provide insights into the mechanisms of CME without angiographic leakage., Methods: Retrospective, interventional case report of a patient with bilateral CME after starting Abraxane therapy for recurrent breast cancer treated with intravitreal bevacizumab (1.25 mg/0.05 mL) every 4 weeks. Records were reviewed for visual acuity and macular edema as assessed by spectral-domain optical coherence tomography (SD-OCT)., Results: A 73-year-old patient with recurrent, metastatic breast cancer presented with bilateral visual loss 3 months after nab-paclitaxel was initiated. Baseline visual acuities (VA) were 20/50 in the right eye (OD) and 20/80 in the left eye (OS). Fundus exam showed marked CME in both eyes (OU). Fluorescein angiography was notable for the marked absence of petalloid late-phase leakage characteristic of vascular, ischemic, and inflammatory causes of CME. SD-OCT showed marked cystoid spaces predominantly involving the outer and inner nuclear layers with central subfield thicknesses (CST) of 398 μm OD and 441 μm OS. Serial intravitreal bevacizumab injections (OD, 2 injections; OS, 3 injections) were administered on a 4-week basis with an improvement and stabilization of VA at 20/50 OD and 20/70 OS. However, CME on SD-OCT persisted with CST of 492 μm OD and 478 μm OS., Conclusions: The pathogenesis of CME without leakage is poorly understood; however, fluid accumulation in Muller cells due to toxicity has been proposed. The persistence of CME suggests that additional nonvascular endothelial growth factor-mediated mechanisms are involved. Improved understanding of the mechanisms underlying paclitaxel-associated CME is needed, especially in patients with limited systemic options for metastatic carcinoma.

Purpose: To compare the effects of straight, oblique, and double-plane tunnel scleral intravitreal injection techniques, on short-term intraocular pressure (IOP) changes, occurrence of vitreous reflux (VR), and/or other complications., Methods: A total of 105 patients were included in this prospective study. Patients were assigned randomly to one of the straight injection group (SI; n=35), oblique injection group (OI; n=35), or double-plane tunnel injection group (DPTI; n=35). The occurrence of VR and preinjection and postinjection IOP at 2 and 6 h were compared between groups, and complications were assessed., Results: The mean patient age was 71.1±6.6 years (range 58 to 86 years; 50 women and 55 men). In the SI, OI, and DPTI groups, VR occurred in 18 (51.4%), 12 (34.3%), and 6 patients (17.1%), respectively. Mean preinjection IOPs were 15.4, 14.8, and 15.6 mmHg, and changed to 17.3, 18.0, and 20.0 mmHg at the second hour, and 15.7, 16.2, and 16.1 mmHg at the sixth hour, respectively. No significant differences among the groups were found in terms of complications such as transient mild uveitis or subconjunctival hemorrhage., Conclusion: Double-plane tunnel injection prevents VR from the injection site and has no additional complications than other techniques.

Aim: To investigate the association between VEGF gene SNPs and early response to intravitreal ranibizumab for exudative age-related macular degeneration., Materials & Methods: Sixty-four patients (64 eyes) were prospectively enrolled and treated for neovascular age-related macular degeneration with ranibizumab monotherapy. Visual acuity was measured using the ETDRS chart. A loading phase of 3 monthly intravitreal injections of ranibizumab 0.5 mg/0.05 ml was performed. The analyzed VEGF-A gene SNPs were rs699947 (-2578A/C) and rs1570360 (-1154G/A); the allelic discrimination was performed in real-time PCR platform. The difference of best corrected visual acuity (ETDRS letters) read before and after treatment was considered as functional outcome., Results: Ranibizumab was significantly more effective as measured by best corrected visual acuity in patients harboring the VEGF-A -2578C allele (from +6.26 to +7.44 ETDRS letters), whereas patients carrying the VEGF-A -2578AA genotype revealed an absence of early functional response to ranibizumab (-1.78 ETDRS letters; p = 0.0192)., Conclusion: This study suggests that the VEGF-A -2578A/C SNP may represent an important molecular determinant of the early functional outcome of ranibizumab. Original submitted 3 December 2012; Revision submitted 18 February 2013.

Purpose: To asses the anatomical and functional results after intravitreal bevacizumab administration in choroidal neovascularization secondary to pathologic myopia; To asses the safety and results stability;, Methods: Prospective, interventional case study of 18 eyes with choroidal neovascularization secondary to pathologic myopia treated with 1.25 mg. intravitreal bevacizumab (AVASTIN). Intravitreal injection was repeated, if needed, at 4-6 weeks until leakage stopped. In all cases fluorescein angiograms and Spectral 3D OCTs were performed. Visual acuity was measured with ETDRS optotype. Cases were followed-up at least 6 months. Statistical analysis was performed using ANOVA and Wilcoxon tests., Results: Mean age of patients in the study was 43.86%--6.32 years (ranging 24-62 years). The mean number of intravitreal injections was 2.62%--0.53 (ranging between 1 - 4 injections). Mean visual acuity improved in all cases. An increase of more than 15 letters was noted in 44.44.% of the cases. OCT confirmed a reduced depth of lesion and also a reduced lesion volume after treatment. No major local or systemic side-effects were noted. At 6 months follow-up the choroidal neovascularization reappeared in 5 cases (27.77%) requiring additional treatment., Conclusions: These results confirm the efficacy and safety of intravitreal bevacizumab in controlling the choroidal neovascularization secondary to pathologic myopia. More than 40% of the cases regained at least 3 lines in ETDRS chart but a recurrence was noted in 27.77% of the cases at 6 months.

Background: The preservation of globe integrity has always been a major concern during the treatment of retinoblastoma for fear of extraocular or metastatic spread. Intravitreal chemotherapy has been attempted as a desperate salvage therapy only for eyes with refractory retinoblastoma. Published data on the safety and efficacy of this route are, however, limited., Methods: A modified technique of intravitreal injection in eyes with retinoblastoma is described. All children with retinoblastoma who received one or more intravitreal injections using this technique were retrospectively reviewed concerning ocular complications of the injection procedure as well as clinical or histopathological evidence of tumour spread., Results: 30 eyes of 30 children with retinoblastoma received a total of 135 intravitreal injections, with a median follw-up duration of 13.5 months. No extraocular spread was seen on clinical follow-up in any patients and there was no tumour contamination of the retrieved entry sites histopathologically analysed among the five enucleated eyes. No significant ocular side effects were observed except transient localised vitreous haemorrhage (3/135)., Conclusion: This technique is potentially safe and effective at a low cost and may play a promising role, especially in the treatment of recurrent and/or resistant vitreous disease in retinoblastoma, as an alternative to enucleation and/or external beam radiotherapy. However, this treatment should not replace the primary standard of care of retinoblastoma and should not be considered in group E eyes. Its application should be approved by an ophthalmological-oncological team and it should be performed by an experienced eye surgeon in a tertiary referral centre after careful selection of a tumour-free injection site.

Maleic acid was formulated in 0.7% saline and injected intravitreally in rabbits in order to evaluate ocular safety and tolerability. Maleic acid was formulated within a narrow pH range (2-3), administered in a fixed volume (100 µl), and concentrations ranged from 0.00 to 2.00 mg/eye (0.00 to 12.30 mM vitreous). Ocular evaluations were conducted at 2, 4, and 8 days post injection. Ocular irritation responses were observed at doses from 0.50 mg/eye (3.07 mM vitreous) to 2.00 mg/eye (12.30 mM vitreous) and included conjunctival redness and scleral swelling. Chemosis was observed at 2.00 mg/eye (12.30 mM vitreous). Funduscopic evaluations revealed enlarged retinal blood vessels and optic disk swelling at doses ≥1.50 mg/eye (9.22 mM vitreous), retinal folds and retinal discoloration at 2.00 mg/eye (12.30 mM vitreous). Histopathologic evaluations on days 4 and 8 post injection revealed retinal degeneration at doses ≥1.0 mg/eye (6.15 mM vitreous), conjunctival inflammation at doses ≥1.5 mg/eye (9.22 mM vitreous), and retinal pigment epithelial hypertrophy, optic nerve demyelination, anterior chamber fluid, and conjunctival fibrosis at 2.00 mg/eye (12.30 mM vitreous) maleic acid. The data suggest that maleic acid formulations at ≥1.00 mg/eye (6.15 mM vitreous) were not suitable for intraocular indications.

Purpose: Malignant hypertensive retinopathy is a rare, but serious, complication of uncontrolled systemic hypertension for which no treatment has been established yet. We report 2 patients with malignant hypertensive retinopathy who recovered promptly following intravitreal bevacizumab injection., Methods: Intravitreal bevacizumab (1.25 mg/0.05 mL) was injected in 4 eyes of 2 patients having malignant hypertensive retinopathy with optic disc edema, macular edema, and retinal exudates. A complete ophthalmic examination, including the best-corrected visual acuity (BCVA), central macular thickness (CMT) on optical coherence tomography (OCT), and fluorescein angiography (FAG), was performed before and after the treatments., Results: Two eyes in 1 patient received two intravitreal injections of bevacizumab, whereas 2 eyes in the other patient received a single treatment. All 4 eyes had improvement of macular edema on OCT at 1 month and decreased fluorescein leakage on FAG 3 months after the treatment, which led to improvements in the BCVA in 3 eyes. In 1 eye with foveal atrophy, no change in the BCVA occurred despite the improved macular edema on OCT., Conclusions: The results suggest that intravitreal bevacizumab injections might be a useful adjunctive treatment of malignant hypertensive retinopathy in some selected cases. However, further studies are mandatory to determine the safety and the efficacy of such injections in this disease.

Eye drops have long been the primary ocular drug delivery dosage form used to treat ocular disorders ranging from superficial conditions to intravitreal diseases. The ocular anatomical structure and physiological protective mechanisms are one of the most formidable barriers to drug penetration that have significantly reduced the drug's efficacy and target selectivity while sometimes causing ocular tissue damage. There are many new and innovative advances in ocular drug delivery due to better understanding of the structure and function of the eye, the nature of its diseases, and how to overcome or utilize its protective barrier(s), which resulted in increased bioavailability and longer duration of action of the administered drugs, therefore, more effective disease management. We seek in this article to present a comprehensive overview of the basic required knowledge about the barriers for drug delivery to the eye and the major breakthroughs and advances in ocular drug delivery to the anterior, posterior and intravitreal segments of the eye.

Case Report: We report 2 cases of pseudoxanthoma elasticum with angioid streaks and choroidal neovascularization (CNV) in both eyes. Intravitreal ranibizumab (Lucentis) was administered with successful results in both cases., Discussion: CNV has been reported to occur in 72% to 86% of patients with angioid streaks. Although uncommon, the impact of CNV is important because it tends to affect people of working age. Based on the effectiveness of ranibizumab in other secondary CNVs, we decided to use it in our patients, observing the functional and anatomical improvement., (Copyright © 2011 Sociedad Española de Oftalmología. Published by Elsevier Espana. All rights reserved.)

Purpose: To determine whether there is a difference in anesthetic effect between topical proparacaine drops, 4% lidocaine solution, or 3.5% lidocaine gel, and whether this has an impact on the overall injection experience., Methods: One hundred and twenty sequential patients undergoing intravitreal injections were randomized to 1 of 3 groups: proparacaine 0.5% drops (Group 1), proparacaine + 4% lidocaine-soaked cotton tipped swabs (Group 2), or 3.5% lidocaine gel (Group 3). Discomfort associated with the lid speculum, with the needle, and with burning sensation was graded on a scale of 0 to 10 (0 = no pain, 10 = worst pain ever). The overall injection experience was graded as Excellent, Very Good, Fair, Poor, or Awful., Results: The average lid speculum pain score for Group 1 was 0.85, Group 2 was 0.50, and Group 3 was 0.65 (P = 0.32). The average needle pain score for Group 1 was 1.78, Group 2 was 1.75, and Group 3 was 1.48 (P = 0.38). The average burning pain score for Group 1 was 1.45, Group 2 was 1.58, and Group 3 was 1.13 (P = 0.23). Overall satisfaction was rated as Excellent or Very Good in 95%, 97.5%, and 92.5% of Group 1, 2, and 3 patients, respectively (P = 0.64)., Conclusion: The use of topical proparacaine drops provides very effective and cost-effective anesthesia during office-based intravitreal injections.

To investigate a simple and effective intraocular xenotransplant technique of rhesus monkey neural progenitor cells to rats, mechanical injury was induced in the rat's right retina. And the GFP-labeled rhesus monkey neural progenitor cells suspension was slowly injected into the vitreous space of the right injured and left control eye. Confocal image suggested that the xenografted cells survived in both the injured and control eye, meanwhile the cells integrated in the injured right retina. The results demonstrated that intravitreal xenotransplant could be adopted as a simple and reliable method.

Drug delivery to the eye remains a key challenge, due to limitations inherent to prevailing delivery techniques. For example, while topical delivery offers simplicity and safety, its efficacy is often limited by poor bioavailability, due to natural transport barriers and clearance mechanisms. Similarly, while intravitreal injections performed across the ocular tunic provide means for circumventing such limitations, non-negligible potential for retinal detachment and other complications adversely affects safety. Herein, we discuss our initial efforts to address these limitations through development of titanium-based microneedles (MNs) which seek to provide a safer, simpler, and more efficacious means of ocular drug delivery. Devices with in-plane geometry and through-thickness fenestrations that serve as drug reservoirs for passive delivery via diffusive transport from fast-dissolving coatings are demonstrated. Details regarding device design, fabrication, and mechanical testing are presented, as are results from preliminary coating characterization and insertion testing in ex vivo rabbit cornea.

Intravitreal injections are very commonly performed in the daily practice of Ophthalmology and become a leading procedure in the management of age-related macular degeneration, diabetic retinopathy, infectious endophthalmitis or retinitis, uveitis and retinal vein occlusions. Based on the comments of a group of experts, including ophthalmologists, pharmacists and hygienists, the French Agency for the Safety of Health Products (AFSSAPS) edited a guide to good practice of intravitreal injections, revisiting those previously published in 2006. The overall experience accumulated during time is a valuable source of information to determine the most appropriate protocol. Therefore, the simplification of the procedure is reasonably proposed even though safety remains a major issue, in order to avoid complications, especially infections., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

Introduction: Intravitreal injections are a very common procedure and are the most effective route of drug delivery to the retina. There are currently several drugs available and even more are in development; therefore, safety is a very important concern., Areas Covered: The toxicological considerations of the most common drugs used for intravitreal pharmacotherapy such as anti-VEGFs, corticosteroids and antibiotics. Emerging agents such as anti-TNFs, VEGF-trap and kinase inhibitors are also discussed. An assessment of the efficacy and safety issues of the most relevant drugs including bevacizumab, ranibizumab and triamcinolone is presented., Expert Opinion: The toxicology and safety profiles are available for several drugs that are either in use or will be available for intravitreal injections. Retinal pharmacotherapy is very effective for different retinal diseases; however safety is a very important issue when intravitreal injections are applied and the possibility of retinal toxicity should always be kept in mind. Bevacizumab and ranibizumab are effective for the therapy of wet-age-related macular degeneration and macular edema, while triamcinolone remains an alternative agent to treat secondary macular edema. It is important, as some of these drugs will be used for extended periods of time, that their long-term toxicological effects are better understood.

Purpose: To determine whether bevacizumab and ranibizumab remain confined within the vitreous cavity after intravitreal injection and to determine the pharmacokinetic properties of these agents within the vitreous cavity., Methods: Radiolabeling with I-124 was completed using a modified Iodogen method. After testing for radiochemical purity, three anesthetized Dutch-belted rabbits underwent intravitreal injection with I-124 bevacizumab, and three underwent it with I-124 ranibizumab. All rabbits were imaged with a Micro PET-CT scanner on days 0, 2, 5, 7, 14, 21, 28, and 35., Results: The intravitreally placed radiolabeled agents were found to be contained within the vitreous cavity for the duration of the study with no extravasation into the central nervous system or elsewhere. I-124 bevacizumab was detectable until day 28, whereas I-124 ranibizumab was detectable until day 21. The kinetic model appears to represent a two-compartment model, and the average retention times for bevacizumab and ranibizumab after correction for radioactive decay were found to be 4.2 days and 2.8 days, respectively., Conclusions: There was no significant escape of bevacizumab and ranibizumab from the vitreous cavity after intravitreal injection. After correction for radioactive decay, both agents remained detectable until 28 and 21 days, respectively, with retention properties that validated those methods reported in previous studies.

Purpose: To assess the efficacy of early injection of intravitreal triamcinolone acetonide (IVTA) versus delayed injection for macular edema from retinal vein occlusion., Methods: This was a retrospective monocentric study. Forty-four patients received an IVTA (4 mg) for macular edema resulting from central retinal vein or branch retinal vein occlusion. The patients were assigned to two groups: group 1 consisted of patients who received an IVTA less than 6 weeks after the diagnosis of macular edema, while group 2 consisted of patients who received the injection more than 6 weeks after. All patients underwent a comprehensive ophthalmological examination before the injection and 1, 3, and 6 months after. Each visit included best-corrected visual acuity measurement (BCVA), slit lamp examination, intraocular pressure measurement, fundus examination and central macular thickness (CMT) measurement by OCT., Results: The two groups were comparable in terms of age, sex-ratio, and the percentage of branch retinal vein occlusion (54 and 61% in groups 1 and 2, respectively). In group 1, the BCVA (logMAR) was 0.87 before the IVTA and significantly improved at 1 and 3 months (0.46 and 0.48, respectively; P<0.05) before worsening at the 6-month visit (0.62; P>0.05). The mean CMT was also significantly improved (from 567 μm before the injection to 276, 307, and 386 μm at the 1-, 3-, and 6-month visits, respectively) (P<0.05 at 1 and 3 months). In group 2, there were no significant differences in visual acuity at any time point (0.86 before the IVTA, 0.76, 0.76, and 0.78 at the 1-, 3-, and 6-month visits; P>0.05). The CMT was reduced after the injection from 552 μm to 294, 446, and 456 μm at the 1-, 3-, and 6-month visits, respectively (P<0.05 at 1 month)., Conclusion: Patients with macular edema due to retinal vein occlusions, who received a single intravitreal injection of triamcinolone acetate less than 6 months after the diagnosis, displayed both anatomical and functional improvement, whereas patients injected more than 6 weeks after the diagnosis of macular edema showed a CMT reduction but with less improvement in visual acuity. The difference observed at 1 month disappeared after 6 months., (Copyright © 2011. Published by Elsevier Masson SAS.)

As the intravitreal injection of therapeutic medication plays an increasingly large role in ophthalmology, its implementation continues to be modified and refined. Variations in injection technique are discussed, and the authors combine their clinical and research experience with a review of the literature to propose a recommended intravitreal injection protocol.

Background: To assess the techniques and materials used in intravitreal injections., Design: Descriptive study realized at the Vision Institute of the Federal University of São Paulo, Brazil., Samples: Different brands of needles and syringes, as well as enucleated porcine eyeballs., Methods: The ultra-structures of commonly used needles were analysed by scanning electron microscope, and they were compared using different criteria, such as irregularities and debris from the lubrication process. The scleral incision was also assessed using needles of different brands and sizes. Accuracies in drug administration were studied by comparing the residual and delivered volume of needles and also by the analysis of reflux after intravitreal injections., Main Outcome Measures: Efficiency and quality of materials used in intravitreal injections., Results: Ultra-structure analyses showed that all needles had different types of irregularities. Some photographs showed debris from the lubrication process, especially in BD needles. Scleral incision analysis showed a tendency of reducing the ocular damage with increasing gauge (P=0.024). The investigation of delivery accuracy showed that almost all needles underdosed the amount injected (P<0.05), and that the reflux could be minimized by tunnelled injections with thinner needles., Conclusion: Needles used in intravitreal injections possess many irregularities in their structures, which may cause different injection outcomes. Analyses of scleral incisions showed that the larger the needle gauge, the lesser the scleral damage and the risk of complications. Moreover, drug administration inaccuracies might be one of the causes for some unsuccessful attempts of treatment., (© 2010 The Authors. Clinical and Experimental Ophthalmology © 2010 Royal Australian and New Zealand College of Ophthalmologists.)

Purpose: To evaluate the amount of reflux and degree of pain with intravitreal injection (IVT) using 6 different types of syringes/needles and 5 techniques of scleral incision, including 3 modifications of a beveled scleral incision., Methods: This was a study conducted in 205 eyes of 205 patients. IVT of bevacizumab for retinal pharmacotherapy with 6 types of needles and 5 techniques of scleral incision. The severity of subjectively evaluated pain (0-10) and the width of the subconjunctival bleb arising from the vitreal reflux. Secondary outcomes were increase in intraocular pressure and complication rate., Results: The straight technique caused greater vitreal reflux than the beveled approaches, when compared individually or as a group (P < 0.01). No difference in the severity of pain was found among all 5 types of incisions (P > 0.05). There was greater reflux with 26- and 27-gauge needles in comparison to 29- and 30-gauge needles (P < 0.001); however, the width of the needle significantly affected the degree of reflux only when using the nonbeveled incision (P < 0.001). The patients injected with the 26- or 27-gauge needle experienced more pain matched to the 29- and 30-gauge needles (P < 0.001). No difference was found between the incision technique or width of subconjunctival reflux and the increase in intraocular pressure (P > 0.05). Postinjection events included transient mild uveitis, disease-related vitreous hemorrhage, foreign body sensation, conjunctival hemorrhage, and mild punctuate keratitis., Conclusions: The beveled scleral incision showed benefit in performing IVTs. The 29- and 30-gauge needles caused less pain.

Diabetic retinopathy remains a major worldwide cause of preventable visual loss. Although photocoagulation and improved metabolic control are effective for patients with diabetic macular edema and proliferative diabetic retinopathy, some patients continue to lose vision despite treatment. Various classes of pharmacotherapy have shown promise in the treatment of diabetic retinopathy, including corticosteroids, anti-vascular endothelial growth factor agents, and others. Off-label intravitreal corticosteroids are associated with short-term anatomic and visual improvement in some patients, but these patients may require repeated intravitreal injections with cumulative risks of cataract formation, intraocular pressure elevation, and endophthalmitis. Various sustained-release corticosteroid delivery systems have been investigated for this purpose. The first to become widely available is the fluocinolone acetonide intravitreal implant (Retisert, Bausch & Lomb, Rochester, NY), which received U.S. Food and Drug Administration approval to treat chronic, noninfectious posterior segment uveitis in 2005. This device also has been investigated as a treatment for diabetic macular edema. Multiple randomized clinical trials have demonstrated medium-term anatomic and visual improvement, but the device is associated with high risks of cataract formation and intraocular pressure elevation. At this time, the device is not widely used in the treatment of diabetic retinopathy. A smaller device, designed to be injected in a clinic setting (Iluvien, Alimera Sciences, Alpharetta, GA) is currently being investigated for the treatment of diabetic macular edema. Results from a phase 3 randomized controlled trial have recently reported medium-term efficacy and safety in the treatment of diabetic macular edema. Combination photocoagulation and pharmacotherapy with these devices has not yet been reported.

Purpose: To assess serum level changes of antiretinal antibodies (ARA) in patients with exudative age-related macular degeneration (AMD), treated with transpupillary thermotherapy (TTT) alone and with TTT combined with injection of triamcinolone acetonide (sTTA) under posterior Tenon's capsule and to compare the efficacy of TTT and TTT+sTTA. The purpose of the study was also to estimate if serum ARA may act as the biomarker of AMD., Material and Methods: This prospective study comprised 46 patients (46 eyes) with exudative AMD. Patients were assigned into: group I (n = 24) received TTT alone and group II (n = 20) received TTT with sTTA. Follow-up was at 3, 6, 9 and 12 months, when best-corrected visual acuity (BCVA), Amsler grid-test, intraocular pressure (IOP), fluorescein angiography (FA) and central retinal thickness (CRT) by optical coherence tomography (OCT) were assessed. In all patients serum ARA was determined using indirect immunofluorescence (IIF) method on normal monkey retina as antigens substrate and FITC--labelled goat's anti-human IgA, G, M serum as the secondary antibody., Results: Baseline serum ARA titres in group I ranged from 1: 40 to 1: 5120 and in group II--1: 40 to 1: 1280 (p = 0.1). In control group serum ARA was present in 46.4% of sera in titres from 1: 10 to 1: 40. These differences were statistcally significant (p < 0.001). Nine fluorescence patterns of ARA were detected by IIF method in both groups of AMD patients, while control sera showed only three types of reaction. Statistically significant correlation was found between CNV size, CRT and serum ARA titres in both groups of patients (p < 0.01). In a follow-up period decreasing serum ARA titres were noted, specially for subjects treated with combined therapy, however it was not statistically significant at 3, 6 and 9 months while achieved significance (p < 0.01) at month 12. BCVA improvement or stabilization was observed in 64% of eyes in group I and in 75%--in group II (p = 0.1). No leakage on FA was found in 66.7% and 70% of cases, in group I and II, respectively (p = 0.01). CRT reduction was observed in 50% (group I) and in 70% (group II) of eyes (p = 0.01) at month 12., Conclusions: Our preliminary observations indicate that serum ARA changes may reflect the activity of CNV in a course of AMD and may act as the biomarker of treatment efficacy. The use of sTTA in conjunction with TTT for CNV in AMD showed a tendency towards lower serum ARA titres and better functional results after treatment as compared with eyes treated with TTT alone.

Unlabelled: Endophthalmitis is one of the most dangerous complications after intravitreous drug injection. Preparing a patient to the injection general and topical endophtalmitis development risk factors should be eliminated. Antibiotic injection prophylaxis is still an important issue., Purpose: This research has to evaluate effectiveness and tolerance of Azithromycin (Azyter, Thea), in injection as an antibiotic prophylaxis in patients suffering from age-related macular degeneration (AMD)., Material and Methods: The study was conducted in Ophtalmology Department (Medical Military Institute, Warsaw, Poland), in the group of 52 patients, who underwent 52 intraocular injections of anti-VEGF because of AMD. Topical Azithromycin had been administrated twice a day to both eyes in 2 days before injection. On the third day injection was performed in aseptic conditions. One drop of Azithromycin had been administrated to each eye directly before injection and one drop after the procedure. At that moment antibiotic prophylaxis was terminated., Results: Topical tolerance and effectiveness were evaluated. In 2 cases (3.8%) intensive allergic reaction was reported (significant conjuctives oedema, itch, bloodshot), what caused change of antibiotic. In 5 cases (9%) light bloodshot was reported. 12 patients (23%) reported light or moderate foreign body sensation and in 2 cases (3.8%) the sensation was significant. No reaction of ophthalmic inflammation was reported 5 days after injection, moreover foreign body sensation and bloodshot were absent. 30 patients (57%) were satisfied with new and simplier scheme of antibiotic injection prophylaxis (twice a day for 3 days)., Conclusions: Azithromycin is a comfortable alternative for other topical antibiotics, especially in repetitive procedures like anti-VEGF injections. High Azithromycin concentration in tissues, tear film, and on the ophthalmic surface, protects injection site and inhibits growth of primary and mutual bacterial colonies. Short-term exposition to Azithromycin decrases risk of drug resistance development.