Naresh Mandava

Sustained elevation of intraocular pressure after intravitreal injections of anti-VEGF agents

Aims To report the rate of intraocular pressure (IOP) elevation associated with repeated intravitreal injections of antivascular endothelial growth factor (VEGF) agents and to determine if a pre-existing diagnosis of glaucoma is a risk factor for this phenomenon. Methods The charts of 215 eyes undergoing intravitreal injection with anti-VEGF agents for wet age-related macular degeneration (AMD) were retrospectively examined with respect to frequency of injections, number of injections and changes in IOP. Data were analysed independently for two groups (1) pre-existing glaucoma and (2) no history of glaucoma. Results Of the 215 eyes receiving injections with bevacizumab and/or ranibizumab, 6% (n=13) had sustained IOP elevation requiring medical or laser interventions. Of the eyes receiving only bevacizumab, 9.9% (10/101) had sustained elevated IOP, while 3.1% (3/96) of eyes receiving only ranibizumab experienced increases (p=0.049). Patients with pre-existing glaucoma experienced higher rates of elevated IOP when compared with patients without pre-existing glaucoma (33% vs 3.1% respectively; p<0.001). The glaucoma subgroup had a lower median number of injections (6; interquartile range 5–10) compared with the non-glaucoma group (9.5; interquartile range 6–13.7; p=0.031). Conclusions The incidence of sustained elevated IOP in patients receiving intravitreal anti-VEGF injections is significant. Additionally, these data suggest the possibility of a heightened risk for further elevation of IOP in patients with pre-existing glaucoma who receive either bevacizumab or ranibizumab. Prospective studies are needed to verify these results and better understand the implications of these findings.

VEGF Trap-Eye for the treatment of neovascular age-related macular degeneration

Background: Age-related macular degeneration (AMD) affects > 14 million individuals worldwide. Although 90% of patients with AMD have the dry form, neovascular AMD accounts for the vast majority of patients who develop legal blindness. Until recently, few treatment options existed for treatment of neovascular AMD. The advent of anti-VEGF therapy has significantly improved the safe and effective treatment of neovascular AMD. In addition to two anti-VEGF drugs currently in widespread use, ranibizumab and bevacizumab, a number of medications that interrupt angiogenesis are currently under investigation. One promising new drug is aflibercept (VEGF Trap-Eye), a fusion protein that blocks all isoforms of VEGF-A and placental growth factors-1 and -2. Objective: To review the current literature and clinical trial data regarding VEGF Trap-Eye for the treatment of neovascular AMD. Methods: Literature review. Results/conclusion: VEGF Trap-Eye is a novel anti-VEGF therapy, with Phase I and II trial data indicating safety, tolerability and efficacy for the treatment of neovascular AMD. Two Phase III clinical trials (VIEW-1 and VIEW-2) comparing VEGF Trap-Eye to ranibizumab are currently continuing and will provide vital insight into the clinical applicability of this drug.

Silicone Oil Microdroplets and Protein Aggregates in Repackaged Bevacizumab and Ranibizumab: Effects of Long-term Storage and Product Mishandling

PURPOSE To quantify levels of subvisible particles and protein aggregates in repackaged bevacizumab obtained from compounding pharmacies, as well as in samples of bevacizumab and ranibizumab tested in controlled laboratory experiments. METHODS Repackaged bevacizumab was purchased from four external compounding pharmacies. For controlled laboratory studies, bevacizumab and placebo were drawn into plastic syringes and incubated at -20°C, 4°C, and room temperature (with and without exposure to light) for 12 weeks. In addition, mechanical shock occurring during shipping was mimicked with syringes containing bevacizumab. Particle counts and size distributions were quantified by particle characterization technology. Levels of monomer and soluble aggregates of bevacizumab were determined with size-exclusion high-performance liquid chromatography (SE-HPLC). RESULTS Repackaged bevacizumab from the compounding pharmacies had a wide range of particle counts (89,006 ± 56,406 to 602,062 ± 18,349/mL). Bevacizumab sampled directly from the original glass vial had particle counts of 63,839 ± 349/mL. There was up to a 10% monomer loss in the repackaged bevacizumab. Laboratory samples of repackaged bevacizumab and placebo had initial particle counts, respectively, of 283,675 ± 60,494/mL and 492,314 ± 389,361/mL. Freeze-thawing of both bevacizumab and placebo samples led to >1.2 million particles/mL. In all repackaged samples, most of the particles were due to silicone oil. SE-HPLC showed no significant differences for repackaged samples incubated in the laboratory under various conditions, compared with bevacizumab directly from vial. However, repeated freeze-thawing caused a more than 10% monomer loss. CONCLUSIONS Bevacizumab repackaged in plastic syringes could contain protein aggregates and is contaminated by silicone oil microdroplets. Freeze-thawing or other mishandling can further increase levels of particle contaminants.

Prevalence and distribution of VZV in temporal arteries of patients with giant cell arteritis

Objective: Varicella-zoster virus (VZV) infection may trigger the inflammatory cascade that characterizes giant cell arteritis (GCA). Methods: Formalin-fixed, paraffin-embedded GCA-positive temporal artery (TA) biopsies (50 sections/TA) including adjacent skeletal muscle and normal TAs obtained postmortem from subjects >50 years of age were examined by immunohistochemistry for presence and distribution of VZV antigen and by ultrastructural examination for virions. Adjacent regions were examined by hematoxylin & eosin staining. VZV antigen–positive slides were analyzed by PCR for VZV DNA. Results: VZV antigen was found in 61/82 (74%) GCA-positive TAs compared with 1/13 (8%) normal TAs (p < 0.0001, relative risk 9.67, 95% confidence interval 1.46, 63.69). Most GCA-positive TAs contained viral antigen in skip areas. VZV antigen was present mostly in adventitia, followed by media and intima. VZV antigen was found in 12/32 (38%) skeletal muscles adjacent to VZV antigen–positive TAs. Despite formalin fixation, VZV DNA was detected in 18/45 (40%) GCA-positive VZV antigen–positive TAs, in 6/10 (60%) VZV antigen–positive skeletal muscles, and in one VZV antigen–positive normal TA. Varicella-zoster virions were found in a GCA-positive TA. In sections adjacent to those containing VZV, GCA pathology was seen in 89% of GCA-positive TAs but in none of 18 adjacent sections from normal TAs. Conclusions: Most GCA-positive TAs contained VZV in skip areas that correlated with adjacent GCA pathology, supporting the hypothesis that VZV triggers GCA immunopathology. Antiviral treatment may confer additional benefit to patients with GCA treated with corticosteroids, although the optimal antiviral regimen remains to be determined.

Sustained Elevation in Intraocular Pressure Associated With Intravitreal Bevacizumab Injections

This retrospective case series reports sustained elevation of intraocular pressure (IOP) after single or repeated intravitreal injections of bevacizumab (Avastin; Genentech, San Francisco, CA) for wet age-related macular degeneration (AMD). All six cases experienced significant and sustained elevation in IOP after single or repeated intravitreal injections of bevacizumab. Initiation or advancement of IOP-lowering therapy was required in all cases. The results support the need for further studies investigating the incidence of this potential side effect and the need for close long-term surveillance of IOP after injection of bevacizumab, particularly in patients with glaucoma or suspected glaucoma. Future in vitro and in vivo studies are needed to better understand the reasons for this observed phenomenon.

Comparison of Retinal Nerve Fiber Layer Thickness in Normal Eyes Using Time-Domain and Spectral-Domain Optical Coherence Tomography

PURPOSE To compare retinal nerve fiber layer (RNFL) thickness measurements between 3 different spectral-domain optical coherence tomography (SD-OCT) instruments (Spectralis; Heidelberg Engineering; Cirrus; Carl Zeiss Meditec; RTVue; Optovue, Inc) and one time-domain OCT (Stratus; Carl Zeiss Meditec). DESIGN Prospective, cross-sectional study. METHODS RNFL thickness was measured on both eyes of 40 normal subjects using Stratus, Spectralis, RTVue, and Cirrus OCT on the same day. Scans were repeated 2 to 8 weeks later in the same fashion. Agreement with Stratus was evaluated for each SD-OCT and intervisit reproducibility was assessed for all machines. RESULTS Mean RNFL thickness determined by each of the 3 SD-OCT instruments was highly correlated with Stratus (r = 0.87-0.91). The mean RNFL thickness (mean ± standard deviation) was 110.1 ± 12.8 μm for Stratus, 106.6 ± 12.8 μm for Spectralis, 98.7 ± 10.9 μm for Cirrus, and 112.8 ± 13.2 μm for RTVue. The average differences between each SD-OCT and Stratus for mean RNFL thickness were all statistically significant (P ≤ .001), as were most quadrant measurements. All 4 instruments demonstrated excellent intraclass correlation coefficient values for mean RNFL thickness (0.90-0.97). However, intervisit variability was lowest for RTVue as evidenced by reproducibility values, followed by Stratus, Cirrus, and Spectralis (6.59, 8.83, 8.89, and 11.72 μm, respectively). CONCLUSIONS RNFL measurements taken with Spectralis, RTVue, and Cirrus all have excellent correlation to Stratus, with good reproducibility in normal eyes. Despite high correlations, RNFL values are significantly different between instruments and should not be used interchangeably.

Measurement of Subfoveal Choroidal Thickness Using Spectral Domain Optical Coherence Tomography

BACKGROUND AND OBJECTIVE To compare subfoveal choroidal thickness (SFCT) in normal patients and those with known ocular pathology using spectral domain optical coherence tomography (SD-OCT). PATIENTS AND METHODS This retrospective, observational case series was conducted at a tertiary care center where 194 consecutive eyes from 102 patients were imaged. Patients were not included or excluded based on presence or absence of pathology. One masked observer imaged the choroid and a second masked observer measured SFCT. Multivariate analysis was used and a statistical model created to analyze the changes in SFCT induced by age, diabetic retinopathy, glaucoma, wet and dry age-related macular degeneration, and other posterior pole pathology. RESULTS The mean SFCT of the 194 eyes studied was 246.59 ± 93.17 μm with a mean age of 55.50 ± 19.70 years. A strong negative relationship was found between age and SFCT (R(2) = 0.42), with an average 3.09-μm decrease in SFCT per additional year of age. Subgroup analysis demonstrated that patients with diabetic retinopathy, wet or dry age-related macular degeneration, and glaucoma all had SFCT measurements that were statistically significantly less than those of normal patients. However, when regression analysis was used to control for age, this difference was no longer significant. CONCLUSION No differences were found in SFCT in patients with glaucoma, macular degeneration, or diabetic retinopathy compared to eyes lacking pathology when age was counted as a confounding variable. Age has a strong inverse relationship with SFCT, independently confirming prior studies and creating a foundation for more research on the relationship between ocular pathology and choroidal thickness.

Retinal Nerve Fiber Layer Thickness in Patients Receiving Chronic Anti–Vascular Endothelial Growth Factor Therapy

PURPOSE To evaluate the effects of multiple intravitreal injections of anti-vascular endothelial growth factor (VEGF) agents on the thickness of the retinal nerve fiber layer (RNFL) in patients with wet age-related macular degeneration (ARMD). DESIGN Retrospective, observational, consecutive case series of patients diagnosed with wet ARMD. METHODS Forty-one eyes of 37 consecutive patients (25 female and 12 male; mean age 79.2 ± 8.7 years) who underwent treatment with pegaptanib, bevacizumab, and/or ranibizumab for ARMD followed by sequential RNFL thickness measurement by optical coherence tomography (OCT) were studied. Patients were included in the analyses if they had greater than 10 total anti-VEGF injections, RNFL measurements prior to the first injection, and at least 12 months of follow-up. Patients were divided into 3 groups depending on which anti-VEGF agent(s) they received. The OCT RNFL measurements at the initial and final follow-up were used for analyses. RESULTS Average follow-up for all patients was 27.0 ± 9.7 months and they received an average of 16.0 ± 5.5 intravitreal injections. The average RNFL thickness at presentation was 92.4 ± 15.2 μm and at last follow-up was 93.8 ± 15.2 μm (P = .68). There were no statistically significant differences in RNFL measurements when comparing between individual anti-VEGF treatment groups. CONCLUSION Long-term treatment with anti-VEGF agents did not lead to significant changes in RNFL thickness in a patient population with wet ARMD. Despite the possibility of repeated intraocular pressure (IOP) fluctuations after intravitreal injections and known neurotrophic properties of VEGF in the eye, chronic therapy with intravitreal anti-VEGF agents does not appear to adversely affect RNFL thickness. Further prospective studies with longer follow-up are needed to corroborate the findings of this study.

Treatment of multidrug‐resistant cytomegalovirus retinitis with systemically administered leflunomide

Abstract: Multiresistant cytomegalovirus (CMV) infection is increasingly recognized in solid organ transplant recipients. Leflunomide is a novel drug with both immunosuppressive and anti‐CMV properties. Herein we report a case of a renal transplant recipient treated with leflunomide for multiresistant CMV retinitis, and provide correlation between serum and vitreous levels of leflunomide. She had stabilization of her retinitis and measurable levels of drug in her vitreous fluid and serum. These initial findings suggest that leflunomide may be useful in the treatment of CMV disease, including retinitis in patients after solid organ transplantation.

Current knowledge and trends in age-related macular degeneration: genetics, epidemiology, and prevention.

Purpose: To address the most dynamic and current issues concerning human genetics, risk factors, pharmacoeconomics, and prevention regarding age-related macular degeneration. Methods: An online review of the database Pubmed and Ovid was performed, searching for the key words: age-related macular degeneration, AMD, pharmacoeconomics, risk factors, VEGF, prevention, genetics and their compound phrases. The search was limited to articles published since 1985 to date. All returned articles were carefully screened and their references were manually reviewed for additional relevant data. The webpage www.clinicaltrials.gov was also accessed in search of relevant research trials. Results: A total of 366 articles were reviewed, including 64 additional articles extracted from the references and 25 webpages and online databases from different institutions. At the end, only 244 references were included in this review. Conclusion: Age-related macular degeneration is a complex multifactorial disease that has an uneven manifestation around the world but with one common denominator, it is increasing and spreading. The economic burden that this disease poses in developed nations will increase in the coming years. Effective preventive therapies need to be developed in the near future.